Biology subjects

McDougle, M.

Publications and source records attributed to McDougle, M..

4 recordsLinked to original sources

bioRxiv2026

A Neurotensin Brake on Exploratory Drive under Persistent Threat

Avoidance behavior is an adaptive response that delays exploration to promote survival. Avoidance is enhanced by psychological stress and is a hallmark of many neuropsychiatric disorders. Neural circuits that control avoidance by integrating stressful stimuli and modulating exploratory behavior remain underexplored. Elucidating the functional dynamics of this highly conserved phenomenon and the underlying neural mechanism of avoidance is an important open-ended question, with relevance to understanding both innate behaviors and neuropsychiatric disorders. Using predator odor as an innate, chronic stressor to increase avoidance behaviors in mice, we identified a neural population in the lateral septum (LS) that integrates threat information and modulates latency to explore. Calcium recordings in freely exploring mice combined with activity-based transcriptomics revealed that predator-responsive LS neurons are GABAergic and express neurotensin (LSNT). Further, single nuclei RNA-seq analysis revealed that among predator-responsive neurons, NT-enriched inhibitory clusters are predominant. Chronic activation of LSNT neurons induces avoidance behaviors in the absence of predator odor, while synaptic silencing of this population abrogates predator-enhanced avoidance. Using transgenic mouse models to indelibly tag predator-responsive neurons, we defined the downstream circuit that connects the encoding of predator odor information to the lateral hypothalamus. Projection-specific activation of LSNT[->]LHA neurons recapitulate stress-induced avoidance behaviors in mice. Finally, we showed that deletion of neurotensin from LS neurons prevented the effects of predator odor on exploration. Together, these findings offer a genetically-and projection-defined, top-down circuit linking the limbic neurotensinergic system to chronic psychological stress and avoidance behaviors in mice.

neuroscience↗

bioRxiv2026

Efficacy of glucocorticoid modulator PT150 as a weight loss strategy

Obesity affects millions of people worldwide and has serious complications such as cardiovascular disease and diabetes. Current treatments for obesity target proteins such as the receptors for glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP) and/or glucagon (GCG). These interventions have revolutionized the treatment of obesity and represent first-line pharmacotherapeutic strategies. One major weakness to these strategies is that once drug treatment stops, most patients are unable to maintain the new body weight setpoint, often gaining weight back rapidly. Thus, the identification of new therapies that focus on the ability to maintain homeostatic setpoint are necessary. The glucocorticoid receptor (GR) has been implicated in several pathways including reward-seeking, inflammation, stress and energy balance. Here, we investigated the effects of 30 days treatment with PT150 (40 mg/kg), a novel GR antagonist, alone and in combination with semaglutide (30 nmol/kg) on food intake, glucose homeostasis, body weight and setpoint maintenance using a C57Bl/6 diet-induced obesity (DIO) mouse model. We monitored food intake and body weight throughout treatment and after drug washout for 20 days to evaluate defended body weight maintenance (body weight setpoint). Our results indicate that treatment with PT150 alone does not significantly alter body weight but in combination with semaglutide it shows the most promising effects in body weight reduction and homeostatic setpoint maintenance. Together, these data suggest that PT150, a GR modulator, may be effective as a homeostatic setpoint modulator when combined with semaglutide.

physiology↗

bioRxiv2023

Asymmetric control of food intake by left and right vagal sensory neurons

We investigated the lateralization of gut-innervating vagal sensory neurons and their roles in feeding behavior. Using genetic, anatomical, and behavioral analyses, we discovered a subset of highly lateralized vagal sensory neurons with distinct sensory responses to intestinal stimuli. Our results demonstrated that left vagal sensory neurons (LNG) are crucial for distension-induced satiety, while right vagal sensory neurons (RNG) mediate preference for nutritive foods. Furthermore, these lateralized neurons engage different central circuits, with LNG neurons recruiting brain regions associated with energy balance and RNG neurons activating areas related to salience, memory, and reward. Altogether, our findings unveil the diverse roles of asymmetrical gut-vagal-brain circuits in feeding behavior, offering new insights for potential therapeutic interventions targeting vagal nerve stimulation in metabolic and neuropsychiatric diseases. One Sentence SummaryLateralized gut-brain circuits respond to different sensory modalities and control distinct feeding behaviors.

neuroscience↗

bioRxiv2022

Labeled lines for fat and sugar reward combine to promote overeating

Food is a powerful natural reinforcer that guides feeding decisions. The vagus nerve conveys internal sensory information from the gut to the brain about nutritional value; however, the cellular and molecular basis of macronutrient-specific reward circuits are poorly understood. Here, we monitor in vivo calcium dynamics to provide direct evidence of independent vagal sensing pathways for detection of dietary fats and sugars. Using activity-dependent genetic capture of nutrient-specific vagal neurons activated in response gut infusions, we demonstrate the existence of separate hard-wired reward circuits for fat and sugar that are necessary and sufficient for nutrient-specific reinforcement. Even when controlling for calories, combined activation of fat and sugar circuits increases overeating compared to fat or sugar alone. This work provides new insight on the complex sensory circuitry that mediates motivated behavior and suggests that a subconscious internal drive to consume obesogenic diets (e.g., those high in both fat and sugar) may impede conscious dieting efforts.

neuroscience↗