Environmental enrichment protects against the effects of chronic stress on cognitive and morphological measures of hippocampal integrity
Highlights
► Enriched environment (EE) attenuated spatial memory deficits after chronic stress. ► Spatial memory outcomes paralleled alterations in hippocampal dendritic complexity. ► EE restored corticosterone levels of chronically stressed rats to control levels.
Introduction
Stressful life events are a critical determinant in depression, a disorder that is predicted to lead the disability and disease burden by 2020 (WHO, 2002). The stress response may be intertwined with depression because of overlapping brain regions, circuitries and mediators (Gold & Chrousos, 2002). Paradigms incorporating chronic stress in animal models reveal many core physiological and behavioral characteristics of depression that include anhedonia, hypothalamic–pituitary–adrenal (HPA) disruptions, motivational deficits and cognitive impairment (Willner, 2005). Additional works with chronically stressed rodents report that the hippocampus, a region important for the formation of spatial memories (Eichenbaum, 2000, O’Keefe and Nadel, 1978, Tolman, 1948), exhibits decrements in neurotrophic factors (Duman and Monteggia, 2006, Monteggia et al., 2004, Smith et al., 1995, Xu et al., 2006, Xu et al., 2007), decreased neurogenesis (Czéh et al., 2001, Mirescu and Gould, 2006, Oomen et al., 2007, Pham et al., 2003, Xu et al., 2006, Xu et al., 2007) and marked alterations in neuronal dendritic complexity and spine density (Conrad, 2006, Magariños et al., 1996, McLaughlin et al., 2007, Sunanda et al., 1995), with a range of antidepressants reversing these effects (Czéh et al., 2001, Duman and Monteggia, 2006, Magariños et al., 1996, Malberg et al., 2000, Nestler et al., 2002). Reports that depressed individuals express similar alterations in the hippocampus that can also be reversed by antidepressants helped inspire a novel hypothesis that depression and chronic stress hinder neuroplasticity and function similarly, especially within the hippocampus (Pittenger & Duman, 2008). Therefore, understanding the neurobiology underlying these changes in hippocampal structure and function induced by stress in animal models is important to elucidate novel directions for the treatment of depression and other disorders with similar etiologies.
Environmental enrichment (EE) has a long record of promoting brain development, plasticity and cognitive performance, especially within the hippocampus (Fox et al., 2006, Hebb, 1947, Kramer et al., 2004, Rosenzweig and Bennett, 1996, van Praag et al., 2000). Investigations commonly implement EE paradigms in young rodents during development to compare the physiological and behavioral outcomes to standard or isolated housing conditions (Rosenzweig & Bennett, 1996). More recently, research has focused on either behavioral or neurobiological consequences of EE on the damaged or diseased brain (Dhanushkodi and Shetty, 2008, Fox et al., 2006, Mohammed et al., 2002, Rampon et al., 2000, Sifonios et al., 2009, van Praag et al., 2000, Yang et al., 2007) and after stress in adolescents (Cui et al., 2006, Yang et al., 2007). Importantly, the beneficial effects of the exposure to EE are evident not only when EE precedes, but also when EE follows a brain challenge. However, in spite of the bulk of studies on EE effects on brain functions, less is known about the effects of EE exposure on chronic stress, and in particular whether the detrimental effects of chronic stress in adulthood on neuromorphology and function can be blocked. As such, this is the first study to investigate the impact of EE and chronic stress in adulthood on hippocampal plasticity and resilience, by examining morphological and behavioral measures within the same subjects. We hypothesized that adult-onset EE, begun before or after the onset of chronic stress, would prevent dendritic retraction and mitigate the detrimental effects of chronic stress on hippocampus-dependent spatial learning and memory.
Section snippets
Subjects
Upon arrival, male Sprague–Dawley rats (275 gm, Charles River Laboratories, Wilmington, MA) were pair-housed in temperature (18–21 °C) and sound controlled chambers on a reversed light cycle (lights off 0600-h). Food and water were freely available unless otherwise noted. Rats acclimated for at least a week before procedures started. Body weights were taken weekly throughout the studies. Arizona State University Institutional Animal Care and Use Committee approved the procedures, which followed
Experiment 1: Prevention: EE started before chronic stress
In experiment 1, EE was initiated one week prior to chronic stress and then continued until the end of the chronic stress regimen. Chronic stress and EE altered the prevalence of first-time entry errors, but not repeat entry errors in the 6-arm RAWM (for first-time entry errors, there was a significant stress x EE x block interaction, F5,195 = 3.74, p < 0.005, a significant stress x block interaction, F5,195 = 2.51, p < 0.05, a significant repeated effect of block, F5,195 = 25.40, p < 0.0001, and a
Discussion
The current studies support the hypothesis that in adult rats, EE attenuates the detrimental effects of chronic stress on hippocampal morphology and function whether initiated prior to chronic stress or 2 weeks after the onset of chronic stress. Past reports provide clear evidence that chronic stress alters hippocampal structure by changing the hippocampal morphology in rats and tree shrews, including reversible remodeling of dendrites in the CA3 region (Conrad et al., 1999, Kleen et al., 2006,
Acknowledgments
Supported by funds from the Arizona Biomedical Research Commission (Conrad) MH64727 (Conrad), the Arizona State University School of Life Sciences, the Howard Hughes Medical Institute through the Undergraduate Science Education Program (Anouti, Ortiz, and Mika), and the VA Merit Review and Career Scientist Awards (Diamond). The authors gratefully acknowledge Charles Armstrong, Sarah Baran, Heather Bimonte-Nelson, Krystal Carpenter, Natalie Conboy, Renée Dille, Mariam, El-Ashmawy, Gillian
References (102)
- et al.
The effects of long-term corticosterone administration on hippocampal morphology and cognitive performance of middle-aged rats
Brain Research
(1994) - et al.
Chronic corticosterone treatment impairs spontaneous alternation behavior in rats
Behavioral and Neural Biology
(1994) - et al.
Peripubertal anxiety profile can predict spatial memory impairments following chronic stress
Behavioural Brain Research
(2006) - et al.
Environmental enrichment lowers stress-responsive hormones in singly housed male and female rats
Pharmacology Biochemistry and Behavior
(2003) A study of some enriching variables in a free-environment for rats
Journal of Psychosomatic Research
(1973)- et al.
Environmental enrichment and chronic restraint stress in ICR mice: Effects on prepulse inhibition of startle and Y-maze spatial recognition memory
Behavioral Brain Research
(2010) - et al.
Chronic corticosterone affects brain weight, and mitochondrial, but not glial volume fraction in hippocampal area CA3
Neuroscience
(2004) - et al.
Longitudinal application of cognitive function measures in a defined population of community-dwelling elders
Annals in Epidemiology
(1991) - et al.
Sex differences in spatial and non-spatial Y-maze performance after chronic stress
The Neurobiology of Learning and Memory
(2003) A critical review of chronic stress effects on spatial learning and memory
Progress in Neuro-Psychopharmacology & Biological Psychiatry
(2010)
Impact of the hypothalamic-pituitary-adrenal/gonadal axes on trajectory of age-related cognitive decline
Enriched environment experience overcomes the memory deficits and depressive-like behavior induced by early life stress
Neuroscience Letters
Cognitive deficits induced in young rats by long-term corticosterone administration
Behavioral and Neural Biology
Is exposure to enriched environment beneficial for functional post-lesional recovery in temporal lobe epilepsy?
Neuroscience and Biobehavioral Reviews
A neurotrophic model for stress-related mood disorders
Biological Psychiatry
Therapeutic and protective effect of environmental enrichment against psychogenic and neurogenic stress
Behavioral Brain Research
An active and socially integrated lifestyle in late life might protect against dementia
Lancet Neurology
The consequences of uncontrollable stress are sensitive to duration of prior wheel running
Brain Research
The physical context of previous stress exposure modifies hypothalamic-pituitary-adrenal responses to a subsequent homotypic stress
Hormones and Behavior
Gender-dependent alterations in corticosteroid receptor status and spatial performance following 21 days of restraint stress
Neuroscience
Different types of environmental enrichment have discrepant effects on spatial memory and synaptophysin levels in female mice
Neurobiology of Learning and Memory
Psychological stress and environmental adaptation in enriched vs impoverished housed rats
Pharmacology Biochemistry and Behavior
Repeated stress causes reversible impairments of spatial memory performance
Brain Research
Effects of chronic corticosterone ingestion on spatial memory performance and hippocampal serotonergic function
Brain Research
Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: Involvement of glucocorticoid secretion and excitatory amino acid receptors
Neuroscience
Chronic stress enhances spatial memory in ovariectomized female rats despite CA3 dendritic retraction: Possible involvement of CA1 neurons
Neuroscience
The effects of chronic stress on hippocampal morphology and function: An evaluation of chronic restraint paradigms
Brain Research
Environmental influences on the central nervous system and their implications for the aging rat
Behavioural Brain Research
Environmental enrichment and the brain
Progress in Brain Research
Aging, plasticity and environmental enrichment: Structural changes and neurotransmitter dynamics in several areas of the brain
Brain Research Reviews
Neurobiology of depression
Neuron
The effects of forced exercise on hippocampal plasticity in the rat: A comparison of LTP, spatial- and non-spatial learning
Behavioural Brain Research
Chronic psychosocial stress impairs learning and memory and increases sensitivity to yohimbine in rats
Biological Psychiatry
Changes in brain nerve growth factor levels and nerve growth factor receptors in rats exposed to environmental enrichment for one year
Neuroscience
Psychobiology of plasticity: Effects of training and experience on brain and behavior
Behavioural Brain Research
An enriched environment restores normal behavior while providing cytoskeletal restoration and synaptic changes in the hippocampus of rats exposed to an experimental model of depression
Neuroscience
Reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral improvement
Neuroscience
Effect of chronic restraint stress on dendritic spines and excrescences of hippocampal CA3 pyramidal neurons – A quantitative study
Brain Research
Recovery after chronic stress fails to reverse amygdaloid neuronal hypertrophy and enhanced anxiety-like behavior
Neuroscience
Enriched environment prevents chronic stress-induced spatial learning and memory deficits
Behavioural Brain Research
Curcumin reverses impaired hippocampal neurogenesis and increases serotonin receptor 1A mRNA and brain-derived neurotrophic factor expression in chronically stressed rats
Brain Research
Cardiovascular fitness is associated with cognition in young adulthood
Proceedings of the National Academy of Science U S A
Two-day radial-arm water maze learning and memory task: Robust resolution of amyloid-related memory deficits in transgenic mice
Nature Protocols
Physical exercise at midlife and risk of dementia three decades later: A population-based study of Swedish twins
Journal of Gerontology. Series A, Biological Sciences and Medical Sciences
Exercise treatment for major depression: Maintenance of therapeutic benefit at 10 months
Psychosomatic Medicine
Effects of cognitive training interventions with older adults: A randomized controlled trial
JAMA
Social resources and cognitive decline in a population of older African Americans and whites
Neurology
Enduring effects of chronic corticosterone treatment on spatial learning, synaptic plasticity, and hippocampal neuropathology in young and mid-aged rats
The Journal of Neuroscience
Hypothalamic pituitary adrenal axis responses to low-intensity stressors are reduced after voluntary wheel running in rats
Journal of Neuroendocrinology
Cited by (78)
Effects of a combined enrichment intervention on the behavioural and physiological welfare of captive Asiatic lions (Panthera leo persica)
2021, Applied Animal Behaviour ScienceDifferential impact of stress and environmental enrichment on corticolimbic circuits
2020, Pharmacology Biochemistry and BehaviorNon-pharmacological and pharmacological approaches for psychiatric disorders: Re-appraisal and insights from zebrafish models
2020, Pharmacology Biochemistry and Behavior