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