Norepinephrine Neurons in the Nucleus of the Solitary Tract Suppress Luteinizing Hormone Secretion in Female Mice
Open accessAbstract
Stress impairs fertility, at least in part, via inhibition of gonadotropin secretion. Luteinizing hormone (LH) is an important gonadotropin that is released in a pulsatile pattern in males and in females throughout the majority of the ovarian cycle. Several models of stress, including acute metabolic stress, suppress LH pulses via inhibition of neurons in the arcuate nucleus of the hypothalamus that coexpress kisspeptin, neurokinin B, and dynorphin (termed KNDy cells) which form the pulse generator. The mechanism for inhibition of KNDy neurons during stress, however, remains a significant outstanding question. Here, we investigated a population of catecholamine neurons in the nucleus of the solitary tract (NTS), marked by expression of the enzyme dopamine beta-hydroxylase (DBH), in female mice. First, we found that a subpopulation of DBH neurons in the NTS is activated (express c-Fos) during metabolic stress. Then, using chemogenetics, we determined that activation of these cells is sufficient to suppress LH pulses, augment corticosterone secretion, and induce sickness-like behavior. In subsequent studies, we identified evidence for suppression of KNDy cells (rather than downstream signaling pathways) and determined that the suppression of LH pulses was not dependent on the acute rise in glucocorticoids. Together these data support the hypothesis that DBH cells in the NTS are important for regulation of neuroendocrine and behavioral responses to stress.
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Acute metabolic stress or chemogenetic activation of A2 neurons evokes sickness behavior associated with a reduction in pulsatile LH secretion that is thought to occur indirectly through paraventricular nucleus corticotrophin-releasing hormone neurons.
“For example, acute metabolic stress or the chemogenetic activation of A2 neurons evokes sickness behavior associated with a reduction in the pulsatile LH secretion that is thought to occur indirectly through paraventricular nucleus corticotrophin-releasing hormone neurons16,57,58.”
From Brainstem noradrenergic modulation of the kisspeptin neuron GnRH pulse generator in mice (2025) · cites this paper as [58]
Cites
Definition of the hypothalamic GnRH pulse generator in mice
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The Gonadotropin-Releasing Hormone Pulse Generator
Herbison, A. E. (2018) · Endocrinology · doi:10.1210/en.2018-00653 · Cited by 261 · see citing works
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Self-citationLuo, E., Stephens, S. B. Z., Chaing, S., Munaganuru, N., Kauffman, A. S., & Breen, K. M. (2016) · Endocrinology · doi:10.1210/en.2015-1711 · Cited by 83 · see citing works
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Neural and endocrine mechanisms underlying stress-induced suppression of pulsatile LH secretion
McCosh, R. B., Breen, K. M., & Kauffman, A. S. (2019) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2019.110579 · Cited by 65 · see citing works
Self-citationKreisman, M. J., McCosh, R. B., Tian, K., Song, C. I., & Breen, K. M. (2020) · Neuroendocrinology · doi:10.1159/000502978 · Cited by 42 · see citing works
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Flowers, J. C., Vetter, P. E., Wiles, M. J., Roh, S. H., Black, E. R., Bouckova, E., Wustrau, M. H., Lee, R., Lee, S.-H., & Kim, S. (2025) · The FASEB Journal · doi:10.1096/fj.202501763r · Cited by 9 · see citing works
“Corticosterone levels in mice were measured as described previously [71, 72].”
Brainstem noradrenergic modulation of the kisspeptin neuron GnRH pulse generator in mice
Vas, S., Morris, P. G., Gul, Z., Ruiz-Cruz, M., Han, S. Y., & Herbison, A. E. (2025) · Nature Communications · doi:10.1038/s41467-025-60837-8 · Cited by 7 · see citing works
Suppression of Luteinizing Hormone Secretion in Female Mice by a Urocortin 2–CRHR2 Signaling Pathway
McCosh, R., Bell, H. F., Kreisman, M. J., Tian, K., & Breen, K. M. (2025) · Endocrinology · doi:10.1210/endocr/bqaf042 · Cited by 4 · see citing works
“We recently demonstrated that chemogenetic activation of NTS DBH cells is sufficient to rapidly suppress LH pulses in OVX mice (15).”
InfluentialSelf-citationBehavioral impact of chemogenetic manipulations of 5-HT DRN neurons in transgenic Tph2-iCre rats
McCloskey, N. S., Li, C., & Kirby, L. G. (2025) · Psychopharmacology · doi:10.1007/s00213-025-06947-z · Cited by 1 · see citing works
“While there is no standardized threshold for the count of labeled cells that indicates successful viral expression, a few precedents in the chemogenetics literature can guide establishment of a cutoff: Aery Jones, et al. (2021) excluded an animal for having fewer than 50 mCherry + cells; McCosh et al. (2024); excluded…”
Maciejewska, N., Gower, R. M., Grillo, C., Tasker, J., Reagan, L. P., & dos-Santos, R. (2026) · Brain, behavior, and immunity · doi:10.1016/j.bbi.2026.107085
Intracerebroventricular injection of neuropeptide Y suppresses luteinizing hormone pulses in mice
Young, L. A., Hurtado, E. R., Jacobs, K. D., Lee, Z. M. M., Nestor, C. C., & McCosh, R. B. (2026) · Journal of Neuroendocrinology · doi:10.1111/jne.70265
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- Authors
- McCosh, R. B., Kreisman, M. J., Tian, K., Thomas, S. A., & Breen, K. M.
- Affiliations
- University of California San Diego (US)
- University of Pennsylvania (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2024-07-22
- Volume
- 44
- Issue
- 34
- Pages
- e0084242024
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC11340281
- OpenAlex
- W4400878236
- Cited by
- 8
- References
- 0
- Citations by year
- 2026: 3 · 2025: 5
- FWCI
- 3.14
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
- Funders
- HHS | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD103725, R21HD105103, P50HD012303, K99/R00HD104994, F32HD096811, T32HD007203)
- 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
- noradrenergic neurons, nucleus tractus solitarius, luteinizing hormone secretion, LH pulsatility, metabolic stress, dopamine beta-hydroxylase, KNDy neurons, kisspeptin, neurokinin B, dynorphin, corticosterone, sickness behavior, female mice, chemogenetics
- MeSH terms
- Animals, Corticosterone, Dopamine beta-Hydroxylase, Female, Luteinizing Hormone, Mice, Inbred C57BL, Mice, Transgenic, Norepinephrine, Stress, Physiological, Neurokinin B, Proto-Oncogene Proteins c-fos, Solitary Nucleus, Mice, Adrenergic Neurons, Kisspeptins
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