Individual differences in cognitive aging: implication of pregnenolone sulfate

In humans and animals, individual differences in aging of cognitive functions are classically reported. Some old individuals exhibit performances similar to those of young subjects while others are severely impaired. In senescent animals, we have previously demonstrated a significant correlation between the cognitive performance and the cerebral concentration of a neurosteroid, the pregnenolone sulfate (PREG-S). Neurotransmitter systems modulated by this neurosteroid were unknown until our recent report of an enhancement of acetylcholine (ACh) release in basolateral amygdala, cortex and hippocampus induced by intracerebroventricular (i.c.v.) or intracerebral administrations of PREG-S. Central ACh neurotransmission is known to be involved in the regulation of memory processes and is affected in normal aging and severely altered in human neurodegenerative pathologies like Alzheimer's disease. In the central nervous system, ACh neurotransmission is also involved in the modulation of sleep-wakefulness cycle, and particularly the paradoxical sleep (PS). Relationships between paradoxical sleep and memory are documented in the literature in old animals in which the spatial memory performance positively correlates with the basal amounts of paradoxical sleep. PREG-S infused at the level of ACh cell bodies (nucleus basalis magnocellularis, NBM, or pedunculopontine nucleus, PPT) increases paradoxical sleep in young animals.Finally, aging related cognitive dysfunctions, particularly those observed in Alzheimer's disease, have also been related to alterations of mechanisms underlying cerebral plasticity. Amongst these mechanisms, neurogenesis has been extensively studied recently. Our data demonstrate that PREG-S central infusions dramatically increase neurogenesis, this effect could be related to the negative modulator properties of this steroid at the GABA(A) receptor level. Taken together these data suggest that neurosteroids can influence cognitive processes, particularly in senescent subjects, through a modulation of ACh neurotransmission associated with paradoxical sleep modifications; furthermore, our recent data suggest a critical role for neurosteroids in the modulation of cerebral plasticity, mainly on hippocampal neurogenesis.