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Objective: Although the metabolic state of an organism affects olfactory function, the precise mechanisms and their impact on behavior and metabolism remain unknown. Here, we assess whether ghrelin receptors (GHSRs) in the olfactory bulb (OB) increase olfactory function and influence foraging behaviors and metabolism., Methods: We performed a detailed behavioural and metabolic analysis in mice lacking GHSRs in the OB (OB GHSR deletion). We also analsyed OB scRNA-seq and spatial transcriptomic datasets to assess GHSR+ cells in the main and accessory olfactory bulbs, as well as the anterior olfactory nucleus., Results: OB GHSR deletion affected olfactory discrimination and habituation to both food and non-food odors. Anxiety-like and depression-like behaviors were significantly greater after OB GHSR deletion, whereas exploratory behavior was reduced, with the greatest effect under fasted conditions. OB GHSR deletion impacted feeding behavior as evidenced by altered bout number and duration, as well as buried food-seeking. OB GHSR deletion increased body weight and fat mass, spared fat utilisation on a chow diet and impaired glucose metabolism indicating metabolic dysfunction. Cross referenced analysis of OB scRNA-seq and spatial transcriptomic datasets revealed GHSR+ glutamate neurons in the main and accessory olfactory bulbs, as well as the anterior olfactory nucleus. Ablation of glutamate neurons in the OB reduced ghrelin-induced food finding and phenocopied results seen after OB GHSR deletion., Conclusions: OB GHSRs help to maintain olfactory function, particularly during hunger, and facilitate behavioral adaptations that optimise food-seeking in anxiogenic environments, priming metabolic pathways in preparation for food consumption., Competing Interests: Declaration of competing interest J.M.Z. receives research funding from Novo Nordisk for another project and consulted for Helsinn Healthcare S.A. and Dexcel Pharma Technologies Ltd. during the time these studies were performed. The other authors have nothing to disclose. All other authors report no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Hunger increases the motivation for calorie consumption, often at the expense of low-taste appeal. However, the neural mechanisms integrating calorie-sensing with increased motivation for calorie consumption remain unknown. Agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus sense hunger, and the ingestion of caloric solutions promotes dopamine release in the absence of sweet taste perception. Therefore, we hypothesised that metabolic-sensing of hunger by AgRP neurons would be essential to promote dopamine release in the nucleus accumbens in response to caloric, but not non-caloric solutions. Moreover, we examined whether metabolic sensing in AgRP neurons affected taste preference for bitter solutions under conditions of energy need. Here we show that impaired metabolic sensing in AgRP neurons attenuated nucleus accumbens dopamine release in response to sucrose, but not saccharin, consumption. Furthermore, metabolic sensing in AgRP neurons was essential to distinguish nucleus accumbens dopamine response to sucrose consumption when compared with saccharin. Under conditions of hunger, metabolic sensing in AgRP neurons increased the preference for sucrose solutions laced with the bitter tastant, quinine, to ensure calorie consumption, whereas mice with impaired metabolic sensing in AgRP neurons maintained a strong aversion to sucrose/quinine solutions despite ongoing hunger. In conclusion, we demonstrate normal metabolic sensing in AgRP neurons drives the preference for calorie consumption, primarily when needed, by engaging dopamine release in the nucleus accumbens., (© 2024 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Objective: The sensory detection of food and food cues suppresses Agouti related peptide (AgRP) neuronal activity prior to consumption with greatest suppression occurring in response to highly caloric food or interoceptive energy need. However, the interoceptive mechanisms priming an appropriate AgRP neural response to external sensory information of food availability remain unexplored. Since hunger increases plasma ghrelin, we hypothesized that ghrelin receptor (GHSR) signalling on AgRP neurons is a key interoceptive mechanism integrating energy need with external sensory cues predicting caloric availability., Methods: We used in vivo photometry to measure the effects of ghrelin administration or fasting on AgRP neural activity with GCaMP6s and dopamine release in the nucleus accumbens with GRAB-DA in mice lacking ghrelin receptors in AgRP neurons., Results: The deletion of GHSR on AgRP neurons prevented ghrelin-induced food intake, motivation and AgRP activity. The presentation of food (peanut butter pellet) or a wooden dowel suppressed AgRP activity in fasted WT but not mice lacking GHSRs in AgRP neurons. Similarly, peanut butter and a wooden dowel increased dopamine release in the nucleus accumbens after ip ghrelin injection in WT but not mice lacking GHSRs in AgRP neurons. No difference in dopamine release was observed in fasted mice. Finally, ip ghrelin administration did not directly increase dopamine neural activity in the ventral tegmental area., Conclusions: Our results suggest that AgRP GHSRs integrate an interoceptive state of energy need with external sensory information to produce an optimal change in AgRP neural activity. Thus, ghrelin signalling on AgRP neurons is more than just a feedback signal to increase AgRP activity during hunger., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Objective: An environmental context, which reliably predicts food availability, can increase the appetitive food drive within the same environment context. However, hunger is required for the development of such a context-induced feeding (CIF) response, suggesting the neural circuits sensitive to hunger link an internal energy state with a particular environment context. Since Agouti related peptide (AgRP) neurons are activated by energy deficit, we hypothesised that AgRP neurons are both necessary and sufficient to drive CIF., Methods: To examine the role of AgRP neurons in the CIF process, we used fibre photometry with GCaMP7f, chemogenetic activation of AgRP neurons, as well as optogenetic control of AgRP neurons to facilitate acute temporal control not permitted with chemogenetics., Results: A CIF response at test was only observed when mice were fasted during context training and AgRP population activity at test showed an attenuated inhibitory response to food, suggesting increased food-seeking and/or decreased satiety signalling drives the increased feeding response at test. Intriguingly, chemogenetic activation of AgRP neurons during context training did not increase CIF, suggesting precise temporal firing properties may be required. Indeed, termination of AgRP neuronal photostimulation during context training (ON-OFF in context), in the presence or absence of food, increased CIF. Moreover, photoinhibition of AgRP neurons during context training in fasted mice was sufficient to drive a subsequent CIF in the absence of food., Conclusions: Our results suggest that AgRP neurons regulate the acquisition of CIF when the acute inhibition of AgRP activity is temporally matched to context exposure. These results establish acute AgRP inhibition as a salient neural event underscoring the effect of hunger on associative learning., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Anorexia nervosa has among the highest mortality rates of any psychiatric disorder and is characterized by cognitive inflexibility that persists after weight recovery and contributes to the chronic nature of the condition. What remains unknown is whether cognitive inflexibility predisposes individuals to anorexia nervosa, a question that is difficult to address in human studies. Our previous work using the most well-established animal model of anorexia nervosa, known as activity-based anorexia (ABA) identified a neurobiological link between cognitive inflexibility and susceptibility to pathological weight loss in female rats. However, testing flexible learning prior to exposure to ABA in the same animals has been thus far impossible due to the length of training required and the necessity of daily handling, which can itself influence the development of ABA. Here, we describe experiments that validate and optimize the first fully-automated and experimenter-free touchscreen cognitive testing system for rats and use this novel system to examine the reciprocal links between reversal learning (an assay of cognitive flexibility) and weight loss in the ABA model. First, we show substantially reduced testing time and increased throughput compared to conventional touchscreen testing methods because animals engage in test sessions at their own direction and can complete multiple sessions per day without experimenter involvement. We also show that, contrary to expectations, cognitive inflexibility measured by this reversal learning task does not predispose rats to pathological weight loss in ABA. Instead, rats that were predisposed to weight loss in ABA were more quickly able to learn this reversal task prior to ABA exposure. Intriguingly, we show reciprocal links between ABA exposure and cognitive flexibility, with ABA-exposed (but weight-recovered) rats performing much worse than ABA naïve rats on the reversal learning task, an impairment that did not occur to the same extent in rats exposed to food restriction conditions alone. On the other hand, animals that had been trained on reversal learning were better able to resist weight loss upon subsequent exposure to the ABA model. We also uncovered some stable behavioral differences between ABA susceptible versus resistant rats during touchscreen test sessions using machine learning tools that highlight possible predictors of anorectic phenotypes. These findings shed new light on the relationship between cognitive inflexibility and pathological weight loss and provide targets for future studies using the ABA model to investigate potential novel pharmacotherapies for anorexia nervosa., Competing Interests: KH, LM, HD, SP, KC, ZA, CF No competing interests declared, (© 2023, Huang, Milton et al.)

Background: A greater understanding of how the brain controls appetite is fundamental to developing new approaches for treating diseases characterized by dysfunctional feeding behavior, such as obesity and anorexia nervosa., Methods: By modeling neural network dynamics related to homeostatic state and body mass index, we identified a novel pathway projecting from the medial prefrontal cortex (mPFC) to the lateral hypothalamus (LH) in humans (n = 53). We then assessed the physiological role and dissected the function of this mPFC-LH circuit in mice., Results: In vivo recordings of population calcium activity revealed that this glutamatergic mPFC-LH pathway is activated in response to acute stressors and inhibited during food consumption, suggesting a role in stress-related control over food intake. Consistent with this role, inhibition of this circuit increased feeding and sucrose seeking during mild stressors, but not under nonstressful conditions. Finally, chemogenetic or optogenetic activation of the mPFC-LH pathway is sufficient to suppress food intake and sucrose seeking in mice., Conclusions: These studies identify a glutamatergic mPFC-LH circuit as a novel stress-sensitive anorexigenic neural pathway involved in the cortical control of food intake., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To compare patient-reported anxiety, depression and quality-of-life (QoL) outcomes, with data registered in patients' primary care electronic health record (EHR)., Design: Cross-sectional study., Setting: Primary care in the UK., Participants: A convenience sample of 608 women registered in the Clinical Practice Research Datalink GOLD primary care database (data from a previous study on 356 breast cancer survivors (8.1 years postdiagnosis) and 252 women with no prior cancer)., Outcome Measures: Patient-reported data on anxiety, depression and QoL, collected through postal questionnaires, and compared with coded information in EHR up to 2 years prior., Results: Abnormal anxiety symptoms were reported by 118 of 599 women who answered the relevant questions (21%); 59/118 (50%) had general practitioner (GP)-recorded anxiolytic/antidepressant use, and 2 (1.6%) had anxiety coded in the EHR. 26/601 women (11%) reported depression symptoms, of whom 17 (65.4%) had GP-recorded antidepressant use and none had depression coded. 65 of 123 women reporting distress on the pain QoL domain (52.8%) had a corresponding record in the EHR <3 months before and 92 (74.8%) <24 months before. No patients reporting fatigue (n=157), sexual health problems (156), social avoidance (82) or cognitive problems (93) had corresponding codes in the EHR. There were no meaningful differences in the concordance results between breast cancer survivors and women with no history of cancer., Conclusion: Many patients reporting mental health and QoL problems had no record of this in coded primary care data. This finding suggests that coded data does not fully reflect the burden of disease. Further research is needed to understand whether or not GPs are aware of patient distress in cases where codes have not been recorded., Competing Interests: Competing interests: KB reports grants from Wellcome Trust, the Royal Society, Medical Research Council and British Heart Foundation, outside the submitted work. RW and HD report that CPRD has financial relationships with its clients, including the London School of Hygiene and Tropical Medicine, in relation to providing access to research data and services outside the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

The ventromedial hypothalamic (VMH) nucleus is a well-established hub for energy and glucose homeostasis. In particular, VMH neurons are thought to be important for initiating the counterregulatory response to hypoglycemia, and ex vivo electrophysiology and immunohistochemistry data indicate a clear role for VMH neurons in sensing glucose concentration. However, the temporal response of VMH neurons to physiologically relevant changes in glucose availability in vivo has been hampered by a lack of available tools for measuring neuronal activity over time. Since the majority of neurons within the VMH are glutamatergic and can be targeted using the vesicular glutamate transporter Vglut2, we expressed cre-dependent GCaMP7s in Vglut2 cre mice and examined the response profile of VMH to intraperitoneal injections of glucose, insulin, and 2-deoxyglucose (2DG). We show that reduced available glucose via insulin-induced hypoglycemia and 2DG-induced glucoprivation, but not hyperglycemia induced by glucose injection, inhibits VMH Vglut2 neuronal population activity in vivo. Surprisingly, this inhibition was maintained for at least 45 minutes despite prolonged hypoglycemia and initiation of a counterregulatory response. Thus, although VMH stimulation, via pharmacological, electrical, or optogenetic approaches, is sufficient to drive a counterregulatory response, our data suggest VMH Vglut2 neurons are not the main drivers required to do so, since VMH Vglut2 neuronal population activity remains suppressed during hypoglycemia and glucoprivation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Agouti-related peptide (AgRP) neurons increase motivation for food, however, whether metabolic sensing of homeostatic state in AgRP neurons potentiates motivation by interacting with dopamine reward systems is unexplored. As a model of impaired metabolic-sensing, we used the AgRP-specific deletion of carnitine acetyltransferase ( Crat ) in mice. We hypothesised that metabolic sensing in AgRP neurons is required to increase motivation for food reward by modulating accumbal or striatal dopamine release. Studies confirmed that Crat deletion in AgRP neurons (KO) impaired ex vivo glucose-sensing, as well as in vivo responses to peripheral glucose injection or repeated palatable food presentation and consumption. Impaired metabolic-sensing in AgPP neurons reduced acute dopamine release (seconds) to palatable food consumption and during operant responding, as assessed by GRAB-DA photometry in the nucleus accumbens, but not the dorsal striatum. Impaired metabolic-sensing in AgRP neurons suppressed radiolabelled 18F-fDOPA accumulation after ~30 min in the dorsal striatum but not the nucleus accumbens. Impaired metabolic sensing in AgRP neurons suppressed motivated operant responding for sucrose rewards during fasting. Thus, metabolic-sensing in AgRP neurons is required for the appropriate temporal integration and transmission of homeostatic hunger-sensing to dopamine signalling in the striatum., Competing Interests: AR, RC, RS, SL, MM, HD, SR, FR, TS, MD, AM, JN, DS, RM, AK, CD, RB, ZA No competing interests declared, (© 2022, Reichenbach et al.)

Purpose: There is limited high-quality evidence on quality of life, anxiety, and depressive symptoms in breast cancer survivors and women with no history of cancer. We aimed to address this by comparing patient-reported outcomes between breast cancer survivors and women with no history of breast cancer., Methods: Breast cancer survivors and women with no prior cancer were selected from the UK Clinical Practice Research Datalink GOLD primary care database, which includes population-based primary care electronic health record data. Breast cancer survivors and controls were frequency matched by age and primary care practice. Outcomes were assessed with validated instruments via postal questionnaire. Linear and logistic regression models were fitted to estimate adjusted associations between breast cancer survivorship and outcomes., Results: A total of 356 breast cancer survivors (8.1 years post diagnosis) and 252 women with no prior cancer participated in the study. Compared with non-cancer controls, breast cancer survivors had poorer QoL in the domains of cognitive problems (adjusted β (aβ) = 1.4, p = 0.01), sexual function (aβ = 1.7, p = 0.02) and fatigue (aβ = 1.3, p = 0.01), but no difference in negative feelings, positive feelings, pain, or social avoidance. Breast cancer survivors had higher odds of borderline-probable anxiety (score ≥ 8) (adjusted OR = 1.47, 95%CI:1.15-1.87), but no differences in depression. Advanced stage at diagnosis and chemotherapy treatment were associated with poorer QoL., Conclusions: Compared with women with no history of cancer, breast cancer survivors report more problems with cognition, sexual function, fatigue, and anxiety, particularly where their cancer was advanced and/or treated with chemotherapy., Implications for Cancer Survivors: Breast cancer survivors with more advanced disease and/or treated with chemotherapy should be closely monitored and, when possible, offered evidence-based intervention for fatigue, cognitive dysfunction, and sexual problems., (© 2020. The Author(s).)

Purpose: The goal of this study was to develop a short-term, practical, yet effective regimen for the perioperative use of recombinant human erythropoietin (r-HuEPO) as an alternative to autologous blood donation and/or homologous transfusion. In addition, changes in iron kinetics during accelerated erythropoiesis were examined., Patients and Methods: A randomized trial was performed on 24 healthy, iron-replete men. Subjects were given r-HuEPO in one of three dosage schedules, receiving a total dose of 1200 U/kg r-HuEPO subcutaneously: Group I--300 U/kg on Days 1, 4, 7, and 10; Group II--400 U/kg on Days 1, 5, and 9; Group III--600 U/kg on Days 1 and 10. All subjects received 300 mg of elemental iron orally each day for 10 days beginning on Day 1. Complete blood counts (CBC), absolute reticulocyte counts, serum ferritin, serum iron, serum total iron-binding capacity (TIBC), and serum transferrin receptor protein concentrations were measured periodically during the 24-day study period., Results: All groups showed a statistically significant increase in hematocrit, hemoglobin, and absolute reticulocyte count. There was no significant difference in response among the three groups with respect to hemoglobin and hematocrit. The mean maximum increases in hematocrit were 5.4 +/- 1.7, 6.0 +/- 2.1, and 7.2 +/- 2.6 in groups I, II, and III, respectively. The increase in hematocrit positively correlated with log baseline ferritin (r = 0.682, p < 0.001). Administration of r-HuEPO was associated with a highly significant (p < or = 0.0005) 74% decrease in serum ferritin, as well as a marked decrease in percent saturation of TIBC from 39% +/- 14% to 14% +/- 4% (p < or = 0.0005). This was despite the fact that subjects lost less than 250 mL of blood as a result of venipunctures during the entire course of the study., Conclusion: Each of these r-HuEPO dose schedules provides an effective, convenient regimen for perisurgical use. However, "normal" iron stores for basal erythropoiesis may not always be sufficient to supply optimal amounts of iron for the accelerated erythropoiesis associated with acute r-HuEPO administration, even with oral iron supplementation. Nonetheless, these findings provide support for further study of the use of r-HuEPO as an alternative to autologous blood donation in the perisurgical setting.