Environmental enrichment protects against the effects of chronic stress on cognitive and morphological measures of hippocampal integrity

https://doi.org/10.1016/j.nlm.2012.01.003Get rights and content

Abstract

Chronic stress has detrimental effects on hippocampal integrity, while environmental enrichment (EE) has beneficial effects when initiated early in development. In this study, we investigated whether EE initiated in adulthood would mitigate chronic stress effects on cognitive function and hippocampal neuronal architecture, when EE started one week before chronic stress began, or two weeks after chronic stress onset. Adult male Sprague Dawley rats were chronically restrained (6 h/d) or assigned as non-stressed controls and subdivided into EE or non-EE housing. After restraint ended, rats were tested on a radial arm water maze (RAWM) for 2-d to assess spatial learning and memory. The first study showed that when EE began prior to 3-weeks of chronic stress, EE attenuated chronic stress-induced impairments in acquisition, which corresponded with the prevention of chronic stress-induced reductions in CA3 apical dendritic length. A second study showed that when EE began 2-weeks after the onset of a 5-week stress regimen, EE blocked chronic stress-induced impairments in acquisition and retention at 1-h and 24-h delays. RAWM performance corresponded with CA3 apical dendritic complexity. Moreover, rats in EE housing (control or stress) exhibited similar corticosterone profiles across weeks, which differed from the muted corticosterone response to restraint by the chronically stressed pair-housed rats. These data support the interpretation that chronic stress and EE may act on similar mechanisms within the hippocampus, and that manipulation of these factors may yield new directions for optimizing brain integrity and resilience under chronic stress or stress related neuropsychological disorders in the adult.

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)

  • C.D. Conrad et al.

    Impact of the hypothalamic-pituitary-adrenal/gonadal axes on trajectory of age-related cognitive decline

  • M. Cui et al.

    Enriched environment experience overcomes the memory deficits and depressive-like behavior induced by early life stress

    Neuroscience Letters

    (2006)
  • S. Dachir et al.

    Cognitive deficits induced in young rats by long-term corticosterone administration

    Behavioral and Neural Biology

    (1993)
  • A. Dhanushkodi et al.

    Is exposure to enriched environment beneficial for functional post-lesional recovery in temporal lobe epilepsy?

    Neuroscience and Biobehavioral Reviews

    (2008)
  • R.S. Duman et al.

    A neurotrophic model for stress-related mood disorders

    Biological Psychiatry

    (2006)
  • C. Fox et al.

    Therapeutic and protective effect of environmental enrichment against psychogenic and neurogenic stress

    Behavioral Brain Research

    (2006)
  • L. Fratiglioni et al.

    An active and socially integrated lifestyle in late life might protect against dementia

    Lancet Neurology

    (2004)
  • B.N. Greenwood et al.

    The consequences of uncontrollable stress are sensitive to duration of prior wheel running

    Brain Research

    (2005)
  • N. Grissom et al.

    The physical context of previous stress exposure modifies hypothalamic-pituitary-adrenal responses to a subsequent homotypic stress

    Hormones and Behavior

    (2007)
  • E. Kitraki et al.

    Gender-dependent alterations in corticosteroid receptor status and spatial performance following 21 days of restraint stress

    Neuroscience

    (2004)
  • T.J. Lambert et al.

    Different types of environmental enrichment have discrepant effects on spatial memory and synaptophysin levels in female mice

    Neurobiology of Learning and Memory

    (2005)
  • F. Larsson et al.

    Psychological stress and environmental adaptation in enriched vs impoverished housed rats

    Pharmacology Biochemistry and Behavior

    (2002)
  • V. Luine et al.

    Repeated stress causes reversible impairments of spatial memory performance

    Brain Research

    (1994)
  • V.N. Luine et al.

    Effects of chronic corticosterone ingestion on spatial memory performance and hippocampal serotonergic function

    Brain Research

    (1993)
  • A.M. Magariños et al.

    Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: Involvement of glucocorticoid secretion and excitatory amino acid receptors

    Neuroscience

    (1995)
  • K.J. McLaughlin et al.

    Chronic stress enhances spatial memory in ovariectomized female rats despite CA3 dendritic retraction: Possible involvement of CA1 neurons

    Neuroscience

    (2005)
  • K.J. McLaughlin et al.

    The effects of chronic stress on hippocampal morphology and function: An evaluation of chronic restraint paradigms

    Brain Research

    (2007)
  • A.H. Mohammed et al.

    Environmental influences on the central nervous system and their implications for the aging rat

    Behavioural Brain Research

    (1993)
  • A.H. Mohammed et al.

    Environmental enrichment and the brain

    Progress in Brain Research

    (2002)
  • F. Mora et al.

    Aging, plasticity and environmental enrichment: Structural changes and neurotransmitter dynamics in several areas of the brain

    Brain Research Reviews

    (2007)
  • E.J. Nestler et al.

    Neurobiology of depression

    Neuron

    (2002)
  • R.M. O’Callaghan et al.

    The effects of forced exercise on hippocampal plasticity in the rat: A comparison of LTP, spatial- and non-spatial learning

    Behavioural Brain Research

    (2007)
  • C.R. Park et al.

    Chronic psychosocial stress impairs learning and memory and increases sensitivity to yohimbine in rats

    Biological Psychiatry

    (2001)
  • T.M. Pham et al.

    Changes in brain nerve growth factor levels and nerve growth factor receptors in rats exposed to environmental enrichment for one year

    Neuroscience

    (1999)
  • M.R. Rosenzweig et al.

    Psychobiology of plasticity: Effects of training and experience on brain and behavior

    Behavioural Brain Research

    (1996)
  • L. Sifonios et al.

    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

    (2009)
  • N. Sousa et al.

    Reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral improvement

    Neuroscience

    (2000)
  • Sunanda et al.

    Effect of chronic restraint stress on dendritic spines and excrescences of hippocampal CA3 pyramidal neurons – A quantitative study

    Brain Research

    (1995)
  • A. Vyas et al.

    Recovery after chronic stress fails to reverse amygdaloid neuronal hypertrophy and enhanced anxiety-like behavior

    Neuroscience

    (2004)
  • R.L. Wright et al.

    Enriched environment prevents chronic stress-induced spatial learning and memory deficits

    Behavioural Brain Research

    (2008)
  • Y. Xu et al.

    Curcumin reverses impaired hippocampal neurogenesis and increases serotonin receptor 1A mRNA and brain-derived neurotrophic factor expression in chronically stressed rats

    Brain Research

    (2007)
  • M.A. Aberg et al.

    Cardiovascular fitness is associated with cognition in young adulthood

    Proceedings of the National Academy of Science U S A

    (2009)
  • J. Alamed et al.

    Two-day radial-arm water maze learning and memory task: Robust resolution of amyloid-related memory deficits in transgenic mice

    Nature Protocols

    (2006)
  • R. Andel et al.

    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

    (2008)
  • M. Babyak et al.

    Exercise treatment for major depression: Maintenance of therapeutic benefit at 10 months

    Psychosomatic Medicine

    (2000)
  • K. Ball et al.

    Effects of cognitive training interventions with older adults: A randomized controlled trial

    JAMA

    (2002)
  • L.L. Barnes et al.

    Social resources and cognitive decline in a population of older African Americans and whites

    Neurology

    (2004)
  • Barton, J., Griffin, M., & Pretty, J. (2011). Exercise-, nature- and socially interactive-based initiatives improve...
  • S.R. Bodnoff et al.

    Enduring effects of chronic corticosterone treatment on spatial learning, synaptic plasticity, and hippocampal neuropathology in young and mid-aged rats

    The Journal of Neuroscience

    (1995)
  • S. Campeau et al.

    Hypothalamic pituitary adrenal axis responses to low-intensity stressors are reduced after voluntary wheel running in rats

    Journal of Neuroendocrinology

    (2010)
  • Cited by (78)

    View all citing articles on Scopus
    View full text