Inputs into the central amygdala

The numerous intra- and inter-connections between different amygdala nuclei provide inputs to the CeA^{(Reference Gilpin, Herman and Roberto35)}. For instance, the BLA affects the CeA through its protein phosphatase 1 regulatory subunit 1B⁺ (Ppp1r1b⁺) parvocellular neurons and R-spondin2⁺ (Rspo2⁺) magnocellular neurons^{(Reference Kim, Zhang and Muralidhar21,Reference Ye and Veinante26)} . As represented in Fig. 1, the Ppp1r1b⁺ and Rspo2⁺ neurons provoke and inhibit appetitive behaviours which are normally regulated in the CeA^{(Reference Kim, Zhang and Muralidhar21)}. However, the glutamatergic neurons in the LA and BLA have synapses with GABAergic neurons in the medial intercalated cells that are located between the BLA and CeA. It can be seen in Fig. 2 that these GABAergic medial intercalated cells connect the LA, BLA and CeA areas^{(Reference Ehrlich, Humeau and Grenier17,Reference Gilpin, Herman and Roberto35,Reference Pape and Pare37)} . Also, the BLA and LA send glutamatergic outputs, respectively, to the CeL/M and CeL subdivisions of the amygdala^{(Reference Gilpin, Herman and Roberto35,Reference Pape and Pare37)} . In Fig. 2, the CeL and CeM make local inhibitory circuits together due to sending γ-aminobutyric acid (GABA) interneurons^{(Reference Gilpin, Herman and Roberto35,Reference Pape and Pare37)} . Hence, a distinct population of neurons in the CeA perform an opposing role in feeding^{(Reference Zhang-Molina, Schmit and Cai32)}. The GABAergic protein kinase C-delta (PKC-δ ⁺) neurons in the CeL suppress feeding^{(Reference Wang, Shen and Jiang25,Reference Zhang-Molina, Schmit and Cai32)} . By contrast, the serotonin receptor 2a (Htr2a⁺/PKC-δ ^–) neurons in the CeL stimulate food intake^{(Reference Douglass8,Reference Zhang-Molina, Schmit and Cai32,Reference Wang, Kim and Schmit45)} . The activation of PKC-δ ⁺ neurons in both CeC and CeL leads to the inhibition of appetitive behaviours. These two types of appetite suppression happened via threat stimuli and aversive tastes in the CeC, as well as through satiety in the CeL^{(Reference Kim, Zhang and Muralidhar21)}. Also, BLA Rspo2⁺ and calcitonin-gene-related peptide (CGRP) of the lateral parabrachial nucleus (LPBN) neurons would mediate food consumption via projecting to PKC-δ ⁺ neurons in the CeC; however, Kim et al. (2017) demonstrated that BLA Ppp1r1b⁺ modulates appetitive behaviour via projecting to PKC-δ ⁺ neurons in the CeL^{(Reference Kim, Zhang and Muralidhar21)}. As represented in Fig. 1, both CeL and CeM seem to promote reward-related behaviours by receiving inputs from the BLA Ppp1r1b^{+(Reference Kim, Zhang and Muralidhar21)}.

Fig. 2. The schematic illustration of internal and external input/outputs of the central amygdala (CeA). The lateral amygdala (LA) and basolateral amygdala (BLA) affect synapse on medial intercalated cells (mITC) (which is connected to the CeA) via their glutamatergic neurons. The CeA is composed of medial part of the CeA (CeM), capsular part of the CeA (CeC) and lateral part of the CeA (CeL) mostly with GABAergic neurons. The LA and BLA excite CeL and CeL/M, respectively, via glutamatergic projections. The CeA receives internal LA and BLA inputs in the amygdala circuits. Additionally, it receives information from multiple regions, such as the periaqueductal grey (PAG), locus coeruleus (LC), nucleus tracts solitaries (NTS), dorsal raphe, ventral tegmental area (VTA), substantia nigra (SN) and bed nucleus of the stria terminalis (BNST). Also, the CeA and mostly the CeM exert outputs to the brains tem and hypothalamus. PKC-δ⁺, protein kinase C-delta⁺; Htr2a⁺, serotonin receptor 2a⁺; PSTN, parasubthalamic nucleus; DMC, dorsal motor complex; Hypo: hypothalamus. , Input; , Output; , Excitatory; , Inhibitory; , Inhibitory Interneurons.

Furthermore, the CeA receives a huge amount of information from multiple regions of the brain^{(Reference Douglass8,Reference Gilpin, Herman and Roberto35,Reference Verma, Wood and Lach46)} . The sensory and cortical inputs come from the ventral tegmental area, locus coeruleus, nucleus tractus solitarius (NTS), periaqueductal grey, bed nucleus of the stria terminalis, parasubthalamic nucleus, substantia nigra and, finally, dorsal raphe nucleus^{(Reference Douglass, Kucukdereli and Ponserre5,Reference Douglass8,Reference Gilpin, Herman and Roberto35,Reference Pape and Pare37)} (Fig. 2).

The NTS terminates food intake with glutamatergic input projections from the tyrosine hydroxylase and cholecystokinin cells to the PKC-δ ⁺ neurons of both CeL and CeC; also, the NTS activates CGRP of the LPBN neurons^{(Reference Douglass8,Reference Lu, Chen and Wei14,Reference Ye and Veinante26,Reference Hardaway, Halladay and Mazzone41,Reference Andermann and Lowell47–Reference Carter, Soden and Zweifel49)} . Moreover, the CGRP receptors in PKC-δ ⁺ neurons are probably the aim of CGRP neurons in the LPBN^{(Reference Campos, Bowen and Schwartz48,Reference Han, Soleiman and Soden50)} . However, Wang et al. (2019) indicated that the CGRP neurons in the LPBN suppress food consumption via excitatory projection to Htr2a⁺ neurons in the CeA^{(Reference Wang, Kim and Schmit45)}.

Satiety is the feeling of fullness and suppression of appetite and hunger. The satiety-related signals from LPBN projections excite PKC-δ ⁺ neurons in the CeA and mediate appetite by suppressing food intake^{(Reference Douglass8,Reference Fadok, Markovic and Tovote18,Reference Ye and Veinante26,Reference Andermann and Lowell47)} . Therefore, these signals mainly suppress appetite drive and create the feeling of satiety by releasing GABA from LPBN to PKC-δ ⁺ neurons in the CeA^{(Reference Fadok, Markovic and Tovote18,Reference Hardaway, Halladay and Mazzone41)} .

Another pathway for transporting food intake information is the insula-CeA connection^{(Reference Zhang-Molina, Schmit and Cai32)}. The insula activates two opposite ways in modulating the feeding behaviour via non-selective connections with both PKC-δ ⁺ and Htr2a⁺ neurons in the CeA^{(Reference Zhang-Molina, Schmit and Cai32)}. Despite similar synaptic strength of the insula-CeA pathways in both PKC-δ ⁺ and Htr2a⁺ neurons, food consumption behaviour will be decreased^{(Reference Zhang-Molina, Schmit and Cai32)}.

Outputs of the central amygdala

As illustrated in Fig. 2, the CeA has connections with almost all brain regions, such as the bed nucleus of the stria terminalis, lateral hypothalamus, PVN, ventral tegmental area, PBN, NTS, dorsal vagal complex and substantia nigra^{(Reference Douglass8,Reference Qiao, Ren and Li13,Reference Pape and Pare37,Reference Holt, Pomeranz and Beier51–Reference Veening, Swanson and Sawchenko54)} . There are numerous projections from the CeA to different brain regions^{(Reference Douglass8,Reference Qiao, Ren and Li13,Reference Pang, Chen and Xue31,Reference Pape and Pare37,Reference Takayama, Johno and Hayashi52)} . However, the CeM, unlike the CeL, seems to be more responsible for sending output projections to brain areas, such as the brain stem and hypothalamus^{(Reference Ehrlich, Humeau and Grenier17,Reference Pape and Pare37)} . Similarly, the CeL sends projection to different brain regions, including the preproglucagon neurons in the NTS^{(Reference Holt, Pomeranz and Beier51)}, periaqueductal grey and PVN of the thalamus^{(Reference Penzo, Robert and Li55)}. The terminal projections from CeC to the periaqueductal grey, PBN, NTS and ventromedial medulla have been observed too^{(Reference Lu, Chen and Wei14)}.

The central amygdala and different receptors as well as neurotransmitters/neuropeptides

The CeA contains receptors that are related to food consumption^{(Reference van den Burg and Stoop38)}. There is evidence of opioid receptors containing kappa (κ) and mu (μ) receptors that mediated food consumption in the CeA^{(Reference Giraudo, Billington and Levine56,Reference Kim, Shi and Olszewski57)} . Moreover, a unilateral opioid–opioid pathway from the CeA to PVN increased food intake via μ receptors^{(Reference Giraudo, Billington and Levine56)}. The CeA contains GABA and glutamate receptors that act differently^{(Reference Patel3)}. For instance, the direct injection of glutamate receptor agonist N-methyl-D-aspartate in the CeA increased food consumption^{(Reference Patel3)}.

Similar to various biochemical factors, different receptors could also exhibit different effects on food consumption by activating different CeA neurons^{(Reference Jin, Jiang and Luan30,Reference Pang, Chen and Xue31)} . A study has shown that direct injection of GABA_A receptor agonist in the CeA decreased food consumption^{(Reference Patel3)}. According to Anesten et al. (2019), the stimulation of glucagon-like peptide-1 receptors in the CeA nucleus reduces food intake^{(Reference Anesten, Dalmau Gasull and Richard12)}. Food consumption may be decreased by the microinjection of IL-6 into the CeA via the enhancement of glucagon-like peptide-1 receptors^{(Reference Anesten, Dalmau Gasull and Richard12)}. Moreover, Anderberg et al. (2014) demonstrated the anorectic effects of dopamine which are caused by the activation of the D₂ receptor in the CeA^{(Reference Anderberg, Anefors and Bergquist39)}. Furthermore, Pang et al. (2015) reported that secretin administration excited its receptors in the CeA. Also, the inhibitory effects of these receptors were mediated on food intake through the spontaneous electrical activity of GABAergic neurons and cAMP-protein kinase in the CeA^{(Reference Pang, Chen and Xue31)}. According to some studies, approximately all neural populations of the CeA are GABAergic neurons^{(Reference Douglass8,Reference Zhang-Molina, Schmit and Cai32,Reference Pape and Pare37,Reference Butler, Oliver and Sharko58)} . The pituitary adenylate cyclase-activating peptide, which is a very important regulatory peptide in food consumption as well as its PAC1 receptors, all was highly expressed in the CeA^{(Reference Iemolo, Ferragud and Cottone59)}. Also, pituitary adenylate cyclase-activating peptide-induced anorexia and weight loss activate the local melanocortin and tropomyosin-related kinase receptor type B^{(Reference Iemolo, Ferragud and Cottone59)} (Fig. 3). Notably, orexin-A (a prominent neuropeptide in modulating food consumption) could mediate the orexigenic effects on the CeA via the OX1 receptors^{(Reference Jin, Jiang and Luan30)}.

Fig. 3. The schematic diagram of gene expression in different parts of the central amygdala (CeA) and the effects of neurotransmitters/neuropeptides on food intake in the CeA. Corticotropin-releasing hormone (CRH), Tachykinin 2 (Tac2), serotonin receptor 2a⁺ (Htr2a⁺), somatostatin (Sst), Protein kinase C-delta⁺ (PKC-δ⁺) and neurotensin (Nts) are expressed in the lateral part of the CeA (CeL). The calcitonin receptor-like (Calcrl) and PKC-δ are expressed in the capsular part of the CeA (CeC). Htr2⁺, Sst and Nts are expressed in the medial part of the CeA (CeM). Glucagon-like peptide-1 (GLP-1), pituitary adenylate cyclase-activating peptide (PACAP), CRH, dopamine, gamma-aminobutyric acid (GABA) and secretin decrease. Orexin-A, glutamate, μ and κ increase the food intake through their specific receptors in the CeA. Drd2, dopamine receptor 2. , Increase; , Decrease.

The central amygdala and gene expression

In previous studies on gene expression, it was reported that various genes were expressed in different CeA subdivisions that could have affected CeA functions in mediating feeding behaviour. The corticotropin-releasing hormone (CRH), Htr2a, neurotensin (Nts), dopamine receptor 2, PKC-δ, somatostatin and tachykinin 2 were expressed in the CeL, while calcitonin receptor-like, dopamine receptor 2 and PKC-δ were all expressed in the CeC^{(Reference Kim, Zhang and Muralidhar21,Reference McCullough, Morrison and Hartmann22)} . However, electrophysiological studies have mostly documented PKC-δ ⁺ and Htr2a⁺ neurons under a category of neurons with delayed firing patterns^{(Reference Douglass, Kucukdereli and Ponserre5,Reference Zhang-Molina, Schmit and Cai32)} , yet, their roles were seen to be different in determining food intake behaviour^{(Reference Zhang-Molina, Schmit and Cai32)} (Fig. 3). Also, it was indicated that Htr2a, Nts, somatostatin, CRF, PKC-δ, dopamine receptor 2 and tachykinin 2 were expressed in the CeM^{(Reference Kim, Zhang and Muralidhar21,Reference McCullough, Morrison and Hartmann22)} . Finally, similar to other neurons, the electrophysiological characterisation of GABAergic neurons in the CeA depends on their specific gene expression^{(Reference Ehrlich, Humeau and Grenier17,Reference Zhang-Molina, Schmit and Cai32)} . Among these genes, CeL somatostatin, CRH, Nts, tachykinin 2, CeM Nts, somatostatin and tachykinin 2 provide an appetitive drive basis, while CeL PKC-δ would modulate appetitive behaviour negatively^{(Reference Kim, Zhang and Muralidhar21)}.

The central amygdala and reward system

The brain’s reward circuitry is one of the systems that are related to feeding behaviour^{(Reference Douglass8)}. This system includes various nuclei, such as the CeA, nucleus accumbens, midbrain dopaminergic system, cholinergic basal forebrain system, orbitofrontal cortex and anterior cingulate cortex^{(Reference Zhang, Li and Guo27)}. Among these cores, the CeA not only has anatomical and electrical connections to different nuclei in the reward system but also reacts to motivational and emotional stimuli^{(Reference Merali, McIntosh and Kent28)}. Hence, it plays an important role in regulating food intake behaviour^{(Reference Fadok, Markovic and Tovote18)} and seems to be involved in food-seeking and appetite responses of the reward circuit as well. This might be due to its connection to the reward system, as well as the brain’s gustatory and feeding centres^{(Reference Fadok, Markovic and Tovote18)}.

Similarly, some studies have reported that the CeA circuits were activated with food-predictive cues (eating for hedonistic purposes or reward-associated reasons) via a population of the prepronociceptin-expressing cells in the CeA, which reinforce the rewarding properties of palatable food^{(Reference Hardaway, Halladay and Mazzone41,Reference Herzog60)} . The prepronociceptin-expressing cells make a network of connections and projections to the ventral bed nucleus of the stria terminalis, PBN and NTS to process reward behaviours^{(Reference Hardaway, Halladay and Mazzone41)} and promote high-fat diet consumption that leads to obesity^{(Reference Hardaway, Halladay and Mazzone41)}. Even though they promote reward behaviour, their effects are not significant for the metabolism and energy homoeostasis^{(Reference Hardaway, Halladay and Mazzone41)}. Moreover, Torruella-Suárez et al. (2020) have reported the subset of Nts neurons in the CeA that lead to a hedonic consumption paradigm^{(Reference Torruella-Suarez, Vandenberg and Cogan61)}. The Nts and Htr2a⁺ make fundamental pathways neurons by projecting from the CeA to the PBN, respectively, in palatable drinking and eating patterns^{(Reference Torruella-Suarez, Vandenberg and Cogan61)}.

Overall, somatostatin and PKC-δ neurons in the CeL provide a basis for the correct response to the appropriate predictive cue (e.g. responding to the sweet water-predictive cue and not the bitterness-predictive one) via receiving excitatory inputs from the insular cortex^{(Reference Petrovich33,Reference Schiff, Bouhuis and Yu62)} . However, in this continually changeable environment, predicting the consequent events is not an easy task^{(Reference Badrinarayan, Prater and Orsini63)}; the outcome of this cue will inevitably depend on the CeA interactions^{(Reference Badrinarayan, Prater and Orsini63)}.

The central amygdala and digestive system

In previous studies, the anatomical evidence has supported the hypothesis regarding the reciprocal connections of the CeA with both NTS and dorsal vagal complex (two regions with neuromodulatory roles in gastric motility). Hence, the connections to the NTS and dorsal vagal complex make the CeA to operate as a gateway between them and the digestive system^{(Reference Jin, Jiang and Luan30,Reference Liubashina, Jolkkonen and Pitkänen64,Reference Zhang, Cui and Tan65)} .

It is suggested that administration of orexin-A in the CeA could increase the gastrointestinal motility (for both contraction and emptying) through signals from the CeA to the dorsal motor nuclear complex and efferent activation of the vagus nerve (CeA–dorsal motor nucleus of the vagus–gastrointestinal tract axis)^{(Reference Jin, Jiang and Luan30)}.

Following the intravenous injection of ghrelin, an increase of gastric acid secretion may happen in response to ghrelin via the excitation of the neurons in the CeA^{(Reference Takayama, Johno and Hayashi52)}. In this way, the projection of excited neurons from the CeA to the LPBN acts as a mediator that first excites the NTS and dorsal motor nucleus of the vagus (with direct innervation) and subsequently the neural system of the stomach^{(Reference Takayama, Johno and Hayashi52)}. The increase of gastric acid secretion was shown to have followed the gastrin injection and subsequently activated the expression of c-Fos protein in the CeA neurons^{(Reference Yakabi, Iwabuchi and Nakamura66)}. Hence, CeA seems to act as a mediator between the nervous and endocrine systems in association with different brain areas from the brain stem to the cortex^{(Reference Petrovich and Gallagher23)}. The relationship between CeA and other systems (e.g. the endocrine system) shows the importance of CeA in determining feeding behaviour. Therefore, this core facilitates the extensive connections between the brain, gastrointestinal tract and digestive hormones^{(Reference Jin, Jiang and Luan30)}. It is suggested to further investigate this perspective in future studies.

The central amygdala and different emotional states

Feeding behaviour and other lifestyle habits may considerably influence health and optimise obesity control in today’s societies enduring various inconvenient emotional states^{(Reference Hurt, Kulisek and Buchanan67,Reference Izadi, Radahmadi and Ghasemi68)} . Apart from eating essential nutrients for metabolic functions and energy requirements, feelings are key factors that may affect food consumption^{(Reference Zhang, Li and Guo27,Reference Herzog60,Reference la Fleur69)} . For example, stress can lead to overeating to relieve stress and relax, while severe stress can cause undereating^{(Reference la Fleur69)}. Hence, the relevant CeA pathways, involved in feeding behaviour, would additionally be affected by different factors, such as emotional states like fear and stress^{(Reference Iemolo, Ferragud and Cottone59)}.