IMPACT OF STRESS AND DEPRESSION ON THE REGULATION OF ACTIN-BINDING PROTEINS IN THE MURINE HIPPOCAMPUS

Chronic stress represents a major risk factor for major depressive disorder (MDD). Sustained glucocorticoid exposure in response to chronic stress can disrupt neuronal function and thereby contribute to MDD. At the circuit and structural levels, chronic stress is associated with reduced neurogenesis, dendritic spine shrinkage and loss, and hippocampal atrophy. Because the actin cytoskeleton provides the structural basis for synaptic plasticity, stress-induced alterations in actin dynamics are likely to be a key mechanistic component of these pathologies. However, actin-dependent mechanisms remain underexplored in the context of MDD.
Here, we investigate how acute and chronic restraint stress in female mice affects hippocampal neurons, with a particular focus on actin regulatory pathways. Chronically restrained mice exhibit impaired spatial learning in the Morris Water Maze (MWM) and increased depression-related behavior in the dark-light box. At the structural level, chronic stress reduces CA1 spine density following MWM training, without detectable changes in mean spine head size.
Using a Tet-On/Tet-Off labeling system, we show that this structural remodeling is particularly pronounced in stress engram neurons – i.e., neurons that encode the stress context. In parallel, the actin-stabilizing protein caldesmon is significantly downregulated.
By targeting caldesmon as a mechanistic entry point, we aim to test whether normalizing actin dynamics in CA1 engram neurons can reverse maladaptive spine remodeling and restore cognitive and affective function. Together, this work links molecular regulation of the actin cytoskeleton to engram-specific plasticity and stress-related cognitive dysfunction in a sex-specific context, providing both conceptual insight and a tractable intervention target for MDD-relevant pathology.