Neural Architecture Underlying Thirst Regulation

An important aspect of thirst is its quick quenching. When thirsty, you drink a glass of water for a few seconds; the water travels from the mouth to the stomach and you are satiated. The water has not yet been absorbed into the blood, so the brain needs to have mechanisms to signal stopping of drinking. It cannot simply depend on the body, as the body takes a good 15 - 30 minutes to even start absorption. In this dissertation, I describe dynamic thirst circuits that integrate the homeostatic-instinctive requirement for fluids, the consequent drinking behavior, and reward processing to maintain internal water balance. In Chapter 1, I show how neural populations in the lamina terminalis, a forebrain structure, form a hierarchical circuit architecture to regulate thirst. Among them, excitatory neurons in the median preoptic nucleus (MnPO) are essential for the integration of signals from the thirst-driving neurons of the subfornical organ (SFO). Thirst-driving neurons in the SFO receive temporarily distinct preabsorptive inhibition by drinking action and gastrointestinal osmolality sensing. A distinct inhibitory circuit, involving MnPO GABAergic neurons that express glucagon-like peptide 1 receptor (GLP1R), is activated immediately upon drinking and monosynaptically inhibits SFO thirst neurons. These responses are induced by the ingestion of fluids but not solids, and are time-locked to the onset and offset of drinking. Furthermore, loss-of-function manipulations of these neurons lead to a polydipsic, overdrinking phenotype. These neurons therefore facilitate rapid satiety of thirst by monitoring real-time fluid ingestion. In Chapters 2 and 3, I talk about how thirst triggers a strong motivational state that drives animals toward drinking behavior. The consequent fluid intake provides both satiation and pleasure of drinking to animals. However, how these two factors are processed and represented by the brain remains poorly understood. Here I will use in vivo optical recording, genetics, and intragastric infusion approaches to dissect thirst satiation circuits and their contribution to reward signals. Thirst-driving neurons in the subfornical organ (SFO) receive multiple temporally-distinct satiation signals prior to the homeostatic recovery: oropharyngeal stimuli induced by drinking action and gastrointestinal sensing of osmolality changes. In chapter 1, I have shown that drinking action is represented by inhibitory neurons in the median preoptic nucleus (MnPO). Here, I demonstrate that gut osmolality signals are mediated by specific GABAergic neurons in the SFO. These neurons were selectively activated by hypo-osmotic stimuli in the gut independent of drinking action. Optogenetic gain- and loss-of-function of this inhibitory population suppressed and increased water intake in thirsty animals, respectively. These results indicate that oropharyngeal- and gastrointestinal-driven satiation signals are transmitted to thirst neurons through different neural pathways. Furthermore, I investigated the contribution of thirst satiation signals to the reward circuit using a genetically-encoded ultrafast dopamine (DA) sensor. Interestingly, oral ingestion but not gut osmolality changes triggered robust DA release. Importantly, chemogenetic activation of thirst-quenching neurons did not induce DA release in water-deprived animals. Together, this dissected genetically-defined thirst satiation circuits, the activity of which are functionally separable from reward-related brain activity. Taken together, these finding provide answers to some longstanding questions in the neural control of fluid intake, and appetite in general.</p

Neural populations for maintaining body fluid balance

Fine balance between loss-of water and gain-of water is essential for maintaining body fluid homeostasis. The development of neural manipulation and mapping tools has opened up new avenues to dissect the neural circuits underlying body fluid regulation. Recent studies have identified several nodes in the brain that positively and negatively regulate thirst. The next step forward would be to elucidate how neural populations interact with each other to control drinking behavior

Neural populations for maintaining body fluid balance

Fine balance between loss-of water and gain-of water is essential for maintaining body fluid homeostasis. The development of neural manipulation and mapping tools has opened up new avenues to dissect the neural circuits underlying body fluid regulation. Recent studies have identified several nodes in the brain that positively and negatively regulate thirst. The next step forward would be to elucidate how neural populations interact with each other to control drinking behavior

Neural Control and Modulation of Thirst, Sodium Appetite, and Hunger

The function of central appetite neurons is instructing animals to ingest specific nutrient factors that the body needs. Emerging evidence suggests that individual appetite circuits for major nutrients—water, sodium, and food—operate on unique driving and quenching mechanisms. This review focuses on two aspects of appetite regulation. First, we describe the temporal relationship between appetite neuron activity and consumption behaviors. Second, we summarize ingestion-related satiation signals that differentially quench individual appetite circuits. We further discuss how distinct appetite and satiation systems for each factor may contribute to nutrient homeostasis from the functional and evolutional perspectives

Peripheral and Central Nutrient Sensing Underlying Appetite Regulation

The precise regulation of fluid and energy homeostasis is essential for survival. It is well appreciated that ingestive behaviors are tightly regulated by both peripheral sensory inputs and central appetite signals. With recent neurogenetic technologies, considerable progress has been made in our understanding of basic taste qualities, the molecular and/or cellular basis of taste sensing, and the central circuits for thirst and hunger. In this review, we first highlight the functional similarities and differences between mammalian and invertebrate taste processing. We then discuss how central thirst and hunger signals interact with peripheral sensory signals to regulate ingestive behaviors. We finally indicate some of the directions for future research

Peripheral and Central Nutrient Sensing Underlying Appetite Regulation

The precise regulation of fluid and energy homeostasis is essential for survival. It is well appreciated that ingestive behaviors are tightly regulated by both peripheral sensory inputs and central appetite signals. With recent neurogenetic technologies, considerable progress has been made in our understanding of basic taste qualities, the molecular and/or cellular basis of taste sensing, and the central circuits for thirst and hunger. In this review, we first highlight the functional similarities and differences between mammalian and invertebrate taste processing. We then discuss how central thirst and hunger signals interact with peripheral sensory signals to regulate ingestive behaviors. We finally indicate some of the directions for future research

Temporally and Spatially Distinct Thirst Satiation Signals

For thirsty animals, fluid intake provides both satiation and pleasure of drinking. How the brain processes these factors is currently unknown. Here, we identified neural circuits underlying thirst satiation and examined their contribution to reward signals. We show that thirst-driving neurons receive temporally distinct satiation signals by liquid-gulping-induced oropharyngeal stimuli and gut osmolality sensing. We demonstrate that individual thirst satiation signals are mediated by anatomically distinct inhibitory neural circuits in the lamina terminalis. Moreover, we used an ultrafast dopamine (DA) sensor to examine whether thirst satiation itself stimulates the reward-related circuits. Interestingly, spontaneous drinking behavior but not thirst drive reduction triggered DA release. Importantly, chemogenetic stimulation of thirst satiation neurons did not activate DA neurons under water-restricted conditions. Together, this study dissected the thirst satiation circuit, the activity of which is functionally separable from reward-related brain activity

Chemosensory modulation of neural circuits for sodium appetite

Sodium is the main cation in the extracellular fluid and it regulates various physiological functions. Depletion of sodium in the body increases the hedonic value of sodium taste, which drives animals towards sodium consumption. By contrast, oral sodium detection rapidly quenches sodium appetite, suggesting that taste signals have a central role in sodium appetite and its satiation. Nevertheless, the neural mechanisms of chemosensory-based appetite regulation remain poorly understood. Here we identify genetically defined neural circuits in mice that control sodium intake by integrating chemosensory and internal depletion signals. We show that a subset of excitatory neurons in the pre-locus coeruleus express prodynorphin, and that these neurons are a critical neural substrate for sodium-intake behaviour. Acute stimulation of this population triggered robust ingestion of sodium even from rock salt, while evoking aversive signals. Inhibition of the same neurons reduced sodium consumption selectively. We further demonstrate that the oral detection of sodium rapidly suppresses these sodium-appetite neurons. Simultaneous in vivo optical recording and gastric infusion revealed that sodium taste—but not sodium ingestion per se—is required for the acute modulation of neurons in the pre-locus coeruleus that express prodynorphin, and for satiation of sodium appetite. Moreover, retrograde-virus tracing showed that sensory modulation is in part mediated by specific GABA (γ-aminobutyric acid)-producing neurons in the bed nucleus of the stria terminalis. This inhibitory neural population is activated by sodium ingestion, and sends rapid inhibitory signals to sodium-appetite neurons. Together, this study reveals a neural architecture that integrates chemosensory signals and the internal need to maintain sodium balance

Temporally and Spatially Distinct Thirst Satiation Signals

For thirsty animals, fluid intake provides both satiation and pleasure of drinking. How the brain processes these factors is currently unknown. Here, we identified neural circuits underlying thirst satiation and examined their contribution to reward signals. We show that thirst-driving neurons receive temporally distinct satiation signals by liquid-gulping-induced oropharyngeal stimuli and gut osmolality sensing. We demonstrate that individual thirst satiation signals are mediated by anatomically distinct inhibitory neural circuits in the lamina terminalis. Moreover, we used an ultrafast dopamine (DA) sensor to examine whether thirst satiation itself stimulates the reward-related circuits. Interestingly, spontaneous drinking behavior but not thirst drive reduction triggered DA release. Importantly, chemogenetic stimulation of thirst satiation neurons did not activate DA neurons under water-restricted conditions. Together, this study dissected the thirst satiation circuit, the activity of which is functionally separable from reward-related brain activity