Jason received his bachelors degree in biology and philosophy from Union College. He spent three years as a Post-Baccalaureate IRTA fellow at the National Institute of Neurological Disorders and Stroke investigating and developing MRI reportable contrast agents to map neuronal connectivity. Following this he entered the Medical Scientist Training Program (MD/PhD) at SUNY Stony Brook University. There he completed a doctoral dissertation in neuroscience under the mentorship Dr. Josh Huang at Cold Spring Harbor Laboratory. His thesis work employed mouse genetic dissections of excitatory and inhibitory cortical circuits with a focus on the circuitry of chandelier inhibitory interneurons in prefrontal cortex. He is currently a resident physician in Stanford Psychiatry and Behavioral Sciences’ research residency track. His research interests include uncovering circuit mechanisms of psychiatric disorders with hopeful applications to novel therapeutics.
A Genetically Defined Compartmentalized Striatal Direct Pathway for Negative Reinforcement
2020; 183 (1): 211-+
View details for Web of Science ID 000576772900018
Genetic Single Neuron Anatomy Reveals Fine Granularity of Cortical Axo-Axonic Cells.
2019; 26 (11): 3145–59.e5
Parsing diverse nerve cells into biological types is necessary for understanding neural circuit organization. Morphology is an intuitive criterion for neuronal classification and a proxy of connectivity, but morphological diversity and variability often preclude resolving the granularity of neuron types. Combining genetic labeling with high-resolution, large-volume light microscopy, we established a single neuron anatomy platform that resolves, registers, and quantifies complete neuron morphologies in the mouse brain. We discovered that cortical axo-axonic cells (AACs), a cardinal GABAergic interneuron type that controls pyramidal neuron (PyN) spiking at axon initial segments, consist of multiple subtypes distinguished by highly laminar-specific soma position and dendritic and axonal arborization patterns. Whereas the laminar arrangements of AAC dendrites reflect differential recruitment by input streams, the laminar distribution and local geometry of AAC axons enable differential innervation of PyN ensembles. This platform will facilitate genetically targeted, high-resolution, and scalable single neuron anatomy in the mouse brain.
View details for DOI 10.1016/j.celrep.2019.02.040
View details for PubMedID 30865900
Selective inhibitory control of pyramidal neuron ensembles and cortical subnetworks by chandelier cells.
The neocortex comprises multiple information processing streams mediated by subsets of glutamatergic pyramidal cells (PCs) that receive diverse inputs and project to distinct targets. How GABAergic interneurons regulate the segregation and communication among intermingled PC subsets that contribute to separate brain networks remains unclear. Here we demonstrate that a subset of GABAergic chandelier cells (ChCs) in the prelimbic cortex, which innervate PCs at spike initiation site, selectively control PCs projecting to the basolateral amygdala (BLAPC) compared to those projecting to contralateral cortex (CCPC). These ChCs in turn receive preferential input from local and contralateral CCPCs as opposed to BLAPCs and BLA neurons (the prelimbic cortex-BLA network). Accordingly, optogenetic activation of ChCs rapidly suppresses BLAPCs and BLA activity in freely behaving mice. Thus, the exquisite connectivity of ChCs not only mediates directional inhibition between local PC ensembles but may also shape communication hierarchies between global networks.
View details for DOI 10.1038/nn.4624
View details for PubMedID 28825718
Evaluation of the appropriate use of a CIWA-Ar alcohol withdrawal protocol in the general hospital setting.
The American journal of drug and alcohol abuse
The Clinical Institute Withdrawal Assessment-Alcohol, Revised (CIWA-Ar) is an assessment tool used to quantify alcohol withdrawal syndrome (AWS) severity and inform benzodiazepine treatment for alcohol withdrawal.To evaluate the prescribing patterns and appropriate use of the CIWA-Ar protocol in a general hospital setting, as determined by the presence or absence of documented AWS risk factors, patients' ability to communicate, and provider awareness of the CIWA-Ar order.This retrospective chart review included 118 encounters of hospitalized patients placed on a CIWA-Ar protocol during one year. The following data were collected for each encounter: patient demographics, admitting diagnosis, ability to communicate, and admission blood alcohol level; and medical specialty of the clinician ordering CIWA-Ar, documentation of the presence or absence of established AWS risk factors, specific parameters of the protocol ordered, service admitted to, provider documentation of awareness of the active protocol within 48 h of initial order, total benzodiazepine dose equivalents administered and associated adverse events.57% of patients who started on a CIWA-Ar protocol had either zero or one documented risk factor for AWS (19% and 38% respectively). 20% had no documentation of recent alcohol use. 14% were unable to communicate. 19% of medical records lacked documentation of provider awareness of the ordered protocol. Benzodiazepine associated adverse events were documented in 15% of encounters.The judicious use of CIWA-Ar protocols in general hospitals requires mechanisms to ensure assessment of validated alcohol withdrawal risk factors, exclusion of patients who cannot communicate, and continuity of care during transitions.
View details for DOI 10.1080/00952990.2017.1362418
View details for PubMedID 28981333
A basal ganglia circuit for evaluating action outcomes
2016; 539 (7628): 289-?
The basal ganglia, a group of subcortical nuclei, play a crucial role in decision-making by selecting actions and evaluating their outcomes. While much is known about the function of the basal ganglia circuitry in selection, how these nuclei contribute to outcome evaluation is less clear. Here we show that neurons in the habenula-projecting globus pallidus (GPh) in mice are essential for evaluating action outcomes and are regulated by a specific set of inputs from the basal ganglia. We find in a classical conditioning task that individual mouse GPh neurons bidirectionally encode whether an outcome is better or worse than expected. Mimicking these evaluation signals with optogenetic inhibition or excitation is sufficient to reinforce or discourage actions in a decision-making task. Moreover, cell-type-specific synaptic manipulations reveal that the inhibitory and excitatory inputs to the GPh are necessary for mice to appropriately evaluate positive and negative feedback, respectively. Finally, using rabies-virus-assisted monosynaptic tracing, we show that the GPh is embedded in a basal ganglia circuit wherein it receives inhibitory input from both striosomal and matrix compartments of the striatum, and excitatory input from the 'limbic' regions of the subthalamic nucleus. Our results provide evidence that information about the selection and evaluation of actions is channelled through distinct sets of basal ganglia circuits, with the GPh representing a key locus in which information of opposing valence is integrated to determine whether action outcomes are better or worse than expected.
View details for DOI 10.1038/nature19845
View details for Web of Science ID 000387318500045
View details for PubMedID 27652894
View details for PubMedCentralID PMC5161609
Strategies and Tools for Combinatorial Targeting of GABAergic Neurons in Mouse Cerebral Cortex
2016; 91 (6): 1228-1243
Systematic genetic access to GABAergic cell types will facilitate studying the function and development of inhibitory circuitry. However, single gene-driven recombinase lines mark relatively broad and heterogeneous cell populations. Although intersectional approaches improve precision, it remains unclear whether they can capture cell types defined by multiple features. Here we demonstrate that combinatorial genetic and viral approaches target restricted GABAergic subpopulations and cell types characterized by distinct laminar location, morphology, axonal projection, and electrophysiological properties. Intersectional embryonic transcription factor drivers allow finer fate mapping of progenitor pools that give rise to distinct GABAergic populations, including laminar cohorts. Conversion of progenitor fate restriction signals to constitutive recombinase expression enables viral targeting of cell types based on their lineage and birth time. Properly designed intersection, subtraction, conversion, and multi-color reporters enhance the precision and versatility of drivers and viral vectors. These strategies and tools will facilitate studying GABAergic neurons throughout the mouse brain.
View details for DOI 10.1016/j.neuron.2016.08.021
View details for Web of Science ID 000386760300009
View details for PubMedID 27618674
View details for PubMedCentralID PMC5223593
Cooperative Subnetworks of Molecularly Similar Interneurons in Mouse Neocortex
2016; 90 (1): 86-100
Simultaneous co-activation of neocortical neurons is likely critical for brain computations ranging from perception and motor control to memory and cognition. While co-activation of excitatory principal cells (PCs) during ongoing activity has been extensively studied, that of inhibitory interneurons (INs) has received little attention. Here, we show in vivo and in vitro that members of two non-overlapping neocortical IN populations, expressing somatostatin (SOM) or vasoactive intestinal peptide (VIP), are active as populations rather than individually. We demonstrate a variety of synergistic mechanisms, involving population-specific local excitation, GABAergic disinhibition and excitation through electrical coupling, which likely underlie IN population co-activity. Firing of a few SOM or VIP INs recruits additional members within the cell type via GABAergic and cholinergic mechanisms, thereby amplifying the output of the population as a whole. Our data suggest that IN populations work as cooperative units, thus generating an amplifying nonlinearity in their circuit output.
View details for DOI 10.1016/j.neuron.2016.02.037
View details for Web of Science ID 000373565800011
View details for PubMedID 27021171
View details for PubMedCentralID PMC4961215
The Mediodorsal Thalamus Drives Feedforward Inhibition in the Anterior Cingulate Cortex via Parvalbumin Interneurons
JOURNAL OF NEUROSCIENCE
2015; 35 (14): 5743-5753
Although the medial prefrontal cortex (mPFC) is classically defined by its reciprocal connections with the mediodorsal thalamic nucleus (MD), the nature of information transfer between MD and mPFC is poorly understood. In sensory thalamocortical pathways, thalamic recruitment of feedforward inhibition mediated by fast-spiking, putative parvalbumin-expressing (PV) interneurons is a key feature that enables cortical neurons to represent sensory stimuli with high temporal fidelity. Whether a similar circuit mechanism is in place for the projection from the MD (a higher-order thalamic nucleus that does not receive direct input from the periphery) to the mPFC is unknown. Here we show in mice that inputs from the MD drive disynaptic feedforward inhibition in the dorsal anterior cingulate cortex (dACC) subregion of the mPFC. In particular, we demonstrate that axons arising from MD neurons directly synapse onto and excite PV interneurons that in turn mediate feedforward inhibition of pyramidal neurons in layer 3 of the dACC. This feedforward inhibition in the dACC limits the time window during which pyramidal neurons integrate excitatory synaptic inputs and fire action potentials, but in a manner that allows for greater flexibility than in sensory cortex. These findings provide a foundation for understanding the role of MD-PFC circuit function in cognition.
View details for DOI 10.1523/JNEUROSCI.4565-14.2015
View details for Web of Science ID 000353054900024
View details for PubMedID 25855185
View details for PubMedCentralID PMC4388929
The paraventricular thalamus controls a central amygdala fear circuit
2015; 519 (7544): 455-?
Appropriate responses to an imminent threat brace us for adversities. The ability to sense and predict threatening or stressful events is essential for such adaptive behaviour. In the mammalian brain, one putative stress sensor is the paraventricular nucleus of the thalamus (PVT), an area that is readily activated by both physical and psychological stressors. However, the role of the PVT in the establishment of adaptive behavioural responses remains unclear. Here we show in mice that the PVT regulates fear processing in the lateral division of the central amygdala (CeL), a structure that orchestrates fear learning and expression. Selective inactivation of CeL-projecting PVT neurons prevented fear conditioning, an effect that can be accounted for by an impairment in fear-conditioning-induced synaptic potentiation onto somatostatin-expressing (SOM(+)) CeL neurons, which has previously been shown to store fear memory. Consistently, we found that PVT neurons preferentially innervate SOM(+) neurons in the CeL, and stimulation of PVT afferents facilitated SOM(+) neuron activity and promoted intra-CeL inhibition, two processes that are critical for fear learning and expression. Notably, PVT modulation of SOM(+) CeL neurons was mediated by activation of the brain-derived neurotrophic factor (BDNF) receptor tropomysin-related kinase B (TrkB). As a result, selective deletion of either Bdnf in the PVT or Trkb in SOM(+) CeL neurons impaired fear conditioning, while infusion of BDNF into the CeL enhanced fear learning and elicited unconditioned fear responses. Our results demonstrate that the PVT-CeL pathway constitutes a novel circuit essential for both the establishment of fear memory and the expression of fear responses, and uncover mechanisms linking stress detection in PVT with the emergence of adaptive behaviour.
View details for DOI 10.1038/nature13978
View details for Web of Science ID 000351602800053
View details for PubMedID 25600269
View details for PubMedCentralID PMC4376633
Input-specific maturation of synaptic dynamics of parvalbumin interneurons in primary visual cortex
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2014; 111 (47): 16895-16900
Cortical networks consist of local recurrent circuits and long-range pathways from other brain areas. Parvalbumin-positive interneurons (PVNs) regulate the dynamic operation of local ensembles as well as the temporal precision of afferent signals. The synaptic recruitment of PVNs that support these circuit operations is not well-understood. Here we demonstrate that the synaptic dynamics of PVN recruitment in mouse visual cortex are customized according to input source with distinct maturation profiles. Whereas the long-range inputs to PVNs show strong short-term depression throughout postnatal maturation, local inputs from nearby pyramidal neurons progressively lose such depression. This enhanced local recruitment depends on PVN-mediated reciprocal inhibition and results from both pre- and postsynaptic mechanisms, including calcium-permeable AMPA receptors at PVN postsynaptic sites. Although short-term depression of long-range inputs is well-suited for afferent signal detection, the robust dynamics of local inputs may facilitate rapid and proportional PVN recruitment in regulating local circuit operations.
View details for DOI 10.1073/pnas.1400694111
View details for Web of Science ID 000345662700060
View details for PubMedID 25385583
View details for PubMedCentralID PMC4250102
Targeting cells with single vectors using multiple-feature Boolean logic.
2014; 11 (7): 763-772
Precisely defining the roles of specific cell types is an intriguing frontier in the study of intact biological systems and has stimulated the rapid development of genetically encoded tools for observation and control. However, targeting these tools with adequate specificity remains challenging: most cell types are best defined by the intersection of two or more features such as active promoter elements, location and connectivity. Here we have combined engineered introns with specific recombinases to achieve expression of genetically encoded tools that is conditional upon multiple cell-type features, using Boolean logical operations all governed by a single versatile vector. We used this approach to target intersectionally specified populations of inhibitory interneurons in mammalian hippocampus and neurons of the ventral tegmental area defined by both genetic and wiring properties. This flexible and modular approach may expand the application of genetically encoded interventional and observational tools for intact-systems biology.
View details for DOI 10.1038/nmeth.2996
View details for PubMedID 24908100
A Cortical Circuit for Gain Control by Behavioral State
2014; 156 (6): 1139-1152
The brain's response to sensory input is strikingly modulated by behavioral state. Notably, the visual response of mouse primary visual cortex (V1) is enhanced by locomotion, a tractable and accessible example of a time-locked change in cortical state. The neural circuits that transmit behavioral state to sensory cortex to produce this modulation are unknown. In vivo calcium imaging of behaving animals revealed that locomotion activates vasoactive intestinal peptide (VIP)-positive neurons in mouse V1 independent of visual stimulation and largely through nicotinic inputs from basal forebrain. Optogenetic activation of VIP neurons increased V1 visual responses in stationary awake mice, artificially mimicking the effect of locomotion, and photolytic damage of VIP neurons abolished the enhancement of V1 responses by locomotion. These findings establish a cortical circuit for the enhancement of visual response by locomotion and provide a potential common circuit for the modulation of sensory processing by behavioral state.
View details for DOI 10.1016/j.cell.2014.01.050
View details for Web of Science ID 000332945100006
View details for PubMedID 24630718
View details for PubMedCentralID PMC4041382
Layer specific tracing of corticocortical and thalamocortical connectivity in the rodent using manganese enhanced MRI
2009; 44 (3): 923-931
Information about layer specific connections in the brain comes mainly from classical neuronal tracers that rely on histology. Manganese Enhanced MRI (MEMRI) has mapped connectivity along a number of brain pathways in several animal models. It is not clear at what level of specificity neuronal connectivity measured using MEMRI tracing can resolve. The goal of this work was to determine if neural tracing using MEMRI could distinguish layer inputs of major pathways of the cortex. To accomplish this, tracing was performed between hemispheres of the somatosensory (S1) cortex and between the thalamus and S1 cortex. T(1) mapping and T(1) weighted pulse sequences detected layer specific tracing after local injection of MnCl(2). Approximately 12 h following injections into S1 cortex, maximal T(1) reductions were observed at 0.6+/-0.07 and 1.1+/-0.12 mm from the brain surface in the contralateral S1. These distances correspond to the positions of layer 3 and 5 consistent with the known callosal inputs along this pathway. Four to six hours following injection of MnCl(2) into the thalamus there were maximal T(1) reductions between 0.7+/-0.08 and 0.8+/-0.08 mm from the surface of the brain, which corresponds to layer 4. This is consistent with terminations of the known thalamocortical projections. In order to observe the first synapse projection, it was critical to perform MRI at the right time after injections to detect layer specificity with MEMRI. At later time points, tracing through the cortical network led to more uniform contrast throughout the cortex due to its complex neuronal connections. These results are consistent with well established neuronal pathways within the somatosensory cortex and demonstrate that layer specific somatosensory connections can be detected in vivo using MEMRI.
View details for DOI 10.1016/j.neuroimage.2008.07.036
View details for Web of Science ID 000262301500032
View details for PubMedID 18755280
Detection of cortical laminar architecture using manganese-enhanced MRI
JOURNAL OF NEUROSCIENCE METHODS
2008; 167 (2): 246-257
Changes in manganese-enhanced MRI (MEMRI) contrast across the rodent somatosensory cortex were compared to the cortical laminae as identified by tissue histology and administration of an anatomical tracer to cortex and thalamus. Across the cortical thickness, MEMRI signal intensity was low in layer I, increased in layer II, decreased in layer III until mid-layer IV, and increased again, peaking in layer V, before decreasing through layer VI. The reeler mouse mutant was used to confirm that the cortical alternation in MEMRI contrast was related to laminar architecture. Unlike in wild-type mice, the reeler cortex showed no appreciable changes in MEMRI signal, consistent with absence of cortical laminae in histological slides. The tract tracing ability of MEMRI was used to further confirm assignments and demonstrate laminar specificity. Twelve to 16 h after stereotaxic injections of MnCl(2) to the ventroposterior thalamic nuclei, an overall increase in signal intensity was detected in primary somatosensory cortex compared to other brain regions. Maximum intensity projection images revealed a distinctly bright stripe located 600-700 microm below the pial surface, in layer IV. The data show that both systemic and tract tracing forms of MEMRI are useful for studying laminar architecture in the brain.
View details for DOI 10.1016/j.jneumeth.2007.08.020
View details for Web of Science ID 000252938400015
View details for PubMedID 17936913
View details for PubMedCentralID PMC2266830