Ph.Ds in Press

Part 3 in a semi-annual feature, highlighting recently published articles featuring an author (or authors) who is a current member of the Stanford Neuroscience Ph.D program. (Part 1, Part 2) [Note regarding the mechanics of this feature: This is purely through the magic of an ongoing My NCBI search for the names of Neuro PhD students. I wouldn't be surprised if there were some false negatives in the data set. Neuro students - let me know if I've missed your paper, and I'll gladly add it.]

Without further ado, and with many congratulations to the authors, the papers:

First Author papers:

Magali Arons: Autism-associated mutations in ProSAP2/Shank3 impair synaptic transmission and neurexin-neuroligin-mediated transsynaptic signaling (Arons et al 2012). **Thesis Research**

Corbett Bennett and Sergio Arroyo (co-first authors): Mechanisms generating dual-component nicotinic EPSCs in cortical interneurons (Bennett et al 2012).

Mridu Kapur: Calcium tips the balance: a microtubule plus end to lattice binding switch operates in the carboxyl terminus of BPAG1n4 (Kapur et al 2012)

Kira Mosher: Neural progenitor cells regulate microglia functions and activity (Mosher et al 2012).

Suraj Pardhan: Commentary: Progressive inflammation as a contributing factor to early development of Parkinson's disease (Pradhan and Andreasson 2012).

Rohit Prakash: Two-photon optogenetic toolbox for fast inhibition, excitation and bistable modulation. (Prakash et al 2012)

Matthew Sacchet:

• Volitional control of neuromagnetic coherence (Sacchet et al 2012)
• Spatial smoothing systematically biases the localization of reward-related brain activity (Sacchet and Knutson 2012)

Second through n-th Author papers:

Dominic Berns: Mechanisms generating dual-component nicotinic EPSCs in cortical interneurons (Bennett et al 2012).

Michael Betley: Input-specific control of reward and aversion in the ventral tegmental area (Lammel et al 2012).

Gregor Bieri: Neural progenitor cells regulate microglia functions and activity (Mosher et al 2012).

Emily Ferenczi: Dopamine neurons modulation neural encoding and expression of depression-related behaviour (Tye et al 2012).

Matt Figley: Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models (Armakola et al 2012)

William Joo: The transcriptional regulator lola is required for stem cell maintenance and germ cell differentiation in the Drosophila testis (Davies et al 2012).

Sung-Yon Kim:

• Dopamine neurons modulation neural encoding and expression of depression-related behaviour (Tye et al 2012).
• A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge (Warden et al 2012).

Ivan Millan:

• Calcium tips the balance: a microtubule plus end to lattice binding switch operates in the carboxyl terminus of BPAG1n4 (Kapur et al 2012)
• Parkinson's disease-associated kinase PINK1 regulates Miro protein level and axonal transport of mitochondria (Liu et al 2012)

Matthew Sacchet: Toward an affective neuroscience account of financial risk taking (Wu et al 2012).

First Author Papers

Arons, Thynne, Grabrucker, Li, Schoen, Cheyne, Boeckers, Montgomery, Garner (2012). Autism-associated mutations in ProSAP2/Shank3 impair synaptic transmission and neurexin-neuroligin-mediated transsynaptic signaling. J Neurosci 32(43): 14966-78. (Link)

Abstract: Mutations in several postsynaptic proteins have recently been implicated in the molecular pathogenesis of autism and autism spectrum disorders (ASDs), including Neuroligins, Neurexins, and members of the ProSAP/Shank family, thereby suggesting that these genetic forms of autism may share common synaptic mechanisms. Initial studies of ASD-associated mutations in ProSAP2/Shank3 support a role for this protein in glutamate receptor function and spine morphology, but these synaptic phenotypes are not universally penetrant, indicating that other core facets of ProSAP2/Shank3 function must underlie synaptic deficits in patients with ASDs. In the present study, we have examined whether the ability of ProSAP2/Shank3 to interact with the cytoplasmic tail of Neuroligins functions to coordinate pre/postsynaptic signaling through the Neurexin-Neuroligin signaling complex in hippocampal neurons of Rattus norvegicus. Indeed, we find that synaptic levels of ProSAP2/Shank3 regulate AMPA and NMDA receptor-mediated synaptic transmission and induce widespread changes in the levels of presynaptic and postsynaptic proteins via Neurexin-Neuroligin transsynaptic signaling. ASD-associated mutations in ProSAP2/Shank3 disrupt not only postsynaptic AMPA and NMDA receptor signaling but also interfere with the ability of ProSAP2/Shank3 to signal across the synapse to alter presynaptic structure and function. These data indicate that ASD-associated mutations in a subset of synaptic proteins may target core cellular pathways that coordinate the functional matching and maturation of excitatory synapses in the CNS.

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Bennett, Arroyo, Berns, Hestrin (2012). Mechanisms generating dual-component nicotinic EPSCs in cortical interneurons. J Neurosci 32(48): 17287-96. (Link).

Abstract: Activation of cortical nicotinic receptors by cholinergic axons from the basal forebrain (BF) significantly impacts cortical function, and the loss of nicotinic receptors is a hallmark of aging and neurodegenerative disease. We have previously shown that stimulation of BF axons generates a fast α7 and a slow non-α7 receptor-dependent response in cortical interneurons. However, the synaptic mechanisms that underlie this dual-component nicotinic response remain unclear. Here, we report that fast α7 receptor-mediated EPSCs in the mouse cortex are highly variable and insensitive to perturbations of acetylcholinesterase (AChE), while slow non-α7 receptor-mediated EPSCs are reliable and highly sensitive to AChE activity. Based on these data, we propose that the fast and slow nicotinic responses reflect differences in synaptic structure between cholinergic varicosities activating α7 and non-α7 classes of nicotinic receptors.

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Kapur, Wang, Maloney, Millan, Lundin, Tran and Yang (2012). Calcium tips the balance: a microtubule plus end to lattice binding switch operates in the carboxyl terminus of BPAG1n4. EMBO reports 13, 1021-1029. (Link)

Abstract: Microtubules (MTs) are integral to numerous cellular functions, such as cell adhesion, differentiation and intracellular transport. Their dynamics are largely controlled by diverse MT-interacting proteins, but the signalling mechanisms that regulate these interactions remain elusive. In this report, we identify a rapid, calcium-regulated switch between MT plus end interaction and lattice binding within the carboxyl terminus of BPAG1n4. This switch is EF-hand dependent, and mutations of the EF-hands abolish this dynamic behaviour. Our study thus uncovers a new, calcium-dependent regulatory mechanism for a spectraplakin, BPAG1n4, at the MT plus end.

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Mosher, Andres, Fukuhara, Bieri, Hasegawa-Moriyama, He, Guzman, Wyss-Coray (2012). Neural progenitor cells regulate microglia functions and activity. Nat Neurosci 15(11): 1485-7. (Link)

Abstract: We found mouse neural progenitor cells (NPCs) to have a secretory protein profile distinct from other brain cells and to modulate microglial activation, proliferation and phagocytosis. NPC-derived vascular endothelial growth factor was necessary and sufficient to exert at least some of these effects in mice. Thus, neural precursor cells may not only be shaped by microglia, but also regulate microglia functions and activity.

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Pradhan and Andreasson (2012). Commentary: Progressive Inflammation as a contributing factor to early development of Parkinson's disease. Exp Neurol. pii: S0014-4886(12)00456-6. (Link)

Abstract: Parkinson's disease (PD) is a progressive neurodegenerative disorder with three cardinal features of pathology: 1. Aggregation of α-synuclein into intraneuronal structures called Lewy bodies and Lewy neurites. 2. Dysregulated immune activation in the substantia nigra (SN). 3. Degeneration of dopaminergic neurons in the nigrostriatal circuit. The largely correlative nature of evidence in humans has precluded a decisive verdict on the relationship between α-synuclein pathology, inflammation, and neuronal damage. Furthermore, it is unclear whether inflammation plays a role in the early prodromal stages of PD before neuronal damage has occurred and Parkinsonian motor symptoms become apparent. To gain insight into the interaction between the inflammatory response and the development of neuronal pathology in PD, Watson et al. characterized neuroinflammation in a wild-type α-synuclein overexpressing mouse model of prodromal PD. They demonstrate, for the first time, the existence of early and sustained microglial mediated innate inflammation that precedes damage to the nigrostriatal circuit. Additionally they observe the spread of inflammation from the striatum to the SN. This study suggests that early dysregulated inflammation may contribute to progressive nigrostriatal pathology in PD, although the initiating factor that triggers the inflammatory response remains elusive. The novel concept of an early inflammatory response in the development of PD has important implications for preventive and therapeutic strategies for PD.

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Prakash, Yizhar, Grewe, Ramakrishnan, Wang, Goshen, Packer, Peterka, Yuste, Schnitzer, Deisseroth (2012). Two-photon optogenetic toolbox for fast inhibition, excitation and bistable modulation. Nat Methods, doi: 10.1038/nmeth.2215. (Link).

Abstract: Optogenetics with microbial opsin genes has enabled high-speed control of genetically specified cell populations in intact tissue. However, it remains a challenge to independently control subsets of cells within the genetically targeted population. Although spatially precise excitation of target molecules can be achieved using two-photon laser-scanning microscopy (TPLSM) hardware, the integration of two-photon excitation with optogenetics has thus far required specialized equipment or scanning and has not yet been widely adopted. Here we take a complementary approach, developing opsins with custom kinetic, expression and spectral properties uniquely suited to scan times typical of the raster approach that is ubiquitous in TPLSM laboratories. We use a range of culture, slice and mammalian in vivo preparations to demonstrate the versatility of this toolbox, and we quantitatively map parameter space for fast excitation, inhibition and bistable control. Together these advances may help enable broad adoption of integrated optogenetic and TPLSM technologies across experimental fields and systems.

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Sacchet and Knutson (2012). Spatial smoothing systematically biases the localization of reward-related brain activity. Neuroimage 66C:270-277. (Link)

Abstract: Neuroimaging methods with enhanced spatial resolution such as functional magnetic resonance imaging (FMRI) suggest that the subcortical striatum plays a critical role in human reward processing. Analysis of FMRI data requires several preprocessing steps, some of which entail tradeoffs. For instance, while spatial smoothing can enhance statistical power, it may also bias localization towards regions that contain more gray than white matter. In a meta-analysis and reanalysis of an existing dataset, we sought to determine whether spatial smoothing could systematically bias the spatial localization of foci related to reward anticipation in the nucleus accumbens (NAcc). An activation likelihood estimate (ALE) meta-analysis revealed that peak ventral striatal ALE foci for studies that used smaller spatial smoothing kernels (i.e. <6mm FWHM) were more anterior than those identified for studies that used larger kernels (i.e. >7mm FWHM). Additionally, subtraction analysis of findings for studies that used smaller versus larger smoothing kernels revealed a significant cluster of differential activity in the left relatively anterior NAcc (Talairach coordinates: -10, 9, -1). A second meta-analysis revealed that larger smoothing kernels were correlated with more posterior localizations of NAcc activation foci (p<0.015), but revealed no significant associations with other potentially relevant parameters (including voxel volume, magnet strength, and publication date). Finally, repeated analysis of a representative dataset processed at different smoothing kernels (i.e., 0-12mm) also indicated that smoothing systematically yielded more posterior activation foci in the NAcc (p<0.005). Taken together, these findings indicate that spatial smoothing can systematically bias the spatial localization of striatal activity. These findings have implications both for historical interpretation of past findings related to reward processing and for the analysis of future studies.

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Sacchet, Mellinger, Sitaram, Braun, Birbaumer, Fetz (2012). Volitional control of neuromagnetic coherence. Front Neurosci. 6: 189. (Link)

Abstract: Coherence of neural activity between circumscribed brain regions has been implicated as an indicator of intracerebral communication in various cognitive processes. While neural activity can be volitionally controlled with neurofeedback, the volitional control of coherence has not yet been explored. Learned volitional control of coherence could elucidate mechanisms of associations between cortical areas and its cognitive correlates and may have clinical implications. Neural coherence may also provide a signal for brain-computer interfaces (BCI). In the present study we used the Weighted Overlapping Segment Averaging method to assess coherence between bilateral magnetoencephalograph sensors during voluntary digit movement as a basis for BCI control. Participants controlled an onscreen cursor, with a success rate of 124 of 180 (68.9%, sign-test p < 0.001) and 84 out of 100 (84%, sign-test p < 0.001). The present findings suggest that neural coherence may be volitionally controlled and may have specific behavioral correlates.

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Second through n-th Author Papers

Armakola, Higgins, Figley, Barmada, Scarborough, Diaz, Fang, Shorter, Krogan, Finkbeiner, Farese, Gitler (2012). Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models. Nat Genet. 44(12): 1302-9. (Link)

Abstract: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease primarily affecting motor neurons. Mutations in the gene encoding TDP-43 cause some forms of the disease, and cytoplasmic TDP-43 aggregates accumulate in degenerating neurons of most individuals with ALS. Thus, strategies aimed at targeting the toxicity of cytoplasmic TDP-43 aggregates may be effective. Here, we report results from two genome-wide loss-of-function TDP-43 toxicity suppressor screens in yeast. The strongest suppressor of TDP-43 toxicity was deletion of DBR1, which encodes an RNA lariat debranching enzyme. We show that, in the absence of Dbr1 enzymatic activity, intronic lariats accumulate in the cytoplasm and likely act as decoys to sequester TDP-43, preventing it from interfering with essential cellular RNAs and RNA-binding proteins. Knockdown of Dbr1 in a human neuronal cell line or in primary rat neurons is also sufficient to rescue TDP-43 toxicity. Our findings provide insight into TDP-43-mediated cytotoxicity and suggest that decreasing Dbr1 activity could be a potential therapeutic approach for ALS.

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Davies, Lim, Joo, Tam, Fuller (2012). The transcriptional regulator lola is required for stem cell maintenance and germ cell differentiation in the Drosophila testis. Dev Bio 373(2): 310-21. (Link)

Abstract: Stem cell behavior is regulated by extrinsic signals from specialized microenvironments, or niches, and intrinsic factors required for execution of context-appropriate responses to niche signals. Here we show that function of the transcriptional regulator longitudinals lacking (lola) is required cell autonomously for germline stem cell and somatic cyst stem cell maintenance in the Drosophila testis. In addition, lola is also required for proper execution of key developmental transitions during male germ cell differentiation, including the switch from transit amplifying progenitor to spermatocyte growth and differentiation, as well as meiotic cell cycle progression and spermiogenesis. Different lola isoforms, each having unique C-termini and zinc finger domains, may control different aspects of proliferation and differentiation in the male germline and somatic cyst stem cell lineages.

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Lammel, Lim, Ran, Huang, Betley, Tye, Deisseroth, Malenka (2012). Input-specific control of reward and aversion in the ventral tegmental area. Nature 491(7423):212-7. (Link)

Abstract: Ventral tegmental area (VTA) dopamine neurons have important roles in adaptive and pathological brain functions related to reward and motivation. However, it is unknown whether subpopulations of VTA dopamine neurons participate in distinct circuits that encode different motivational signatures, and whether inputs to the VTA differentially modulate such circuits. Here we show that, because of differences in synaptic connectivity, activation of inputs to the VTA from the laterodorsal tegmentum and the lateral habenula elicit reward and aversion in mice, respectively. Laterodorsal tegmentum neurons preferentially synapse on dopamine neurons projecting to the nucleus accumbens lateral shell, whereas lateral habenula neurons synapse primarily on dopamine neurons projecting to the medial prefrontal cortex as well as on GABAergic (γ-aminobutyric-acid-containing) neurons in the rostromedial tegmental nucleus. These results establish that distinct VTA circuits generate reward and aversion, and thereby provide a new framework for understanding the circuit basis of adaptive and pathological motivated behaviours.

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Liu, Sawada, Lee, Yu, Silverio, Alapatt, Millan, Shen, Saxton, Kanao, Takahashi, Hattori, Imai, Lu (2012). Parkinson's disease-associated kinase PINK1 regulates Miro protein level and axonal transport of mitochondria. PLoS Genet. 8(3): e1002537. (Link)

Abstract: Mutations in Pten-induced kinase 1 (PINK1) are linked to early-onset familial Parkinson's disease (FPD). PINK1 has previously been implicated in mitochondrial fission/fusion dynamics, quality control, and electron transport chain function. However, it is not clear how these processes are interconnected and whether they are sufficient to explain all aspects of PINK1 pathogenesis. Here we show that PINK1 also controls mitochondrial motility. InDrosophila, downregulation of dMiro or other components of the mitochondrial transport machinery rescued dPINK1 mutant phenotypes in the muscle and dopaminergic (DA) neurons, whereas dMiro overexpression alone caused DA neuron loss. dMiro protein level was increased in dPINK1 mutant but decreased in dPINK1 or dParkin overexpression conditions. In Drosophila larval motor neurons, overexpression of dPINK1 inhibited axonal mitochondria transport in both anterograde and retrograde directions, whereas dPINK1 knockdown promoted anterograde transport. In HeLa cells, overexpressed hPINK1 worked together with hParkin, another FPD gene, to regulate the ubiquitination and degradation of hMiro1 and hMiro2, apparently in a Ser-156 phosphorylation-independent manner. Also in HeLa cells, loss of hMiro promoted the perinuclear clustering of mitochondria and facilitated autophagy of damaged mitochondria, effects previously associated with activation of the PINK1/Parkin pathway. These newly identified functions of PINK1/Parkin and Miro in mitochondrial transport and mitophagy contribute to our understanding of the complex interplays in mitochondrial quality control that are critically involved in PD pathogenesis, and they may explain the peripheral neuropathy symptoms seen in some PD patients carrying particular PINK1 or Parkinmutations. Moreover, the different effects of loss of PINK1 function on Miro protein level inDrosophila and mouse cells may offer one explanation of the distinct phenotypic manifestations of PINK1 mutants in these two species.

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Tye, Mirzabekov, Warden, Ferenczi, Tsai, Finkelstein, Kim, Adhikari, Thompson, Andalman, Gunaydin, Witten, Deisseroth (2012). Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature. doi: 10.1038/nature11740. (Link)

Abstract: Major depression is characterized by diverse debilitating symptoms that include hopelessness and anhedonia. Dopamine neurons involved in reward and motivation are among many neural populations that have been hypothesized to be relevant, and certain antidepressant treatments, including medications and brain stimulation therapies, can influence the complex dopamine system. Until now it has not been possible to test this hypothesis directly, even in animal models, as existing therapeutic interventions are unable to specifically target dopamine neurons. Here we investigated directly the causal contributions of defined dopamine neurons to multidimensional depression-like phenotypes induced by chronic mild stress, by integrating behavioural, pharmacological, optogenetic and electrophysiological methods in freely moving rodents. We found that bidirectional control (inhibition or excitation) of specified midbrain dopamine neurons immediately and bidirectionally modulates (induces or relieves) multiple independent depression symptoms caused by chronic stress. By probing the circuit implementation of these effects, we observed that optogenetic recruitment of these dopamine neurons potently alters the neural encoding of depression-related behaviours in the downstream nucleus accumbens of freely moving rodents, suggesting that processes affecting depression symptoms may involve alterations in the neural encoding of action in limbic circuitry.

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Warden, Selimbeyoglu, Mirzabekov, Lo, Thompson, Kim, Adhikari, Tye, Frank, Deisseroth (2012). A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge. Nature 492(7429):428-32. (Link).

Abstract: The prefrontal cortex (PFC) is thought to participate in high-level control of the generation of behaviours (including the decision to execute actions); indeed, imaging and lesion studies in human beings have revealed that PFC dysfunction can lead to either impulsive states with increased tendency to initiate action, or to amotivational states characterized by symptoms such as reduced activity, hopelessness and depressed mood. Considering the opposite valence of these two phenotypes as well as the broad complexity of other tasks attributed to PFC, we sought to elucidate the PFC circuitry that favours effortful behavioural responses to challenging situations. Here we develop and use a quantitative method for the continuous assessment and control of active response to a behavioural challenge, synchronized with single-unit electrophysiology and optogenetics in freely moving rats. In recording from the medial PFC (mPFC), we observed that many neurons were not simply movement-related in their spike-firing patterns but instead were selectively modulated from moment to moment, according to the animal's decision to act in a challenging situation. Surprisingly, we next found that direct activation of principal neurons in the mPFC had no detectable causal effect on this behaviour. We tested whether this behaviour could be causally mediated by only a subclass of mPFC cells defined by specific downstream wiring. Indeed, by leveraging optogenetic projection-targeting to control cells with specific efferent wiring patterns, we found that selective activation of those mPFC cells projecting to the brainstem dorsal raphe nucleus (DRN), a serotonergic nucleus implicated in major depressive disorder, induced a profound, rapid and reversible effect on selection of the active behavioural state. These results may be of importance in understanding the neural circuitry underlying normal and pathological patterns of action selection and motivation in behaviour.

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Wu, Sacchet, Knuston (2012). Toward an affective neuroscience account of financial risk taking. Front Neurosci 6: 159. (

Dr. Saul Villeda, you are proper famous.

Hat tip to Kelly Z. for alerting me that recent Stanford alumn (and current USCF Faculty Fellow) Saul Villeda has been enjoying some recent press coverage. For those of you unfamiliar with Saul's thesis work, I'm going to lift the description of Saul's research interests straight from the his lab website:

Our lab is interested in understanding what drives regenerative and cognitive impairments in the aging brain, and moreover how the effects of aging can be reversed in the old brain. Our lab is focused on three areas. First, we are looking at how immune-related changes in old blood contribute to impairments in neural stem cell function and associated cognitive functions. Second, we are looking at the contribution of the innate immune system to age-related impairments in synaptic plasticity and cognitive function. Third, we are looking at how exposure to young blood rejuvenates neural stem cell function, synaptic plasticity and cognitive function in the old brain. Ultimately, our goal is to elucidate cellular and molecular mechanisms that promote brain rejuvenation as a means by which to combat age-related neurodegeneration and cognitive dysfunction. (Villeda lab website)

And now, on to the press coverage of Saul's research, which he recently presented at the Society for Neuroscience Conference.

• The good: Coverage by the Guardian, entitled: "Young blood can reverse some effects of ageing, study finds"
• The hilarious: Coverage by Jezebel, entitled: "Turns Out, Baby Blood Might Be the Actual Fountain of Youth"

Saul: I think I speak for the entire Stanford Neuro student community, when I saw congratulations on your new fame. We're so proud. And amused. But mostly pretty darn proud.

Final note: those curious for more details may want to peruse Saul's Nature paper (found online here, although pay-wall warning).

Final, final note: The Villeda lab is looking for folks to join their research group! Qualified individuals should head on over to the Villeda lab website for contact details.

Update 10/22/12: The fame, it spreads. I09 picks up the story from the Guardian.

New Orleans, baby! StanfordNeuro at SFN12

The Society for Neuroscience Conference is back in New Orleans! And both students and faculty affiliated with our PhD Program will be presenting their work. Are you in The Big Easy for SFN12? Then visit the posters/presentations of our happy community.

The full list Stanford Neuroscience PhD Program affiliates presenting their research at SFN12 is below, separated by date.

Saturday, Oct 13 :

3:00-4:00 pm : Kira Mosher

Title: Neural progenitor cells regulate microglia functions and activity states in vivo.

Location: Q5

4:00-5:00 pm : Gregor Bieri

Title: Proteolytic cleavage of Beclin 1 exacerbates neurodegeneration.

Location: U1

Sunday, Oct 14 :

8:00-9:00 am : Dan O'Shea

Title: Optogenetic perturbation of motor preparation in primate dorsal premotor cortex.

Location: DDD48

9:00-10:00 am : John Huguenard (aka our valiant Program Director)

Title: Selective optical inhibition of thalamocortical neurons as a novel tool to reliably drive thalamocortical oscillations and sleep-spindles.

Location: E50

9:00-10:00 am : Sung-Yon Kim

Title: Optogenetic dissection of the function of the amygdala-BNST circuitry in anxiety.

Location: DDD49

9:15-9:35: Tony Wyss-Coray

Title: Systemic plasma factors in brain aging and neurodegeneration.

Location: New Orleans Theater A

10:00-11:00 am : Emily Ferenczi

Title: ofMRI refinement: High resolution BOLD fMRI in combination with stable optogenetic stimulation for characterization of neural circuits in awake rodents.

Location: DDD46

10:00-11:00 am : Eric Trautmann

Title: Thalamic spindle-like oscillations in VB thalamus induced in vitro by optical stimulation of corticothalamic axons.

Location: E51

2:00-3:00 am : Christine Lee

Title: Effect of Group III metabotropic receptors on corticothalamic tranmission and absence epilepsy.

Location: H21

4:00-5:00 pm: Patrick House

Title: The functional consequences of Toxoplasma gondii invasion in the mouse CNS.

Location: O3

Monday, Oct 15 :

8:00-9:00 am : Nicholas Steinmetz

Title: Simultaneous measurement of visual response modulation across cortical layers in area V4 during covert attention and saccade preparation.

Location: NN12

9:45-10:20 am: Mark Schnitzer

Title: Visualizing the neuronal orchestra: large-scale imaging of neural dynamics in awake behaving animals.

Location: Room 345

10:20-10:55: Karl Deisseroth Title: Cracking neural codes with photons: optogenetics as an integral tool for systems neuroscience. Location: Room 345

11:15-11:30: Josef Parvizi

Title: Electrical stimulation of human fusiform face-selective regions distorts face perception.

Location: Room 383

3:00-4:00pm: Kati Andreasson

Title: Prostaglandin EP4 receptor signaling in microglia reduces inflammatory responses to Amyloid-beta and reduces amyloid burden in models of Alzheimer's disease.

Location: D39

3:00-4:00 pm: Olivia Winter

Title: Is motor learning encoded by structural alterations in cerebellar parallel fibers?

Location: LL16

5:15-6:25: Carla Shatz

Title: Circuit Tuning During Developmental Critical Periods

Location: Hall D

Tuesday, Oct 16

9:00-10:00 am : David Bochner

Title: Pirb actively represses ocular dominance plasticity

Location: GG3

10:00-11:00 am : Jaimie Adelson

Title: Adult ocular dominance lasticity is limited by MHCI molecules.

Location: GG4

1:45-2:00 pm : David Kastner

Title: Optimal placement of dynamic range by coordinated populations of retinal ganglion cells.

Location: Room 391

2:30-2:45 pm : Nathan Woodling

Title: Ibuprofen prevents memory decline and modulates hippocampal monoamine levels in a mouse model of Alzheimer's disease through amyloid- and inflammation-independent mechanisms.

Location: Room 395

2:45-3:20: Frank Longo

Title: Targeting Alzheimer's-related mechanisms with p75 ligands.

Location: La Nouvelle C

Wednesday, Oct 17 :

8:45-9:00am: Matt Kaufman

=Title: Decision and indecision on single trials of a monkey maze-reaching task.

Location: Room 395

9:45-10:00 am : Nick Weiler

Title: Characterization of synapse molecular architecture in functinoally defined barrel columns using array tomography.

Location: Room 268

1:45-2:00 pm : Matthew Sacchet

Title: Frontal lobe contributions of deterministic and probabilisitc learning: evidence for dissociable feedback-related processes.

Location: Room 291

4:00-5:00 pm : Egle Cekanaviciute

Title: Astrocytic TGFbeta signaling limits the spread of immune responses and improves functional outcome after stroke.

Location: M11

4:00-5:00 am : Suraj Pradhan

Title: Investigating the role of prostaglandin E2 mediated neuroinflammation in models of parkinsonism.

Location: Q3

Ph.Ds in press #2

#2 in a semi-annual feature, highlighting recently published articles featuring an author (or authors) who is a current member of the Stanford Neuroscience Ph.D program. (For part 1, go here) [Note regarding the mechanics of this feature: This is purely through the magic of an ongoing My NCBI search for the names of Neuro PhD students. I wouldn't be surprised if there were some false negatives in the data set. Neuro students - let me know if I've missed your paper, and I'll gladly add it.]

[Additional Note: Links in the list below access anchor links within the main body of the post (which contains full titles, abstracts, and additional links to the article themselves). To allow link functionality, please continue reading this post below the fold.]

Without further ado, and with many congratulations to the authors, the papers:

First Author papers:

• Kelsey Clark *Thesis Research!*

Persistent Spatial Information in the Frontal Eye Field during Object-Based Short-Term Memory. (Clark et al 2012)

• Jacqueline Grant *Thesis Research!*

Reversal of Paralysis and Reduced Inflammation from Peripheral Administration of B-Amyloid in TH1 and TH17 Versions of Experimental Autoimmune Encephalomyelitis. (Grant et al 2012)

• Emily Ferenczi

When the electricity (and the lights) go out: transient changes in excitability. (Nat. Neuro preview, Ferenczi and Deisseroth 2012)

• Jack Wang

Axon degeneration: where the Wlds things are. (review, Wang and Barres 2012).

Second through n-th Author papers:

• Astra Bryant

Thalamic Excitation and Network Oscillations in Stargazer Mice. (Lacey et al 2012)

• Egle Cekanaviciute

Delayed administration of a small molecule tropomyosin-related kinase B ligand promotes recovery after hypoxic-ischemic stroke. (Han et al 2012)

• Matt Kaufman

Neural population dynamics during reaching. (Churchland et al 2012)

• Joline Fan* and Sergey Stavisky

A recurrent neural network for closed-loop intracortical brain-machine interface decoders. (Sussillo et al 2012) *technically Bioengineering PhD

• Ivan Millan

Nemitin, a novel Map8/Map1s interacting protein with Wd40 repeats. (Wang et al 2012)

• Rohit Prakash

Multiscale computational models for optogenetic control of cardiac function. (Abilez et al 2011)

• Forea Wang

Division and subtraction by distinct cortical inhibitory networks in vivo (Wilson et al 2012)

• Nicholas Weiler

Deep molecular diversity of mammalian synapses: why it matters and how to measure it. (O'Rourke et al 2012)

[Continue reading below the fold to allow link functionality above]

First Author Papers

Clark, Noudoost, Moore (2012). Persistent Spatial Information in the Frontal Eye Field during Object-Based Short-Term Memory. J. Neurosci 32(32):10907-10914. (Link)

Abstract: Spatial attention is known to gate entry into visual short-term memory, and some evidence suggests that spatial signals may also play a role in binding features or protecting object representations during memory maintenance. To examine the persistence of spatial signals during object short-term memory, the activity of neurons in the frontal eye field (FEF) of macaque monkeys was recorded during an object-based delayed match-to-sample task. In this task, monkeys were trained to remember an object image over a brief delay, regardless of the locations of the sample or target presentation. FEF neurons exhibited visual, delay, and target period activity, including selectivity for sample location and target location. Delay period activity represented the sample location throughout the delay, despite the irrelevance of spatial information for successful task completion. Furthermore, neurons continued to encode sample position in a variant of the task in which the matching stimulus never appeared in their response field, confirming that FEF maintains sample location independent of subsequent behavioral relevance. FEF neurons also exhibited target-position-dependent anticipatory activity immediately before target onset, suggesting that monkeys predicted target position within blocks. These results show that FEF neurons maintain spatial information during short-term memory, even when that information is irrelevant for task performance.

Grant, Ghosn, Axtell, Herges, Kuipers, Woodling, Andreasson, Herzenberg, Herzenberg, Steinman (2012). Reversal of Paralysis and Reduced Inflammation from Peripheral Administration of B-Amyloid in TH1 and TH17 Versions of Experimental Autoimmune Encephalomyelitis. Sci Transl Med. 4(145):145ra105. (Link)

Abstract: β-Amyloid 42 (Aβ42) and β-amyloid 40 (Aβ40), major components of senile plaque deposits in Alzheimer's disease, are considered neurotoxic and proinflammatory. In multiple sclerosis, Aβ42 is up-regulated in brain lesions and damaged axons. We found, unexpectedly, that treatment with either Aβ42 or Aβ40 peptides reduced motor paralysis and brain inflammation in four different models of experimental autoimmune encephalomyelitis (EAE) with attenuation of motor paralysis, reduction of inflammatory lesions in the central nervous system (CNS), and suppression of lymphocyte activation. Aβ42 and Aβ40 treatments were effective in reducing ongoing paralysis induced with adoptive transfer of either autoreactive T helper 1 (T(H)1) or T(H)17 cells. High-dimensional 14-parameter flow cytometry of peripheral immune cell populations after in vivo Aβ42 and Aβ40 treatment revealed substantial modulations in the percentage of lymphoid and myeloid subsets during EAE. Major proinflammatory cytokines and chemokines were reduced in the blood after Aβ peptide treatment. Protection conferred by Aβ treatment did not require its delivery to the brain: Adoptive transfer with lymphocytes from donors treated with Aβ42 attenuated EAE in wild-type recipient mice, and Aβ deposition in the brain was not detected in treated EAE mice by immunohistochemical analysis. In contrast to the improvement in EAE with Aβ treatment, EAE was worse in mice with genetic deletion of the amyloid precursor protein. Therefore, in the absence of Aβ, there is exacerbated clinical EAE disease progression. Because Aβ42 and Aβ40 ameliorate experimental autoimmune inflammation targeting the CNS, we might now consider its potential anti-inflammatory role in other neuropathological conditions.

Ferenczi and Deisseroth (2012). When the electricity (and the lights) go out: transient changes in excitability. Nat. Neurosci. 15(8):1058-60. (Link)

Abstract: News and Views regarding Raimondo, J.V., Kay, L., Ellender, T.J. & Akerman, C.J. Nat. Neurosci. 15, 1102–1104 (2012).

Wang and Barres (2012). Axon degeneration: where the Wlds things are. Curr Biol 22(7):R221-3. (Link)

Abstract: Expression of the Wld(s) protein significantly delays axon degeneration in injuries and diseases, but the mechanism for this protection is unknown. Two recent reports present evidence that axonal mitochondria are required for Wld(S)-mediated axon protection.

Second through n-th author papers

Abilez, Wong, Prakash, Deisseroth, Zarins, Kuhl (2011). Multiscale computational models for optogenetic control of cardiac function. Biophys J, 101(6):1326-34. (Link)

Abstract: The ability to stimulate mammalian cells with light has significantly changed our understanding of electrically excitable tissues in health and disease, paving the way toward various novel therapeutic applications. Here, we demonstrate the potential of optogenetic control in cardiac cells using a hybrid experimental/computational technique. Experimentally, we introduced channelrhodopsin-2 into undifferentiated human embryonic stem cells via a lentiviral vector, and sorted and expanded the genetically engineered cells. Via directed differentiation, we created channelrhodopsin-expressing cardiomyocytes, which we subjected to optical stimulation. To quantify the impact of photostimulation, we assessed electrical, biochemical, and mechanical signals using patch-clamping, multielectrode array recordings, and video microscopy. Computationally, we introduced channelrhodopsin-2 into a classic autorhythmic cardiac cell model via an additional photocurrent governed by a light-sensitive gating variable. Upon optical stimulation, the channel opens and allows sodium ions to enter the cell, inducing a fast upstroke of the transmembrane potential. We calibrated the channelrhodopsin-expressing cell model using single action potential readings for different photostimulation amplitudes, pulse widths, and frequencies. To illustrate the potential of the proposed approach, we virtually injected channelrhodopsin-expressing cells into different locations of a human heart, and explored its activation sequences upon optical stimulation. Our experimentally calibrated computational toolbox allows us to virtually probe landscapes of process parameters, and identify optimal photostimulation sequences toward pacing hearts with light.

Churchland, Cunningham, Kaufman, Foster, Nuyujukian, Ryu, Shenoy (2012). Neural population dynamics during reaching. Nature, 487(7405):51-6. (Link).

Abstract: Most theories of motor cortex have assumed that neural activity represents movement parameters. This view derives from what is known about primary visual cortex, where neural activity represents patterns of light. Yet it is unclear how well the analogy between motor and visual cortex holds. Single-neuron responses in motor cortex are complex, and there is marked disagreement regarding which movement parameters are represented. A better analogy might be with other motor systems, where a common principle is rhythmic neural activity. Here we find that motor cortex responses during reaching contain a brief but strong oscillatory component, something quite unexpected for a non-periodic behaviour. Oscillation amplitude and phase followed naturally from the preparatory state, suggesting a mechanistic role for preparatory neural activity. These results demonstrate an unexpected yet surprisingly simple structure in the population response. This underlying structure explains many of the confusing features of individual neural responses.

Han, Pollak, Yang, Siddiqui, Doyle, Taravosh-Lahn, Cekanaviciute, Han, Goodman, Jones, Jing, Massa, Longo, Buckwalter (2012). Delayed administration of a small molecule tropomyosin-related kinase B ligand promotes recovery after hypoxic-ischemic stroke. Stroke 43(7):1918-24. (Link)

Abstract: Stroke is the leading cause of long-term disability in the United States, yet no drugs are available that are proven to improve recovery. Brain-derived neurotrophic factor stimulates neurogenesis and plasticity, processes that are implicated in stroke recovery. It binds to both the tropomyosin-related kinase B and p75 neurotrophin receptors. However, brain-derived neurotrophic factor is not a feasible therapeutic agent, and no small molecule exists that can reproduce its binding to both receptors. We tested the hypothesis that a small molecule (LM22A-4) that selectively targets tropomyosin-related kinase B would promote neurogenesis and functional recovery after stroke.

Lacey, Bryant, Brill, Huguenard (2012). Thalamic Excitation and Network Oscillations in Stargazer Mice. J Neurosci 32(32): 11067-11081. (Link)

Abstract: Disturbances in corticothalamic circuitry can lead to absence epilepsy. The reticular thalamic nucleus (RTN) plays a pivotal role in that it receives excitation from cortex and thalamus and, when strongly activated, can generate excessive inhibitory output and epileptic thalamocortical oscillations that depend on postinhibitory rebound. Stargazer (stg) mice have prominent absence seizures resulting from a mutant form of the AMPAR auxiliary protein stargazin. Reduced AMPAR excitation in RTN has been demonstrated previously in stg, yet the mechanisms leading from RTN hypoexcitation to epilepsy are unknown and unexpected because thalamic epileptiform oscillatory activity requires AMPARs. We demonstrate hyperexcitability in stg thalamic slices and further characterize the various excitatory inputs to RTN using electrical stimulation and laser scanning photostimulation. Patch-clamp recordings of spontaneous and evoked EPSCs in RTN neurons demonstrate reduced amplitude and increased duration of the AMPAR component with an increased amplitude NMDAR component. Short 200 Hz stimulus trains evoked a gradual approximately threefold increase in NMDAR EPSCs compared with single stimuli in wild-type (WT), indicating progressive NMDAR recruitment, whereas in stg cells, NMDAR responses were nearly maximal with single stimuli. Array tomography revealed lower synaptic, but higher perisynaptic, AMPAR density in stg RTN. Increasing NMDAR activity via reduced [Mg²⁺]_o in WT phenocopied the thalamic hyperexcitability observed in stg, whereas changing [Mg²⁺]_o had no effect on stg slices. These findings suggest that, in stg, a trafficking defect in synaptic AMPARs in RTN cells leads to a compensatory increase in synaptic NMDARs and enhanced thalamic excitability.

O'Rourke, Weiler, Micheva, Smith (2012). Deep molecular diversity of mammalian synapses: why it matters and how to measure it. Nat. Rev. Neurosci. 13(6):365-79. (Link)

Abstract: Pioneering studies in the middle of the twentieth century revealed substantial diversity among mammalian chemical synapses and led to a widely accepted classification of synapse type on the basis of neurotransmitter molecule identity. Subsequently, powerful new physiological, genetic and structural methods have enabled the discovery of much deeper functional and molecular diversity within each traditional neurotransmitter type. Today, this deep diversity continues to pose both daunting challenges and exciting new opportunities for neuroscience. Our growing understanding of deep synapse diversity may transform how we think about and study neural circuit development, structure and function.

Sussillo, Nuyujukian, Fan, Kao, Stavisky, Ryu, Shenoy (2012). A recurrent neural network for closed-loop intracortical brain-machine interface decoders. J. Neural Eng. 9(2):026027. (Link)

Abstract: Recurrent neural networks (RNNs) are useful tools for learning nonlinear relationships in time series data with complex temporal dependences. In this paper, we explore the ability of a simplified type of RNN, one with limited modifications to the internal weights called an echostate network (ESN), to effectively and continuously decode monkey reaches during a standard center-out reach task using a cortical brain-machine interface (BMI) in a closed loop. We demonstrate that the RNN, an ESN implementation termed a FORCE decoder (from first order reduced and controlled error learning), learns the task quickly and significantly outperforms the current state-of-the-art method, the velocity Kalman filter (VKF), using the measure of target acquire time. We also demonstrate that the FORCE decoder generalizes to a more difficult task by successfully operating the BMI in a randomized point-to-point task. The FORCE decoder is also robust as measured by the success rate over extended sessions. Finally, we show that decoded cursor dynamics are more like naturalistic hand movements than those of the VKF. Taken together, these results suggest that RNNs in general, and the FORCE decoder in particular, are powerful tools for BMI decoder applications.

Wang, Lundin, Millan, Zeng, Chen, Yang, Allen, Chen, Bach, Hsu, Maloney, Kapur, Yang (2012). Nemitin, a novel Map8/Map1s interacting protein with Wd40 repeats. PLoS One. 7(4):e33094. (Link)

Abstract: In neurons, a highly regulated microtubule cytoskeleton is essential for many cellular functions. These include axonal transport, regional specialization and synaptic function. Given the critical roles of microtubule-associated proteins (MAPs) in maintaining and regulating microtubule stability and dynamics, we sought to understand how this regulation is achieved. Here, we identify a novel LisH/WD40 repeat protein, tentatively named nemitin (neuronal enriched MAP interacting protein), as a potential regulator of MAP8-associated microtubule function. Based on expression at both the mRNA and protein levels, nemitin is enriched in the nervous system. Its protein expression is detected as early as embryonic day 11 and continues through adulthood. Interestingly, when expressed in non-neuronal cells, nemitin displays a diffuse pattern with puncta, although at the ultrastructural level it localizes along the microtubule network in vivo in sciatic nerves. These results suggest that the association of nemitin to microtubules may require an intermediary protein. Indeed, co-expression of nemitin with microtubule-associated protein 8 (MAP8) results in nemitin losing its diffuse pattern, instead decorating microtubules uniformly along with MAP8. Together, these results imply that nemitin may play an important role in regulating the neuronal cytoskeleton through an interaction with MAP8.

Wilson, Runyan, Wang, Sur (2012). Division and subtraction by distinct cortical inhibitory networks in vivo. Nature. 488(7410) (Link)

Abstract: Brain circuits process information through specialized neuronal subclasses interacting within a network. Revealing their interplay requires activating specific cells while monitoring others in a functioning circuit. Here we use a new platform for two-way light-based circuit interrogation in visual cortex in vivo to show the computational implications of modulating different subclasses of inhibitory neurons during sensory processing. We find that soma-targeting, parvalbumin-expressing (PV) neurons principally divide responses but preserve stimulus selectivity, whereas dendrite-targeting, somatostatin-expressing (SOM) neurons principally subtract from excitatory responses and sharpen selectivity. Visualized in vivo cell-attached recordings show that division by PV neurons alters response gain, whereas subtraction by SOM neurons shifts response levels. Finally, stimulating identified neurons while scanning many target cells reveals that single PV and SOM neurons functionally impact only specific subsets of neurons in their projection fields. These findings provide direct evidence that inhibitory neuronal subclasses have distinct and complementary roles in cortical computations.

PhDs in Press

While scouring Pubmed for published articles featuring Stanford Neuro-student authors for a recent post, I had two thoughts. 1) Students in the Stanford Neuro program were on a hell of a lot of papers

2) There was definitely a better way to highlight those papers than a retrospective every 6-months that took forever to type up and even longer to actually read (see thought 1).

Thus was born a new semi-regular feature for the neuroblog: PhDs in Press - of which this post is the first example.

Part shameless publicity, part proud bragging, part intra-program PSA, this feature will highlight recently published articles featuring an author (or authors) who is a current member of the Stanford Neuroscience Ph.D program.

[Note regarding the mechanics of this feature: This is purely through the magic of an ongoing My NCBI search for the names of Neuro PhD students. I wouldn't be surprised if there were some false negatives in the data set. Neuro students - let me know if I've missed your paper, and I'll gladly add it.]

[Additional Note: Links in the list below access anchor links within the main body of the post (which contains full titles, abstracts, and additional links to the article themselves). To allow link functionality, please continue reading this post below the fold.]

Without further ado, and with many congratulations to the authors, the papers:

First Author papers:

• Jaimie Adelson (Adelson et al 2012)
• Niru Maheswaranathan (Maheswaranathan et al 2012)
• Jack Wang (Wang et al 2012)

Second through n-th Author papers:

• Branden Cord (Byers et al 2012)
• Lief Fenno (Byers et al 2012)
• Emily Ferenczi (Akam et al 2012)
• William Joo (Tasic et al 2012)

[Continue reading below the fold to allow link functionality above]

First Author Papers

Adelson et al 2012. Neuroprotection from Stroke in the Absence of MHCI or PirB. Neuron. 2012 Mar 22;73(6):1100-7. Epub 2012 Mar 21.

Abstract: Recovery from stroke engages mechanisms of neural plasticity. Here we examine a role for MHC class I (MHCI) H2-Kb and H2-Db, as well as PirB receptor. These molecules restrict synaptic plasticity and motor learning in the healthy brain. Stroke elevates neuronal expression not only of H2-Kb and H2-Db, but also of PirB and downstream signaling. KbDb knockout (KO) or PirB KO mice have smaller infarcts and enhanced motor recovery. KO hippocampal organotypic slices, which lack an intact peripheral immune response, have less cell death after in vitro ischemia. In PirB KO mice, corticospinal projections from the motor cortex are enhanced, and the reactive astrocytic response is dampened after MCAO. Thus, molecules that function in the immune system act not only to limit synaptic plasticity in healthy neurons, but also to exacerbate brain injury after ischemia. These results suggest therapies for stroke by targeting MHCI and PirB.

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Maheswaranathan et al 2012. Emergent bursting and synchrony in computer simulations of neuronal cultures. Front. Comput. Neurosci. 6:15. doi: 10.3389/fncom.2012.00015

Abstract: Experimental studies of neuronal cultures have revealed a wide variety of spiking network activity ranging from sparse, asynchronous firing to distinct, network-wide synchronous bursting. However, the functional mechanisms driving these observed firing patterns are not well understood. In this work, we develop an in silico network of cortical neurons based on known features of similar in vitro networks. The activity from these simulations is found to closely mimic experimental data. Furthermore, the strength or degree of network bursting is found to depend on a few parameters: the density of the culture, the type of synaptic connections, and the ratio of excitatory to inhibitory connections. Network bursting gradually becomes more prominent as either the density, the fraction of long range connections, or the fraction of excitatory neurons is increased. Interestingly, biologically prevalent values of parameters result in networks that are at the transition between strong bursting and sparse firing. Using principal components analysis, we show that a large fraction of the variance in firing rates is captured by the first component for bursting networks. These results have implications for understanding how information is encoded at the population level as well as for why certain network parameters are ubiquitous in cortical tissue.

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Wang et al 2012. Axon degeneration: molecular mechanisms of a self-destruction pathway. J Cell Biol. 2012 Jan 9;196(1):7-18. Review.

Abstract: Axon degeneration is a characteristic event in many neurodegenerative conditions including stroke, glaucoma, and motor neuropathies. However, the molecular pathways that regulate this process remain unclear. Axon loss in chronic neurodegenerative diseases share many morphological features with those in acute injuries, and expression of the Wallerian degeneration slow (WldS) transgene delays nerve degeneration in both events, indicating a common mechanism of axonal self-destruction in traumatic injuries and degenerative diseases. A proposed model of axon degeneration is that nerve insults lead to impaired delivery or expression of a local axonal survival factor, which results in increased intra-axonal calcium levels and calcium-dependent cytoskeletal breakdown.

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Second through Nth-Author Papers

Byers et al 2012. SNCA triplication Parkinson's patient's iPSC-derived DA neurons accumulate α-synuclein and are susceptible to oxidative stress. PLoS One. 2011;6(11):e26159. Epub 2011 Nov 16.

Abstract: Parkinson's disease (PD) is an incurable age-related neurodegenerative disorder affecting both the central and peripheral nervous systems. Although common, the etiology of PD remains poorly understood. Genetic studies infer that the disease results from a complex interaction between genetics and environment and there is growing evidence that PD may represent a constellation of diseases with overlapping yet distinct underlying mechanisms. Novel clinical approaches will require a better understanding of the mechanisms at work within an individual as well as methods to identify the specific array of mechanisms that have contributed to the disease. Induced pluripotent stem cell (iPSC) strategies provide an opportunity to directly study the affected neuronal subtypes in a given patient. Here we report the generation of iPSC-derived midbrain dopaminergic neurons from a patient with a triplication in the α-synuclein gene (SNCA). We observed that the iPSCs readily differentiated into functional neurons. Importantly, the PD-affected line exhibited disease-related phenotypes in culture: accumulation of α-synuclein, inherent overexpression of markers of oxidative stress, and sensitivity to peroxide induced oxidative stress. These findings show that the dominantly-acting PD mutation is intrinsically capable of perturbing normal cell function in culture and confirm that these features reflect, at least in part, a cell autonomous disease process that is independent of exposure to the entire complexity of the diseased brain.

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Akam et al 2012. Oscillatory dynamics in the hippocampus support dentate gyrus-CA3 coupling. Nat Neurosci. 2012 Apr 1. doi: 10.1038/nn.3081.

Abstract: Gamma oscillations in the dentate gyrus and hippocampal CA3 show variable coherence in vivo, but the mechanisms and relevance for information flow are unknown. We found that carbachol-induced oscillations in rat CA3 have biphasic phase-response curves, consistent with the ability to couple with oscillations in afferent projections. Differences in response to stimulation of either the intrinsic feedback circuit or the dentate gyrus were well described by varying an impulse vector in a two-dimensional dynamical system, representing the relative input to excitatory and inhibitory neurons. Responses to sinusoidally modulated optogenetic stimulation confirmed that the CA3 network oscillation can entrain to periodic inputs, with a steep dependence of entrainment phase on input frequency. CA3 oscillations are therefore suited to coupling with oscillations in the dentate gyrus over a broad range of frequencies.

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Tasic et al 2012. Extensions of MADM (Mosaic Analysis with Double Markers) in Mice. PLoS One. 2012;7(3):e33332. Epub 2012 Mar 27.

Abstract: Mosaic Analysis with Double Markers (MADM) is a method for generating genetically mosaic mice, in which sibling mutant and wild-type cells are labeled with different fluorescent markers. It is a powerful tool that enables analysis of gene function at the single cell level in vivo. It requires transgenic cassettes to be located between the centromere and the mutation in the gene of interest on the same chromosome. Here we compare procedures for introduction of MADM cassettes into new loci in the mouse genome, and describe new approaches for expanding the utility of MADM. We show that: 1) Targeted homologous recombination outperforms random transgenesis in generation of reliably expressed MADM cassettes, 2) MADM cassettes in new genomic loci need to be validated for biallelic and ubiquitous expression, 3) Recombination between MADM cassettes on different chromosomes can be used to study reciprocal chromosomal deletions/duplications, and 4) MADM can be modified to permit transgene expression by combining it with a binary expression system. The advances described in this study expand current, and enable new and more versatile applications of MADM

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Stanford Neuro Peer-Reviewed Publications

Part shameless publicity, part proud bragging, part intra-program PSA, this post is all about articles, published in peer-reviewed scientific journals, featuring work by the students of the Stanford Neuroscience Ph.D program. Since last July, the current graduate researchers (and recently-minted alumni) have produced an admirable volume of scientific research, some of which has been published in the form of journal articles. As the authors in question tend not to go around bragging, I'll be doing so on their behalf.

To that end, what follows are two lists detailing the results of an afternoon spent spelunking through Pubmed. The first list contains the names of current (or recently graduated) Stanford Neuro students who are first authors on articles published since around June '11 (date arbitrarily chosen). The second list contains the names of Stanford Neuro students who are second through n-th authors on papers published within the same time period. Click on an individuals name to see the full paper title and abstract.

Congratulations to all the recently published authors in the Stanford Neuro program!

(Grad students: Apologies for any author/paper left off the list - let me know and I will gladly add you - Astra) First Author papers:

• Sergio Arroyo (Arroyo et al 2012 *co-first with Corbett)
• Corbett Bennett (Arroyo et al 2012 *co-first with Sergio)
• Poh Hui Chia (Chia et al 2012 )
• Lief Fenno (Tye et al 2011 *co-first with Kay Tye, Sung-yon Kim and Rohit Prakash)
• Emily Ferenczi (Mattis et al 2011 *co-first with Joanna Mattis and Kay Tye)
• Patrick House (House et al 2011)
• Mariko Howe (Howe and Barres 2012)
• David Kastner (Kastner and Baccus 2012)
• Sung-yon Kim (Tye et al 2011 *co-first with Kay Tye, Rohit Prakash and Lief Fenno)
• Joanna Mattis (Mattis et al 2011 *co-first with Joanna Mattis and Kay Tye)
• Rohit Prakash (Tye et al 2011 *co-first with Kay Tye, Sung-yon Kim and Lief Fenno)
• Andreas Rauschecker (Rauschecker et al 2011)
• Jana Schiach Borg (Schaich Borg et al 2012)
• Nicholas Steinmetz (Steinmetz and Moore 2012, review of Gregoriou et al 2012)
• Saul Villeda (Villeda et al 2011)
• Jack Wang (Wang et al 2012)

Second through n-th Author papers:

• Ron Alfa (Bader et al 2011)
• Astra Bryant (Paz et al 2011)
• Matt Carter (de Lecea et al 2012)
• Branden Cord (Pasca et al 2011, Byers et al 2011)
• Lief Fenno (Byers et al 2011, Mattis et al 2011, Paz et al 2011, Tye et al 2011, Yizhar et al 2011, Zhang et al 2011)
• Lisa Gunaydin (Mattis et al 2011, Anikeeva et al 2011)
• Logan Grosenick (Anikeeva et al 2011, Tye et al 2011)
• William Joo (Sweeney et al 2011)
• Li Li (Yoo et al 2011)
• Jana Lim (Greer et al 2011)
• Ivan Millan (Liu et al 2012)
• Kira Mosher (Villeda et al 2011)
• Daniel O'Shea (Mattis et al 2011, Yizhar et al 2011)
• Scott Owen (Bader et al 2011)
• Georgia Panagiotakos (Osterhout et al 2011)
• Rohit Prakash (Mattis et al 2011, Goshen et al 2011, Abilez et al 2011)
• Aslihan Selimbeyoglu (Rauschecker et al 2011)
• Sergey Stavisky (Sussillo et al 2012)
• Gabriela Suarez-Mier (Taniguchi et al 2011)
• Nathan Woodling (Liang et al 2011, Grabrucker et al 2011)
• Kelly Zalocusky (Witten et al 2011)

[Continue reading below the fold to allow link functionality above]

First Author Papers

Arroyo et al (2012). Prolonged Disynaptic Inhibition in the Cortex Mediated by Slow, Non-α7 Nicotinic Excitation of a Specific Subset of Cortical Interneurons. J Neursci 32(11):3859-64.

Cholinergic activation of nicotinic receptors in the cortex plays a critical role in arousal, attention, and learning. Here we demonstrate that cholinergic axons from the basal forebrain of mice excite a specific subset of cortical interneurons via a remarkably slow, non-α7 nicotinic receptor-mediated conductance. In turn, these inhibitory cells generate a delayed and prolonged wave of disynaptic inhibition in neighboring cortical neurons, altering the spatiotemporal pattern of inhibition in cortical circuits.

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Chia et al (2012). NAB-1 instructs synapse assembly by linking adhesion molecules and F-actin to active zone proteins. Nat. Neurosci 15(2):234-42.

During synaptogenesis, macromolecular protein complexes assemble at the pre- and postsynaptic membrane. Extensive literature identifies many transmembrane molecules sufficient to induce synapse formation and several intracellular scaffolding molecules responsible for assembling active zones and recruiting synaptic vesicles. However, little is known about the molecular mechanisms coupling membrane receptors to active zone molecules during development. Using Caenorhabditis elegans, we identify an F-actin network present at nascent presynaptic terminals and required for presynaptic assembly. We unravel a sequence of events whereby specificity-determining adhesion molecules define the location of developing synapses and locally assemble F-actin. Next, the adaptor protein NAB-1 (neurabin) binds to F-actin and recruits active zone proteins SYD-1 and SYD-2 (liprin-α) by forming a tripartite complex. NAB-1 localizes transiently to synapses during development and is required for presynaptic assembly. Altogether, we identify a role for the actin cytoskeleton during presynaptic development and characterize a molecular pathway whereby NAB-1 links synaptic partner recognition to active zone assembly.

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House et al (2011). Predator cat odors activate sexual arousal pathways in brains of Toxoplasma gondii infected rats. PLoS One. 6(8):e23277

Cat odors induce rapid, innate and stereotyped defensive behaviors in rats at first exposure, a presumed response to the evolutionary pressures of predation. Bizarrely, rats infected with the brain parasite Toxoplasma gondii approach the cat odors they typically avoid. Since the protozoan Toxoplasma requires the cat to sexually reproduce, this change in host behavior is thought to be a remarkable example of a parasite manipulating a mammalian host for its own benefit. Toxoplasma does not influence host response to non-feline predator odor nor does it alter behavior on olfactory, social, fear or anxiety tests, arguing for specific manipulation in the processing of cat odor. We report that Toxoplasma infection alters neural activity in limbic brain areas necessary for innate defensive behavior in response to cat odor. Moreover, Toxoplasma increases activity in nearby limbic regions of sexual attraction when the rat is exposed to cat urine, compelling evidence that Toxoplasma overwhelms the innate fear response by causing, in its stead, a type of sexual attraction to the normally aversive cat odor.

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Howe and Barres (2012). A novel role for microglia in minimizing excitotoxicity. BMC Biol 10:7.

Microglia are the abundant, resident myeloid cells of the central nervous system (CNS) that become rapidly activated in response to injury or inflammation. While most studies of microglia focus on this phenomenon, little is known about the function of 'resting' microglia, which possess fine, branching cellular processes. Biber and colleagues, in a recent paper in Journal of Neuroinflammation, report that ramified microglia can limit excitotoxicity, an important insight for understanding mechanisms that limit neuron death in CNS disease.

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Kastner and Baccus (2011). Coordinated dynamic encoding in the retina using opposing forms of plasticity. Nat. Neursci 12(10):1317-22.

The range of natural inputs encoded by a neuron often exceeds its dynamic range. To overcome this limitation, neural populations divide their inputs among different cell classes, as with rod and cone photoreceptors, and adapt by shifting their dynamic range. We report that the dynamic behavior of retinal ganglion cells in salamanders, mice and rabbits is divided into two opposing forms of short-term plasticity in different cell classes. One population of cells exhibited sensitization-a persistent elevated sensitivity following a strong stimulus. This newly observed dynamic behavior compensates for the information loss caused by the known process of adaptation occurring in a separate cell population. The two populations divide the dynamic range of inputs, with sensitizing cells encoding weak signals and adapting cells encoding strong signals. In the two populations, the linear, threshold and adaptive properties are linked to preserve responsiveness when stimulus statistics change, with one population maintaining the ability to respond when the other fails.

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Mattis et al (2011). Principles for applying optogenetic tools derived from direct comparative analysis of microbial opsins. Nat. Methods 9(2):159-72.

Diverse optogenetic tools have allowed versatile control over neural activity. Many depolarizing and hyperpolarizing tools have now been developed in multiple laboratories and tested across different preparations, presenting opportunities but also making it difficult to draw direct comparisons. This challenge has been compounded by the dependence of performance on parameters such as vector, promoter, expression time, illumination, cell type and many other variables. As a result, it has become increasingly complicated for end users to select the optimal reagents for their experimental needs. For a rapidly growing field, critical figures of merit should be formalized both to establish a framework for further development and so that end users can readily understand how these standardized parameters translate into performance. Here we systematically compared microbial opsins under matched experimental conditions to extract essential principles and identify key parameters for the conduct, design and interpretation of experiments involving optogenetic techniques.

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Rauschecker et al (2011). Illusions of visual motion elicited by electrical stimulation of human MT complex. PLoS One. 6(7):e21798.

Human cortical area MT(+) (hMT(+)) is known to respond to visual motion stimuli, but its causal role in the conscious experience of motion remains largely unexplored. Studies in non-human primates demonstrate that altering activity in area MT can influence motion perception judgments, but animal studies are inherently limited in assessing subjective conscious experience. In the current study, we use functional magnetic resonance imaging (fMRI), intracranial electrocorticography (ECoG), and electrical brain stimulation (EBS) in three patients implanted with intracranial electrodes to address the role of area hMT(+) in conscious visual motion perception. We show that in conscious human subjects, reproducible illusory motion can be elicited by electrical stimulation of hMT(+). These visual motion percepts only occurred when the site of stimulation overlapped directly with the region of the brain that had increased fMRI and electrophysiological activity during moving compared to static visual stimuli in the same individual subjects. Electrical stimulation in neighboring regions failed to produce illusory motion. Our study provides evidence for the sufficient causal link between the hMT(+) network and the human conscious experience of visual motion. It also suggests a clear spatial relationship between fMRI signal and ECoG activity in the human brain.

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Schaich Borg et al (2011). Neural Basis of moral verdict and moral deliberation. Soc Neurosci 6(4):398-413.

How people judge something to be morally right or wrong is a fundamental question of both the sciences and the humanities. Here we aim to identify the neural processes that underlie the specific conclusion that something is morally wrong. To do this, we introduce a novel distinction between "moral deliberation," or the weighing of moral considerations, and the formation of a "moral verdict," or the commitment to one moral conclusion. We predict and identify hemodynamic activity in the bilateral anterior insula and basal ganglia that correlates with committing to the moral verdict "this is morally wrong" as opposed to "this is morally not-wrong," a finding that is consistent with research from economic decision-making. Using comparisons of deliberation-locked vs. verdict-locked analyses, we also demonstrate that hemodynamic activity in high-level cortical regions previously implicated in morality--including the ventromedial prefrontal cortex, posterior cingulate cortex, and temporoparietal junction--correlates primarily with moral deliberation as opposed to moral verdicts. These findings provide new insights into what types of processes comprise the enterprise of moral judgment, and in doing so point to a framework for resolving why some clinical patients, including psychopaths, may have intact moral judgment but impaired moral behavior.

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Steinmetz and Moore (2012). Lumping and splitting the neural circuitry of visual attention. Neuron 73(3):410-2.

Shifts of gaze and of covert attention rely on tightly linked yet divergent neural mechanisms. In this issue of Neuron, Gregoriou et al. (2012) provide interesting evidence that different functional classes of neurons within the frontal eye field contribute uniquely to these two functions.

Personal Note: Contains an excellent pun.

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Tye et al (2011). Amygdala circuitry mediating reversible and bidirectional control of anxiety. Nature 471: 358-362.

Anxiety—a sustained state of heightened apprehension in the absence of immediate threat—becomes severely debilitating in disease states¹. Anxiety disorders represent the most common of psychiatric diseases (28% lifetime prevalence)² and contribute to the aetiology of major depression and substance abuse^3, 4. Although it has been proposed that the amygdala, a brain region important for emotional processing^{5, 6, 7, 8}, has a role in anxiety^{9, 10, 11, 12, 13}, the neural mechanisms that control anxiety remain unclear. Here we explore the neural circuits underlying anxiety-related behaviours by using optogenetics with two-photon microscopy, anxiety assays in freely moving mice, and electrophysiology. With the capability of optogenetics^14, 15, 16 to control not only cell types but also specific connections between cells, we observed that temporally precise optogenetic stimulation of basolateral amygdala (BLA) terminals in the central nucleus of the amygdala (CeA)—achieved by viral transduction of the BLA with a codon-optimized channelrhodopsin followed by restricted illumination in the downstream CeA—exerted an acute, reversible anxiolytic effect. Conversely, selective optogenetic inhibition of the same projection with a third-generation halorhodopsin¹⁵(eNpHR3.0) increased anxiety-related behaviours. Importantly, these effects were not observed with direct optogenetic control of BLA somata, possibly owing to recruitment of antagonistic downstream structures. Together, these results implicate specific BLA–CeA projections as critical circuit elements for acute anxiety control in the mammalian brain, and demonstrate the importance of optogenetically targeting defined projections, beyond simply targeting cell types, in the study of circuit function relevant to neuropsychiatric disease.

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Villeda et al (2011). The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477(7362):90-4.

In the central nervous system, ageing results in a precipitous decline in adult neural stem/progenitor cells and neurogenesis, with concomitant impairments in cognitive functions. Interestingly, such impairments can be ameliorated through systemic perturbations such as exercise. Here, using heterochronic parabiosis we show that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age-dependent fashion in mice. Accordingly, exposing a young mouse to an old systemic environment or to plasma from old mice decreased synaptic plasticity, and impaired contextual fear conditioning and spatial learning and memory. We identify chemokines--including CCL11 (also known as eotaxin)--the plasma levels of which correlate with reduced neurogenesis in heterochronic parabionts and aged mice, and the levels of which are increased in the plasma and cerebrospinal fluid of healthy ageing humans. Lastly, increasing peripheral CCL11 chemokine levels in vivo in young mice decreased adult neurogenesis and impaired learning and memory. Together our data indicate that the decline in neurogenesis and cognitive impairments observed during ageing can be in part attributed to changes in blood-borne factors.

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Wang et al (2012). Axon degeneration: molecular mechanisms of a self-destructive pathway. J Cell Biol 196(1):7-18.

Axon degeneration is a characteristic event in many neurodegenerative conditions including stroke, glaucoma, and motor neuropathies. However, the molecular pathways that regulate this process remain unclear. Axon loss in chronic neurodegenerative diseases share many morphological features with those in acute injuries, and expression of the Wallerian degeneration slow (WldS) transgene delays nerve degeneration in both events, indicating a common mechanism of axonal self-destruction in traumatic injuries and degenerative diseases. A proposed model of axon degeneration is that nerve insults lead to impaired delivery or expression of a local axonal survival factor, which results in increased intra-axonal calcium levels and calcium-dependent cytoskeletal breakdown.

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Non-First Author Papers

Abilez et al (2011). Multiscale computations models for optogenetic control of cardiac function. Biophys J 101(6):1326-34.

The ability to stimulate mammalian cells with light has significantly changed our understanding of electrically excitable tissues in health and disease, paving the way toward various novel therapeutic applications. Here, we demonstrate the potential of optogenetic control in cardiac cells using a hybrid experimental/computational technique. Experimentally, we introduced channelrhodopsin-2 into undifferentiated human embryonic stem cells via a lentiviral vector, and sorted and expanded the genetically engineered cells. Via directed differentiation, we created channelrhodopsin-expressing cardiomyocytes, which we subjected to optical stimulation. To quantify the impact of photostimulation, we assessed electrical, biochemical, and mechanical signals using patch-clamping, multielectrode array recordings, and video microscopy. Computationally, we introduced channelrhodopsin-2 into a classic autorhythmic cardiac cell model via an additional photocurrent governed by a light-sensitive gating variable. Upon optical stimulation, the channel opens and allows sodium ions to enter the cell, inducing a fast upstroke of the transmembrane potential. We calibrated the channelrhodopsin-expressing cell model using single action potential readings for different photostimulation amplitudes, pulse widths, and frequencies. To illustrate the potential of the proposed approach, we virtually injected channelrhodopsin-expressing cells into different locations of a human heart, and explored its activation sequences upon optical stimulation. Our experimentally calibrated computational toolbox allows us to virtually probe landscapes of process parameters, and identify optimal photostimulation sequences toward pacing hearts with light.

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Anikeeva et al (2011). Optetrode: a multichannel readout for optogenetic control in freely moving mice. Nat. Neurosci  15(1): 163-70.

Recent advances in optogenetics have improved the precision with which defined circuit elements can be controlled optically in freely moving mammals; in particular, recombinase-dependent opsin viruses, used with a growing pool of transgenic mice expressing recombinases, allow manipulation of specific cell types. However, although optogenetic control has allowed neural circuits to be manipulated in increasingly powerful ways, combining optogenetic stimulation with simultaneous multichannel electrophysiological readout of isolated units in freely moving mice remains a challenge. We designed and validated the optetrode, a device that allows for colocalized multi-tetrode electrophysiological recording and optical stimulation in freely moving mice. Optetrode manufacture employs a unique optical fiber-centric coaxial design approach that yields a lightweight (2 g), compact and robust device that is suitable for behaving mice. This low-cost device is easy to construct (2.5 h to build without specialized equipment). We found that the drive design produced stable high-quality recordings and continued to do so for at least 6 weeks following implantation. We validated the optetrode by quantifying, for the first time, the response of cells in the medial prefrontal cortex to local optical excitation and inhibition, probing multiple different genetically defined classes of cells in the mouse during open field exploration.

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Bader et al (2011). Mouse model of Timothy syndrome recapitulates triad of autistic traits. PNAS 108(37):15432-7.

Autism and autism spectrum disorder (ASD) typically arise from a mixture of environmental influences and multiple genetic alterations. In some rare cases, such as Timothy syndrome (TS), a specific mutation in a single gene can be sufficient to generate autism or ASD in most patients, potentially offering insights into the etiology of autism in general. Both variants of TS (the milder TS1 and the more severe TS2) arise from missense mutations in alternatively spliced exons that cause the same G406R replacement in the Ca(V)1.2 L-type calcium channel. We generated a TS2-like mouse but found that heterozygous (and homozygous) animals were not viable. However, heterozygous TS2 mice that were allowed to keep an inverted neomycin cassette (TS2-neo) survived through adulthood. We attribute the survival to lowering of expression of the G406R L-type channel via transcriptional interference, blunting deleterious effects of mutant L-type channel overactivity, and addressed potential effects of altered gene dosage by studying Ca(V)1.2 knockout heterozygotes. Here we present a thorough behavioral phenotyping of the TS2-neo mouse, capitalizing on this unique opportunity to use the TS mutation to model ASD in mice. Along with normal general health, activity, and anxiety level, TS2-neo mice showed markedly restricted, repetitive, and perseverative behavior, altered social behavior, altered ultrasonic vocalization, and enhanced tone-cued and contextual memory following fear conditioning. Our results suggest that when TS mutant channels are expressed at levels low enough to avoid fatality, they are sufficient to cause multiple, distinct behavioral abnormalities, in line with the core aspects of ASD.

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Byers et al (2011). SNCA triplication Parkinson's patient's iPSC-derived DA neurons accumulate α-synuclein and are susceptible to oxidative stress. PLoS One 6(11):e26159.

Parkinson's disease (PD) is an incurable age-related neurodegenerative disorder affecting both the central and peripheral nervous systems. Although common, the etiology of PD remains poorly understood. Genetic studies infer that the disease results from a complex interaction between genetics and environment and there is growing evidence that PD may represent a constellation of diseases with overlapping yet distinct underlying mechanisms. Novel clinical approaches will require a better understanding of the mechanisms at work within an individual as well as methods to identify the specific array of mechanisms that have contributed to the disease. Induced pluripotent stem cell (iPSC) strategies provide an opportunity to directly study the affected neuronal subtypes in a given patient. Here we report the generation of iPSC-derived midbrain dopaminergic neurons from a patient with a triplication in the α-synuclein gene (SNCA). We observed that the iPSCs readily differentiated into functional neurons. Importantly, the PD-affected line exhibited disease-related phenotypes in culture: accumulation of α-synuclein, inherent overexpression of markers of oxidative stress, and sensitivity to peroxide induced oxidative stress. These findings show that the dominantly-acting PD mutation is intrinsically capable of perturbing normal cell function in culture and confirm that these features reflect, at least in part, a cell autonomous disease process that is independent of exposure to the entire complexity of the diseased brain.

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De Lecea et al (2012). Shining Light on Wakefulness and Arousal. Biol Psychiatry.

Alterations in arousal states are associated with multiple neuropsychiatric disorders, including generalized anxiety disorders, addiction, schizophrenia, and depression. Therefore, elucidating the neurobiological mechanisms controlling the boundaries between arousal, hyperarousal, and hypoarousal is a crucial endeavor in biological psychiatry. Substantial research over several decades has identified distinct arousal-promoting neural populations in the brain; however, how these nuclei act individually and collectively to promote and maintain wakefulness and various arousal states is unknown. We have recently applied optogenetic technology to the repertoire of techniques used to study arousal. Here, we discuss the recent results of these experiments and propose future use of this approach as a way to understand the complex dynamics of neural circuits controlling arousal and arousal-related behaviors.

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Goshen et al (2011). Dynamics of retrieval strategies for remote memories. Cell 147(3):678-89.

Prevailing theory suggests that long-term memories are encoded via a two-phase process requiring early involvement of the hippocampus followed by the neocortex. Contextual fear memories in rodents rely on the hippocampus immediately following training but are unaffected by hippocampal lesions or pharmacological inhibition weeks later. With fast optogenetic methods, we examine the real-time contribution of hippocampal CA1 excitatory neurons to remote memory and find that contextual fear memory recall, even weeks after training, can be reversibly abolished by temporally precise optogenetic inhibition of CA1. When this inhibition is extended to match the typical time course of pharmacological inhibition, remote hippocampus dependence converts to hippocampus independence, suggesting that long-term memory retrieval normally depends on the hippocampus but can adaptively shift to alternate structures. Further revealing the plasticity of mechanisms required for memory recall, we confirm the remote-timescale importance of the anterior cingulate cortex (ACC) and implicate CA1 in ACC recruitment for remote recall.

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Grabrucker et al (2011). Amyloid beta protein-induced zinc sequestration leads to synaptic loss via dysregulation of the ProSAP2/Shank3 scaffold. Mol Neurodegener 6:65.

BACKGROUND: Memory deficits in Alzheimer's disease (AD) manifest together with the loss of synapses caused by the disruption of the postsynaptic density (PSD), a network of scaffold proteins located in dendritic spines. However, the underlying molecular mechanisms remain elusive. Since it was shown that ProSAP2/Shank3 scaffold assembly within the PSD is Zn2+-dependent and that the amyloid beta protein (Aβ) is able to bind Zn2+, we hypothesize that sequestration of Zn2+ ions by Aβ contributes to ProSAP/Shank platform malformation.

RESULTS: To test this hypothesis, we designed multiple in vitro and in vivo assays demonstrating ProSAP/Shank dysregulation in rat hippocampal cultures following Aβ oligomer accumulation. These changes were independent from alterations on ProSAP/Shank transcriptional level. However, application of soluble Aβ prevented association of Zn2+ ions with ProSAP2/Shank3 in a cell-based assay and decreased the concentration of Zn2+ clusters within dendrites. Zn2+ supplementation or saturation of Aβ with Zn2+ ions prior to cell treatment was able to counter the effects induced by Aβ on synapse density and ProSAP2/Shank3 levels at the PSD. Interestingly, intracellular Zn2+ levels in APP-PS1 mice and human AD hippocampus are reduced along with a reduction in synapse density and synaptic ProSAP2/Shank3 and Shank1 protein levels.

CONCLUSIONS: We conclude that sequestration of Zn2+ ions by Aβ significantly contributes to changes in ProSAP2/Shank3 platforms. These changes in turn lead to less consolidated (mature) synapses reflected by a decrease in Shank1 protein levels at the PSD and decreased synapse density in hippocampal neurons.

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Greer et al (2011). Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature 479(7373):365-71.

Chromatin modifiers regulate lifespan in several organisms, raising the question of whether changes in chromatin states in the parental generation could be incompletely reprogrammed in the next generation and thereby affect the lifespan of descendants. The histone H3 lysine 4 trimethylation (H3K4me3) complex, composed of ASH-2, WDR-5 and the histone methyltransferase SET-2, regulates Caenorhabditis elegans lifespan. Here we show that deficiencies in the H3K4me3 chromatin modifiers ASH-2, WDR-5 or SET-2 in the parental generation extend the lifespan of descendants up until the third generation. The transgenerational inheritance of lifespan extension by members of the ASH-2 complex is dependent on the H3K4me3 demethylase RBR-2, and requires the presence of a functioning germline in the descendants. Transgenerational inheritance of lifespan is specific for the H3K4me3 methylation complex and is associated with epigenetic changes in gene expression. Thus, manipulation of specific chromatin modifiers only in parents can induce an epigenetic memory of longevity in descendants.

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Liang et al (2011). Signaling via the prostaglandin E₂ receptor EP4 exerts neuronal and vascular protection in a mouse model of cerebral ischemia. J Clin Invest. 121(11):4362-71.

Stroke is the third leading cause of death in the United States. Fewer than 5% of patients benefit from the only intervention approved to treat stroke. Thus, there is an enormous need to identify new therapeutic targets. The role of inducible cyclooxygenase (COX-2) activity in stroke and other neurologic diseases is complex, as both activation and sustained inhibition can engender cerebral injury. Whether COX-2 induces cerebroprotective or injurious effects is probably dependent on which downstream prostaglandin receptors are activated. Here, we investigated the function of the PGE2 receptor EP4 in a mouse model of cerebral ischemia. Systemic administration of a selective EP4 agonist after ischemia reduced infarct volume and ameliorated long-term behavioral deficits. Expression of EP4 was robust in neurons and markedly induced in endothelial cells after ischemia-reperfusion, suggesting that neuronal and/or endothelial EP4 signaling imparts cerebroprotection. Conditional genetic inactivation of neuronal EP4 worsened stroke outcome, consistent with an endogenous protective role of neuronal EP4 signaling in vivo. However, endothelial deletion of EP4 also worsened stroke injury and decreased cerebral reperfusion. Systemic administration of an EP4 agonist increased levels of activated eNOS in cerebral microvessels, an effect that was abolished with conditional deletion of endothelial EP4. Thus, our data support the concept of targeting protective prostaglandin receptors therapeutically after stroke.

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Liu et al (2012). Parkinson's Disease-Associated Kinase PINK1 Regulates Miro Protein Level and Axonal Transport of Mitochondria. PLoS Genetics 8(3): e1002537.

Mutations in Pten-induced kinase 1 (PINK1) are linked to early-onset familial Parkinson's disease (FPD). PINK1 has previously been implicated in mitochondrial fission/fusion dynamics, quality control, and electron transport chain function. However, it is not clear how these processes are interconnected and whether they are sufficient to explain all aspects of PINK1 pathogenesis. Here we show that PINK1 also controls mitochondrial motility. In Drosophila, downregulation of dMiro or other components of the mitochondrial transport machinery rescued dPINK1 mutant phenotypes in the muscle and dopaminergic (DA) neurons, whereas dMiro overexpression alone caused DA neuron loss. dMiro protein level was increased in dPINK1 mutant but decreased in dPINK1 or dParkin overexpression conditions. In Drosophila larval motor neurons, overexpression of dPINK1 inhibited axonal mitochondria transport in both anterograde and retrograde directions, whereas dPINK1 knockdown promoted anterograde transport. In HeLa cells, overexpressed hPINK1 worked together with hParkin, another FPD gene, to regulate the ubiquitination and degradation of hMiro1 and hMiro2, apparently in a Ser-156 phosphorylation-independent manner. Also in HeLa cells, loss of hMiro promoted the perinuclear clustering of mitochondria and facilitated autophagy of damaged mitochondria, effects previously associated with activation of the PINK1/Parkin pathway. These newly identified functions of PINK1/Parkin and Miro in mitochondrial transport and mitophagy contribute to our understanding of the complex interplays in mitochondrial quality control that are critically involved in PD pathogenesis, and they may explain the peripheral neuropathy symptoms seen in some PD patients carrying particular PINK1 or Parkin mutations. Moreover, the different effects of loss of PINK1 function on Miro protein level in Drosophila and mouse cells may offer one explanation of the distinct phenotypic manifestations of PINK1 mutants in these two species.

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Osterhout et al (2011). Cadherin-6 mediates axon-target matching in a non-image-forming visual circuit. Neuron 71(4):632-9.

Neural circuits consist of highly precise connections among specific types of neurons that serve a common functional goal. How neurons distinguish among different synaptic targets to form functionally precise circuits remains largely unknown. Here, we show that during development, the adhesion molecule cadherin-6 (Cdh6) is expressed by a subset of retinal ganglion cells (RGCs) and also by their targets in the brain. All of the Cdh6-expressing retinorecipient nuclei mediate non-image-forming visual functions. A screen of mice expressing GFP in specific subsets of RGCs revealed that Cdh3-RGCs which also express Cdh6 selectively innervate Cdh6-expressing retinorecipient targets. Moreover, in Cdh6-deficient mice, the axons of Cdh3-RGCs fail to properly innervate their targets and instead project to other visual nuclei. These findings provide functional evidence that classical cadherins promote mammalian CNS circuit development by ensuring that axons of specific cell types connect to their appropriate synaptic targets.

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Pasca et al (2011). Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nat. Med 17(12):1657-62.

Monogenic neurodevelopmental disorders provide key insights into the pathogenesis of disease and help us understand how specific genes control the development of the human brain. Timothy syndrome is caused by a missense mutation in the L-type calcium channel Ca(v)1.2 that is associated with developmental delay and autism. We generated cortical neuronal precursor cells and neurons from induced pluripotent stem cells derived from individuals with Timothy syndrome. Cells from these individuals have defects in calcium (Ca(2+)) signaling and activity-dependent gene expression. They also show abnormalities in differentiation, including decreased expression of genes that are expressed in lower cortical layers and in callosal projection neurons. In addition, neurons derived from individuals with Timothy syndrome show abnormal expression of tyrosine hydroxylase and increased production of norepinephrine and dopamine. This phenotype can be reversed by treatment with roscovitine, a cyclin-dependent kinase inhibitor and atypical L-type-channel blocker. These findings provide strong evidence that Ca(v)1.2 regulates the differentiation of cortical neurons in humans and offer new insights into the causes of autism in individuals with Timothy syndrome.

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Paz et al (2011). A new mode of corticothalamic transmission revealed in the Gria4(-/-) model of absence epilepsy. Nat. Neuro 14(9):1167-73.

Cortico-thalamo-cortical circuits mediate sensation and generate neural network oscillations associated with slow-wave sleep and various epilepsies. Cortical input to sensory thalamus is thought to mainly evoke feed-forward synaptic inhibition of thalamocortical (TC) cells via reticular thalamic nucleus (nRT) neurons, especially during oscillations. This relies on a stronger synaptic strength in the cortico-nRT pathway than in the cortico-TC pathway, allowing the feed-forward inhibition of TC cells to overcome direct cortico-TC excitation. We found a systemic and specific reduction in strength in GluA4-deficient (Gria4(-/-)) mice of one excitatory synapse of the rhythmogenic cortico-thalamo-cortical system, the cortico-nRT projection, and observed that the oscillations could still be initiated by cortical inputs via the cortico-TC-nRT-TC pathway. These results reveal a previously unknown mode of cortico-thalamo-cortical transmission, bypassing direct cortico-nRT excitation, and describe a mechanism for pathological oscillation generation. This mode could be active under other circumstances, representing a previously unknown channel of cortico-thalamo-cortical information processing.

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Sussillo et al (2012). A recurrent neural network for closed-loop intracortical brain-machine interface decoders. J Neural Eng. 19;9(2):026027.

Recurrent neural networks (RNNs) are useful tools for learning nonlinear relationships in time series data with complex temporal dependences. In this paper, we explore the ability of a simplified type of RNN, one with limited modifications to the internal weights called an echostate network (ESN), to effectively and continuously decode monkey reaches during a standard center-out reach task using a cortical brain-machine interface (BMI) in a closed loop. We demonstrate that the RNN, an ESN implementation termed a FORCE decoder (from first order reduced and controlled error learning), learns the task quickly and significantly outperforms the current state-of-the-art method, the velocity Kalman filter (VKF), using the measure of target acquire time. We also demonstrate that the FORCE decoder generalizes to a more difficult task by successfully operating the BMI in a randomized point-to-point task. The FORCE decoder is also robust as measured by the success rate over extended sessions. Finally, we show that decoded cursor dynamics are more like naturalistic hand movements than those of the VKF. Taken together, these results suggest that RNNs in general, and the FORCE decoder in particular, are powerful tools for BMI decoder applications.

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Sweeney et al (2011). Secreted semaphorins from degenerating larval ORN axons direct adult projection neuron dendrite targeting. Neuron 72(5):734-47.

During assembly of the Drosophila olfactory circuit, projection neuron (PN) dendrites prepattern the developing antennal lobe before the arrival of axons from their presynaptic partners, the adult olfactory receptor neurons (ORNs). We previously found that levels of transmembrane Semaphorin-1a, which acts as a receptor, instruct PN dendrite targeting along the dorsolateral-ventromedial axis. Here we show that two secreted semaphorins, Sema-2a and Sema-2b, provide spatial cues for PN dendrite targeting. Sema-2a and Sema-2b proteins are distributed in gradients opposing the Sema-1a protein gradient, and Sema-1a binds to Sema-2a-expressing cells. In Sema-2a and Sema-2b double mutants, PN dendrites that normally target dorsolaterally in the antennal lobe mistarget ventromedially, phenocopying cell-autonomous Sema-1a removal from these PNs. Cell ablation, cell-specific knockdown, and rescue experiments indicate that secreted semaphorins from degenerating larval ORN axons direct dendrite targeting. Thus, a degenerating brain structure instructs the wiring of a developing circuit through the repulsive action of secreted semaphorins.

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Taniguchi et al (2011). Function of prostaglandin E2 EP receptors in the acute outcome of rodent hypoxic ischemic encephalopathy. Neurosci Lett 504(3):185-90.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of severe and permanent neurologic disability after birth. The inducible cyclooxygenase COX-2, which along with COX-1 catalyzes the first committed step in prostaglandin (PG) synthesis, elicits significant brain injury in models of cerebral ischemia; however its downstream PG receptor pathways trigger both toxic and paradoxically protective effects. Here, we investigated the function of PGE(2) E-prostanoid (EP) receptors in the acute outcome of hypoxic-ischemic (HI) injury in the neonatal rat. We determined the temporal and cellular expression patterns of the EP1-4 receptors before and after HIE and tested whether modulation of EP1-4 receptor function could protect against cerebral injury acutely after HIE. All four EP receptors were expressed in forebrain neurons and were induced in endothelial cells after HIE. Inhibition of EP1 signaling with the selective antagonist SC-51089 or co-activation of EP2-4 receptors with the agonist misoprostol significantly reduced HIE cerebral injury 24 h after injury. These receptor ligands also protected brain endothelial cells subjected to oxygen glucose deprivation, suggesting that activation of EP receptor signaling is directly cytoprotective. These data indicate that the G-protein coupled EP receptors may be amenable to pharmacologic targeting in the acute setting of neonatal HIE.

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Witten et al (2011). Recombinase-driver rat lines: tools, techniques, and optogenetic application to dopamine-mediated reinforcement. Neuron 72(5):721-33.

Currently there is no general approach for achieving specific optogenetic control of genetically defined cell types in rats, which provide a powerful experimental system for numerous established neurophysiological and behavioral paradigms. To overcome this challenge we have generated genetically restricted recombinase-driver rat lines suitable for driving gene expression in specific cell types, expressing Cre recombinase under the control of large genomic regulatory regions (200-300 kb). Multiple tyrosine hydroxylase (Th)::Cre and choline acetyltransferase (Chat)::Cre lines were produced that exhibited specific opsin expression in targeted cell types. We additionally developed methods for utilizing optogenetic tools in freely moving rats and leveraged these technologies to clarify the causal relationship between dopamine (DA) neuron firing and positive reinforcement, observing that optical stimulation of DA neurons in the ventral tegmental area (VTA) of Th::Cre rats is sufficient to support vigorous intracranial self-stimulation (ICSS). These studies complement existing targeting approaches by extending the generalizability of optogenetics to traditionally non-genetically-tractable but vital animal models.

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Yizhar et al (2011). Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477(7363):171-8.

Severe behavioural deficits in psychiatric diseases such as autism and schizophrenia have been hypothesized to arise from elevations in the cellular balance of excitation and inhibition (E/I balance) within neural microcircuitry. This hypothesis could unify diverse streams of pathophysiological and genetic evidence, but has not been susceptible to direct testing. Here we design and use several novel optogenetic tools to causally investigate the cellular E/I balance hypothesis in freely moving mammals, and explore the associated circuit physiology. Elevation, but not reduction, of cellular E/I balance within the mouse medial prefrontal cortex was found to elicit a profound impairment in cellular information processing, associated with specific behavioural impairments and increased high-frequency power in the 30-80 Hz range, which have both been observed in clinical conditions in humans. Consistent with the E/I balance hypothesis, compensatory elevation of inhibitory cell excitability partially rescued social deficits caused by E/I balance elevation. These results provide support for the elevated cellular E/I balance hypothesis of severe neuropsychiatric disease-related symptoms.

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Yoo et al (2011). MicroRNA-mediated conversion of human fibroblasts to neurons. Nature 476(7359):228-31.

Neurogenic transcription factors and evolutionarily conserved signalling pathways have been found to be instrumental in the formation of neurons. However, the instructive role of microRNAs (miRNAs) in neurogenesis remains unexplored. We recently discovered that miR-9* and miR-124 instruct compositional changes of SWI/SNF-like BAF chromatin-remodelling complexes, a process important for neuronal differentiation and function. Nearing mitotic exit of neural progenitors, miR-9* and miR-124 repress the BAF53a subunit of the neural-progenitor (np)BAF chromatin-remodelling complex. After mitotic exit, BAF53a is replaced by BAF53b, and BAF45a by BAF45b and BAF45c, which are then incorporated into neuron-specific (n)BAF complexes essential for post-mitotic functions. Because miR-9/9* and miR-124 also control multiple genes regulating neuronal differentiation and function, we proposed that these miRNAs might contribute to neuronal fates. Here we show that expression of miR-9/9* and miR-124 (miR-9/9*-124) in human fibroblasts induces their conversion into neurons, a process facilitated by NEUROD2. Further addition of neurogenic transcription factors ASCL1 and MYT1L enhances the rate of conversion and the maturation of the converted neurons, whereas expression of these transcription factors alone without miR-9/9*-124 was ineffective. These studies indicate that the genetic circuitry involving miR-9/9*-124 can have an instructive role in neural fate determination.

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Zhang et al (2011). The Microbial Opsin Family of Optogenetic Tools. Cell  147(7): 1446-57.

The capture and utilization of light is an exquisitely evolved process. The single-component microbial opsins, although more limited than multicomponent cascades in processing, display unparalleled compactness and speed. Recent advances in understanding microbial opsins have been driven by molecular engineering for optogenetics and by comparative genomics. Here we provide a Primer on these light-activated ion channels and pumps, describe a group of opsins bridging prior categories, and explore the convergence of molecular engineering and genomic discovery for the utilization and understanding of these remarkable molecular machines.

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Stanford At SfN11 - Wednesday Schedule

For those of you still at SfN11 on Wednesday, be sure to visit the final posters from Stanford Neuroscience.

The Stanford Neuroscience affiliates presenting their research on Wednesday, Nov 16 are:

Posters

2:00-3:00 pm: Helen Bronte-Stewart

Program#/Poster#: 888.06/AA34

Title: Evidence for alpha and beta band hypersynchrony at rest in the GPi in generalized dystonia and its attenuation during high frequency GPi DBS in DYT3+ dystonia

Location: Hall A-C

4:00-5:00 pm: Corrina Darian-Smith

Program#/Poster#: 917.04/SS4

Title: Alterations to corticospinal projections following dorsal rhizotomy in the macaque monkey

Location: Hall A-C

Stanford at SfN11 - Tuesday Schedule

What has the Stanford Neuroscience community been up to? Find out by visiting our presentations and posters at SfN2011!

The Stanford Neuroscience affiliates presenting their research on Tuesday, Nov 15 are:

Presentations

9:10-9:45 am: Rob Malenka

Title: Function and plasticity of distinct subtypes of dopamine neurons

Location: Ballroom A

Posters

8:00-9:00 am: Cora Ames (Shenoy Lab)

Program#/Poster#: 591.17/MM25

Title: Neural dynamics of movement execution following incomplete or incorrect planning

Location: Hall A-C

4:00-5:00 pm: Izumi Toyoda (Buckmaster Lab)

Program#/Poster#: 672.04/Y3

Title: Possible mini-seizures in a rat model of temporal lobe epilepsy

Location: Hall A-C

Stanford at SfN11 - Monday Schedule

What has the Stanford Neuroscience community been up to? Find out by visiting our presentations and posters at SfN2011!

The Stanford Neuroscience affiliates presenting their research on Monday, Nov 14 are:

Presentations

10:15-10:35 am: Marius Wernig

Title: Novel reprogramming methods and ways to bypass the pluripotent state by directly converting non-neuronal somatic cells into functional neurons

Location: Ballroom B

Posters

8:00-9:00 am: Brittany Burrows

Program#/Poster#: 405.13/YY63

Title: Effects of reward and FEF microstimulation on choice and visually guided saccades during a free-choice task

Location: Hall A-C

9:00-10:00 am: Lynette Foo (Barres Lab)

Program#/Poster#: 330.02/A32

Title: Development of a novel method to purify and culture rodent astrocytes

Location: Hall A-C

9:00-10:00 am: Nick Steinmetz (Moore and Boahen lab)

Program#/Poster#: 379.06/OO26

Title: Pattern of presaccadic modulation of visual responses in macaque V4 measured simultaneously across cortical layers

Location: Hall A-C

10:00-11:00 am: Gary Steinberg

Program#/Poster#: 362.19/EE19

Title: Functional engraftment of CHR2-expressing human neural stem cells in experimental model of stroke

Location: Hall A-C

1:00-2:00 pm: Andreas Rauschecker

Program#/Poster#: 486.01/OO11

Title: Position-sensitivity in the VWFA measured using fMRI pattern-classification and intracranial recordings in humans

Location: Hall A-C

2:00-3:00 pm: Josef Parvizi

Program#/Poster#: 486.02/OO12

Title: Ventral occipito-temporal circuits for word form recognition elucidated using subdural electrode recordings in humans

Location: Hall A-C

Stanford at SFN11: Sunday Schedule

What has the Stanford Neuroscience community been up to? Find out by visiting our presentations and posters at SFN2011! The Stanford Neuroscience affiliates presenting their research on Sunday, Nov 13 are:

Presentations

8:30-8:45 am: Matt Kaufman (Krishna Shenoy lab)

Title: Changes of mind in a decision-making maze task in monkey

Location: 146A

10:15-10:35 am : Sam McClure

Title: Behavioral implications of relative value coding in the human brain

Location: 207B

1:45-2:00 pm: David Kastner (Stephen Baccus lab)

Title: Mechanism and circuitry underlying retinal sensitization

Location: 152B

Posters

8:00-9:00 am: Mehrdad Shamloo

Program#/Poster#: 152.01/W7

Title: Xamoterol rescues memory deficit in mouse model of down syndrome by activation of beta-1 adrenergic receptor.

Location: Hall A-C

9:00-10:00 am: Jake Rinaldi (Jennifer Raymod lab)

Program#/Poster#: 183.14/QQ25

Title: Climbing fiber activity as an error signal for VOR motor learning

Location: Hall A-C

10:00-11:00 am: Paul Buckmaster

Program#/Poster#: 154.03/Y18

Title: Temporal lobe epilepsy in California sea lions.

Location: Hall A-C

1:00-2:00 pm: Lisa Gunaydin (Karl Deisseroth lab)

Program#/Poster#: 306.05/YY16

Title: Bidirectional modulation of social behavior by optogenetic tuning of mesolimbic dopamine circuitry

Location: Hall A-C

1:00-2:00 pm: Emily Ferenczi (Karl Deisseroth lab)

Program#/Poster#: 306.09/YY20

Title: Stability of optogenetic tool deactivation kinetics under varying stimulation conditions

Location: Hall A-C

2:00-3:00 pm: Kelsey Clark (Tirin Moore lab)

Program#/Poster#: 272.18/JJ23

Title: Role of dopamine-mediated activity in the frontal eye field in spatial working memory

Location: Hall A-C

2:00-3:00 pm: Rohit Prakash (Karl Deisseroth lab)

Program#/Poster#: 306.10/YY21

Title: Development of two-photon optogenetic control by integrating optics with molecular engineering

Location: Hall A-C

3:00-4:00 pm: Lief Fenno (Karl Deisseroth lab)

Program#/Poster#: 306.07/YY18

Title: Combinatorial optogenetics with integrated spectral and temporal control

Location: Hall A-C

3:00-4:00 pm: Dan O'Shea (Krishna Shenoy lab)

Program#/Poster#: 306.11/YY22

Title: Optogenetic control of excitatory neurons via a red-shifted opsin in primate premotor cortex

Location: Hall A-C

4:00-5:00 pm: Joanna Mattis (Karl Deisseroth lab)

Program#/Poster#: 306.12/YY23

Title: Principles for optogenetics derived from direct comparative analysis of microbial opsins

Location: Hall A-C