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Neural Architecture Underlying Thirst Regulation


Augustine, Vineet (2019) Neural Architecture Underlying Thirst Regulation. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/1H4D-7146.


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.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:thirst; brain; mouse; satiation; reward; circuits; gut-brain axis
Degree Grantor:California Institute of Technology
Division:Biology and Biological Engineering
Major Option:Computation and Neural Systems
Awards:Lawrence L. and Audrey W. Ferguson Prize, 2019.
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Oka, Yuki
Thesis Committee:
  • Siapas, Athanassios G. (chair)
  • Anderson, David J.
  • Gradinaru, Viviana
  • Oka, Yuki
Defense Date:13 February 2019
Non-Caltech Author Email:vineet.academic (AT)
Record Number:CaltechThesis:06042019-143921851
Persistent URL:
Related URLs:
URLURL TypeDescription neural architecture underlying thirst regulation and Central Nutrient Sensing Underlying Appetite Regulation and Spatially Distinct Thirst Satiation Signals modulation of neural circuits for sodium appetite populations for maintaining body fluid balance
Augustine, Vineet0000-0003-4431-1663
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:11683
Deposited By: Kathy Johnson
Deposited On:04 Jun 2019 21:42
Last Modified:04 Nov 2021 21:29

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