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Cited by 13Hypothalamic control of reproductive hormonesStress Responses and CortisolNeuropeptides and Animal Physiology

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Function and innervation of the locus ceruleus in a macaque model of Functional Hypothalamic Amenorrhea

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Bethea, Cynthia L., Kim, Aaron, Cameron, Judy L.·2013·Neurobiology of Disease
DOI 10.1016/j.nbd.2012.10.009PMC PMC3533527
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Abstract

A body of knowledge implicates an increase in output from the locus ceruleus (LC) during stress. We questioned the innervation and function of the LC in our macaque model of Functional Hypothalamic Amenorrhea, also known as Stress-Induced Amenorrhea. Cohorts of macaques were initially characterized as highly stress resilient (HSR) or stress-sensitive (SS) based upon the presence or absence of ovulation during a protocol involving 2 menstrual cycles with psychosocial and metabolic stress. Afterwards, the animals were rested until normal menstrual cycles resumed and then euthanized on day 5 of a new menstrual cycle [a] in the absence of further stress; or [b] after 5 days of resumed psychosocial and metabolic stress. In this study, parameters of the LC were examined in HSR and SS animals in the presence and absence of stress (2×2 block design) using ICC and image analysis. Tyrosine hydroxylase (TH) is the rate-limiting enzyme for the synthesis of catecholamines; and the TH level was used to assess by inference, NE output. The pixel area of TH-positive dendrites extending outside the medial border of the LC was significantly increased by stress to a similar degree in both HSR and SS animals (p<0.0001). There is a significant CRF innervation of the LC. The positive pixel area of CRF boutons, lateral to the LC, was higher in SS than HSR animals in the absence of stress. Five days of moderate stress significantly increased the CRF-positive bouton pixel area in the HSR group (p<0.02), but not in the SS group. There is also a significant serotonin innervation of the LC. A marked increase in medial serotonin dendrite swelling and beading was observed in the SS+stress group, which may be a consequence of excitotoxicity. The dendrite beading interfered with analysis of axonal boutons. However, at one anatomical level, the serotonin-positive bouton area was obtained between the LC and the superior cerebellar peduncle. Serotonin-positive bouton pixel area was significantly higher in HSR than SS animals (p<0.04). There was no change in either group after 5 days of moderate stress. The ratio of serotonin/TH correlates with ovarian estrogen production with a sensitivity×stress interaction. Therefore, it appears that the serotonin system determines stress sensitivity and the NE system responds to stress. We hypothesize that elevated NE with low serotonin functionality ultimately leads to stress-induced infertility. In contrast, high serotonin functionality maintains ovulation in the presence of stress even with elevated NE.

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  • The actions of norepinephrine are exaggerated with chronic stress exposure: there is increased expression of the synthetic enzymes tyrosine hydroxylase and dopamine β-hydroxylase in noradrenergic neurons and axons in both rats and primates.

    “The actions of norepinephrine are exaggerated with chronic stress exposure: there is increased expression of the synthetic enzymes tyrosine hydroxylase and dopamine β-hydroxylase in noradrenergic neurons and axons in both rats83–85 and primates86.”

    From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [86]

    The Results (‘TH Immunostaining Increases with Stress’; page not provided) report increased tyrosine hydroxylase staining in locus ceruleus dendrites of macaques after five days of stress, with increased norepinephrine transmission inferred rather than measured. This supports the primate TH portion, but the paper does not establish increased dopamine β-hydroxylase or enzyme expression in axons, and its five-day exposure does not establish the claim about chronic stress. The rat findings are attached to other citations in the citing sentence. (LLM, conf=0.89)

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Metadata

Authors
Bethea, C. L., Kim, A., & Cameron, J. L.
Affiliations
  • Oregon National Primate Research Center (US)
  • University of Pittsburgh (US)
Corresponding author
Bethea, Cynthia L.
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2013-02
Volume
50
Pages
96-106
ISSN
0969-9961 (ISSN-L)
DOI
10.1016/j.nbd.2012.10.009
PMC
PMC3533527
OpenAlex
W2013928018
Cited by
13
References
2
Citations by year
2022: 1 · 2020: 1 · 2019: 1 · 2018: 1 · 2016: 1 · 2015: 1 · 2014: 5 · 2013: 2
FWCI
2.99
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Neurobiology of Disease (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
NIH (HD62618, P30-NS06180, 8P51-OD011092)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
locus coeruleus, functional hypothalamic amenorrhea, stress resilience, stress sensitivity, tyrosine hydroxylase, norepinephrine, serotonin, corticotropin-releasing factor, excitotoxicity, ovarian estrogen, macaque model, psychosocial stress, metabolic stress, superior cerebellar peduncle
MeSH terms
Amenorrhea, Animals, Disease Models, Animal, Female, Immunohistochemistry, Locus Coeruleus, Macaca, Norepinephrine, Serotonin, Stress, Physiological, Stress, Psychological, Tyrosine 3-Monooxygenase

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