Terrestrial animals, including humans, have mechanisms that maintain body fluid homeostasis under various body
fluid conditions. For example, thirst and the avoidance of salty food are associated with dehydration. To achieve this,
the brain continuously monitors body fluid conditions and controls thirst and salt appetite. The monitoring loci responsible
have been suggested to be at sensory circumventricular organs (sCVOs) because they lack a blood-brain barrier, but
contain neurons. sCVOs consist of the subfornical organ (SFO), organum vasculosum of the lamina terminalis (OVLT), and
area postrema (AP). We recently revealed the neural mechanisms responsible for the intake of water and salt that
originate from these organs.
The peptide hormone, angiotensin II (ang II), the levels of which increases in blood under water- as well as sodium
(Na)-depleted conditions, stimulates the intake of water and salt. We previously identified a subset of neurons that
drive thirst and salt appetite in the SFO, referred to as “water neurons” and “salt neurons”, respectively 1) . Both of these
neurons expressed ang II receptors (AT1a). Under water-depleted conditions, glial cells expressing Na x channels in the SFO
detected an increase in Na + levels ([Na + ]) in body fluids, and activated GABAergic inhibitory neurons to suppress
“salt neurons” through the secretion of lactate. As a result, water-intake behavior was selectively induced under
water-depleted conditions 1-3) (Figs. 1, 2). In contrast, under Na-depleted conditions, the activation of other GABAergic neurons
suppressed “water neurons” in response to cholecystokinin (CCK), and, thus, selectively induced salt-intake behavior 1) . We also
demonstrated that Na x channels in the OVLT detected an increase in [Na + ] in body fluids and induced the secretion of
epoxyeicosatrienoic acids (EETs) from Na x -positive glial cells 4) . This resulted in the activation of TRPV4-positive
neurons to induce water-intake behavior.
Fig. 1: Sensing mechanism of [Na+] in body fluids in the SFO
Fig. 2. Neural mechanism controlling thirst and salt appetite by ang II
However, the osmosensor or neural mechanisms responsible for the detection of osmolality in the brain remain
unclear. We are now attempting to elucidate the whole picture of brain mechanisms underlying the sensing of body fluid conditions
, as well as the integration mechanisms of neural information downstream of the SFO and OVLT. To
achieve this, we are conducting research using advanced neuroscientific techniques, such as optogenetics (Movie 2)
to artificially control neural activities using light, and in vivo calcium imaging, a technique to observe neuronal activities at
the single cell level.
Movie 2. Drinking behavior induced by an optical stimulation
(References)
1. Matsuda T., Hiyama TY, Niimuara F, Matsusaka T, Fukamizu A, Kobayashi K, Kobayashi K and Noda M.
Distinct neural mechanisms for the control of thirst and salt appetite in the subfornical organ. Nature Neurosci.
,20, 230-241, 2017.
2. Hiyama TY, Watanabe E, Ono K, Inenaga K, Tamkun MM, Yoshida S, & Noda M. Na x is involved in the sodium
level sensing in the CNS. Nature Neuroscience, 2002 Jun;5(6): 511-2.
3. Shimizu, H., Watanabe, E., Hiyama, T.Y., Nagakura, A., Fujikawa, A., Okado, H., Yanagawa, Y.,
Obata, K. and Noda, M. Glial Na x channels control lactate signaling to neurons for brain [Na + ] sensing. Neuron
2007, 54: 59- 72.
4. Sakuta H, Nishihara E, Hiyama TY, Lin CH and Noda M. Na x signaling evoked by an increase in [Na + ] inCSF
induces water intake via EET-mediated TRPV4 activation. Am. J. Physiol. Regul. Integr. Comp. Physiol., 311,
R299-306, 2016.