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Cited by 85Stress Responses and CortisolAdrenal Hormones and DisordersRegulation of Appetite and Obesity

Neuroendocrine Function After Hypothalamic Depletion of Glucocorticoid Receptors in Male and Female Mice

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Solomon, Matia B., Loftspring, Matthew, de Kloet, Annette D., Ghosal, Sriparna, Jankord, Ryan, Flak, Jonathan N., Wulsin, Aynara C., Krause, Eric G. +6 more·2015·Endocrinology
DOI 10.1210/en.2015-1276PMC PMC4511133
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Abstract

Glucocorticoids act rapidly at the paraventricular nucleus (PVN) to inhibit stress-excitatory neurons and limit excessive glucocorticoid secretion. The signaling mechanism underlying rapid feedback inhibition remains to be determined. The present study was designed to test the hypothesis that the canonical glucocorticoid receptors (GRs) is required for appropriate hypothalamic-pituitary-adrenal (HPA) axis regulation. Local PVN GR knockdown (KD) was achieved by breeding homozygous floxed GR mice with Sim1-cre recombinase transgenic mice. This genetic approach created mice with a KD of GR primarily confined to hypothalamic cell groups, including the PVN, sparing GR expression in other HPA axis limbic regulatory regions, and the pituitary. There were no differences in circadian nadir and peak corticosterone concentrations between male PVN GR KD mice and male littermate controls. However, reduction of PVN GR increased ACTH and corticosterone responses to acute, but not chronic stress, indicating that PVN GR is critical for limiting neuroendocrine responses to acute stress in males. Loss of PVN GR induced an opposite neuroendocrine phenotype in females, characterized by increased circadian nadir corticosterone levels and suppressed ACTH responses to acute restraint stress, without a concomitant change in corticosterone responses under acute or chronic stress conditions. PVN GR deletion had no effect on depression-like behavior in either sex in the forced swim test. Overall, these findings reveal pronounced sex differences in the PVN GR dependence of acute stress feedback regulation of HPA axis function. In addition, these data further indicate that glucocorticoid control of HPA axis responses after chronic stress operates via a PVN-independent mechanism.

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  • GR negative feedback occurs predominantly at the hypothalamus.

    “indicating that GR negative feedback occurred predominantly at the hypothalamus.”

    From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as Solomon et al., 2015

    The Abstract (page unavailable) reports that hypothalamic PVN glucocorticoid receptors help limit acute stress responses in male mice. It does not establish that GR negative feedback occurs predominantly at the hypothalamus across conditions: the Abstract also reports sex differences and a PVN-independent mechanism after chronic stress. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • In transgenic mice with reduced GR targeted to the PVN, ACTH and CORT levels increase after acute but not chronic stress.

    “Solomon et al. (2015) reported that in a transgenic mouse model, where reductions in the levels of GR were targeted to the PVN, there were corresponding increases in ACTH and CORT levels after acute but not chronic stress”

    From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as Solomon et al., 2015

    The Abstract and Results report increased ACTH and corticosterone responses to acute stress in male PVN GR knockdown mice, but not increased corticosterone responses after chronic stress exposure. The claim omits the sex restriction: the Results report decreased acute-stress ACTH in females and no corresponding increase in corticosterone. The chronic-stress Results report corticosterone, not ACTH, for that comparison. (LLM, conf=0.91)

    Experimental — accuracy not yet measured

  • PVN GR directly mediates negative feedback.

    “thus supporting the hypothesis that PVN GR directly mediates negative feedback.”

    From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as Solomon et al., 2015

    The Abstract reports that reducing PVN GR impairs feedback regulation of acute stress responses in male mice, supporting the hypothesis in that setting. It also reports different effects in females and PVN-independent regulation after chronic stress, so the unqualified claim is broader than the findings. The Discussion describes GR knockdown rather than a complete, exclusively PVN-specific deletion. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Reduction of GR in the PVN increases the diurnal CORT nadir.

    “The same reduction in GR in the PVN increased the levels of the diurnal CORT nadir”

    From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as Solomon et al., 2015

    The Results report that PVN GR knockdown significantly increased circadian corticosterone nadir concentrations in female mice. The same section reports no nadir difference in male mice, so the claim omits an important sex-specific qualifier. Page numbers are not provided in our copy's passages. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • In transgenic female mice with reduced PVN GR, responses to acute and chronic stress-induced ACTH are suppressed.

    “Further, there were suppressed responses to acute and chronic stress-induced ACTH in the transgenic female mice (Solomon et al., 2015)”

    From Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity (2017) · cites this paper as Solomon et al., 2015

    The Results report significantly less ACTH in female PVN GR knockdown mice after acute restraint stress. They do not report suppressed ACTH responses after chronic stress; the chronic-stress Results instead report no genotype-specific difference in corticosterone responses. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

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Research works printed but not linked: 1

  1. [30]30. McClave JTaD, Dietrich FH., II Statistics. 6th ed New York, NY: Dellen-MacMillan; 1994. [Google Scholar]

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Authors
Solomon, M. B., Loftspring, M., de Kloet, A. D., Ghosal, S., Jankord, R., Flak, J. N., Wulsin, A. C., Krause, E. G., Zhang, R., Rice, T., McKlveen, J., Myers, B., Tasker, J. G., & Herman, J. P.
Affiliations
Tulane University (US)
Corresponding author
Solomon, Matia B.
ORCID
Venue
Endocrinology
Publisher
The Endocrine Society
Published
2015-08-01
Volume
156
Issue
8
Pages
2843-2853
ISSN
  • 0013-7227 (ISSN-L)
  • 1945-7170
DOI
10.1210/en.2015-1276
PMC
PMC4511133
OpenAlex
W1894445452
Cited by
85
References
48
Citations by year
2026: 4 · 2025: 6 · 2024: 6 · 2023: 6 · 2022: 5 · 2021: 7 · 2020: 9 · 2019: 10 · 2018: 9 · 2017: 11 · 2016: 7 · 2015: 5
FWCI
5.55
Type
journal article
Language
en
Open access
Locations
  • Endocrinology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • University of Minnesota
  • National Institute of Mental Health (MH066958, R01MH066958, R01MH049698, MH 069725, MH069860, R01MH069860, MH049698, R01MH069725)
  • National Institute of General Medical Sciences (T32GM063483)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK034933, T32DK094775)
  • National Institute of Neurological Disorders and Stroke (F30NS095578)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD051953)
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Keywords
glucocorticoid receptor, paraventricular nucleus, hypothalamic-pituitary-adrenal axis, acute stress, corticosterone, ACTH, sex differences, chronic stress, depression-like behavior, neuroendocrine function
MeSH terms
Animals, Circadian Rhythm, Female, Hypothalamo-Hypophyseal System, Hypothalamus, Male, Mice, Inbred C57BL, Neurosecretory Systems, Pituitary-Adrenal System, Receptors, Glucocorticoid, Stress, Psychological, Gene Deletion, Mice, Knockout, Feedback, Physiological, Mice, Gene Knockdown Techniques

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