What I'm Reading: You patched how many cells now?

This week, the list of journal articles that I simply must manage tofinish reading includes a technical tour de force from the lab of J Julius Zhu (UVA), entitled “The organization of two new cortical interneuronal circuits”. The co-first authors are Xiaolong Jiang (now a Research Assistant Professor at Baylor College of Medicine) and Guangfu Wang (currently a Research Associate at UVA). Now, I’ve not yet finished reading the paper, so I’m not going to be able to provide the kind of in-depth description of its findings/protocols/implication. (It’s only Wednesday, proper article-reading protocol requires at least 2 days of sitting half-read on my desk.) That being said, folks interested in cortical microcircuits, inhibitory networks, and astonishing efforts in patch-clamp electrophysiology would do well to pick up this article.

The general gist of the study: it is a painstaking examination of the connection patterns of two distinct subtypes of cortical layer 1 inhibitory interneurons. The authors provide convincing evidence for two never-before-described circuits, involving these layer 1 interneurons: one circuit serves to enhance a particular form of activation, known as complex spikes, in downstream layer 5 pyramidal neurons; the other circuit suppresses this same form of activation. The two subtypes of layer 1 interneuron generate their opposing effects on layer 5 pyramidal neuron activity via distinct connections with additional interneurons located in layer 2/3.

As I said, I won’t go in depth into the findings of the paper. Instead, I’d like to focus on the methods, which as I mentioned, could be described as a technical tour de force. But really, tour de force doesn’t quite capture the ludicrous amount of work that must have gone into this study. One the surface, the techniques used are fairly straightforward, patch clamp electrophysiology, a technique first developed by Burt Sakmann and Erwin Neher, and used daily by scientists in research labs across the world (including myself). However, it is in the application of the technique, that this study sets itself apart.

Some background for the non-patch-clamp physiologists in the room. Most of the time, patch-clamp electrophysiologists record from individual neurons within a brain slice; if the experimental question requires, sometimes two neurons will be patched simultaneously. Simultaneous recordings can be technically tricky, requiring a stable recording setup and a skilled patch-clamper; so although dual recordings are pretty common these days, they still represent a technical achievement. Simultaneously recording more than 2 neurons (say 3-4)? A rare event.

To demonstrate the patterns of connectivity between the various subtypes of neurons (those located in layer 1, 2/3 and 5), Jiang, Wang and company patch clamped up to 8 neurons simultaneously. In total, they report testing “14,832 connections between 1,703 L1 neurons, 3,310 L2/3 interneurons and/or 3,394 L5 pyramidal neurons in the cortical slices.”

To best illustrate my reaction to reading this particular sentence, I present my marginalia:

As a patch-clamp electrophysiology, I am absolutely staggered by the prospect of patching that many neurons. And to collect those numbers while attempting (and succeeding) in simultaneously patching up to 8 neurons… These folks are crazy.

Take a look at Figure 3, in which the authors characterize the connectivity between 7 simultaneously recorded neurons. Oh, and did I mention that the authors recovered the anatomy of the vast majority of their interneurons and pyramidal cells – 85% and 99%, respectively. (I’ve got a hit rate of 50-60%, on good day. Damn people.)

Technically, this paper is ridiculously impressive, in a “damn-how-long-did-that-take-you-no-wait-how-did-you-do-that-um-can-I-buy-you-a-patch-clamp-machine-please” way. And the science is pretty cool too (although again, I’ve not yet finished the paper, so “pretty cool too” should be seen as an initial impression only. And an understatement.).

But seriously, Xiaolong Jiang, Guangfu Wang, Alice J Lee, Ruth L Stornetta, and lab head J Julius Zhang have produced a paper of breathtaking technical mastery of patch clamp physiology. We all should read it and appreciate their hard, hard work. And then get them one of these: http://autopatcher.org/

Jiang, Wang, Lee, Stornetta and Zhu (2013). The organization of two new cortical interneuronal circuits. Nature Neuroscience, 16(2): 210-218. doi:10.1038/nn.3305. Available online here.

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.

Useful Resource: Clinical Chemistry Guide to Scientific Writing

Hello again, I’m (finally) working on my report on the Colloquium on Rethinking the Future of Scientific Communication (is it May already?), and I remembered that one of the organizers, Nader Rifai, had recommended this great series of articles on scientific writing published by the journal Clinical Chemistry, of which he is editor in chief. So, before I forget, here is the link:

ClinChem Guide to Scientific Writing

By the way, as neuroscientists you may or not be familiar with Clinical Chemistry, but if you are interested in open science and new publication models, Dr. Rifai might be a good person to pay attention to. As the other organizers put it (approximately) over drinks the night before the colloquium, if you want to know how journals should be evolving over the next 5 years, just look at what Nader was doing last year.

That’s all I have for now, but stay tuned for more activity soon!

-Nick

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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