The LeDoux Lab

The Vulnerable Brain Project has supported four studies by my group since the last report. Study 1 is published, Study 2 is under review, Study

3 is being written up for publication and Study 4 is very near completion but requires commercial analysis of one set of data before submitting for publication.

Study 1: Human threat learning is associated with gut microbiota composition  

The ability to learn about threat and safety is critical for survival. Studies in rodent models have shown that the gut microbiota can modulate such behaviors. In humans, evidence showing an association with threat or extinction learning is lacking. Here, we tested whether individual variability in threat and extinction learning was related to gut microbiota composition

in healthy adults. We found that threat, but not extinction learning, varies with individuals’ microbiome composition. Our results provide evidence that the gut microbiota is associated with excitatory threat learning across species.

Study 2: Item recognition is associated with gut microbiota composition in healthy humans

Understanding the relationship between the gut microbiota and human cognition represents a pivotal frontier in neuroscience. Our study dives into this quest by exploring the connection between the indigenous gut microbiota and episodic memory in healthy individuals. While prior research has illuminated this relationship in animal models, our study extends these findings to humans, providing compelling evidence that gut

microbiota diversity and structural composition are associated with differences in episodic memory performance. By shifting the focus from probiotic-based interventions to the study of commensal gut microbes, our findings shed light on how the gut microbiota, in its natural state, could be linked to interindividual differences in human cognition.

Study 3: Cannabinoid Regulation of Proactive Coping Behavior

To survive, organisms must learn how to interact appropriately with their environment by approaching positive stimuli, avoid danger, and engaging in defensive behaviors when danger is unavoidable. In humans, impairments in the control of threats can lead to anxiety. Proactive coping enhances resilience by anticipatory management of stress. Circuits underlying these adaptive behaviors depend on specific brain circuits involving the amygdala and basal ganglia areas of the brain. In studies of rodents, we used state of the art methods (chemo- and opto- genetics, neurophysiology, neuropharmacology, and mass spectrometry) to show how cannabinoids positively regulate the acquisition of pro-active coping.

Study 4: Activation of Cannabinoid receptors in the brain mitigates symptoms of anorexia in an adolescent model of anorexia nervosa in rodents: The role of microbiome diversity

During adolescence, neural circuits that process threats are especially plastic and exhibit a period of vulnerability when physiological disruption is present. In the activity-based model of anorexia, adolescent rodents engage in physical activity (running) in a compulsive manner and experience a progressive decrease in food-consumption and body weight, showing an anorexic phenotype. Using a drug that activates cannabinoid

receptors mitigates the effects of running activity and prevents body weight loss. We are currently characterizing the diversity of the gut microbiome in adolescent females before and after exposure to the anorexia nervosa model to determine the influence of cannabinoids on microbiome diversity. These experiments present a preclinical model in

which cannabinoids could be used to prevent the weight-loss and absence of food-driven motivation in anorexia nervosa.