Little Exercise, Big Effects: Reversing Aging and Infection-Induced Memory Deficits, and Underlying Processes

We have previously found that healthy aged rats are more likely to suffer profound memory impairments following a severe bacterial infection than are younger adult rats. Such a peripheral challenge is capable of producing a neuroinflammatory response, and in the aged brain this response is exaggerated and prolonged. Normal aging primes, or sensitizes, microglia, and this appears to be the source of this amplified inflammatory response. Among the outcomes of this exaggerated neuroinflammatory response are impairments in synaptic plasticity and reductions of brain-derived neurotrophic factor (BDNF), both of which have been associated with cognitive impairments. Since it has been shown that physical exercise increases BDNF mRNA in the hippocampus, the present study examined voluntary exercise in 24-month-old F344×BN rats as a neuroprotective therapeutic in our bacterial infection model. Although aged rats ran only an average of 0.7 km per week, this small amount of exercise was sufficient to completely reverse infection-induced impairments in hippocampus-dependent long-term memory compared with sedentary animals. Strikingly, exercise prevented the infection-induced exaggerated neuroinflammatory response and the blunted BDNF mRNA induction seen in the hippocampus of sedentary rats. Moreover, voluntary exercise abrogated age-related microglial sensitization, suggesting a possible mechanism for exercise-induced neuroprotection in aging.

[1]  S. Maier,et al.  Aging and a Peripheral Immune Challenge Interact to Reduce Mature Brain-Derived Neurotrophic Factor and Activation of TrkB, PLCγ1, and ERK in Hippocampal Synaptoneurosomes , 2011, The Journal of Neuroscience.

[2]  E. McAuley,et al.  Exercise training increases size of hippocampus and improves memory , 2011, Proceedings of the National Academy of Sciences.

[3]  J. Trojanowski,et al.  Exercise and cognition: Results from the National Long Term Care Survey , 2010, Alzheimer's & Dementia.

[4]  Y. Huang,et al.  Protracted downregulation of CX3CR1 on microglia of aged mice after lipopolysaccharide challenge , 2010, Brain, Behavior, and Immunity.

[5]  S. Maier,et al.  Aging sensitizes rapidly isolated hippocampal microglia to LPS ex vivo , 2010, Journal of Neuroimmunology.

[6]  S. Maier,et al.  Synaptic Correlates of Increased Cognitive Vulnerability with Aging: Peripheral Immune Challenge and Aging Interact to Disrupt Theta-Burst Late-Phase Long-Term Potentiation in Hippocampal Area CA1 , 2010, The Journal of Neuroscience.

[7]  S. Maier,et al.  IL-1RA blocks E. coli-induced suppression of Arc and long-term memory in aged F344×BN F1 rats , 2010, Brain, Behavior, and Immunity.

[8]  M. Lynch,et al.  Age-related neuroinfl ammatory changes negatively impact on neuronal function , 2010 .

[9]  M. Fleshner,et al.  A behavioral analysis of the impact of voluntary physical activity on hippocampus‐dependent contextual conditioning , 2009, Hippocampus.

[10]  Y. Huang,et al.  Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1β and anti-inflammatory IL-10 cytokines , 2009, Brain, Behavior, and Immunity.

[11]  J. W. Rudy,et al.  Time course of hippocampal IL-1 β and memory consolidation impairments in aging rats following peripheral infection , 2009, Brain, Behavior, and Immunity.

[12]  Rodney W. Johnson,et al.  Neuroinflammation Associated with Aging Sensitizes the Brain to the Effects of Infection or Stress , 2008, Neuroimmunomodulation.

[13]  J. Holbrook,et al.  Immunomodulatory effects of etanercept in a model of brain injury act through attenuation of the acute‐phase response , 2007, Journal of neurochemistry.

[14]  Carl W. Cotman,et al.  Exercise builds brain health: key roles of growth factor cascades and inflammation , 2007, Trends in Neurosciences.

[15]  M. Lynch,et al.  CD200 Ligand–Receptor Interaction Modulates Microglial Activation In Vivo and In Vitro: A Role for IL-4 , 2007, The Journal of Neuroscience.

[16]  K. Fassbender,et al.  Innate immune receptor expression in normal brain aging , 2007, Neuroscience.

[17]  M. Bianchi.  DAMPs, PAMPs and alarmins: all we need to know about danger , 2007, Journal of leukocyte biology.

[18]  Ulrich Dirnagl,et al.  Physical Activity Improves Long-Term Stroke Outcome via Endothelial Nitric Oxide Synthase–Dependent Augmentation of Neovascularization and Cerebral Blood Flow , 2006, Circulation research.

[19]  C. Bramham,et al.  Brain-derived neurotrophic factor and control of synaptic consolidation in the adult brain. , 2006, Biochemical Society transactions.

[20]  Steffen Jung,et al.  Control of microglial neurotoxicity by the fractalkine receptor , 2006, Nature Neuroscience.

[21]  J. W. Rudy,et al.  Peripheral infection and aging interact to impair hippocampal memory consolidation , 2006, Neurobiology of Aging.

[22]  J. W. Rudy,et al.  mRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging , 2006, Neurobiology of Aging.

[23]  J. Campisi,et al.  Physical activity alters the brain Hsp72 and IL-1beta responses to peripheral E. coli challenge. , 2005, American journal of physiology. Regulatory, integrative and comparative physiology.

[24]  Jing Chen,et al.  Exaggerated neuroinflammation and sickness behavior in aged mice after activation of the peripheral innate immune system , 2005 .

[25]  Victoria M Perreau,et al.  Voluntary Exercise Decreases Amyloid Load in a Transgenic Model of Alzheimer's Disease , 2005, The Journal of Neuroscience.

[26]  Zhe Ying,et al.  Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition , 2004, The European journal of neuroscience.

[27]  J. W. Rudy,et al.  BDNF mRNA expression in rat hippocampus following contextual learning is blocked by intrahippocampal IL-1β administration , 2004, Journal of Neuroimmunology.

[28]  V. Perry.  The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease , 2004, Brain, Behavior, and Immunity.

[29]  S. Maier,et al.  Brain-derived neurotrophic factor mRNA downregulation produced by social isolation is blocked by intrahippocampal interleukin-1 receptor antagonist , 2003, Neuroscience.

[30]  V. Perry,et al.  Systemic infection, interleukin 1β, and cognitive decline in Alzheimer’s disease , 2003, Journal of neurology, neurosurgery, and psychiatry.

[31]  W. Tyler,et al.  From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning. , 2002, Learning & memory.

[32]  R. O’Reilly,et al.  Hippocampal formation supports conditioning to memory of a context. , 2002, Behavioral neuroscience.

[33]  J. Woods,et al.  Can Exercise Training Improve Immune Function in the Aged? , 2002, Annals of the New York Academy of Sciences.

[34]  B. Blom,et al.  Down-regulation of the macrophage lineage through interaction with OX2 (CD200). , 2000, Science.

[35]  Barry J. Everitt,et al.  Rapid and selective induction of BDNF expression in the hippocampus during contextual learning , 2000, Nature Neuroscience.

[36]  Thomas L. Madden,et al.  Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. , 1997, Nucleic acids research.

[37]  J. Bauer,et al.  Endotoxin-induced appearance of immunoreactive interleukin-1β in ramified microglia in rat brain: A light and electron microscopic study , 1995, Neuroscience.

[38]  I. Assenmacher,et al.  Temporal cascade of plasma level surges in ACTH, corticosterone, and cytokines in endotoxin-challenged rats. , 1994, The American journal of physiology.

[39]  F. Hefti,et al.  Systemic interleukin-1β decreases brain-derived neurotrophic factor messenger RNA expression in the rat hippocampal formation , 1993, Neuroscience.

[40]  M. Fanselow.  Factors governing one-trial contextual conditioning , 1990 .

[41]  J. Delgado-García,et al.  Physical exercise protects against Alzheimer's disease in 3xTg-AD mice. , 2011, Journal of Alzheimer's disease : JAD.

[42]  S. Maier,et al.  Memory impairments in healthy aging: Role of aging-induced microglial sensitization. , 2010, Aging and disease.

[43]  P. Bickford,et al.  Interleukin-1ß and Caspase-1: Players in the Regulation of Age-related Cognitive Dysfunction , 2007, Reviews in the neurosciences.

[44]  S. Maier,et al.  Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. , 1998, Psychological review.

[45]  Michael S. Fanselow,et al.  A functional behavioristic approach to aversively motivated behavior: Predatory imminence as a determinant of the topography of defensive behavior. , 1988 .