Honors & Awards
K99/R00 Award, NIMH (2017-2022)
NARSAD Young Investigator Award, Brain and Behavior Research Foundation (2017-2019)
30 under 30 - Science, Forbes (2017)
Best Poster Prize, Gordon Research Conference: “Optogenetic Approaches to Understanding Neural Circuits & Behavior” (2016)
Helen Hay Whitney Foundation Postdoctoral Fellowship, Helen Hay Whitney Foundation (2015-2018)
Donald B Lindsley Prize in Behavioral Neuroscience, Society for Neuroscience (2015)
Dean’s Award for Excellence in Research, Columbia University (2014)
Best Poster Presentation, FENS/IBRO/SfN Causal Neuroscience Summer School (2011)
Graduate Student Travel Award, Kavli Foundation (2011)
Graduate Student Travel Award, Society for Neuroscience (2011)
NSERC Postgraduate Fellowship, Natural Science and Engineering Research Council of Canada (2010-2014)
Certificate of Academic Excellence, Canadian Psychological Association (2009)
W.R. Thompson Prize in Psychology, Queen's University (2009)
Summer Undergraduate Research Fellowship, The Rockefeller University (2008)
Dean's Honor List, Queen's University (2005-2009)
Doctor of Philosophy, Columbia University (2014)
Bachelor of Science, Queens University at Kingston (2009)
Karl Deisseroth, Postdoctoral Faculty Sponsor
Ancestral Circuits for the Coordinated Modulation of Brain State.
2017; 171 (6): 1411–23.e17
Internal states of the brain profoundly influence behavior. Fluctuating states such as alertness can be governed by neuromodulation, but the underlying mechanisms and cell types involved are not fully understood. We developed a method to globally screen for cell types involved in behavior by integrating brain-wide activity imaging with high-content molecular phenotyping and volume registration at cellular resolution. We used this method (MultiMAP) to record from 22 neuromodulatory cell types in behaving zebrafish during a reaction-time task that reports alertness. We identified multiple monoaminergic, cholinergic, and peptidergic cell types linked to alertness and found that activity in these cell types was mutually correlated during heightened alertness. We next recorded from and controlled homologous neuromodulatory cells in mice; alertness-related cell-type dynamics exhibited striking evolutionary conservation and modulated behavior similarly. These experiments establish a method for unbiased discovery of cellular elements underlying behavior and reveal an evolutionarily conserved set of diverse neuromodulatory systems that collectively govern internal state.
View details for DOI 10.1016/j.cell.2017.10.021
View details for PubMedID 29103613
SPED Light Sheet Microscopy: Fast Mapping of Biological System Structure and Function
2015; 163 (7): 1796-1806
The goal of understanding living nervous systems has driven interest in high-speed and large field-of-view volumetric imaging at cellular resolution. Light sheet microscopy approaches have emerged for cellular-resolution functional brain imaging in small organisms such as larval zebrafish, but remain fundamentally limited in speed. Here, we have developed SPED light sheet microscopy, which combines large volumetric field-of-view via an extended depth of field with the optical sectioning of light sheet microscopy, thereby eliminating the need to physically scan detection objectives for volumetric imaging. SPED enables scanning of thousands of volumes-per-second, limited only by camera acquisition rate, through the harnessing of optical mechanisms that normally result in unwanted spherical aberrations. We demonstrate capabilities of SPED microscopy by performing fast sub-cellular resolution imaging of CLARITY mouse brains and cellular-resolution volumetric Ca(2+) imaging of entire zebrafish nervous systems. Together, SPED light sheet methods enable high-speed cellular-resolution volumetric mapping of biological system structure and function.
View details for DOI 10.1016/j.cell.2015.11.061
View details for Web of Science ID 000366854200024
View details for PubMedID 26687363
Dendritic Inhibition in the Hippocampus Supports Fear Learning
2014; 343 (6173): 857-863
Fear memories guide adaptive behavior in contexts associated with aversive events. The hippocampus forms a neural representation of the context that predicts aversive events. Representations of context incorporate multisensory features of the environment, but must somehow exclude sensory features of the aversive event itself. We investigated this selectivity using cell type-specific imaging and inactivation in hippocampal area CA1 of behaving mice. Aversive stimuli activated CA1 dendrite-targeting interneurons via cholinergic input, leading to inhibition of pyramidal cell distal dendrites receiving aversive sensory excitation from the entorhinal cortex. Inactivating dendrite-targeting interneurons during aversive stimuli increased CA1 pyramidal cell population responses and prevented fear learning. We propose subcortical activation of dendritic inhibition as a mechanism for exclusion of aversive stimuli from hippocampal contextual representations during fear learning.
View details for DOI 10.1126/science.1247485
View details for Web of Science ID 000331552600039
View details for PubMedID 24558155
Regulation of neuronal input transformations by tunable dendritic inhibition
2012; 15 (3): 423-U111
Transforming synaptic input into action potential output is a fundamental function of neurons. The pattern of action potential output from principal cells of the mammalian hippocampus encodes spatial and nonspatial information, but the cellular and circuit mechanisms by which neurons transform their synaptic input into a given output are unknown. Using a combination of optical activation and cell type-specific pharmacogenetic silencing in vitro, we found that dendritic inhibition is the primary regulator of input-output transformations in mouse hippocampal CA1 pyramidal cells, and acts by gating the dendritic electrogenesis driving burst spiking. Dendrite-targeting interneurons are themselves modulated by interneurons targeting pyramidal cell somata, providing a synaptic substrate for tuning pyramidal cell output through interactions in the local inhibitory network. These results provide evidence for a division of labor in cortical circuits, where distinct computational functions are implemented by subtypes of local inhibitory neurons.
View details for DOI 10.1038/nn.3024
View details for Web of Science ID 000300793100016
View details for PubMedID 22246433
The hypothalamic NPVF circuit modulates ventral raphe activity during nociception
RFamide neuropeptide VF (NPVF) is expressed by neurons in the hypothalamus and has been implicated in nociception, but the circuit mechanisms remain unexplored. Here, we studied the structural and functional connections from NPVF neurons to downstream targets in the context of nociception, using novel transgenic lines, optogenetics, and calcium imaging in behaving larval zebrafish. We found a specific projection from NPVF neurons to serotonergic neurons in the ventral raphe nucleus (vRN). We showed NPVF neurons and vRN are suppressed and excited by noxious stimuli, respectively. We combined optogenetics with calcium imaging and pharmacology to demonstrate that stimulation of NPVF cells suppresses neuronal activity in vRN. During noxious stimuli, serotonergic neurons activation was due to a suppression of an inhibitory NPVF-ventral raphe peptidergic projection. This study reveals a novel NPVF-vRN functional circuit modulated by noxious stimuli in vertebrates.
View details for DOI 10.1038/srep41528
View details for Web of Science ID 000392959300001
View details for PubMedID 28139691
View details for PubMedCentralID PMC5282529
Distinct Contribution of Adult-Born Hippocampal Granule Cells to Context Encoding
2016; 90 (1): 101-112
Adult-born granule cells (abGCs) have been implicated in cognition and mood; however, it remains unknown how these cells behave in vivo. Here, we have used two-photon calcium imaging to monitor the activity of young abGCs in awake behaving mice. We find that young adult-born neurons fire at a higher rate in vivo but paradoxically exhibit less spatial tuning than their mature counterparts. When presented with different contexts, mature granule cells underwent robust remapping of their spatial representations, and the few spatially tuned adult-born cells remapped to a similar degree. We next used optogenetic silencing to confirm the direct involvement of abGCs in context encoding and discrimination, consistent with their proposed role in pattern separation. These results provide the first in vivo characterization of abGCs and reveal their participation in the encoding of novel information.
View details for DOI 10.1016/j.neuron.2016.02.019
View details for Web of Science ID 000373565800012
View details for PubMedID 26971949
Parvalbumin-Positive Basket Cells Differentiate among Hippocampal Pyramidal Cells
2014; 82 (5): 1129-1144
CA1 pyramidal cells (PCs) are not homogeneous but rather can be grouped by molecular, morphological, and functional properties. However, less is known about synaptic sources differentiating PCs. Using paired recordings in vitro, two-photon Ca(2+) imaging in vivo, and computational modeling, we found that parvalbumin-expressing basket cells (PVBCs) evoked greater inhibition in CA1 PCs located in the deep compared to superficial layer of stratum pyramidale. In turn, analysis of reciprocal connectivity revealed more frequent excitatory inputs to PVBCs by superficial PCs, demonstrating bias in target selection by both the excitatory and inhibitory local connections in CA1. Additionally, PVBCs further segregated among deep PCs, preferentially innervating the amygdala-projecting PCs but receiving preferential excitation from the prefrontal cortex-projecting PCs, thus revealing distinct perisomatic inhibitory interactions between separate output channels. These results demonstrate the presence of heterogeneous PVBC-PC microcircuits, potentially contributing to the sparse and distributed structure of hippocampal network activity.
View details for DOI 10.1016/j.neuron.2014.03.034
View details for Web of Science ID 000337359800018
View details for PubMedID 24836505
Behavioral consequences of GABAergic neuronal diversity
CURRENT OPINION IN NEUROBIOLOGY
2014; 26: 27-33
The majority of cellular diversity in the hippocampus and neocortex derives from a relatively small population of local inhibitory interneurons. Recent technological advances have facilitated the recording and manipulation of defined inhibitory cell classes in awake rodents, revealing new and surprising roles for these cells in local circuit function and behavior. Here we review recent progress in the analysis of inhibitory interneuron subtypes in neocortex and hippocampus during behavior, and suggest opportunities and considerations for extending this research program.
View details for DOI 10.1016/j.conb.2013.11.002
View details for Web of Science ID 000336827800006
View details for PubMedID 24650501
Septo-hippocampal GABAergic signaling across multiple modalities in awake mice
2013; 16 (9): 1182-U31
Hippocampal interneurons receive GABAergic input from the medial septum. Using two-photon Ca(2+) imaging of axonal boutons in hippocampal CA1 of behaving mice, we found that populations of septo-hippocampal GABAergic boutons were activated during locomotion and salient sensory events; sensory responses scaled with stimulus intensity and were abolished by anesthesia. We found similar activity patterns among boutons with common putative postsynaptic targets, with low-dimensional bouton population dynamics being driven primarily by presynaptic spiking.
View details for DOI 10.1038/nn.3482
View details for Web of Science ID 000323597500007
View details for PubMedID 23912949
- Circuits supporting the grid NATURE NEUROSCIENCE 2013; 16 (3): 255-257
Target-Specific Encoding of Response Inhibition: Increased Contribution of AMPA to NMDA Receptors at Excitatory Synapses in the Prefrontal Cortex
JOURNAL OF NEUROSCIENCE
2010; 30 (34): 11493-11500
Impulse control suppresses actions that are inappropriate in one context, but may be beneficial in others. The medial prefrontal cortex (mPFC) mediates this process by providing a top-down signal to inhibit competing responses, although the mechanism by which the mPFC acquires this ability is unknown. To that end, we examined synaptic changes in the mPFC associated with learning to inhibit an incorrect response. Rats were trained in a simple response inhibition task to withhold responding until a signal was presented. We then measured synaptic plasticity of excitatory synapses in the mPFC, using whole-cell patch-clamp recordings, in brain slices prepared from trained rats. Response inhibition training significantly increased the relative contribution of AMPA receptors to the overall EPSC in prelimbic, but not infralimbic, neurons of the mPFC. This potentiation of synaptic transmission closely paralleled the acquisition and extinction of response inhibition. Using a retrograde fluorescent tracer, we observed that these plastic changes were selective for efferents projecting to the ventral striatum, but not the dorsal striatum or amygdala. Therefore, we suggest that response inhibition is encoded by a selective strengthening of a subset of corticostriatal projections, uncovering a synaptic mechanism of impulse control. This information could be exploited in therapeutic interventions for disorders of impulse control, such as addiction, attention deficit-hyperactivity disorder, and schizophrenia.
View details for DOI 10.1523/JNEUROSCI.1550-10.2010
View details for Web of Science ID 000281268200027
View details for PubMedID 20739571
Histaminergic responses by hypothalamic neurons that regulate lordosis and their modulation by estradiol
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2010; 107 (27): 12311-12316
How do fluctuations in the level of generalized arousal of the brain affect the performance of specific motivated behaviors, such as sexual behaviors that depend on sexual arousal? A great deal of previous work has provided us with two important starting points in answering this question: (i) that histamine (HA) serves generalized CNS arousal and (ii) that heightened electrical activity of neurons in the ventromedial nucleus of the hypothalamus (VMN) is necessary and sufficient for facilitating the primary female sex behavior in laboratory animals, lordosis behavior. Here we used patch clamp recording technology to analyze HA effects on VMN neuronal activity. The results show that HA acting through H1 receptors (H1R) depolarizes these neurons. Further, acute administration of estradiol, an estrogen necessary for lordosis behavior to occur, heightens this effect. Hyperpolarization, which tends to decrease excitability and enhance inhibition, was not affected by acute estradiol or mediated by H1R but was mediated by other HA receptor subtypes, H2 and H3. Sampling of mRNA from individual VMN neurons showed colocalization of expression of H1 receptor mRNA with estrogen receptor (ER)-alpha mRNA but also revealed ER colocalization with the other HA receptor subtypes and colocalization of different subtypes with each other. The latter finding provides the molecular basis for complex "push-pull" regulation of VMN neuronal excitability by HA. Thus, in the simplest causal route, HA, acting on VMN neurons through H1R provides a mechanism by which elevated states of generalized CNS arousal can foster a specific estrogen-dependent, aroused behavior, sexual behavior.
View details for DOI 10.1073/pnas.1006049107
View details for Web of Science ID 000279572100049
View details for PubMedID 20562342