Regulation of affect by the lateral septum: implications for neuropsychiatry

Sheehan, Teige P; Chambers, R.Andrew; Russell, David S

doi:10.1016/j.brainresrev.2004.04.009

Cited by 514Neurotransmitter Receptor Influence on BehaviorMemory and Neural MechanismsNeuroscience and Neuropharmacology Research

Regulation of affect by the lateral septum: implications for neuropsychiatry

Sheehan, Teige P, Chambers, R.Andrew, Russell, David S·2004·Brain Research Reviews

DOI 10.1016/j.brainresrev.2004.04.009

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Abstract

Substantial evidence indicates that the lateral septum (LS) plays a critical role in regulating processes related to mood and motivation. This review presents findings from the basic neuroscience literature and from some clinically oriented research, drawing from behavioral, neuroanatomical, electrophysiological, and molecular studies in support of such a role, and articulates models and hypotheses intended to advance our understanding of these functions. Neuroanatomically, the LS is connected with numerous regions known to regulate affect, such as the hippocampus, amygdala, and hypothalamus. Through its connections with the mesocorticolimbic dopamine system, the LS regulates motivation, both by stimulating the activity of midbrain dopamine neurons and regulating the consequences of this activity on the ventral striatum. Evidence that LS function could impact processes related to schizophrenia and other psychotic spectrum disorders, such as alterations in LS function following administration of antipsychotics and psychotomimetics in animals, will also be presented. The LS can also diminish or enable fear responding when its neural activity is stimulated or inhibited, respectively, perhaps through its projections to the hypothalamus. It also regulates behavioral manifestations of depression, with antidepressants stimulating the activity of LS neurons, and depression-like phenotypes corresponding to blunted activity of LS neurons; serotonin likely plays a key role in modulating these functions by influencing the responsiveness of the LS to hippocampal input. In conclusion, a better understanding of the LS may provide important and useful information in the pursuit of better treatments for a wide range of psychiatric conditions typified by disregulation of affective functions.

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The lateral septum serves as a hub in the brain by integrating social, emotional, and contextual information from different brain systems and contributing to the coordination of adaptive context-specific behavioral responses.
“this area serves as a hub in the brain by integrating social, emotional, and contextual information from different brain systems and contributing to the coordination of adaptive context-specific behavioral responses (Sheehan et al., 2004; Luo et al., 2011)”
From Sex-specific modulation of juvenile social play behavior by vasopressin and oxytocin depends on social context (2014) · cites this paper as Sheehan et al., 2004
The lateral septum plays a key role in modulating context-specific motivational states.
“and the lateral septum plays a key role in modulating context-specific motivational states (Sheehan et al., 2004; Luo et al., 2011; Sartor and Aston-Jones, 2012).”
From Sex-specific modulation of juvenile social play behavior by vasopressin and oxytocin depends on social context (2014) · cites this paper as Sheehan et al., 2004
A possible circuit could comprise the hippocampus transmitting contextual information onto the lateral septum which, in turn, relays this information onto areas such as the lateral hypothalamus and the ventral tegmental area to modulate behavioral responses appropriate to particular environmental stimuli.
“A possible circuit could comprise the hippocampus transmitting contextual information onto the lateral septum which, in turn, relays this information onto areas such as the lateral hypothalamus and the ventral tegmental area to modulate behavioral responses appropriate to particular environmental stimuli (Sheehan et al., 2004).”
From Sex-specific modulation of juvenile social play behavior by vasopressin and oxytocin depends on social context (2014) · cites this paper as Sheehan et al., 2004
GABA-A receptor activation presumably will result in decreased LS neuronal output while GABA-A receptor blockade will allow for increased LS output.
“GABA-A receptor activation presumably will result in decreased LS neuronal output while GABA-A receptor blockade will allow for increased LS output (Sheehan et al., 2004).”
From Vasopressin regulates social play behavior in sex-specific ways through glutamate modulation in the lateral septum (2025) · cites this paper as Sheehan et al., 2004
Lesions of other play-associated brain regions also impair locomotor behavior, sensory processing, etc., making it difficult to parse out the specific impact of each region on play itself.
“Following this trend, lesions of other play-associated brain regions also impair locomotor behavior, sensory processing, etc. (Neill et al., 1974; Sheehan et al., 2004; DiBenedictis et al., 2013) making it difficult to parse out the specific impact of each region on play itself.”
From Developmental origins of sex differences in the neural circuitry of play (2020) · cites this paper as Sheehan et al., 2004

The effects of dopamine and norepinephrine in the lateral septum are dependent on additional inputs to the lateral septum.
“Therefore, it is likely known that the effects of DA and NE in the LS are dependent on additional inputs to the LS [19].”
From Involvement of dopamine, but not norepinephrine, in the sex-specific regulation of juvenile socially rewarding behavior by vasopressin (2018) · cites this paper as [19]
Early expression of maternal behavior in virgin rodents correlates with OTR density in the NAC shell, lateral septum, and parts of the extended amygdala.
“Early expression of maternal behavior in virgin rodents is correlated with OTR density in the NAC shell, the lateral septum (LS) and parts of the extended amygdala, all regions implicated in pair bonding and in the regulation of motivated behaviors (Champagne et al 2001; Sheehan et al 2004; Olazabal and Young 2006b; Modi and Young 2011).”
From The behavioral, anatomical and pharmacological parallels between social attachment, love and addiction (2012) · cites this paper as Sheehan et al 2004
A variety of stressors induce immediate early gene (IEG) expression in subsets of LS neurons.
“A variety of stressors induce immediate early gene (IEG) expression in subsets of LS neurons (reviewed in (Sheehan et al., 2004)).”
From Control of Stress-Induced Persistent Anxiety by an Extra-Amygdala Septohypothalamic Circuit (2014) · cites this paper as Sheehan et al., 2004
LS output does not serve exclusively to suppress fear or anxiety in response to stressors.
“Thus LS output does not serve exclusively to suppress fear or anxiety in response to stressors (Sheehan et al., 2004).”
From Control of Stress-Induced Persistent Anxiety by an Extra-Amygdala Septohypothalamic Circuit (2014) · cites this paper as Sheehan et al., 2004
These data argue against the long-standing view that LS output serves primarily to suppress fear or anxiety in response to stressors.
“These data argue against the long standing view that LS output serves primarily to suppress fear or anxiety in response to stressors (Sheehan et al., 2004).”
From Control of Stress-Induced Persistent Anxiety by an Extra-Amygdala Septohypothalamic Circuit (2014) · cites this paper as Sheehan et al., 2004
A prevailing view is that the output of the lateral septum serves to dampen fear and anxiety.
“The robust and dramatic ‘septal rage’ phenotype that results from certain electrolytic, physical, or chemical lesions of the septum (Spiegel et al., 1940; Brady and Nauta, 1953; Albert and Richmond, 1976) have led to a prevailing view that the output of the LS serves to dampen fear and anxiety (Sheehan et al., 2004).”
From Control of Stress-Induced Persistent Anxiety by an Extra-Amygdala Septohypothalamic Circuit (2014) · cites this paper as Sheehan et al., 2004
LS neurons in general send recurrent GABAergic collaterals that terminate on other neurons throughout the LS.
“LS neurons in general are thought to send recurrent GABAergic collaterals that terminate on other neurons throughout the LS (Sheehan et al., 2004).”
From Control of Stress-Induced Persistent Anxiety by an Extra-Amygdala Septohypothalamic Circuit (2014) · cites this paper as Sheehan et al., 2004

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Authors: Sheehan, T. P., Chambers, R. A., & Russell, D. S.
Affiliations: Brown University (US)
Indiana University School of Medicine (US)
Yale University (US)
Corresponding author: Sheehan, Teige P
ORCID: Chambers, R.Andrew
Russell, David S
Venue: Brain Research Reviews
Publisher: Elsevier BV
Published: 2004-08
Volume: 46
Issue: 1
Pages: 71-117
ISSN: 0165-0173 (ISSN-L)
DOI: 10.1016/j.brainresrev.2004.04.009
OpenAlex: W2140977742
Cited by: 514
References: 594
Citations by year: 2026: 31 · 2025: 22 · 2024: 37 · 2023: 14 · 2022: 37 · 2021: 21 · 2020: 18 · 2019: 22 · 2018: 30 · 2017: 29 · 2016: 29 · 2015: 27 · 2014: 28 · 2013: 25 · 2012: 21
FWCI: 1.31
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Brain Research Reviews (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Mental Health (P01MH025642)
National Institute on Drug Abuse (K08DA000302)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: lateral septum, emotion regulation, mood, motivation, mesocorticolimbic dopamine system, ventral striatum, schizophrenia, psychosis spectrum disorders, antipsychotic drugs, psychotomimetics, hypothalamus, depression, antidepressants, serotonin, hippocampus, amygdala, neuropsychiatry
MeSH terms: Animals, Mental Disorders, Humans, Neuropsychology, Septum of Brain

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Regulation of affect by the lateral septum: implications for neuropsychiatry

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