Honors & Awards
Postdoctoral Fellowship, Life Sciences Research Foundation, Simons Foundation sponsor (2013-2016)
Dean's Postdoctoral Fellowship, Stanford University, School of Medicine (2013)
Innovative Research Grant, Kavli Institute for Brain and Mind (2007-2009)
Predoctoral Fellowship, Institute for Neural Computations, University of California San Diego, NIH (2007-2009)
Predoctoral Fellowship, National Science Foundation, Bridge to the Doctorate (2005-2007)
Warner Brown Memorial Prize for Outstanding Promise in Research, University of California Berkeley (2005)
Highest Department Honors, University of California Berkeley (2005)
Predoctoral Fellowship, Alliance for Graduate Education and the Professoriate (2005)
Education & Certifications
Ph.D., University of California San Diego, Neuroscience (2011)
Postdoctoral, The Salk Institute for Biological Studies, Systems Neurobiology (2012)
Extended field-of-view and increased-signal 3D holographic illumination with time-division multiplexing
2015; 23 (25): 32573-32581
Phase spatial light modulators (SLMs) are widely used for generating multifocal three-dimensional (3D) illumination patterns, but these are limited to a field of view constrained by the pixel count or size of the SLM. Further, with two-photon SLM-based excitation, increasing the number of focal spots penalizes the total signal linearly-requiring more laser power than is available or can be tolerated by the sample. Here we analyze and demonstrate a method of using galvanometer mirrors to time-sequentially reposition multiple 3D holograms, both extending the field of view and increasing the total time-averaged two-photon signal. We apply our approach to 3D two-photon in vivo neuronal calcium imaging.
View details for DOI 10.1364/OE.23.032573
View details for Web of Science ID 000366687200093
View details for PubMedID 26699047
Projections from neocortex mediate top-down control of memory retrieval
2015; 526 (7575): 653-659
Top-down prefrontal cortex inputs to the hippocampus have been hypothesized to be important in memory consolidation, retrieval, and the pathophysiology of major psychiatric diseases; however, no such direct projections have been identified and functionally described. Here we report the discovery of a monosynaptic prefrontal cortex (predominantly anterior cingulate) to hippocampus (CA3 to CA1 region) projection in mice, and find that optogenetic manipulation of this projection (here termed AC-CA) is capable of eliciting contextual memory retrieval. To explore the network mechanisms of this process, we developed and applied tools to observe cellular-resolution neural activity in the hippocampus while stimulating AC-CA projections during memory retrieval in mice behaving in virtual-reality environments. Using this approach, we found that learning drives the emergence of a sparse class of neurons in CA2/CA3 that are highly correlated with the local network and that lead synchronous population activity events; these neurons are then preferentially recruited by the AC-CA projection during memory retrieval. These findings reveal a sparsely implemented memory retrieval mechanism in the hippocampus that operates via direct top-down prefrontal input, with implications for the patterning and storage of salient memory representations.
View details for DOI 10.1038/nature15389
View details for Web of Science ID 000363832100039
View details for PubMedID 26436451
Closed-Loop and Activity-Guided Optogenetic Control
2015; 86 (1): 106-139
Advances in optical manipulation and observation of neural activity have set the stage for widespread implementation of closed-loop and activity-guided optical control of neural circuit dynamics. Closing the loop optogenetically (i.e., basing optogenetic stimulation on simultaneously observed dynamics in a principled way) is a powerful strategy for causal investigation of neural circuitry. In particular, observing and feeding back the effects of circuit interventions on physiologically relevant timescales is valuable for directly testing whether inferred models of dynamics, connectivity, and causation are accurate in vivo. Here we highlight technical and theoretical foundations as well as recent advances and opportunities in this area, and we review in detail the known caveats and limitations of optogenetic experimentation in the context of addressing these challenges with closed-loop optogenetic control in behaving animals.
View details for DOI 10.1016/j.neuron.2015.03.034
View details for Web of Science ID 000352552900017
View details for PubMedID 25856490
Topography and Areal Organization of Mouse Visual Cortex
JOURNAL OF NEUROSCIENCE
2014; 34 (37): 12587-12600
To guide future experiments aimed at understanding the mouse visual system, it is essential that we have a solid handle on the global topography of visual cortical areas. Ideally, the method used to measure cortical topography is objective, robust, and simple enough to guide subsequent targeting of visual areas in each subject. We developed an automated method that uses retinotopic maps of mouse visual cortex obtained with intrinsic signal imaging (Schuett et al., 2002; Kalatsky and Stryker, 2003; Marshel et al., 2011) and applies an algorithm to automatically identify cortical regions that satisfy a set of quantifiable criteria for what constitutes a visual area. This approach facilitated detailed parcellation of mouse visual cortex, delineating nine known areas (primary visual cortex, lateromedial area, anterolateral area, rostrolateral area, anteromedial area, posteromedial area, laterointermediate area, posterior area, and postrhinal area), and revealing two additional areas that have not been previously described as visuotopically mapped in mice (laterolateral anterior area and medial area). Using the topographic maps and defined area boundaries from each animal, we characterized several features of map organization, including variability in area position, area size, visual field coverage, and cortical magnification. We demonstrate that higher areas in mice often have representations that are incomplete or biased toward particular regions of visual space, suggestive of specializations for processing specific types of information about the environment. This work provides a comprehensive description of mouse visuotopic organization and describes essential tools for accurate functional localization of visual areas.
View details for DOI 10.1523/JNEUROSCI.1124-14.2014
View details for Web of Science ID 000341766900031
View details for PubMedID 25209296
- Genetically encoded voltage sensor goes live. Nature biotechnology 2013; 31 (11): 994-995
Diverging neural pathways assemble a behavioural state from separable features in anxiety
2013; 496 (7444): 219-223
Behavioural states in mammals, such as the anxious state, are characterized by several features that are coordinately regulated by diverse nervous system outputs, ranging from behavioural choice patterns to changes in physiology (in anxiety, exemplified respectively by risk-avoidance and respiratory rate alterations). Here we investigate if and how defined neural projections arising from a single coordinating brain region in mice could mediate diverse features of anxiety. Integrating behavioural assays, in vivo and in vitro electrophysiology, respiratory physiology and optogenetics, we identify a surprising new role for the bed nucleus of the stria terminalis (BNST) in the coordinated modulation of diverse anxiety features. First, two BNST subregions were unexpectedly found to exert opposite effects on the anxious state: oval BNST activity promoted several independent anxious state features, whereas anterodorsal BNST-associated activity exerted anxiolytic influence for the same features. Notably, we found that three distinct anterodorsal BNST efferent projections-to the lateral hypothalamus, parabrachial nucleus and ventral tegmental area-each implemented an independent feature of anxiolysis: reduced risk-avoidance, reduced respiratory rate, and increased positive valence, respectively. Furthermore, selective inhibition of corresponding circuit elements in freely moving mice showed opposing behavioural effects compared with excitation, and in vivo recordings during free behaviour showed native spiking patterns in anterodorsal BNST neurons that differentiated safe and anxiogenic environments. These results demonstrate that distinct BNST subregions exert opposite effects in modulating anxiety, establish separable anxiolytic roles for different anterodorsal BNST projections, and illustrate circuit mechanisms underlying selection of features for the assembly of the anxious state.
View details for DOI 10.1038/nature12018
View details for Web of Science ID 000317346300041
Anterior-Posterior Direction Opponency in the Superficial Mouse Lateral Geniculate Nucleus
2012; 76 (4): 713-720
We show functional-anatomical organization of motion direction in mouse dorsal lateral geniculate nucleus (dLGN) using two-photon calcium imaging of dense populations in thalamus. Surprisingly, the superficial 75 ?m region contains anterior and posterior direction-selective neurons (DSLGNs) intermingled with nondirection-selective neurons, while upward- and downward-selective neurons are nearly absent. Unexpectedly, the remaining neurons encode both anterior and posterior directions, forming horizontal motion-axis selectivity. A model of random wiring consistent with these results makes quantitative predictions about the connectivity of direction-selective retinal ganglion cell (DSRGC) inputs to the superficial dLGN. DSLGNs are more sharply tuned than DSRGCs. These results suggest that dLGN maintains and sharpens retinal direction selectivity and integrates opposing DSRGC subtypes in a functional-anatomical region, perhaps forming a feature representation for horizontal-axis motion, contrary to dLGN being a simple relay. Furthermore, they support recent conjecture that cortical direction and orientation selectivity emerge in part from a previously undescribed motion-selective retinogeniculate pathway.
View details for DOI 10.1016/j.neuron.2012.09.021
View details for Web of Science ID 000311977900006
View details for PubMedID 23177957
Functional Specialization of Seven Mouse Visual Cortical Areas
2011; 72 (6): 1040-1054
To establish the mouse as a genetically tractable model for high-order visual processing, we characterized fine-scale retinotopic organization of visual cortex and determined functional specialization of layer 2/3 neuronal populations in seven retinotopically identified areas. Each area contains a distinct visuotopic representation and encodes a unique combination of spatiotemporal features. Areas LM, AL, RL, and AM prefer up to three times faster temporal frequencies and significantly lower spatial frequencies than V1, while V1 and PM prefer high spatial and low temporal frequencies. LI prefers both high spatial and temporal frequencies. All extrastriate areas except LI increase orientation selectivity compared to V1, and three areas are significantly more direction selective (AL, RL, and AM). Specific combinations of spatiotemporal representations further distinguish areas. These results reveal that mouse higher visual areas are functionally distinct, and separate groups of areas may be specialized for motion-related versus pattern-related computations, perhaps forming pathways analogous to dorsal and ventral streams in other species.
View details for DOI 10.1016/j.neuron.2011.12.004
View details for Web of Science ID 000298771000017
View details for PubMedID 22196338
New Rabies Virus Variants for Monitoring and Manipulating Activity and Gene Expression in Defined Neural Circuits
2011; 71 (4): 617-631
Glycoprotein-deleted (?G) rabies virus is a powerful tool for studies of neural circuit structure. Here, we describe the development and demonstrate the utility of new resources that allow experiments directly investigating relationships between the structure and function of neural circuits. New methods and reagents allowed efficient production of 12 novel ?G rabies variants from plasmid DNA. These new rabies viruses express useful neuroscience tools, including the Ca(2+) indicator GCaMP3 for monitoring activity; Channelrhodopsin-2 for photoactivation; allatostatin receptor for inactivation by ligand application; and rtTA, ER(T2)CreER(T2), or FLPo, for control of gene expression. These new tools allow neurons targeted on the basis of their connectivity to have their function assayed or their activity or gene expression manipulated. Combining these tools with in vivo imaging and optogenetic methods and/or inducible gene expression in transgenic mice will facilitate experiments investigating neural circuit development, plasticity, and function that have not been possible with existing reagents.
View details for DOI 10.1016/j.neuron.2011.07.005
View details for Web of Science ID 000294521600008
View details for PubMedID 21867879
Targeting Single Neuronal Networks for Gene Expression and Cell Labeling In Vivo
2010; 67 (4): 562-574
To understand fine-scale structure and function of single mammalian neuronal networks, we developed and validated a strategy to genetically target and trace monosynaptic inputs to a single neuron in vitro and in vivo. The strategy independently targets a neuron and its presynaptic network for specific gene expression and fine-scale labeling, using single-cell electroporation of DNA to target infection and monosynaptic retrograde spread of a genetically modifiable rabies virus. The technique is highly reliable, with transsynaptic labeling occurring in every electroporated neuron infected by the virus. Targeting single neocortical neuronal networks in vivo, we found clusters of both spiny and aspiny neurons surrounding the electroporated neuron in each case, in addition to intricately labeled distal cortical and subcortical inputs. This technique, broadly applicable for probing and manipulating single neuronal networks with single-cell resolution in vivo, may help shed new light on fundamental mechanisms underlying circuit development and information processing by neuronal networks throughout the brain.
View details for DOI 10.1016/j.neuron.2010.08.001
View details for Web of Science ID 000281534600007
View details for PubMedID 20797534