<IMG SRC="" CLASS="FR-FIC FR-FIL FR-DIB FR-DRAGGABLE">ADOLESCENT-SPECIFIC CONSEQUENCES OF SLEEP DEPRIVATION: A CRITICAL DEVELOPMENTAL WINDOW LEADING TO PERSISTENT ADULT MEMORY IMPAIRMENT VIA OVERACTIVATION OF HIPPOCAMPAL ASTROCYTIC GR

Adolescent sleep deficiency is clinically significant and has been linked to various developmental disturbances. Building on my previous observation that sleep deprivation (SD) during adolescence impairs adult hippocampus-dependent memory, I investigated the developmental specificity and underlying mechanisms of this vulnerability. Using a 14-day modified multiple platform method (MMPM), I compared the long-term effects of SD in adolescent (PND28) and adult (PND85) mice. Strikingly, only adolescent SD produced persistent memory deficits in middle adulthood (PND142), as demonstrated by passive avoidance, novel object recognition, and Y-maze tests. These behavioral impairments were accompanied by sustained overactivation of glucocorticoid receptors (GR) specifically in hippocampal astrocytes. Astrocytic GR overactivation increased the neurotoxic mediator lipocalin-2 (LCN2), disrupted aquaporin-4 (AQP4)–dependent glymphatic homeostasis and ultimately suppressed adult hippocampal neurogenesis. Notably, pharmacological GR blockade with RU486 fully rescued the long-term memory deficits induced by adolescent SD. Moreover, other stress paradigms, including chronic restraint stress and social isolation stress, did not recapitulate the behavioral or molecular phenotypes induced by adolescent SD. Together, these findings demonstrate that adolescent SD uniquely provokes enduring cognitive impairment through astrocytic GR–mediated hippocampal dysregulation and highlight astrocytic GR signaling as a promising target for preventing the lasting consequences of sleep loss during adolescence.