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

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.

Fig. 1

The intervention surgery itself does not influence memory throughout adulthood. a Experimental design with timeline representing the timing of interventions and testing, and the ages at which they occurred. b, c Minipump surgery had no effect on object recognition memory ratio (b) or discrimination index (c) at 10 months of age. n = 3–7 per group, mean with ± SEM, dots represent individual animals

Fig. 2

CRHR1 blocker administration ameliorates adversity-provoked memory impairments in a task and age-dependent manner. a Animals were trained on ORM for 10 min, 24 h later one object was changed, and animals were testing for object discrimination for 5 min. b There were no effects of CRHR1 antagonist in any of the groups at 4 or 8 months of age, at 12 months of age there was a significant improvement of object discrimination in LBN animals, which received administration of CRHR1 antagonist. c Plot representing individual values for object preference on ORM. d Animals were trained on new objects for the OLM task, and on testing day, one of these objects was moved to the opposite side of the arena. e There was an overall effect of LBN across the ages on the discrimination of the new location, at 12 months of age there was a significant improvement in DI in the LBN animals, which received antagonist. f Plot representing individual values for object preference on OLM. Control veh n = 3, control antag n = 3, LBN veh n = 6, LBN antagonist n = 6. *p < 0.05 (post-test), for b, e symbols represent mean with ± SEM connected by interpolated lines. For c, f bars represent mean and symbols represented individual values. ORM = object recognition memory, OLM = object location memory, veh = vehicle, antag = CRHR1 antagonist, LBN = limited bedding nesting

Fig. 3

Early-life adversity and CRHR1 blocker administration to adult rats have no effects on anxiety- and depression-related phenotypes. There was no effect of LBN or CRHR1 antagonist at any of the ages tested on either % time in the open arm (a) on the elevated plus maze. b Plot representing individual values for arm preference on EPM. c Total immobility time in the forced swim test was not affected by LBN nor CRHR1 antagonist. d Plot representing individual immobility times. Control veh n = 3, control antag n = 3, LBN veh n = 6, LBN antagonist n = 6. *p < 0.05 (post-test for a and c symbols represent mean with ± SEM connected by interpolated lines. For b and d bars represent mean and symbols represented individual values. veh = vehicle, antag = CRHR1 antagonist, LBN = limited bedding nesting

Fig. 4

Proposed mechanism for effect of CRHR1 blocker when given to young adult rats. Following early adversity there is an increase in CRH-positive interneurons (IN) within the hippocampus, which is associated with increases in CRH mRNA and subsequently elevated levels of CRHR1 at the synapse on pyramidal cells (PC). In early-life adversity, this causes reductions of synapses and memory impairments in later life. Blocking CRHR1 with the antagonist for a week in the adult brain, may cause a decrease in CRH binding, which decreases receptor expression at the synapse. By reducing the number of CRH receptors, spines may be less sensitive to increases in CRH thereby making them less prone to collapse and maintaining memory processing over time