Dysregulation of local inhibitory inputs onto laterodorsal tegmental nucleus cholinergic neurons drives depression-like behaviors in mice.

Central cholinergic system plays a vital role in the pathogenesis of major depressive disorder. The cholinergic neurons in laterodorsal tegmental nucleus (LDTg) are the key components of the cholinergic system in brainstem. However, how the LDTg cholinergic neuronal activities are modulated in response to chronic stress remains largely unclear. We reported here that local inhibitory inputs from somatostatin-positive (SST+) interneurons modulated the cholinergic neuronal activities in the LDTg (LDTgSST-ChAT) and adjusted susceptibility to chronic stress in mice. Chronic unpredictable mild stress (CUMS) caused decreased inhibitory inputs, weakened synaptic connections in the LDTgSST-ChAT circuitry and hyperactivity of LDTg cholinergic neurons. Chemogenetic inhibition of LDTg SST+ interneurons disinhibited cholinergic neurons to increase chronic stress susceptibility in mice. Furthermore, preventive chemogenetic activation of LDTg SST+ interneurons mitigated CUMS-induced weakened inhibitory synaptic connections to cholinergic neurons to limit the development of depression-like behaviors. These findings suggested that suppression of LDTgSST-ChAT circuitry has an important role in the development of depression-like behaviors. Therefore, regulating LDTgSST-ChAT circuitry could be a potential therapeutic approach to mitigate the progression of stress-induced depression-like behaviors.