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Cognitive flexibility is a core executive function vital for adaptation and adjustment to new information. The brain-derived neurotrophic factor (BDNF) single nucleotide polymorphism, val66met, has been suggested to modulate cognitive flexibility but it remains unclear how confounding variables such as stress and sex influence this relationship. Environmental enrichment (EE) may protect against stress-induced effects. The aim of this study was to test whether BDNF val66met alters reversal learning, a key component of cognitive flexibility, when tested under stressful water maze conditions. We used a Sprague Dawley val66met rat model where pregnant val/met dams were moved to either low or high EE environments. Dams and offspring stayed in these environments until weaning, after which the offspring was moved to standard, moderate enrichment housing. Adult male and female val/val, val/met and met/met offspring then underwent a water maze reversal learning protocol. All groups rapidly learned the new location of the platform. Mediation analysis showed the relationship between val66met and cognitive flexibility was mediated by differential use of spatial strategies. Sequential clustering analysis demonstrated that val66met interacted with sex to predict cognitive flexibility performance with lower flexibility in met/met males and val/met females compared to other genotypes. EE was not a strong promotor of cognitive flexibility. Water maze testing increased corticosterone levels, confirming the stressful nature of the test. This study demonstrates the importance of considering stress and sex when investigating the role of BDNF val66met in cognitive flexibility. Show less

Huntington's disease (HD) is a progressive neurodegenerative disorder marked by motor, cognitive, and psychiatric impairments, with depression as a major comorbidity. Existing treatments for Huntington-related depression are inadequate, highlighting the need for strategies that target molecular mechanisms underlying mood dysregulation. This review examines the mechanistic interplay between environmental enrichment (EE), a paradigm enhancing sensory, cognitive, and social stimulation and Neuropeptide S (NPS), a neuropeptide involved in stress modulation and emotional regulation. It focuses on their potential synergistic effects in modulating depression-associated molecular pathways in HD. EE activates signalling cascades that promote synaptic plasticity and neurogenesis, including the upregulation of brain-derived neurotrophic factor (BDNF), enhanced activation of cAMP response element-binding protein (CREB), and remodelling of glutamatergic and GABAergic transmission. NPS exerts antidepressant-like effects by attenuating hyperactivity of the hypothalamicpituitary- adrenal (HPA) axis, modulating corticotropin-releasing factor (CRF) signalling, and influencing monoaminergic systems. Evidence indicates that EE may enhance NPS receptor (NPSR1) expression and downstream intracellular calcium signalling, reinforcing adaptive plasticity in the striatum and prefrontal cortex regions vulnerable in HD. Integrating EE with NPS-targeted therapy could provide a multimodal approach to restore molecular homeostasis and alleviate depressive phenotypes in HD. Further research should elucidate optimal intervention timing, dose-response relationships, and potential cross-talk between EE-induced BDNF pathways and NPS-mediated stress resilience for translational application in neurodegenerative depression. Show less

The physical environment modulates the maternal brain and affects maternal-offspring dynamics, with downstream effects on neonatal development. In this study, we examined whether environmental enrichment (EE) influences maternal approach, neonatal ultrasonic vocalizations (USVs), and early neuroendocrine development in mice, focusing on hormonal pathways associated with maternity, stress responsivity, and gonadal hormones. Nulliparous female C57BL/6 mice were housed in EE or standard (ST) conditions prior to mating. EE cages were larger and contained extra bedding and enrichment items. Litters were culled to four pups (2/sex), and maternal approach and pup USVs were recorded on postnatal days (PND) 6 and 8 using a modified three-chamber protocol. EE dams made fewer entries into female interaction zones than ST counterparts. EE also increased USV call numbers and decreased call frequencies among pups. These effects were not sex-dependent, and despite higher emission rates, USV parameters did not correlate with maternal response in the EE group. Gene expression analyses revealed that EE altered stress- and care-related genes in the maternal brain, downregulating Prlr (prolactin receptor) and Nr3c2 (mineralocorticoid receptor) in the cortex and upregulating Prlr while downregulating Nr3c2 and Oxtr (oxytocin receptor) in the diencephalon. Further, EE housing changed neuroendocrine profiles in male pups, but not females, suggesting benefits to neurodevelopment (increased brain-derived neurotrophic factor) and alterations to sexual differentiation (Ar [androgen receptor] and Esr1 [estrogen receptor alpha]) and stress reactivity (Nr3c1 [glucocorticoid receptor] and Nr3c2). These findings highlight how environmental context can shape maternal brain and behaviour and imprint on offspring neuroendocrine development in a sex-dependent manner. Show less

Substance use disorder is characterized by compulsive seeking behavior that is associated with aberrant synaptic plasticity in mature neurons. Environmental enrichment (EE) has been shown to increase adult hippocampal neurogenesis and exert beneficial effects on addictive behaviors. However, the mechanisms of EE's effects on methamphetamine (METH)-induced synaptic plasticity in mature and newborn neurons remain unclear. We reported that EE decreased METH-induced seeking behavior with a decrease in the activity of mature granule cells and an increase in the number of newborn granule cells. Furthermore, the aberrant glutamatergic transmission in hippocampal mature and newborn granule cells was differentially regulated by EE. Moreover, EE restored the normal synaptic plasticity, accompanied by enhancement of brain derived neurotrophic factor (BDNF) expression. Importantly, the intervention of BDNF reversed the effects of EE on METH-induced reinstatement behavior and glutamatergic transmission in both mature and newborn cells. Finally, specifically knocking out the newborn neurons reversed the changes of EE in abnormal plasticity of mature neurons, as well as in seeking and cognitive behaviors. Taken together, regulating synaptic plasticity of mature and newborn neurons is involved in METH-induced seeking behavior and cognitive impairments, which highlights a critical role of adult neurogenesis in the treatment of METH addiction. Show less