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Appetite. Author manuscript; available in PMC 2024 September 01.
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Appetite. 2024 September 01; 200: 107512. doi:10.1016/j.appet.2024.107512.

Neural circuits regulation of satiation

Haijiang Caia,d,*, Wesley I. Schnappa,b, Shivani Manna, Masa Miscevica,c, Matthew B.
Schmita,b, Marco Conterasa, Caohui Fanga
aDepartment of Neuroscience, University of Arizona, Tucson, AZ, 85721, USA
bGraduate Interdisciplinary Program in Neuroscience, University of Arizona, Tucson, AZ, 85721,
USA
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cGraduateInterdisciplinary Program in Physiological Sciences, University of Arizona, Tucson, AZ,

85721, USA
dBio 5 Institute and Department of Neurology, University of Arizona, Tucson, AZ, 85721, USA

Abstract
Terminating a meal after achieving satiation is a critical step in maintaining a healthy energy
balance. Despite the extensive collection of information over the last few decades regarding
the neural mechanisms controlling overall eating, the mechanism underlying different temporal
phases of eating behaviors, especially satiation, remains incompletely understood and is typically
embedded in studies that measure the total amount of food intake. In this review, we
summarize the neural circuits that detect and integrate satiation signals to suppress appetite,
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from interoceptive sensory inputs to the final motor outputs. Due to the well-established role of
cholecystokinin (CCK) in regulating the satiation, we focus on the neural circuits that are involved
in regulating the satiation effect caused by CCK. We also discuss several general principles of how
these neural circuits control satiation, as well as the limitations of our current understanding of the
circuits function. With the application of new techniques involving sophisticated cell-type-specific
manipulation and mapping, as well as real-time recordings, it is now possible to gain a better
understanding of the mechanisms specifically underlying satiation.

1. Introduction
The primary function of the brain is to integrate sensory signals to generate appropriate
behavioral or physiological responses. To accomplish this, the brain has evolved a
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This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

*
Corresponding author. Department of Neuroscience, University of Arizona, Tucson, AZ, 85721, USA. haijiangcai@arizona.edu (H.
Cai).
Ethical statement
Not applicable to the review article. We declare that AI tools were not utilized in writing this manuscript.
CRediT authorship contribution statement
Haijiang Cai: Writing – review & editing, Writing – original draft, Conceptualization. Wesley I. Schnapp: Writing – review &
editing. Shivani Mann: Writing – review & editing. Masa Miscevic: Writing – review & editing. Matthew B. Schmit: Writing –
review & editing. Marco Conteras: Writing – review & editing. Caohui Fang: Writing – review & editing.
Declaration of competing interest
No competing interests of any authors or persons related to this research are declared.
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sophisticated and complicated neural system to regulate behaviors (Albright et al., 2000).
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Here, we discuss how the neural circuits detect and integrate satiation signals to suppress
appetite, which is critical in maintaining a healthy energy balance. For the neural mechanism
of general eating, please refer to this recent comprehensive review (Watts et al., 2022).

Most mammalian species eat several meals at certain times every day in accordance with
the circadian rhythm. For example, nocturnal rodents eat more food in the first hour after
the lights are off than at other times (Zorrilla et al., 2005). Each meal is composed of a
cluster of bouts with a short gap of time (usually less than a minute) (Fig. 1), and each bout
contains several rhythmic jaw movements (Boyle et al., 2012; Davis, 1989). The bouts and
jaw movements reflect a pace of eating that is affected by sensory feedback, including the
swallowing of food in the mouth (van der Bilt et al., 2006). The termination of an individual
bout or jaw movement does not require satiation. For most mammals, satiation is triggered
within a few minutes of eating and accumulates, leading to meal termination, which usually
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occurs in less than an hour. Thus, satiation determines how much food can be consumed
in a meal (Watts et al., 2022). Once satiation is reached, rodents will follow a series of
behaviors related to satiation, including cessation or slowdown of eating, grooming, resting,
and so on (Antin et al., 1975; Rodgers, Holch, & Tallett, 2010). For most animals, several
hours of interval pass until the next meal, which is determined by satiety (Fig. 1). However,
inter-meal intervals vary widely among species. In mice and rats, during the dark phase,
inter-meal intervals are usually only about an hour (Tolkamp et al., 2011). Because satiety
is relatively slow on a scale of hours, signals after digestion play important roles in this
process to suppress appetite, such as emptying of the gut and a decrease in blood glucose
that promote hunger and meal onset (Campfield, Brandon, & Smith, 1985; Valassi, Scacchi,
& Cavagnini, 2008; Wyatt et al., 2021). Neurons in many brain regions also participate
in the regulation of satiety (Andermann et al., 2017; Bruning et al., 2023). For example,
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pro-opiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) decrease eating in a

very slow way over many hours, suggesting they are regulating satiety but not satiation
(Aponte, Atasoy, & Sternson, 2011; Koch et al., 2015; Zhan et al., 2013). Healthy energy
homeostasis is accomplished through adjustments in both satiation and satiety.

Termination of a meal or suppression of appetite during satiation is caused by gastric

distention and secretion of satiation signals, including cholecystokinin (CCK), glucagon-like
peptide (GLP-1), oxytocin, amylin, etc. (Asarian et al., 2014; Dockray, 2014; Powley et al.,
2004). Among these signals, CCK is the most extensively studied, with a well-established
role in satiation for controlling meal size (Dockray, 2012; Ritter, Covasa, & Matson, 1999).
CCK is released from enteroendocrine cells found from the duodenum to ileum in response
to digested nutrients, such as fatty acids and aromatic amino acids (Egerod et al., 2012;
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Gribble et al., 2016; Kaelberer et al., 2018; Polak et al., 1975). Since Gibbs and Smith
first highlighted the critical role of CCK in producing a behaviorally inhibition of eating in
1973 (Gibbs, Young, & Smith, 1973), numerous studies have corroborated its function as
a physiological satiation signal in both humans and animals (Dockray, 2012; Ritter et al.,
1999; Steinert et al., 2017). A significant portion of our understanding regarding the neural
mechanisms of satiation comes from experiments involving the peripheral administration
of CCK in rodents, predominantly through intraperitoneal (IP) injection. Multiple bioactive
CCKs, including the short from of CCK-8 and the longer forms CCK-33 and CCK-58,

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have been identified in different species (Sayegh, 2013). It appears that the longer forms of
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CCKs have a longer half-life in the circulation and may have functions other than satiation
(Overduin et al., 2014). However, the short form CCK-8 has been well demonstrated to
reduce meal size, which was compensated by an increase in meal number (Overduin et al.,
2014; West, Fey, & Woods, 1984), suggesting CCK-8 controls satiation but plays little role
in regulating satiety. Despite the exact dosage of CCK required to replicate endogenous
levels during satiation remaining unknown due to its paracrine or potential synaptic mode of
action (Kaelberer et al., 2018; Reidelberger et al., 1994), a diverse array of tests utilizing the
“physiological range” of CCK has consistently indicated that “premeal intraperitoneal doses
≤5 μg/kg CCK-8 elicit satiation in the absence of side effects, whereas doses ≥10 μg/kg
CCK-8 are aphysiological” (see summary by Nori Geary and others (Geary, 2014; Schwartz
et al., 1998; Smith et al., 1992). Low doses (≤5 μg/kg) of CCK, which do not cross the
blood-brain barrier, induce satiation without causing nausea (Antin et al., 1975; Passaro et
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al., 1982). Therefore, the ensuing discussion will focus on studies involving the peripheral
administration of CCK mostly in rodent animal models.

2. Architecture of the neural circuits for satiation

Over the last few decades, c-Fos expression (widely used to indicate neuron activation)
mapping, lesion studies, and more recent genetic manipulations of specific types of neurons
have identified multiple brain regions responsive to CCK and controlling appetite. Here, we
summarize the major circuits distributed across these brain regions that regulate the satiation
effect caused by CCK (Fig. 2).

2.1. Vagal sensory neurons (VSNs)

The peripheral signals from the gut to the brain are primarily mediated by sensory vagal
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afferents (Berthoud et al., 2000; Zhao et al., 2022). CCK transmits satiation information
through the CCK-A receptor (“A” for alimentary, primarily in the gastrointestinal tract, also
known as the CCK-1 receptor) located on the vagal afferents (Dockray, 2013; Egerod et
al., 2018; Moran et al., 2006). Infusion of the CCK-A receptor antagonist increases meal
size, suggesting that endogenous CCK is an important satiation signal (Beglinger et al.,
2001; Matzinger et al., 1999; Reidelberger et al., 1994). It is important to note that CCK
and CCK receptors are also expressed throughout the brain but may be involved in various
other biological activities, from anxiety to nociception, which are not necessarily directly
related to satiation (Bowers, Choi, & Ressler, 2012; Noble et al., 1999). The vagal sensory
neurons (VSNs) are pseudounipolar cells with cell bodies located in the nodose ganglion
(NG), where one axon branch terminates in the internal organs, and another axon projects to
the brain to form synaptic connections with neurons in the brainstem nuclei, mainly in the
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nucleus of the solitary tract (NTS) and the area postrema (AP). Vagotomy prevents eating
suppression caused by a low volume of stomach distension or IP injection of low doses of
CCK, suggesting that both volumetric and nutritive satiation signals are carried by vagal
afferents (Lorenz et al., 1982; Smith et al., 1981, 1985). Recent studies have employed
different genetic markers to label and manipulate different subsets of VSNs (Bai et al., 2019;
Williams et al., 2016). The activation of two populations of VSNs expressing Oxtr or Glp1r,
both of which also express the CCK-A receptor, is sufficient to suppress food intake (Bai

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et al., 2019). Interestingly, Oxtr+ and Glp1r + VSNs have intraganglionic laminar endings
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(IGLEs), which are proposed to sense stomach stretch (Bai et al., 2019; Zagorodnyuk, Chen,
& Brookes, 2001). These results are consistent with the findings that vagal afferent response
is increased when gastric load and CCK were combined, the effect of CCK’s suppression
of food intake is enhanced when stomach is distended (Kissileff et al., 2003; Moran et al.,
1982; Schwartz, McHugh, & Moran, 1993). Together, these studies suggest that CCK and
gastric distension may synergize to suppress appetite at the vagal afferents level.

2.2. Nucleus of the solitary tract (NTS)

The caudal NTS is the primary target in the brain innervated by vagal afferents and has
been widely studied in eating control (please refer to (Grill et al., 2012; Rinaman, 2010)
for a more complete summary of earlier NTS studies). c-Fos mapping has demonstrated
that neurons in the NTS are robustly activated by CCK or vagal sensory nerve stimulation
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(Appleyard et al., 2005; Bai et al., 2019; Kreisler, Davis, & Rinaman, 2014). Recent in
vivo calcium imaging studies showed that the gastric distension responses of the caudal
NTS neurons were abolished after bilateral subdiaphragmatic vagotomy (Ran et al., 2022).
Consistent with the fact that CCK-A receptors are located on mechanosensitive VSNs, the
imaging study also found that some NTS neurons respond to both nutrients and gastric
distension (Ran et al., 2022). Earlier lesion studies demonstrated that the NTS is required for
the anorexigenic effect of peripheral CCK, suggesting that the NTS is a key brain region for
satiation (Crawley, Kiss, & Mezey, 1984; Rinaman, 2003).

Neurons in the NTS express many different genetic markers, including noradrenergic (NA)
synthetic enzyme dopamine beta hydroxylase (DBH), tyrosine hydroxylase (TH), prolactin-
releasing hormone (PRLH), calcitonin Receptor (CALCR), pre-proglucagon (GCG or PPG)
or glucagon-like-peptide-1 (GLP-1), leptin receptor (LEPR), CCK, POMC, etc. (Ludwig
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et al., 2021). The exact level of overlapping among these neurons and their response to
CCK has not been sufficiently examined. Neurons expressing TH, DBH, CALCR, or PRLH
have significant overlapping and are largely activated by CCK (Cheng et al., 2021; Ly
et al., 2023). These neurons have little overlap with neurons expressing LEPR or GCG,
which are usually not responsive to CCK (Garfield et al., 2012; Ly et al., 2023). However,
activation of most of these neurons, no matter they are responsive to CCK or not, suppresses
food intake, indicating that NTS neurons are involved in various anorexigenic conditions
(Cheng et al., 2020, 2021; Ly et al., 2023; Qiu et al., 2023). It is important to note that
activation of the PRLH neurons, CALCR neurons, or GCG neurons does not induce aversive
behavior, suggesting that these neurons are not involved in visceral malaise or pain (Cheng
et al., 2020, 2021). In contrast, activation of the NTS CCK neurons suppresses food intake
but also triggers aversive behavior, suggesting that these neurons may not be specific to
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satiation and are also involved in other functions, which is consistent with the idea that
CCK in the brain is not necessarily involved in satiation (Qiu et al., 2023; Roman, Sloat, &
Palmiter, 2017; D’Agostino et al., 2016). Chemogenetic or toxin lesion of the NTS A2 DBH
neurons in rats attenuates the anorectic effect of CCK (Murphy et al., 2023; Rinaman, 2003).
Silencing CALCR-expressing neurons also attenuates the suppressed food intake caused
by CCK (Cheng et al., 2020). These studies suggest that the NTS neurons regulating the
satiation effect of CCK overlap with DBH, CALCR, and PRLH neurons. However, PRLH

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neurons are also activated during oral consumption and have a phasic activity pattern that
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is time-locked to ingestion and might be linked to the taste of food (Ly et al., 2023). Thus,
PRLH neurons might have a more complicated function during different phases of eating.
In contrast, NTS GCG neurons are not responsive to IP injection of CCK but are activated
by mechanical feedback from the gut (Ly et al., 2023). However, it was found that NTS
GCG neurons are only activated after consuming a very large meal and thus may not be
related to normal satiation but to over-consumption or long-term satiety (Kreisler et al.,
2014; Ly et al., 2023). While GCG neurons are not responsive to CCK, they are only a
subset of the NTS LEPR neurons (Ly et al., 2023). Knock down of LEPR in NTS also
decreases satiation caused by CCK (Hayes et al., 2010), suggesting some of the LEPR
neurons may also be involved in satiation. NTS POMC neurons are a subset of CALCR
neurons and also activated by CCK or eating-induced satiety, and activation of the neuronal
melanocortin-4 receptor (MC4-R) is required for CCK-induced suppression of eating (Fan
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et al., 2004; Garfield et al., 2012). Importantly, unlike the ARC POMC neurons, activation
of NTS POMC neurons produced an immediate inhibition of eating behavior (Zhan et al.,
2013), suggesting these neurons are involved in satiation.

Together, these results suggest that the exact type of NTS neurons specifically regulating the
satiation effect of CCK is not restricted to any examined genetic marker-labeled neurons.
However, it is convincingly shown that the NTS is a key node required for satiation.

2.3. Paraventricular hypothalamus (PVH)

Earlier tracing studies showed that NTS neurons have strong projections to the PVH
(Ricardo et al., 1978; Rinaman, 2010). Lesions of the NTS A2 DBH neurons prevent
the c-Fos expression in the PVH caused by CCK (Rinaman, 2003). Lesions of the overall
PVH abolish the inhibition of eating induced by CCK (Crawley et al., 1985). Moreover,
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recent studies further showed that activation of the projection from NTS CCK neurons or
NTS A2 neurons to the PVH suppresses food intake (Roman et al., 2017; D’Agostino et
al., 2016; Murphy et al., 2023). Although it has not been tested whether this NTS→PVH
pathway is required for the eating suppression of peripheral CCK directly, these results
suggest that the PVH is a downstream target of the NTS that might regulate satiation.
The PVH is also a heterogeneous region with many different cell types (D’Agostino et al.,
2016; Li et al., 2019a; An et al., 2015; Li et al., 2019b; Liu et al., 2017). Activation of
the NTS CCK or A2 projection to the PVH activates PVH neurons expressing oxytocin,
corticotropin-releasing factor (CRF), and MC4R, and other types of neurons (D’Agostino
et al., 2016; Murphy et al., 2023). However, activation of the PVH oxytocin neurons does
not suppress food intake (Atasoy et al., 2012), suggesting PVH oxytocin neurons do not
regulate satiation. Suppression of satiation is likely to be compensated for by increased
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meal frequency for homeostasis, i.e., the body weight will remain the same. The alpha-
melanocyte-stimulating hormone (α-MSH) and PVH MC4R neurons have been implicated
in eating suppression. However, manipulation of these PVH neurons expressing single
minded-1 (SIM1, a transcription factor expressed by most PVH neurons and necessary for
their development (Holder, Butte, & Zinn, 2000; Michaud et al., 2001)), or prodynorphin
(PDYN), or MC4R causes hyperphagia and changes in body weight (An et al., 2015; Kohno
et al., 2014; Li et al., 2019a; Xi et al., 2012; Xu et al., 2013), suggesting these neurons are

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involved in satiety or long-term energy balance regulation. Consistent with this, activation
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of the ARC POMC neurons, which project to the PVH, requires a long-term (24 h) rather
than a short-term (<2h) time window to decrease eating (Aponte et al., 2011; Koch et al.,
2015; Zhan et al., 2013). Thus, these neurons in the PVH seem to be more tuned for satiety
and hunger regulation, rather than short term satiation for meal termination. However, it
has been suggested that the glutamatergic ARC neurons project to the PVH for rapid eating
suppression (Fenselau et al., 2017). But their role in regulating the effect of satiation has
not been tested yet. Together, whether PVH neurons regulate the anorectic effect of CCK or
short-term satiation remains to be determined.

2.4. Lateral parabrachial nucleus (LPB)

Another major target of NTS neurons that has been demonstrated to regulate satiation is
the LPB (Karimnamazi, Travers, & Travers, 2002; Rinaman, 2010). While lesions of LPB
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abolish the anorectic effect of CCK, they do not affect the c-Fos expression in NTS caused
by CCK, suggesting that the LPB neurons are downstream of NTS in the neural pathway
that regulates the satiation effect of CCK (Becskei et al., 2007; Trifunovic et al., 2001).
Activation of the projection from NTS CALCR neurons to LPB suppresses food intake
but does not cause aversion (Cheng et al., 2020). The different types of LPB neurons
with different genetic markers have not been sufficiently examined yet. One well-studied
subpopulation of LPB neurons is the neurons expressing calcitonin gene-related protein
(CGRP), which are primarily located in the external part of LPB and do not seem to be
targeted by NTS CALCR neurons (Cheng et al., 2020). The c-Fos caused by CCK is located
more in the dorsal and central part of LPB but has mild or no overlap with CGRP expression
(Carter et al., 2013; Han et al., 2018). Accordingly, silencing CGRP neurons in the LPB
shows a trend, but not significant effect in preventing eating suppression caused by CCK
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(Carter et al., 2013). Interestingly, activation of the vagal Oxtr + neurons causes c-Fos
expression primarily in dorsal LPB and less so in external LPB, presumably through NTS
neurons (Bai et al., 2019). Activation of the AGRP projection to LPB has been demonstrated
to attenuate the eating suppression induced by CCK (Essner et al., 2017). Consistent with
the c-Fos expression caused by CCK, most of the terminals from AGRP neurons are located
in the dorsal LPB (Essner et al., 2017; Wu, Boyle, & Palmiter, 2009). Interestingly, CCK
induces an inhibition of AGRP neurons, an effect that can also be blocked by vagotomy
(Alhadeff et al., 2019; Goldstein et al., 2021). Furthermore, activation of LPB CGRP
neurons is aversive (Campos et al., 2018; Palmiter, 2018). These results suggest that the
CGRP neurons are not the neurons in LPB regulating the satiation effect of CCK. A recent
study found that LPB neurons activated by the consumption of palatable food such as milk,
labeled by an activity-dependent method called CANE (Rodriguez et al., 2019), are distinct
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from LPB CGRP neurons (Rodriguez et al., 2019). Activation of these neurons suppresses
eating but causes a positive valence, suggesting these neurons might be the neurons that
encode the satiation effect. However, this possibility remains to be determined. Nevertheless,
the LPB as a node in the satiation pathway is established.

2.5. Central nucleus of amygdala (CEA)

CEA receives inputs from both LPB and NTS (Block, Hoffman, & Kapp, 1989; Ricardo et
al., 1978; Rinaman, 2010). IP injection of CCK induces robust c-Fos expression in CEA,

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and lesion of LPB prevents the CCK-induced c-Fos expression in CEA, suggesting that CEA
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is downstream to LPB in regulating the satiation caused by CCK (Becskei et al., 2007).
However, earlier lesion studies found that lesions of CEA have little effect on food intake
and do not prevent eating suppression caused by CCK (Crawley et al., 1985; Rollins et
al., 2000), leading CEA to be neglected as an important node for satiation or eating for a
long time (King, 2006). The lack of effect on food intake by CEA neurons is likely due
to the heterogeneous populations of CEA neurons, where neurons with opposite functions
on eating are intermingled in the same location (Cai et al., 2014; Douglass et al., 2017;
Kim et al., 2017). Using genetic markers, it was found that CCK activates CEA neurons
preferentially in the population expressing protein kinase C-delta (PKC-δ) (Cai et al., 2014).
Furthermore, silencing of the CEA PKC-δ neurons attenuates the eating suppression caused
by CCK, and activation of these neurons quickly suppresses eating (Cai et al., 2014). These
results suggest that CEA PKC-δ neurons are in the nodes regulating the satiation effect of
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CCK. However, the CEA PKC-δ neurons are also involved in other anorexigenic signals,
including visceral malaise caused by LiCl and bitter taste (Cai et al., 2014). Thus, it should
be a subpopulation of CEA PKC-δ neurons that regulate satiation.

2.6. Parasubthalamic nucleus (PSTN, also called PSTh)

The VSNs and neurons in the NTS and LPB that constitute the satiation neural circuitry
are primarily glutamatergic excitatory neurons. Therefore, glutamate serves as the primary
molecule for transferring satiation information across the synapses. Many of the VSNs
also express the peptide neurotransmitter cocaine-amphetamine regulated transcript (CART)
(Broberger et al., 1999). CCK enhances CART synthesis and infusion of CART suppresses
food intake (Aja et al., 2001; de Lartigue et al., 2007; Lee et al., 2020). Thus, CART
is another important molecule in this neural pathway to regulate satiation. Interestingly,
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unlike VSNs and the neurons in NTS and LPB, almost all neurons in the CEA are
GABAergic inhibitory neurons (Haubensak et al., 2010; Sun et al., 1993), making it difficult
to identify the brain regions downstream of CEA for satiation. Infusion of the GABAergic
transmission blocker bicuculine abolishes the eating suppression caused by activation of
the CEA PKC-δ neurons. Additionally, activation of the CEA PKC-δ negative neurons
attenuates the effect of CCK (Cai et al., 2014). Given that CEA PKC-δ neurons form strong
inhibitory connections on CEA PKC-δ negative cells (Haubensak et al., 2010), these results
suggest that the CEA PKC-δ neuron might regulate the effect of CCK by disinhibiting the
CEA PKC-δ negative cells. Based on this circuit structure, it was reasoned that neurons
downstream of CEA regulating satiation should be activated by both the activation of CEA
PKC-δ neurons and the IP injection of CCK (Sanchez et al., 2022). Using this strategy,
a recent study successfully identified PSTN as one brain region downstream of CEA to
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regulate the satiation effect of CCK (Sanchez et al., 2022). PSTN is a relative new brain
region recently discovered to be involved in eating behaviors (Barbier et al., 2020, 2021;
Sanchez et al., 2022; Shah, Dunning, & Contet, 2022; Zhang et al., 2017; Zseli et al., 2018).
Neurons in PSTN are activated by both CCK administration and the optogenetic activation
of CEA PKC-δ neurons. Correspondingly, silencing PSTN neurons attenuates the eating
suppression caused by CCK, and optogenetic activation of PSTN neurons suppresses food
intake (Sanchez et al., 2022). The role of PSTN neurons in regulating the eating suppression
caused by CCK was also demonstrated by another study using genetic marker tachykinin 1

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(Tac1) in PSTN region (Kim et al., 2022). Thus, PSTN is also a brain region that regulates
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the eating suppression caused by CCK.

2.7. Output neurons for eating suppression caused by satiation

We have traced the possible neural pathways for satiation from the peripheral vagus nerve
to brain regions of PSTN or PVH (Fig. 2). The exact downstream target of PSTN or PVH
that regulates the satiation effect is still unknown. As food intake accumulates, the level of
satiation increases, leading to a decrease in jaw movement and biting, a slowdown in saliva
secretion, adjustments in gastric contractions, increased enzyme production for digestion,
and more (Valassi et al., 2008). During this process, the motivation to eat is suppressed.
Multiple physiological responses contribute to meal termination after satiation, and various
output brain regions should be involved in regulating these responses. However, it is still
unclear how these different aspects of meal termination are regulated.
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A rapid response to terminate eating may be regulated by the preoral motor neurons located
in the brainstem reticular formation (Dempsey et al., 2021; Moore, Kleinfeld, & Wang,
2014; Nakamura et al., 2017; Stanek et al., 2014). Tracing studies have indicated that
neurons in this region receive inputs from NTS, CEA, and other brain regions related to
eating regulation (Han et al., 2017; Valverde, 1962; van der Kooy et al., 1984; Veening,
Swanson, & Sawchenko, 1984), but their role in regulating satiation, such as the eating
suppression caused by CCK, is still unknown. The periaqueductal gray (PAG) also contains
neurons for motor control, and neurons in the PAG receive inputs from various brain regions
related to eating, including the medial part of the CEA (Behbehani, 1995; Han et al., 2017;
Rizvi et al., 1991). Again, their role in controlling the output of eating suppression during
satiation remains to be determined. Vagus efferent neurons, with cell bodies located in the
NTS, have also been suggested to contribute to the eating suppression caused by CCK
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(Moran et al., 1997). However, how these neurons are related to the circuits described above
remains to be determined. Thus, the output for eating suppression caused by satiation is still
unknown.

3. Macro-multi-level circuits control of satiation

The widely distributed neural circuits involved in satiation suggest that satiation might be
controlled by partially independent circuits at various levels (Fig. 3). Interestingly, CCK
still reduces food intake in decerebrate rats, in which the entire forebrain is separated
from the brainstem. When food is placed in their mouths, they eventually reject it in
response to CCK (Grill et al., 1988). This suggests that, at least in rats, brainstem circuitry
alone is sufficient to mediate the satiation effect of CCK reflexively, presumably without
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consciousness. However, numerous loss-of-function studies have shown that silencing or

ablating neurons in LPB, PSTN, CEA, PVH, or overexpressing DMH NPY can significantly
attenuate or abolish the anorectic effect of CCK (Becskei et al., 2007; Cai et al., 2014;
Crawley et al., 1985; de La Serre et al., 2016; Kim et al., 2022; Sanchez et al., 2022;
Trifunovic et al., 2001). Restoration of leptin signaling in the ARC reestablishes the satiating
effect of CCK in rats genetically lacking the leptin receptor (Morton et al., 2005). These
findings are not necessarily contradictory to the observation that CCK can suppress eating in

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decerebrate animals; instead, they suggest that satiation is controlled by semi-independent,

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macro-multi-level neural circuits distributed across the brainstem, midbrain, and forebrain
regions (Cai et al., 2014; Essner et al., 2017; Kim et al., 2022; Li, Wang, & Ritter, 2018;
Sanchez et al., 2022) (Fig. 3). Here, we propose a simple two-level circuit model (Fig. 4)
to explain how neurons in the forebrain CEA could cooperate with brainstem circuits to
regulate the eating suppression caused by CCK. In this model, NTS neurons that receive
CCK information from the vagus nerve send excitatory projections to the output neurons
in the brainstem to suppress appetite. The activity of the output neurons is regulated by
both excitatory and inhibitory inputs, and the level of activation of these neurons determines
the degree of eating suppression. When the forebrain is removed, the remaining brainstem
circuits can still reduce food intake in response to CCK. For example, when NTS neurons
are activated by CCK, the output neurons will increase their activity to terminate eating.
CEA PKC-δ neurons inhibit the PKC-δ negative neurons in CEA, which, in turn, inhibit
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the brainstem output neurons (Cai et al., 2014; Sanchez et al., 2022; Zhang-Molina, Schmit,
& Cai, 2020). When CEA PKC-δ neurons are silenced, the PKC-δ negative neurons are
disinhibited, enhancing the inhibition from PKC-δ negative neurons to the output neurons.
Consequently, even when the output neurons still receive excitation from the NTS neurons,
they will be inhibited, and the eating suppression induced by CCK will be attenuated (Fig.
4). The multi-level control of the satiation circuits might be crucial to ensuring a robust
homeostasis regulation of energy intake.

4. Meso- and micro-loop circuits for homeostasis

As described earlier, neurons from multiple brain regions have been demonstrated to
regulate the satiation effect of CCK. The circuits from the vagus nerve to output motor
neurons appear to form sequential connections to regulate satiation, at least at the nuclei
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level. However, numerous studies have suggested that the circuits are much more complex
than this sequential model. A superficial survey of the circuits studied so far clearly suggests
multiple obvious loop circuits involve reciprocal connections among different neural nodes
(meso-circuits) or neurons within the same nucleus (micro-circuits) that regulate satiation
and other aspect of eating behaviors.

The sequential circuits described above show that CEA is downstream of LPB in regulating
satiation caused by CCK. However, neurons in CEA also project back to LPB, as
demonstrated by many earlier tracing studies (Moga et al., 1990; Reppucci et al., 2016; Zseli
et al., 2016, 2018). While CEA PKC-δ neurons have very limited and weak connections
with LPB neurons, the PKC-δ negative population, including the Htr2a neurons, form
significant connections with LPB neurons, and activation of the projection from CEA
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Htr2a neurons to LPB promotes food intake (Douglass et al., 2017). However, it is still
unclear whether the same LPB neurons that receive inputs from CEA project to CEA.
Even the motor output neurons in the reticular formation send projections back to NTS
(Cheng et al., 2021), suggesting that there is a potential feedback regulation at the brainstem
level. It has been demonstrated that the Tac1 neurons in PSTN, which overlap with the
CCK-activated PSTN neurons, and inhibition of which attenuates the eating suppression
caused by CCK (Kim et al., 2022). The PSTN Tac1 neurons also project to CEA, and
activation of this pathway suppresses food intake (Kim et al., 2022). At the same time, a

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 Cai et al. Page 10

disynaptic disinhibitory circuit from CEA PKC-δ neurons to CEA PKC-δ negative neurons
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and to PSTN neurons was described (Fig. 5) (Sanchez et al., 2022). Using monosynaptic
rabies virus tracing, we also observed that PSTN contains neurons that directly innervate
CEA PKC-δ neurons (unpublished observation). Whether the PSTN neurons that receive
inhibition from CEA PKC-δ negative neurons are the same PSTN neurons that project to
CEA PKC-δ neurons has not been determined yet. However, these data suggest a clear loop
circuit between two brain regions for satiation regulation, and an obvious function of this
CEA-PSTN circuit is the amplification of the satiation signal caused by CCK to ensure a
robust physiological response of meal termination. Thus, the loop circuits between two brain
nuclei exist widely in the satiation pathway.

There are also some loop circuits that involve three or more brain regions. For example,
tracing studies have suggested that CEA neurons project to PSTN and receive inputs from
LPB, which receives inputs from NTS. PSTN neurons also project to CEA, LPB, and NTS
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(Kim et al., 2022). It has also been demonstrated that the PVH neurons receive inputs from
NTS directly and from CEA indirectly but also project to LPB to regulate food intake (Li
et al., 2019a; Tsubouchi et al., 2007). Thus, much more complicated loop circuits also exist.
But the identity and function of the involved neurons and their exact connections are totally
unknown at this moment.

It has been demonstrated that different types of neurons within CEA form mutual inhibitions
or a complicated microcircuit (Cai et al., 2014; Douglass et al., 2017; Haubensak et al.,
2010; Hou et al., 2016; Hunt et al., 2017; Li et al., 2013; Zhang-Molina et al., 2020). The
different electrophysiological properties of these neurons and their micro circuit structure
has been suggested to play an important role in regulating eating behaviors (Zhang-Molina
et al., 2020), which could be involved in satiation. With many different types of neurons
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being discovered in NTS, PBN, and other nodes, an important future direction is to
determine the structure and function of the micro circuits formed by these neurons.

Because eating is a complicated homeostatic behavior that requires sophisticated feedback to

adjust its function, it is not surprising that there are extensive loop circuits among the nodes
for satiation and eating regulation. However, this important feature is largely unstudied
in the past. Thus, it is important in the future to determine the dynamics of these loop
circuits simultaneously in real-time to understand how the feedforward and feedback signals
integrate into functional circuits to regulate delicate behaviors of eating.

5. Limitations
In our discussion here, we focused on neural circuits that use wired transmission, i.e.,
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the information flows from neuron to neuron through axons and synapses, to control
eating behaviors. However, many of the neurons in these pathways also express diverse
neuromodulators and neuromodulator receptors. Thus, it is inevitable that many of their
functions are mediated by neuromodulators that use volume transmission (Blevins et al.,
2003; Daughters et al., 2001; Hayes et al., 2004; Hsu et al., 2015). For a discussion on the
neuromodulation of satiation, please refer to the review (Asarian et al., 2014). The levels
of neuromodulators fluctuate in different states, such as hunger versus satiety, lean versus

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 Cai et al. Page 11

obese, light versus dark, etc., which will affect the function of the neurons. For example, the
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activation of A2, GLP-1, and PVH neurons in response to CCK is significantly modulated
by hunger after overnight food deprivation (Maniscalco et al., 2013); and PVH neurons also
mediates diurnal rhythm of metabolism (Kim et al., 2020). The mechanisms mediating these
controls, however, have not been sufficiently studied yet.

Many early lesion and pharmacological studies use rats, while most recent cell type-specific
manipulations use mice. It should be noted that there are many fundamental differences
between mice and rats, or even among different mice lines. For example, the PKC-δ
neurons in CEA seem to have different electrophysiological properties between mice and
rats (Amano et al., 2012). In mice, the NTS PPG neurons express the leptin receptor and
are directly modulated by leptin, but this effect is not observed in rats. (Huo et al., 2008;
Maniscalco et al., 2014; Trapp et al., 2015). The neural mechanisms underlying rodents
are different from humans, but the differences are still not fully understood. Therefore, the
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conclusions and implications must be considered with caution when translating to effects
and therapeutic development for humans.

Most previous studies were performed in male animals for various reasons. Only recently
have female animals been given attention and used in more studies. However, food intake is
affected by different estrous cycles and sex hormones, adding to the complications but also
the importance of including studies with female rodents (Freeman et al., 2021; Liu et al.,
2020; Young, Nance, & Gorski, 1979). Interestingly, the satiation effect of CCK is mediated
by estrogen in mice and rats, and it probably maps onto a change in food intake in women
during the menstrual cycle (see review (Asarian et al., 2013)). It is essential to explore how
the neural circuits and their dynamics regulate different eating behaviors in both male and
female animals, as well as other biological variables such as age, circadian cycle, etc.
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Recent studies using genetically marked cells have provided an enormous amount of rich
information about the neural circuits and how they regulate eating behaviors in detail, which
has not been achieved before (Andermann et al., 2017; Bruning et al., 2023; Sternson et
al., 2017). However, most of these genetically marked neurons are heterogeneous in their
function in many conditions. Usually, they have some overlap with the CCK-activated
neurons. Thus, the functional studies may include functions other than those related to
CCK or only part of satiation. Another limitation is that many of these genetic markers are
neuromodulators, expression of which may change depending on the states of the animals,
such as stress and hunger/satiety (Zelikowsky et al., 2018). These limitations are still
understudied but should be characterized carefully to understand how eating is controlled.

Finally, some of the studies measure solid food intake while others use liquid food, which
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may also involve different neural mechanisms to regulate (Gordon et al., 1981; Martin-
Iverson et al., 1988; McKay, Galante, & Daniels, 2014; Pan et al., 2011). For example,
lesion of LPB abolish the anorectic effect of CCK on food intake but not milk intake
(Trifunovic et al., 2001, 2003).

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 Cai et al. Page 12

6. Conclusions
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With new in vivo technologies such as optogenetics and real-time imaging with higher time
resolution, a great deal of detailed information about the circuit mechanisms of satiation and
eating control can been achieved. The circuit models we have described here are far from
complete and only provide a framework for us to improve our knowledge. As we mentioned,
the important features of multi-level control and loop circuits are still understudied. Several
significant limitations, such as species and sex differences, still need to be characterized.
Once these questions are resolved, we can understand how satiation and eating, one of the
oldest and most important behaviors for survival, are controlled by neural circuits.

Acknowledgement
We thank the reviewers for their careful reading, insightful comments, and suggestions, which greatly improved the
Author Manuscript

paper. The research reported here was supported by the NIDDK (R01 DK124501) to H.C.

Data availability
No data was used for the research described in the article.

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Fig. 1.
Temporal structure of meals.
Each meal is composed of a cluster of bouts. The satiation signal increases a few minutes
after eating initiation and decreases rapidly after the meal. Satiation determines the size of
a meal, and satiety determines the length of the inter-meal interval. Although satiation
and satiety can be distinguished behaviorally, the underlying neural mechanisms and
neuromodulators may not be well separated and may have overlapping functions.
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Fig. 2.
Major neural circuits that regulate satiation.
The VSNs and major brain regions that regulate the satiation effect caused by CCK are
indicated with light blue color. VSNs, vagal sensory neurons; NTS, nucleus of the solitary
tract; LPB, lateral parabrachial nucleus; CEA, central nucleus of the amygdala; PVH,
paraventricular hypothalamus; PSTN, parasubthalamic nucleus.
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Fig. 3.
Macro-multi-level circuits for satiation control. It should be noted that complex and
extensive interactions exist among these circuits.
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Fig. 4.
Circuits model of how silencing forebrain CEA PKC-δ neurons attenuates the satiation
effect of CCK.
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Fig. 5.
Loop circuits between CEA and PSTN might amplify the satiation signal.
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