Short-term block of CRH receptor in adults mitigates age-related memory impairments provoked by early-life adversity

Abstract

In humans, early-life adversity (ELA) is associated with impairments in learning and memory that may emerge later in life. In rodent models, ELA directly impacts hippocampal neuron structure and connectivity with progressive deficits in long-term potentiation and spatial memory function. Previous work has demonstrated that augmented release and actions of the stressactivated neuropeptide, CRH, contribute to the deleterious effects of ELA on hippocampal structure and memory-function. Early-life adversity increases CRH production and levels, and blocking CRH receptor type 1 (CRHR1) within the hippocampus immediately following adversity prevented the memory and LTP problems caused by ELA. Here we queried if blocking CRHR1 during adulthood ameliorates the adverse impact of ELA on memory in middle age. Blocking CRHR1 for a week in two month old male rats prevented ELA-induced deficits in object recognition memory that emerge during middle age. The intervention failed to mitigate the reduction of spatial memory at 4 and 8 months, but restored hippocampus-dependent location memory in ELA-experiencing rats during middle age (12 months of age).Notably, neither ELA nor blocking CRHR1 influenced anxiety-or depression-related behaviors These findings suggest a sensitive period during which interventions can fully prevent longlasting effects of ELA, yet indicate that interventions later in life offer significant benefits.

Horizons in Human Aging Neuroscience: From Normal Neural Aging to Mental (Fr)Agility

“…Also, high levels of glucocorticoids may accelerate the aging process, by causing further damage to the hippocampus and increasing the exposure to exaggerated inflammatory responses such as priming of microglia (Landfield et al, 2007;Barrientos et al, 2015a,b). Moreover, stressful experiences in early life also enhance and accelerate the aging process in the hippocampus and the cognitive functions it supports (Lupien et al, 1999;Kumar, 2011;Sousa et al, 2014;Short et al, 2020), while manipulations early in life that reduce corticosterone levels in rodents reduce memory impairments later in life (Meaney et al, 1988; for review see Lesuis et al, 2018). Together, these studies suggest that adverse (stressful) environmental experiences can accelerate age-related decline in hippocampal cognitive function.…”

Early-life adversity and neurological disease: age-old questions and novel answers

“…As regards the time frame during which interventions might be effective, studies in orphans suggested that cognitive recovery is lower in individuals who were provided with adoptive families later than 24 months of age than in infants who were adopted earlier 25,29 . Similarly, in experimental models, early interventions using pharmacological and epigenetic approaches enabled restoration of memory in adversity-experiencing rats 91,122 , whereas later interventions were less effective 243 . Together, these findings suggest that lengthening the sensitive period when neuronal and circuit plasticity enables intervention would be a major advance in post hoc interventions after early-life adversity.…”