Basal Forebrain Cholinergic Innervation Induces Depression-Like Behaviors Through Ventral Subiculum Hyperactivation

Area of Science:

• Neuroscience
• Neurobiology
• Psychiatry

Background:

• Ventral subiculum (vSub) dysfunction is linked to major depressive disorder (MDD).
• The medial septum and diagonal band of Broca (MSDB) cholinergic circuit innervates the vSub, but its role in MDD is unknown.

Purpose of the Study:

• To investigate the involvement of the MSDB-vSub cholinergic circuit in depression-like behaviors.
• To elucidate the circuit mechanisms underlying vSub hyperactivation in MDD.

Main Methods:

• Chronic unpredictable mild stress (CUMS) model in mice.
• c-fos staining and whole-cell patch-clamp recordings for neuronal activity.
• Retrograde and anterograde tracing for circuit mapping.
• Chemogenetics and pharmacological interventions (atropine).

Main Results:

• CUMS induced depression-like behaviors and vSub neuronal hyperactivation.
• MSDB-vSub cholinergic pathway activation mimicked depression-like behaviors and vSub hyperactivation.
• Blocking muscarinic receptors in the vSub attenuated stress- and chemogenetic-induced depression-like behaviors.

Conclusions:

• The MSDB-vSub cholinergic pathway activation leads to vSub pyramidal neuron hyperactivation and depression-like behaviors.
• This study reveals a novel neural circuit contributing to vSub hyperactivation and associated depression in MDD.