Negr1 Deficiency Modulates Sex-Specific Neurobehavioral Adaptations to Social Isolation

<b>Objective</b>: Neuronal growth regulator 1 (<i>Negr1</i>) is a GPI-anchored neuronal cell adhesion molecule of the IgLON superfamily associated with multiple psychiatric disorders. This study aimed to investigate behavioral and molecular adaptations to social isolation (SI) stress in <i>Negr1</i>-deficient (<i>Negr1^-/-</i>) mice. <b>Methods</b>: Male and female <i>Negr1^-/-</i> and wild-type (Wt) mice (n = 10 per group) were exposed to two weeks of SI or group housing (Ctl). Behavioral assays assessed exploratory and anxiety-like behavior. Gene expression analyses in the prefrontal cortex and hippocampus were performed using RT-qPCR, focusing on GABAergic, neurotrophic, and IgLON family genes. <b>Results</b>: SI-induced weight loss in <i>Negr1^-/-</i> mice compared to Wt was evident in both sexes but more pronounced in males. Behaviorally, SI Wt males showed stress-induced hyperactivity compared to Ctl Wt, whereas SI <i>Negr1^-/-</i> males exhibited blunted exploratory behavior relative to SI Wt in the open field test (OFT). <i>Negr1^-/-</i> females showed reduced exploration in the elevated plus maze (EPM), suggesting increased anxiety. Hippocampal <i>Pvalb</i> was downregulated in SI <i>Negr1^-/-</i> mice of both sexes compared to Wts, with a stronger decrease in males, indicating heightened male vulnerability in GABAergic interneuron function. In males, SI reduced hippocampal <i>Bdnf</i> in both genotypes, whereas <i>Ntrk2</i> (TrkB) upregulation occurred only in <i>Negr1^-/-</i> mice, suggesting a genotype-specific compensatory response. Hippocampal expression of <i>Fgfr2</i> and IgLON members (<i>Ntm1a/1b</i>, <i>Lsamp1a/1b</i>) was increased in SI <i>Negr1^-/-</i> males compared to SI Wt, with minimal changes in females. <b>Conclusions</b>: <i>Negr1</i> deficiency leads to sex-specific behavioral and molecular adaptations to social isolation stress, highlighting the role of <i>Negr1</i> in modulating neurotrophic and GABAergic signaling pathways under adverse environmental conditions.