The effect of enriched environment across ages: A study of anhedonia and BDNF gene induction

Abstract

Enriched environment treatment (EET) is a potential intervention for depression by inducing brain-derived neurotrophic factor (BDNF). However, its age dependency remains unclear. We recently found that EET during early-life development (ED) was effective in increasing exploratory activity and anti-despair behavior, particularly in promoter IV-driven BDNF deficient mice (KIV), with the largest BDNF protein induction in the hippocampus and frontal cortex. Here, we further determined age dependency of EET effects on anhedonia and promoter-specific BDNF transcription, by using the sucrose preference test and qRT-PCR. Wild-type (WT) and KIV mice received 2 months of EET during ED, young-adulthood and old-adulthood (0-2, 2-4 and 12-14 months, respectively). All KIV groups showed reduced sucrose preference, which EET equally reversed regardless of age. EET increased hippocampal BDNF mRNA levels for all ages and genotypes, but increased frontal cortex BDNF mRNA levels only in ED KIV and old WT mice. Transcription by promoters I and IV was age-dependent in the hippocampus of WT mice: more effective induction of exon IV or I during ED or old-adulthood, respectively. Transcription by almost all 9 promoters was age-specific in the frontal cortex, mostly observed in ED KIV mice. After discontinuance of EET, the EET effects on anti-anhedonia and BDNF transcription in both regions persisted only in ED KIV mice. These results suggested that EET was equally effective in reversing anhedonia and inducing hippocampal BDNF transcription, but was more effective during ED in inducing frontal cortex BDNF transcription and for lasting anti-anhedonic and BDNF effects particularly in promoter IV-BDNF deficiency.

Enrichment Environment Positively Influences Depression- and Anxiety-Like Behavior in Serotonin Transporter Knockout Rats through the Modulation of Neuroplasticity, Spine, and GABAergic Markers

“…In line with our previous results [ 24 ], we found reduced mBDNF protein levels, as well as of the pool of the long transcripts of Bdnf in SERT −/− rats with a normalization, due to EE exposure. This perfectly fits the increase in neurotrophin levels after positive environmental stimuli that are often paralleled by improvements at a behavioral level [ 39 , 52 ].…”

BDNF deficiency and enriched environment treatment affect neurotransmitter gene expression differently across ages

“…To compensate for deficiency of promoter IV‐driven BDNF expression (pIV‐BDNF deficiency), we found that enriched environmental treatment (EET) is more effective than chronic drug treatment with four classes of antidepressants (SSRI: selective serotonin transporter reuptake inhibitor, SNRI: serotonin‐norepinephrine reuptake inhibitor, TCA: tricyclic antidepressant, and MAOI: monoamine oxidase inhibitor) (Jha, Dong, & Sakata, 2011; Sakata, Mastin, et al, 2013). EET, which combines physical exercise, mental stimulation, and social interaction (van Praag, Kempermann, & Gage, 2000), activates almost all other BDNF promoters (Adlard, Perreau, Engesser‐Cesar, & Cotman, 2004; Dong, Xue, & Sakata, 2018; Jha et al, 2011; Russo‐Neustadt, Beard, Huang, & Cotman, 2000; Zajac et al, 2010), whereas the drug treatments activate only a few BDNF promoters (Sakata, 2011; Sakata, Mastin, et al, 2013). EET ameliorate defects caused by BDNF deficiency (Chourbaji et al, 2008; Rossi et al, 2006; Zhu et al, 2009).…”

Exploring Brain Derived Neurotrophic Factor and Cell Adhesion Molecules as Biomarkers for the Transdiagnostic Symptom Anhedonia in Alcohol Use Disorder and Comorbid Depression

“…Though our findings should be considered preliminary due to limited sample size and the cross-sectional nature of our pilot study impedes any causal inferences, it is tempting to speculate about potential mechanisms involved in our findings. Several animal studies show that BDNF deficiency reduces sucrose preference, a loss of sensitivity to reward which has been suggested to model anhedonia (45)(46)(47)(48). Anhedonia is a core symptom of depression, and also plays an essential role in addictive disorders (49,50).…”