Regulation of Nervous System Function by Circumventricular Organs

Abstract

In this chapter, we highlight the specialized features of the sensory circumventricular organs (CVO) as central nervous system (CNS) structures located at the blood-brain interface. These structures appear to play critical roles in sensing and integrating information regarding autonomic status derived from circulating signals that do not readily cross the BBB. Intriguingly, while the majority of the original literature highlighting such roles attributed primarily fluid balance and cardiovascular functions to the subfornical organ (SFO) and metabolic function to the area postrema (AP), more recent work as highlighted in this chapter has clearly demonstrated, not only overlap in these physiological roles in SFO and AP, but also additional roles for these CVOs in reproductive and of primary importance to this chapter immune signaling from the circulation to the CNS. Within not only SFO and AP, but also the organum vasculosum of the lamina terminalis, the emerging literature supports the conclusion that single neurons in these CVOs sense, and presumably integrate, signals related to all of these separately classified autonomic functions. In recognizing the potential for such integration in the sensory CVOs, it becomes important to also understand that optimal health is associated with the ability of our physiological systems to regulate these functions in an integrated rather than separate manner.

Full text

25© Springer International Publishing Switzerland 2017
T. Ikezu, H.E. Gendelman (eds.), Neuroimmune Pharmacology, DOI 10.1007/978-3-319-44022-4_3
Regulation of Nervous System Function
by Circumventricular Organs
Emily A.E. Black, Nicole M. Cancelliere,
and Alastair V. Ferguson
Abstract
In this chapter, we highlight the specialized features of the sensory circumventricular organs
(CVO) as central nervous system (CNS) structures located at the blood-brain interface.
These structures appear to play critical roles in sensing and integrating information regard-
ing autonomic status derived from circulating signals that do not readily cross the BBB.
Intriguingly, while the majority of the original literature highlighting such roles attributed
primarily fluid balance and cardiovascular functions to the subfornical organ (SFO) and
metabolic function to the area postrema (AP), more recent work as highlighted in this chap-
ter has clearly demonstrated, not only overlap in these physiological roles in SFO and AP,
but also additional roles for these CVOs in reproductive and of primary importance to this
chapter immune signaling from the circulation to the CNS. Within not only SFO and AP, but
also the organum vasculosum of the lamina terminalis, the emerging literature supports the
conclusion that single neurons in these CVOs sense, and presumably integrate, signals
related to all of these separately classified autonomic functions. In recognizing the potential
for such integration in the sensory CVOs, it becomes important to also understand that
optimal health is associated with the ability of our physiological systems to regulate these
functions in an integrated rather than separate manner.
Keywords
Area postrema • Blood brain barrier • Central autonomic control • Circulating signals •
Circumventricular organ • Subfornical organ
E.A.E. Black • N.M. Cancelliere • A.V. Ferguson (*)
Department of Biomedical and Molecular Sciences, Queen’s
University, Kingston, ON, Canada, K7L 3N6
e-mail: avf@queensu.ca
3
3.1 Introduction
It is well accepted that the central nervous system (CNS) is
the “command center” of the body, being the system that not
only collects and integrates critical autonomic information
coming from either the internal or external environment of
the organism, but also initiates appropriate physiological
responses. Information regarding these autonomic systems
comes from a variety of sensors including thermoreceptors,
baroreceptors, chemoreceptors, as well as those monitoring
fluid volume, metabolic state, and immune status. It is pri-
marily conveyed in the form of signaling molecules released
from one cell to influence the function of another, such as
amino acids, peptides, gases, and larger macromolecules,
delivered to their site of action in target cells by: the blood
(hormones), synaptic terminals (neurotransmitters) or local
mechanisms (paracrine). Neuronal systems (autonomic con-
trol centers) within the CNS detect these molecules and
adjust physiological systems of the body accordingly in
order to maintain the critical “milieu interieur” of a well
regulated homeostatic system.
Importantly, many of these signaling molecules which
originate in the periphery and play important roles in the
central regulation of immune function (e.g. IL-1, IL-6,

26
TNFalpha) are large and/or lipophobic and thus do not readily
cross the blood-brain barrier (BBB), an endothelial/glial
cell barrier separating the CNS from the periphery. The BBB
is comprised of three layers of cells: the endothelial cells of
the capillaries (this layer “faces” the interstitial fluid), the
epithelial cells of the choroid plexus, and the arachnoid epi-
thelium (an avascular layer of cells surrounding the CNS).
The processes of the astroglial cells are also an important
component. The cells forming these layers are connected via
tight junctions and express transporters for specific mole-
cules, both of which allow the BBB to fulfill its function of
selectively excluding macromolecules and polar solutes
(Abbott et al. 2006).
3.2 The Circumventricular Organs
In view of this lack of permeability, the BBB would make it
difficult for the CNS structures protected by the barrier to
detect critical signaling molecules in the general circulation,
and thus nearly impossible for these structures to appropri-
ately respond to these signals. How does the CNS then man-
age to interpret the information provided by the peripheral
systems of the body? A few mechanisms of communication
between the periphery and CNS exist, such as diffusion and
active transport. However, the number of substances that are
able to cross the BBB using either method is limited since
diffusion only allows small, non-polar molecules to cross
this CNS barrier. In contrast, larger lipophobic substances
require a suitable transporter to cross the BBB and to date,
few specific transporters have been identified.
A solution to this apparent dilemma presents itself in the
form of the circumventricular organs (CVOs) of the brain.
These specialized structures are highly vascularized areas of
the brain whose capillaries do not contain the tight junctions
of the BBB but are instead fenestrated, meaning that gaps
exist between the endothelial cells leading to the formation
of Virchow-Robin Spaces (Price et al. 2008) that allows cir-
culating blood containing large lipophobic signals to enter
and pool, facilitating free exchange between the blood and
nervous tissue of the body. The CVOs can be primarily clas-
sified as either secretory (neurohypophysis, median emi-
nence, intermediate lobe, and pineal), or sensory (area
postrema, subfornical organ and organum vasculosum of the
lamina terminalis) (Fig. 3.1), while the subcommisural organ
does not fit readily into either of the categories and will not
be discussed further here.
3.3 The Secretory CVOs
The primary focus of this chapter will be on the sensory CVOs,
but we will first very briefly highlight roles of the secretory
CVOs in the release of centrally synthetized lipophobic hor-
mones directly into the circulation or cerebrospinal fluid. The
secreted products are synthesized in parts of the brain that are
protected by the BBB such as the supraoptic, paraventricular,
and arcuate nuclei; and thus, these specialized areas of fenes-
trated capillaries permit the release of synthesized lipophobic
products into general circulation. The neurohypophysis is the
posterior lobe of the pituitary gland and secretes oxytocin and
vasopressin, hormones involved in reproduction and fluid bal-
ance, directly into general circulation (Sofroniew 1983;
Sofroniew et al. 1981). The intermediate lobe of the pituitary
gland, which separates the anterior and posterior lobes of this
endocrine gland in humans, synthesizes and secretes melano-
cyte-stimulating hormone (MSH). The median eminence
(ME), perhaps the most important of the secretory CVOs, con-
sists of neuronal terminals which “synapse” on the hypophy-
seal portal capillaries, the entry point for hypothalamic trophic
Subfornical Organ
Area Postrema
Subfornical
Organ
Area Postre
ma
OVLT
Median
Eminence Posterior Pituitary
Intermediate
Pituitary
Sensory CVOs
Secretory CVOs
Pineal Gland
Fig. 3.1 Anatomical locations of the sensory and secretory circumventricular organs of the rat brain. Midsagittal section of the rat brain. CVOs
circumventricular organs, OVLT organum vasculosum of the lamina terminalis
E.A.E. Black et al.

27
hormones controlling the extensive endocrine roles of the
anterior pituitary. The hormones secreted by the ME include
gonadotropin- releasing hormone, growth hormone-releasing
hormone, dopamine, thyrotropin-releasing hormone, and
corticotropin- releasing hormone. The pineal gland is the final
secretory CVO which produces melatonin, a critical compo-
nent in the regulation of circadian rhythms. It secretes this hor-
mone not only into the circulation but also into the cerebrospinal
fluid (Cassone et al. 1993).
3.4 Sensory CVOs
The sensory CVOs are, in many ways, contrasting structures to
the secretory CVOs in that their primary function is to detect,
rather than release, signals at the blood-brain interface. The
three sensory CVOs are characterized by high expression lev-
els of a variety of receptors and their resulting ability to inte-
grate a multitude of signals. These are: the area postrema (AP),
the subfornical organ (SFO), and the organum vasculosum of
the lamina terminalis (OVLT). Another defining characteristic
of these areas is the minimal afferent input they seem to receive
relative to their extensive neural outputs. Additionally, most of
the afferent input received by these three CVOs seems to come
from the very structures onto which they project, indicating the
probability of reciprocal communication between the sensory
CVOs and the other structures. They are primarily known for
their involvement in cardiovascular regulation and fluid bal-
ance; however, these structures have also been shown to be
involved in the regulation of other processes such as energy
metabolism, reproduction, and immune response.
3.4.1 Neuroanatomy and Connectivity
of Sensory CVOs
The anatomy and connectivity of the CVOs provide valuable
insight into their roles in the regulation of nervous system
function. This section will outline the anatomical location
and connections associated with the various sensory CVOs
in order to provide a framework for the understanding of
their central roles in immune function and regulation of auto-
nomic state.
3.4.1.1 Subfornical Organ
The SFO is a highly vascularized, translucent midline struc-
ture protruding from the rostral wall of the third ventricle in
the dorsal region of the lamina terminalis. It lies between the
columns of the fornix, and its dorsal end is attached to the
hippocampal commissure. It consists of a ventral stalk and
dorsal crest, which connects to the median preoptic nucleus
and the tela choroidea of the third ventricle, respectively
(McKinley et al. 2003). The rich capillary network that sur-
rounds the SFO is formed by an anastomosis between
branches of the anterior cerebral artery and the posterior cho-
roidal artery. It is so dense that it must be peeled away during
microdissection in order to see the SFO. Upon histological
assessment, the SFO can be divided into three distinct areas
based on morphology: The core region is the largest and is
exclusively composed of neuronal cell bodies and glial cells.
The rostral and caudal regions surround the core, and contain
very few neurons and glial cells, consisting mainly of nerve
fibers (Dellmann and Simpson 1979).
The major contributions to the current understanding of
the SFO’s neurocircuitry can be attributed to the comprehen-
sive studies by the labs of Hernesniemi et al. (1972), Miselis
(1981, 1982), and Lind et al. (1982). The earlier study used
lesion techniques and Golgi staining methods (Hernesniemi
et al. 1972), and the latter investigations used horseradish
peroxidase injections to follow anterograde and retrograde
transport of labeled proteins through axons (Miselis 1981,
1982; Lind et al. 1982). Evidence for these connections is
supported in studies using electrophysiological stimulation
(Ferguson and Bains 1996; Bains and Ferguson 1995).
A summary of the major and minor afferent and efferent
neuronal connections to and from the SFO are outlined in
Fig. 3.2. The major efferents can be grouped into two general
areas:
3.4.1.2 The Neuroendocrine and Autonomic
Control Centers of the Hypothalamus
Direct (monosynaptic) and indirect (polysynaptic) efferent
projections terminate in the anterior and tuberal supraoptic
nuclei (SONa and SONt), and the paraventricular nucleus
(PVN) including its rostral accessory cluster, respectively.
Electrophysiology studies demonstrated excitatory SFO pro-
jections to vasopressin- and oxytocin-secreting magnocellular
neurons in the SON and PVN, as well as in parvocellular areas
of the PVN, which, in turn, project either to the median emi-
nence, the medulla, or the spinal cord. Many efferent fibers to
the hypothalamus emerge from the rostral SFO and enter the
columns of the fornix, diverge with the ventral stria medullari
to disperse medially and laterally over the columns of the for-
nix and along their dorsal border at the anterior dorsal level of
the columns trajectory through the hypothalamus.
3.4.1.3 The Anteroventral Third Ventricular
(AV3V) Area
This includes the median preoptic nucleus (MnPO), the ante-
rior periventricular (Pe) area of the hypothalamus, and the
organum vasculosum of the lamina terminalis (OVLT)—
another sensory CVO to be discussed later. Many efferent
fibers to this area emerge from the rostral SFO, pass anteri-
orly over the anterior commissure in the midline and either
descend along the anterior border of the MnPO or enter the
Pe dorsally just beneath the anterior commissure.
3 Regulation of Ner vous System Function by Circumventricular Organs

28
It is important to note that dendritic trees of SFO neurons
are relatively compact, and the extent of afferent connectiv-
ity is not nearly as elaborate as the efferents (Dellmann and
Simpson 1979). These neuroanatomical findings suggest that
there is reciprocal communication occurring between these
brain regions and that perhaps the SFO’s primary afferent
information is received from circulating signals in the
peripheral circulation as opposed to signals from other brain
regions.
3.4.1.4 Organum Vasculosum of the Lamina
Terminalis
The organum vasculosum of the lamina terminalis (OVLT) is a
midline structure in the anterior wall of the third cerebral ven-
tricle, located ventral to the MnPO and immediately dorsal to
the optic chiasm. The OVLT, like the other sensory CVOs, con-
tains a rich arterial blood supply and aggregation of neuronal
cell bodies. In 1969, Duvernoy et al. published a detailed study
illustrating the four major arterial sources of the human
OVLT—a superior median source branching from the anterior
communicating artery, two lateral sources from arteries which
branch off from each anterior cerebral artery below the anterior
communicating artery, and an inferior median source ascend-
ing from below the optic chiasm (Duvernoy et al. 1969).
The OVLT can be grouped into two major regions, the dorsal
cap and the lateral regions, which each display unique projection
patterns. As is the case for the SFO, much of what is known
about the neuronal connections to and from the OVLT can be
attributed to a few key tracer studies conducted in the late 1970s
and early 1980s that utilized the axonal transport of marker mol-
ecules, such as tritiated amino acids and horseradish peroxidase
(HRP), in experimental models such as rats and sheep (Camacho
and Phillips 1981; Phillips and Camacho 1987; Oldfield et al.
1991; ter Horst and Luiten 1986). The OVLT’s main afferent and
efferent projections are summarized in Fig. 3.3. Much like the
SFO, the OVLT’s dominant efferents project to magnocellular
neurons of the PVN and SON (either directly or indirectly
through the MnPO); and afferents are derived from the MnPO,
SFO, and a variety of hypothalamic regions. Efferent connec-
tions have also been found to corticotrophin releasing factor-rich
neurons in the PVN (Saper and Levisohn 1983). As in the case of
SFO, outlined above, there is again a pattern of small dendritic
trees of OVLT neurons, minimal afferent neural inputs, and
reciprocal communication between afferent and efferent projec-
tion sites.
3.4.1.5 Area Postrema
The AP is a midline hindbrain structure located on the dorsal
surface of the medulla oblongata, immediately adjacent to the
NTS seen protruding into the fourth ventricle (Wislocki and
Putnam 1920). The three regions of the AP include the ventral
zone, which contains mostly glia (McKinley et al. 2003), and
Subfornical Organ
Area Postrema
Subfornical
Organ
Efferent connections:
•Paraventricular nucleus
•Supraoptic nucleus
•Median Preoptic nucleus
•Lateral hypothalamus
•OVLT
•Arcuate nucleus
Afferent connections:
•Lateral parabrachial nucleus
•Nucleus of the solitary tract
•Median preoptic nucleus
•Lateral hypothalamus
•OVLT
PVNLH
Arc
SON
MnPO
OVLT
Efferent Connection
Reciprocal Connection
NTS
Afferent Connection
LPBN
Fig. 3.2 Primary neuronal connections of the subfornical organ. A
midsagittal section of rat brain representing major afferent and efferent
projections of subfornical organ. Afferent pathways are represented by
yellow arrows, efferent pathways are represented by blue arrows, and
reciprocal projections are represented by purple arrows. OVLT orga-
num vasculosum of the lamina terminalis; Hypothalamic structures:
MnPO median preoptic nucleus, SON supraoptic nucleus, PVN para-
ventricular nucleus, LH lateral hypothalamus, Arc arcuate nucleus;
Hindbrain structures: LPBN lateral parabrachial nucleus, NTS nucleus
of the solitary tract
E.A.E. Black et al.

29
the mantle zone and central zone, which are rich with neuronal
cell bodies and axons situated next to ependymal cells.
Separating the AP and NTS is a layer of tanycytes called the
funiculus separans that function much like the BBB. Like the
other two sensory CVOs, the AP is one of the most highly
vascularized regions in the entire mammalian brain, showing
a 150-fold increase in the surface area to permeability ratio
when compared with the adjacent regions of the dorsomedial
medulla (Gross 1991).
The AP was for decades known as the “chemoreceptor
trigger zone” where noxious chemicals in the circulation
acted to induce an emetic reflex (Borison and Brizzee 1951;
Miller and Leslie 1994). However, despite this well studied
functional role, more recent evidence suggests that the AP,
like the other sensory CVOs, is also involved in various
autonomic functions (to be discussed below).
Much of what is known about the anatomical connections
of the AP is derived from retrograde tracing studies per-
formed in the early- to mid-1980s. Using wheat germ agglu-
tinin HRP (van der Kooy and Koda 1983) and cholera-toxin
HRP (Shapiro and Miselis 1985), the studies illustrate the
connections of the AP to and from various autonomic control
centers in the medulla, pons, and hypothalamus. The AP has
strong reciprocal connections to and from the lateral parabra-
chial nucleus of the pons (LPBN) and the NTS—two multi-
functional integrative brainstem structures. It also receives
substantial input from the parvocellular regions of the
paraventricular and dorsomedial nuclei of the hypothalamus,
in addition to peripheral information from vagal and carotid
sinus nerve afferents originating from the respiratory, gastro-
intestinal, and cardiovascular systems (Fig. 3.4).
Despite each sensory CVOs distinct neuroanatomy and
afferent and efferent projection sites, the SFO, OVLT, and AP
do share various similarities that provide us with a framework
for understanding and further investigating their functional
roles. Each lack a BBB, are highly vascularized, efficaciously
located at an interface between the brain and the circulation,
display elaborate efferent connections with few afferents, and
express receptors for numerous circulating signals.
Additionally, the main projection sites are reciprocated and
target various secretory and integrative nuclei in the hypo-
thalamus and brainstem that are involved in the regulation of
broad ranging autonomic functions including cardiovascular
control, body fluid homeostasis, reproductive function,
energy homeostasis, and immune regulation. This neuroana-
tomical data suggests that the sensory CVOs are integrative
structures involved in communicating various autonomic sig-
nals from the circulation to the central nervous system.
This concept has developed over the last few decades as
a consequence of data derived from various experimental
methods including electrophysiological whole-cell record-
ings from individual neurons both in vitro and in vivo
Subfornical Organ
Area Postrema
Efferent connections:
•Paraventricular nucleus
•Supraoptic nucleus
•Median preoptic nucleus
•SFO
Afferent connections:
•Median preoptic nucleus
•SFO
•Superchiasmatic nucleus
OVLT PVN
SON
MnPO
SFO
Efferent Connection
Reciprocal Connection
Afferent Connection
SCN
Fig. 3.3 Primary neuronal connections of the organum vasculosum of
the lamina terminalis. A midsagittal section of rat brain showing major
afferent and efferent projections of the organum vasculosum of the lam-
ina terminalis (OVLT). Afferent pathways are represented by yellow
arrows, efferent pathways are represented by blue arrows, and reciprocal
projections are represented by purple arrows. SFO subfornical organ;
Hypothalamic structures: MnPO median preoptic nucleus, SCN suprachi-
asmatic nucleus, SON supraoptic nucleus, PVN paraventricular nucleus
3 Regulation of Ner vous System Function by Circumventricular Organs

30
recordings, behavioral studies using intraperitoneal injec-
tions of various circulatory signaling peptides or immune
modulators, as well as electrical stimulation or lesion/abla-
tion techniques to manipulate or disrupt signaling pathways
originating in these CVOs. The following section will high-
light these data to emphasize the critical role CVOs play in
the regulation of autonomic and immune function.
3.5 CVO Functional Roles
Autonomic state is a term we have used to describe the com-
bined physiological status of an organism, which results from
the collective integrated homeostatic processes regulating
multiple controlled variables at any one point in time. This
incorporates metabolic rate, fluid levels, cardiac regulation,
glucose levels, and immune function, to name a few, as our
physiological systems work to maintain the aforementioned
parameters at set values that are ideal for optimal physiologi-
cal function. As variables deviate from ideal values, there is a
systemic response, which activates or inhibits the appropriate
functions, returning those variables toward the homeostatic
value. In order to correctly respond to a deviation from regu-
lated set points, systems for detection of such changes are
clearly essential, and it is here that the importance of the sen-
sory CVOs becomes evident. Many circulating signaling
molecules provide continuously updated information indicat-
ing the state of the peripheral systems. Leptin levels in circula-
tion, for instance, will increase or decrease according to the
metabolic status, angiotensin II (ANG) with fluid balance, and
cytokines with immune function of the body. As previously
discussed in this chapter, the majority of the CNS is protected
by the BBB and therefore cannot detect changing levels of any
of these signals that do not readily cross the BBB. However,
neurons in the specialized sensory CVOs are able to detect
such fluctuations and transmit this information to autonomic
control centers protected by the BBB by CVO efferents. Of
course, there are numerous signaling molecules circulating in
the periphery at any given time, and the ability of the three
sensory CVOs to each detect many of these signals allows
them to collect and integrate such complex information; thus,
they are ideally positioned as critical enablers for communica-
tion between the periphery and the CNS.
3.5.1 Cardiovascular Regulation and Fluid
Balance
Cardiovascular function and fluid balance are two systems;
the homeostatic regulation of which are so clearly integrated
that it perhaps serves no function to attempt to separate them.
They are also the functions in which the sensory CVOs are
Subfornical Organ
Area Postrema
Efferent connections:
•Lateral parabrachial nucleus
•Nucleus of the solitary tract
•Nucleus ambiguous
•Dorsal motor nucleus of the vagus
Afferent connections:
•Lateral parabrachial nucleus
•Nucleus of the solitary tract
•Paraventricular nucleus
•Dorsomedial hypothalamus
•Vagus& carotid sinus nerves
Area Postrema
NTS
LPBN
PVN
DMH
Vagus &
carotid sinus
nerves
Amb
Efferent Connection
Reciprocal Connection
Afferent Connection
DMN
Fig. 3.4 Primary neuronal connections of the area postrema. A midsagit-
tal section of a rat brain showing major afferent and efferent projections of
the area postrema. Afferent pathways are represented by yellow arrows,
efferent pathways are represented by blue arrows, and reciprocal projec-
tions are represented by purple arrows. Hypothalamic structures: DMH
dorsal medial hypothalamus, PVN paraventricular nucleus; Hindbrain
structures: LPBN lateral parabrachial nucleus, Amb nucleus ambiguous,
NTS nucleus of the solitary tract, DMN dorsal motor nucleus of the vagus
E.A.E. Black et al.

31
primarily known to be involved, and thus it is in this area that
many of the initial discoveries regarding sensory CVO func-
tions were made. It is now well established that activation of
SFO neurons causes rapid increases in blood pressure
(Ferguson and Renaud 1984) as well as drinking (Smith
et al. 1995), while activation of AP neurons also rapidly
changes blood pressure (Ferguson et al. 1988), and also
modulates baroreflex sensitivity (Bishop and Sanderford
2000). These two systems are dependent on appropriate bal-
ance of osmolarity, fluid volume, and electrolytes in combi-
nation with cardiac output and vascular tone, all of which
can be regulated by a combination of AP, OVLT and SFO
efferents. Many circulating signals provide information
regarding the integrated cardiovascular and fluid balance sta-
tus of an individual, and a number of these are known to be
monitored by specific neurons in the sensory CVOs, some of
which will be discussed below.
ANG, a peptide hormone, the concentrations of which in
the circulation are regulated by BP and [Na+] does not cross
the BBB. Despite this fact, circulating ANG very clearly
exerts effects on autonomic output through action of the
CNS, causing vasoconstriction, water intake, vasopressin,
and ACTH secretion all of which contribute to an increase in
BP. The SFO and AP in particular are known to express very
high levels of the ANG receptor AT1 (Gehlert et al. 1990),
and single neuron recordings have clearly demonstrated that
ANG excites the majority of neurons in these areas (Ferguson
and Bains 1996). In vivo experiments performed by directly
injecting ANG into the SFO result in increases in BP. What
is even more convincing are the experiments in which effects
of circulating ANG on drinking, BP, and hormone release are
abolished by lesion of the SFO, while effects on baroreflex
sensitivity are lost following AP destruction (Liu et al. 1999;
Ferguson and Bains 1997). Finally, it should also be empha-
sized that ANG receptors have also been demonstrated in
many CNS sites protected by the BBB, and it has been sug-
gested that ANG may even be synthesized in certain areas of
the CNS. Such observations clearly suggest that the CNS
also uses ANG as a neurotransmitter in specific ANGergic
pathways. Such a scenario only remains functionally viable
where the BBB protects these areas of the CNS from circu-
lating ANG, which would otherwise continuously activate
such ANGergic synapses. Many other circulating peptides
known to play critical roles in the regulation of blood pres-
sure and body fluids have also been shown to act in the SFO
and/or (Hasser and Bishop 1990) AP including vasopressin
(Washburn et al. 1999b; Bishop and Hay 1993), atrial natri-
uretic peptides (Saavedra et al. 1987; Brown and Czarnecki
1990), endothelin (Wall et al. 1992; Ferguson and Smith
1991), and obestatin (Samson et al. 2007).
SFO and OVLT neurons have also been demonstrated to
be intrinsically osmosensitive; and thus, both represent sites
at which changes in circulating osmolarity can act to regulate
the complex circuitry controlling integrated cardiovascular
and fluid regulation. SFO neurons have also been shown to
sense calcium through the calcium sensing receptor
(Washburn et al. 1999a) and sodium through modulation of
the NaX channel (Hiyama et al. 2004).
As reviewed in this section of the chapter, the three sen-
sory CVOs are essential in the homeostatic regulation of car-
diovascular function and fluid balance. Their unique ability
to detect multiple peripheral signals describing the body’s
fluid and vascular status allows them to be a critical first step
in the integrated regulation of cardiovascular function and
fluid balance.
3.5.2 Reproduction
The sensory CVOs have also been shown to play roles in the
regulation of reproductive function, presumably again as a
consequence of their ability to detect reproductive hormones
in the circulation, thus closing the loops in critical feedback
control circuitry. Hamster food deprivation suppresses the
normal progression of the estrous cycle, and lesion of the AP
has been shown to abolish this effect (Panicker et al. 1998).
Similarly, destruction of both the SFO or OVLT cause a dis-
ruption in the secretion of reproductive hormones, with
OVLT lesion reducing the luteinizing hormone (LH) surge
which normally induces ovulation (Piva et al. 1982), while
SFO lesions have been shown to influence the proestrous fol-
licle stimulating hormone (FSH) surge, and perhaps more
importantly block normal estrous cyclicity in 50 % of ani-
mals (Limonta et al. 1981).
All three sensory CVOs have been found to express mul-
tiple signaling molecules and receptors associated with
reproductive function including gonadotropin-releasing hor-
mone (GnRH) and oxytocin, as well as estrogen, prolactin
and relaxin receptors (Summerlee and Wilson 1994), further
supporting their involvement in reproductive function.
Activation of estrogen (Pamidimukkala and Hay 2003), pro-
lactin (Black et al. 2014), and relaxin (Sunn et al. 2002)
receptors have all also been shown to influence the excitabil-
ity of neurons in these CVOs. Collectively, these data sup-
port important roles for the sensory CVOs in the regulation
of reproduction and the potential integration of reproductive
function with other homeostatic variables.
3.5.3 Feeding and Metabolism
Before, after, and between meals exists a complex system of
hormonal signaling that aids in the digestion and regulation
of food intake and metabolism. Production and secretion of
various blood-borne peptides are stimulated by specific
physiological events or conditions, each of which has the
potential to be influenced by physiological state. For exam-
ple, ghrelin is a peptide produced by ghrelin cells in the gas-
3 Regulation of Ner vous System Function by Circumventricular Organs

32
trointestinal (GI) tract when the stomach is empty and
increases gastric acid secretion and GI motility to prepare the
body for food intake. During meal consumption, the intro-
duction of chyme (containing fatty acids, certain amino
acids, and nutrients) from the stomach into the small intes-
tine stimulates the I- and L-cells in the mucosa of the gastro-
intestinal tract to release various gut hormones such as
cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1),
and peptide YY (PYY). These peptides then enter the blood-
stream and travel to effector organs to perform a multitude of
functions including signaling the release of various digestive
enzymes and bile from the pancreas and gallbladder (role of
CCK), stimulating the release of peptides hormones such as
insulin or glucagon from the pancreas (role of GLP-1), or
inhibiting gastric motility (role of PYY). Insulin and amylin
are co-secreted from pancreatic beta cells in response to ris-
ing glucose levels and function to prevent post-prandial
spikes in blood glucose levels. Between meals, adipocytes,
or fat cells, release the protein hormones adiponectin and
leptin that are responsible for regulating metabolic processes
involved in energy homeostasis such as glucose regulation
and fatty acid oxidation.
Interestingly, in addition to their unique roles in digestion
and energy metabolism, these blood-borne peptides all pos-
sess the ability to act as hunger or satiety signals in the cen-
tral nervous system. They can be simplistically categorized
into two types: orexigenic—causing a sensation of hunger
and promoting food intake (only known GI peptide to date is
ghrelin), or anorexigenic—causing a sensation of satiety and
inhibiting food intake (i.e. CCK, GLP-1, PYY, adiponectin,
and leptin). However, due to the lipophilic nature of these
peripheral signals, they are unable to cross the BBB; and
therefore, alternative methods through which they communi-
cate with the brain have been proposed, one being by actions
in the sensory CVOs.
Over the past few decades there has been growing evi-
dence to support the idea that sensory CVOs, initially the AP
and more recently the SFO, are involved in the neural cir-
cuitry underlying hunger and satiation, specifically by acting
as an integrative ‘gate keeper’ that senses various circulating
hormones and transmits the information to areas of the hypo-
thalamus and brainstem.
The presence of receptors in the AP and SFO for these
various gastrointestinal hormones involved in energy homeo-
stasis has been confirmed using various scientific approaches
including immunostaining, in situ hybridization, as well as
pharmacological approaches. Many of these peptide hor-
mones cause increased c-fos expression (an indirect marker
of neuronal activity) in the AP and SFO when injected intra-
peritoneally, and/or have been shown to cause changes in the
excitability of AP and SFO neurons in dissociated or slice
preparations. The AP expresses receptors for and can respond
to: adiponectin, leptin, amylin, ANG, CCK, ghrelin, GLP-1,
oxyntomodulin, vasopressin and PYY (Baraboi et al. 2010a);
while the SFO can sense and respond to ANG, calcitonin,
amylin, ghrelin, leptin, adiponectin, CCK, and PYY (see
Fig. 3.3) as described in reviews (Cottrell et al. 2004; Hoyda
et al. 2009; Smith et al. 2010). These data are important as
they show that the receptors expressed by these sensory
CVOs are in fact able to continuously monitor these circulat-
ing signals involved in energy homeostasis.
Behavioral studies have also demonstrated critical roles
for the sensory CVOs in regulation of energy balance.
Lesioning the AP results in significant hypophagia and loss
of body weight (Hyde and Miselis 1983; Bird et al. 1983;
Contreras et al. 1982), while Potes et al. demonstrated that
lesioning noradrenergic AP neurons abolished subcutane-
ously injected amylin induced hypophagia (Potes et al.
2010). Jordi et al. assessed the effect of oral ingestion of 20
amino acids and found that food intake was most potently
reduced by l-arginine (Arg), l-lysine (Lys), and l-glutamic
acid (Glu), effects that were accompanied by increased neu-
ronal activity in the AP and NTS. Interestingly, when the AP
was surgically lesioned, the anorectic response and increased
neuronal activity in the AP and NTS, in response to Arg and
Glu, was abolished suggesting that the AP is not only a sen-
sor of circulating GI peptide hormones released when food is
ingested, but also a sensor of metabolic food products them-
selves (Jordi et al. 2013). Although the majority of work
involving lesioning the SFO has focused on effects on fluid
balance, a recent study has shown that, while lesion of just
the SFO has no effect on body weight, combined lesion of
SFO and AP has long lasting effects on body weight gain
(Baraboi et al. 2010b). In addition, we have recently shown
that electrical activation of SFO neurons in satiated rats
induces feeding as well as drinking (Smith et al. 2010).
Collectively, these data support the conclusion that the AP
and SFO, through their connections to the brainstem and
hypothalamus, play an important role in central nervous sys-
tem control of energy homeostasis as components of an inte-
grated network.
3.5.4 Immune Function and Temperature
Regulation
The continuous crosstalk between the nervous and immune
systems is critical to the integrated mechanisms through
which the nervous system can regulate specific immune sys-
tem functions through the production of neuroregulators
(neurotransmitters, neuromodulators, and neuropeptides).
Additionally, the peripheral immune system has the ability to
regulate specific nervous system functions through the pro-
duction of immunoregulators (immunomodulators and
immunopeptides) (see Fig. 3.5). For example, classical neu-
rotransmitters such as norepinephrine and serotonin are able
E.A.E. Black et al.

33
to induce immunosuppression (Walker and Codd 1985),
while lymphocytes and leukocytes express receptors for and
can synthesize biologically active neuroendocrine peptide
hormones (i.e. growth hormone and adrenocorticotropic hor-
mone), which can not only influence nervous system func-
tion, but can also modulate the proliferation and differentiation
of T-lymphocytes [for review see (Weigent and Blalock
1987)].
Immunomodulators, such as interleukin 1 (IL-1) and
tumor necrosis factor (TNF), are important regulators of
immune responses and inflammatory reactions. Bacterial
endotoxins, such as lipopolysaccharide (LPS), can bind to
immune cells, such as monocytes and macrophages, and pro-
mote secretion of these pro-inflammatory cytokines.
Interestingly, the biological actions of IL-1 and TNF are not
restricted to the immune system. They have been found to
have various actions in the nervous system, including pyro-
genic, thermogenic, and somnogenic effects, influence on
growth and differentiation, as well as suppression of food
intake [for review see (Plata-Salaman 1991). This seems
logical seeing as sickness is often associated with fever,
tiredness, and decreased appetite. While the way in which
these two systems communicate to coordinate integrated
responses is not yet fully understood, the CVOs, with their
Immune System
Microbial products,
toxins, inflammation
Neuroregulators Immunoregulators
SubfornicalOrgan
Area Postrema
Subfornical
Organ
Area Postrema
OVLT
Median
Eminence
Posterior Pituitary
Intermediate
Pituitary
Sensory CVOs
Secretory CVOs
Pineal Gland
Fig. 3.5 Communication between the
nervous and immune systems. The
nervous system and immune system
communicate and influence one another
via neuro-immune and immuno-neural
pathways utilizing neuroregulators and
immunoregulators, respectively. Microbial
products, toxins, and inflammation can
trigger synthesis and release of
immunoregulators from immune or CNS
cells, signals that are integrated at the
circumventricular organs
3 Regulation of Ner vous System Function by Circumventricular Organs

34
lack of a BBB, represent an access point for circulating
cytokines and endotoxins to directly influence the CNS (see
Table 3.1). Furthermore, because of their connections to
critical autonomic control centers, the CVOs have been sug-
gested as integrators for the multiple components of these
coordinated responses.
Using in situ hybridization, receptors for IL-1β (IL-1R)
(Ericsson et al. 1995), TNF (p55) (Nadeau and Rivest 1999),
and bacterial LPS (mCD14 and toll-like receptor 4 (TLR-4))
(Laflamme and Rivest 2001) have been shown to be expressed
by the sensory CVOs. The SFO also expresses receptor
mRNA for ciliary neurotrophic factor (Hindmarch et al.
2008), another mediator of the immune response.
In vitro and in vivo techniques that examine neuronal activ-
ity have been used to examine the effects of activation of these
receptors. Peripheral administration of IL-1β increases c-fos
expression in the AP, OVLT, SFO, PVN, NTS, and PBN (Brady
et al. 1994; Day and Akil 1996), and has also shown to induce
phosphorylation of extracellular signal-regulated protein
kinase 1 and 2 (ERK1/2) in the CVOs, PVN, and SON (Nadjar
et al. 2005). Peripheral administration of TNF-α has been
shown to cause upregulation of mRNA for both TNF receptors
(p55 and p75) in the CVOs, while also increasing c-fos expres-
sion in the CVOs, PVN, and NTS (Nadeau and Rivest 1999).
Additionally, one hour after intravenous TNF-α administration,
PVN expression of corticotropin-releasing factor increased, an
effect that was associated with increases in the plasma corticos-
terone levels (Nadeau and Rivest 1999). Systemic administra-
tion of LPS has been shown to rapidly stimulate transcription
of IL-6 mRNA and biosynthesis of IL-6 receptor (IL-6R) in the
sensory CVOs (Vallieres and Rivest 1997). Pretreated OVLT
and AP microcultures with IL-10 antibodies before incubation
with LPS show significantly enhanced LPS-induced increase
in TNF-α and IL-6 in the microculture supernatant (Harden
et al. 2013), which suggests that the CVOs may have a key role
to play in both the initiation and modulation of neuroinflamma-
tion. An in vivo example of CVO involvement during the
development of neuroinflammation can be seen when Wuerfel
et al. demonstrated increased signal intensity in the SFO and
AP on gadofluorine M-enhanced MRI scans during autoim-
mune encephalomyelitis (Wuerfel et al. 2010).
Gerstberger et al. have shown that AP and OVLT neurons
respond to LPS, TNF-α, and IL-1β with increases in intracel-
lular calcium (Wuchert et al. 2008, 2009; Ott et al. 2010).
Interestingly, the 2008 study also showed that LPS-induced
calcium signaling can be suppressed by pre-incubating AP
microcultures with LPS for 18 h, suggesting that AP cannot
only sense circulating LPS but also has the capacity to
develop endotoxin-tolerance. Patch clamp recordings from
dissociated SFO neurons have also shown that physiological
(subseptic) bath application of IL-1β cause depolarization
with increased spike frequency due to activation of a non-
selective cationic current (Desson and Ferguson 2003).
Additionally, OVLT neurons in slice preparations have been
shown to increase firing frequency in response TNF-α and
interferon α-2 (Shibata and Blatteis 1991).
Finally, we turn our attention to CVO ablation and lesion
studies that present evidence for CVO involvement in fever pro-
duction and neuroendocrine activation during the immune
response. The OVLT was originally hypothesized to be involved
in the febrile response due to its proximity and reciprocal neuro-
nal connections to the median preoptic nucleus (MnPO) and the
medial preoptic area (MPO), both critical hypothalamic sites for
central thermoregulation and fever production (Nakamura and
Morrison 2008; Lazarus et al. 2007). Blatteis et al. ablated the
anteroventral third ventricular (AV3V) area, which included the
Table 3.1 Blood-borne immunomodulators that influence CVO neurons
Data source IL-1βTNF LPS
SFO mRNA √ √
c-fos √ √ √
Immunohistochemistry √
Intracellular Ca2+
Single Unit Recording √
AP mRNA √ √ √
c-fos √ √ √
Immunohistochemistry √
Intracellular Ca2+ √ √ √
Single Unit Recording
OV LT mRNA √ √
c-fos √ √ √
Immunohistochemistry √
Intracellular Ca2+ √
Single Unit Recording √
IL-1β interleukin 1 beta, TNF tissue necrosis factor, LPS lipopolysaccharide
E.A.E. Black et al.

35
OVLT, in guinea pigs and sheep and found that these animals
were no longer capable of developing a fever in response to sys-
temic endogenous pyrogens (Blatteis et al. 1983, 1987).
Conversely, Stitt (1985) found OVLT (not AV3V) lesion-induced
fever enhancement in rabbits and rats; whereas, Takahashi et al.
(1997) found that lesioning the OVLT or AP had no effect on
fever while SFO lesion significantly reduce LPS-induced fevers.
As might be expected, the cause for such discrepancies between
results was then sought. A more recent study, which reappraised
these previous experiments, demonstrated that lesioning the
OVLT resulted in many “side effects,” which were not properly
controlled for, including acute adipsia and gross emaciation, and
chronic hypernatremia, hyperosmolality, a suppressed drinking
response to hypertonic saline, and previously unrecognized long
lasting hyperthermia (2 °C for >3 weeks) (Romanovsky et al.
2003). After recovery from acute, but not chronic, side effects,
rats were still unable to elicit a febrile response to injected IL-1β.
The authors note, however, that rats were in a hyperthermic state
at the time of injection, and that this may have been the underly-
ing explanation for the lack of febrile response, not a disruption
of a febrigenic-signaling pathway.
The previously described SFO ablation induced reduction
of febrile response seen by Takahashi et al. in 1997 gained
support in 1999 when Cartmell et al. who demonstrated that
microinjection of the IL-1 receptor antagonist into the SFO
attenuated LPS induced fever (Cartmell et al. 1999) also
showed that antagonist injection into the OVLT had no effect
on febrile response. This further supports the hypothesis that
the attenuation of febrile response seen in previous studies
may not have been attributed to a disruption in the febrigenic-
signaling pathway, as was previously suggested.
Studies examining the neuroendocrine response to IL-1β
have suggested roles for the AP as the large elevations in
adrenocorticotropic hormone (ACTH) and corticosterone lev-
els in the plasma in response to systemic IL-1β and increases
in fos expression in AP, NTS, and PVN are attenuated by AP
lesion (Lee et al. 1998). This suggests that the AP and adja-
cent NTS play a critical role in sensing and transducing this
circulating cytokine signal to the hypothalamic- pituitary-
adrenal axis thereby indirectly influencing the release of
ACTH and corticosterone into the bloodstream. Peripherally
administered IL-1β has also been shown to increase extracel-
lular norepinephrine concentration in the PVN of the hypo-
thalamus, an effect that is also attenuated in AP-lesioned rats
(Ishizuka et al. 1997).
3.6 Review Questions
1. What are some defining characteristics of sensory CVOs?
2. What makes the sensory CVOs ideal integrative sites?
3. Can most cytokines and peptides cross the blood- brain
barrier?
4. What are ways in which the peptides and cytokines can
access the CNS?
5. Name two critical neuroendocrine nuclei in the hypothal-
amus onto which CVOs project.
6. (a) What are the differences between sensory and secre-
tory CVOs?
(b) Why is it important that these areas lack a normal
blood-brain barrier?
7. A female rat that is a subject in your study does not dis-
play the usual increase in blood pressure in response to
ANG injection. Her estrous cycle has been disrupted and
her febrile response to lipopolysaccharides (LPS) is much
smaller than expected. Based on these observations,
which CVO would you say has been damaged in the
subject?
3.7 Answers
1. Lack a blood-brain barrier (fenestrated capillaries) High
expression of peptide and hormone receptors. Extensive
efferent projections, fewer afferent
2. The defining characteristics of: lack of a blood-brain bar-
rier, high receptor expression and extensive efferent pro-
jections enable the sensory CVOs to interpret information
from different systems, whether it be electrical or chemi-
cal, and convey this integrated information to autonomic
control centers protected by the BBB.
3. No, many are too large or lipophobic
4. Diffusion across the BBB; Active transport across the
BBB; Binding to receptors in the sensory CVOs, which
aren’t protected by the BBB
5. Paraventricular Nucleus (PVN); Supraoptic Nucleus (SON)
6. (a) Sensory CVOs detect signals circulating in the
periphery; whereas, secretory CVOs secrete hor-
mones directly into the circulation.
(b) In order to detect peripheral signals, sensory CVOs
need direct access to the circulatory system. Similarly,
secretory CVOs need direct access in order to secrete
their respective hormones into circulation.
7. Subfornical Organ (SFO)
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3 Regulation of Ner vous System Function by Circumventricular Organs