Ph.Ds in press #2

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#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.