The olfactory bulb: A neuroendocrine spotlight on feeding and metabolism

Olfaction is the most ancient sense and is needed for food‐seeking, danger protection, mating and survival. It is often the first sensory modality to perceive changes in the external environment, before sight, taste or sound. Odour molecules activate olfactory sensory neurons that reside on the olfactory epithelium in the nasal cavity, which transmits this odour‐specific information to the olfactory bulb (OB), where it is relayed to higher brain regions involved in olfactory perception and behaviour. Besides odour processing, recent studies suggest that the OB extends its function into the regulation of food intake and energy balance. Furthermore, numerous hormone receptors associated with appetite and metabolism are expressed within the OB, suggesting a neuroendocrine role outside the hypothalamus. Olfactory cues are important to promote food preparatory behaviours and consumption, such as enhancing appetite and salivation. In addition, altered metabolism or energy state (fasting, satiety and overnutrition) can change olfactory processing and perception. Similarly, various animal models and human pathologies indicate a strong link between olfactory impairment and metabolic dysfunction. Therefore, understanding the nature of this reciprocal relationship is critical to understand how olfactory or metabolic disorders arise. This present review elaborates on the connection between olfaction, feeding behaviour and metabolism and will shed light on the neuroendocrine role of the OB as an interface between the external and internal environments. Elucidating the specific mechanisms by which olfactory signals are integrated and translated into metabolic responses holds promise for the development of targeted therapeutic strategies and interventions aimed at modulating appetite and promoting metabolic health.


| INTRODUCTION: EXPLORING THE ROLE OF THE OLFACTORY BULB IN FEEDING AND METABOLISM
The escalating prevalence of obesity and eating disorders, such as anorexia, presents profound challenges to public health worldwide.
[3] For decades, attempts to understand how the brain regulates body weight have largely focused on examining the hypothalamic or brainstem control of feeding behaviour and energy homeostasis.However, this has delivered very few therapeutic approaches to treat human obesity or eating disorders in the long term.With this in mind, an understanding of how additional brain regions and neural circuits interact to influence food intake and energy metabolism is required without delay.This review directs attention to the olfactory bulb (OB) as a metabolic sensor outside the hypothalamus 4 and how it integrates environmental information to guide behaviour and metabolism (Figure 1).The sense of smell, or olfaction, in terms of evolution, is the most ancient sensory modality, capable of detecting, encoding, and discriminating a myriad of environmental volatiles (odourants) crucial for identifying food and potential hazards.Beyond mere odour identification, olfaction adds emotional attributes to subjects, objects or events, influences preferences, mood and cognition, and facilitates social interactions.For most organisms smell serves as the primary sense for interacting with and interpreting the surrounding. 5By elucidating the intricate relationship between olfaction and metabolism, this review endeavours to ignite novel approaches to tackle the global rise of obesity, eating disorders and related metabolic pathologies.

| THE OLFACTORY SYSTEM
The olfactory system consists of a sensory peripheral (olfactory epithelium) and a central part (olfactory bulb) as well as specific olfactory brain regions (primary and secondary olfactory cortex).Odourants are small airborne chemicals that can evoke sensations in the olfactory system, a result of odourant binding to specific olfactory receptors (ORs) expressed by olfactory receptor neurons (ORNs) in the epithelial tissue that lines the nasal cavities, the olfactory epithelium (OE).The OE contains millions of these specialized ORNs and notably, can regenerate throughout adulthood. 6,7Olfactory receptors belong to a family of around 1000 genes encoding G-protein-coupled receptors (GPCRs), comprising the largest gene family in the vertebrate genome. 8While the majority of mammals have most OR genes, humans exhibit approximately one-third of the OR genes compared with mice. 9This reduction was previously thought to reflect the poor sense of smell in humans compared with other species.However, with $400 different functional ORs, 10 humans can discriminate approximately more than 1 trillion odours. 11Although each ORN has only one type of receptor protein, the ability to discriminate an enormously large range of odours comes from specific features of odourant molecules, which exhibit varying binding affinities to different receptors.In this way, each molecule interacts with more than one type of receptor, thereby generating a complex odour sensory signal. 12Each ORN is connected to a distinct spherical neuropil structure beneath the surface of the OB, called glomerulus.Each individual glomerulus represents a single OR type and receives the inputs from multiple ORNs, so that when odourants activate ORNs a unique glomerular activity pattern is created. 13Given that in nature, perceived odours are a blend of different chemicals, the mechanisms involved in the detection of various odours are complex.The OB functions as the central hub, and coordinator of olfactory transmission within the olfactory pathway, initially processing olfactory sensory information before transmitting it to the primary olfactory cortex (POC). 14A distinguishing characteristic of the olfactory system is that olfactory sensory signals are directly received in the OB and transmitted to the POC, bypassing thalamic relay centers. 15Consequently, the OB is often mentioned as the 'olfactory thalamus' as it processes sensory information before dissemination to other brain areas. 16The POC engages with various cortical and limbic structures, facilitating the integration of smell with memory, emotion and taste.Thus, the olfactory system not only shapes odour perception but also influences mood and cognition due to its close association with brain areas responsible for these functions.This connection has led to olfaction being described as 'the window to the mind and brain'. 17,18

| THE OLFACTORY BULB: GATEWAY TO SCENT AND PERCEPTION
The OB is the first relay station between the external environment and the brain, receiving odour-specific inputs from ORNs, and processing this information before sending output signals to olfactory target areas.
The OB is an egg-shaped onion-like concentric layered structure, and located in the anterior region of the brain, above the cribriform plate of the ethmoid bone, 19,20 (Figure 2).The distinct layers of the OB accommodate specific cell types.At the outermost layer, the olfactory nerve layer (ONL) contains axons of ORNs originating from the OE.These axons synapse onto the dendrites of mitral (MCs) and tufted cells (TCs) within the glomerular layer (GL), forming small round clusters, the glomeruli.Glomeruli are the primary site of odour input integration.Interneurons such as periglomerular, external tufted cells and granule cells (GC) modulate synaptic activity within the GL.Periglomerular cells surround the entire glomeruli and maintain reciprocal dendrodendritic synapses with MCs and TCs.Beneath the GL lies the external plexiform layer (EPL) and the mitral cell layer (MCL), containing the cell bodies of TCs or MCs, respectively. 21MCs and TCs are the principal output neurons of the OB.Their axons form bundles that pass through the OB, merging to form the olfactory tract.Most central is the granule cell layer (GCL) containing granule cells (GC), the most abundant neurons in the OB and provide inhibitory feedback onto MCs and TCs.This intricate organization of cell types within the OB enables the integration and processing of olfactory signals, ultimately shaping odour perception.
F I G U R E 1 Representation of the olfactory bulb as an environmental sensor and integral component of the neuroendocrine system.A simplified ventrolateral schematic of the brain is shown.Hedonic odour signals are detected by specialized cells (olfactory sensory neurons, OSNs) in the olfactory epithelium (OE) that project to the olfactory bulb (OB) where mitral cells (MCs) and tufted cells (TCs) are activated.M/TCs are excitatory glutamatergic cells and are the main projecting neurons of the OB, conveying odour information to various regions in the olfactory cortex for odour recognition and processing, or further modulating secondary olfactory structures, such as the hypothalamus (HYPO).MCs project their axons dispersedly to the olfactory cortex, including the anterior olfactory nucleus (AON), piriform cortex (PC), amygdala (AMY), entorhinal cortex (EC), olfactory tubercle (OT) and tenia tecta (TT), while TCs only innervate the anterior parts of the AON, OT and PC.M/TCs also make connections with inhibitory GABAergic granule cells (GCs).Besides sensing odours, the OB is a metabolic sensor, sensing homeostatic signals (hormones, nutrients) from the periphery delivered by the stomach, intestine, pancreas, liver, and adipose.Thus, the OB integrates internal and external signals and guides behaviours and physiological responses (cognition, digestion, metabolism) by modulating olfaction performance and other brain areas.

| OLFACTION
Odourants are either inhaled during the breathing cycle into the nose (orthonasal-from outside) or from the back of the mouth while chewing (retronasal), thus contributing to flavour perception.Upon entering the nasal cavity, odourants bind ORs and depolarise ORNs. 22ORNs are bipolar cells, with cell bodies located in the OE and dendrites extending to the surface of the OE, where several cilia emerge expressing ORs.Axons from ORNs travel from the OE through the cribriform plate to the OB and converge to make up the first cranial nerve, which is responsible for transmitting olfactory information to the brain.
ORNs form synaptic connections in the OB with dendrites of MCs, TCs and axon-less interneurons within the glomeruli. 7After receiving synaptic information, MCs and TCs directly convey this olfactory information via the olfactory tract to the POC.While the axons of MCs project throughout the olfactory cortex, TC project their axons only to the anteromedial portion of the olfactory cortex. 23The key brain regions that make up the POC, include the piriform cortex (PC), periamygdaloid cortex, entorhinal cortex (EC), anterior olfactory nucleus (AON) and the olfactory tubercle (OT) of the ventral striatum.While the POC is part of the limbic system linking olfaction with emotions, secondary targets include the hypothalamus, hippocampus, thalamus, orbitofrontal cortex (OFC) and insular cortex, which help to integrate olfaction with metabolism, learning and memory (Figure 3). 24Thus, the OB is only 1 synapse away from ORNs, which are exposed to the external world, and just a few synapses away from critical central structures regulating metabolism and cognition.While the OB processes sensory signals and coordinates their transmission, the OB also receives modulatory feedback from the cortex, and subcortical regions.The subsequent section explores the modulation of olfactory function through both intrinsic and extrinsic mechanisms.

| MODULATION OF OB FUNCTION
Olfactory processing can be modulated by intrinsic (from within the OB) and extrinsic (from outside) mechanisms.

| Intrinsic modulation
MCs and TCs possess an apical dendrite, which targets a single glomerulus, and several lateral dendrites.Olfactory sensory information from ORNs is received by the apical dendrites and transmitted via the lateral dendrites.Their activity is modulated by inhibitory interneurons, mainly periglomerular and granule cells (GCs), controlling the gain and strength of sensory information projected to downstream targets in a spatial and temporal manner.Interestingly, inhibitory GABAergic GCs are axon-less, instead possessing a basal and a branched apical dendrite.The basal dendrite and the unbranched initial parts of the apical dendrite receive excitatory glutamatergic inputs from M/TCs and the olfactory cortex. 25,26This unique ability to modulate dendro-dendritic connections between GCs and lateral dendrites of M/TCs is called lateral inhibition. 27

| Extrinsic modulation
Extrinsic efferent sensory inputs include those from the olfactory epithelium (centripetal) and olfactory cortex (centrifugal), 28,29 and extrinsic centrifugal inputs can even outweigh the sensory information from the nose. 29In particular, the glomerular layer receives extrinsic centrifugal modulation, whereas some of these inputs stem from the brain, including neural fibres, neuromodulators, neuropeptides, and hormones.[33][34] However, methodologies such as horseradish peroxidase tracing, 33 OT lesion approaches 31,32 or anterograde viral injections into the OT 34 are prone to off-target effects. 30Subsequent studies utilizing three independent retrograde labelling approaches confirmed the absence of direct projections from the OT to the OB. 30 The OT may potentially play a role in modulating OB activity in a top-down, statedependent manner. 31,35If such modulation occurs, it likely involves indirect pathways, possibly through structures like the AON or PC.Future investigations employing optogenetic and electrophysiological methods could shed light on these indirect pathways and their influence on OB activity.
Among locally produced neuropeptides that modulate olfactory processing by acting on their respective receptors in the OB are somatostatin and glucagon-like peptide 1 (GLP-1). 54Oxytocin is a hormone produced in the hypothalamus, and oxytocin receptors are found in the OB 55,56 and adjacent AON 57 suggesting oxytocin may influence social behaviour by regulating olfactory processes.Further, orexinpositive fibres, originating from cell bodies in the lateral hypothalamus (LH), have been found in the OB. 53Orexin neurons are important in sleep/wakes cycles, arousal and feeding behaviour and can modulate olfactory sensitivity based on satiety levels. 539][60] However, several other brain areas also express these receptors, including the OB.Thus, centrifugal fibres and hormonal inputs are ways in which olfactory processing and feeding behaviour can interact (a comprehensive list of hormones and neuropeptides Tables 1 and 2).

| Feeding-related centrifugal projections to the OB
In regard to feeding and energy homeostasis, the olfactory system receives information from numerous brain regions involved in both homeostatic regulation and motivation/reward processing. 61,629][70][71] Retrograde transsynaptic tracing experiments found indirect projections (involving two to three synapses) extending toward the OB from multiple hypothalamic nuclei, including the arcuate nucleus (ARC), ventromedial hypothalamic nucleus (VMH), the paraventricular nucleus (PVN) and the dorsomedial hypothalamic nucleus (DMH). 70All these nuclei play crucial roles in the regulation of appetite and energy metabolism, this study showed that the OB receives both direct and indirect projections from the lateral hypothalamus (LH), with some direct projections originating from melanin-concentrating hormone and orexin neurons, 70,72 which are known to regulate body weight, appetite and arousal. 53,73Similarly, F I G U R E 3 Scheme of olfactory bulb projections discussed in this review.The olfactory nerve, formed by axons from the OSNs in the OE directly project to the olfactory bulb (OB).The neurons in the OB send their axons (forming the lateral olfactory tract) to the primary olfactory cortex (blue), important for odour discrimination and identification.Among the primary olfactory cortex are the anterior olfactory nucleus (AON), the olfactory tubercule (OT), the piriform cortex, the amygdala and the entorhinal cortex.Secondary olfactory targets (green) are brain areas receiving direct projections from the primary olfactory cortex forming intracortical connections.These include parts of the prefrontal cortex and neocortex, such as the orbitofrontal cortex (OFC), hypothalamus, thalamus, and hippocampus.Due to the OB's connections with other brain regions, it comes as no surprise that odours can regulate emotion, fear, cognition or appetite.For example, the OB directly connects via the piriform cortex to the amygdala, where emotion processing and associative learning occur.The amygdala is also involved in social behaviours.The OB also communicates via the entorhinal cortex with the hippocampus, important for odour identification, memory and learning.The orbitofrontal cortex plays a role in sensory integration, flavour perception and odour-reward associations.The olfactory cortex also connects to the hypothalamus, a brain region regulating feeding, metabolism and reproduction.The thalamus is the information relay station of all sensory modalities except smell and has a role in sleep, wakefulness, memory and learning.The ventral tegmental area (VTA) has a function in the rewarding aspects of odours.The ventral pallidum (VP) plays a role in motivated behaviours.The insula activates in response to olfactory and gustatory stimuli, especially when unpleasant, and plays a role in pain perception and emotional processing.Centrifugal efferent projections originating from olfactory cortical structures and neuromodulatory centres, such as substantia nigra (SN, dopaminergic), the locus coeruleus (noradrenergic), the horizontal limb of the diagonal band of Broca (cholinergic), and the raphe nucleus (serotonergic), do not directly impact odour discrimination, but play a crucial role in maintaining the oscillatory dynamics of the OB and mediate learning and memory processes important for odour-reward associations.This underscores that olfactory processing is strongly modulated by experience.In addition, efferent feedback may also facilitate attentional processes in olfaction, resembling the role of thalamic gating observed in other sensory modalities.Afferent projections are marked with blue arrows, reciprocal-connection are orange arrows, and efferent projections are marked with white arrows.LH, lateral hypothalamus.
T A B L E 2 Appetite and olfactory performance regulating neuropeptides/hormones and their receptors expressed in the olfactory bulb.
Reproduction, modification of olfactory information, olfactory sensitivity to pheromones [331-338]   Hypothalamus and periphery +/+ GL, MCL, GCL [275,278,339-342]  the nucleus tractus solitarius (NTS), implicated in energy homeostasis, also contributes indirect projections to the OB, as well as the rostroventrolateral reticular nucleus (RVLM). 70ong the reward pathways, the ventral tegmental area (VTA) and ventral pallidum (VP) send direct projections, whereas the nucleus accumbens (Acb) and lateral habenular nucleus (LHb) have indirect projections.Other authors also reported a projection from the substantia nigra to the OB. 37Direct projections originating either from homeostatic or hedonic brain regions, such as VTA and LH, 74 suggest that these projections may act together to modify the odour value depending on the energy state (fasted/satiated). 70Other food-related indirect projections were observed from the laterodorsal tegmental nucleus (LDT, reward processing) and as well as basolateral amygdaloid nucleus (BLA, positive and negative odour memory formation). 70l these brain areas (Acb, LHb, LDT and BLA) have links with the VTA and thus contribute to the brain reward circuitry.Further centrifugal direct projections arise from primary olfactory regions (piriform cortex, nucleus of the lateral olfactory tract, anterior cortical amygdaloid area, dorsolateral entorhinal cortex), except for the olfactory tubercle.
A direct projection to the OB was also identified from the CA1 subdivision of the ventral hippocampus and may be involved in the processing of fear-and aversive-related odours. 70

| SCENTSORY INTELLIGENCE: ADAPTING OLFACTORY PERCEPTION TO METABOLIC NEEDS
The OB is a key site for hormonal and nutritional access due to the highly permeable and highly vascularized local blood-brain barrier (BBB). 75,76Hormones and nutrients act on the olfactory system to adjust olfactory physiology and structure, olfactory function, odour detection and ultimately feeding behaviour.Thus, it is not surprising that the OB has high expression of numerous metabolic hormone receptors, such as insulin, leptin, GLP-1 and ghrelin. 4,61,62Aligned to their appetite-regulating function, orexigenic hormones, such as ghrelin, most likely increase olfactory sensitivity, whereas anorexigenic hormones, such as leptin, may decrease olfactory sensitivity (Table 1).
While current dogma indicates these key metabolic hormones regulate food intake, body weight and peripheral metabolic processing through hypothalamic circuits, the privileged access of the OB to these hormones suggests an important and unexplored influence of olfactory information to regulate feeding behaviours and feeding-related neural circuits.Indeed, hormonal uptake into the OB is faster than anywhere else in the brain making it an ideal neuroendocrine regulator of appetite and metabolism. 779][80][81][82] In addition, OB neurons also respond to nutrients, such as glucose, amino acids and fats, an essential function of energy-sensing brain regions like the hypothalamus (Table 3), which may fine-tune olfactory neuronal activity to metabolic requirements. 4For example, OB neurons express hallmarks of glucose sensing cells [83][84][85][86][87] and several glucose transporters have been  4 The abundant need for glucose processing machinery comes from the high energy demand for accurate odour processing in olfactory areas, including the OB. 88However, the presence of metabolic machinery in the OB is not limited to glucose processing and includes amino acid transporters, receptors, and intracellular molecules, as well as various fatty acid solute carrier transporters. 4Thus, glucose-sensing, protein sensing and lipid-sensing in the OB are all likely to play a pivotal role in controlling metabolic-related olfactory function.[91] Metabolic disorders such as obesity are associated with impaired olfactory ability, giving further indication that olfaction is modulated by metabolic factors, 61 including adiposity, blood glucose and endocrine feedback. 92,93In addition to metabolic factors, olfactory sensitivity follows a circadian sleep/wake cycle, similar to many physiological processes, such as feeding, locomotor activity and hormone secretion. 94The OB also expresses the receptor for melatonin, 95 providing a potential mechanism for circadian regulation.Certainly, a post-ingestive rise in glucose, insulin or GLP-1 will impact olfactory abilities indicating how feeding state can directly affect olfactory processing.Indeed, hunger and energy deprivation increase olfactory discrimination and sensitivity, [96][97][98][99] whereas satiety reduces the pleasantness of food-related odours. 100

| NEUROENDOCRINE CONTROL OF THE OB AND METABOLISM
Hormones can potentially modify the perception and pleasantness of specific odours as well as olfactory processing.This includes a direct interaction with receptors in the olfactory system or through indirect control mechanisms involving the interplay between olfaction, appetite regulation, memory, and motivation.The OB expresses receptors for several metabolic hormones, associated with increased (orexigenic) or decreased (anorexigenic) feeding (Tables 1 and 2).Thus, the OB serves as a crossroads for neuroendocrine signals, where various hormones associated with appetite modulation converge.This intriguing revelation suggests that the OB acts as a pivotal node in the intricate web of neuroendocrine communication that influences our food cravings, energy balance, and overall metabolic well-being.

| Orexigenic hormones
Orexins (Orexin A and B or hypocretin-1 and hypocretin-2) play a role in feeding behaviours, 81 and central injections of orexins stimulate food intake, locomotor activity, grooming and foraging behaviours. 101ditionally, orexins impact energy metabolism by stimulating metabolic rate independently of changes in food intake. 102Notably, orexins enhance sympathetic tone, leading to increased blood pressure, heart rate, and other physiological responses such as gastric acid secretion or luteinizing hormone release.[105][106] Both orexin A and B are produced in the hypothalamus and released into the OB by centrifugal hypothalamic fibres, where they bind to two G-protein coupled receptors, OX1 and OX2. 67While orexin A can bind both receptors, orexin B selectively binds to OX2 and is less potent.Hypothalamic orexin neuronal projections exhibit widespread distribution throughout the central nervous system 80 and olfactory sensory processing is modulated by orexigenic fibres from the hypothalamus. 53,72Indeed, retrograde labelling experiments revealed that a small fraction of hypothalamic orexin A neurons directly innervate the main OB. 72In the rat OB orexin-containing fibres were found in the glomerular, mitral and granular cell layer, and are originating from the lateral and posterior hypothalamus and the perifornical area. 81,107The presence of orexin-containing fibres in the OB, originating from the hypothalamus, exemplifies how different brain structures influence olfactory modulation.Moreover, the responsiveness of hypothalamic orexin neurons to nutritional fluctuations, 108,109 such as fasting, lipid load and refeeding, underscores the metabolic impact on olfactory performance.
Postnatally, orexin receptors are expressed primarily in mitral cells, with additional expression in periglomerular, tufted, and granule cells. 81munoreactivity was also observed in dendrites and processes of mitral/tufted and granule cells. 81Orexin administration, either in vivo via intracerebroventricular injections or locally in OB-slices, induced a significant decrease in mitral cell spontaneous firing activity, 80 and either resulted in depolarisation (7%) or hyperpolarisation (30%) of mitral cells. 81Further, intracerebroventricular injection of orexin enhanced olfactory sensitivity, as indicated by increased avoidance behaviour of isoamyl acetate odourised water, in comparison to saline. 51relin is produced by endocrine stomach cells and signals low body energy supplies by acting on ghrelin receptors (GHSR, Growth Hormone Secretagogue Receptor). 59GHSRs are expressed throughout the CNS with significant research focusing on neuronal populations in the hypothalamus, midbrain and hindbrain. 1104][115] Ghrelin is transported through the BBB and has a high uptake into the OB 116,117 where it is linked to increase olfactory performance and exploratory sniffing behaviour in rats and humans. 49In addition, ghrelin influx across the BBB is highest during fasting and lowest in obesity. 118Ghrelin administration also markedly increases OB c-fos immunoreactivity, 119 augments the percentage of c-fos activated OB neurons in response to the odorant 2,3-hexanedione 48 and activates new adult-born OB cells. 115In humans, ghrelin also enhances food odour conditioning and sniffing. 49though ghrelin is known to promote food intake, reduces anxiety, 120 increases motivation, exploration and food-seeking, 121 these studies also highlight exogenous ghrelin affects olfaction.Likewise, a positive correlation between ghrelin levels and human odour intensity ratings has been demonstrated, 47 and postprandial changes in ghrelin affected neural responses to odours. 122Low ghrelin levels were associated with decreased olfactory sensitivity and suppression of odour-evoked fMRI activity in brain regions involved in olfactory processing, including olfactory cortices.This could be driven by the effects of ghrelin on the OB.Since hunger and high levels of ghrelin increase olfactory sensitivity, 49 we recently examined whether ghrelin links hunger with olfaction and the implications of disrupting this feedback on food intake, metabolism and related foraging behaviours. 112To investigate the behavioural and metabolic actions of GHSRs in the OB (OB GHSR ), we deleted OB GHSR in adult mice and discovered OB GHSR deletion decreased olfactory sensitivity to food and non-food odours in various olfactory performance tasks.Although daily total food intake or ghrelin-induced food intake were not different, OB GHSR deletion altered feeding behaviour with mice displaying decreased number of feeding bouts in the dark phase, anhedonia, impaired food finding, and exploratory behaviour.Unexpectedly, OB GHSR deletion increased body weight, fat mass accumulation and impaired glucose tolerance.Thus, GHSR signalling in the OB is an example of how a metabolic-signalling mechanism links metabolic state to olfaction and regulates olfactory sensitivity, exploratory, feeding behaviour and peripheral energy and glucose metabolism.
Glucocorticoids are steroid hormones secreted by the adrenal glands, and play a pivotal role in maintaining basal metabolism, immunity and stress-related adaptations.Glucocorticoids have been found to boost food intake by exerting their influence either directly or indirectly on brain regions responsible for regulating appetite. 123For the stress response, glucocorticoids primarily act on the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis. 124Glucocorticoid actions are facilitated through the intracellular glucocorticoid receptor (GR), which belongs to the nuclear transactivating superfamily, encompassing the steroid/sterol/thyroid/retinoid/orphan receptors. 125Research involving whole-body knockdown studies of GR has uncovered its significance in processes like gluconeogenesis during fasting and erythropoiesis under stress conditions. 126,127Additionally, studies on mice with forebrainspecific GR gene knockout have shed light on the vital role of GR in emotional and anxiety-related behaviours as well as stress-related behaviours. 128,129Mice exhibited depressive symptoms, including hyperactivity and altered stress-induced locomotion with impaired HPA axis activation, underscoring the importance of GR actions in the forebrain, which also encompasses limbic structures such as the OB.In the OB the GR was found in a few cells within the glomerular and mitral cell layer, and higher presence in the granule cell layer. 130Although less established, there is some evidence suggesting an olfactory regulatory influence of glucocorticoids since stress is associated with improved olfactory performance. 131fear-inducing test involving public speaking in men elevated plasma cortisol levels and resulted in anger, while also enhancing olfactory sensitivity. 132Moreover, subjects exposed to a stressful public mental arithmetic task, elevating cortisol levels, exhibited improved detection of the pungent smell of 2-mercaptoethanol. 133In women, cortisol had an impact on olfactory detection through the menstrual cycle, with heightened cortisol levels correlating with enhanced odour detection capabilities. 134Furthermore, higher cortisol levels in new mothers postpartum were linked to increased attraction and improved recognition of their infants' odours. 1353][134][135] However, in mice subjected to chronic corticosterone treatment through their drinking water, the outcome is quite different.
Chronic exposure resulted in the development of anxiety and depressive-like disorders, accompanied by alterations in cell survival in the OB and a decline in olfactory discrimination, acuity, and memory. 136 patients with adrenal insufficiency and chronically reduced cortisol production, there was a decrease in olfactory perception threshold, indicating enhanced olfactory sensitivity.This effect was reversed by steroid supplementation. 137However, studies in rat models are conflicting.After adrenalectomy, olfactory performance was either reduced 138 or remained unchanged. 139It is important to note that individuals or animals with compromised adrenal gland function often experience more severe health problems beyond alterations in their sense of smell, suggesting the involvement of other confounding factors, such as other hormones produced in the adrenal glands, including other stress hormones with receptors identified in the OB, for example corticotropin-releasing hormone (CRH) 140 and adrenalin. 141Intranasal glucocorticoids are widely used to relieve symptoms of nasal congestion, irritation and discomfort from allergies or hay fever.While considered safe a negative impact on paediatric growth is discussed in the literature. 142,143Further, chronic intranasal corticosteroid treatment is associated with impaired olfactory function due to neuronal degeneration. 144 is worth mentioning that certain odours can lessen manifestations of the stress response, while other odours can induce stress. 145r example, predator odours are known to induce a stress response in animals, leading to elevated blood pressure and increased plasma corticosterone or cortisol concentrations. 146This stress response, in turn, impacts various physiological processes, including behaviours, such as freezing, protective burying, avoidance and delayed or decreased food consumption. 147This neuroendocrine activation pathway serves as a compelling example of close neuroanatomical connections between olfactory and stress response pathways.

| Anorexigenic hormones
Insulin is secreted from the pancreas in proportion with body fat when blood sugar levels rise 148 and promotes glucose uptake into peripheral tissues. 1491][152] The actions of insulin in the olfactory system are probably the most well-described amongst the feeding-related hormones. 624][155] Hence, IR signalling occurs from the first step of odour detection in the OE to signal transduction and odour processing in the OB and beyond.In the OB, IRs are located in the external plexiform layer, the glomerular layer, granule cell layer and mitral cell layer.The highest expressions of IRs are found in mitral cells. 448][159][160] Moreover, insulin binding in the OB increases or decreases with feeding and prolonged starvation respectively, 161 suggesting metabolic state also influences the actions of insulin in the OB, 44 and linking olfactory capabilities with metabolic state by modifying odour processing within the OB. 45deed, elevated blood plasma insulin levels (or reduced ghrelin levels) following a meal were linked to decreased olfactory sensitivity, perceiving odours as less intense, and accompanied by a widespread suppression of odour-evoked activity across the primary olfactory cortex and hypothalamus.These effects were observed in response to both food and non-food odours. 122In line with this, administering a single intracerebroventricular bolus of insulin to fasted rats to mimic satiety, reduced odour detection in a conditioned odour aversion paradigm and sniffing frequency when exposed to a food odour compared with controls. 44Insulin may influence olfactory sensitivity by exerting its effects on neurons within the OB.Patch-clamp recordings of rat OB slices showed that bath-administered insulin had divergent effects on distinct neurons within the OB network 45 : While in mitral cells (MCs), insulin increased the excitability by likely inhibiting two voltage-gated potassium channels, it modified the GABAergic and glutamatergic synaptic activity in interneurons that connect to MCs, generally decreasing synaptic activity.Furthermore, insulin exerted varied effects on olfactory nerve (ON)-evoked excitatory postsynaptic currents in MCs by either decreasing or increasing them depending on the initial firing rate of ON-evoked neurons.Insulin tended to reduce high firing rates and elevate low firing rates, thus decreasing inter-mitral cell response firing variability.This in turn most likely affects MCs' olfactory performance, mainly decreasing olfactory detection, depending on the quality of the odour being processed and aligning the valence of an odour with feeding signals. 45Also, excitability on the level of the OE and OSNs varies depending on the nutritional status.When exposed to an odour OSNs exhibit increased excitability and firing frequency. 46wever, administration of insulin on the mucosa mimicked a postprandial insulin rise and reduced the amplitude of electro-olfactogram in response to odours by 30%. 82These results suggest that although insulin improves the firing rate of individual OSNs, the number of odour-activated OSNs is reduced, hence decreasing the signal-to-noise ratio after a meal, 46 ultimately reducing the clarity of information sent to other brain regions.Again, this highlights the importance of the metabolic status on odour perception.
Chronic insulin exposure in obesity or diabetes is linked to impaired neural function in the olfactory system and individuals with impaired insulin sensitivity show poor olfactory performance. 162Dietinduced obese mice showed altered MC action potentials and clustering, and acute insulin reduced or eliminated the response.Intranasal insulin was shown to activate IR signalling in the OB and modulate olfactory discrimination and detection. 153Further, intranasal insulin caused a 5% body weight drop in rodents over 7 days. 153Clinical studies also indicate that insulin via the nasal route improves cognition and memory, 163 however, whether IR in the OB regulate hypothalamic feeding circuits and contributes to the development of metabolic diseases (obesity, diabetes) is not known.
Leptin is predominantly secreted by white adipocytes in proportion to body fat.When leptin binds to hypothalamic leptin receptors (LepR), it suppresses food intake and thereby regulates long-term energy-balance and body weight.Although the majority of LepR are expressed in the hypothalamus, high expression is found in the OB 164 as well as the OSNs of the OE. 165Within the OB, LepR are found in mitral cells, granule cells as well as astrocytes in the glomerular and granule cell layer. 164Patch-clamp recordings of rat OSNs revealed that leptin heightens the excitability of OSNs in the absence of odours.However, it diminished the activity triggered by odours in the OE. 46Similar to insulin signalling in the OB, an elevation of leptin following a meal is likely to reduce the overall signal-to-noise ratio within the OE, 46 as it simultaneously increases spontaneous firing frequency while decreasing odour-evoked activity.Indeed, leptin inhibited neuronal mitral/tufted cell activity in the OB by acting on voltage-dependent potassium channels and ultimately decreasing olfactory function in mice, 166 and ICV leptin administration decreased olfactory sensitivity in an odour-conditioned avoidance paradigm. 51ese leptin-deficient ob/ob mice perform better in a buried food paradigm 167 and an odour discrimination learning task, which was associated with neuronal oscillations in the OB. 168Leptin replacement in ob/ob mice modified food-finding times similar to wildtypes, suggesting that impaired olfaction in obese conditions is primarily linked to high plasma leptin.Although research in rodents has demonstrated that administered leptin reduces olfactory discrimination and suppresses odour-evoked activity in OSNs, 46,166 the effects of meal-related increased leptin levels in humans appear to differ.Leptin levels were not found to be correlate with olfactory performance or odour-evoked fMRI brain activity. 47,122ucagon-like peptide-1 (GLP-1) is an incretin hormone, released from the small intestine in response to a meal and promotes lowering blood glucose by promoting insulin release from the pancreas. 169 addition, GLP-1 suppresses food intake via neuroendocrine actions in the brain.Interestingly, GLP-1 producing cells and GLP-1 receptors (GLP-1R) expressing cells are found on mitral cells and granular cells in the OB, suggesting the presence of an endogenous GLP-1 system in the OB.In addition, fluorescence labelled stable analogue exendin-4 was shown to arrive in the OB when given intranasally or intraperitoneally, 62,170 indicating an additional neuroendocrine role in the OB.Unlike leptin, GLP-1 increases the excitability and firing frequency of mitral cells via dampening the activity of voltage-dependent potassium channels (Kv1.3). 170Moreover, GLP-1 signalling in the OB boosted olfactory function in obese mice by restoring the loss of foraging behaviour and enhancing odour-induced insulin release in the cephalic phase. 54The injection of GLP-1 antagonist exendin-9 in the OB of lean mice impaired food retrieval time in a buried foodfinding test, whereas the agonist Exendin-4 rescued the lack of foraging behaviour of obese mice and increased olfactory sensitivity.
Although the direct actions of GLP-1 signalling in the OB on food intake and metabolism were not examined, there is an interesting discordance between insulin, leptin and GLP-1 and olfaction.All three hormones are considered anorexigenic as they suppress food intake, but leptin and insulin suppress olfactory function whereas GLP-1 seems to promote olfaction, at least in a diet-induced obese model.
Future studies are required to address this observation as this could be a highly relevant obesity pharmacotherapy since GLP-1R mimetics are now commonly used in the treatment of obesity or diabetes. 170olecystokinin (CCK, pancreozymin), a peptide hormone of the small intestine, mediates gut motility and digestion by regulating pancreatic enzymes and gallbladder contraction important for fat and protein digestion.Its sulphated octapeptide is widely distributed in the CNS. 43In the OB, CCK peptide is found in the soma of tufted cells, and fibres of the external and internal plexiform layer. 43CCK binds to two types of receptors: CCK-1R and CCK-2R, both of which are found in the OB, [171][172][173] whereas CCK-2R is generally the dominant form in the brain and involved in the satiety response, memory, cognition and anxiety. 171,172CCK-2R occurs in the inner margins of the glomerular layer, on mitral/tufted and juxtaglomerular cells and external plexiform layer, but not on granule cell bodies. 43In contrast, CCK-1R was found in the internal granular layer 173 as well as lateral olfactory tract. 174Patchclamp recordings showed that CCK excites mitral cells postsynaptically through CCK-1R and CCK-2R, 43 however, CCK-1R has stimulatory and CCK-2R inhibitory effects on olfactory performance. 41CCK via CCK-2R selectively activates short axon cells by engaging with glomerular circuits to enhance the inhibition of OB output neurons.This modulation was suggested to either prevent saturation in response to high odour concentrations or increase the signal-to-noise ratio to help with the detection of low odour concentrations. 42Intraperitoneal injection of CCK-1R agonists, or CCK-2R antagonists suggests that CCK enhances olfactory recognition and memory. 41Chemogenetic activation of mitral cells and odour presentation suggested that stressful smells like the predator-odour Trimethylthiazoline (TMT) can increase energy expenditure, particularly in females, 175 and confirmed the involvement of CCK-expressing neurons in the dorsomedial hypothalamus (DMH).The findings also shed light on stress-induced thermogenesis and feeding suppression triggered by predator odour detection and underscores the enduring question of whether a particular olfactory cue possesses the ability to modulate energy metabolism.
Oxytocin is produced in the paraventricular nucleus and supraoptic nucleus of the hypothalamus and released in circulation from the posterior pituitary.In addition, these neurons send axonal projections to areas in the brain relevant for food intake regulation, including areas also receiving inputs from the OB, for example, nucleus accumbens, amygdala, hippocampus, and anterior olfactory nucleus. 20Although the OB does not receive direct oxytocinergic projections from oxytocinproducing neurons in the hypothalamus, oxytocin receptors (OXTR) are expressed in the OB, suggesting the neuroendocrine regulation of OXTR neurons in the OB. 20In the OB, the OXTR is expressed in periglomerular cells and the glomerular cell layer, as well as mitral cells and the granule cell layer. 55,56,176,177Oxytocin is well described to affect social behaviour and reproductive function but also has an anorexigenic effect on food intake via meal size control and meal cessation. 178,179nctional MRI studies in humans indicated that oxytocin administered via the intranasal route reduced calorie intake by enhancing the activity of feeding relevant brain areas that control reward and cognition. 179Of note, intranasal oxytocin did not alter olfactory function nor appetite or food choice.In mice, oxytocin infusion into the OB increased social interaction. 180On a neuronal level, oxytocin enhanced odour discrimination and odour-induced mitral/tufted cell activity but reduced the spontaneous firing rate of mitral/tufted cells and odour-evoked calcium activity in granule cells. 180In this manner, oxytocin increases the signalto-noise ratio for accurate odour detection.

| Orexigenic/anorexigenic hormones
Adiponectin is predominantly produced in adipose tissue and plasma levels are inversely correlated to body mass. 181Within the olfactory system, the adiponectin receptor (adipoR1) is expressed in OE and OE electro-olfactogram recordings suggest that it increases ORNs responsiveness to odourants as well as nearby OB. 182 In the OB, both receptors (adipoR1 and 2) have been identified in the periglomerular, mitral and granular cell layers. 183,184In a rat model adiponectin prevented olfactory impairment induced by amyloid-beta accumulation, probably due to its described neuroprotective effects. 185Interestingly, plasma adiponectin concentrations correlate with greater olfactory sensitivity in women, but not men. 186Further, it has been suggested that adiponectin may modulate insulin signalling in the OB, possibly contributing to olfactory performance. 184OB adiponectin injections slightly decreased IR protein content, IR phosphorylation and downstream phosphorylation of Akt.
Although a role for adiponectin acting in the OB to influence metabolism is yet to be established, its ability to modulate insulin signalling and the link to nutritional status, 187 suggests this is a strong possibility.
The studies highlighted above collectively demonstrate a novel neuroendocrine role in olfactory function.In some cases, the direct hormonal action in the OB regulates food intake and metabolism, but in most the metabolic role has yet to be addressed.Future studies are required to address these gaps in the literature.

| OLFACTION-FEEDING INTERPLAY: THE IMPORTANCE OF SMELL FOR FEEDING AND HEDONIA
The impact of smell on appetite, food consumption and enjoyment of food is widely recognized.Indeed, one way the brain regulates food intake behaviour is by changing the perception and pleasantness of food-related odours, a concept termed 'alliesthesia' 188 and 'sensory specific satiety'. 100,189This refers to how an organism's internal state alters the perceived pleasure or displeasure of external stimuli.For instance, food is more pleasant when hungry.And the pleasantness of food-related odours decreases when full, 100 or following a gastric or duodenal glucose load administered directly through a nasogastric tube.This suggests that nutrient-sensing in the digestive tract may influence the pleasantness of food-related odours. 190Conversely, the 'satiety effect' can be induced by chewing or smelling food for a similar duration to a typical meal without the food entering the gastrointestinal system or calorie ingestion. 1002][193] These observations have important implications for food intake control and our understanding of how the brain processes sensory-specific signals.So, what is the mechanism involved?Why does a whiff of freshly baked bread make you hungry or why does olfactory perception change when you are full?
Olfactory sensory inputs from ORs in the nasal cavity travel to the OB, the first port for sensory information to reach the brain, before touch, taste and sight. 194These inputs are often decisive cues that help organisms assess whether food is available, palatable, or potentially toxic.This is an important point since feeding behaviour is not only driven by homeostatic signals but also by sensory environmental cues predicting the availability of tasty calorie-dense foods or potential external threats. 195,196Further, animals exhibit different behavioural responses to the same sensory cue depending on the internal metabolic state at a given moment. 197Olfaction plays a pivotal role in this intricate interplay between homeostatic and hedonic circuits, as alterations in internal conditions like hunger or satiety intricately influence the pleasurable value of odours. 61Homeostasis is based on the metabolic state, wherein energy depletion and hunger amplify the motivation for food consumption.Furthermore, increased olfactory discrimination and sensitivity facilitate the detection of food cues in food-scarce environments.Contrary, olfactory sensitivity decreases during satiation and gastric distension.Besides the nutritional state, olfactory performance also depends on adiposity and is also influenced by pathologic conditions (obesity, metabolic or neurogenerative disorders). 61,62,198On the other side, hedonic processes are entwined with the sensory attributes of food and the associated rewards, reflecting olfactory inputs in brain reward and motivational systems. 199For example, specific food odours increase appetite and subsequent consumption of food matched to the odour. 200nsory information from olfactory circuits uniquely bypasses the thalamus, which explains emotional imprinting, lasting memory, and evocative power of olfactory experiences. 201Olfactory learning, involving dopamine-dependent strengthening, 202 influences motivation for food acquisition, food preferences, and meal size. 189,203factory cues contribute to the 'cephalic phase', preparing the body for an incoming meal by triggering processes such as salivation, gastric acid secretion and insulin release. 189,204,205And odours paired with palatable food increase appetite in both rodents and humans. 191,206is was classically demonstrated by Pavlovian conditioning of appetitive behaviours. 194,207As such, olfactory cues are crucial for forming dynamic value judgments of the surroundings and optimizing behavioural responses, such as food choice and consumption.This underscores that olfactory ability is shaped not only by internal metabolic factors but also by external olfactory cues, all impacting eating behaviour. 189,208Thus, there seems to be a reciprocal relationship between olfaction and metabolism, 92 where olfactory information alters feeding behaviour and metabolic factors influence olfactory performance.
Hence, olfaction emerges as a potent mediator of food consumption, with the potential to influence energy balance and body weight. 92,175,209Consequently, the OB allows for the integration of food odours and internal metabolic-dependent signals, like hormones or nutrients, and highlights the OB's role in regulating both sides of the energy balance equation, namely feeding and energy metabolism.

| 'SCENT-SATIONAL HYPOTHALAMIC CONNECTIONS' : THE OLFACTORY BULB'S INFLUENCE ON APPETITE AND METABOLISM
In the hypothalamus two critical neurons are involved in hunger and satiety signalling; namely Arcuate agouti-protein related peptide (AgRP) neurons as well as Pro-opiomelanocortin (POMC) neurons.
While AgRP neurons promote food intake by releasing orexigenic peptides such as AgRP, NPY or GABA, POMC neurons inhibit food intake by releasing anorectic peptides, such as alphamelanocyte-stimulating hormone (α-MSH). 210Ablation of these pathways results in starvation or obesity, respectively. 211,212AgRP and POMC neurons have long been believed to respond primarily to changes in energy state, with AgRP neurons increasing food intake in response to energy need and POMC suppressing food intake in response to sufficient consumption.In this feedback model, AgRP neuron activity would be expected to remain elevated until all calories required to reinstate homeostasis have been consumed.Similarly, for POMC neurons, activity should remain low until sufficient calories have been consumed.However, this is clearly not the case as studies show sensory cues of food availability inhibit and activate AgRP and POMC neurons, respectively, immediately before food intake. 213terestingly, the response magnitude of AgRP or POMC to sensory cues depends on metabolic state, food accessibility, and palatability. 213Moreover, sustained changes in activity require calorie consumption since exposure to non-accessible caged food only produces short-lived changes in AgRP or POMC neuronal activity. 213These studies highlight that AgRP and POMC neurons do not just react to metabolic changes but respond to sensory cues of food availability and palatability to prepare for perceived future energy demands.The model highlights the importance of sensory inputs in regulating feeding circuits and has recently been termed energy allostasis. 66This new model is relevant to human behaviour since humans often eat in the absence of hunger or restrict food intake in the presence of hunger.
Olfactory sensory input may be even more important due to the potential ability to transmit both novel food-odour information and learned odour associations to hypothalamic feeding circuits.And food odours have been shown to trigger metabolic responses, such as increase of appetite, salivation and the release of digestive enzymes, thus preparing the body for the incoming meal.This interaction between energy metabolism and olfactory perception appears to work both ways, as hunger signals released during fasting (orexigenic hormones) increase olfactory function, potentially aiding in food location, 97,112 and AgRP activity increases preference for food odours over pheromone odours. 214Recent research has unveiled that both AgRP and POMC neurons receive indirect inputs from overlapping regions within the olfactory cortex, pinpointing the origins of odour-related signals. 215

| SCENTLESS SUFFERING: OLFACTORY CHANGES AND HEALTH IMPLICATIONS
Olfaction affects appetite, hedonic aspects of food, mood and cognition, 216,217 and individuals who cannot smell experience depression, abnormal food perception (pleasantness/intensity), and changes in food consumption and enjoyment as well as cognition. 218Anosmia, the loss of olfactory function, goes often unnoticed and is diagnosed late, leading to long-term implications on well-being and quality of life. 218,219[222] Besides altered eating behaviours and anhedonia associated with olfactory impairments, olfactory loss also affects food preparation or the detection of spoiled foods and hazards. 218,219mmon causes include sinus-nasal disease, upper respiratory infections, traumatic brain injuries, cancer, and post-viral olfactory loss, as seen in COVID-19 patients. 221,223Neurodegenerative diseases and environmental toxins can also lead to olfactory impairments. 2249][230] Also, the opposite cannot be ruled out: Olfactory dysfunction causes, or at least contributes to changes in metabolism and contributes to weight gain in obesity 209 or impaired glycaemic control in diabetes. 231,232Evidence for such a link that olfactory impairments affect metabolic parameters comes from various animal models (Table 4) and human pathologies (Table 5).In humans, a common biallelic gene deletion encoding olfactory receptors was found in children of obese parents, suggesting olfactory dysfunction contributes toward the development of obesity. 2335][236] Collectively, these studies show that human obesity can be linked to genes affecting olfaction.8][239] Transgenic mice with increased olfactory sensitivity are resistant to weight gain when placed on high-fat diet (HFD), 239 whereas impairing olfactory sensitivity predisposes to weight gain and obesity. 112,240,241One mechanistic possibility argues that an impaired sense of smell delays the immediate sensory processing of food and thus delays satiety processing, resulting in overconsumption and ultimately weight increase. 209Of note, despite lower olfactory performance in obesity, obese individuals show an increased preference for odours associated with palatable energy-dense foods, 242 with enhanced activation of reward regions. 243,244This indicates that the olfactory system is closely linked to hypothalamic circuits controlling metabolism and reward.Indeed, a recent study demonstrated that hypothalamic hunger circuits directly control dopamine release and reward processing. 245Thus, the inability of olfactory information to control feeding circuits may make obese individuals more prone to external palatable food cues affecting food consumption/choices. 246 This idea is supported by studies showing that the ablation of hypothalamic hunger circuits promotes dopaminedriven reward eating. 247Understanding the complex relationship between olfactory integration of metabolic information and hypothalamic circuits to control feeding behaviour and reward may provide new therapeutic opportunities to treat metabolism and associated diseases.

| CONCLUDING REMARKS
Here we suggest the OB should be considered as another neuroendocrine brain region, similar to the hypothalamus.It consists of cells that produce and respond to hormonal signals, which project to higher brain regions.OB neurons are regulated by feedback signals from afferents from higher brain centres, endocrine glands, and other circulating factors, including peripheral signals carried in the blood.Thus, together the OB monitors many bodily functions via these higher brain regions and circulating factors while also integrating environmental stimuli.This puts the OB in a unique position to regulate energy homeostasis and metabolism by adjusting olfactory sensitivity, guiding eating behaviour and influencing other brain regulatory systems to maintain a balanced supply of energy and nutrients.
The OB can be considered as the sensory neuroendocrine powerhouse, nestled in the brain with a window to the outside world, perceiving, recognizing, and processing odours as well as a multifaceted role in metabolic regulation, similar but not equal to the T A B L E 4 Rodent models of altered olfactory function showing the link between olfaction, behaviour and metabolism.

F
I G U R E 2 Neural Architecture of Olfactory Processing.Different odourants (represented by different colours) bind to specific olfactory receptors (ORs) expressed on olfactory sensory neurons (OSNs) within the olfactory epithelium.OSNs expressing the same ORs project their axons to specific spherical structures in the OB called glomeruli (shown by colour) and are the first olfactory processing station.Within the glomeruli OSNs axons reciprocally synapse with apical dendrites of glutamatergic OB output neurons (Mitral and Tufted cells, M/TCs) and various juxtaglomerular interneurons that include periglomerular (PG) neurons, external tufted cells and short axon cells (SACs).These interneurons are on the surface of glomeruli and form reciprocal synapses with OB neurons and OSNs axons, modulating olfactory information transmission: PG neurons provide GABAergic inhibition to other neurons as well as to OSNs within the glomerulus.Similarly, SACs mediate lateral inhibition among glomeruli.M/TCs are second-order olfactory neurons.Their apical dendrite establishes reciprocal synapses with OSNs and juxtaglomerular cells within the glomerulus, while their axons project to the olfactory cortex and higher cortical structures for further processing of olfactory information.MCs' lateral dendrites form reciprocal synapses with inhibitory GABAergic granule cell (GC) dendrites whose cell bodies are in the inner part of the OB and are the most numerous cells in the OB.Granule cells and SACs receive centrifugal feedback from olfactory cortices, which inhibits or disinhibits M/TCs.Due to different cell types and composition, the OB has a layered structure: glomerular layer (GL); external plexiform layer (EPL), mitral cell layer (MCL); internal plexiform layer (IPL); and granule cell layer (GCL).The EPL and IPL are neuropil layers, mainly composed of dendrites from M/TCs and GCs. Green plus signs (+) indicate excitatory synapses, while red minus signs (À) indicate inhibitory synapses.
Furthermore, neurons of other brain areas positioned directly upstream of AgRP or POMC neurons have been identified (VMH, DMH), potentially connecting the olfactory cortex and AgRP or POMC neurons.While some AgRP and POMC neurons received olfactory inputs from both piriform cortex, medial amygdala and posteromedial cortical amygdala, there were also unique inputs to AgRP neurons from posterolateral cortical amygdaloid area and olfactory tubercle or POMC neurons from the anterior cortical amygdaloid area and lateral entorhinal cortex.
Transporters involved in nutrient sensing expressed in the olfactory bulb.
Human pathologies showing a link between olfaction, behaviour and metabolism.