Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2024 Sep 1.
Published in final edited form as: Appetite. 2024 May 25;200:107512. doi: 10.1016/j.appet.2024.107512

Neural circuits regulation of satiation

Haijiang Cai a,d,*, Wesley I Schnapp a,b, Shivani Mann a, Masa Miscevic a,c, Matthew B Schmit a,b, Marco Conteras a, Caohui Fang a
PMCID: PMC11227400  NIHMSID: NIHMS1998609  PMID: 38801994

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, 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 sophisticated and complicated neural system to regulate behaviors (Albright et al., 2000). 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 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, 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.

Fig. 1.

Fig. 1.

Open in a new tab

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.

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; 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, have been identified in different species (Sayegh, 2013). It appears that the longer forms of 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 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).

Fig. 2.

Fig. 2.

Open in a new tab

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.

2.1. Vagal sensory neurons (VSNs)

The peripheral signals from the gut to the brain are primarily mediated by sensory vagal 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 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 et al., 2019). Interestingly, Oxtr+ and Glp1r + VSNs have intraganglionic laminar endings (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 (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 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 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 neurons are also activated during oral consumption and have a phasic activity pattern that 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 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, 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 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 involved in satiety or long-term energy balance regulation. Consistent with this, activation 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 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 (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 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, and lesion of LPB prevents the CCK-induced c-Fos expression in CEA, suggesting that CEA 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 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, 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 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 (Tac1) in PSTN region (Kim et al., 2022). Thus, PSTN is also a brain region that regulates 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.

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

Fig. 3.

Fig. 3.

Open in a new tab

Macro-multi-level circuits for satiation control. It should be noted that complex and extensive interactions exist among these circuits.

Fig. 4.

Fig. 4.

Open in a new tab

Circuits model of how silencing forebrain CEA PKC-δ neurons attenuates the satiation effect of CCK.

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 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 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 disynaptic disinhibitory circuit from CEA PKC-δ neurons to CEA PKC-δ negative neurons 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.

Fig. 5.

Fig. 5.

Open in a new tab

Loop circuits between CEA and PSTN might amplify the satiation signal.

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 (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 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., 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 obese, light versus dark, etc., which will affect the function of the neurons. For example, the 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 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.

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 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).

6. Conclusions

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

Footnotes

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.

Data availability

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

References

  1. Aja S, et al. (2001). Intracerebroventricular CART peptide reduces food intake and alters motor behavior at a hindbrain site. American Journal of Physiology - Regulatory, Integrative and Comparative Physiology, 281(6), R1862, 7. [DOI] [PubMed] [Google Scholar]
  2. Albright TD, et al. (2000). Neural science: A century of progress and the mysteries that remain. Neuron. 25 Suppl, S1–S55. [DOI] [PubMed] [Google Scholar]
  3. Alhadeff AL, et al. (2019). Natural and Drug Rewards Engage distinct pathways that Converge on Coordinated hypothalamic and Reward circuits. Neuron, 103(5), 891–908. e6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Amano T, et al. (2012). Morphology, PKCdelta expression, and synaptic responsiveness of different types of rat central lateral amygdala neurons. J Neurophysiol. 108(12), 3196–3205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. An JJ, et al. (2015). Discrete BDNF neurons in the paraventricular hypothalamus control feeding and energy expenditure. Cell Metab. 22(1), 175–188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Andermann ML, & Lowell BB (2017). Toward a wiring Diagram understanding of appetite control. Neuron, 95(4), 757–778. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Antin J, et al. (1975). Cholecystokinin elicits the complete behavioral sequence of satiety in rats. Journal of Comparative & Physiological Psychology, 89(7), 784–790. [DOI] [PubMed] [Google Scholar]
  8. Aponte Y, Atasoy D, & Sternson SM (2011). AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat Neurosci. 14(3), 351–355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Appleyard SM, et al. (2005). Proopiomelanocortin neurons in nucleus tractus solitarius are activated by visceral afferents: Regulation by cholecystokinin and opioids. Journal of Neuroscience, 25(14), 3578–3585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Asarian L, & Bachler T. (2014). Neuroendocrine control of satiation. Hormone Molecular Biology and Clinical Investigation, 19(3), 163–192. [DOI] [PubMed] [Google Scholar]
  11. Asarian L, & Geary N. (2013). Sex differences in the physiology of eating. Am J Physiol Regul Integr Comp Physiol, 67. 305(11), R1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Atasoy D, et al. (2012). Deconstruction of a neural circuit for hunger. Nature, 488 (7410), 172–177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Bai L, et al. (2019). Genetic identification of vagal sensory neurons that control feeding. Cell, 179(5), 1129–1143. e23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Barbier M, et al. (2020). A basal ganglia-like cortical-amygdalar-hypothalamic network mediates feeding behavior. Proceedings of the National Academy of Sciences of the U S A, 117(27), 15967–15976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Barbier M, & Risold PY (2021). Understanding the significance of the hypothalamic Nature of the Subthalamic nucleus. eNeuro, 8(5). [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Becskei C, et al. (2007). Lesion of the lateral parabrachial nucleus attenuates the anorectic effect of peripheral amylin and CCK. Brain Research, 1162, 76–84. [DOI] [PubMed] [Google Scholar]
  17. Beglinger C, et al. (2001). Loxiglumide, a CCK-A receptor antagonist, stimulates calorie intake and hunger feelings in humans. Am J Physiol Regul Integr Comp Physiol, 54. 280(4), Article R1149. [DOI] [PubMed] [Google Scholar]
  18. Behbehani MM (1995). Functional characteristics of the midbrain periaqueductal gray. Progress in Neurobiology, 46(6), 575–605. [DOI] [PubMed] [Google Scholar]
  19. Berthoud HR, & Neuhuber WL (2000). Functional and chemical anatomy of the afferent vagal system. Autonomic Neuroscience, 85(1–3), 1–17. [DOI] [PubMed] [Google Scholar]
  20. Blevins JE, et al. (2003). Oxytocin innervation of caudal brainstem nuclei activated by cholecystokinin. Brain Research, 993(1–2), 30–41. [DOI] [PubMed] [Google Scholar]
  21. Block CH, Hoffman G, & Kapp BS (1989). Peptide-containing pathways from the parabrachial complex to the central nucleus of the amygdala. Peptides, 10(2), 465–471. [DOI] [PubMed] [Google Scholar]
  22. Bowers ME, Choi DC, & Ressler KJ (2012). Neuropeptide regulation of fear and anxiety: Implications of cholecystokinin, endogenous opioids, and neuropeptide Y. Physiology & Behavior, 107(5), 699–710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Boyle CN, et al. (2012). Dehydration-anorexia derives from a reduction in meal size, but not meal number. Physiology & Behavior, 105(2), 305–314. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Broberger C, et al. (1999). Cocaine- and amphetamine-regulated transcript in the rat vagus nerve: A putative mediator of cholecystokinin-induced satiety. Proceedings of the National Academy of Sciences of the U S A, 96(23), 13506–13511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Bruning JC, & Fenselau H. (2023). Integrative neurocircuits that control metabolism and food intake. Science, 381(6665), Article eabl7398. [DOI] [PubMed] [Google Scholar]
  26. Cai H, et al. (2014). Central amygdala PKC-delta(+) neurons mediate the influence of multiple anorexigenic signals. Nat Neurosci. 17(9), 1240–1248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Campfield LA, Brandon P, & Smith FJ (1985). On-line continuous measurement of blood glucose and meal pattern in free-feeding rats: The role of glucose in meal initiation. Brain Research Bulletin, 14(6), 605–616. [DOI] [PubMed] [Google Scholar]
  28. Campos CA, et al. (2018). Encoding of danger by parabrachial CGRP neurons. Nature, 555(7698), 617–622. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Carter ME, et al. (2013). Genetic identification of a neural circuit that suppresses appetite. Nature, 503(7474), 111–114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Cheng W, et al. (2020). Calcitonin receptor neurons in the mouse nucleus tractus solitarius control energy balance via the non-aversive suppression of feeding. Cell Metabolism, 31(2), 301–312. e5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Cheng W, et al. (2021). NTS Prlh overcomes orexigenic stimuli and ameliorates dietary and genetic forms of obesity. Nat Commun. 12(1), 5175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Crawley JN, & Kiss JZ (1985). Paraventricular nucleus lesions abolish the inhibition of feeding induced by systemic cholecystokinin. Peptides, 6(5), 927–935. [DOI] [PubMed] [Google Scholar]
  33. Crawley JN, Kiss JZ, & Mezey E. (1984). Bilateral midbrain transections block the behavioral effects of cholecystokinin on feeding and exploration in rats. Brain Research, 322(2), 316–321. [DOI] [PubMed] [Google Scholar]
  34. D’Agostino G, et al. (2016). Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit. Elife, 5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Daughters RS, et al. (2001). Ondansetron attenuates CCK induced satiety and c-fos labeling in the dorsal medulla. Peptides. 22(8), 1331–1338. [DOI] [PubMed] [Google Scholar]
  36. Davis JD (1989). The microstructure of ingestive behavior. Annals of the New York Academy of Sciences, 575, 106–119. discussion 120–1. [DOI] [PubMed] [Google Scholar]
  37. de La Serre CB, et al. (2016). Dorsomedial hypothalamic NPY affects cholecystokinin-induced satiety via modulation of brain stem catecholamine neuronal signaling. Am J Physiol Regul Integr Comp Physiol. 311(5), R930–R939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. de Lartigue G, et al. (2007). Cocaine- and amphetamine-regulated transcript: Stimulation of expression in rat vagal afferent neurons by cholecystokinin and suppression by ghrelin. Journal of Neuroscience, 27(11), 2876–2882. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Dempsey B, et al. (2021). A medullary centre for lapping in mice. Nat Commun. 12(1), 6307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Dockray GJ (2012). Cholecystokinin. Curr Opin Endocrinol Diabetes Obes. 19(1), 8–12. [DOI] [PubMed] [Google Scholar]
  41. Dockray GJ (2013). Enteroendocrine cell signalling via the vagus nerve. Current Opinion in Pharmacology, 13(6), 954–958. [DOI] [PubMed] [Google Scholar]
  42. Dockray GJ (2014). Gastrointestinal hormones and the dialogue between gut and brain. The Journal of Physiology, 592(14), 2927–2941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Douglass AM, et al. (2017). Central amygdala circuits modulate food consumption through a positive-valence mechanism. Nature Neuroscience, 20(10), 1384–1394. [DOI] [PubMed] [Google Scholar]
  44. Egerod KL, et al. (2012). A major lineage of enteroendocrine cells coexpress CCK, secretin, GIP, GLP-1, PYY, and neurotensin but not somatostatin. Endocrinology. 153 (12), 5782–5795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Egerod KL, et al. (2018). Profiling of G protein-coupled receptors in vagal afferents reveals novel gut-to-brain sensing mechanisms. Mol Metab. 12, 62–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Essner RA, et al. (2017). AgRP neurons can increase food intake during conditions of appetite suppression and inhibit anorexigenic parabrachial neurons. J Neurosci. 37 (36), 8678–8687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Fan W, et al. (2004). Cholecystokinin-mediated suppression of feeding involves the brainstem melanocortin system. Nature Neuroscience, 7(4), 335–336. [DOI] [PubMed] [Google Scholar]
  48. Fenselau H, et al. (2017). A rapidly acting glutamatergic ARC–>PVH satiety circuit postsynaptically regulated by alpha-MSH. Nature Neuroscience, 20(1), 42–51. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Freeman LR, et al. (2021). Sex differences in Demand for highly palatable foods: Role of the Orexin system. The International Journal of Neuropsychopharmacology, 24(1), 54–63. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Garfield AS, et al. (2012). Neurochemical characterization of body weight-regulating leptin receptor neurons in the nucleus of the solitary tract. Endocrinology, 153(10), 4600–4607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Geary N. (2014). A physiological perspective on the neuroscience of eating. Physiol Behav. 136, 3–14. [DOI] [PubMed] [Google Scholar]
  52. Gibbs J, Young RC, & Smith GP (1973). Cholecystokinin decreases food intake in rats. Journal of Comparative & Physiological Psychology, 84(3), 488–495. [DOI] [PubMed] [Google Scholar]
  53. Goldstein N, et al. (2021). Hypothalamic detection of macronutrients via multiple gut-brain pathways. Cell Metabolism, 33(3), 676–687. e5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Gordon FJ, & Johnson AK (1981). Electrical stimulation of the septal area in the rat: Prolonged suppression of water intake and correlation with self-stimulation. Brain Research, 206(2), 421–430. [DOI] [PubMed] [Google Scholar]
  55. Gribble FM, & Reimann F. (2016). Enteroendocrine cells: Chemosensors in the intestinal Epithelium. Annual Review of Physiology, 78, 277–299. [DOI] [PubMed] [Google Scholar]
  56. Grill HJ, & Hayes MR (2012). Hindbrain neurons as an essential hub in the neuroanatomically distributed control of energy balance. Cell Metabolism, 16(3), 296–309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Grill HJ, & Smith GP (1988). Cholecystokinin decreases sucrose intake in chronic decerebrate rats. American Journal of Physiology, 254(6 Pt 2), R853, 6. [DOI] [PubMed] [Google Scholar]
  58. Han W, et al. (2017). Integrated control of Predatory Hunting by the central nucleus of the amygdala. Cell, 168(1–2), 311–324. e18. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Han W, et al. (2018). A neural circuit for gut-induced Reward. Cell. e23. 175(3), 665–678. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Haubensak W, et al. (2010). Genetic dissection of an amygdala microcircuit that gates conditioned fear. Nature, 468(7321), 270–276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Hayes MR, et al. (2004). 5-HT3 receptors participate in CCK-induced suppression of food intake by delaying gastric emptying. Am J Physiol Regul Integr Comp Physiol, 23. 287(4), R817. [DOI] [PubMed] [Google Scholar]
  62. Hayes MR, et al. (2010). Endogenous leptin signaling in the caudal nucleus tractus solitarius and area postrema is required for energy balance regulation. Cell Metabolism, 11(1), 77–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Holder JL Jr., Butte NF, & Zinn AR (2000). Profound obesity associated with a balanced translocation that disrupts the SIM1 gene. Human Molecular Genetics, 9(1), 101–108. [DOI] [PubMed] [Google Scholar]
  64. Hou WH, et al. (2016). Wiring Specificity and synaptic Diversity in the mouse lateral central amygdala. Journal of Neuroscience, 36(16), 4549–4563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Hsu TM, et al. (2015). Hippocampal GLP-1 receptors influence food intake, meal size, and effort-based responding for food through volume transmission. Neuropsychopharmacology. 40(2), 327–337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Hunt S, et al. (2017). Intrinsic circuits in the lateral central amygdala. eNeuro, 4(1). [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Huo L, et al. (2008). Divergent leptin signaling in proglucagon neurons of the nucleus of the solitary tract in mice and rats. Endocrinology, 149(2), 492–497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Kaelberer MM, et al. (2018). A gut-brain neural circuit for nutrient sensory transduction. Science. 361(6408). [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Karimnamazi H, Travers SP, & Travers JB (2002). Oral and gastric input to the parabrachial nucleus of the rat. Brain Research, 957(2), 193–206. [DOI] [PubMed] [Google Scholar]
  70. Kim J, et al. (2017). Basolateral to central amygdala neural circuits for appetitive behaviors. Neuron, 93(6), 1464–1479. e5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Kim ER, et al. (2020). Paraventricular hypothalamus mediates diurnal rhythm of metabolism. Nature Communications, 11(1), 3794. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Kim JH, et al. (2022). A discrete parasubthalamic nucleus subpopulation plays a critical role in appetite suppression. Elife, 11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. King BM (2006). Amygdaloid lesion-induced obesity: Relation to sexual behavior, olfaction, and the ventromedial hypothalamus. American Journal of Physiology - Regulatory, Integrative and Comparative Physiology, 291(5), R1201, 14. [DOI] [PubMed] [Google Scholar]
  74. Kissileff HR, et al. (2003). Cholecystokinin and stomach distension combine to reduce food intake in humans. American Journal of Physiology - Regulatory, Integrative and Comparative Physiology, 285(5), R992, 8. [DOI] [PubMed] [Google Scholar]
  75. Koch M, et al. (2015). Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature. 519(7541), 45–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
  76. Kohno D, et al. (2014). Dnmt3a in Sim1 neurons is necessary for normal energy homeostasis. J Neurosci. 34(46), 15288–15296. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Kreisler AD, Davis EA, & Rinaman L. (2014). Differential activation of chemically identified neurons in the caudal nucleus of the solitary tract in non-entrained rats after intake of satiating vs. non-satiating meals. Physiology & Behavior, 136, 47–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Lee SJ, et al. (2020). Blunted vagal cocaine- and amphetamine-regulated transcript promotes hyperphagia and weight gain. Cell Reports, 30(6), 2028–2039. e4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Li H, et al. (2013). Experience-dependent modification of a central amygdala fear circuit. Nature Neuroscience, 16(3), 332–339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Li MM, et al. (2019a). The paraventricular hypothalamus regulates satiety and prevents obesity via two genetically distinct circuits. Neuron, 102(3), 653–667. e6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Li C, et al. (2019b). Defined paraventricular hypothalamic populations Exhibit Differential responses to food Contingent on caloric state. Cell Metabolism, 29(3), 681–694. e5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Li AJ, Wang Q, & Ritter S. (2018). Activation of catecholamine neurons in the ventral medulla reduces CCK-induced hypophagia and c-Fos activation in dorsal medullary catecholamine neurons. Am J Physiol Regul Integr Comp Physiol. 315(3), R442–R452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Liu J, et al. (2017). Enhanced AMPA receptor Trafficking mediates the anorexigenic effect of endogenous glucagon-like peptide-1 in the paraventricular hypothalamus. Neuron, 96(4), 897–909. e5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Liu CM, et al. (2020). Sex differences and estrous Influences on oxytocin control of food intake. Neuroscience, 447, 63–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Lorenz DN, & Goldman SA (1982). Vagal mediation of the cholecystokinin satiety effect in rats. Physiology & Behavior, 29(4), 599–604. [DOI] [PubMed] [Google Scholar]
  86. Ludwig MQ, et al. (2021). A genetic map of the mouse dorsal vagal complex and its role in obesity. Nat Metab. 3(4), 530–545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Ly T, et al. (2023). Sequential appetite suppression by oral and visceral feedback to the brainstem. Nature, 624(7990), 130–137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Maniscalco JW, & Rinaman L. (2013). Overnight food deprivation markedly attenuates hindbrain noradrenergic, glucagon-like peptide-1, and hypothalamic neural responses to exogenous cholecystokinin in male rats. Physiology & Behavior, 121, 35–42. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Maniscalco JW, & Rinaman L. (2014). Systemic leptin dose-dependently increases STAT3 phosphorylation within hypothalamic and hindbrain nuclei. Am J Physiol Regul Integr Comp Physiol, 85. 306(8), R576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  90. Martin-Iverson MT, & Dourish CT (1988). Role of dopamine D-1 and D-2 receptor subtypes in mediating dopamine agonist effects on food consumption in rats. Psychopharmacology (Berl), 96(3), 370–374. [DOI] [PubMed] [Google Scholar]
  91. Matzinger D, et al. (1999). Inhibition of food intake in response to intestinal lipid is mediated by cholecystokinin in humans. American Journal of Physiology, 277(6), Article R1718, 24. [DOI] [PubMed] [Google Scholar]
  92. McKay NJ, Galante DL, & Daniels D. (2014). Endogenous glucagon-like peptide-1 reduces drinking behavior and is differentially engaged by water and food intakes in rats. J Neurosci. 34(49), 16417–16423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Michaud JL, et al. (2001). Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus. Human Molecular Genetics, 10(14), 1465–1473. [DOI] [PubMed] [Google Scholar]
  94. Moga MM, et al. (1990). Organization of cortical, basal forebrain, and hypothalamic afferents to the parabrachial nucleus in the rat. J Comp Neurol. 295(4), 624–661. [DOI] [PubMed] [Google Scholar]
  95. Moore JD, Kleinfeld D, & Wang F. (2014). How the brainstem controls orofacial behaviors comprised of rhythmic actions. Trends in Neurosciences, 37(7), 370–380. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Moran TH, & Bi S. (2006). Hyperphagia and obesity in OLETF rats lacking CCK-1 receptors. Philos Trans R Soc Lond B Biol Sci. 361(1471), 1211–1218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  97. Moran TH, et al. (1997). Vagal afferent and efferent contributions to the inhibition of food intake by cholecystokinin. American Journal of Physiology, 272(4 Pt 2), R1245, 51. [DOI] [PubMed] [Google Scholar]
  98. Moran TH, & McHugh PR (1982). Cholecystokinin suppresses food intake by inhibiting gastric emptying. American Journal of Physiology, 242(5), R491, 7. [DOI] [PubMed] [Google Scholar]
  99. Morton GJ, et al. (2005). Leptin action in the forebrain regulates the hindbrain response to satiety signals. Journal of Clinical Investigation, 115(3), 703–710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Murphy S, et al. (2023). Nucleus of the solitary tract A2 neurons control feeding behaviors via projections to the paraventricular hypothalamus. Neuropsychopharmacology, 48(2), 351–361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Nakamura Y, et al. (2017). Medullary reticular neurons mediate neuropeptide Y-induced metabolic inhibition and mastication. Cell Metabolism, 25(2), 322–334. [DOI] [PMC free article] [PubMed] [Google Scholar]
  102. Noble F, et al. (1999). International union of pharmacology. XXI. Structure, Distribution, and Functions of Cholecystokinin Receptors. Pharmacol Rev, 51(4), 745–781. [PubMed] [Google Scholar]
  103. Overduin J, et al. (2014). CCK-58 elicits both satiety and satiation in rats while CCK-8 elicits only satiation. Peptides. 54, 71–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
  104. Palmiter RD (2018). The parabrachial nucleus: CGRP neurons function as a general Alarm. Trends Neurosci. 41(5), 280–293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  105. Pan A, & Hu FB (2011). Effects of carbohydrates on satiety: Differences between liquid and solid food. Current Opinion in Clinical Nutrition and Metabolic Care, 14(4), 385–390. [DOI] [PubMed] [Google Scholar]
  106. Passaro E Jr., et al. (1982). Rapid appearance of intraventricularly administered neuropeptides in the peripheral circulation. Brain Research, 241(2), 335–340. [PubMed] [Google Scholar]
  107. Polak JM, et al. (1975). Identification of cholecystokinin-secreting cells. Lancet, 2 (7943), 1016–1018. [DOI] [PubMed] [Google Scholar]
  108. Powley TL, & Phillips RJ (2004). Gastric satiation is volumetric, intestinal satiation is nutritive. Physiology & Behavior, 82(1), 69–74. [DOI] [PubMed] [Google Scholar]
  109. Qiu W, et al. (2023). Multiple NTS neuron populations cumulatively suppress food intake. Elife, 12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  110. Ran C, et al. (2022). A brainstem map for visceral sensations. Nature. 609(7926), 320–326. [DOI] [PMC free article] [PubMed] [Google Scholar]
  111. Reidelberger RD, et al. (1994). Cholecystokinin suppresses food intake by a nonendocrine mechanism in rats. American Journal of Physiology, 267(4 Pt 2), R901, 8. [DOI] [PubMed] [Google Scholar]
  112. Reppucci CJ, & Petrovich GD (2016). Organization of connections between the amygdala, medial prefrontal cortex, and lateral hypothalamus: A single and double retrograde tracing study in rats. Brain Structure and Function, 221(6), 2937–2962. [DOI] [PMC free article] [PubMed] [Google Scholar]
  113. Ricardo JA, & Koh ET (1978). Anatomical evidence of direct projections from the nucleus of the solitary tract to the hypothalamus, amygdala, and other forebrain structures in the rat. Brain Research, 153(1), 1–26. [DOI] [PubMed] [Google Scholar]
  114. Rinaman L. (2003). Hindbrain noradrenergic lesions attenuate anorexia and alter central cFos expression in rats after gastric viscerosensory stimulation. Journal of Neuroscience, 23(31), 10084–10092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  115. Rinaman L. (2010). Ascending projections from the caudal visceral nucleus of the solitary tract to brain regions involved in food intake and energy expenditure. Brain Research, 1350, 18–34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  116. Ritter RC, Covasa M, & Matson CA (1999). Cholecystokinin: Proofs and prospects for involvement in control of food intake and body weight. Neuropeptides. 33(5), 387–399. [DOI] [PubMed] [Google Scholar]
  117. Rizvi TA, et al. (1991). Connections between the central nucleus of the amygdala and the midbrain periaqueductal gray: Topography and reciprocity. The Journal of Comparative Neurology, 303(1), 121–131. [DOI] [PubMed] [Google Scholar]
  118. Rodgers RJ, Holch P, & Tallett AJ (2010). Behavioural satiety sequence (BSS): Separating wheat from chaff in the behavioural pharmacology of appetite. Pharmacology Biochemistry and Behavior, 97(1), 3–14. [DOI] [PubMed] [Google Scholar]
  119. Rodriguez E, et al. (2019). Identifying parabrachial neurons Selectively regulating satiety for highly palatable food in mice. eNeuro, 6(6). [DOI] [PMC free article] [PubMed] [Google Scholar]
  120. Rollins BL, & King BM (2000). Amygdala-lesion obesity: What is the role of the various amygdaloid nuclei? American Journal of Physiology - Regulatory, Integrative and Comparative Physiology, 279(4), R1348, 56. [DOI] [PubMed] [Google Scholar]
  121. Roman CW, Sloat SR, & Palmiter RD (2017). A tale of two circuits: CCK(NTS) neuron stimulation controls appetite and induces opposing motivational states by projections to distinct brain regions. Neuroscience. 358, 316–324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  122. Sanchez MR, et al. (2022). Dissecting a disynaptic central amygdala-parasubthalamic nucleus neural circuit that mediates cholecystokinin-induced eating suppression. Molecular Metabolism, 58, Article 101443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  123. Sayegh AI (2013). The role of cholecystokinin receptors in the short-term control of food intake. Program Molcular Biology Translation Science, 114, 277–316. [DOI] [PubMed] [Google Scholar]
  124. Schwartz GJ, McHugh PR, & Moran TH (1993). Gastric loads and cholecystokinin synergistically stimulate rat gastric vagal afferents. American Journal of Physiology, 265(4 Pt 2), R872, 6. [DOI] [PubMed] [Google Scholar]
  125. Schwartz GJ, & Moran TH (1998). Integrative gastrointestinal actions of the brain-gut peptide cholecystokinin in satiety. Progress in Psychobiology and Physiological Psychology, 17(17), 1–34. [Google Scholar]
  126. Shah T, Dunning JL, & Contet C. (2022). At the heart of the interoception network: Influence of the parasubthalamic nucleus on autonomic functions and motivated behaviors. Neuropharmacology, 204, Article 108906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  127. Smith GP, et al. (1981). Abdominal vagotomy blocks the satiety effect of cholecystokinin in the rat. Science, 213(4511), 1036–1037. [DOI] [PubMed] [Google Scholar]
  128. Smith GP, & Gibbs J. (1992). The development and proof of the CCK hypothesis of satiety. Multiple cholecystokinin receptors in the CNS. Oxford: Oxford University Press. [Google Scholar]
  129. Smith GP, Jerome C, & Norgren R. (1985). Afferent axons in abdominal vagus mediate satiety effect of cholecystokinin in rats. American Journal of Physiology, 249 (5 Pt 2), R638, 41. [DOI] [PubMed] [Google Scholar]
  130. Stanek E.t., et al. (2014). Monosynaptic premotor circuit tracing reveals neural substrates for oro-motor coordination. Elife, 3, Article e02511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  131. Steinert RE, et al. (2017). Ghrelin, CCK, GLP-1, and PYY(3–36): Secretory controls and physiological roles in eating and Glycemia in Health, obesity, and after RYGB. Physiol Rev. 97(1), 411–463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  132. Sternson SM, & Eiselt AK (2017). Three Pillars for the neural control of appetite. Annual Review of Physiology, 79, 401–423. [DOI] [PubMed] [Google Scholar]
  133. Sun N, & Cassell MD (1993). Intrinsic GABAergic neurons in the rat central extended amygdala. J Comp Neurol. 330(3), 381–404. [DOI] [PubMed] [Google Scholar]
  134. Tolkamp BJ, et al. (2011). The temporal structure of feeding behavior. American Journal of Physiology - Regulatory, Integrative and Comparative Physiology, 301(2), R378, 93. [DOI] [PubMed] [Google Scholar]
  135. Trapp S, & Cork SC (2015). PPG neurons of the lower brain stem and their role in brain GLP-1 receptor activation. Am J Physiol Regul Integr Comp Physiol, 804. 309 (8), R795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  136. Trifunovic R, & Reilly S. (2001). Medial versus lateral parabrachial nucleus lesions in the rat: Effects on cholecystokinin- and D-fenfluramine-induced anorexia. Brain Research, 894(2), 288–296. [DOI] [PubMed] [Google Scholar]
  137. Trifunovic R, & Reilly S. (2003). Excitotoxic lesions of the lateral parabrachial nucleus do not prevent cholecystokinin-induced suppression of milk intake in rats. Neuroscience Letters, 348(2), 109–112. [DOI] [PubMed] [Google Scholar]
  138. Tsubouchi K, et al. (2007). A disynaptic pathway from the central amygdaloid nucleus to the paraventricular hypothalamic nucleus via the parastrial nucleus in the rat. Neurosci Res. 59(4), 390–398. [DOI] [PubMed] [Google Scholar]
  139. Valassi E, Scacchi M, & Cavagnini F. (2008). Neuroendocrine control of food intake. Nutrition, Metabolism, and Cardiovascular Diseases, 18(2), 158–168. [DOI] [PubMed] [Google Scholar]
  140. Valverde F. (1962). Reticular formation of the albino rat’s brain stem cytoarchitecture and corticofugal connections. The Journal of Comparative Neurology, 119, 25–53. [DOI] [PubMed] [Google Scholar]
  141. van der Bilt A, et al. (2006). Oral physiology and mastication. Physiology & Behavior, 89 (1), 22–27. [DOI] [PubMed] [Google Scholar]
  142. van der Kooy D, et al. (1984). The organization of projections from the cortex, amygdala, and hypothalamus to the nucleus of the solitary tract in rat. The Journal of Comparative Neurology, 224(1), 1–24. [DOI] [PubMed] [Google Scholar]
  143. Veening JG, Swanson LW, & Sawchenko PE (1984). The organization of projections from the central nucleus of the amygdala to brainstem sites involved in central autonomic regulation: A combined retrograde transport-immunohistochemical study. Brain Research, 303(2), 337–357. [DOI] [PubMed] [Google Scholar]
  144. Watts AG, et al. (2022). The physiological control of eating: Signals, neurons, and networks. Physiological Reviews, 102(2), 689–813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  145. West DB, Fey D, & Woods SC (1984). Cholecystokinin persistently suppresses meal size but not food intake in free-feeding rats. American Journal of Physiology, 246(5 Pt 2), R776, 87. [DOI] [PubMed] [Google Scholar]
  146. Williams EK, et al. (2016). Sensory neurons that detect stretch and nutrients in the digestive system. Cell, 166(1), 209–221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  147. Wu Q, Boyle MP, & Palmiter RD (2009). Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation. Cell. 137(7), 1225–1234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  148. Wyatt P, et al. (2021). Postprandial glycaemic dips predict appetite and energy intake in healthy individuals. Nature Metabolism, 3(4), 523–529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  149. Xi D, et al. (2012). Ablation of Sim1 neurons causes obesity through hyperphagia and reduced energy expenditure. PLoS One, 7(4), Article e36453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  150. Xu Y, et al. (2013). Glutamate mediates the function of melanocortin receptor 4 on Sim1 neurons in body weight regulation. Cell Metabolism, 18(6), 860–870. [DOI] [PMC free article] [PubMed] [Google Scholar]
  151. Young JK, Nance DM, & Gorski RA (1979). Sexual dimorphism in the regulation of caloric intake and body weight of rats fed different diets. Physiology & Behavior, 23 (3), 577–582. [DOI] [PubMed] [Google Scholar]
  152. Zagorodnyuk VP, Chen BN, & Brookes SJ (2001). Intraganglionic laminar endings are mechano-transduction sites of vagal tension receptors in the Guinea-pig stomach. The Journal of Physiology, 534(Pt 1), 255–268. [DOI] [PMC free article] [PubMed] [Google Scholar]
  153. Zelikowsky M, et al. (2018). The neuropeptide Tac 2 controls a distributed brain state induced by chronic Social Isolation stress. Cell. e19. 173(5), 1265–1279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  154. Zhan C, et al. (2013). Acute and long-term suppression of feeding behavior by POMC neurons in the brainstem and hypothalamus, respectively. Journal of Neuroscience, 33 (8), 3624–3632. [DOI] [PMC free article] [PubMed] [Google Scholar]
  155. Zhang X, & van den Pol AN (2017). Rapid binge-like eating and body weight gain driven by zona incerta GABA neuron activation. Science, 356(6340), 853–859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  156. Zhang-Molina C, Schmit MB, & Cai H. (2020). Neural circuit mechanism underlying the feeding controlled by Insula-central amygdala pathway. iScience, 23(4), Article 101033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  157. Zhao Q, et al. (2022). A multidimensional coding architecture of the vagal interoceptive system. Nature. 603(7903), 878–884. [DOI] [PMC free article] [PubMed] [Google Scholar]
  158. Zorrilla EP, et al. (2005). Measuring meals: Structure of prandial food and water intake of rats. Am J Physiol Regul Integr Comp Physiol, 67. 288(6), R1450. [DOI] [PubMed] [Google Scholar]
  159. Zseli G, et al. (2016). Elucidation of the anatomy of a satiety network: Focus on connectivity of the parabrachial nucleus in the adult rat. The Journal of Comparative Neurology, 524(14), 2803–2827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  160. Zseli G, et al. (2018). Neuronal connections of the central amygdalar nucleus with refeeding-activated brain areas in rats. Brain Structure and Function, 223(1), 391–414. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

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

RESOURCES