Juvenile behavioral alterations and sex-dependent deficits in hippocampal neurogenesis following early-life stress in rats

Abstract

Early-life adversity during critical developmental windows markedly increases vulnerability to neuropsychiatric disorders later in life. Although adult behavioral and neurobiological alterations following early stress are well documented, the early emerging phenotypes and their underlying cellular and molecular mechanisms during juvenile development remain poorly understood. In this study, we utilized the translational Scarcity-Adversity Model (SAM) to investigate early behavioral alterations and hippocampal neuroplasticity in juvenile offspring. We characterized the behavioral profile of juvenile subjects exposed to SAM to identify early manifestations of vulnerability. Next, we evaluated hippocampal neurogenesis by quantifying neural progenitor cell proliferation immediately following stress exposure (at postnatal day 13, PND 13) and the short-term survival of newborn neurons (1 week post-labeling) in the dentate gyrus of juvenile offspring. Furthermore, given the functional compartmentalization of the hippocampus, we measured the protein expression of mature BDNF (mBDNF) and its precursor proBDNF across both dorsal and ventral domains. At the behavioral level, SAM-exposed juvenile offspring exhibited increased immobility in the forced swim test alongside impaired spatial memory in the novel object location task. Regarding hippocampal neurogenesis, SAM exposure did not alter immediate progenitor proliferation at PND 13; however, it produced a significant, male-specific reduction in newborn neuron survival, concomitant with a trend toward decreased mBDNF levels in males. Together, these results provide critical insight into the early neurodevelopmental trajectories triggered by early-life adversity, identifying early behavioral impairments and male-specific neuroplastic deficits as key juvenile markers of vulnerability preceding adult psychopathology.