Serotonergic fast lane from taste detection to preparatory digestive actions

Abstract

Nutrient detection through the taste system triggers various physiological changes in the body. In this issue of Neuron, Yao and Scott (2022) identify two distinct classes of serotonergic neurons in Drosophila that transform sweet and bitter taste signals into endocrine and digestive responses.

Just a bite of the food triggers a cascade of responses from salivary secretion and intestinal movement to gastric acid secretion, getting our body ready for the feast. How does the brain swiftly orchestrate these physiological responses upon sensory detection? Currently, the circuit-level mechanisms that achieve these functions remain mostly obscure. Yao and Scott now uncover the role of the serotonergic system in taste-driven priming of the endocrine and digestive systems (Yao and Scott, 2022).

Traditional view of nutrient homeostasis is a feedback model in which nutrient depletion drives ingestion and nutrient absorption quenches appetite. Besides this basic mechanism, several recent studies have shed light on startling feedforward mechanisms that peripheral nutrient detection rapidly modulates the activity of brain appetite circuits (Augustine et al., 2020). These feedforward signals enable animals to optimize internal milieu from as early as foraging and gustatory evaluation of food. To date, many studies have investigated how the brain activity is regulated by peripheral sensory signals. But much less attention has been paid to how the brain controls various physiological responses in a feedforward fashion.

Taste is the primary sensory modality for assessing nutrient quality. The taste system has similar coding logic between vertebrates and invertebrates. Specialized primary gustatory neurons are tuned to detect one of the basic taste qualities. Pathways for the two most salient tastes, sweet and bitter, are segregated from sensory input to higher relays in the brain areas. Past studies suggested that taste detection itself drives rapid physiological changes. For example, sweet taste signals trigger insulin release preceding any blood glucose change, preparing animals for a surge of food ingestion and facilitating rapid restoration of energy balance (Tonosaki et al., 2007).

Given such behavioral/physiological evidence, the next key step is to understand the neural mechanisms underlying taste-induced physiological effects. The brain serotonergic circuits have been a promising candidate because serotonin (5-hydroxytryptophan, 5-HT) was implicated in appetite regulation across species (Tecott, 2007). A challenging aspect of studying the serotonergic system is that it is involved in multiple functions, including food intake, satiety, sleep, and learning.

In this issue of Neuron, Yao and Scott (2022) have now dissected two distinct serotonergic neuron classes in Drosophila that link taste signals with endocrine and digestive functions (Figure 1). Using in vivo GCaMP6s calcium imaging, the authors found that sweet and bitter taste stimuli activated a distinct subset of 5-HT neurons in the lateral subesophageal ganglion (SEL). Using specific split-Gal4 lines, the authors gained a genetic handle over the discovered serotonergic sugar- and bitter-responding cell classes, namely “sugar SEL” and “bitter SEL.” Optogenetic activation of peripheral sugar (Gr64c+) and bitter (Gr66a+) gustatory receptor neurons selectively activated sweet and bitter SEL neurons (SELs), respectively.

Figure 1. Serotonergic circuits linking taste detection to digestive preparation.

Two distinct serotonergic neuron classes in the lateral subesophageal ganglion (SEL) coordinate taste-driven anticipatory endocrine and digestive action. Sugar detection on proboscis activated sugar SEL neurons (sugar SELs) to secret insulin and suppress feeding. Bitter signals from both proboscis and legs stimulate bitter SEL neurons (bitter SELs) to trigger contractions of the crop, a temporary food-storage organ.

What are the physiological roles of taste-responsive SEL neurons? The first hint emerged by anatomical observation. Interestingly, Yao and Scott (2022) noticed extensive projections from sugar SELs to median neurosecretory cells in the pars intercerebralis, which is a major neuroendocrine organ in the insect brain. This area contains insulin-producing cells (IPCs) that secrete Drosophila insulin-like peptides (DILPs), and IPCs express a serotonin receptor subtype (Luo et al., 2012). Thus, the authors suspected that sugar SELs directly regulate insulin release by stimulating IPCs. Indeed, optogenetic experiments demonstrated direct synaptic connection between sugar SEL neurons and IPCs. Moreover, responses in IPCs by sugar SELs were greatly suppressed by serotonin receptor antagonist. A general function of insulin is to help store blood glucose. The findings by Yao and Scott (2022) explain how insulin secretion is induced by nutrient detection. The authors also demonstrated that activation of sugar SELs suppresses sugar intake presumably through an IPC-independent mechanism. These results indicate that one serotonergic population has dual functions to regulate both hormonal secretion and behavioral output.

Unlike with sugar SEL neurons, Yao and Scott (2022) did not find direct causal link between the activity of bitter SEL neurons and food consumption. Unexpectedly, they found that bitter SELs project to specific peripheral ganglia, called the hypocerebral ganglion (HCG), which is a major component of the enteric nervous system. A line of experiments showed that HCG expresses serotonin receptors, and stimulation of bitter SELs activates HCG cells. Importantly, optogenetic stimulation of this population immediately triggered contractions of the crop, a specialized organ to store food temporarily. From these results, the authors speculated that a potential malnutrition environment promotes energy replenishment by emptying food from the crop.

This study by Yao and Scott (2022) convincingly showed how specific components of the serotonergic system mediate selective endocrine and digestive functions in response to taste detection. Besides the two types of SELs identified in this study, an additional serotonergic population was previously reported to drive appetite (Albin et al., 2015). Thus, it appears that a complex serotonergic signal contributes to appetite regulation in the fly brain. A careful cell-type-specific dissection demonstrated by Yao and Scott is critical for serotonergic and other neuromodulatory systems (Pool and Scott, 2014).

There are several questions stemming from this study that are ready to be addressed. For example, this study demonstrated that sweet SELs stimulate IPCs. However, these cells secrete other neuropeptides besides insulin (Söderberg et al., 2012). Investigating the function of insulin and non-insulin factors would reveal molecular mechanisms underlying different feedforward physiological effects. Moreover, IPCs are activated by both feedforward (taste) and feedback (absorption) signals (Oh et al., 2019). Studying how temporary distinct physiological signals are integrated to regulate neuroendocrine response is an exciting future research topic.

Another question has to do with internal-state dependency of the physiological effects caused by taste SELs. It is currently unknown whether SEL-mediated endocrine/digestive responses are modulated by internal state. For example, animals are willing to ingest unpalatable food (e.g., slightly bitter food) under hungry states. Under such conditions, do bitter SELs still drive crop contractions? Linking sensory and physiological responses under distinct internal states would offer a better understanding of flexible regulation of body functions by serotonergic circuits.

The numerical simplicity and tool availability in the fruit fly brings the systemic approach within reach: cell-type-specific interactions between sensory detection, central processing, and endocrine/digestive regulation. How do these results illuminate the role of serotonergic regulation of anticipatory function in mammals? In fact, similarly to current work in the fruit fly, anatomically intermingled serotonergic cells display significant genetic diversity (Ren et al., 2019). Future work is needed to dissect the serotonergic circuits in appetite and endocrine regulation. With the field just beginning to elucidate the circuit elements and neuroendocrine mechanisms for anticipatory nutritional regulation, the work by Yao and Scott provides an instructive example and roadmap to exploring other molecular signaling pathways for mediating anticipatory regulation.