A limbic circuit selectively linking active escape to food suppression

Abstract

1Anorexia Nervosa (AN) is an eating disorder characterized by severe voluntary food 2 restriction 1 . Stress is known to be a precipitating factor in AN 2-5 , but the underlying biology 3 linking stress to feeding is not well understood. Here we describe a novel population of 4 stress-responsive neurons in the lateral septum (LS) that express neurotensin (Nts LS ) and 5 negatively regulate food intake. We used in vivo fiber photometry and chemo/optogenetics 6 to show that Nts LS neurons are activated by stressful experiences, including active escape 7 in a predator-induced stress paradigm, and specifically decrease food intake in mice, 8 without altering anxiety or locomotor behaviors. These neurons co-express Glp1r, and 9 pharmacologic or genetic manipulations of Glp1r signaling in the LS recapitulate the 10 behavioral findings shown using chemo/optogenetics. Finally, we mapped the outputs of 11Nts LS neurons and show that activation of Nts LS neuronal terminals in the lateral 12 hypothalamus (LH) also decrease food intake. Taken together, these results show that 13 NTS LS neurons serve as a potential link between stress and anorexia and act by modulating 14 hypothalamic pathways regulating feeding . 15 16 17 18 19 20 21 22 Voluntary food restriction, often to the point of starvation, is the canonical symptom 1 of Anorexia Nervosa (AN), which has the highest mortality rate of any psychiatric illness 1 . 2 Clinically, AN is often comorbid with depression, anxiety and stress disorders. Indeed, 3 stress is considered to be a common precipitating factor in the pathogenesis of the disease 2-4 5 . In a recent report, we found that a projection from Drd2-expressing neurons in the 5 hippocampus to the septal region reduces food intake 6 . Consistent with this, a prior study 6 showed that inhibitory neurons in the lateral septum (LS) have been implicated in the 7 modulation of appetite 7 . Because the LS is part of the anterior limbic system which 8 regulates emotional behaviors, particularly stress, anxiety and aggression 8-9 , we considered 9 the possibility that this region might link stress to reduced food intake. 10 We first exposed mice to acute restraint stress and examined the pattern of c-fos 11 within the LS. Consistent with previous experiments 10 , restraint stress was associated with 12 an increase in the number of c-fos+ cells in LS compared to controls ( Fig. 1a, Student's t-13 test, *p<0.05). Restraint stress also led to a decrease in food intake for the ensuing 2 hours 14 ( Fig. 1b, Two-way ANOVA with Bonferroni post-hoc, *p<0.05, ***P<0.001). Separate 15 studies previously identified a subpopulation of Neurotensin-expressing (Nts) neurons in 16 the LS 11 , and modulation of hypothalamic Nts neurons regulates feeding [12][13][14][15][16] . Therefore, 17we hypothesized that these neurons might respond to stress, and thus, modulate food intake. 18We first examined whether stress leads to activation of Nts LS neurons and whether 19 this accounted for the observed increase of c-fos activation ...

Routing of Hippocampal Ripples to Subcortical Structures via the Lateral Septum

“…Following LS lesion, Brady and Nauta (1953) originally described changes in ''general emotional reactivity'' (Brady and Nauta, 1953; see also Spiegel et al, 1940). Subsequently, different authors have attributed specific roles of the LS in anxiety (Chee and Menard, 2013;Parfitt et al, 2017), arousal (Li et al, 2015), aggression (Wong et al, 2016), contextual memory (Besnard et al, 2019;Jarrard, 1993;Leutgeb and Mizumori, 2002;Vouimba et al, 1998), food intake (Azevedo et al, 2019;Scopinho et al, 2008;Yang, 2015, 2016;Terrill et al, 2016), spatial memory (Jaffard et al, 1996;Simon et al, 1986), sexual behavior (Tsukahara et al, 2014), sexually dimorphic social play (Veenema et al, 2013), social preference (Shin et al, 2018), social memory (Leroy et al, 2018;Lukas et al, 2013), reward and addiction (Cornish et al, 2012;Heath, 1963;Luo et al, 2011;McGlinchey and Aston-Jones, 2018;Le Merrer et al, 2007;Olds and Milner, 1954;Sartor and Aston-Jones, 2012;Zahm et al, 2010), gastric motility (Gong et al, 2013), and endocrine responses to stress (Anthony et al, 2014;Usher et al, 1974;Yadin and Thomas, 1996). It remains to be seen whether multiple descending circuits operate in parallel, each with a unique behavioral function, or whether the behavioral phenotypes observed with LS manipulation are aspects of a single corticofugal computation.…”

The role of the lateral septum in neuropsychiatric disease

“…Nevertheless, considering the lack of human studies, understanding the neural mechanisms behind these behaviors may provide insight into the development of these complex conditions. Recently, Azevedo et al ( 2020) have identified a group of neurotensin expressing neurons within the LS that specifically act to suppress food intake during active escape, having no effect on the other aspects of the stress response (Azevedo et al, 2020). This suggests that a specific group of neurons exist within the LS that functions solely to inhibit food intake during stress, and supports the idea that the relationship between stress and food may, in part, be mediated by the LS.…”

Alternative Frameworks for Advancing the Study of Eating Disorders

“…In mice, stimulation of the bed nucleus of stria terminalis (BNST) ➔ lateral hypothalamus (LH) pathway induced binge eating-like behavior [33], amygdala prepronociceptin neurons mediate palatable food consumption [34], and, similarly, unpublished work reported that an insular cortex ➔ central amygdala pathway mediates cue-induced overconsumption [35]. Limbic circuits that specifically mediate suppression of feeding include a lateral septum (LS) ➔ LH circuit that is specifically activated by stress [36] and a paraventricular hypothalamus (PVH) ➔ LS circuit that mediates feeding and anxiety-like behavior [37]. The reasons for the discrepancy between neuroimaging and animal model research is not obvious, but may be due to methodological factors as well as historical predispositions.…”