HOMER 1A MODULATION IN A RODENT MODEL OF PERINATAL STRESS: TRANSLATIONAL INFERENCE FROM POSTSYNAPTIC DENSITY IMMEDIATE-EARLY GENE-BASED NETWORK ANALYSES. IMPLICATION FOR NEURODEVELOPMENTAL DISORDERS

Abstract Background Stress is responsible for impacting brain regions’ synaptic changes and functional connectivity modifications that hesitate in several cognitive processes such as spatial and declarative memory, fear, and memories of emotionally charged events, executive functions and fear extinction that are all cross-functional in the functioning of neurodevelopmental disorders. Aims We investigated the transcript of Homer1a, an Immediate Early Gene, which encodes a crucial molecule of the dendritic spine involved in synaptic plasticity processes. It represents a molecular sensor of glutamatergic synaptic plasticity events relevant for monitoring potential changes and activity in brain network and regional interactivity among brain regions of male rats exposed and not exposed to perinatal stress. Methods We performed a quantitation of Homer1a transcripts derived by in situ hybridization protocol and analyzed the pattern of expression in a connectivity-based framework. Pregnant female Sprague– Dawley rats were randomly divided into two experimental groups: one exposed to three 45-minute stress sessions daily until delivery and the other one represented a control group without stress exposure. Homer1 expression was evaluated in 88 brain regions of interest (ROIs) in the brain of male offspring defining perinatal stress group (PRS) (n=5) and control group (n=5) and differences were evaluated through Student’ s t-test via IBM SPSS 26. We computed all possible pairwise Spearmann’ s correlations and generated the adjacency matrices and network for each experimental group via RStudio and Cytoscape software to define differences in brain network properties. Finally, we studied brain network centrality measures. Results We found a reduction in Homer1a expression in PRS cortical, thalamic, and striatal ROIs involved in executive control, strongly impaired in neurodevelopmental disorders. The study of adjacency matrices showed a tendency to aberrant functional connectivity among several insular and cortical ROIs (in the PRS group compared to CTRL which could be responsible for learning and memory impairment, hippocampal dysfunctions, sociability, memory, and motor control and lack of the integration of information in the whole brain. The study of centrality misuses among networks showed an increase in anteroventral thalamic nucleus, ventrolateral part degree of CTRL group compared to PRS; an increase in betweenness centrality of the claustrum and several striatal regions (such as dorsomedial caudate putamen, accumbens nucleus, core, accumbens nucleus, shell, and amygdaloid nuclei) as well as a decrease in nucleus of ventral anterior thalamic nucleus of PRS group compared to CTRL. Finally, we found a significant increase in eigenvector centrality in thalamic nuclei of PRS group, and an increase in the same parameter in amygdaloid nuclei of CTRL group. Discussion and conclusion By examining the effects on neuronal circuits that we explored through the evaluation of co-activation of brain areas, the current work has confirmed that perinatal-stress exposure strongly impacts synaptic plasticity processes. It has also demonstrated that changes in functional connectivity could help to predict aberrant behavioral phenotype of male stress-exposed rats compared to control group leading to the conclusion that perinatal stress exposure represents a significant vulnerable factor for psychiatric disorders in translational point of view.