Mapping GABAergic projections that mediate feeding

Neuroscience offers important insights into the pathogenesis and treatment of obesity by investigating neural circuits underpinning appetite and feeding. Gamma-aminobutyric acid (GABA), one of the most abundant neurotransmitters in the brain, and its associated receptors represent an array of pharmacologically targetable mediators of appetite signalling. Targeting the GABAergic system is therefore an increasingly investigated approach to obesity treatment


Introduction
Obesity, affecting more than 1 billion people worldwide, stands as one of the most pressing public health crises today (Dragano et al., 2020;World Health Organisation, 2024).Associated with increased incidence of comorbidities such as cardiovascular disease, stroke, type-II diabetes mellitus, and various types of cancer, obesity ranks as the fifth leading cause of death globally (Li et al., 2015;World Health Organisation, 2024).Despite efforts focused on behavioural approaches and limited patient eligibility for treatments such as bariatric surgery, there is a growing need for new drugs to effectively and safely reduce body mass (Dragano et al., 2020).
Recent research into addiction, impulsivity and reward circuits has elucidated the integral role of neural pathways in the regulation of feeding, weight gain and obesity (Adan et al., 2008).GABA, along with the excitatory neurotransmitter glutamate, modulates the excitatory-inhibitory balance essential for brain function (C.Wu and Sun, 2015).As one of the most prominent mammalian neurotransmitters, gamma-aminobutyric acid (GABA) mediates many psychobehavioural phenomena, including appetite (Suyama and Yada, 2018;C. Wu and Sun, 2015).GABA exerts its function through a plethora of receptor subtypes which may therefore constitute numerous pharmacological targets for restoring physiological appetite.Mapping appetite-regulating GABAergic circuits in the brain may therefore lead to novel discoveries for obesity pathogenesis and treatment.Developments of chemogenetic and optogenetic methods in the 21st century allow neuroscientists to perform in vivo, region-specific/ projection-specific/promoter-specific circuit manipulations and immediately assess the impact of these manipulations on rodent feeding (J.Wang et al., 2023).Recent studies have thus been able to rigorously conclude whether specific neuronal populations regulate feeding behaviour.Therefore, this review will evaluate existing literature reporting on GABAergic projections that mediate feeding in an effort to develop a mechanistic neuroanatomical map of appetite regulation that may be used to develop drugs to treat obesity.Searches were performed using the PubMed and Google Scholar databases to identify relevant articles.A combination of GABA-related terms (e.g.GABAergic receptor ligand names or GABA synthesising enzymes) as well as neuroanatomical terms (e.g.arcuate nucleus) and appetite-related terms (e.g.feeding, appetite, hunger) were used as keywords during these searches.Initial searches were limited to 2007 onwards since chemogenetic and optogenetic approaches were invented around this time.Both relevant cited and citing literature in the identified articles were also explored to identify both foundational early work and the most recent research directions.Following a brief overview of GABA neurochemistry, the findings of this literature review are presented in order of the complexity/specificity of the research methods used to identify GABAergic appetite-regulating neural mechanisms.While a majority of identified circuits originate and/or terminate within the hypothalamus, extrahypothalamic circuits are also presented.

Neurochemistry of GABA
GABA is synthesised from the decarboxylation of glutamic acid in vivo, which is catalysed by glutamate decarboxylase in both neurons and glia (Martínez-Rodríguez et al., 1993).The two isozymes of glutamate decarboxylase, GAD65 and GAD67 (transcribed from Gad2 and Gad1 genes respectively) are therefore common markers used to identify GABAergic neurons (Buddhala et al., 2009).Once synthesised, GABA is packaged into synaptic vesicles through the vesicular GABA transporter (VGAT) to await exocytosis.When neurotransmission occurs, GABA released from GABAergic neurons binds to two types of receptors -GABA A and GABA B receptors (Enna, 2007).
GABA A Rs, also termed ionotropic GABA receptors, are the most common type of GABA receptor in the brain and are responsible for a majority of neuronal inhibition (Ghit et al., 2021).Alternatively, GABA B receptors mediate slow and prolonged inhibitory action (Terunuma, 2018).Given the ubiquity of GABA signalling, it is unsurprisingly implicated in various addiction disorders, influencing personality traits like impulsivity and aspects of reward processing associated with substance use and behavioural addictions (Baskin-Sommers and Foti, 2015;Duka et al., 2017;Skóra et al., 2020;Stephens et al., 2017).The involvement of the GABAergic system in addiction, impulsivity and aspects of reward processing suggest that being able to manage its function could aid in the treatment of obesity.
Given the importance of GABA in neural processes and the structurally distinct GABAR subtypes that regulate these processes, GABARs have become a useful and adjustable therapeutic target.This is evident by its targeting to successfully treat a wide range of CNS disorders, including but not limited to schizophrenia, anxiety and depression (Braat and Kooy, 2015;Heaney and Kinney, 2016).Despite these advancements, the collective mapping of GABAergic projections mediating feeding remains incomplete, hindering the development of pharmacological agents to treat obesity.
GABA A Rs are ligand-gated chloride channels with a pentameric structure (S.Zhu et al., 2018).Upon GABA binding to a postsynaptic GABA A R, chloride influx usually occurs resulting in an inhibitory potential.However, emerging evidence suggests that this chloride potential may be reversed in circumstances where canonical gradients of chloride are disrupted by alterations in neuronal potassium-chloride co-transporters (Chamma et al., 2012).GABA A Rs may therefore also produce excitatory potentials in the adult brain, however further investigations are required to assess the prevalence of these potentials.
GABA A Rs are extremely heterogeneous due to the multitude of potential subunit compositions.Mammalian genomes contain genes for 16 different GABA A R subunits (Barnard et al., 1998), however the subunit composition of these receptors appears limited by various stoichiometric requirements (Has and Chebib, 2018;Patel et al., 2014).GABA A Rs are composed of five subunits that can belong to eight different subunit classes (Olsen and Sieghart, 2009;Sieghart and Sperk, 2002).Different subtypes of GABA A Rs exist depending on their subunit composition, each exhibiting distinct pharmacological and electrophysiological properties (Olsen and Sieghart, 2009;Sieghart and Sperk, 2002).Certain subunit combinations dominate, for example most receptors follow a structure with two α, two β and one γ subunit (Baumann et al., 2001), which is the only formation that has had its structure resolved in vitro (S.Zhu et al., 2018).Different GABA A Rs are differentially expressed across the brain (Mortensen et al., 2012), and respond differently to internal Fig. 1.Representative schematic of ionotropic GABA neurotransmission.GABA is produced from glutamate in a reaction catalysed by GAD65 or GAD67.It is then packaged into synaptic vesicles through VGAT.Upon release, GABA binds to GABA A Rs on the postsynaptic membrane to mediate a phasic chloride ion influx, inhibiting the neuron.If excessive GABA is released into the synaptic cleft (top half of image), extrasynaptic GABA A Rs are also activated causing tonic inhibition.While phasic inhibition is confined to the post-synaptic membrane, tonic inhibition may also occur on neighbouring neurons that are not direct post-synaptic targets.modulators such as neurosteroids (Belelli et al., 2002;Mihalek et al., 1999;Porcello et al., 2003;Wohlfarth et al., 2002) providing this system with immense spatial complexity.
GABA A Rs are also located extrasynaptically (Salin & Prince, 1996).The activation of extrasynaptic GABA A Rs relies on volume transmission to send a paracrine inhibitory signal as opposed to a classic inhibitory synapse (Oláh et al., 2009).GABA is able to diffuse to extrasynaptic receptors when there is an excess of GABA release at the synapse (Wei et al., 2003) (Fig. 1).Extrasynaptic GABA signalling provides a tonic inhibition to all neurons within range of this diffusion (V. Lee and Maguire, 2014).The membrane localisation of GABA A Rs is also subunit dependent; for example α1, α2, α3 β1, β2, β3 and γ2-containing GABA A R isoforms are predominately expressed postsynpatically (Sassoè-Pognetto et al., 2000).However, there are exceptions to these trends.For example, a3-containing GABA A R isoforms can be located extrasynaptically within the amygdala (Marowsky et al., 2012).

GABA signalling and feedingsystemic administration studies
The effect of GABA on feeding was originally investigated using simple in vivo experiment designs, measuring food consumption in response to the administration of GABAR ligands.Not surprisingly, GABA A R ligands were more commonly studied due to the abundance of ionotropic GABA receptors within the brain (Bowery et al., 1987).Brain region-specific microinjection studies were rare at the time (Kelly et al., 1979), with most methods instead opting for a whole-brain approach.Although this could be easily achieved through oral or intraperitoneal administration, the difficulty of reaching an effective drug concentration through these routes was repeatedly noted (Ebenezer and Baldwin, 1990;Nobrega et al., 1988).Therefore, a majority of landmark GABA pharmacological studies used either intracerebroventricular (ICV) or intracisternal (IC) injection (Table 1).Although these initial studies generated conflicting data, they do show a clear role for both ionotropic and metabotropic GABA signalling in the regulation of feeding.Interestingly, the modulation of GABA signalling produced variable responses depending on the fed state of the animal (Pu et al., 1999;Takagi, Bungo, et al., 2003), suggesting that GABA's modulation of food intake is responsive to the metabolic state of the organism.
Although whole-brain administration of GABA-receptor ligands laid the foundations for the field, there are limitations to this methodology.ICV and IC administrations may have produced artefacts which impact the data.For example, differences in the orexigenic capacity of muscimol ICV administration have been noted in rodents housed at different temperatures (Kurose and Yano, 1989).Although this difference was hypothesised to be due to a temperature-dependent change in muscimol metabolism, it is now known that body temperature impacts the flux of brain parenchymal extracellular fluid (Agnati and Fuxe, 2014).Additionally, the physical separation of the cerebrospinal fluid (CSF) and brain parenchyma is species-specific and dependent on metabolic state.

Species
Drug Route of admin

Reference Comments
Pig GABA ICV Increase (Baldwin et al., 1990 (Kurose and Yano, 1989;Morley et al., 1981;Olgiati et al., 1980;Pu et al., 1999) Effect antagonized by bicuculline.Effect amplified by co-administration of NPY in sated rats (Pu et al., 1999).Decrease (Cooper et al., 1980 Tanycytes, modified ependymoglial cells lining the ventral portion of the 3rd ventricle, alter their morphology in response to caloric excess (Prezotto et al., 2020).They also alter their permeability to the CSF and hypophyseal portal blood in response to diet (Langlet, 2014).Therefore, discrepancies in GABA function seen between fed-states of animals (Olgiati et al., 1980) may be due simply to altered pharmacokinetics or Blocking GABA release at the PVH from ARC PDX-1 neurons inhibited feeding and reduced developmental growth.
ARC POMC DMH (Trotta et al., 2020) Silencing of POMC expressing in ARC increased NPY expression in the DMH and increased feeding.Immunohistochemistry showed DMH as a major projection site for POMC neurons.
Targeted Gad2 in silencing experiment.
In a separate circuit mapping experiment, postsynaptic currents at the PVH were blocked by the administration of picrotoxin (prototypic antagonist of GABA A Rs). PVN-T (C.Wang et al., 2021) Optogenetic inhibition impaired food seeking.Targeted AgRP which is expressed exclusively in GABAergic neurons.PBN (Q.Wu et al., 2009) Administration of bretnazil at the PBN rescued ARC AGRP -ablated mice from starvation.
Bretnazil is a GABA A R agonist.
Bicuculline is a GABA A R competitive antagonist.
ARC RIP-Cre PVH (Rother et al., 2012) Ablation of all ARC RIP-Cre neurons decreased food intake and increased c-FOS activity in the PVH.Tracing showed ARC RIP-Cre efferents terminating at the PVH.(Kong et al., 2012) VGAT deletion in ARC RIP-Cre neurons resulted in diet-induced obesity.
Translating ribosome affinity purification and subsequent pathway analysis of mRNA sequencing confirmed ARC PNOC neurons are GABAergic.
VGAT Slc32a1 targeted in optogenetic manipulation.ligand-specific differences in transport to the brain parenchyma.

GABA signalling and feedinglocalisation
In addition to the limited validity of ICV/IC administration, the ultimate interpretations that can be made from these studies are constrained.The global activation of GABA receptors does not provide a nuanced analysis of the many brain regions responsible for food intake.This limitation necessitated the use of lesion and microinjection studies, where specific brain-regions are altered, and the resulting feeding behaviour of the animal assessed.With recent advances in genetic engineering, chemogenetics and optogenetics have allowed subsequent investigations to dissect the function of GABA with greater spatial and temporal resolution.
Although the reward pathway regulates the pleasure and motivational drive associated with binge eating and other substance addictions, there are additional neural circuits dedicated to the regulation of appetite.Some of the first investigations on brain-region-specific feeding modulation were conducted on the hypothalamus (Kelly and Grossman, 1979).It was discovered that ionotropic GABA signalling within the paraventricular hypothalamus (PVH) and ventromedial hypothalamus (VMH) promotes food intake, while the same signalling within the lateral hypothalamus (LH) suppresses feeding (Kelly and Grossman, 1979).As is common with most neural circuit research, these regional investigations provided a starting point for future optogenetic/chemogenetic approaches to identify the projection-specific neuronal populations responsible for appetite (for a detailed explanation of these methods and their general use in appetitive neuroscience, refer to (J.Wang et al., 2023)).
The arcuate nucleus (ARC) is uniquely positioned around the ventral portion of the 3rd ventricle.The tanycytes lining the ventricular space adjacent to the ARC show greater permeability than other ependymal locations in the brain (Mullier et al., 2010).This allows the appetite-regulating hormones leptin and ghrelin, secreted from adipose tissue and the gastrointestinal tract respectively, to directly modify the activity of ARC neurons (Nakazato et al., 2001;Pinto et al., 2004;van den Top et al., 2004).Additionally, tanycytes actively modulate GABAergic ARC neuronal subpopulations depending on the metabolic signals they receive from the CSF (Bolborea et al., 2020).Therefore, the ARC is the canonical location for sensing peripheral metabolic signals (Parton et al., 2007).Recently, chemogenetic manipulation of all GABAergic neuronal populations within the ARC has shown that the activity of these neurons promote feeding and obesity (C.Zhu et al., 2020).However, the ARC has immense cellular heterogeneity, with different neuronal subpopulations co-releasing GABA with an array of neuropeptides and neuromodulators (Romanov et al., 2017).This section will discuss the primary control centre for the neural regulation of appetite: ARC (Table 2, Fig. 2).

AGRP neurons
ARC neurons that contain the neuropeptides Agouti-related peptide (AgRP) and neuropeptide Y (NPY) are the canonical orexigenic neurons in the mammalian brain (Hao et al., 2020;Luquet et al., 2005).Most of these neurons are located outside of the blood-brain barrier (Yulyaningsih et al., 2017) and are GABAergic (Ovesjö et al., 2001).AgRP-neuron-specific GABA synthesis/transport ablation decreases orexigenic behaviour (Tong et al., 2008;Q. Wu et al., 2009).This correlates with ablation studies on AgRP neurons reporting a hypophagic phenotype (Aponte et al., 2011;Gropp et al., 2005;Krashes et al., 2011).The hypophagia produced by AgRP neuronal ablation can be reversed with the chronic subcutaneous administration of bretazenila GABA A partial agonist (Q.Wu et al., 2009).Specifically, the same reversal of hypophagia can be achieved by the administration of bretazenil at the PBN (Q.Wu et al., 2009;Q. Wu and Palmiter, 2011).These studies confirm a GABAergic projection from ARC AgRP neurons to the PBN that promotes feeding.ARC AgRP neurons also promote feeding (Stachniak et al., 2014) through the release of GABA at the PVH (Atasoy et al., 2012;Betley et al., 2013) and PVN-T (C.Wang et al., 2021).The DMH (Bouret et al., 2004) and LH (Jhanwar-Uniyal et al., 1993) are also projection sites for ARC neurons, however the GABAergic nature of these projections and their role in feeding is yet to be confirmed through chemogenetics.AgRP neurons also demonstrate plasticity in response to prolonged dietary alterations.A high-fat diet desensitises AgRP neurons to metabolic signals of caloric repletion (Beutler et al., 2020).Fasting increases AgRP neuron's sensitivity to ghrelin (Luquet et al., 2007) and resultantly increases its synaptic input at the DMH (Cabral et al., 2020).Taken together, these studies demonstrate that AgRP neurons represent a crucial point of GABA-mediated appetite control which can be altered by the nutritional state of the organism.

POMC/CART neurons
Approximately 50% of pro-opiomelanocortin/cocaine-and amphetamine-regulated transcript (POMC/CART) neurons, the major anorexigenic neurons within the ARC, release GABA (Dicken et al., 2012;Hentges et al., 2004;Jarvie and Hentges, 2012;Wittmann et al., 2013).In POMC-ablated mice, the genetic rescue of POMC within this GABAergic subpopulation causes a hypophagic response stronger than non-specifically targeting a similar number of POMC neurons (Trotta et al., 2020).Additionally, POMC within GABAergic POMC neurons are responsible for modulating neuropeptide Y (NPY) levels within the dorsomedial hypothalamic nucleus (DMH) (Trotta et al., 2020) which ultimately promotes feeding (Bi et al., 2012).Deleting Gad65/67 within ARC POMC neurons does not actually impact eating or metabolic parameters (Rau et al., 2020).However, GABA may be synthesised through a GAD-independent metabolic pathway (J.-I.Kim et al., 2015) given the expression of the GABA-synthesising enzymes aldehyde dehydrogenase and diamine oxidase within the ARC (Taksande et al., 2014).Therefore, electrophysiological data is required to confirm the results of (Rau et al., 2020) and determine if GABA co-transmission in POMC-neurons modulates feeding.POMC neurons receive GABAergic inhibitory input from local AgRP neurons (Rau and Hentges, 2019).The inhibitory effect of GABA is plastic and can be blunted/increased in response to leptin signalling, blood-glucose alterations (Parton et al., 2007), as well as high-fat diet (D.K. Lee et al., 2015).The GABAergic activity of POMC neurons themselves is also plastic; caloric deficit decreases the expression of Gad1 mRNA within POMC neurons (Jarvie et al., 2017).

TH neurons
Within the arcuate nucleus, there is another subpopulation of neurons that express neither POMC nor AgRP, but tyrosine hydroxylase (TH): the enzyme responsible for the production of the neuromodulator dopamine (Yip et al., 2018;Zoli et al., 1993).These neurons co-express GABA (Everitt et al., 2008;Zhang and van den Pol, 2015) and are sexually dimorphic, with male mice possessing a higher proportion of TH positive arcuate nucleus GABAergic neurons (Marshall et al., 2016).Some emerging single-cell transcriptomics suggests that these neurons may also be cholinergic and function as effectors of leptin (Jeong et al., 2016).The function of dopamine signalling within the arcuate nucleus has been under-investigated, however it has long been known that dopamine has the ability to modulate POMC expression within the ARC (Matera and Wardlaw, 2008).
There is now recent evidence to suggest that dopaminergic ARC neuronal subpopulations are also key regulators of feeding.Zhang and van den Pol (2015) demonstrated that these neurons are activated by fasting and are directly depolarised by ghrelin.Optogenetic activation of these neurons increases food intake, while the chronic silencing of these neurons decreased weight gain (Zhang and van den Pol, 2015).The same study also investigated the synaptic efferents of these neurons, discovering that dopamine and GABA synergistically inhibit POMC ARC neurons through a classical synaptic mechanism, while no direct synapses between ARC TH neurons and AgRP neurons were found (Zhang and van den Pol, 2015).Additionally, the dopaminergic modulation of AgRP neurons occurs independently of GABA (Zhang and van den Pol, 2015).Given that POMC offers only long-term control over feeding (Zhan et al., 2013), the acute feeding response caused by the activation of dopaminergic ARC neurons may be due to the activation of AgRP neurons via dopamine volume transmission.

RIP neurons
Another distinct ARC subpopulation are neurons that express ratinsulin-promoter (RIP), which have no immunohistochemical overlap with AgRP or NPY (Choudhury et al., 2005) and are likely to be leptin-responsive (Romanov et al., 2017).These neurons release GABA at the PVH (Kong et al., 2012;Rother et al., 2012) where they ultimately affect feeding and energy intake.Ablation of these neurons causes hypophagia and weight loss (Rother et al., 2012), whereas selective ablation of VGAT in ARC RIP neurons increased body weight.It is therefore likely that GABA transmission in these neurons plays an anorexigenic role, however co-transmitters may also impact feeding in the opposite manner.However, to the best of the authors' knowledge, further dissection of these neurons' circuitry has not been conducted since these original studies in 2012.

PDX-1 neurons
A subset of ARC neurons express pancreatic duodenal homeobox-1 (PDX-1).Interestingly, the gene encoding GAD67 is transcriptionally responsive to glucose (Pedersen et al., 2001) through the function of PDX-1 (Pedersen et al., 2002).The activity of GAD67 is also the limiting factor in GABA transmission (Dicken et al., 2015;Lau and Murthy, 2012;L. Wang et al., 2013).Together these data suggest the existence of a biochemical mechanism that links glucose sensing with GABA signalling.Since PDX-1 ARC neurons are in close apposition to the median eminence, it is possible that the metabolic state of the organism is reflected in its glycorrachia/glycaemia which may subsequently alter GABA synthesis and transmission in PDX-1 ARC neurons.Although this mechanism has not been fully elucidated, it is known that these neurons release GABA at the PVH and requires NPY co-transmission from another source to promote feeding (J.-I.Kim et al., 2015).Chemogenetic and/or optogenetic targeting of PDX-1-expressing ARC neurons is needed to assess the relationship between GABA signalling and appetite in this neuronal population.

SST neurons
A newly discovered neuronal subpopulation in the ARC are the somatostatin-expressing (SST) neurons.While 10% of SST neurons coexpress AgRP, the remaining 90% are immunohistochemically unique (Luo et al., 2018).Although research on these neurons is sparse, Gad1 targeted in optogenetic manipulation.
Peri-LC (Marino et al., 2020) Lesioning peri-LC neurons reduced feeding and food approach, thereby reversing the effect of LH stimulation.
VGAT targeted in lesioning experiment.Photostimulation increased consumption of high-fat or high-sugar food, but not standard chow.
Septum LH (Sweeney and Yang, 2016) Chemogenetic and optogenetic activation of septum-LH projection reduced food intake.Inhibition increased food intake.
VGAT targeted for optogenetic and chemogenetic manipulations.chemogenetic activation of ARC SST neurons promotes feeding (Luo et al., 2018).A subset of these neurons co-express growth hormone receptor (GHR) which increases food intake upon chemogenetic activation (Lima et al., 2020).They also express nNOS (Zou et al., 2015), which has a large overlap in expression with VGAT (Marshall et al., 2016).This suggests that a majority of these ARC-SST neurons are GABAergic.However, it is currently not possible to determine if the hyperphagic effects of these neurons are caused by and/or correlated with GABA release.It is also unknown which brain regions receive projections from these neurons.Therefore, further optogenetic/chemogenetic investigations are required to further characterise this novel class of appetite-regulating neurons.
The studies above have highlighted the pivotal role of GABAergic neurons within the hypothalamic feeding center, particularly in the ARC, in promoting food intake.Beyond the well-known NPY/AgRP neurons in the ARC, other GABAergic neurons also contribute to orexigenic functions.Utilising advanced technologies such as optogenetics, in vivo Ca2+ imaging, and single-cell RNA-seq, researchers have made significant strides in understanding these neuronal populations and their role in feeding regulation (see review (Suyama and Yada, 2018)).While the ARC plays a crucial role in the reward pathway associated with feeding and other substance addictions, it is important to recognise that appetite regulation involves a network of neural circuits beyond the ARC.In addition to the ARC, other brain regions, including GABAergic projections highlighted in Table 3, are implicated in mediating feeding behaviour, underscoring the complexity of appetite regulation.

Conclusion
Obesity remains a significant global health challenge necessitating innovative approaches for effective management.The central role of GABA signalling in regulating feeding behaviour highlights its potential as a therapeutic target for obesity treatment.Throughout this review, we extensively investigated the literature surrounding GABAergic outputs from the arcuate nucleus (ARC) and beyond, recognising the complex neural circuits involved in feeding regulation.Advanced neuroscientific techniques have enabled the identification of specific neuronal populations regulating feeding behaviour, facilitating targeted therapeutic interventions.However, further specificity and circuit dissection is required to develop targeted, GABA-receptor subtype-specific pharmacological treatments for people with obesity.
Fig. 1.Representative schematic of ionotropic GABA neurotransmission.GABA is produced from glutamate in a reaction catalysed by GAD65 or GAD67.It is then packaged into synaptic vesicles through VGAT.Upon release, GABA binds to GABA A Rs on the postsynaptic membrane to mediate a phasic chloride ion influx, inhibiting the neuron.If excessive GABA is released into the synaptic cleft (top half of image), extrasynaptic GABA A Rs are also activated causing tonic inhibition.While phasic inhibition is confined to the post-synaptic membrane, tonic inhibition may also occur on neighbouring neurons that are not direct post-synaptic targets.Figure produced using Biorender software.

Fig. 2 .
Fig. 2. GABAergic outputs from the arcuate nucleus (ARC) that alter feeding behaviour.Neurons within the ARC are sensitive to metabolic signals from the systemic circuit, such as glucose, leptin and ghrelin.Different neuronal subpopulations within the ARC then respond to these signals by modulating the activity of a variety of other brain regions, partly through the release of GABA.Key: PDX-1 -pancreatic and duodenal homeobox 1; THtyrosine hydroxylase; POMC/CARTproopiomelanocortin/cocaine-and amphetamine-regulated transcript; AgRP/NPYagouti-related peptide/neuropeptide Y; RIPrat-insulin-promoter neurons in ventromedial hypothalamus; PNOCprepronociceptin; DMH -Dorsomedial Hypothalamic Nucleus; PVHhypothalamic paraventricular nucleus; PVN-Tparaventricular nucleus of the thalamus; PBNparabrachial nucleus; BNSTbed nucleus of the stria terminalis.Figure produced using Biorender software.

Table 2
GABAergic projections that mediate feeding in the ARC.

Table 3
GABAergic projections that mediate feeding outside the ARC.