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Research Articles, Behavioral/Cognitive

Glutamate Within the Marmoset Anterior Hippocampus Interacts with Area 25 to Regulate the Behavioral and Cardiovascular Correlates of High-Trait Anxiety

Jorge L. Zeredo, Shaun K.L. Quah, Chloe U. Wallis, Laith Alexander, Gemma J. Cockcroft, Andrea M. Santangelo, Jing Xia, Yoshiro Shiba, Jeffrey W. Dalley, Rudolf N. Cardinal, Angela C. Roberts and Hannah F. Clarke
Journal of Neuroscience 17 April 2019, 39 (16) 3094-3107; DOI: https://doi.org/10.1523/JNEUROSCI.2451-18.2018
Jorge L. Zeredo
1Graduate Program in Health Science and Technology, University of Brasilia, Brasilia, Brazil,
2Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom,
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Shaun K.L. Quah
2Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom,
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Chloe U. Wallis
2Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom,
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Laith Alexander
2Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom,
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Gemma J. Cockcroft
2Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom,
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Andrea M. Santangelo
2Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom,
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Jing Xia
3Department of Psychology, University of Cambridge, Cambridge, CB2 3EB, United Kingdom,
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Yoshiro Shiba
2Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom,
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Jeffrey W. Dalley
3Department of Psychology, University of Cambridge, Cambridge, CB2 3EB, United Kingdom,
4Department of Psychiatry, and
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Rudolf N. Cardinal
4Department of Psychiatry, and
5Liaison Psychiatry Service, Cambridge and Peterborough NHS Foundation Trust, Cambridge Biomedical Campus, Cambridg, CB2 OQQ, United Kingdom
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Angela C. Roberts
2Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom,
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Hannah F. Clarke
2Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, United Kingdom,
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Abstract

High-trait anxiety is a risk factor for the development of affective disorders and has been associated with decreased cardiovascular and behavioral responsivity to acute stressors in humans that may increase the risk of developing cardiovascular disease. Although human neuroimaging studies of high-trait anxiety reveals dysregulation in primate cingulate areas 25 and 32 and the anterior hippocampus (aHipp) and rodent studies reveal the importance of aHipp glutamatergic hypofunction, the causal involvement of aHipp glutamate and its interaction with these areas in the primate brain is unknown. Accordingly, we correlated marmoset trait anxiety scores to their postmortem aHipp glutamate levels and showed that low glutamate in the right aHipp is associated with high-trait anxiety in marmosets. Moreover, pharmacologically increasing aHipp glutamate reduced anxiety levels in highly anxious marmosets in two uncertainty-based tests of anxiety: exposure to a human intruder with uncertain intent and unpredictable loud noise. In the human intruder test, increasing aHipp glutamate decreased anxiety by increasing approach to the intruder. In the unpredictable threat test, animals showed blunted behavioral and cardiovascular responsivity after control infusions, which was normalized by increasing aHipp glutamate. However, this aHipp-mediated anxiolytic effect was blocked by simultaneous pharmacological inactivation of area 25, but not area 32, areas which when inactivated independently reduced and had no effect on anxiety, respectively. These findings provide causal evidence in male and female primates that aHipp glutamatergic hypofunction and its regulation by area 25 contribute to the behavioral and cardiovascular symptoms of endogenous high-trait anxiety.

SIGNIFICANCE STATEMENT High-trait anxiety predisposes sufferers to the development of anxiety and depression. Although neuroimaging of these disorders and rodent modeling implicate dysregulation in hippocampal glutamate and the subgenual/perigenual cingulate cortices (areas 25/32), the causal involvement of these structures in endogenous high-trait anxiety and their interaction are unknown. Here, we demonstrate that increased trait anxiety in marmoset monkeys correlates with reduced hippocampal glutamate and that increasing hippocampal glutamate release in high-trait-anxious monkeys normalizes the aberrant behavioral and cardiovascular responsivity to potential threats. This normalization was blocked by simultaneous inactivation of area 25, but not area 32. These findings provide casual evidence in primates that hippocampal glutamatergic hypofunction regulates endogenous high-trait anxiety and the hippocampal–area 25 circuit is a potential therapeutic target.

  • anxiety
  • area 25
  • cardiovascular
  • glutamate
  • hippocampus
  • marmoset

This is an open-access article distributed under the terms of the Creative Commons Attribution License Creative Commons Attribution 4.0 International, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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The Journal of Neuroscience: 39 (16)
Journal of Neuroscience
Vol. 39, Issue 16
17 Apr 2019
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Glutamate Within the Marmoset Anterior Hippocampus Interacts with Area 25 to Regulate the Behavioral and Cardiovascular Correlates of High-Trait Anxiety
Jorge L. Zeredo, Shaun K.L. Quah, Chloe U. Wallis, Laith Alexander, Gemma J. Cockcroft, Andrea M. Santangelo, Jing Xia, Yoshiro Shiba, Jeffrey W. Dalley, Rudolf N. Cardinal, Angela C. Roberts, Hannah F. Clarke
Journal of Neuroscience 17 April 2019, 39 (16) 3094-3107; DOI: 10.1523/JNEUROSCI.2451-18.2018

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Glutamate Within the Marmoset Anterior Hippocampus Interacts with Area 25 to Regulate the Behavioral and Cardiovascular Correlates of High-Trait Anxiety
Jorge L. Zeredo, Shaun K.L. Quah, Chloe U. Wallis, Laith Alexander, Gemma J. Cockcroft, Andrea M. Santangelo, Jing Xia, Yoshiro Shiba, Jeffrey W. Dalley, Rudolf N. Cardinal, Angela C. Roberts, Hannah F. Clarke
Journal of Neuroscience 17 April 2019, 39 (16) 3094-3107; DOI: 10.1523/JNEUROSCI.2451-18.2018
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Keywords

  • anxiety
  • area 25
  • cardiovascular
  • glutamate
  • hippocampus
  • marmoset

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  • RE: Low Glutamate may be Caused by Low Dehydroepiandrosterone (DHEA)
    James M. Howard
    Published on: 05 February 2019
  • Published on: (5 February 2019)
    Page navigation anchor for RE: Low Glutamate may be Caused by Low Dehydroepiandrosterone (DHEA)
    RE: Low Glutamate may be Caused by Low Dehydroepiandrosterone (DHEA)
    • James M. Howard, Biologist, Independent

    I suggest the basis of the findings of Zeredo, et al., is reduced dehydroepiandrosterone (DHEA). DHEA has been found to significantly increase glutamate release (Pharmacol Biochem Behav. 2004 Mar;77(3):601-6). I first suggested that low DHEA is involved in depression in 1985, subsequently, low levels of DHEA were reported some years later. ("A Theory of the Control of the Ontogeny and Phylogeny of Homo sapiens by the Interaction of Dehydroepiandrosterone and the Amygdala," Copyright 1985, James Michael Howard, Fayetteville, Arkansas, U.S.A. (Registered Copyright TXu220580).) Zeredo, et al., do not mention DHEA.

    Competing Interests: None declared.

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