Corticotropin-Releasing Factor Receptor 1 Activation During Exposure to Novelty Stress Protects Against Alzheimer's Disease-Like Cognitive Decline in AβPP/PS1 Mice

Abstract

A lifestyle rich in physical and mental activities protects against Alzheimer's disease (AD) but the underlying mechanisms are unclear. We have proposed that this is mediated by a stress response and have shown that repeated exposure to novelty stress, which induces physical and exploratory activities, delays the progression of AD-like pathology in the TASTPM mouse model. Here, we aimed to establish the role played by corticotrophin-releasing factor receptor 1 (CRFR1), a major component of the stress axis, in TASTPM's behavioral and neuroendocrine responses to novelty and related protective effects. We show that the stress response of TASTPM mice is altered with reduced CRFR1-mediated neuroendocrine and behavioral responses to novelty and a distinct profile of behavioral responses. Repeated novelty-induced CRFR1 activation, however, mediated the improved contextual fear memory and extinction performance of TASTPM mice and increased hippocampal and fronto-cortical levels of synaptophysin, a marker of synaptic density, and fronto-cortical levels of the post-synaptic marker PSD95. The N-methyl-D-aspartate receptor (NMDAR) is the major receptor for synaptic plasticity underlying learning and memory. Although novelty-induced NMDAR activation contributed to enhancement of fear memory and synaptophysin levels, antagonism of CRFR1 and NMDAR prevented the novelty-induced increase in hippocampal synaptophysin levels but reversed the other effects of CRFR1 inactivation, i.e., the enhancement of contextual fear extinction and fronto-cortical synaptophysin and PSD95 levels. These findings suggest a novel mechanism whereby a stimulating environment can delay AD symptoms through CRFR1 activation, facilitating NMDAR-mediated synaptic plasticity and synaptogenesis in a region-dependent manner, either directly, or indirectly, by modulating PSD95.

Corticosterone and dopamine D2/D3 receptors mediate the motivation for voluntary wheel running in C57BL/6J mice

“…First, we found previously that the repeated stress of injection impairs memory in C57BL/6J mice [35], but it had no impact on running activity and behavioural effects of exercise in the present study. Novelty and environmental enrichment can also contribute to the positive effects of exercise [41] but this was not the case here.…”

“…Novelty and environmental enrichment can also contribute to the positive effects of exercise [41] but this was not the case here. We showed previously that repeated exposure to a novel environment, which also induces physical exercise, improved memory in a mouse model of Alzheimer's disease but not in wild-type C57BL/6J mice [35,42,43] while exposure to a static wheel was sufficient to improve some cognitive measures in another Alzheimer's mouse model [44]. Altogether, this suggests that the enrichment aspect of exercise may only beneficial to cognitive performance in animals with pre-existing memory impairments.…”

“…Because we have previously found that repeated injections affect memory performance in C57bl/6 mice [35], and to assess whether it also altered running levels, a separate non-injected group was also included (n=8). The effects of injection or static wheel exposure were assessed by comparing performance with vehicletreated mice using one way ANOVAs with repeated measure ANOVA for running distances and unpaired t-tests for all other variables.…”

Lifestyle Choices and Brain Health

“…Significant adverse events early in life can render people vulnerable to mental illness later in life (22). Even during the time of gestation, exposure to excessive levels of cortisone resulting from high levels of stress can have long lasting effects by influencing brain development, subsequently lowering future levels of mental well-being (23–27). For example, researchers have specifically evaluated the effects of early-life adversity (28–32).…”