Τhe neuroprotective role of environmental enrichment against behavioral, morphological, neuroendocrine and molecular changes following chronic unpredictable mild stress: A systematic review

Abstract

Environmental factors interact with biological and genetic factors influencing the development and well‐being of an organism. The interest in better understanding the role of environment on behavior and physiology led to the development of animal models of environmental manipulations. Environmental enrichment (EE), an environmental condition that allows cognitive and sensory stimulation as well as social interaction, improves cognitive function, reduces anxiety and depressive‐like behavior and promotes neuroplasticity. In addition, it exerts protection against neurodegenerative disorders, cognitive aging and deficits aggravated by stressful experiences. Given the beneficial effects of EE on the brain and behavior, preclinical studies have focused on its protective role as an alternative, non‐invasive manipulation, to help an organism to cope better with stress. A valid, reliable and effective animal model of chronic stress that enhances anxiety and depression‐like behavior is the chronic unpredictable mild stress (CUMS). The variety of stressors and the unpredictability in the time and sequence of exposure to prevent habituation, render CUMS an ethologically relevant model. CUMS has been associated with dysregulation of the hypothalamic–pituitary–adrenal axis, elevation in the basal levels of stress hormones, reduction in brain volume, dendritic atrophy and alterations in markers of synaptic plasticity. Although numerous studies have underlined the compensatory role of EE against the negative effects of various chronic stress regimens (e.g. restraint and social isolation), research concerning the interaction between EE and CUMS is sparse. The purpose of the current systematic review is to present up‐to‐date research findings regarding the protective role of EE against the negative effects of CUMS.

‘Unpredictable chronic mild stress does not exacerbate memory impairment or altered neuronal and glial plasticity in the hippocampus of middle‐aged vitamin D deficient mice’

“…According to our initial hypothesis, long‐term VDD would exacerbate the detrimental effects of chronic stress on depressive‐like behaviour and memory in middle‐aged mice. This hypothesis was based on preclinical studies demonstrating decreased neuroplasticity and dysregulated neuroinflammation in response to UCMS (Dandi et al, 2023; Farooq et al, 2012; Koo et al, 2019; Mineur et al, 2007; Toth et al, 2008; Zhang et al, 2015) as well as the neuroprotective and anti‐inflammatory benefits of vitamin D (Boontanrart et al, 2016; Calvello et al, 2017; Dulla et al, 2016; Mayne & Burne, 2019). Although long‐term VDD during adulthood independently induced cognitive decline and reduced self‐care in middle‐aged mice, VDD did not exacerbate the negative effects of UCMS, disproving our initial hypothesis.…”

Sex-Specific Differences and the Role of Environmental Enrichment in the Expression of Hippocampal CB1 Receptors following Chronic Unpredictable Stress

“…The aim of the present investigation was to explore the impact of CUS and EE on the expression of CB 1 receptors in the hippocampus of adult male and female Wistar rats. To date, relatively few investigations on EE-CUS interaction have been carried out, with the majority of these studies mainly employing male animals (for a review, see [27]).…”

“…In the CUS paradigm, animals are exposed daily to a variety of stressors over a specific period of time. The variety of stressors and the unpredictability in the timing and sequence of stressor administration to prevent habituation render CUS paradigm an ethologically relevant model for studying the effects of psychological stress in humans [24][25][26][27]. Research findings from studies in which CUS was implemented indicate a reduction in CB 1 receptor expression in the hippocampus, while increased expression is observed in the amygdala and prefrontal cortex (PFC) [28,29].…”

“…Recent evidence-based research has underscored the significance of including both sexes for direct comparison. However, only a restricted amount of research has explored the potential positive impacts of EE against chronic stress in both sexes simultaneously [27]. Interestingly, studies encompassing both sexes have demonstrated that CUS decreases hippocampal CB 1 expression in males, whereas it increases their expression in females [32,33].…”

“…In animal studies, the EE condition refers to the housing of more than two same-sex animals in large cages equipped with various objects of varying shapes and sizes along with running wheels. This environmental manipulation offers cognitive and sensory stimulation while encouraging exploration and social interaction among animals [27,42]. Numerous studies have demonstrated that EE delays the onset and progression of psychiatric disorders and neurological diseases in different animal models [43].…”