Review
Oxidative stress and redox regulation on hippocampal-dependent cognitive functions

https://doi.org/10.1016/j.abb.2015.03.014Get rights and content

Highlights

  • Hippocampus is central to learning and memory, but is sensitive to oxidative stress.

  • Reduced hippocampal neurogenesis and dendritic complexity affect memory formation.

  • Aging, SOD deficiency and radiation exposure cause oxidative stress in hippocampus.

  • Redox imbalance alters hippocampal neurogenesis, dendritic complexity, and learning.

  • Redox control may play important roles in hippocampal-dependent cognitive functions.

Abstract

Hippocampal-dependent cognitive functions rely on production of new neurons and maintenance of dendritic structures to provide the synaptic plasticity needed for learning and formation of new memories. Hippocampal formation is exquisitely sensitive to patho-physiological changes, and reduced antioxidant capacity and exposure to low dose irradiation can significantly impede hippocampal-dependent functions of learning and memory by reducing the production of new neurons and alter dendritic structures in the hippocampus. Although the mechanism leading to impaired cognitive functions is complex, persistent oxidative stress likely plays an important role in the SOD-deficient and radiation-exposed hippocampal environment. Aging is associated with increased production of pro-oxidants and accumulation of oxidative end products. Similar to the hippocampal defects observed in SOD-deficient mice and mice exposed to low dose irradiation, reduced capacity in learning and memory, diminishing hippocampal neurogenesis, and altered dendritic network are universal in the aging brains. Given the similarities in cellular and structural changes in the aged, SOD-deficient, and radiation-exposed hippocampal environment and the corresponding changes in cognitive decline, understanding the shared underlying mechanism will provide more flexible and efficient use of SOD deficiency or irradiation to model age-related changes in cognitive functions and identify potential therapeutic or intervention methods.

Section snippets

Hippocampal-dependent learning and memory

Hippocampus is critical for the acquisition (learning), consolidation and retrieval of declarative memories (reviewed in [1]). It is also important for the formation of spatial memory [2], [3]. The hippocampus is located in the medial temporal lobe of the brain and is composed of two separate structures: the dentate gyrus (DG)

Redox potential and cell fate decision

Changes in intracellular redox potential and the extracellular microenvironment can impact cell fate decisions, including entering or exiting cell cycle, proliferation or differentiation, and survival or cell death. Redox couples, such as GSH/GSSG and NADPH/NADP+ are presence in high abundance in cells and the status of these redox couples can serve as important indicators for the reduction potential of intracellular environment, which then influence the activity of redox-sensitive proteins

Redox balance and hippocampal neurogenesis

Stem cells usually reside in an environment with low oxygen tension, and recent studies suggest that activation of hypoxia-inducible factor 1 alpha (HIF-1α) in low oxygen environment facilitates signaling pathways that favors self renewal and inhibits pathways that promote differentiation [67]. In addition to the external environment, intracellular ROS production increases as cells proceed through the differentiation process. Within the hippocampal redox environment that favors differentiation,

Redox balance and dendritic structure

Hippocampal-dependent learning is mainly mediated by excitatory neurons with granule cells in the dentate gyrus and pyramidal cells in the CA areas. Granule cells and pyramidal cells put out extensive dendrites that synapse with axons and dendrites from other neurons for proper control of synaptic transmissions. Dendritic spines are small protrusions on dendrites that receive input from synapses on axons. They constitute the post synaptic element of excitatory synapses and mediate the majority

Redox balance and hippocampal-dependent learning and memory

Several behavioral studies are designed based on the natural curiosity of rodents to explore novel objects and locations or their natural instincts to freeze when frightened to examine hippocampal-dependent and independent cognitive functions. In the novel object recognition paradigm, mice have the natural tendency to spend relatively more time exploring a novel object when it is presented with a familiar object at the same time. Such recognition memory depends on multiple brain areas, but most

Radiation, oxidative stress, and hippocampal functions

The brain is exposed to ionizing radiation in a number of clinical situations, predominantly in those involving cancer treatments. Radiation brain injury could involve macroscopic tissue destruction after relatively high doses of irradiation [81]. Less severe morphologic injury also occurs after radiotherapy and this injury can result in variable degrees of cognitive dysfunction [82], [83]. Such cognitive changes can occur in both pediatric and adult patients, and are often manifested as

Oxidative stress and age-related cognitive decline

Tissue levels of protein oxidation, lipid peroxidation, and DNA/RNA oxidation all go up with age [88], [89], [90], [91], and this is impart due to increased production of reactive oxygen species (ROS) and in part, due to decreased repair. Age-related increase of superoxide radicals in the brain can be visually illustrated by in vivo conversion of dihydroethidium (DHE) into its oxidized products, 2-hydroethidium and ethidium, which are DNA and RNA interchelating fluorescent dyes [92]. Whereas

Acknowledgments

This work was supported by VA Merit Review, Geriatric Research, Education, and clinical Center (GRECC), and the use of facility and resources at the VA Palo Alto Health Care System.

References (107)

  • H. Eichenbaum

    Behav. Brain Res.

    (2001)
  • D.G. Amaral et al.

    Neuroscience

    (1989)
  • D.G. MacKay et al.

    Neuropsychologia

    (2013)
  • F.L. Margolis et al.

    Prog. Brain Res.

    (1991)
  • N.M. Ben Abdallah et al.

    Neurobiol. Aging

    (2010)
  • J. Prickaerts et al.

    Neurobiol. Learn. Mem.

    (2004)
  • F.Q. Schafer et al.

    Free Radical Biol. Med.

    (2001)
  • T.T. Huang et al.

    Semin. Cell Dev. Biol.

    (2012)
  • L.A. Sturtz et al.

    J. Biol. Chem.

    (2001)
  • T.T. Huang

    Arch. Biochem. Biophys.

    (1997)
  • T.T. Huang

    Free Radical Biol. Med.

    (2001)
  • E.H. Sarsour et al.

    J. Biol. Chem.

    (2005)
  • S.K. Dhar et al.

    Free Radical Biol. Med.

    (2012)
  • A. Kim

    Free Radical Biol. Med.

    (2010)
  • M.J. Hitchler et al.

    Free Radical Biol. Med.

    (2008)
  • A.C. Ranganathan

    J. Biol. Chem.

    (2001)
  • R.P. Bowler

    J. Biol. Chem.

    (2002)
  • M.L. Sentman

    J. Biol. Chem.

    (2006)
  • S.G. Rhee et al.

    J. Biol. Chem.

    (2012)
  • Y. Yan et al.

    Cell

    (2009)
  • K. Fishman

    Free Radical Biol. Med.

    (2009)
  • R. Rola

    Free Radical Biol. Med.

    (2007)
  • S.U. Kim

    Neurobiol. Aging

    (2011)
  • G.E. Sheline et al.

    Int. J. Radiat. Oncol. Biol. Phys.

    (1980)
  • J. Grill

    Int. J. Radiat. Oncol. Biol. Phys.

    (1999)
  • C.A. Meyers et al.

    Int. J. Radiat. Oncol. Biol. Phys.

    (2000)
  • K. Motomura et al.

    Neurosci. Lett.

    (2010)
  • R.L. Levine et al.

    Exp. Gerontol.

    (2001)
  • R. Pamplona

    Biochim. Biophys. Acta

    (2008)
  • M. Gallagher et al.

    Neurobiol. Aging

    (1988)
  • A.E. Budson

    Neurologist

    (2009)
  • G. Papp et al.

    Learn Mem.

    (2007)
  • S. Zola-Morgan et al.

    Annu. Rev. Neurosci.

    (1993)
  • D.G. Amaral et al.

    Prog. Brain Res.

    (2007)
  • L.R. Squire et al.

    Proc. Natl. Acad. Sci. U.S.A.

    (1996)
  • S.M. Braun et al.

    Development

    (2014)
  • A. Stuchlik

    Front. Behav. Neurosci.

    (2014)
  • Y. Gu et al.

    Curr. Top. Behav. Neurosci.

    (2013)
  • G.L. Ming et al.

    Annu. Rev. Neurosci.

    (2005)
  • P.S. Eriksson

    Nat. Med.

    (1998)
  • H.G. Kuhn et al.

    J. Neurosci.

    (1996)
  • E.A. Markakis et al.

    J. Comp. Neurol.

    (1999)
  • V. Ramirez-Amaya et al.

    J. Neurosci.

    (2006)
  • H. van Praag et al.

    Proc. Natl. Acad. Sci. U.S.A.

    (1999)
  • H. van Praag et al.

    Nat. Neurosci.

    (1999)
  • C. Zhao et al.

    J. Neurosci.

    (2006)
  • G. Kempermann et al.

    Nature

    (1997)
  • G. Kempermann

    J. Neurosci.

    (2002)
  • G. Kempermann et al.

    Curr. Biol.

    (1998)
  • G. Kempermann et al.

    J. Neurosci.

    (1998)
  • Cited by (111)

    View all citing articles on Scopus
    View full text