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

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-HT1A 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-HT1A receptors and does not involve a glucocorticoid mediated feedback mechanism.

Prefrontal/Amygdalar System Determines Stress Coping Behavior Through 5-HT/GABA Connection

“…Here evidence is reported of a brain system which, through modulation of GABA in the amygdala prefrontal cortical 5-HT, controls behavioral responses to stressful experiences sustaining immobility in the forced swimming paradigm that models depressive-like outcomes in rodents (Ebner et al, 2005(Ebner et al, , 2008Singewald et al, 2011). It was first demonstrated that, in mice, a stressful experience such as restraint induces a time-dependent increase of 5-HT output in the mpFC and of GABA in the BLA, in agreement with previous reports (Reznikov et al, 2009;Pascucci et al, 2009), and that selective depletion of cortical 5-HT canceled out these stress-induced responses, thus pointing to a controlling role of GABAergic transmission in amygdala by prefrontal 5-HT during stress.…”

“…This suggests that 5-HT transmission in the mpFC is likely to engage GABA in the amygdala in stressful situations in order to determine coping outcomes. Here, using mice, it was attempted to assess whether amygdalar GABA regulation by prefrontal cortical 5-HT is a common neural substrate involved in processing stressful experiences and in determining active or passive coping behavior during forced swimming (Ebner et al, 2005(Ebner et al, , 2008Singewald et al, 2011). In particular, it was investigated whether 5-HT in prefrontal cortex is involved in brain response to uncontrollable stress through its modulating action on GABA in amygdala and whether these brain areas are part of a neural system necessary for the implementation of adaptive coping strategies.…”

How do individuals cope with stress? Behavioural, physiological and neuronal differences between proactive and reactive coping styles in fish

“…The fish's dorsomedial (Dm) and dorsolateral (Dl) pallium have been characterised as functional homologues of the mammalian amygdala and hippocampus, respectively, and are implicated in stimuli salience, memory and learning (Goodson and Kingsbury, 2013;O'Connell and Hofmann, 2011;Vargas et al, 2009). Furthermore, in terms of stimuli salience and emotional coding, the mammalian lateral septum appears to work in conjunction with the amygdala and hippocampus to regulate emotional reactivity and goal-oriented behaviour, respectively (Luo et al, 2011;Singewald et al, 2011). The ventral part of the ventral telencephalon (Vv) in fish has been proposed as a putative homologue to the mammalian lateral septum (Goodson and Kingsbury, 2013;O'Connell and Hofmann, 2011).…”

Region-specific up-regulation of oxytocin receptor binding in the brain of mice following chronic nicotine administration

“…This upregulation of the OTR was specifically localized in the amygdala, a region involved in stress and emotional regulation [25,26]. Therefore, this oxytocinergic system alteration may be involved in the modulation of long-term behavioural adaptations induced by chronic nicotine exposure.…”