Progress in Neuro-Psychopharmacology and Biological Psychiatry
Mechanisms mediating brain and cognitive reserve: Experience-dependent neuroprotection and functional compensation in animal models of neurodegenerative diseases
Research Highlights
► Brain and cognitive reserve (BCR) can provide neuroprotective and compensatory capacities. ► The neurobiology of BCR has been informed by environmental manipulations of animal models. ► Beneficial effects of environmental enrichment have been studied in brain disease models. ► Enhanced sensory, cognitive and motor activity has molecular, cellular and behavioural effects. ► Animal models of BCR may aid development of novel therapeutics (e.g. enviromimetics).
Introduction
A theory of ‘brain reserve’ has been developed to conceptualise the neuroprotective brain capacity that can be induced when mental, as well as physical, activity chronically enhanced (Katzman, 1993, Satz et al., 1993, Stern et al., 1995, Mortimer, 1997, Schmand et al., 1997, Valenzuela and Sachdev, 2006a, Valenzuela and Sachdev, 2006b; reviewed by Valenzuela, 2008). The associated term ‘cognitive reserve’ was originally used to help explain epidemiological data which suggested that increased cognitive function and enhanced complex mental activity provided a functional reserve that could compensate for the pathogenic processes associated with brain disorders such as AD and dementia (Graves et al., 1996, Stern, 2002, Scarmeas and Stern, 2003, Stern et al., 2003, Scarmeas and Stern, 2004, Whalley et al., 2004, Le Carret et al., 2005, Mortimer et al., 2005, Richards and Deary, 2005, Stern et al., 2005, Andel et al., 2006; reviewed by Stern, 2009). The terms have often been used somewhat interchangeably, as it is difficult to distinguish reserves at the level of brain or cognition, and therefore it is simpler to refer to these ideas collectively as a broad theory of ‘brain and cognitive reserve’ (BCR; Nithianantharajah and Hannan, 2009).
BCR may provide neuroprotective and compensatory capacities not only for AD and dementia, but also a wide range of other brain disorders (reviewed by Nithianantharajah and Hannan, 2009). The neurobiology of BCR has been informed by environmental manipulations of animal models. Environmental enrichment, which enhances mental and physical activity levels, has been found to induce beneficial effects in rodent models of neurodegenerative diseases including HD (van Dellen et al., 2000, Hockly et al., 2002), AD (Levi et al., 2003, Arendash et al., 2004, Jankowsky et al., 2005, Lazarov et al., 2005), Parkinson's disease (Bezard et al., 2003, Faherty et al., 2005), amyotrophic lateral sclerosis (Stam et al., 2008) and multiple sclerosis (Magalon et al., 2007). However, the scope of this article will be restricted to BCR and specific neurodegenerative brain diseases, with HD and AD used as key examples. While we will touch on the epidemiology and clinical data, which has recently been reviewed elsewhere (e.g. Valenzuela et al., 2007, Valenzuela, 2008), the main focus will be on evidence for BCR, and its underlying mechanisms, in animal models of HD and AD.
Section snippets
Huntington's disease: gene–environment interactions and experience-dependent plasticity in animal models
HD is a neurodegenerative disorder involving psychiatric symptoms (e.g. depression), cognitive deficits (culminating in dementia) and motor abnormalities (e.g. chorea), first described in 1872 by George Huntington. In 1993, it was discovered that HD is caused by a trinucleotide (CAG) repeat expansion, encoding an extended tract of glutamines, in the huntingtin protein. This discovery paved the way for a range of molecular, cellular and behavioural experiments to determine mechanisms of
Alzheimer's disease: experience-dependent plasticity modelling BCR in animal models
AD is a neurodegenerative disorder characterized by progressive memory deficits and cognitive decline. The major neuropathological changes occur primarily in the hippocampus and cortex, followed by subcortical structures. Analysis of postmortem human AD brains in the early 1900s first led to the identification of what are still considered the two pathological hallmarks of the disease — senile plaques composed of extracellular deposits of amyloid-β (Aβ) derived by proteolytic cleavage of the
Modelling BCR through environmental enrichment — some key issues
A key question posed by the effects of EE observed in these animal models, involves the relative contributions of enhanced mental and physical activity to the observed beneficial effects. The simplest way to address this issue is to specifically enhance voluntary physical activity by the addition of running wheels to the home cage. Commencing wheel running when HD mice had already reached adulthood was found to delay onset of hippocampal-dependent cognitive deficits and motor deficits (Pang et
Conclusions
At a time when the percentage of elderly in the population is increasing, the question of how to promote successful cognitive ageing has become of fundamental importance in neuroscience and medical research. Increasing epidemiological evidence supports the idea that BCR may delay the onset of a range of brain disorders as well as possibly decrease the rate of normal brain aging. While prospective studies and intervention trials have begun to identify aspects of environmental factors associated
Acknowledgments
We would like to thank past and present members of the Hannan Laboratory for useful discussions and experimental findings that have contributed to this article. AJH has been supported by Project Grants from the NHMRC and a Pfizer Australia Research Fellowship.
References (109)
- et al.
Reduction of amyloid angiopathy and Abeta plaque burden after enriched housing in TgCRND8 mice: involvement of multiple pathways
Am J Pathol
(2006) - et al.
Tau, tangles, and Alzheimer's disease
Biochim Biophys Acta
(2005) - et al.
Magnetic resonance imaging as an approach towards identifying neuropathological biomarkers for Huntington's disease
Brain Res Rev
(2008) - et al.
Effects of environmental enrichment and physical activity on neurogenesis in transgenic PS1/APP mice
Brain Res
(2009) - et al.
Non-cell-autonomous effects of presenilin 1 variants on enrichment-mediated hippocampal progenitor cell proliferation and differentiation
Neuron
(2008) - et al.
Enrichment improves cognition in AD mice by amyloid-related and unrelated mechanisms
Neurobiol Aging
(2007) - et al.
Enhanced cognitive activity–over and above social or physical activity–is required to protect Alzheimer's mice against cognitive impairment, reduce Abeta deposition, and increase synaptic immunoreactivity
Neurobiol Learn Mem
(2007) - et al.
Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation
Cell
(1997) - et al.
Environmental enrichment in adulthood eliminates neuronal death in experimental Parkinsonism
Brain Res Mol Brain Res
(2005) - et al.
Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces
Neuron
(2001)
Simple sequence repeats: genetic modulators of brain function and behavior
Trends Neurosci
The R6 lines of transgenic mice: a model for screening new therapies for Huntington's disease
Brain Res Rev
Reduced hippocampal neurogenesis in R6/2 transgenic Huntington's disease mice
Neurobiol Dis
Delayed onset of Huntington's disease in mice in an enriched environment correlates with delayed loss of cannabinoid CB1 receptors
Neuroscience
Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein
Biochem Biophys Res Commun
Effects of environmental enrichment on exploration, anxiety, and memory in female TgCRND8 Alzheimer mice
Behav Brain Rev
Environmental enrichment enhances cellular plasticity in transgenic mice with Alzheimer-like pathology
Exp Neurol
Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice
Cell
ApoE4 impairs hippocampal plasticity isoform-specifically and blocks the environmental stimulation of synaptogenesis and memory
Neurobiol Dis
Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice
Cell
The neurobiology of brain and cognitive reserve: mental and physical activity as modulators of brain disorders
Prog Neurobiol
Environmental enrichment results in cortical and subcortical changes in levels of synaptophysin and PSD-95 proteins
Neurobiol Learn Mem
Gene–environment interactions modulating cognitive function and molecular correlates of synaptic plasticity in Huntington's disease transgenic mice
Neurobiol Dis
Modeling brain reserve: experience-dependent neuronal plasticity in healthy and Huntington's disease transgenic mice
Am J Geriatr Psychiatry
Tracking mutant huntingtin aggregation kinetics in cells reveals three major populations including an invariant oligomer pool
J Biol Chem
Differential effects of voluntary physical exercise on behavioral and brain-derived neurotrophic factor expression deficits in Huntington's disease transgenic mice
Neuroscience
Repeated novel cage exposure-induced improvement of early Alzheimer's-like cognitive and amyloid changes in TASTPM mice is unrelated to changes in brain endocannabinoids levels
Neurobiol Aging
Wheel-running in a transgenic mouse model of Alzheimer's disease: protection or symptom?
Behav Brain Res
Environmental, pharmacological, and genetic modulation of the HD phenotype in transgenic mice
Exp Neurol
Hydrogen peroxide promotes Abeta production through JNK-dependent activation of gamma-secretase
J Biol Chem
Tau pathophysiology in neurodegeneration: a tangled issue
Trends Neurosci
Cognitive reserve
Neuropsychologia
Voluntary exercise decreases amyloid load in transgenic model of Alzheimer's disease
J Neurosci
The effect of education and occupational complexity on rate of cognitive decline in Alzheimer's patients
J Int Neuropsychol Soc
Dopamine and glutamate in Huntington's disease: a balancing act
CNS Neurosci Ther
Environmental enrichment improves cognition in aged Alzheimer's transgenic mice despite stable beta-amyloid deposition
NeuroReport
Neuropathology of older persons without cognitive impairment from two community-based studies
Neurology
Environmental enrichment delays the onset of memory deficits and reduces neuropathological hallmarks in a mouse model of Alzheimer-like neurodegeneration
J Alzheimers Dis
Enriched environment confers resistance to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine and cocaine: involvement of dopamine transporter and trophic factors
J Neurosci
Environmental enrichment fails to rescue working memory deficits, neuron loss, and neurogenesis in APP/PS1KI mice
Neurobiol Aging
Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain
Science
Environment enrichment rescues the neurodegenerative phenotypes in presenilins-deficient mice
Eur J Neurosci
Factors associated with resistance to dementia despite high Alzheimer disease pathology
Neurology
Animal models of Alzheimer's disease and frontotemporal dementia
Nat Rev Neurosci
Head circumference as a measure of cognitive reserve. Association with severity of impairment in Alzheimer's disease
Br J Psychiatry
Cognitive disorders and neurogenesis deficits in Huntington's disease mice are rescued by fluoxetine
Eur J Neurosci
Differential vulnerability of neurons in Huntington's disease: the role of cell type-specific features
J Neurochem
Protein misfolding inside cells: the case of huntingtin and Huntington's disease
IUBMB Life
Environmental enrichment counteracts Alzheimer's neurovascular dysfunction in TgCRND8 mice
Brain Pathol
Reduction of cerebral oxidative stress following environmental enrichment in mice with Alzheimer-like pathology
Brain Pathol
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2016, Neuroscience LettersCitation Excerpt :Such detailed clinical studies on stress have not yet been done in HD families, but should be guided by these important animal findings. Environmental enrichment, which enhances mental and physical activity levels, has been found to induce beneficial effects in rodent models of neurodegenerative diseases including HD (reviewed in [45]). Translation of these findings to clinical benefit has been less clear, however, recent studies have shown that physical activity can stave off symptoms in HD [46,47].