Environmental Enrichment Increases Glucocorticoid Receptors and Decreases GluA2 and Protein Kinase M Zeta (PKMζ) Trafficking During Chronic Stress: A Protective Mechanism?

Abstract

Environmental enrichment (EE) housing paradigms have long been shown beneficial for brain function involving neural growth and activity, learning and memory capacity, and for developing stress resiliency. The expression of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA2, which is important for synaptic plasticity and memory, is increased with corticosterone (CORT), undermining synaptic plasticity and memory. Thus, we determined the effect of EE and stress on modulating GluA2 expression in Sprague-Dawley male rats. Several markers were evaluated which include: plasma CORT, the glucocorticoid receptor (GR), GluA2, and the atypical protein kinase M zeta (PKMζ). For 1 week standard-(ST) or EE-housed animals were treated with one of the following four conditions: (1) no stress; (2) acute stress (forced swim test, FST; on day 7); (3) chronic restraint stress (6 h/day for 7 days); and (4) chronic + acute stress (restraint stress 6 h/day for 7 days + FST on day 7). Hippocampi were collected on day 7. Our results show that EE animals had reduced time immobile on the FST across all conditions. After chronic + acute stress EE animals showed increased GR levels with no change in synaptic GluA2/PKMζ. ST-housed animals showed the reverse pattern with decreased GR levels and a significant increase in synaptic GluA2/PKMζ. These results suggest that EE produces an adaptive response to chronic stress allowing for increased GR levels, which lowers neuronal excitability reducing GluA2/PKMζ trafficking. We discuss this EE adaptive response to stress as a potential underlying mechanism that is protective for retaining synaptic plasticity and memory function.

Developmental transitions in amygdala PKC isoforms and AMPA receptor expression associated with threat memory in infant rats

“…Importantly, MET injections to block CORT did not disrupt learning in the oldest pups (PN16) 58 and memory-associated molecular changes were preserved 24 hr later. It should be noted that, although stress hormones have been shown to increase synaptic PKMζ and AMPA receptor trafficking 33 , 63 , our pup injections manipulating CORT occurred before acquisition and were timed to peak during acquisition and return to baseline soon post-conditioning 59 . While many reports show cytosolic PKMζ increases following synaptic plasticity and memory 54 in adults, our PN8 CORT-treated pups did not show cytosolic changes.…”

Developmental origins of cardiovascular disease: Impact of early life stress in humans and rodents

“…In animal models, positive experiences after weaning, such as being exposed to an environment rich in opportunities for exploration and social play have been shown to compensate to some degree for the negative behavioral consequences of prenatal stress and postnatal neglect (Reynolds et al, 2010; Zanca et al, 2015). This compensation involves adaptive changes in both the architecture and the chemistry of the developing brain.…”

Paternal environmental enrichment transgenerationally alters affective behavioral and neuroendocrine phenotypes

“…In contrast, the antidepressive effects of enrichment remain controversial. While there are reports that even a short 7-day period of environmental enrichment reduces forced-swim test (FST) immobility time in rats (Zanca et al, 2015), other evidence in rats and mice suggest that EE does not alter latency to immobility and total immobility time in the FST (Leger et al, 2015;Possamai et al, 2014).…”