Age, experience, and neurobehavioral domain: dissociable effects of environmental enrichment and social isolation on brain and behavior in adult and aged rats

Abstract

In rats, environmental enrichment (EE) is a form of physical-social stimulation used for modeling the impact of optimal developmental conditions on animal’s phenotype. When implemented during early life, EE improves animal’s cognitive skills, reduces anxiety-like traits, and promotes different forms of brain plasticity. Conversely, young animals raised on impoverished conditions like social isolation (SI), developed poor cognitive skills and increased the reactivity to stress. The sensitive windows for neurobehavioral plasticity become narrower as organisms grow up. It is somewhat unclear, however, to which extent positive or negative experiences throughout adulthood are still able to benefit or compromise behavioral, emotional, and cognitive domains and neural plasticity. To this aim, middle-aged (120 PND) and aged (330 PND) Wistar rats (n=8 per age/group) were reared in EE (large cage filled with ethologically relevant stimuli; group housed), SH (standard housing in polycarbonate cage; 4 per cage), and SI (individually housed in stainless-steel cages) during two months. Afterwards, risk-assessment behaviors (i.e., defensiveness) and novelty habituation (i.e., kinetics of locomotion, rearing, and grooming) were measured in two, consecutive open-field tests (OFT). We found that EE reduced risk-assessment behaviors and improved habituation in both age groups, but only middle-aged rats showed an increasing in complex forms of grooming. In SH and SI rats, those behaviors were strongly modulated by age rather than by housing conditions. After the OFT, latencies to scape in the Barnes maze test (i.e., spatial memory) were measured. There, EE also improved spatial memory especially in aged rats, whereas SI caused no particular impairments on this parameter. After testing, we analyzed the expression of different genes closely related to functional and structural neural plasticity (BDNF, GluA1, GluA2, NR2B, CFL1, p250GAP, DNMT3A) in the medial prefrontal cortex (mPFC), the nucleus accumbens (NAcc), and the ventral and dorsal hippocampus (HPC). We found that SI changed the gene expression of the glutamate receptors subunits (e.g., NR2B, GluA1, and GluA2) in the dorsal HPC and NAcc. DNMT3A expression increased especially in the ventral HPC of aged SI rats. The main effect of aging on gene expression resembled the pattern observed in SI rats. In general, the effect of EE and SI conditions dissociated between the behavioral and molecular phenotype they induced and between the two age periods, with SI affecting almost all genes in one brain region or another.