Sex-Dependent Effects of Environmental Enrichment on Spatial Memory and Brain-Derived Neurotrophic Factor (BDNF) Signaling in a Developmental “Two-Hit” Mouse Model Combining BDNF Haploinsufficiency and Chronic Glucocorticoid Stimulation

Abstract

Neurodevelopmental disorders are thought to be caused by a combination of adverse genetic and environmental insults. The “two-hit” hypothesis suggests that an early first “hit” primes the developing brain to be vulnerable to a second “hit” during adolescence which triggers behavioral dysfunction. We have previously modeled this scenario in mice and found that the combined effect of a genetic hapolinsuffuciency in the brain-derived neurotrophic factor (BDNF) gene (1st hit) and chronic corticosterone (CORT) treatment during adolescence (2nd hit), caused spatial memory impairments in adulthood. Environmental enrichment (EE) protocols are designed to stimulate experience-dependent plasticity and have shown therapeutic actions. This study investigated whether EE can reverse these spatial memory impairments. Wild-type (WT) and BDNF heterozygous (HET) mice were treated with corticosterone (CORT) in their drinking water (50 mg/L) from weeks 6 to 8 and exposed to EE from 7 to 9 weeks. Enriched housing included open top cages with additional toys, tunnels, housing, and platforms. Y-maze novel preference testing, to assess short-term spatial memory, was performed at 10 weeks of age. At week 16 dorsal hippocampus tissue was obtained for Western blot analysis of expression levels of BDNF, the BDNF receptor TrkB, and NMDA receptor subunits, GluNR1, 2A and 2B. As in our previous studies, spatial memory was impaired in our two-hit (BDNF HET + CORT) mice. Simultaneous EE prevented these impairments. However, EE appeared to worsen spatial memory performance in WT mice, particularly those exposed to CORT. While BDNF levels were lower in BDNF HET mice as expected, there were no further effects of CORT or EE in males but a close to significant female CORT × EE × genotype interaction which qualitatively corresponded with Y-maze performance. However, EE caused both sex- and genotype-specific effects on phosphorylated TrkB residues and GluNR expression within the dorsal hippocampus, with GluNR2B levels in males changing in parallel with spatial memory performance. In conclusion, beneficial effects of EE on spatial memory emerge only following two developmental disruptions. The mechanisms by which EE exerts its effects are likely via regulation of multiple activity-dependent pathways, including TrkB and NMDA receptor signaling.

A Novel and Selective Dopamine Transporter Inhibitor, (S)-MK-26, Promotes Hippocampal Synaptic Plasticity and Restores Effort-Related Motivational Dysfunctions

“…All these different factors (e.g., strain, sex, etc. ; [ 55 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 ]) could thus distinctly influence the outcome of the ( S )-MK-26 pharmacological treatment. Indeed, several reports have described that brain physiological processes and dopamine-associated neuropathological maladies are differentially manifested depending on the sex of the patient [ 176 , 177 , 178 , 179 ], as is the case for Parkinson’s disease, which manifests predominantly in aged men.…”

The Molecular Effects of Environmental Enrichment on Alzheimer’s Disease

“…A recent study also found EE to differentially activate neural circuits in FVB/N mice, promoting social interactions in female mice but aggressive behaviors in male mice [ 242 ]. Additionally, many studies have also noted the sex-dependent effects of EE in their respective investigations [ 243 , 244 ].…”

Maintaining a Dynamic Brain: A Review of Empirical Findings Describing the Roles of Exercise, Learning, and Environmental Enrichment in Neuroplasticity from 2017-2023

“…In another “two-hit” model of perinatal neuroimmune activation, two weeks of EE in late adolescence was shown to increase BDNF expression, TrkB expression, upregulate the expression of several excitatory-related receptors (NMDA, GluNR1, 2A and 2B) in “two-hit” mice compared to controls. Moreover, this was correlated with improved spatial working memory performance [ 115 ]. Additionally, Zajac et al found that two weeks of voluntary exercise and EE in late adolescence had unique effects on serotonergic receptor expression in a transgenic mouse model of Huntington’s Disease.…”