Blocking CRH receptors in adults mitigates age-related memory impairments provoked by early-life adversity

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In humans, early-life adversity is associated with impairments in learning and memory that may emerge later in life. In rodent models, early-life adversity 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 stress-activated neuropeptide, CRH, contribute to the deleterious effects of early-life adversity on hippocampal dendritic arborization, synapse number and memory-function. Early-life adversity increases hippocampal CRH expression, and blocking hippocampal CRH receptor type-1 (CRHR1) immediately following early-life adversity prevented the consequent memory and LTP defects. Here, we tested if blocking CRHR1 in young adults ameliorates early-life adversity-provoked memory deficits later in life. A weeklong course of a CRHR1 antagonist in 2-month-old male rats prevented early-life adversity-induced deficits in object recognition memory that emerged by 12 months of age. Surprisingly, whereas the intervention did not mitigate early-life adversity-induced spatial memory losses at 4 and 8 months, it restored hippocampus-dependent location memory in 12-month-old rats that experienced early-life adversity. Neither early-life adversity nor CRHR1 blockade in the adult influenced anxiety- or depression-related behaviors. Altogether, these findings suggest that cognitive deficits attributable to adversity during early-life-sensitive periods are at least partially amenable to interventions later in life.

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The authors declare no competing interests. Work was supported by NIH grants NS28912, MH73136, and MH096889.

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Correspondence to Annabel K. Short.

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Short, A.K., Maras, P.M., Pham, A.L. et al. Blocking CRH receptors in adults mitigates age-related memory impairments provoked by early-life adversity. Neuropsychopharmacol. (2019) doi:10.1038/s41386-019-0562-x

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