Serotonergic neuron subtypes and how they regulate feeding and energy balance

Serotonin (or 5-hydroxytryptamine, 5-HT) is one of the most ancient neurotransmitters. Serotonergic neurons in the brain potently regulate appetite and feeding, and represent a promising therapeutic target to treat obesity. However, serotonergic neurons are highly diverse, and we do not fully understand which specific serotonergic neurons regulate feeding and how precisely they regulate feeding.

In our recent work (Yao and Scott, Neuron 2022), we used the fruit fly as a model and identified two distinct classes of serotonergic neurons in the fly feeding center that are activated by sugar and bitter taste detection respectively, and regulate feeding as well as endocrine and digestive function in anticipation of food availability. This work highlights the complexity of serotonergic regulation of feeding, and identifies serotonergic neurons as a critical node linking sensory detection, feeding, and anticipatory hormonal and digestive adaptations to maintain energy balance.

In our ongoing work, we are further characterizing the other serotonergic neurons using a combination of advanced fly genetics, in vivo calcium imaging, optogenetics, connectomics, and behavioral approaches. Our studies will provide a detailed characterization of the individual serotonergic neurons in the fly feeding center and reveal the neural circuit mechanisms by which they regulate feeding and energy balance, informing similar studies in other systems.

(Yao and Scott, Neuron 2022)

Regulation of feeding by gut-brain communication

The gut-brain communication informs the brain of internal nutrient status and is critical for the homeostatic regulation of feeding. Decades of studies have revealed hormones, cytokines, as well as direct neural pathways that mediate gut-brain communication. However, how neural circuits in the central brain receive and integrate gut sensory information to guide feeding decisions is not fully understood.

The fruit fly, with its sophisticated genetic tools to target single neurons and a whole-brain connectome available, offers an exciting opportunity for us to investigate how central brain circuits process the diverse gut sensory information, such as the stretch of the gut or the nutrient contents in the gut, to regulate feeding. For example, recent studies have identified two classes of gut sensory neurons that detect gut stretch and sugar contents in the gut, respectively (see figure). We are working to trace their projections into the central brain and identify their downstream brain circuits using transsynaptic tracing, calcium imaging, and connectomics. We are particularly interested in the possibility that the serotonergic neurons we identified may integrate both external taste sensory cues and internal gut sensory information to regulate feeding and energy balance. These studies will help delineate the neural circuit pathways for gut-brain communication with single-neuron resolution that remains challenging to achieve in most vertebrate models.

Representative images (left) and schematics (right) showing the Piezo neurons that detect gut stretch (A-B) (Min et al, Elife 2021) and the Gr43a neurons that detect sugar contents in the gut (C-D) (Miyamoto et al, Cell 2012). The digestive tract was stained with phalloidin (blue).

Autophagy in rare diseases

Autophagy ("self-eating") is a conserved degradation and recycling process of the cell that removes unnecessary or toxic components – such as misfolded proteins and damaged organelles – through the lysosomes. Autophagy is important for cellular homeostasis and autophagy dysregulation is linked to many diseases, including cancers, neurodegenerative diseases, and multiple rare diseases. We are particularly interested in rare diseases because they are much understudied.

In collaboration with Dr. Meiyan Jin, an expert in autophagy, human induced pluripotent stem cells (hiPSCs), and live-cell imaging, we propose to combine the Drosophila and hiPSC models to study the roles of autophagy in several rare diseases. We will take advantage of the large collection of tissue-specific drivers in Drosophila to identify the specific tissue(s) and developmental stage(s) in which the disease-causing mutations in autophagy genes are critical for disease manifestation. This will guide our use of hiPSC-derived tissues (genome-edited or patient-derived) to model the disease conditions and study the underlying mechanisms.

We think that the combination of Drosophila and hiPSC models offer a fast and cost-effective way to study rare disease mechanisms with direct human relevance. We are very excited about this new frontier of the lab. Stay tuned.

Each rare disease affects fewer than 1 in 2,000 people, but the 6,000+ rare diseases collectively afflict over 300 million people worldwide. Read Zixuan's story from