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

• Published in: Molecular psychiatry Vol. 26; no. 6; pp. 1860 - 1879
• Main Authors: Pignatelli, Marco, Tejeda, Hugo A., Barker, David J., Bontempi, Leonardo, Wu, Jocelyn, Lopez, Alejandra, Palma Ribeiro, Sissi, Lucantonio, Federica, Parise, Eric M., Torres-Berrio, Angélica, Alvarez-Bagnarol, Yocasta, Marino, Rosa A. M., Cai, Zhao-Lin, Xue, Mingshan, Morales, Marisela, Tamminga, Carol A., Nestler, Eric J., Bonci, Antonello
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2021; Nature Publishing Group
• Subjects: 14; 14/19; 631/378; 631/443; 64/110; 9/74; Adaptation; Addictive behaviors; Affect (Psychology); Anhedonia; Anxiety; Behavior; Behavioral Sciences; Biological Psychology; Brain research; Coping; Development and progression; Drug abuse; Emotional behavior; Health aspects; Hedonic response; Hypothalamus (lateral); Luteinizing hormone; Medicine; Medicine & Public Health; Neural circuitry; Neuroplasticity; Neurosciences; Nucleus accumbens; Pharmacotherapy; Physiological aspects; Potassium channels (inwardly-rectifying); Psychiatry; Reinforcement; Risk factors; Spiny neurons; Stress; Stress (Psychology); Sucrose; Synapses; Synaptic plasticity; Synaptic strength; United States
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-020-0686-8

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.