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

Neuropsychopharmacology. 2020 Feb;45(3):515-523. doi: 10.1038/s41386-019-0562-x. Epub 2019 Nov 7.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Age Factors
  • Aging / drug effects
  • Aging / physiology
  • Aging / psychology*
  • Animals
  • Animals, Newborn
  • Female
  • Injections, Intraventricular
  • Male
  • Memory Disorders / etiology
  • Memory Disorders / prevention & control*
  • Memory Disorders / psychology*
  • Pregnancy
  • Pyrimidines / administration & dosage
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
  • Receptors, Corticotropin-Releasing Hormone / physiology
  • Stress, Psychological / complications
  • Stress, Psychological / drug therapy*
  • Stress, Psychological / psychology*

Substances

  • Pyrimidines
  • R 121919
  • Receptors, Corticotropin-Releasing Hormone
  • CRF receptor type 1