SEX-DEPENDENT STRESS PROGRAMMING OF EMOTIONAL CIRCUITS: A C-FOS ACTIVATION STUDY IN MICE

Early stress episodes have long-lasting effects on brain development and behavior, and are related to increased risk of developing stress-induced depression in adulthood. However, little is known about the sexual differences in this process. Our aim is to study how stress in different developmental periods affects brain connectivity, including a sexual perspective.
For this purpose, male and female C57BL/6J mice were assigned to four experimental groups: control (C) Juvenile stress (JS), adult stress (AS), and combined juvenile and adult
stress (DE).
Neural activation was analyzed in adulthood by assessing c-Fos expression to identify differences in key brain regions of the emotional circuitry. Brain regions included limbic structures (hippocampus, amygdala, and habenula), hypothalamic stress-related nuclei (paraventricular nucleus of the hypothalamus), and striatal regions involved in motivation and reward processing (nucleus accumbens and caudoputamen), among others.
In females, stress exposure induced alterations in hippocampal and habenular activation. Specifically, reduced expression was observed in the dorsal CA3 and CA1 hippocampal subregions, as well as the habenula, in the JE group, consistent with previously observed behavioral patterns. In males, stress-related differences were detected in the ventral dentate gyrus, with increased activation in the DE group, compared to C and JE.
Furthermore, correlation analyses across brain regions revealed distinct connectivity patterns shaped by sex and the developmental timing of stress exposure. These findings point to sex and stress-specific trajectories of network reorganization, underscoring the critical role of developmental stage in modulating neural responses to stress.