An excitatory projection from the basal forebrain to the ventral tegmental area that underlies anorexia-like phenotypes

Authors: CAI, JING - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER; JIANG, YANYAN - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER; XU, YUANZHONG - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER; JIANG, ZHIYING - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER; YOUNG, CLAIRE - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER; LI, HONGLI - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER; ORTIZ-GUZMAN, JOSHUA - BAYLOR COLLEGE OF MEDICINE; ZHUO, YIZHOU - PEKING UNIVERSITY; LI, YULONG - PEKING UNIVERSITY; XU, YONG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); ARENKIEL, BENJAMIN - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); TONG, QINGCHUN - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER

Submitted to: Neuron
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/3/2023
Publication Date: 2/7/2024
Citation: Cai, J., Jiang, Y., Xu, Y., Jiang, Z., Young, C., Li, H., Ortiz-Guzman, J., Zhuo, Y., Li, Y., Xu, Y., Arenkiel, B.R., Tong, Q. 2024. An excitatory projection from the basal forebrain to the ventral tegmental area that underlies anorexia-like phenotypes. Neuron. 112(3):458-472. https://doi.org/10.1016/j.neuron.2023.11.001.
DOI: https://doi.org/10.1016/j.neuron.2023.11.001

Interpretive Summary: Simply put, when the body struggles to manage its energy needs and respond to threats, it can lead to eating disorders. In our research with mice, we found that a part of the brain called the basal forebrain (BF) communicates with another area, the ventral tegmental area (VTA), using a type of signal called glutamatergic projections. Both regions' nerve cells react similarly to stress. When we controlled the BF's signals to the VTA in live mice, it resulted in reduced appetite, increased movement, and avoidance of certain things. Activating the nerve cells in the VTA caused weight loss, reduced interest in food, and increased activity with signs of anxiety, resembling symptoms seen in anorexia. Importantly, activating the BF's signals to the VTA led to a decrease in the release of dopamine in a specific brain area called the nucleus accumbens. This suggests that an overactive BF -> VTA communication circuit could potentially be a cause of anorexia-like symptoms by affecting dopamine release.

Technical Abstract: Maladaptation in balancing internal energy needs and external threat cues may result in eating disorders. However, brain mechanisms underlying such maladaptations remain elusive. Here, we identified that the basal forebrain (BF) sends glutamatergic projections to glutamatergic neurons in the ventral tegmental area (VTA) in mice. Glutamatergic neurons in both regions displayed correlated responses to various stressors. Notably, in vivo manipulation of BF terminals in the VTA revealed that the glutamatergic BF -> VTA circuit reduces appetite, increases locomotion, and elicits avoidance. Consistently, activation of VTA glutamatergic neurons reduced body weight, blunted food motivation, and caused hyperactivity with behavioral signs of anxiety, all hallmarks of typical anorexia symptoms. Importantly, activation of BF glutamatergic terminals in the VTA reduced dopamine release in the nucleus accumbens. Collectively, our results point to overactivation of the glutamatergic BF -> VTA circuit as a potential cause of anorexia-like phenotypes involving reduced dopamine release.