mGluR5 in EC^CCK to BLA Circuit Modulates Depressive-Like Phenotypes through CCK Signaling

Area of Science:

• Neuroscience
• Molecular Psychiatry
• Circuit mechanisms of mood disorders

Background:

• Dysregulated metabotropic glutamate receptor 5 (mGluR5) and cholecystokinin (CCK) signaling are linked to major depressive disorder (MDD).
• The specific neural circuits and mechanisms underlying these associations remain largely undefined.

Purpose of the Study:

• To elucidate the role of mGluR5 in regulating depressive-like behaviors via CCK signaling within the entorhinal cortex (EC) to basolateral amygdala (BLA) pathway.
• To investigate the impact of chronic social defeat stress (CSDS) on this circuit and its molecular components.

Main Methods:

• Utilized anatomical tracing and optogenetics to map and manipulate the EC^CCK→BLA circuit.
• Employed expansion microscopy to examine postsynaptic mGluR5 localization.
• Investigated the effects of pharmacological mGluR5 modulation and CCK knockout in behavioral models of depression.
• Performed circuit-specific knockdown of mGluR5 in the EC^CCK→BLA pathway.

Main Results:

• CCK-expressing neurons in the EC project to the BLA, modulating glutamatergic activity.
• Optogenetic stimulation of this pathway induced, while inhibition alleviated, depressive-like behaviors.
• CSDS downregulated mGluR5 in the BLA; mGluR5 antagonism mimicked CCK-driven pro-depressive effects.
• mGluR5 agonism suppressed CCK release, impaired BLA long-term potentiation, and reduced CSDS-induced behaviors.

Conclusions:

• Identified a critical mGluR5-CCK signaling axis within the EC^CCK→BLA circuit that governs stress-induced affective states.
• This pathway represents a potential therapeutic target for major depressive disorder.