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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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Figures

Figure 1 Placement and extent of bilateral LS lesions. (a) Schematic drawing of a coronal section illustrating the dorsal, intermediate, and ventral part of the LS (left panel), and photomicrographs showing cresyl-stained coronal sections of a lesioned and sham-lesioned control animal (right panel). LS lesions reduced the number of cells in the LS. Neuronal cell degeneration and cell loss was found in all subregions of the LS. (b) Schematic coronal sections of the rat brain adapted from the atlas of (Paxinos and Watson, 1998) illustrating rostrocaudal extension of lesions in the LS. The largest (bright gray) and smallest (dark gray) lesions are plotted at different levels through the LS. ac, anterior commissure; cc, corpus callosum; LSd, lateral septum dorsal; LSi, lateral septum intermediate; LSv, lateral septum ventral.
Figure 1 Placement and extent of bilateral LS lesions. (a) Schematic drawing of a coronal section illustrating the dorsal, intermediate, and ventral part of the LS (left panel), and photomicrographs showing cresyl-stained coronal sections of a lesioned and sham-lesioned control animal (right panel). LS lesions reduced the number of cells in the LS. Neuronal cell degeneration and cell loss was found in all subregions of the LS. (b) Schematic coronal sections of the rat brain adapted from the atlas of (Paxinos and Watson, 1998) illustrating rostrocaudal extension of lesions in the LS. The largest (bright gray) and smallest (dark gray) lesions are plotted at different levels through the LS. ac, anterior commissure; cc, corpus callosum; LSd, lateral septum dorsal; LSi, lateral septum intermediate; LSv, lateral septum ventral.CC BY-NC-ND · PubMed Central
Figure 2 Schematic drawing and representative microphotographs of cresyl-stained coronal sections of the rat brain showing the localization of bilaterally implanted microinjection cannulae (left) and the active membrane tip of a microdialysis probe (right) within the LS. ac, anterior commissure; cc, corpus callosum; LV, lateral ventricle; MS, medial septum.
Figure 2 Schematic drawing and representative microphotographs of cresyl-stained coronal sections of the rat brain showing the localization of bilaterally implanted microinjection cannulae (left) and the active membrane tip of a microdialysis probe (right) within the LS. ac, anterior commissure; cc, corpus callosum; LV, lateral ventricle; MS, medial septum.CC BY-NC-ND · PubMed Central
Figure 3 Effects of LS lesions on HPA axis responses to forced swimming. (a) Plasma ACTH (left) and corticosterone (CORT, right panel) responses to forced swimming (FS; 5 min, 20°C, gray shaded bars). Swim stress caused a significant increase in plasma ACTH and corticosterone concentrations in both LS-lesioned and sham-lesioned animals. Compared with sham-lesioned animals, LS-lesioned animals showed a higher plasma ACTH and corticosterone levels during and after forced swimming but not under basal conditions. (b) Effects of LS lesions on swim stress-induced c-Fos expression in the mpPVN. Depicted are representative bright field photomicrographs (left panel) and c-Fos quantification presented as bar graphs (right panel) illustrating higher c-Fos expression in the mpPVN in lesioned animals compared with sham-lesioned controls. 3V, third ventricle; mPVN, magnocellular PVN; vPVN, ventral PVN; mpPVN, medial parvicellular PVN. Data expressed as means+SEM. *p<0.05, **p<0.01 vs basal value; #p<0.05, ##p<0.01 vs respective value in the sham-lesioned controls. ++p<0.001 vs sham-lesioned controls (Newman–Keuls post hoc test or Student's t-test).
Figure 3 Effects of LS lesions on HPA axis responses to forced swimming. (a) Plasma ACTH (left) and corticosterone (CORT, right panel) responses to forced swimming (FS; 5 min, 20°C, gray shaded bars). Swim stress caused a significant increase in plasma ACTH and corticosterone concentrations in both LS-lesioned and sham-lesioned animals. Compared with sham-lesioned animals, LS-lesioned animals showed a higher plasma ACTH and corticosterone levels during and after forced swimming but not under basal conditions. (b) Effects of LS lesions on swim stress-induced c-Fos expression in the mpPVN. Depicted are representative bright field photomicrographs (left panel) and c-Fos quantification presented as bar graphs (right panel) illustrating higher c-Fos expression in the mpPVN in lesioned animals compared with sham-lesioned controls. 3V, third ventricle; mPVN, magnocellular PVN; vPVN, ventral PVN; mpPVN, medial parvicellular PVN. Data expressed as means+SEM. *p<0.05, **p<0.01 vs basal value; #p<0.05, ##p<0.01 vs respective value in the sham-lesioned controls. ++p<0.001 vs sham-lesioned controls (Newman–Keuls post hoc test or Student's t-test).CC BY-NC-ND · PubMed Central
Figure 4 Effects of LS lesions on stress coping parameters during a 5-min forced swimming session as indicated by the time the animals spent struggling, swimming, and floating. Lesioned animals showed less active coping indicated by reduced time struggling and swimming and enhanced immobility (floating behavior) than sham-lesioned controls. Data are expressed as means+SEM. **p<0.001 vs sham-lesioned controls (Student's t-test).
Figure 4 Effects of LS lesions on stress coping parameters during a 5-min forced swimming session as indicated by the time the animals spent struggling, swimming, and floating. Lesioned animals showed less active coping indicated by reduced time struggling and swimming and enhanced immobility (floating behavior) than sham-lesioned controls. Data are expressed as means+SEM. **p<0.001 vs sham-lesioned controls (Student's t-test).CC BY-NC-ND · PubMed Central
Figure 5 Effects of intraseptal administration of the glucocorticoid receptor antagonist mifepristone (20 or 100 ng/side; black arrow) on neuroendocrine and behavioral stress response. Administration of mifepristone had no effect on either basal or stress-induced increase of plasma ACTH (a) or corticosterone (CORT, b) levels because there was no significant difference between mifepristone-treated animals and controls. (c) Mifepristone-injected animals showed an increased active coping style indicated by an enhancement of struggling and swimming and a reduction of floating behavior during the forced swim exposure. Data are expressed as means+SEM. **p<0.01 vs basal values; ++p<0.001 vs vehicle-treated controls (Newman–Keuls post hoc test or Student's t-test).
Figure 5 Effects of intraseptal administration of the glucocorticoid receptor antagonist mifepristone (20 or 100 ng/side; black arrow) on neuroendocrine and behavioral stress response. Administration of mifepristone had no effect on either basal or stress-induced increase of plasma ACTH (a) or corticosterone (CORT, b) levels because there was no significant difference between mifepristone-treated animals and controls. (c) Mifepristone-injected animals showed an increased active coping style indicated by an enhancement of struggling and swimming and a reduction of floating behavior during the forced swim exposure. Data are expressed as means+SEM. **p<0.01 vs basal values; ++p<0.001 vs vehicle-treated controls (Newman–Keuls post hoc test or Student's t-test).CC BY-NC-ND · PubMed Central
Figure 6 Effects of intraseptal administration of the 5-HT1A receptor agonist 8-OH-DPAT (10 μg/side; black arrow) on neuroendocrine and behavioral stress response. Plasma ACTH (a) and corticosterone (CORT, b) responses to forced swimming were significantly attenuated by the 8-OH-DPAT treatment. However, basal levels did not differ between groups. (c) Rats injected with 8-OH-DPAT showed an increased active coping style indicated by an enhanced time the animals spent struggling and swimming, and reduced floating behavior during the forced swim exposure. Data are expressed as means+SEM. *p<0.05, **p<0.01 vs basal; #p<0.05, ##p<0.01 vs respective value in the vehicle-treated controls; ++p<0.001 vs vehicle-treated controls (Newman–Keuls post hoc test or Student's t-test).
Figure 6 Effects of intraseptal administration of the 5-HT1A receptor agonist 8-OH-DPAT (10 μg/side; black arrow) on neuroendocrine and behavioral stress response. Plasma ACTH (a) and corticosterone (CORT, b) responses to forced swimming were significantly attenuated by the 8-OH-DPAT treatment. However, basal levels did not differ between groups. (c) Rats injected with 8-OH-DPAT showed an increased active coping style indicated by an enhanced time the animals spent struggling and swimming, and reduced floating behavior during the forced swim exposure. Data are expressed as means+SEM. *p<0.05, **p<0.01 vs basal; #p<0.05, ##p<0.01 vs respective value in the vehicle-treated controls; ++p<0.001 vs vehicle-treated controls (Newman–Keuls post hoc test or Student's t-test).CC BY-NC-ND · PubMed Central
Figure 7 Effects of intraseptal infusion of the 5-HT1A receptor antagonist WAY-100635 (10 μM) via retrodialysis (black bar) on basal and swim stress-induced ACTH (a) or corticosterone levels (CORT, b). Although basal ACTH and corticosterone levels did not differ between groups, the forced swim stress-induced ACTH and corticosterone levels were significantly higher in WAY-100635-treated animals compared with controls. Data are expressed as means+SEM. **p<0.01 vs basal values; ##p<0.01 vs vehicle-treated controls (Newman–Keuls post hoc test).
Figure 7 Effects of intraseptal infusion of the 5-HT1A receptor antagonist WAY-100635 (10 μM) via retrodialysis (black bar) on basal and swim stress-induced ACTH (a) or corticosterone levels (CORT, b). Although basal ACTH and corticosterone levels did not differ between groups, the forced swim stress-induced ACTH and corticosterone levels were significantly higher in WAY-100635-treated animals compared with controls. Data are expressed as means+SEM. **p<0.01 vs basal values; ##p<0.01 vs vehicle-treated controls (Newman–Keuls post hoc test).CC BY-NC-ND · PubMed Central

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Metadata

Authors
Singewald, G. M., Rjabokon, A., Singewald, N., & Ebner, K.
Affiliations
Universität Innsbruck (AT)
Corresponding author
Ebner, Karl
ORCID
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
Licence
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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