Pregnenolone sulfate and aging of cognitive functions: Behavioral, neurochemical, and morphological investigations

Neurosteroids are a subclass of steroids that can be synthesized in the cen tral nervous system independently of peripheral sources. Several neurostero ids influence cognitive functions. Indeed, in senescent animals we have pre viously demonstrated a significant correlation between the cerebral concent ration of pregnenolone sulfate (PREG-S) and cognitive performance. Indeed, rats with memory impairments exhibited low PREG-S concentrations compared t o animals with correct memory performance. Furthermore, these memory defici ts can be reversed by intracerebral infusions of PREG-S. Neurotransmitter s ystems modulated by this neurosteroid were unknown until our recent report of an enhancement of acetylcholine (ACh) release in basolateral amygdala, c ortex, and hippocampus induced by central administrations of PREG-S. Centra l ACh neurotransmission is involved in the regulation of memory processes a nd is affected in normal aging and in human neurodegenerative pathologies l ike Alzheimer's disease. ACh neurotransmission is also involved in the modu lation of sleep-wakefulness cycle and relationships between paradoxical sle ep and memory are well documented in the literature. PREG-S infused at the level of ACh cell bodies induces a dramatic increase of paradoxical sleep i n young animals. Cognitive dysfunctions, particularly those observed in Alz heimer's disease, have also been related to alterations of cerebral plastic ity. Among these mechanisms, neurogenesis has been recently studied. Prelim inary data suggest that PREG-S central infusions dramatically increase neur ogenesis. Taken together these data suggest that PREG-S can influence cogni tive processes, particularly in senescent subjects, through a modulation of ACh neurotransmission associated with paradoxical sleep modifications; fur thermore our recent data suggest a role for neurosteroids in the modulation of hippocampal neurogenesis. (C) 2001 Academic Press.