Identification of a Stress-Sensitive Anorexigenic Neurocircuit From Medial Prefrontal Cortex to Lateral Hypothalamus

Clarke, Rachel E.; Voigt, Katharina; Reichenbach, Alex; Stark, Romana; Bharania, Urvi; Dempsey, Harry; Lockie, Sarah H.; Méquinion, Mathieu; Lemus, Moyra B; Wei, Bowen; Reed, Felicia; Rawlinson, Sasha; Nunez-Iglesias, Juan; Foldi, Claire J.; Kravitz, Alexxai V.; Verdejo-García, Antonio; Andrews, Zane B.

doi:10.1016/j.biopsych.2022.08.022

Cited by 12 publications

(14 citation statements)

References 78 publications

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“…The chemogenetic data regarding experiments performing mPFC-LHA inhibition are also in accordance with such a conditional role of this pathway in food intake. Inhibition of the pathway under normal conditions did not alter food intake, of neither chow nor fat, in accordance with an earlier study 21 . Instead, we show that after a social stress experience that drives excess intake of specifically palatable food (hyperphagia) 3 , inhibition of the pathway abolishes only the amount of excess fat intake due to stress.…”

Section: Discussionsupporting

confidence: 92%

“…Importantly, while both TRAP2 transgenic mice, and VGAT-Cre / VGLUT2-Cre transgenic mice, rely on conditional expression via the same Cre-LoxP system, the viral injection scheme in this case avoided interference between this. First, we avoided mPFC CoChR expression in a manner not linked to the TRAPing of an ensemble in the VGLUT2-Cre mice, on the basis of mPFC neurons expressing VGLUT1 rather than VGLUT2 21,31 (Suppl. Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies have shown that the mPFC-LHA pathway is sensitive to social information 20,31,42 , and bulk population-level recordings showed that the pathway exhibits calcium responses to an air puff 21 . Here we captured single cell dynamics of mPFC cells projecting to the LHA during social stress experiences with in vivo electrophysiology.…”

Section: Discussionmentioning

confidence: 99%

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A prefrontal cortex-lateral hypothalamus circuit controls stress-driven food intake

Supiot,

Benschop,

Nicolson

et al. 2024

Preprint

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Stress can drive excessive intake of palatable high-caloric food. The medial prefrontal cortex (mPFC) is implicated in this, but through unknown downstream circuits and mechanisms. Here we show, in mice, that the projection from the mPFC to the lateral hypothalamus (LHA) is a critical substrate for stress-driven fat intake. We show that optogenetic stimulation of the mPFC-LHA increases fat intake under naive conditions. Using in vivo electrophysiology and ensemble tagging, we demonstrate that the mPFC-LHA network acutely responds to social stress. Combining patch clamp and optogenetics, we show that after social stress, plasticity occurs specifically at mPFC synapses onto LHA glutamatergic (but not GABAergic) neurons. Prior social stress primes the efficacy with which optogenetic stimulation of mPFC-LHA pathways drives fat intake, while chemogenetic inhibition of this network specifically blocks stress-driven increased fat intake. Our findings identify the mPFC as a top-down regulator of distinct LHA feeding networks, necessary for stress-eating behavior.

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Section: Discussionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A prefrontal cortex-lateral hypothalamus circuit controls stress-driven food intake

Supiot,

Benschop,

Nicolson

et al. 2024

Preprint

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“…The increased switching rates due to PFC-hM4Di were accompanied by decreased food-to-food transitions (Figure 7), similar to food deprivation (Figure 5B), suggesting that PFC-hM4Di affected maintenance of the feeding drive. Of note, we did not find an overall change in food consumed, similar to a recent study of chow consumption in the home cage 41 . The pattern of motivational transitions affected by PFC-hM4Di was distinct from that induced by swapping the goal modules (Figure 5C), which was accompanied by increased food-to-drink and drink-to-food transitions, as expected from an action-outcome mismatch.…”

Section: Discussionsupporting

confidence: 90%

“…A broad perifornical region of the hypothalamus, containing the lateral, dorsomedial and tuberal areas, regulates feeding, potentially through primary effects on arousal, locomotion and metabolism [34][35][36] , and contains intermingled feeding promoting and inhibiting refereed preprint April 19, 2024 neural populations [37][38][39] . The medial PFC sends axonal projections to this hypothalamic area, affecting feeding in a complex manner depending on behavioural context 40,41 . To test the role of these neural populations in drive switching, we expressed the inhibitory DREADD, hM4Di in either PFC output neurons to the hypothalamus (PFC-hM4Di) or in the perifornical hypothalamus (H-hM4Di).…”

Section: Neural Control Of Msr Drive Switchingmentioning

confidence: 99%

The Switchmaze: an open-design device for measuring motivation and drive switching in mice

Hartmann,

Mahajan,

Borges

et al. 2024

Preprint

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Animals need to switch between motivated behaviours, like drinking, feeding or social interaction, to meet environmental availability, internal needs and more complex ethological needs such as hiding future actions from competitors. Inflexible, repetitive behaviours are a hallmark of many neuropsychiatric disorders. However, how the brain orchestrates switching between the neural mechanisms controlling motivated behaviours, or drives, is unknown. This is partly due to a lack appropriate measurement systems. We designed an automated extended home-cage, the Switchmaze, using open source hardware and software. In this study, we use it to establish a behavioural assay of motivational switching, measured as the ratio of single probe entries to continuous exploitation runs. Behavioural transition analysis is used to further dissect altered motivational switching. As proof-of-concept, we show environmental manipulation, and targeted brain manipulation experiments which altered motivational switching without effect on traditional behavioural parameters. Chemogenetic inhibition of the prefrontal-hypothalamic axis increased the rate of motivation switching, highlighting the involvement of this pathway in drive switching. This work demonstrates the utility of open-design in understanding animal behaviour and its neural correlates.

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Dynamic fronto‐amygdalar interactions underlying emotion‐regulation deficits in women at higher weight

Maturana‐Quijada,

Steward,

Vilarrasa

et al. 2023

Obesity

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ObjectiveThe regulation of negative emotions entails the modulation of subcortical regions, such as the amygdala, by prefrontal regions. There is preliminary evidence suggesting that individuals at higher weight may present with hypoactivity in prefrontal regulatory systems during emotional regulation, although the directionality of these pathways has not been tested. In this study, we compared fronto‐amygdalar effective connectivity during cognitive reappraisal as a function of BMI in 48 adult women with obesity and 54 control participants.MethodsDynamic causal modeling and parametric empirical Bayes were used to map effective connectivity between the dorsomedial prefrontal cortex, orbitofrontal cortex, dorsolateral prefrontal cortex, and the amygdala.ResultsDifficulty in Emotion Regulation Scale scores were higher in the obesity group compared with control participants (p < 0.001). A top‐down cortical model best explained our functional magnetic resonance imaging data (posterior probability = 86%). Participants at higher BMI were less effective at inhibiting activity in the amygdala via the orbitofrontal cortex and dorsomedial prefrontal cortex during reappraisal compared with those at lower BMI. In contrast, increased excitatory modulation of dorsolateral prefrontal cortex‐to‐amygdalar connectivity was found in participants at lower BMI.ConclusionsThese findings support a framework involving alterations in fronto‐amygdalar connectivity contributing to difficulties in regulating negative affect in individuals at higher weight.

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Identification of a Stress-Sensitive Anorexigenic Neurocircuit From Medial Prefrontal Cortex to Lateral Hypothalamus

Cited by 12 publications

References 78 publications

A prefrontal cortex-lateral hypothalamus circuit controls stress-driven food intake

A prefrontal cortex-lateral hypothalamus circuit controls stress-driven food intake

The Switchmaze: an open-design device for measuring motivation and drive switching in mice

Dynamic fronto‐amygdalar interactions underlying emotion‐regulation deficits in women at higher weight

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