Cooperative synaptic and intrinsic plasticity in a disynaptic limbic circuit drive stress-induced anhedonia and passive coping in mice

Marco Pignatelli, Hugo A. Tejeda, David J. Barker, Leonardo Bontempi, Jocelyn Wu, Alejandra Lopez, Sissi Palma Ribeiro, Federica Lucantonio, Eric M. Parise, Angélica Torres-Berrio, Yocasta Alvarez-Bagnarol, Rosa A.M. Marino, Zhao Lin Cai, Mingshan Xue, Marisela Morales, Carol A. Tamminga, Eric J. Nestler, Antonello Bonci

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Stress promotes negative affective states, which include anhedonia and passive coping. While these features are in part mediated by neuroadaptations in brain reward circuitry, a comprehensive framework of how stress-induced negative affect may be encoded within key nodes of this circuit is lacking. Here, we show in a mouse model for stress-induced anhedonia and passive coping that these phenomena are associated with increased synaptic strength of ventral hippocampus (VH) excitatory synapses onto D1 medium spiny neurons (D1-MSNs) in the nucleus accumbens medial shell (NAcmSh), and with lateral hypothalamus (LH)-projecting D1-MSN hyperexcitability mediated by decreased inwardly rectifying potassium channel (IRK) function. Stress-induced negative affective states are prevented by depotentiation of VH to NAcmSh synapses, restoring Kir2.1 function in D1R-MSNs, or disrupting co-participation of these synaptic and intrinsic adaptations in D1-MSNs. In conclusion, our data provide strong evidence for a disynaptic pathway controlling maladaptive emotional behavior.

Original languageEnglish (US)
Pages (from-to)1860-1879
Number of pages20
JournalMolecular psychiatry
Volume26
Issue number6
DOIs
StatePublished - Jun 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

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