Christina develops both optical and molecular tools for the detection and control of activated neural ensembles in living animals. She trained during her undergraduate career with Professor David Tank at Princeton University, generating transgenic strains of larval zebrafish for whole-brain, intact calcium imaging using 2-photon microscopy. She obtained a PhD in Neuroscience with Professor Karl Deisseroth at Stanford University, where she developed a microscope capable of simultaneously recording calcium activity from up to 7 different brain regions in a freely moving mouse. She also implemented simultaneous cellular-resolution calcium imaging and optogenetic stimulation of individual neurons to modulate behavior and probe causal circuit dynamics in mice. As a Postdoctoral Researcher with Professor Alice Ting at Stanford University, she is developing whole-brain techniques for coupling neural activity to transcriptomic molecular identity with precise temporal resolution.
Honors & Awards
Career Awards at the Scientific Interfaces, Burroughs Wellcome Fund (2019)
Allison Doupe Fellowship, The McKnight Foundation (2018)
Hanna H. Gray Fellow Finalist Research Award, Howard Hughes Medical Institute (2018)
Sammy Kuo Award for Neuroscience, 2nd place, Stanford Neurosciences Institute (2017)
Walter V. and Idun Berry Postdoctoral Fellow, Stanford School of Medicine (2017)
Ruth L. Kirschstein NRSA Individual Predoctoral Fellowship, National Institutes of Drug Addiction (2016-2017)
Graduate Research Fellowship Program, National Science Foundation (2012-2014)
Molecular Biology Senior Thesis Prize, Princeton University (2011)
The John Brinster, Class of 1943, Prize in Neuroscience, Princeton University (2011)
Shapiro Fund for Undergraduate Research in Neuroscience Award, Princeton University (2010)
Doctor of Philosophy, Stanford University, NEURS-PHD (2017)
Bachelor of Arts, Princeton University, Molecular Biology (2011)
Alice Ting, Postdoctoral Faculty Sponsor
Christina Kim, Samuel Yang, Karl Deisseroth, Isaac Kauvar. "United States Patent 62257140 Method and Systems for Measuring Neural Activity", The Board of Trustees of the Leland Stanford Junior University, Nov 18, 2015
Current Research and Scholarly Interests
Simultaneous recording and manipulation of neural activity:
I actively pursue the development and application of techniques for all-optical recording and manipulation of neural activity in living animals. During my PhD I developed a microscope capable of performing bulk calcium recording and optogenetic stimulation in freely moving animals (Frame-projected Independent-fiber Photometry). We demonstrated its utility by recording from sparse dopaminergic axon terminals distributed throughout the brain during rewarding versus aversive stimuli, and by recording from up to 7 different brain regions during a social interaction test. Using simultaneous optogenetics and calcium recording, we could then fine-tune the optogenetic stimulation of dopamine neurons to produce activity that mimicked the naturally-occurring response profiles during behavior. This work was published in Nature Methods, and has been patented and licensed to a company that has commercialized the microscope (www.neurophotometrics.com).
Molecular tools for imaging and recording neuronal activity.
Nature chemical biology
2019; 15 (2): 101–10
To understand how the brain relates to behavior, it is essential to record neural activity in awake, behaving animals. To achieve this goal, a large variety of genetically encoded sensors have been developed to monitor and record the series of events following neuronal firing, including action potentials, intracellular calcium rise, neurotransmitter release and immediate early gene expression. In this Review, we discuss the existing genetically encoded tools for detecting and integrating neuronal activity in animals and highlight the remaining challenges and future opportunities for molecular biologists.
View details for PubMedID 30659298
Interacting neural ensembles in orbitofrontal cortex for social and feeding behaviour.
Categorically distinct basic drives (for example, for social versus feeding behaviour1-3) can exert potent influences on each other; such interactions are likely to have important adaptive consequences (such as appropriate regulation of feeding in the context of social hierarchies) and can become maladaptive (such as in clinical settings involving anorexia). It is known that neural systems regulating natural and adaptive caloric intake, and those regulating social behaviours, involve related circuitry4-7, butthe causal circuit mechanisms of these drive adjudications are not clear. Here we investigate the causal role in behaviour of cellular-resolution experience-specific neuronal populations in the orbitofrontal cortex, a major reward-processing hub thatcontains diverse activity-specific neuronal populations that respond differentially to various aspects of caloric intake8-13 and social stimuli14,15. We coupled genetically encoded activity imaging with thedevelopment and application of methods for optogenetic control of multiple individually defined cells, to both optically monitor and manipulate the activity of many orbitofrontal cortex neurons at the single-cell level in real time during rewarding experiences (caloric consumption and socialinteraction). We identified distinct populations within the orbitofrontal cortex that selectively responded to either caloric rewards or social stimuli, and found that activity of individually specified naturally feeding-responsive neurons was causally linked to increased feeding behaviour; this effect was selective as, by contrast, single-cell resolution activation of naturally social-responsive neurons inhibited feeding, and activation of neurons responsive to neither feeding nor social stimuli did not alter feeding behaviour. These results reveal the presence of potent cellular-level subnetworks within the orbitofrontal cortex that can be precisely engaged to bidirectionally control feeding behaviours subject to, for example, social influences.
View details for PubMedID 30651638
A Neural Circuit Mechanism for Encoding Aversive Stimuli in the Mesolimbic Dopamine System.
Ventral tegmental area (VTA) dopamine (DA) neurons play a central role in mediating motivated behaviors, but the circuitry through which they signal positive and negative motivational stimuli is incompletely understood. Using invivo fiber photometry, we simultaneously recorded activity in DA terminals in different nucleus accumbens (NAc) subnuclei during an aversive and reward conditioning task. We find that DA terminals in the ventral NAc medial shell (vNAcMed) are excited by unexpected aversive outcomes and to cues that predict them, whereas DA terminals in other NAc subregions are persistently depressed. Excitation to reward-predictive cues dominated in the NAc lateral shell and was largely absent in the vNAcMed. Moreover, we demonstrate that glutamatergic (VGLUT2-expressing) neurons in the lateral hypothalamus represent a key afferent input for providing information about aversive outcomes to vNAcMed-projecting DA neurons. Collectively, we reveal the distinct functional contributions of separate mesolimbic DA subsystems and their afferent pathways underlying motivated behaviors.
View details for PubMedID 30503173
Integration of optogenetics with complementary methodologies in systems neuroscience
NATURE REVIEWS NEUROSCIENCE
2017; 18 (4): 222-235
Modern optogenetics can be tuned to evoke activity that corresponds to naturally occurring local or global activity in timing, magnitude or individual-cell patterning. This outcome has been facilitated not only by the development of core features of optogenetics over the past 10 years (microbial-opsin variants, opsin-targeting strategies and light-targeting devices) but also by the recent integration of optogenetics with complementary technologies, spanning electrophysiology, activity imaging and anatomical methods for structural and molecular analysis. This integrated approach now supports optogenetic identification of the native, necessary and sufficient causal underpinnings of physiology and behaviour on acute or chronic timescales and across cellular, circuit-level or brain-wide spatial scales.
View details for DOI 10.1038/nrn.2017.15
View details for Web of Science ID 000396325500008
View details for PubMedID 28303019
Modulation of prefrontal cortex excitation/inhibition balance rescues social behavior in CNTNAP2-deficient mice.
Science translational medicine
2017; 9 (401)
Alterations in the balance between neuronal excitation and inhibition (E:I balance) have been implicated in the neural circuit activity-based processes that contribute to autism phenotypes. We investigated whether acutely reducing E:I balance in mouse brain could correct deficits in social behavior. We used mice lacking the CNTNAP2 gene, which has been implicated in autism, and achieved a temporally precise reduction in E:I balance in the medial prefrontal cortex (mPFC) either by optogenetically increasing the excitability of inhibitory parvalbumin (PV) neurons or decreasing the excitability of excitatory pyramidal neurons. Surprisingly, both of these distinct, real-time, and reversible optogenetic modulations acutely rescued deficits in social behavior and hyperactivity in adult mice lacking CNTNAP2 Using fiber photometry, we discovered that native mPFC PV neuronal activity differed between CNTNAP2 knockout and wild-type mice. During social interactions with other mice, PV neuron activity increased in wild-type mice compared to interactions with a novel object, whereas this difference was not observed in CNTNAP2 knockout mice. Together, these results suggest that real-time modulation of E:I balance in the mouse prefrontal cortex can rescue social behavior deficits reminiscent of autism phenotypes.
View details for PubMedID 28768803
Molecular and Circuit-Dynamical Identification of Top-Down Neural Mechanisms for Restraint of Reward Seeking.
2017; 170 (5): 1013–27.e14
Reward-seeking behavior is fundamental to survival, but suppression of this behavior can be essential as well, even for rewards of high value. In humans and rodents, the medial prefrontal cortex (mPFC) has been implicated in suppressing reward seeking; however, despite vital significance in health and disease, the neural circuitry through which mPFC regulates reward seeking remains incompletely understood. Here, we show that a specific subset of superficial mPFC projections to a subfield of nucleus accumbens (NAc) neurons naturally encodes the decision to initiate or suppress reward seeking when faced with risk of punishment. A highly resolved subpopulation of these top-down projecting neurons, identified by 2-photon Ca(2+) imaging and activity-dependent labeling to recruit the relevant neurons, was found capable of suppressing reward seeking. This natural activity-resolved mPFC-to-NAc projection displayed unique molecular-genetic and microcircuit-level features concordant with a conserved role in the regulation of reward-seeking behavior, providing cellular and anatomical identifiers of behavioral and possible therapeutic significance.
View details for PubMedID 28823561
Rabies screen reveals GPe control of cocaine-triggered plasticity.
Identification of neural circuit changes that contribute to behavioural plasticity has routinely been conducted on candidate circuits that were preselected on the basis of previous results. Here we present an unbiased method for identifying experience-triggered circuit-level changes in neuronal ensembles in mice. Using rabies virus monosynaptic tracing, we mapped cocaine-induced global changes in inputs onto neurons in the ventral tegmental area. Cocaine increased rabies-labelled inputs from the globus pallidus externus (GPe), a basal ganglia nucleus not previously known to participate in behavioural plasticity triggered by drugs of abuse. We demonstrated that cocaine increased GPe neuron activity, which accounted for the increase in GPe labelling. Inhibition of GPe activity revealed that it contributes to two forms of cocaine-triggered behavioural plasticity, at least in part by disinhibiting dopamine neurons in the ventral tegmental area. These results suggest that rabies-based unbiased screening of changes in input populations can identify previously unappreciated circuit elements that critically support behavioural adaptations.
View details for PubMedID 28902833
Simultaneous fast measurement of circuit dynamics at multiple sites across the mammalian brain.
2016; 13 (4): 325-328
Real-time activity measurements from multiple specific cell populations and projections are likely to be important for understanding the brain as a dynamical system. Here we developed frame-projected independent-fiber photometry (FIP), which we used to record fluorescence activity signals from many brain regions simultaneously in freely behaving mice. We explored the versatility of the FIP microscope by quantifying real-time activity relationships among many brain regions during social behavior, simultaneously recording activity along multiple axonal pathways during sensory experience, performing simultaneous two-color activity recording, and applying optical perturbation tuned to elicit dynamics that match naturally occurring patterns observed during behavior.
View details for DOI 10.1038/nmeth.3770
View details for PubMedID 26878381
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
View details for PubMedCentralID PMC4775739
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 PubMedID 26436451
Prolonged, brain-wide expression of nuclear-localized GCaMP3 for functional circuit mapping
FRONTIERS IN NEURAL CIRCUITS
Larval zebrafish offer the potential for large-scale optical imaging of neural activity throughout the central nervous system; however, several barriers challenge their utility. First, ~panneuronal probe expression has to date only been demonstrated at early larval stages up to 7 days post-fertilization (dpf), precluding imaging at later time points when circuits are more mature. Second, nuclear exclusion of genetically-encoded calcium indicators (GECIs) limits the resolution of functional fluorescence signals collected during imaging. Here, we report the creation of transgenic zebrafish strains exhibiting robust, nuclearly targeted expression of GCaMP3 across the brain up to at least 14 dpf utilizing a previously described optimized Gal4-UAS system. We confirmed both nuclear targeting and functionality of the modified probe in vitro and measured its kinetics in response to action potentials (APs). We then demonstrated in vivo functionality of nuclear-localized GCaMP3 in transgenic zebrafish strains by identifying eye position-sensitive fluorescence fluctuations in caudal hindbrain neurons during spontaneous eye movements. Our methodological approach will facilitate studies of larval zebrafish circuitry by both improving resolution of functional Ca(2+) signals and by allowing brain-wide expression of improved GECIs, or potentially any probe, further into development.
View details for DOI 10.3389/fncir.2014.00138
View details for Web of Science ID 000346556700001
View details for PubMedID 25505384
View details for PubMedCentralID PMC4244806
Gating of neural error signals during motor learning.
Cerebellar climbing fiber activity encodes performance errors during many motor learning tasks, but the role of these error signals in learning has been controversial. We compared two motor learning paradigms that elicited equally robust putative error signals in the same climbing fibers: learned increases and decreases in the gain of the vestibulo-ocular reflex (VOR). During VOR-increase training, climbing fiber activity on one trial predicted changes in cerebellar output on the next trial, and optogenetic activation of climbing fibers to mimic their encoding of performance errors was sufficient to implant a motor memory. In contrast, during VOR-decrease training, there was no trial-by-trial correlation between climbing fiber activity and changes in cerebellar output, and climbing fiber activation did not induce VOR-decrease learning. Our data suggest that the ability of climbing fibers to induce plasticity can be dynamically gated in vivo, even under conditions where climbing fibers are robustly activated by performance errors. DOI: http://dx.doi.org/10.7554/eLife.02076.001.
View details for DOI 10.7554/eLife.02076
View details for PubMedID 24755290
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 PubMedID 23515158