Left hippocampal subiculum-hypothalamus hyperconnectivity as a neural correlate of stress vulnerability

The neurobiological mechanisms underlying individual differences in susceptibility to depression remain unclear. This study combined behavioral tests and resting-state functional magnetic resonance imaging (r-fMRI) to investigate how chronic unpredictable mild stress (CUMS) affects brain function and behavior in rats, and to identify neural markers that distinguish depression-susceptible (SUS) from resilient (RES) individuals.

Thirty-one rats (CTRL group, n = 9; CUMS group, n = 22) underwent baseline r-fMRI scans before CUMS exposure. After 5 weeks of CUMS, behavioral tests, including sucrose preference test (SPT), forced swim test (FST), open field test (OFT), elevated plus maze (EPM), and novel object recognition test (NORT) were conducted, followed by post-stress r-fMRI. Rats were classified into SUS and RES groups based primarily on SPT and FST performance.

CUMS induced depression-like behaviors in SUS rats, such as reduced sucrose preference, while RES rats remained comparable to controls. RsFC analysis revealed that SUS rats exhibited enhanced functional connectivity between the hippocampal subiculum and right hypothalamus/left hypothalamus after CUMS. Critically, at baseline, SUS rats already showed stronger left subiculum-left hypothalamic connectivity than RES rats, a difference not observed on the right side.

These findings reveal that individual susceptibility to depression is associated with distinct patterns of functional connectivity involving the hippocampal subiculum, hypothalamus, and amygdala. Critically, pre-existing hyperconnectivity between the left subiculum and left medial hypothalamus may distinguish SUS from RES rats before stress exposure. This specific neural signature may represent a potential vulnerability factor and could inform the development of biomarkers for early risk identification.