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Blood flow and a hormone called ghrelin help new neurons travel to where they are meant to be in the brain of adult mice.Blood flow and a hormone called ghrelin help new neurons travel to where they are meant to be in the brain of adult mice.

Homeostasis is a biological principle for regulation of essential physiological parameters within a set range. Behavioural responses due to deviation from homeostasis are critical for survival, but motivational processes engaged by physiological need states are incompletely understood. We examined motivational characteristics of two separate neuron populations that regulate energy and fluid homeostasis by using cell-type-specific activity manipulations in mice. We found that starvation-sensitive AGRP neurons exhibit properties consistent with a negative-valence teaching signal. Mice avoided activation of AGRP neurons, indicating that AGRP neuron activity has negative valence. AGRP neuron inhibition conditioned preference for flavours and places. Correspondingly, deep-brain calcium imaging revealed that AGRP neuron activity rapidly reduced in response to food-related cues. Complementary experiments activating thirst-promoting neurons also conditioned avoidance. Therefore, these need-sensing neurons condition preference for environmental cues associated with nutrient or water ingestion, which is learned through reduction of negative-valence signals during restoration of homeostasis. Cell-type-specific electrical activity manipulations and deep-brain imaging in mice of neuronal populations associated with homeostasis of nutrient or fluid intake reveals that learning is conditioned by a negative-valence signal from the hunger-mediating AGRP neurons and also from the thirst-mediating neurons in the subfornical organ. A mixed response to hunger and thirst Animals respond to deviations in physiological balance with specific behaviours designed to rebalance their state. The motivational drive underlying these adjustments in pursuit of homeostasis are not well understood. Here, Scott Sternson and colleagues investigate the motivational processes mediated by homeostatic neurons for hunger and thirst. They find that as well as promoting food or water seeking behaviours, starvation-sensitive AGRP neurons and thirst-promoting neurons transmit negative valence teaching signals that are actively avoided. The net effect may be to condition the animal to have a preference for cues associated with food intake, offsetting negative valence signals as the animal achieves physiological balance through food and water intake.

The neuronal substrate for binge eating, which can at times lead to obesity, is not clear. We find that optogenetic stimulation of mouse zona incerta (ZI) γ-aminobutyric acid (GABA) neurons or their axonal projections to paraventricular thalamus (PVT) excitatory neurons immediately (in 2 to 3 seconds) evoked binge-like eating. Minimal intermittent stimulation led to body weight gain; ZI GABA neuron ablation reduced weight. ZI stimulation generated 35% of normal 24-hour food intake in just 10 minutes. The ZI cells were excited by food deprivation and the gut hunger signal ghrelin. In contrast, stimulation of excitatory axons from the parasubthalamic nucleus to PVT or direct stimulation of PVT glutamate neurons reduced food intake. These data suggest an unexpected robust orexigenic potential for the ZI GABA neurons.

The AgRP-expressing neurons in the arcuate nucleus drive food-seeking behaviours during caloric restriction; a mouse study of monosynaptic retrograde rabies spread and optogenetic circuit mapping reveals that these neurons are activated by input from hypothalamic paraventricular nucleus cells and their activation or inhibition can modulate feeding behaviour. The neurons that prescribe hunger Increasing activity of the AgRP neurons in the hypothalamus drives food-seeking behaviours during periods of calorie restriction. The source of the input that provokes this hunger response was unknown. Bradford Lowell and colleagues have now mapped the inputs into these AgRP neurons and demonstrate that the paraventricular nucleus, normally thought of as a satiety centre, contains orexigenic neurons that drive AgRP neurons and food-seeking in mice, even when the mouse was otherwise sated. This work establishes specific populations of paraventricular nucleus neurons as drivers of a powerful hub within the feeding circuit. Hunger is a hard-wired motivational state essential for survival. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus (ARC) at the base of the hypothalamus are crucial to the control of hunger. They are activated by caloric deficiency and, when naturally or artificially stimulated, they potently induce intense hunger and subsequent food intake 1 , 2 , 3 , 4 , 5 . Consistent with their obligatory role in regulating appetite, genetic ablation or chemogenetic inhibition of AgRP neurons decreases feeding 3 , 6 , 7 . Excitatory input to AgRP neurons is important in caloric-deficiency-induced activation, and is notable for its remarkable degree of caloric-state-dependent synaptic plasticity 8 , 9 , 10 . Despite the important role of excitatory input, its source(s) has been unknown. Here, through the use of Cre-recombinase-enabled, cell-specific neuron mapping techniques in mice, we have discovered strong excitatory drive that, unexpectedly, emanates from the hypothalamic paraventricular nucleus, specifically from subsets of neurons expressing thyrotropin-releasing hormone (TRH) and pituitary adenylate cyclase-activating polypeptide (PACAP, also known as ADCYAP1). Chemogenetic stimulation of these afferent neurons in sated mice markedly activates AgRP neurons and induces intense feeding. Conversely, acute inhibition in mice with caloric-deficiency-induced hunger decreases feeding. Discovery of these afferent neurons capable of triggering hunger advances understanding of how this intense motivational state is regulated.

When people are forced to be isolated from each other, do they crave social interactions? To address this question, we used functional magnetic resonance imaging to measure neural responses evoked by food and social cues after participants (n = 40) experienced 10 h of mandated fasting or total social isolation. After isolation, people felt lonely and craved social interaction. Midbrain regions showed selective activation to food cues after fasting and to social cues after isolation; these responses were correlated with self-reported craving. By contrast, striatal and cortical regions differentiated between craving food and craving social interaction. Across deprivation sessions, we found that deprivation narrows and focuses the brain’s motivational responses to the deprived target. Our results support the intuitive idea that acute isolation causes social craving, similar to the way fasting causes hunger.When people are isolated, they crave social interactions. Midbrain craving regions were activated by food in hungry people, and by social interactions in people mandated to be isolated.

Mineral phosphorus (P) fertilizers support high crop yields and contribute to feeding the teeming global population. However, complex edaphic processes cause P to be immobilized in soil, hampering its timely and sufficient availability for uptake by plants. The resultant low use efficiency of current water-soluble P fertilizers creates significant environmental and human health problems. Current practices to increase P use efficiency have been inadequate to curtail these problems. We advocate for the understanding of plant physiological processes, such as physiological P requirement, storage of excess P as phytate, and plant uptake mechanisms, to identify novel ways of designing and delivering P fertilizers to plants for improved uptake. We note the importance and implications of the contrasting role of micronutrients such as zinc and iron in stimulating P availability under low soil P content, while inhibiting P uptake under high P fertilization; this could provide an avenue for managing P for plant use under different P fertilization regimes. We argue that the improvement of the nutritional value of crops, especially cereals, through reduced phytic acid and increased zinc and iron contents should be among the most important drivers toward the development of innovative fertilizer products and fertilization technologies. In this paper, we present various pathways in support of this argument. Retuning P fertilizer products and application strategies will contribute to fighting hunger and micronutrient deficiencies in humans. Moreover, direct soil P losses will be reduced as a result of improved P absorption by plants.

Tryptophan is an essential amino acid critical for protein synthesis in humans that has emerged as a key player in the microbiota-gut-brain axis. It is the only precursor for the neurotransmitter serotonin, which is vital for the processing of emotional regulation, hunger, sleep, and pain, as well as colonic motility and secretory activity in the gut. Tryptophan catabolites from the kynurenine degradation pathway also modulate neural activity and are active in the systemic inflammatory cascade. Additionally, tryptophan and its metabolites support the development of the central and enteric nervous systems. Accordingly, dysregulation of tryptophan metabolites plays a central role in the pathogenesis of many neurologic and psychiatric disorders. Gut microbes influence tryptophan metabolism directly and indirectly, with corresponding changes in behavior and cognition. The gut microbiome has thus garnered much attention as a therapeutic target for both neurologic and psychiatric disorders where tryptophan and its metabolites play a prominent role. In this review, we will touch upon some of these features and their involvement in health and disease.

RationaleHunger is controlled by the brain, which receives input from signals of the GI tract (GIT). During fasting, GIT displays a cyclical motor pattern, the migrating motor complex (MMC), regulated by motilin.ObjectivesTo study the relationship between hunger and MMC phases (I–III), focusing on spontaneous and pharmacologically induced phase III and the correlation with plasma motilin and ghrelin levels. The role of phase III was also studied in the return of hunger after a meal in healthy individuals and in patients with loss of appetite.FindingsIn fasting healthy volunteers, mean hunger ratings during a gastric (62.5±7.5) but not a duodenal (40.4±5.4) phase III were higher (p<0.0005) than during phase I (27.4±4.7) and phase II (37±4.5). The motilin agonist erythromycin, but not the cholinesterase inhibitor neostigmine, induced a premature gastric phase III, which coincided with an increase in hunger scores from 29.2±7 to 61.7±8. The somatostatin analogue octreotide induced a premature intestinal phase III without a rise in hunger scores. Hunger ratings significantly correlated (β=0.05; p=0.01) with motilin plasma levels, and this relationship was lost after erythromycin administration. Motilin, but not ghrelin administration, induced a premature gastric phase III and a rise in hunger scores. In contrast to octreotide, postprandial administration of erythromycin induced a premature gastric phase III accompanied by an early rise in hunger ratings. In patients with unexplained loss of appetite, gastric phase III was absent and hunger ratings were lower.ConclusionsMotilin-induced gastric phase III is a hunger signal from GIT in man.

Hunger is a complex behavioural state that elicits intense food seeking and consumption. These behaviours are rapidly recapitulated by activation of starvation-sensitive AGRP neurons, which present an entry point for reverse-engineering neural circuits for hunger. Here we mapped synaptic interactions of AGRP neurons with multiple cell populations in mice and probed the contribution of these distinct circuits to feeding behaviour using optogenetic and pharmacogenetic techniques. An inhibitory circuit with paraventricular hypothalamus (PVH) neurons substantially accounted for acute AGRP neuron-evoked eating, whereas two other prominent circuits were insufficient. Within the PVH, we found that AGRP neurons target and inhibit oxytocin neurons, a small population that is selectively lost in Prader–Willi syndrome, a condition involving insatiable hunger. By developing strategies for evaluating molecularly defined circuits, we show that AGRP neuron suppression of oxytocin neurons is critical for evoked feeding. These experiments reveal a new neural circuit that regulates hunger state and pathways associated with overeating disorders. Using optogenetic and pharmacogenetic techniques, the authors find that AGRP neurons suppress oxytocin-releasing neurons, which is a critical interaction for evoked feeding; thus they identify a circuit potentially involved in regulating hunger state. Neural aspects of feeling hungry Stimulation of neurons expressing agouti-related peptide (AGRP) in the hypothalamus of mice evokes the behavioural responses to hunger — an intense search for food and copious eating. Taking advantage of the fact that these starvation-sensitive neurons are accessible to genetic manipulation, this study 'reverse engineers' a neural circuit for hunger, using optogenetics and pharmacogenetics. AGRP-expressing neurons are shown to suppress oxytocin-releasing neurons, a small neuronal population that is lost in Prader–Willi syndrome, a condition involving insatiable hunger. The inhibitory circuit involving oxytocin neurons is a prerequisite for AGRP-expressing-neuron-evoked eating, a finding that establishes this previously unknown neural circuit in the regulation of the hunger state and pathways associated with overeating disorders.

The human circadian system regulates hunger independently of behavioral factors, resulting in a trough in the biological morning and a peak in the biological evening. However, the role of the only known orexigenic hormone, ghrelin, in this circadian rhythm is unknown. Furthermore, although shift work is an obesity risk factor, the separate effects of the endogenous circadian system, the behavioral cycle, and circadian misalignment on ghrelin has not been systematically studied. Here we show—by using two 8-day laboratory protocols—that circulating active (acylated) ghrelin levels are significantly impacted by endogenous circadian phase in healthy adults. Active ghrelin levels were higher in the biological evening than the biological morning (fasting +15.1%, P = 0.0001; postprandial +10.4%, P = 0.0002), consistent with the circadian variation in hunger (P = 0.028). Moreover, circadian misalignment itself (12-h behavioral cycle inversion) increased postprandial active ghrelin levels (+5.4%; P = 0.04). While not significantly influencing hunger (P > 0.08), circadian misalignment increased appetite for energy-dense foods (all P < 0.05). Our results provide possible mechanisms for the endogenous circadian rhythm in hunger, as well as for the increased risk of obesity among shift workers.