Chronic social defeat stress (CSDS) is a trauma based paradigm used to model depression- and anxiety-like behavior in rodents. We found previously that CSDS increases glutamatergic synapses on nucleus accumbens (NAc) medium spiny neurons, however the detailed circuitry meditating these effects is unclear. Previous work shows that the NAc receives dense glutamatergic innervation from the intralaminar thalamus (ILT) and prefrontal cortex (PFC). Thus, we analyzed levels of vesicular glutamate transporter 2 (VGLUT2) and VGLUT1, which are predominately found in ILT-NAc or PFC-NAc synapses, respectively. We found increased levels of VGLUT2 in susceptible mice that negatively correlated with social interaction ratio, suggesting that changes in ILT-NAc circuitry may regulate depression- or anxiety-like behavioral phenotypes following CSDS. To establish the functional relevance of these circuits in CSDS-induced depression- or anxiety-like behavior, we utilized circuit specific optogenetic approaches to modulate activity of the ILT-NAc or PFC-NAc. Our results show that rapid activation of the ILT-NAc circuit is both necessary and sufficient for the expression of stress-induced behavior, while rapid stimulation of PFC-NAc circuit had no effect. Interestingly, we also find that the ILT-NAc circuit selectively regulates activity of cholinergic interneurons, which seem to be necessary for the pro-depressant effects of ILT stimulation. In sum, our results identify circuit specific effects of different glutamate inputs wihin the NAc that control depression- or anxiety-like behavioral phenotypes. This provides us with unique insight into how stress impacts NAc circuitry and may inform a greater understanding of the mechanisms by which NAc deep brain stimulation is antidepressant in humans.

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Chronic stress induces postsynaptic remodeling of glutamatergic synapses on nucleus accumbens (NAc) medium spiny neurons (MSNs); however, it is unclear which presynaptic glutamate inputs are involved. In this proposal we find evidence of synaptic plasticity within intralaminar thalamus (ILT)-NAc projecting neurons that control depression and anxiety-like behavior.

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National Institute of Mental Health (NIMH)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Tonelli, Leonardo H
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Icahn School of Medicine at Mount Sinai
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Pfau, Madeline L; Ménard, Caroline; Russo, Scott J (2018) Inflammatory Mediators in Mood Disorders: Therapeutic Opportunities. Annu Rev Pharmacol Toxicol 58:411-428
Aleyasin, Hossein; Flanigan, Meghan E; Golden, Sam A et al. (2018) Cell-Type-Specific Role of ?FosB in Nucleus Accumbens In Modulating Intermale Aggression. J Neurosci 38:5913-5924
Lorsch, Zachary S; Loh, Yong-Hwee Eddie; Purushothaman, Immanuel et al. (2018) Estrogen receptor ? drives pro-resilient transcription in mouse models of depression. Nat Commun 9:1116
Aleyasin, Hossein; Flanigan, Meghan E; Russo, Scott J (2018) Neurocircuitry of aggression and aggression seeking behavior: nose poking into brain circuitry controlling aggression. Curr Opin Neurobiol 49:184-191
Zhang, Song; Zhang, Hongxing; Ku, Stacy M et al. (2018) Sex Differences in the Neuroadaptations of Reward-related Circuits in Response to Subchronic Variable Stress. Neuroscience 376:108-116
Takahashi, Aki; Flanigan, Meghan E; McEwen, Bruce S et al. (2018) Aggression, Social Stress, and the Immune System in Humans and Animal Models. Front Behav Neurosci 12:56
Liu, Jia; Dietz, Karen; Hodes, Georgia E et al. (2018) Widespread transcriptional alternations in oligodendrocytes in the adult mouse brain following chronic stress. Dev Neurobiol 78:152-162
Heshmati, Mitra; Aleyasin, Hossein; Menard, Caroline et al. (2018) Cell-type-specific role for nucleus accumbens neuroligin-2 in depression and stress susceptibility. Proc Natl Acad Sci U S A 115:1111-1116
Wang, Jun; Hodes, Georgia E; Zhang, Hongxing et al. (2018) Epigenetic modulation of inflammation and synaptic plasticity promotes resilience against stress in mice. Nat Commun 9:477
Jiang, C; Lin, W-J; Sadahiro, M et al. (2018) VGF function in depression and antidepressant efficacy. Mol Psychiatry 23:1632-1642

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