Cited by 149Stress Responses and CortisolNeuropeptides and Animal PhysiologyNeurotransmitter Receptor Influence on Behavior

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The Modulatory Role of the Lateral Septum on Neuroendocrine and Behavioral Stress Responses

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Singewald, Georg M, Rjabokon, Alesja, Singewald, Nicolas, Ebner, Karl·2011·Neuropsychopharmacology

DOI 10.1038/npp.2010.213PMC PMC3055728

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Abstract

The lateral septum (LS) has been shown to have a key role in emotional processes and stress responses. However, the exact role of the LS on stress modulation is not clear, as previous lesion studies mostly used electrolytic lesions, thereby destroying the whole septal area, including medial components and/or fibers of passage. The aim of the present study was therefore, to investigate the effects of selective excitotoxic ablation of the LS on neuroendocrine and behavioral stress responses in rats. Bilateral ibotenic acid lesions of the LS increased hypothalamo-pituitary-adrenocortical (HPA) axis responses to forced swim stress indicated by enhanced plasma ACTH and corticosterone responses and higher stress-induced c-Fos-like immunoreactivity in the paraventricular hypothalamic nucleus. Moreover, LS-lesioned animals showed a more passive coping style in the forced swim test indicated by increased floating and reduced struggling/swimming behavior compared with sham-lesioned controls. Interestingly, intraseptal corticosteroid receptor blockade modulated behavioral stress coping but failed to change HPA axis stress responses. Further experiments aimed at elucidating underlying neurochemical mechanisms revealed that intraseptal administration of the selective 5-HT(1A) receptor antagonist WAY-100635 increased and prolonged stress-induced ACTH and corticosterone levels mimicking lesion effects, while the agonist 8-OH-DPAT suppressed HPA axis activity facilitating the inhibitory role of the LS. In addition, 8-OH-DPAT-injected animals showed increased active and decreased passive coping strategies during forced swimming suggesting antidepressant efficacy. Taken together, our data suggest that the LS promotes active stress coping behavior and is involved in a HPA-inhibitory mechanism that is at least in part mediated by septal 5-HT(1A) receptors and does not involve a glucocorticoid mediated feedback mechanism.

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Background
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“This is interesting in light of the documented role of the LS in regulating behavioral despair (43).”
Background
Activation of septal OXTr neurons induces anxiety- but not depressive-like behaviors
Huang, T., Guan, F., Licinio, J., Wong, M., & Yang, Y. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01283-y · Cited by 28
Changes in c-Fos Expression in the Forced Swimming Test: Common and Distinct Modulation in Rat Brain by Desipramine and Citalopram
Choi, S. H., Chung, S., Cho, J. H., Cho, Y. H., Kim, J. W., Kim, J., Kim, H. J., Kim, H. J., & Shin, K. H. (2013) · Korean Journal of Physiology and Pharmacology · doi:10.4196/kjpp.2013.17.4.321 · Cited by 27
Dorsolateral septum GLP-1R neurons regulate feeding via lateral hypothalamic projections
Lu, Y., Wang, L., Luo, F., Savani, R. H., Rossi, M. A., & Pang, Z. P. (2024) · Molecular Metabolism · doi:10.1016/j.molmet.2024.101960 · Cited by 26
The stress-inducible actin-interacting protein DRR1 shapes social behavior
Masana, M., Su, Y., Liebl, C., Wang, X., Jansen, L., Westerholz, S., Wagner, K. V., Labermaier, C., Scharf, S. H., Santarelli, S., et al. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.06.009 · Cited by 27
Pattern of c-Fos expression induced by tail suspension test in the mouse brain
Hiraoka, K., Motomura, K., Yanagida, S., Ohashi, A., Ishisaka-Furuno, N., & Kanba, S. (2017) · Heliyon · doi:10.1016/j.heliyon.2017.e00316 · Cited by 26
“Moreover, lesioning the lateral septum extends the immobility time [36, 37] and increases the response of the hypothalamic–pituitary–adrenal axis in the forced swim test in rats [37].”
Background
A circuit of COCH neurons encodes social-stress-induced anxiety via MTF1 activation of Cacna1h
Jing, W., Zhang, T., Liu, J., Huang, X., Yu, Q., Yu, H., Zhang, Q., Li, H., Deng, M., Zhu, L., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.110177 · Cited by 25
Region-specific up-regulation of oxytocin receptor binding in the brain of mice following chronic nicotine administration
Zanos, P., Georgiou, P., Metaxas, A., Kitchen, I., Winsky‐Sommerer, R., & Bailey, A. (2015) · Neuroscience Letters · doi:10.1016/j.neulet.2015.05.054 · Cited by 23
“All statistical analyses were performed using Statistica 8.0 (Statsoft Inc., France).”
MethodInfluential
Inhibition in the lateral septum increases sucrose intake and decreases anorectic effects of stress
Mitra, A., Lenglos, C., & Timofeeva, E. (2014) · European Journal of Neuroscience · doi:10.1111/ejn.12798 · Cited by 23
“In addition, LS neurons are sensitive to stress and can modulate the activity of the hypothalamic–pituitary–adrenal (HPA) axis (Martin & Timofeeva, 2010; Singewald et al., 2011; Anthony et al., 2014).”
Background
The role of the lateral septum in neuropsychiatric disease
Patel, H. (2022) · Journal of Neuroscience Research · doi:10.1002/jnr.25052 · Cited by 28
Perfluorooctanesulfonic acid exposure altered hypothalamic metabolism and disturbed male fecundity
Li, Z., Lin, Z., Ji, S., Lai, K. P., Wan, H., Wong, C. K. C., & Li, L. (2022) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2022.156881 · Cited by 23
Antidepressant-like effects of mineralocorticoid but not glucocorticoid antagonists in the lateral septum: Interactions with the serotonergic system
Mostalac-Preciado, C. R., de Gortari, P., & López‐Rubalcava, C. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.04.008 · Cited by 23
Neurobiology of Wild and Hatchery-Reared Atlantic Salmon: How Nurture Drives Neuroplasticity
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Enhanced Responsiveness to Selective Serotonin Reuptake Inhibitors during Lactation
Jury, N. J., McCormick, B. A., Horseman, N. D., Benoit, S. C., & Gregerson, K. A. (2015) · PLoS ONE · doi:10.1371/journal.pone.0117339 · Cited by 23
“Both the amygdala and the lateral septum are key components in the brain’s emotional circuitry that modulates affective behavior and stress responses [65,66].”
Background
Glutamic acid decarboxylase 65 and 67 expression in the lateral septum is up-regulated in association with the postpartum period in mice
Zhao, C., Driessen, T. M., & Gammie, S. C. (2012) · Brain Research · doi:10.1016/j.brainres.2012.06.002 · Cited by 22
“LS is a core brain region linked to emotional state (e.g., anxiety, fear and depression) and stress reactivity (Sheehan et al., 2004; Singewald et al., 2011).”
Regional distribution of cholinergic, catecholaminergic, serotonergic and orexinergic neurons in the brain of two carnivore species: The feliform banded mongoose ( Mungos mungo ) and the caniform domestic ferret ( Mustela putorius furo )
Pillay, S., Bhagwandin, A., Bertelsen, M. F., Patzke, N., Engler, G., Engel, A. K., & Manger, P. R. (2017) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2017.04.001 · Cited by 21
“The lateral septal nucleus is thought to be involved in active coping strategies during exposure to stress, by promoting a hypothalamo-pituitary-adrenocortical axis neuroendocrine inhibitory mechanism (Singewald et al., 2011).”
Reelin deficiency contributes to long-term behavioral abnormalities induced by chronic adolescent exposure to Δ9-tetrahydrocannabinol in mice
Iemolo, A., Montilla‐Perez, P., Nguyen, J. D., Risbrough, V. B., Taffe, M. A., & Telese, F. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2021.108495 · Cited by 18
PACAP regulates neuroendocrine and behavioral stress responses via CRF-containing neurons of the rat hypothalamic paraventricular nucleus
Ebner, K., Fontebasso, V., Ferro, F., Singewald, N., & Hannibal, J. (2024) · Neuropsychopharmacology · doi:10.1038/s41386-024-02016-9 · Cited by 20
“All surgical procedures were performed under sterile conditions as previously described [52, 53].”
Activation of Somatostatin-Expressing Neurons in the Lateral Septum Improves Stress-Induced Depressive-like Behaviors in Mice
Li, H., Sung, H. H., & Lau, C. G. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14102253 · Cited by 18
“The LS has been implicated in stress responses [57].”
Background
Effect of acute imipramine administration on the pattern of forced swim-induced c-Fos expression in the mouse brain
Yanagida, S., Motomura, K., Ohashi, A., Hiraoka, K., Miura, T., & Kanba, S. (2016) · Neuroscience Letters · doi:10.1016/j.neulet.2016.06.059 · Cited by 20
Inhibitory Function of the Dorsomedial Hypothalamic Nucleus on the Hypothalamic–Pituitary–Adrenal Axis Response to an Emotional Stressor but not Immune Challenge
Ebner, K., Muigg, P., & Singewald, N. (2013) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2012.02369.x · Cited by 18
High fat diet blunts stress-induced hypophagia and activation of Glp1r dorsal lateral septum neurons in male but not in female mice
Bales, M. B., Centanni, S. W., Luchsinger, J. R., Fathi, P. A., Biddinger, J. E., Le, T. D. V., Nwaba, K. G., Paldrmic, I. M., Winder, D. G., & Ayala, J. E. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101571 · Cited by 19
“…suggest that obese individuals are more susceptible to the negative effects of stress, such as depression, which can lead to a deleterious feed-forward cycle of “comfort feeding” (Slochower et al., 1981; Boggiano et al., 2015; Laitinen et al., 2002; Barrington et al., 2014, Coulthard et al., 2021).”
Background
Re-evaluation of Adrenocorticotropic Hormone and Melanocyte Stimulating Hormone Activation of GPR139 in Vitro
Nepomuceno, D. H., Kuei, C., Dvorak, C. A., Lovenberg, T. W., Liu, C., & Bonaventure, P. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00157 · Cited by 18
“Neurons from the lateral septum have been shown to modulate neuroendocrine and behavioral stress response (Singewald et al., 2011).”
Background
In vivo Characterization of a Selective, Orally Available, and Brain Penetrant Small Molecule GPR139 Agonist
Shoblock, J. R., Welty, N., Fraser, I. C., Wyatt, R. M., Lord, B., Lovenberg, T. W., Liu, C., & Bonaventure, P. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00273 · Cited by 18
Distinct patterns of brain Fos expression in Carioca High- and Low-conditioned Freezing Rats
León, L. A., Brandão, M. L., Cárdenas, F. P., Parra, D., Krahe, T. E., Cruz, A. P. D. M., & Landeira-Fernández, J. (2020) · PLoS ONE · doi:10.1371/journal.pone.0236039 · Cited by 18
“Excitotoxic lesions of the LS increased ACTH and corticosterone levels and Fos expression in the PVN in rats that were exposed to the forced swim test [58], suggesting that the LS might play an inhibitory role in the HPA axis response.”
Background
Epigenetics of amphetamine-induced sensitization: HDAC5 expression and microRNA in neural remodeling
Liu, P. K., & Liu, C. H. (2016) · Journal of Biomedical Science · doi:10.1186/s12929-016-0294-8 · Cited by 19
Functional Neuroimaging of Human Hypothalamus in Socioemotional Behavior: A Systematic Review
Carìa, A., & Dall‘O’, G. M. (2022) · Brain Sciences · doi:10.3390/brainsci12060707 · Cited by 20
“Though, a positive coupling between the septo-hypothalamic area was associated with less cortisol reactivity during distressed conditions [58], indicating that hypothalamus–septal interactions might mediate down-regulation of stress-related cortisol reactivity [80] so as to appropriately tune parental behavior [81].”
Background
Elucidation of the neural circuits activated by a GABAB receptor positive modulator: Relevance to anxiety
Pizzo, R., O’Leary, O. F., & Cryan, J. F. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.07.021 · Cited by 19
Lateral septum mu opioid receptors in stimulation of feeding
Calderwood, M. T., Tseng, A., & Stanley, B. G. (2020) · Brain Research · doi:10.1016/j.brainres.2020.146648 · Cited by 19
Cellular and serotonergic correlates of habituated neuroendocrine responses in male and female rats.
Goel, N., Philippe, T. J., Chang, J., Koblanski, M. E., & Viau, V. (2021) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2021.105599 · Cited by 17
Systems Genetics of the Lateral Septal Nucleus in Mouse: Heritability, Genetic Control, and Covariation with Behavioral and Morphological Traits
Talishinsky, A., & Rosen, G. D. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044236 · Cited by 17
“In contrast, the lateral septum has strong projections to hypothalamic and midbrain regions, and has been associated with the modulation of social behavior [3], anxiety as assessed by lateral plus maze or a forced swim test [4–6], the expression of contextual fear”
Background
Characterization of Social Hierarchy Formation and Maintenance in Same-Sex, Group-Housed Male and Female C57BL/6J Mice
Fulenwider, H. D., Zhang, Y., & Ryabinin, A. E. (2023) · Hormones and Behavior · doi:10.1016/j.yhbeh.2023.105452 · Cited by 15
Regional specific modulation of neuronal activation associated with nitric oxide synthase inhibitors in an animal model of antidepressant activity
Sherwin, E., Gigliucci, V., & Harkin, A. (2016) · Behavioural Brain Research · doi:10.1016/j.bbr.2016.08.049 · Cited by 16
The unique expression profile of FAM19A1 in the mouse brain and its association with hyperactivity, long-term memory and fear acquisition
Yong, H. J., Ha, N., Cho, E. B., Yun, S., Kim, H., Hwang, J., & Seong, J. Y. (2020) · Scientific Reports · doi:10.1038/s41598-020-60266-1 · Cited by 15
Co-transmitting neurons in the lateral septal nucleus exhibit features of neurotransmitter switching
Hunt, P. J., Kochukov, M. Y., Pekarek, B. T., Belfort, B. D. W., Romero, J. M., Swanson, J., & Arenkiel, B. R. (2022) · IBRO Neuroscience Reports · doi:10.1016/j.ibneur.2022.05.003 · Cited by 15
Corticotropin-Releasing Factor Receptor 1 in the Anterior Cingulate Cortex Mediates Maternal Absence-Induced Attenuation of Transport Response in Mouse Pups
Yoshida, S., Ohnishi, R., Tsuneoka, Y., Yuka, Y.-M., Muramatsu, R., Kato, T., Funato, H., & Kuroda, K. O. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00204 · Cited by 14
“LSI receives massive inputs from hippocampal formation, sends bidirectional projections with the preoptic and hypothalamic areas, and has been consistently found to be involved in stress responses (Risold, 2004; Singewald et al., 2011; Nishi et al., 2013).”
Background
Persistent Inequality: A Neurosociological Perspective
Davis, J. (2012) · Handbooks of sociology and social research · doi:10.1007/978-94-007-4473-8_21 · Cited by 14
Novel Antidepressant-Like Properties of the Iron Chelator Deferiprone in a Mouse Model of Depression
Uzungil, V., Tran, H., Aitken, C. M., Wilson, C., Opazo, C., Li, S., Payet, J. M., Mawal, C., Bush, A. I., Hale, M. W., et al. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01257-0 · Cited by 15
“Lesions to the lateral septum have been shown to increase immobility time in the PST indicating a link between the function of this region and behavioural response [92].”
Background
Activation of GABAA and GABAB receptors in the lateral septum increases sucrose intake by differential stimulation of sucrose licking activity
Mitra, A., Lenglos, C., & Timofeeva, E. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.07.035 · Cited by 13
mGlu2/3 receptors within the ventral part of the lateral septal nuclei modulate stress resilience and vulnerability in mice
Wang, Y., Jiang, Y., Song, B.-L., Zou, H.-W., Li, Z.-L., Li, L., & Liu, Y.-J. (2022) · Brain Research · doi:10.1016/j.brainres.2022.147783 · Cited by 13
A double-hit model of stress dysregulation in rats: implications for limbic corticosteroid receptors and anxious behavior under amitriptyline treatment
Cotella, E. M., Durando, P. E., & Suárez, M. M. (2014) · Stress · doi:10.3109/10253890.2014.910649 · Cited by 12
Chronic baclofen desensitizes GABAB-mediated G-protein activation and stimulates phosphorylation of kinases in mesocorticolimbic rat brain
Keegan, B. M., Beveridge, T. J. R., Pezor, J. J., Xiao, R., Sexton, T., Childers, S. R., & Howlett, A. C. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.02.021 · Cited by 11
Influence of chronic stress on the mechanism of the cytotoxic system in common carp (Cyprinuscarpio)
Shimon‐Hophy, M., & Avtalion, R. R. (2021) · Immunology · doi:10.1111/imm.13345 · Cited by 11
Remote CB1 receptor antagonist administration reveals multiple sites of tonic and phasic endocannabinoid neuroendocrine regulation
Newsom, R. J., Garcia, R. J., Stafford, J., Osterlund, C., O’Neill, C. E., Day, H. E. W., & Campeau, S. (2019) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2019.104549 · Cited by 11
“CB1R signaling in these regions may not only contribute to acute neuroendocrine reactivity to stress, but also regulation of behavioral (Crestani et al., 2013; Singewald et al., 2011), and sympathetic reactivity (Gomes-de-Souza et al.”
Background

Authors: Singewald, G. M., Rjabokon, A., Singewald, N., & Ebner, K.
Affiliations: Universität Innsbruck (AT)
Corresponding author: Ebner, Karl
ORCID: Singewald, Nicolas
Ebner, Karl
Venue: Neuropsychopharmacology
Publisher: Springer Science and Business Media LLC
Published: 2010-12-15
Volume: 36
Issue: 4
Pages: 793-804
ISSN: 0893-133X (ISSN-L)
1740-634X
DOI: 10.1038/npp.2010.213
PMC: PMC3055728
OpenAlex: W1987515936
Cited by: 149
References: 84
Citations by year: 2026: 5 · 2025: 7 · 2024: 9 · 2023: 4 · 2022: 17 · 2021: 9 · 2020: 10 · 2019: 12 · 2018: 9 · 2017: 11 · 2016: 8 · 2015: 9 · 2014: 16 · 2013: 6 · 2012: 10
FWCI: 3.03
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
www.springer.com/tdm (unspecified)
Locations: Neuropsychopharmacology (publishedVersion, cc-by-nc-nd)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
HAL (submittedVersion, other-oa)
Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
Funders: Austrian Science Fund
Topics: Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords: lateral septum, stress response, hypothalamic-pituitary-adrenal axis, forced swim test, passive coping, active coping, ACTH, corticosterone, paraventricular nucleus, c-fos, 5-HT1A receptor, 8-OH-DPAT, WAY-100635, excitotoxic lesions, antidepressant efficacy, glucocorticoid feedback
MeSH terms: Adaptation, Psychological, Adrenocorticotropic Hormone, Animals, Corticosterone, Male, Neurosecretory Systems, Stress, Psychological, Rats, Sprague-Dawley, Septum of Brain, Rats

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The Modulatory Role of the Lateral Septum on Neuroendocrine and Behavioral Stress Responses

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