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Pass the salt: the central control of sodium intake

Amber L Alhadeff & J Nicholas Betley
The biological drive to consume salt ensures that we consume adequate sodium for survival. In this issue of Nature
Neuroscience, two articles provide insight into the neurons and circuits that regulate sodium appetite.

Through the ages, salt has been highly valued.
Salacia, the Roman goddess of salt water; wars
waged over access to salt; and references to salt
in the works of Shakespeare and in the Bible
all highlight the anthropological significance
of this mineral over centuries1. The cultural
importance ascribed to salt perhaps reflects
© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
they demonstrate that HSD2 neurons in the
nucleus of the solitary tract are both neces-
sary and sufficient for the full expression of
sodium appetite. Jarvie and Palmiter5 further
show that HSD2 neurons project to the ventral
bed nucleus of the stria terminalis, the medial
central lateral parabrachial nucleus and pre-
role of these individual projections. Overall,
these data pave the way for future studies to
further define this circuit in the nucleus of the
solitary tract and establish the importance of
identifying postsynaptic target neurons that
mediate the effects of HSD2 neuron activity.
Building on work implicating the circum-

the strong biological drive to consume salt
when deprived of sodium. While the negative
health outcomes of high dietary sodium are
often highlighted in modern society, the physi-
ological value of sodium is less appreciated.
Indeed, low sodium levels have health conse-
quences that are detrimental to normal muscle
and neural function and that in extreme cases
may compromise survival.
Studies on the regulation of sodium appetite
were pioneered by Curt Richter’s classic stud-
ies showing that the drive to consume sodium
is hormonally regulated2. Sodium deprivation
and/or hypovolemia increase circulating levels
of hormones such as aldosterone and angio-
tensin II, both of which regulate physiological
osmolarity1,3,4. The identification of these hor-
mone systems has pointed to specific regions
of the brain as central regulators of osmotic
balance. In this issue of Nature Neuroscience,
Jarvie and Palmiter5 and Matsuda et al.6 target
distinct populations of neurons that are sen-
sitive to hormones involved in sodium appe-
tite and manipulate neural activity to dissect
the functions of these neurons. These studies
advance the field of sodium appetite by identi-
fying discrete, genetically defined neurons that
can be exploited to elucidate the anatomical
and functional organization of circuits promot-
locus coeruleus. Their analyses of immediate-
early gene expression changes following
sodium deprivation or activation of HSD2
neurons suggest that the medial central lateral
parabrachial nucleus and pre-locus coeruleus
help mediate the effects of HSD2 neuron acti-
vation. Functional assessment of these distinct
projections, as well as neural activity monitor-
ing during sodium deficiency, will clarify the
a
vBNST
SFO PBN
Pre-LC
OVLT
b NaX-expressing
inhibitory
interneuron
ventricular subfornical organ (SFO) in osmo-
regulation10–13, Matsuda et al.6 performed
experiments that substantially increase our
understanding of functional SFO neuron
subtypes. Through a series of experiments
that extensively characterized the anatomi-
cal and functional connectivity of excitatory
angiotensin II receptor 1a-expressing (AT1a)
neurons in the SFO, this study revealed the
Osmoregulatory neurons
AT1a neurons OVLT (thirst)
AT1a neurons BNST (salt appetite)
HSD2 neurons of the NTS (salt appetite)
Osmoregulatory projections
Thirst
Salt appetite
NTS Salt appetite (putative)
CCK-sensitive
inhibitory
interneuron
Debbie Maizels / Springer Nature

ing this fundamental survival need (Fig. 1a).

Guided by observations that aldosterone-
sensitive neurons in the hindbrain influence
sodium appetite7–9, Jarvie and Palmiter5 gen-
erated mice that allow the selective mapping
and manipulation of aldosterone-sensitive
11β-hydroxysteroid dehydrogenase type 2
(HSD2) neurons. Harnessing bidirectional
chemogenetic control of neural activity,
Amber L. Alhadeff and J. Nicholas Betley are in the
Department of Biology, University of Pennsylvania,
Philadelphia, Pennsylvania, USA.
e-mail: jnbetley@sas.upenn.edu
AT1a neurons of the SFO
(excitatory projections)
Figure 1 Neural circuits involved in osmoregulation. (a) Jarvie and Palmiter5 describe a population of
aldosterone-sensitive nucleus of the solitary tract (NTS) HSD2 neurons that increase sodium intake and
project to the medial central lateral parabrachial nucleus (PBN), the pre-locus coeruleus (pre-LC) and the
ventral bed nucleus of the stria terminalis (vBNST). Matsuda et al.6 characterize two populations of SFO
AT1a neurons that project to the organum vasculosum of the lamina terminalis (OVLT) and vBNST and
increase water and sodium intake, respectively. (b) Matsuda et al.6 identified a population of SFO AT1a
neurons that receive inhibitory drive from cholecystokinin (CCK)-sensitive interneurons, project to the
OVLT and increase water intake. A separate population of SFO AT1a neurons receives inhibitory projections
from sodium (Nax)-channel-expressing neurons, project to the vBNST and increase sodium intake.

130 volume 20 | number 2 | February 2017 nature neuroscience


existence of two distinct AT1a circuits that
drive water or sodium intake. Matsuda et al.6
demonstrated that one AT1a neuron popu-
lation receives inhibitory drive from chole-
cystokinin-sensitive interneurons, projects
to the organum vasculosum of the lamina
terminalis and is necessary and sufficient
for thirst. A separate AT1a population in the
SFO is inhibited by local sodium-channel-
expressing neurons, projects to the ventral
bed nucleus of the stria terminalis and is
necessary and sufficient for sodium appetite
(Fig. 1b). This study defines the anatomical
organization, physiological properties and
molecular mechanisms of AT1a neuron popu-
lations in the SFO, substantially broadening
our knowledge of circuit connectivity and
© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
effectively dissociating neural circuits that
promote water versus sodium intake.
These formative studies define indepen-
dent circuits that are required for the full
expression of sodium appetite. The circuits
described are distinct not only with respect
to the molecular phenotypes of the respec-
tive neural populations but also with regard
to anatomical location. Jarvie and Palmiter5
point toward functional projections resid-
ing primarily in brainstem regions, whereas
New building blocks for navigation
Jeffrey S Taube
Many spatial correlates have been identified that form the neural basis for navigation. Two studies have now uncovered
a new cell type: bidirectional cells, which fire when the head is pointing in one of two opposing directions.
Place cells, head direction cells, grid cells,
border cells, angular head velocity cells, speed
cells, pitch cells and various combinations of
these parameters have been identified over
the past five decades1,2. Since the first report
of place cells in 1971, these cells have formed
the building blocks for understanding how
the brain forms an awareness of perceived ori-
entation, which allows organisms to navigate
successfully. This issue of Nature Neuroscience
adds two new spatial cell types to this
mix: axis-tuned cells3 and bidirectional head
direction (HD) cells4.
Both of these new cell types can be consid-
ered variants of the well-studied HD cell, first
discovered by James Ranck in 1984 (ref. 1).
Jeffrey S. Taube is in the Department of
Psychological & Brain Sciences, Dartmouth College,
Hanover, New Hampshire, USA.
e-mail: jeffrey.taube@dartmouth.edu
nature neuroscience volume 20 | number 2 | February 2017
Matsuda et al.6 outline circuits with nodes in
the forebrain. Together, these studies point
to the redundant nature of the circuitry that
drives sodium intake, perhaps akin to the
redundant circuitry mediating energy bal-
ance control14,15. Determining the interac-
tion between these distinct circuit nodes will
be an important step forward in understand-
ing how the brain integrates signals of need
to drive sodium intake. Do several distinct,
non-overlapping circuits exist to ensure ade-
quate sodium intake? Alternatively, do these
circuits converge on a master regulator of
fluid homeostasis or interact with a distrib-
uted and elaborate network that regulates
osmolarity? Further, what behavioral and
motivational mechanisms are recruited by
activity in these neurons, and are they similar
to other biological survival drives? Of course,
osmoregulation is a complex physiological
process that likely requires the coordination
of need sensing with a motivated response
in order to resolve the appropriate need,
perhaps indicating the necessity of multiple
circuits that influence discrete and identifi-
able aspects of behavior. Since a central goal
of neuroscience is to understand how the
brain orchestrates behavioral responses to
HD cells discharge as a function of the animal’s
perceived heading in the horizontal plane,
independently of the animal’s location and
behavior (Fig. 1a). Each HD cell is tuned to
a single direction, referred to as the cell’s pre-
ferred firing direction, and the cell’s firing rate
decreases linearly as the head deviates from
this direction. A population of HD cells is
similar to a collection of compasses with each
one tuned to a different direction.
HD cells were originally identified in the
dorsal presubiculum, often referred to as the
postsubiculum. The presubiculum is one of
the three primary areas of the subicular complex,
which also includes the subiculum and para-
subiculum. Each of these three areas has its
own connectivity and contains both afferent
and efferent connections with the hippocam-
pus and entorhinal cortex. Thus, the subicu-
lar complex is an important node integrating
information with the hippocampus. HD cells
are found in many brain areas throughout
news and views
physiological needs, the identification of neu-
ral circuits that coordinate sodium appetite
represents an important step toward unravel-
ing this complex and multifaceted problem.
COMPETING FINANCIAL INTERESTS
The authors declare no competing financial interests.
1. Geerling, J.C. & Loewy, A.D. Exp. Physiol. 93,
177–209 (2008).
2. Richter, C.F. Am. J. Physiol. 115, 155–161 (1936).
3. McEwen, B.S., Lambdin, L.T., Rainbow, T.C. &
De Nicola, A.F. Neuroendocrinology 43, 38–43 (1986).
4. Buggy, J. & Fisher, A.E. Nature 250, 733–735 (1974).
5. Jarvie, B.C. & Palmiter, R.D. Nat. Neurosci. 20,
167–169 (2017).
6. Matsuda, T. et al. Nat. Neurosci. 20, 230–241 (2017).
7. Formenti, S. et al. Am. J. Physiol. Regul. Integr. Comp.
Physiol. 304, R252–R259 (2013).
8. Geerling, J.C., Engeland, W.C., Kawata, M. & Loewy, A.D.
J. Neurosci. 26, 411–417 (2006).
9. Geerling, J.C. & Loewy, A.D. J. Comp. Neurol. 497,
223–250 (2006).
10. Oka, Y., Ye, M. & Zuker, C.S. Nature 520, 349–352
(2015).
11. Johnson, R.F., Beltz, T.G., Thunhorst, R.L. & Johnson, A.K.
Am. J. Physiol. Regul. Integr. Comp. Physiol. 285,
R394–R403 (2003).
12. Nation, H.L., Nicoleau, M., Kinsman, B.J., Browning, K.N.
& Stocker, S.D. J. Neurophysiol. 115, 3123–3129
(2016).
13. Betley, J.N. et al. Nature 521, 180–185 (2015).
14. Betley, J.N., Cao, Z.F., Ritola, K.D. & Sternson, S.M.
Cell 155, 1337–1350 (2013).
15. Grill, H.J. Obesity (Silver Spring) 14 (Suppl. 5),
216S–221S (2006).
the limbic system, and several brainstem sites
are responsible for generating the signal1.
Self-movement cues are integrated in these
brainstem areas, and the processed HD signal
propagates rostrally through a network that
includes the lateral mammillary nuclei, antero-
dorsal thalamus, postsubiculum and entorhi-
nal cortex. Visual landmark information is
integrated into this circuit via direct projec-
tions from visual cortex to the postsubiculum,
but the retrosplenial cortex (RSC) also plays a
role—a point that we will return to below.
Until now, all studies on HD cells had found
them to be unidirectional, with each cell tuned
to only one direction. The two studies in this
issue report cells that are tuned to two differ-
ent head directions, even in the same environ-
ment. In the first study, Olson, Tongprasearth
and Nitz3 recorded from cells in the subiculum
proper while rats traversed a complex maze
(Fig. 1b). The researchers found cells that fired
in two different directions, always ~180° apart
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