Maternal Separation Reduces Hypothalamic <i>Interleukin‐6</i> Expression and Enhances Microglial Activation During Critical Developmental Windows

Early life stress, caused by maternal separation (MS), increases hippocampal inflammatory markers in neonates. However, the effects of MS on hypothalamic neuroimmune development and the peripheral immune response have not yet been assessed. This study examined the effect of MS on neuroimmune and synaptic development by evaluating the expression of pro- and anti-inflammatory cytokines and their association with synaptic plasticity markers in the hypothalamus and hippocampus throughout postnatal development. Microglial activation was analyzed in both brain regions at postnatal day 15 (P15), and the systemic immune response was measured through hemolytic capacity. Cytokine and synaptophysin expression showed dynamic, region-specific changes across postnatal development. MS reduced hypothalamic interleukin 6 expression at P6 and P12, enhanced microglial activation at P15, and blunted the developmental increase in hemolytic capacity seen in controls at P21. While control animals exhibited region-specific associations between cytokines and synaptic markers, these relationships were attenuated in the MS group, including a differential interleukin 6-synaptophysin association. These results suggest that MS alters hypothalamic neuroimmune relationships and systemic immune responses during critical developmental windows. Additionally, increased microglial activation at P15 suggests that MS induced proinflammatory, region-specific changes. These alterations may contribute to heightened vulnerability to mental disease later in life.