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.
Highlights
Environmental enrichment (EE) has long been known beneficial for brain function
Our results identify that EE provides an adaptive response to chronic + acute stress that involves the upregulation of glucocorticoid receptor (GR), but not GluA2 or PKMζ
There was a significant difference in the levels of CORT mounted between EE- and ST-housed animals after acute stress, both conditions showed a significant reduction in CORT after chronic stress compared to their respective acute stress treatments [ST: t(30) = 4.24, p < 0.01; EE: t(30) = 9.793, p < 0.01]
Summary
Environmental enrichment (EE) has long been known beneficial for brain function. Such studies support a role for both physical and cognitive activity in reducing neurodegenerative disorders including Alzheimer’s disease and dementia (Laurin et al, 2001; Vaillant and Mukamal, 2001; Valenzuela et al, 2008; Nithianantharajah and Hannan, 2009; Petrosini et al, 2009). Administration of a GR antagonist or a GR antisense oligonucleotide directly into the hippocampus before learning impaired retention for the forced swim test (FST; De Kloet et al, 1988) and GR-knockout mice show impaired memory consolidation (Oitzl et al, 1997) These results suggest that increases in GR underlie a reduction in fearfulness and anxiety, and contribute to improved learning and memory capacity. Other studies indicate the opposite effect, showing that GR activation disrupts learning and memory processes (reviewed in Roozendaal, 2002; Joels et al, 2006; Sandi, 2011; Schwabe et al, 2012) These reports suggest that the protective effects against stress-induced cognitive deficits are based on the levels of GR present at the time of stress (Prager and Johnson, 2009). We used EE to modulate GR expression and examined the consequences on synaptic trafficking of proteins that are important for long-term memory and synaptic plasticity
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