A thalamic circuit facilitates stress susceptibility via melanocortin 4 receptor‐mediated activation of nucleus accumbens shell

Aims Central melanocortin 4 receptor (MC4R) has been reported to induce anhedonia via eliciting dysfunction of excitatory synapses. It is evident that metabolic signals are closely related to chronic stress‐induced depression. Here, we investigated that a neural circuit is involved in melanocortin signaling contributing to susceptibility to stress. Methods Chronic social defeat stress (CSDS) was used to develop depressive‐like behavior. Electrophysiologic and chemogenetic approaches were performed to evaluate the role of paraventricular thalamus (PVT) glutamatergic to nucleus accumbens shell (NAcsh) circuit in stress susceptibility. Pharmacological and genetic manipulations were applied to investigate the molecular mechanisms of melanocortin signaling in the circuit. Results CSDS increases the excitatory neurotransmission in NAcsh through MC4R signaling. The enhanced excitatory synaptic input in NAcsh is projected from PVT glutamatergic neurons. Moreover, chemogenetic manipulation of PVTGlu‐NAcsh projection mediates the susceptibility to stress, which is dependent on MC4R signaling. Overall, these results reveal that the strengthened excitatory neurotransmission in NAcsh originates from PVT glutamatergic neurons, facilitating the susceptibility to stress through melanocortin signaling. Conclusions Our results make a strong case for harnessing a thalamic circuit to reorganize excitatory synaptic transmission in relieving stress susceptibility and provide insights gained on metabolic underpinnings of protection against stress‐induced depressive‐like behavior. The schematic representation of the proposed model describing the PVT‐NAcsh circuit diagram encountered with social stress. CSDS induces activation of MC4R signaling and consequently strengthens excitatory synaptic transmission in NAcsh. Furthermore, the enhanced excitatory synaptic input in NAcsh originates from PVT glutamatergic neurons, which is dependent on MC4R signaling. This process participates in susceptibility to stress.