Yang
et al
. eLife 2021;10:e74551. DOI: https:// doi. org/ 10. 7554/ eLife. 74551
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VASOPRESSIN
Predicting changes
in osmolality
Two neural circuits control the release of vasopressin in response to
eating and drinking before there are any detectable changes in blood
water levels.
ZHE YANG, TONGTONG WANG AND YUKI OKA
T
he balance between water and solutes in
our blood, known as osmolality, must be
tightly controlled for our bodies to work
properly. Both eating and drinking have profound
effects on osmolality in our body. For example,
after several bites of food the brain rapidly trig-
gers a feeling of thirst to increase our uptake of
water (
Leib et al., 2017
;
Matsuda et al., 2017
).
In addition, when fluid balance is disturbed, the
brain releases a hormone called vasopressin that
travels to the kidneys to reduce the excretion
of water (
Geelen et al., 1984
;
Thrasher et al.,
1981
). While much is known about how the brain
controls drinking behavior, it is less clear how it
regulates the hormonal response.
Vasopressin is primarily secreted by Arginine-
vasopressin (AVP) neurons in the supraoptic and
paraventricular nucleus of the hypothalamus.
These neurons not only respond to actual distur
-
bances in water balance, but also anticipate
future osmotic changes that occur after eating
and drinking. In 2017, a group of researchers
discovered that AVP neurons respond to food
and water by rapidly decreasing or increasing
their activity, respectively, before there are any
detectable changes in osmolality (
Mandelblat-
Cerf et al., 2017
). Now, in eLife, researchers
from Harvard Medical School – including Angela
Kim as first author and corresponding author
Bradford Lowell – report the neural pathways
underlying this drinking- and feeding-
induced
regulation of vasopressin (
Kim et al., 2021
).
AVP neurons receive signals from the lamina
terminalis, a brain structure that detects changes
in osmolality and modulates thirst and water
retention (
McKinley, 2003
). Using virus tracing
techniques, the team (which includes some of the
researchers involved in the 2017 study) mapped
neurons in the lamina terminalis that are directly
connected to AVP neurons in mice. This revealed
that excitatory and inhibitory neurons in two
regions of the lamina terminalis (called MnPO
and OVLT) send direct inputs to AVP neurons.
Kim et al. then examined whether these
neurons in the lamina terminalis responded to
drinking and water-
predicting cues (such as
seeing a bowl of water being placed down;
Figure 1
). Excitatory neurons that drive thirst
and stimulate vasopressin release were rapidly
suppressed by both drinking and water-
predictive cues before there were any detect-
able changes in blood osmolality. Conversely,
inhibitory neurons showed the opposite
response, and were activated following bowl
placement and water consumption. This
suggests that excitatory and inhibitory neurons
in the lamina terminalis help anticipate future
osmotic changes by reducing the activity of
AVP neurons in response to drinking and water-
predictive cues.
Related research article
Kim A, Madara
JC, Wu C, Andermann ML, Lowell BB.
2021. Neural basis for regulation of vaso-
pressin secretion by anticipated distur
-
bances in osmolality.
eLife
10
:e66609. doi:
10.7554/eLife.66609
Insight
Yang
et al
. eLife 2021;10:e74551. DOI: https:// doi. org/ 10. 7554/ eLife. 74551
2 of 3
Vasopressin | Predicting changes in osmolality
Further experiments showed that food intake
– but not food-
predicting cues – stimulates
AVP neurons to release vasopressin prior to an
increase in blood osmolality. However, Kim et
al. found that neurons in the lamina terminalis
are unlikely to be involved in this process, as
they did not respond to food consumption as
quickly as AVP neurons. Instead, they discov-
ered that these feeding-
induced signals came
from an undefined neuronal population in the
arcuate nucleus, the hunger center in the brain
that houses the neurons that promote and inhibit
feeding (
Figure 1
;
Atasoy et al., 2012
). Unlike
other neurons involved in hunger, these cells
did not appear to respond to food-
predicting
cues. Molecular data on the different cell types
in the arcuate nucleus could be used to identify
this new population, potentially revealing a new
hunger-
related neural mechanism (
Campbell
et al., 2017
).
Taken together, the findings of Kim et al.
reveal that eating and drinking alter the activity
of AVP neurons via two distinct neural circuits
(
Figure 1
). There are, however, a few limita-
tions to this study. For instance, the regulation
of lamina terminalis neurons and vasopressin is
inseparable. Indeed, manipulation of the lamina
terminalis neurons inevitably changes thirst drive,
water intake and the activity of AVP neurons. This
makes it difficult to pinpoint the source of predic-
tive signals in AVP neurons.
Another question has to do with the physio-
logical significance of the anticipatory regulation
of lamina terminalis neurons and AVP neurons.
If water-
predicting cues suppress excitatory
neurons in the lamina terminalis, how does the
brain maintain the desire to drink? This issue is
particularly important for the thirst system since
thirst-
driving neurons can have acute effects on
drinking behavior (
Augustine et al., 2020
). It
is possible that the lamina terminalis regulates
thirst and vasopressin secretion through different
populations of neurons. Future work could inves-
tigate if the neurons directly connected to AVP
neurons are different to the ones that drive thirst.
Identifying the individual components of the
behavioral and hormonal response may provide
new insights into how the brain regulates the
uptake and excretion of fluids.
Zhe Yang
is in the Division of Biology and Biological
Engineering, California Institute of Technology,
Pasadena, United States
Tongtong Wang
is in the Division of Biology and
Biological Engineering, California Institute of
Technology, Pasadena, United States
Yuki Oka
is in the Division of Biology and Biological
Engineering, California Institute of Technology,
Pasadena, United States
yoka@ caltech. edu
http:// orcid. org/ 0000- 0003- 2686- 0677
Competing interests:
The authors declare that no
competing interests exist.
Published
18 November 2021
References
Atasoy D
, Betley JN, Su HH, Sternson SM. 2012.
Deconstruction of a neural circuit for hunger.
Nature
Figure 1.
How drinking and eating alter the activity of AVP neurons.
AVP neurons (middle) help maintain
osmolality by releasing a hormone called vasopressin, which reduces the amount of fluids excreted from the
kidneys. Eating and drinking have been shown to alter the activity of AVP neurons before there are any detectable
changes in blood osmolality. Water cues (such as the presence of a glass) and drinking suppress the release of
vasopressin (red line) by activating inhibitory neurons (blue circle) in the MnPO and OVLT regions of the lamina
terminalis. Eating, on the other hand, stimulates AVP neurons to release vasopressin (green line) through an
unknown population of neurons (red circle) in the arcuate nucleus, the region of the brain that regulates hunger.
These neural circuits allow the body to react quickly to the osmotic changes caused by eating and drinking before
the balance of fluids in our blood is disrupted.
Insight
Yang
et al
. eLife 2021;10:e74551. DOI: https:// doi. org/ 10. 7554/ eLife. 74551
3 of 3
Vasopressin | Predicting changes in osmolality
488
: 172–177.
DOI: https:// doi. org/ 10. 1038/
nature11270
,
PMID: 22801496
Augustine V
, Lee S, Oka Y. 2020. Neural control and
modulation of thirst, sodium appetite, and hunger.
Cell
180
: 25–32.
DOI: https:// doi. org/ 10. 1016/ j. cell.
2019. 11. 040
,
PMID: 31923398
Campbell JN
, Macosko EZ, Fenselau H, Pers TH,
Lyubetskaya A, Tenen D, Goldman M, Verstegen AMJ,
Resch JM, McCarroll SA, Rosen ED, Lowell BB, Tsai LT.
2017. A molecular census of arcuate hypothalamus
and median eminence cell types.
Nature Neuroscience
20
: 484–496.
DOI: https:// doi. org/ 10. 1038/ nn. 4495
,
PMID: 28166221
Geelen G
, Keil LC, Kravik SE, Wade CE, Thrasher TN,
Barnes PR, Pyka G, Nesvig C, Greenleaf JE. 1984.
Inhibition of plasma vasopressin after drinking in
dehydrated humans.
The American Journal of
Physiology
247
: R968-R971.
DOI: https:// doi. org/ 10.
1152/ ajpregu. 1984. 247. 6. R968
,
PMID: 6507654
Kim A
, Madara JC, Wu C, Andermann ML, Lowell BB.
2021. Neural basis for regulation of vasopressin
secretion by anticipated disturbances in osmolality.
eLife
10
: e66609.
DOI: https:// doi. org/ 10. 7554/ eLife.
66609
,
PMID: 34585668
Leib DE
, Zimmerman CA, Poormoghaddam A,
Huey EL, Ahn JS, Lin Y-
C, Tan CL, Chen Y, Knight ZA.
2017. The forebrain thirst circuit drives drinking
through negative reinforcement.
Neuron
96
: 1272-
1281..
DOI: https:// doi. org/ 10. 1016/ j. neuron. 2017. 11.
041
,
PMID: 29268095
Mandelblat- Cerf Y
, Kim A, Burgess CR,
Subramanian S, Tannous BA, Lowell BB,
Andermann ML. 2017. Bidirectional anticipation of
future osmotic challenges by vasopressin neurons.
Neuron
93
: 57–65.
DOI: https:// doi. org/ 10. 1016/ j.
neuron. 2016. 11. 021
,
PMID: 27989461
Matsuda T
, Hiyama TY, Niimura F, Matsusaka T,
Fukamizu A, Kobayashi K, Kobayashi K, Noda M. 2017.
Distinct neural mechanisms for the control of thirst and
salt appetite in the subfornical organ.
Nature
Neuroscience
20
: 230–241.
DOI: https:// doi. org/ 10.
1038/ nn. 4463
,
PMID: 27991901
McKinley MJ
. 2003. The sensory circumventricular
organs of the mammalian brain.
Advances in Anatomy,
Embryology, and Cell Biology
172
: 1–122.
DOI:
https:// doi. org/ 10. 1007/ 978- 3- 642- 55532-9
Thrasher TN
, Nistal-
Herrera JF, Keil LC, Ramsay DJ.
1981. Satiety and inhibition of vasopressin secretion
after drinking in dehydrated dogs.
The American
Journal of Physiology
240
: E394-E401.
DOI: https://
doi. org/ 10. 1152/ ajpendo. 1981. 240. 4. E394
,
PMID:
7013497