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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH090264-10
Application #
9815969
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Tonelli, Leonardo H
Project Start
2010-04-01
Project End
2020-11-30
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Neurosciences
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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