Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Thirst Driving and Suppressing Signals Encoded Distinctly in the Brain


Nature  520, 349–352 (16 April 2015)

Thirst driving and suppressing signals encoded by distinct neural populations in the brain

Yuki Oka,

Department of Biochemistry and Molecular Biophysics, Columbia College of Physicians and Surgeons, Howard Hughes Medical Institute, Columbia University, New York, New York 10032, USA

Department of Neuroscience, Columbia College of Physicians and Surgeons, Howard Hughes Medical Institute, Columbia University, New York, New York 10032, USA


Thirst is the basic instinct to drink water. Previously, it was shown that neurons in several circumventricular organs of the hypothalamus are activated by thirst-inducing conditions1. Here we identify two distinct, genetically separable neural populations in the subfornical organ that trigger or suppress thirst. We show that optogenetic activation of subfornical organ excitatory neurons, marked by the expression of the transcription factor ETV-1, evokes intense drinking behaviour, and does so even in fully water-satiated animals. The light-induced response is highly specific for water, immediate and strictly locked to the laser stimulus. In contrast, activation of a second population of subfornical organ neurons, marked by expression of the vesicular GABA transporter VGAT, drastically suppresses drinking, even in water-craving thirsty animals. These results reveal an innate brain circuit that can turn an animal’s water-drinking behaviour on and off, and probably functions as a centre for thirst control in the mammalian brain.

Body fluid homeostasis regulates the internal salt and water balance; as this balance shifts, the brain senses these changes and triggers specific goal-oriented intake behaviours. For instance, salt-deprived animals may actively consume salty solutions, even though such high levels of salt are normally strongly aversive. Similarly, dehydrated animals are strongly motivated to consume water. Previous studies have shown that various regions in the circumventricular organs (CVO) of the hypothalamus are activated in response to dehydration. In addition, intracranial injection of angiotensin, a vasoactive hormone that stimulates drinking, has been shown to activate CVO neurons in several species, and electrical stimulation of CVO nuclei increased fluid consumption in rodents.

The subfornical organ (SFO) is one of several CVO nuclei activated by thirst-inducing stimuli (for example, water-deprivation). This nucleus lacks the normal blood–brain barrier, and has been proposed to function as an osmolality sensor in the brain. We reasoned that if we could identify a selective population of neurons in the SFO that respond to dehydration, they might provide a genetic handle to explore the neural control of thirst and water-drinking behaviour.

Thirst is a fundamental physiological state representing a basic and innate response to dehydration. Earlier studies using micro-electrical stimulation and hormonal injections implicated the SFO in fluid homeostasis, and possibly salt appetite. Here we have shown that the craving for water can be controlled with cell-type-specific precision in the SFO.

We used a combination of genetic and optogenetic tools in awake, behaving animals to demonstrate that the ETV-1- and Vgat-positive neurons of the SFO evoke or suppress the motivation to drink, respectively. We have shown that activation of either population instantly triggers the behaviour, be it water-seeking and drinking in normal or water-satiated animals, or strong suppression of drinking in thirsty animals; these responses are selective to water-drinking, with no effect on feeding or salt appetite. Significantly, most of the neurons in the SFO are either ETV-1-positive or Vgat-positive, strongly arguing that the SFO is a dedicated brain system for thirst, functioning possibly at the interface between the physiological/internal state of the organism and the motivation to drink water. Interestingly, the ETV-1 neuronal population selectively expresses the angiotensin receptor AT1, identifying these neurons as a possible target of angiotensin-mediated drinking responses.

In addition to the SFO, dehydration activates several other brain regions, including the organum vasculosum of the lamina terminalis1, another hypothalamic nucleus lacking the blood–brain barrier. Notably, this nucleus has direct connections to the SFO. Indeed, as an entry to dissect the circuit for thirst further, we surveyed the axonal projections from the ETV-1 and Vgat-expressing neurons in the SFO. Our results show that both classes of SFO neurons project to the organum vasculosum of the lamina terminalis and the median preoptic nucleus. Interestingly, the glutamatergic neurons (that is, excitatory), unlike the GABAergic neurons, also project to the supraioptic nucleus and the paravenrtricular hypothalamic nucleus. Future physiological and behavioural studies should help reveal the role of these nodes in the neural circuitry mediating thirst, and their association with brain centres involved in other motivational states.



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