Spatial synaptic pruning mechanism of NAC microglia in differential regulation of PTSD- and depression-like behaviors

Post-traumatic stress disorder (PTSD) comorbid with depression is a prevalent, treatment-refractory clinical syndrome. Emerging evidence indicates shared microglial alterations in PTSD and depression, suggesting it may represent a common pathological substrate. However, the underlying neuroimmune mechanisms remain unclear.

PTSD- and depression-like behaviors were induced in rats by using single prolonged stress combined with foot shock (SPS&S). Cellular activity, spatial distribution, and morphology were assessed using qPCR, immunofluorescence, and Golgi-Cox staining. Microglial activity was inhibited using clodronate liposomes (CDSlip) and minocycline. Bulk RNA sequencing was performed to profile neuroimmune-related signaling molecules.

Stress induced PTSD- and depression-like behaviors, accompanied by region-specific enhanced microglial activity in the anterior-medial NAC core (amNACc) and lateral NAC shell (LNACsh). Selective depletion of microglia in amNACc and LNACsh via CDSlip specifically alleviated stress induced PTSD- and depression-like behaviors, respectively. Morphological and functional analyses in each region revealed that microglia reshaped the spatial pattern of neuronal structure and function, manifested by enhanced in amNAC and inhibited in LNACsh, via differentially pruning adjacent inhibitory synapses in corresponding region. Further transcriptomic analysis of synaptic pruning relevant signaling pathway showed upregulated expression of "Eat me" signal molecules (particularly Mertk) in the amNAC and downregulated expression of "Find me" signal molecules (particularly Cx3cr1) in the LNACsh, consistent with the observed spatial synaptic pruning profiles. Minocycline administration reversed stress-induced PTSD and depression-like behaviors while normalizing the region-specific alterations in synaptic pruning signaling molecules.

Stress may elicit two regionally heterogeneous microglial subpopulations within NAC: phagocytosis-enhanced and recognition-impaired, which remodel the structure and function of local neural networks by differential pruning of inhibitory synapses, thereby driving the manifestation of PTSD- and depression-like behaviors, separately. These findings deepen our understanding of the neuroinflammatory mechanisms underlying trauma-related psychiatric disorders and identify novel targets for immunomodulation-based targets for transdiagnostic interventions .