Hypothalamic Neurochemical and Microglial Suppression in Long-Standing Human Hibernation-Like Syndrome

Seasonally recurring hibernation-like states are exceptionally rare in humans, and their neural substrates remain unknown. We investigated the brain of a 57-year-old woman with a > 30-year history of winter-associated hypothermia, neuroendocrine instability, psychomotor suppression and circannual rhythmicity. Postmortem neuropathological analysis revealed preserved hypothalamic and basal forebrain anatomy but profound neurochemical abnormalities. Key peptidergic neuronal populations involved in circadian and neuroendocrine regulation, including arginine vasopressin (AVP), oxytocin (OXT), corticotropin-releasing hormone (CRH) and thyrotropin-releasing hormone (TRH) neurons, showed near-complete loss of immunoreactivity in the SCN, SON and PVN. Immunoreactivity for vasoactive intestinal peptide (VIP) and neurotensin (NT) in the SCN was markedly reduced. These changes were accompanied by markedly reduced synaptophysin immunoreactivity in all hypothalamic regions examined, whereas catecholaminergic neurons were relatively preserved in the PVN and SON. Beyond the hypothalamus, cholinergic neurons in the NBM showed a moderate reduction without evidence of Alzheimer-related pathology. Microglial immunoreactivity was nearly absent in the hypothalamic and extrahypothalamic regions examined, contrasting with preserved GFAP and AQP4 immunoreactivity. Moreover, myelination and microvascular architecture also remained intact. These findings identify a selective hypothalamic and microglial suppression associated with a rare human hibernation-like phenotype and indicate markedly reduced output of core neuroendocrine and circadian circuits during long-standing hypometabolic states. The case also illustrates that recurrent, profound hypothermia can be tolerated over decades without systemic organ failure, highlighting an unexpected degree of human metabolic resilience.