GnRH and Cognition.

Abstract

GnRH is traditionally recognized as the central regulator of reproduction through its pulsatile secretion, which governs the hypothalamic-pituitary-gonadal axis. However, recent evidence has highlighted its broader role in brain development and function, including in cognitive and higher intellectual processes. GnRH production follows distinct phases, from its early activation during minipuberty-the first postnatal activation of GnRH neurons during the infantile period-, its reactivation and stabilization starting at puberty, and its eventual decline with age and the loss of gonadal steroid feedback. This evolution depends on the establishment, maturation and activation of GnRH neurons, a complex process regulated by the cellular and molecular environment of these neurons, including multiple neuronal and glial types as well as a minipubertal "switch" in gene expression, the perturbation of which may have long-term or delayed consequences for both reproductive and cognitive function. The cognitive role of GnRH may be related to its recently revealed involvement in maintaining myelination and synaptic plasticity, whereas disruptions in its finely tuned rhythmic secretion, either age-related or pathological, are associated with cognitive decline and neurodegenerative disorders. Restoring physiological GnRH levels and pulsatility can reverse age-related cognitive decline and improve sensory functions even in adulthood, suggesting a mobilization of the "cognitive reserve" in both animal models and human patients. This review highlights recent advances in our understanding of the GnRH system and the therapeutic potential of pulsatile GnRH therapy to mitigate age-related cognitive decline and neurodegenerative processes.