Honors & Awards


Professional Education

  • Doctor of Philosphy, Icahn School of Medicine at Mount Sinai, Neuroscience (2014)
  • Bachelor of Arts, New York University (2004)

Stanford Advisors

Current Research and Scholarly Interests

Our experiences come to shape our future behaviors and can having lasting effects on our quality of life. My research aims to understand how chronic exposure to particular stimuli (i.e. stress, food, drugs) alters the functioning of specific neural circuits. Following identification of the relevant circuits, I investigate the mechanisms that regulate these experience-dependent changes. This ultimately aids in our understanding of how maladaptive changes in brain function occur and how these changes result in psychiatric disorders.

My current focus is on specific neural circuits involved in reward processing and feeding behavior. I am discovering how various excitatory inputs to the nucleus accumbens, a critical brain node involved in processing the salience of events, modulate reward - related behaviors utilizing converging lines of inquiry. Specifically, I observe neuronal activity in awake behaving mice, and assess the mechanisms underlying changes in activity with electrophysiology. Finally, I then modulate specific circuits using optogenetics, a technique that provides spatio-temporal control over genetically identified cells, to determine the causal role of these circuits in the approach and consumption of palatable foods.

All Publications

  • 5-HT release in nucleus accumbens rescues social deficits in mouse autism model. Nature Walsh, J. J., Christoffel, D. J., Heifets, B. D., Ben-Dor, G. A., Selimbeyoglu, A., Hung, L. W., Deisseroth, K., Malenka, R. C. 2018


    Dysfunction in prosocial interactions is a core symptom of autism spectrum disorder. However, the neural mechanisms that underlie sociability are poorly understood, limiting the rational development of therapies to treat social deficits. Here we show in mice that bidirectional modulation of the release of serotonin (5-HT) from dorsal raphe neurons in the nucleus accumbens bidirectionally modifies sociability. In a mouse model of a common genetic cause of autism spectrum disorder-a copy number variation on chromosome 16p11.2-genetic deletion of the syntenic region from 5-HT neurons induces deficits in social behaviour and decreases dorsal raphe 5-HT neuronal activity. These sociability deficits can be rescued by optogenetic activation of dorsal raphe 5-HT neurons, an effect requiring and mimicked by activation of 5-HT1b receptors in the nucleus accumbens. These results demonstrate an unexpected role for 5-HT action in the nucleus accumbens in social behaviours, and suggest that targeting this mechanism may prove therapeutically beneficial.

    View details for DOI 10.1038/s41586-018-0416-4

    View details for PubMedID 30089910

  • Parallel circuits from the bed nuclei of stria terminalis to the lateral hypothalamus drive opposing emotional states. Nature neuroscience Giardino, W. J., Eban-Rothschild, A., Christoffel, D. J., Li, S., Malenka, R. C., de Lecea, L. 2018


    Lateral hypothalamus (LH) neurons containing the neuropeptide hypocretin (HCRT; orexin) modulate affective components of arousal, but their relevant synaptic inputs remain poorly defined. Here we identified inputs onto LH neurons that originate from neuronal populations in the bed nuclei of stria terminalis (BNST; a heterogeneous region of extended amygdala). We characterized two non-overlapping LH-projecting GABAergic BNST subpopulations that express distinct neuropeptides (corticotropin-releasing factor, CRF, and cholecystokinin, CCK). To functionally interrogate BNSTLH circuitry, we used tools for monitoring and manipulating neural activity with cell-type-specific resolution in freely behaving mice. We found that Crf-BNST and Cck-BNST neurons respectively provide abundant and sparse inputs onto Hcrt-LH neurons, display discrete physiological responses to salient stimuli, drive opposite emotionally valenced behaviors, and receive different proportions of inputs from upstream networks. Together, our data provide an advanced model for how parallel BNSTLH pathways promote divergent emotional states via connectivity patterns of genetically defined, circuit-specific neuronal subpopulations.

    View details for DOI 10.1038/s41593-018-0198-x

    View details for PubMedID 30038273

  • Closing the loop on impulsivity via nucleus accumbens delta-band activity in mice and man. Proceedings of the National Academy of Sciences of the United States of America Wu, H., Miller, K. J., Blumenfeld, Z., Williams, N. R., Ravikumar, V. K., Lee, K. E., Kakusa, B., Sacchet, M. D., Wintermark, M., Christoffel, D. J., Rutt, B. K., Bronte-Stewart, H., Knutson, B., Malenka, R. C., Halpern, C. H. 2018; 115 (1): 192–97


    Reward hypersensitization is a common feature of neuropsychiatric disorders, manifesting as impulsivity for anticipated incentives. Temporally specific changes in activity within the nucleus accumbens (NAc), which occur during anticipatory periods preceding consummatory behavior, represent a critical opportunity for intervention. However, no available therapy is capable of automatically sensing and therapeutically responding to this vulnerable moment in time when anticipation-related neural signals may be present. To identify translatable biomarkers for an off-the-shelf responsive neurostimulation system, we record local field potentials from the NAc of mice and a human anticipating conventional rewards. We find increased power in 1- to 4-Hz oscillations predominate during reward anticipation, which can effectively trigger neurostimulation that reduces consummatory behavior in mice sensitized to highly palatable food. Similar oscillations are present in human NAc during reward anticipation, highlighting the translational potential of our findings in the development of a treatment for a major unmet need.

    View details for DOI 10.1073/pnas.1712214114

    View details for PubMedID 29255043

    View details for PubMedCentralID PMC5776799

  • Basal forebrain projections to the lateral habenula modulate aggression reward NATURE Golden, S. A., Heshmati, M., Flanigan, M., Christoffel, D. J., Guise, K., Pfau, M. L., Aleyasin, H., Menard, C., Zhang, H., Hodes, G. E., Bregman, D., Khibnik, L., Tai, J., Rebusi, N., Krawitz, B., Chaudhury, D., Walsh, J. J., Han, M., Shapiro, M. L., Russo, S. J. 2016; 534 (7609): 688-?


    Maladaptive aggressive behaviour is associated with a number of neuropsychiatric disorders and is thought to result partly from the inappropriate activation of brain reward systems in response to aggressive or violent social stimuli. Nuclei within the ventromedial hypothalamus, extended amygdala and limbic circuits are known to encode initiation of aggression; however, little is known about the neural mechanisms that directly modulate the motivational component of aggressive behaviour. Here we established a mouse model to measure the valence of aggressive inter-male social interaction with a smaller subordinate intruder as reinforcement for the development of conditioned place preference (CPP). Aggressors develop a CPP, whereas non-aggressors develop a conditioned place aversion to the intruder-paired context. Furthermore, we identify a functional GABAergic projection from the basal forebrain (BF) to the lateral habenula (lHb) that bi-directionally controls the valence of aggressive interactions. Circuit-specific silencing of GABAergic BF-lHb terminals of aggressors with halorhodopsin (NpHR3.0) increases lHb neuronal firing and abolishes CPP to the intruder-paired context. Activation of GABAergic BF-lHb terminals of non-aggressors with channelrhodopsin (ChR2) decreases lHb neuronal firing and promotes CPP to the intruder-paired context. Finally, we show that altering inhibitory transmission at BF-lHb terminals does not control the initiation of aggressive behaviour. These results demonstrate that the BF-lHb circuit has a critical role in regulating the valence of inter-male aggressive behaviour and provide novel mechanistic insight into the neural circuits modulating aggression reward processing.

    View details for DOI 10.1038/nature18601

    View details for Web of Science ID 000378676000037

    View details for PubMedID 27357796

    View details for PubMedCentralID PMC4930107

  • Excitatory transmission at thalamo-striatal synapses mediates susceptibility to social stress. Nature neuroscience Christoffel, D. J., Golden, S. A., Walsh, J. J., Guise, K. G., Heshmati, M., Friedman, A. K., Dey, A., Smith, M., Rebusi, N., Pfau, M., Ables, J. L., Aleyasin, H., Khibnik, L. A., Hodes, G. E., Ben-Dor, G. A., Deisseroth, K., Shapiro, M. L., Malenka, R. C., Ibanez-Tallon, I., Han, M., Russo, S. J. 2015; 18 (7): 962-964


    Postsynaptic remodeling of glutamatergic synapses on ventral striatum (vSTR) medium spiny neurons (MSNs) is critical for shaping stress responses. However, it is unclear which presynaptic inputs are involved. Susceptible mice exhibited increased synaptic strength at intralaminar thalamus (ILT), but not prefrontal cortex (PFC), inputs to vSTR MSNs following chronic social stress. Modulation of ILT-vSTR versus PFC-vSTR neuronal activity differentially regulated dendritic spine plasticity and social avoidance.

    View details for DOI 10.1038/nn.4034

    View details for PubMedID 26030846

  • Illuminating circuitry relevant to psychiatric disorders with optogenetics CURRENT OPINION IN NEUROBIOLOGY Steinberg, E. E., Christoffel, D. J., Deisseroth, K., Malenka, R. C. 2015; 30: 9-16


    The brain's remarkable capacity to generate cognition and behavior is mediated by an extraordinarily complex set of neural interactions that remain largely mysterious. This complexity poses a significant challenge in developing therapeutic interventions to ameliorate psychiatric disease. Accordingly, few new classes of drugs have been made available for patients with mental illness since the 1950s. Optogenetics offers the ability to selectively manipulate individual neural circuit elements that underlie disease-relevant behaviors and is currently accelerating the pace of preclinical research into neurobiological mechanisms of disease. In this review, we highlight recent findings from studies that employ optogenetic approaches to gain insight into normal and aberrant brain function relevant to mental illness. Emerging data from these efforts offers an exquisitely detailed picture of disease-relevant neural circuits in action, and hints at the potential of optogenetics to open up entirely new avenues in the treatment of psychiatric disorders.

    View details for DOI 10.1016/j.conb.2014.08.004

    View details for Web of Science ID 000348337600002

    View details for PubMedID 25215625

  • IkappaB kinase regulates social defeat stress induced synaptic and behavioral plasticity Neuropsychopharmacology Christoffel, D. J., et al 2012; 37 (12): 2615-23
  • IkappaB kinase regulates social defeat stress induced synaptic and behavioral plasticity Journal of Neuroscience Christoffel, D. J., et al 2011; 32 (1): 314-21
  • Cell-type-specific role for nucleus accumbens neuroligin-2 in depression and stress susceptibility. Proceedings of the National Academy of Sciences of the United States of America Heshmati, M., Aleyasin, H., Menard, C., Christoffel, D. J., Flanigan, M. E., Pfau, M. L., Hodes, G. E., Lepack, A. E., Bicks, L. K., Takahashi, A., Chandra, R., Turecki, G., Lobo, M. K., Maze, I., Golden, S. A., Russo, S. J. 2018; 115 (5): 1111–16


    Behavioral coping strategies are critical for active resilience to stress and depression; here we describe a role for neuroligin-2 (NLGN-2) in the nucleus accumbens (NAc). Neuroligins (NLGN) are a family of neuronal postsynaptic cell adhesion proteins that are constituents of the excitatory and inhibitory synapse. Importantly, NLGN-3 and NLGN-4 mutations are strongly implicated as candidates underlying the development of neuropsychiatric disorders with social disturbances such as autism, but the role of NLGN-2 in neuropsychiatric disease states is unclear. Here we show a reduction in NLGN-2 gene expression in the NAc of patients with major depressive disorder. Chronic social defeat stress in mice also decreases NLGN-2 selectively in dopamine D1-positive cells, but not dopamine D2-positive cells, within the NAc of stress-susceptible mice. Functional NLGN-2 knockdown produces bidirectional, cell-type-specific effects: knockdown in dopamine D1-positive cells promotes subordination and stress susceptibility, whereas knockdown in dopamine D2-positive cells mediates active defensive behavior. These findings establish a behavioral role for NAc NLGN-2 in stress and depression; provide a basis for targeted, cell-type specific therapy; and highlight the role of active behavioral coping mechanisms in stress susceptibility.

    View details for DOI 10.1073/pnas.1719014115

    View details for PubMedID 29339486

    View details for PubMedCentralID PMC5798379

  • Susceptibility to chronic social stress increases plaque progression, vulnerability and platelet activation THROMBOSIS AND HAEMOSTASIS Giannarelli, C., Rodriguez, D. T., Zafar, M. U., Christoffel, D., Vialou, V., Pena, C., Badimon, A., Hodes, G. F., Mury, P., Rabkin, J., Alique, M., Villa, G., Argmann, C., Nestler, E. J., Russo, S. J., Badimon, J. J. 2017; 117 (4): 816-818

    View details for DOI 10.1160/TH16-10-0817

    View details for Web of Science ID 000398880400020

    View details for PubMedID 28078352

    View details for PubMedCentralID PMC5490439

  • Antipsychotic-induced Hdac2 transcription via NF-κB leads to synaptic and cognitive side effects. Nature neuroscience Ibi, D., de la Fuente Revenga, M., Kezunovic, N., Muguruza, C., Saunders, J. M., Gaitonde, S. A., Moreno, J. L., Ijaz, M. K., Santosh, V., Kozlenkov, A., Holloway, T., Seto, J., García-Bea, A., Kurita, M., Mosley, G. E., Jiang, Y., Christoffel, D. J., Callado, L. F., Russo, S. J., Dracheva, S., López-Giménez, J. F., Ge, Y., Escalante, C. R., Meana, J. J., Akbarian, S., Huntley, G. W., González-Maeso, J. 2017; 20 (9): 1247–59


    Antipsychotic drugs remain the standard for schizophrenia treatment. Despite their effectiveness in treating hallucinations and delusions, prolonged exposure to antipsychotic medications leads to cognitive deficits in both schizophrenia patients and animal models. The molecular mechanisms underlying these negative effects on cognition remain to be elucidated. Here we demonstrate that chronic antipsychotic drug exposure increases nuclear translocation of NF-κB in both mouse and human frontal cortex, a trafficking event triggered via 5-HT2A-receptor-dependent downregulation of the NF-κB repressor IκBα. This upregulation of NF-κB activity led to its increased binding at the Hdac2 promoter, thereby augmenting Hdac2 transcription. Deletion of HDAC2 in forebrain pyramidal neurons prevented the negative effects of antipsychotic treatment on synaptic remodeling and cognition. Conversely, virally mediated activation of NF-κB signaling decreased cortical synaptic plasticity via HDAC2. Together, these observations may aid in developing therapeutic strategies to improve the outcome of schizophrenia treatment.

    View details for DOI 10.1038/nn.4616

    View details for PubMedID 28783139

    View details for PubMedCentralID PMC5675106

  • Stress and CRF gate neural activation of BDNF in the mesolimbic reward pathway NATURE NEUROSCIENCE Walsh, J. J., Friedman, A. K., Sun, H., Heller, E. A., Ku, S. M., Juarez, B., Burnham, V. L., Mazei-Robison, M. S., Ferguson, D., Golden, S. A., Koo, J. W., Chaudhury, D., Christoffe, D. J., Pomeranz, L., Friedman, J. M., Russo, S. J., Nestler, E. J., Han, M. 2014; 17 (1): 27-29


    Mechanisms controlling release of brain-derived neurotrophic factor (BDNF) in the mesolimbic dopamine reward pathway remain unknown. We report that phasic optogenetic activation of this pathway increases BDNF amounts in the nucleus accumbens (NAc) of socially stressed mice but not of stress-naive mice. This stress gating of BDNF signaling is mediated by corticotrophin-releasing factor (CRF) acting in the NAc. These results unravel a stress context-detecting function of the brain's mesolimbic circuit.

    View details for DOI 10.1038/nn.3591

    View details for Web of Science ID 000329080000009

    View details for PubMedID 24270188

  • Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proceedings of the National Academy of Sciences of the United States of America Hodes, G. E., Pfau, M. L., Leboeuf, M., Golden, S. A., Christoffel, D. J., Bregman, D., Rebusi, N., Heshmati, M., Aleyasin, H., Warren, B. L., Lebonté, B., Horn, S., Lapidus, K. A., Stelzhammer, V., Wong, E. H., Bahn, S., Krishnan, V., Bolaños-Guzman, C. A., Murrough, J. W., Merad, M., Russo, S. J. 2014; 111 (45): 16136–41


    Depression and anxiety disorders are associated with increased release of peripheral cytokines; however, their functional relevance remains unknown. Using a social stress model in mice, we find preexisting individual differences in the sensitivity of the peripheral immune system that predict and promote vulnerability to social stress. Cytokine profiles were obtained 20 min after the first social stress exposure. Of the cytokines regulated by stress, IL-6 was most highly up-regulated only in mice that ultimately developed a susceptible behavioral phenotype following a subsequent chronic stress, and levels remained elevated for at least 1 mo. We confirmed a similar elevation of serum IL-6 in two separate cohorts of patients with treatment-resistant major depressive disorder. Before any physical contact in mice, we observed individual differences in IL-6 levels from ex vivo stimulated leukocytes that predict susceptibility versus resilience to a subsequent stressor. To shift the sensitivity of the peripheral immune system to a pro- or antidepressant state, bone marrow (BM) chimeras were generated by transplanting hematopoietic progenitor cells from stress-susceptible mice releasing high IL-6 or from IL-6 knockout (IL-6(-/-)) mice. Stress-susceptible BM chimeras exhibited increased social avoidance behavior after exposure to either subthreshold repeated social defeat stress (RSDS) or a purely emotional stressor termed witness defeat. IL-6(-/-) BM chimeric and IL-6(-/-) mice, as well as those treated with a systemic IL-6 monoclonal antibody, were resilient to social stress. These data establish that preexisting differences in stress-responsive IL-6 release from BM-derived leukocytes functionally contribute to social stress-induced behavioral abnormalities.

    View details for DOI 10.1073/pnas.1415191111

    View details for PubMedID 25331895

  • Kalirin-7 Mediates Cocaine-Induced AMPA Receptor and Spine Plasticity, Enabling Incentive Sensitization JOURNAL OF NEUROSCIENCE Wang, X., Cahill, M. E., Werner, C. T., Christoffel, D. J., Golden, S. A., Xie, Z., Loweth, J. A., Marinelli, M., Russo, S. J., Penzes, P., Wolf, M. E. 2013; 33 (27): 11012-U410


    It is well established that behavioral sensitization to cocaine is accompanied by increased spine density and AMPA receptor (AMPAR) transmission in the nucleus accumbens (NAc), but two major questions remain unanswered. Are these adaptations mechanistically coupled? And, given that they can be dissociated from locomotor sensitization, what is their functional significance? We tested the hypothesis that the guanine-nucleotide exchange factor Kalirin-7 (Kal-7) couples cocaine-induced AMPAR and spine upregulation and that these adaptations underlie sensitization of cocaine's incentive-motivational properties-the properties that make it "wanted." Rats received eight daily injections of saline or cocaine. On withdrawal day 14, we found that Kal-7 levels and activation of its downstream effectors Rac-1 and PAK were increased in the NAc of cocaine-sensitized rats. Furthermore, AMPAR surface expression and spine density were increased, as expected. To determine whether these changes require Kal-7, a lentiviral vector expressing Kal-7 shRNA was injected into the NAc core before cocaine exposure. Knocking down Kal-7 abolished the AMPAR and spine upregulation normally seen during cocaine withdrawal. Despite the absence of these adaptations, rats with reduced Kal-7 levels developed locomotor sensitization. However, incentive sensitization, which was assessed by how rapidly rats learned to self-administer a threshold dose of cocaine, was severely impaired. These results identify a signaling pathway coordinating AMPAR and spine upregulation during cocaine withdrawal, demonstrate that locomotor and incentive sensitization involve divergent mechanisms, and link enhanced excitatory transmission in the NAc to incentive sensitization.

    View details for DOI 10.1523/JNEUROSCI.1097-13.2013

    View details for Web of Science ID 000321258000008

    View details for PubMedID 23825406

  • Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression NATURE MEDICINE Golden, S. A., Christoffel, D. J., Heshmati, M., Hodes, G. E., Magida, J., Davis, K., Cahill, M. E., Dias, C., Ribeiro, E., Ables, J. L., Kennedy, P. J., Robison, A. J., Gonzalez-Maeso, J., Neve, R. L., Turecki, G., Ghose, S., Tamminga, C. A., Russo, S. J. 2013; 19 (3): 337-344


    Depression induces structural and functional synaptic plasticity in brain reward circuits, although the mechanisms promoting these changes and their relevance to behavioral outcomes are unknown. Transcriptional profiling of the nucleus accumbens (NAc) for Rho GTPase-related genes, which are known regulators of synaptic structure, revealed a sustained reduction in RAS-related C3 botulinum toxin substrate 1 (Rac1) expression after chronic social defeat stress. This was associated with a repressive chromatin state surrounding the proximal promoter of Rac1. Inhibition of class 1 histone deacetylases (HDACs) with MS-275 rescued both the decrease in Rac1 transcription after social defeat stress and depression-related behavior, such as social avoidance. We found a similar repressive chromatin state surrounding the RAC1 promoter in the NAc of subjects with depression, which corresponded with reduced RAC1 transcription. Viral-mediated reduction of Rac1 expression or inhibition of Rac1 activity in the NAc increases social defeat-induced social avoidance and anhedonia in mice. Chronic social defeat stress induces the formation of stubby excitatory spines through a Rac1-dependent mechanism involving the redistribution of synaptic cofilin, an actin-severing protein downstream of Rac1. Overexpression of constitutively active Rac1 in the NAc of mice after chronic social defeat stress reverses depression-related behaviors and prunes stubby spines. Taken together, our data identify epigenetic regulation of RAC1 in the NAc as a disease mechanism in depression and reveal a functional role for Rac1 in rodents in regulating stress-related behaviors.

    View details for DOI 10.1038/nm.3090

    View details for Web of Science ID 000316040700027

    View details for PubMedID 23416703

  • Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons NATURE Chaudhury, D., Walsh, J. J., Friedman, A. K., Juarez, B., Ku, S. M., Koo, J. W., Ferguson, D., Tsai, H., Pomeranz, L., Christoffel, D. J., Nectow, A. R., Ekstrand, M., Domingos, A., Mazei-Robison, M. S., Mouzon, E., Lobo, M. K., Neve, R. L., Friedman, J. M., Russo, S. J., Deisseroth, K., Nestler, E. J., Han, M. 2013; 493 (7433): 532-?


    Ventral tegmental area (VTA) dopamine neurons in the brain's reward circuit have a crucial role in mediating stress responses, including determining susceptibility versus resilience to social-stress-induced behavioural abnormalities. VTA dopamine neurons show two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing. Phasic firing of the neurons, which is well known to encode reward signals, is upregulated by repeated social-defeat stress, a highly validated mouse model of depression. Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no apparent change in firing rate in resilient individuals. However, direct evidence--in real time--linking dopamine neuron phasic firing in promoting the susceptible (depression-like) phenotype is lacking. Here we took advantage of the temporal precision and cell-type and projection-pathway specificity of optogenetics to show that enhanced phasic firing of these neurons mediates susceptibility to social-defeat stress in freely behaving mice. We show that optogenetic induction of phasic, but not tonic, firing in VTA dopamine neurons of mice undergoing a subthreshold social-defeat paradigm rapidly induced a susceptible phenotype as measured by social avoidance and decreased sucrose preference. Optogenetic phasic stimulation of these neurons also quickly induced a susceptible phenotype in previously resilient mice that had been subjected to repeated social-defeat stress. Furthermore, we show differences in projection-pathway specificity in promoting stress susceptibility: phasic activation of VTA neurons projecting to the nucleus accumbens (NAc), but not to the medial prefrontal cortex (mPFC), induced susceptibility to social-defeat stress. Conversely, optogenetic inhibition of the VTA-NAc projection induced resilience, whereas inhibition of the VTA-mPFC projection promoted susceptibility. Overall, these studies reveal novel firing-pattern- and neural-circuit-specific mechanisms of depression.

    View details for DOI 10.1038/nature11713

    View details for Web of Science ID 000313871400038

    View details for PubMedID 23235832

    View details for PubMedCentralID PMC3554860