Identification and Delineation of Neuronal Pathways Underlying Hypophagia

Author

Jing CaiFollow

Author ORCID Identifier

https://orcid.org/0000-0001-8448-8151

Date of Graduation

12-2023

Document Type

Dissertation (PhD)

Program Affiliation

Neuroscience

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Qingchun Tong

Committee Member

Benjamin R. Arenkiel

Committee Member

Kristin Eckel-Mahan

Committee Member

Fabricio H. Do Monte

Committee Member

Fudong Liu

Abstract

In terms of metabolism, eating disorders manifest in two extreme directions: overnutrition, which can lead to obesity, and malnutrition, which can result in underweight or even starvation. Both extremes compromise the quality of life. According to the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) standard, eating disorders affect up to 17.9% of young women and 2.4% of young men. Although eating disorders are primarily defined as mental disorders rather than metabolic disorders, they are intertwined with complex emotions and sensory perceptions. However, in contemporary animal research related to eating disorders and feeding behaviors, the majority of neuroscientists still examine how the hypothalamus regulates hunger-driven and satiety-regulating feeding behaviors.

This body of work includes two projects I led and conducted on mice during the PhD journey. The first project, a collaborative endeavor with Jing Chen from the University of Science and Technology of China (USTC), challenges the prevailing belief in the field. We demonstrated that the arcuate nucleus of the hypothalamus (ARC) agouti-related protein (AgRP) neurons are not essential for maintaining body weight in mice. Specifically, I found that the near-ablation of AgRP neurons had no impact on ad libitum food intake and survival, which overturned the dogma that adult deletion of these neurons led to lethal phenotype. Interestingly, I did observe that these neurons are required for fasting-induced refeeding. This finding supports the "thrive gene" theory, which suggests that throughout millions of years of evolution, the central nervous system regulating homeostatic feeding has evolved to push body weight towards an energy surplus rather than an energy deficit to better adapt to harsh environments.

The second project goes beyond the hypothalamus, targeting an excitatory brain circuit from the basal forebrain (BF) to the ventral tegmental area (VTA). The BF is recognized as a sensory hub that incorporates environmental information and the VTA is a well-known reward-processing center. This project is associated with driving anorexia-like phenotypes. My research showed that the BF→VTA circuit is highly sensitive to environmental stress. Overactivation of this circuit can lead to a loss of appetite, reduced food motivation, hyperactivity, anxiety-like behaviors, and eventually, significant weight loss — all of which are characteristic symptoms of anorexia nervosa. This research underscores the idea that feeding is a multifaceted behavior, extending beyond the simple regulation by the hypothalamus in response to energy needs.

Keywords

Basal forebrain, VTA, glutamatergic neurons, feeding, stress, anorexia, dopamine