Altered motivated behaviour is a cardinal feature of several neuropsychiatric conditions including mood disorders. One well-characterized antecedent to the development of mood disorders is exposure to early life stress (ELS). A key brain substrate controlling motivated behaviour is the lateral hypothalamus (LH). Here, we examined the effect of ELS on LH activation and the motivation to self-administer sucrose. We tested whether chemogenetic activation of LH circuits could modify sucrose responding in ELS rats and examined the impact on LH cell populations. Male rat pups were maternally separated for 0 or 3 h on postnatal days 2-14. During adolescence, rats received bilateral injections of hM3D(Gq), the excitatory designer receptor exclusively activated by designer drugs, into LH. In adulthood, rats were trained to self-administer sucrose and tested under a progressive ratio schedule to determine their motivation for reward following injection with either vehicle or 5 mg/kg clozapine-N-oxide. Brains were processed for Fos-protein immunohistochemistry. ELS significantly suppressed lever responding for sucrose, indicating a long-lasting impact of ELS on motivation circuits. hM3D(Gq) activation of LH increased responding, normalizing deficits in ELS rats, and increased Fos-positive orexin and MCH cell numbers within LH. Our findings indicate that despite being susceptible to environmental stressors, LH circuits retain the capacity to overcome ELS-induced deficits in motivated behaviour.

Animals must find and consume food to meet intake demands and maintain energy balance. The regulation of food intake is dependent on many factors, including environment, energy stores, peripheral hormone secretion, and their feedback to homeostatic and hedonic brain circuits. Importantly, disruption to the balance of food intake and energy expenditure leads to weight and metabolism-related pathologies, including obesity and type II diabetes. 1 As a result of the worldwide obesity epidemic of recent decades, an improved understanding of the regulation of food intake via integration of peripheral signals and central nervous system (CNS) circuits may lead to novel treatment approaches for obesity.Insulin, a pancreatic hormone released in response to elevated blood glucose, was first discovered by Banting and Best in the pancreatic extracts of dogs 100 years ago. 2 Insulin is primarily known as a peripheral regulator of blood glucose levels and, hence, has been used as a treatment for both type I and type II diabetes mellitus, diseases affecting over 450 million people globally. 3 Following an increase in blood glucose levels (ie, when a meal is consumed), the release of insulin is stimulated, which circulates in the bloodstream and binds to insulin receptors on cell membranes in tissues such as the liver, muscle and adipose tissue. This binding of insulin at its receptor results in phosphorylation of insulin receptor substrate proteins 1 and 2 (IRS1 and IRS2), ultimately activating the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway. 4 PI3K activation

Obesogenic diets can produce hippocampal insulin resistance and impairments to hippocampal-dependent cognition. This study investigated the effect of disrupted insulin signaling in Neuropeptide Y (NPY) neurons on diet-induced deficits in hippocampal-dependent memory. Wild-type mice and mice that had a targeted knockout of insulin receptors on NPY cells (IRlox/lox;NPYCre/+) were given ad libitum access to a high-fat diet (high fat; HF), 10% sucrose solution (high sugar; HS), both high-fat diet and sucrose solution (high fat, high sugar; HFHS), or a normal fat control chow for 12 weeks. Mice were tested in the Morris Water Maze (MWM), a hippocampal-dependent spatial memory task. Glucose homeostasis was assessed via a glucose tolerance test. Independent of genotype, consumption of HF, but not HS, diet increased energy intake, body weight, and plasma leptin, and impaired glucose tolerance. Disrupted insulin signaling in NPY cells and dietary interventions did not significantly affect the ability of mice to learn the location of the platform in the MWM. However, for IRlox/lox control mice, consumption of HF, but not HS, diet resulted in reduced time spent in the target quadrant during the probe trial, suggesting a hippocampal-dependent memory deficit. IRlox/lox;NPYCre/+ mice had poor performance in the probe trial regardless of diet, suggesting a floor effect. This study did not find adverse effects of chronic sucrose intake on metabolic outcomes or hippocampal-dependent memory. These data also suggest that the effects of HF diet on hippocampal-dependent memory may be dependent on insulin signaling in hippocampal NPY cells.

Feeding is at once both a basic biological need and a function set in a complex system of competing motivational drivers. Orexin/hypocretin neurons are located exclusively within the lateral hypothalamus (LH) and are commonly implicated in feeding, arousal, and motivated behavior, although largely based on studies employing long-term systemic manipulations. Here we show how orexin neurons in freely behaving mice respond in real time to food presentations, and how this response is modulated by differences in metabolic state and salience. Orexin neurons increased activity during approach to food, and this activity declined to baseline at the start of consummatory behavior. Furthermore, the activity of orexin neurons on approach was enhanced by manipulations of metabolic state, and increased food salience. We investigated the nucleus accumbens shell (NAcSh) as a candidate afferent region to inhibit LH orexin neurons following approach, and using projection and cell type-specific electrophysiology, demonstrated that the NAcSh forms both direct and indirect inhibitory projections to LH orexin cells. Together these findings reveal that the activity of orexin neurons is associated with food approach rather than consumption, is modulated by motivationally relevant factors, and that the NAcSh-LH pathway is capable of suppressing orexin cell recruitment.Keywords orexin, hypocretin, lateral hypothalamus, nucleus accumbens, feeding, approach NAcSh projections to the LH control food consummatory and approach behavioursWe posited that the NAcSh could be an afferent structure that modulates LH orexin cell activity with respect to food approach and consumption. In support, activation of terminals in the LH that originate from the NAcSh inhibited food and alcohol seeking (Gibson et al., 2018;O'Connor et al., 2015). To confirm that activation of NAcSh terminals in the LH would suppress food consumption in the orexin-Cre mice and our behavioral model we injected AAV-ChR2-YFP or AAV-YFP into the NAcSh, and implanted fiber optic cannulae above the LH (Fig. 2A). The AAV-Chrimson-tdTomato construct was also used instead of ChR2 in some animals, and results were pooled (see Fig. 2). Optogenetic stimulation produced a significant disruption of feeding, measured as a reduced latency to terminate feeding (Fig. 2B). ChR2-YFP and Chrimson mice also displayed a significant increase in locomotor activity ( Fig. 2C). Together these data confirm that optogenetic activation of NAcSh LH terminals can disrupt consummatory actions, like previous reports (Gibson et al., 2018;O'Connor et al., 2015). ChR2-assisted circuit mapping of NAcSh inputs to LH orexin neuronsActivation of orexin neurons was highest during food approach, and optogenetic stimulation of NAcSh terminals in the LH disrupted consummatory actions. Therefore, we asked whether NAcSh terminals might influence LH orexin cells. To address this question, we prepared Vgat-Cre mice with NAcSh-directed injections of AAV5-DIO-ChR2-YFP, and AAV8-h-orexin-tdTomato into the LH to visualize orexin ...

Insulin is known to act in the central nervous system to regulate several physiological and behavioural outcomes, including energy balance, glucose homeostasis and cognitive functioning. However, the neuronal populations through which insulin enhances cognitive performance remain unidentified. Insulin receptors are found in neuropeptide-Y (NPY) expressing neurons, which are abundant in the hypothalamus and hippocampus; regions involved in feeding behaviour and spatial memory, respectively. Here we show that mice with a tissue specific knockout of insulin receptors in NPY expressing neurons (IR lox/lox ; NPY Cre/+ ) display an impaired performance in the probe trial of the Morris Water Maze compared with control mice at both the 6 and the 12, but not at the 24 months time point, consistent with a crucial role of insulin and NPY in cognitive functioning. By 24 months of age all groups demonstrated similar reductions in spatial memory performance. Together, these data suggest that the mechanisms through which insulin in luences cognitive functioning are, at least in part, via insulin receptor signaling in NPY expressing neurons. These results also highlight that cognitive impairments observed in aging may be due to impaired insulin signaling.

A case is presented of a young boy in whom features of Trevor's dysplasia epiphysealis hemimelica and Ollier's enchondromatosis coexisted in a single extremity, the right upper. As Trevor disease consists of osteochondromas of epiphyses and their equivalents, such as carpal and tarsal bones, it is of interest that exostosis-like centers of the neck of radius and perhaps the proximal third metacarpal are present as well. Advanced maturation of selected centers was most marked at the right scaphoid. The child shows alignment abnormalities as a consequence of the varied lesions, including a varus of the right wrist. The coexistence of these varied osteochondromatous abnormalities in one extremity suggests a relationship in their etiologies.

Obesity is a growing health problem worldwide. The renin-angiotensin system (RAS) is present in adipose tissue, and evidence suggests that it is involved in both diet-induced obesity and the inflammation associated with obesity. The present experiments determined the effect of (1) different angiotensin-converting enzyme (ACE) inhibitors (captopril, perindopril, enalapril) and angiotensin receptor blockers (ARBs: telmisartan, losartan) on adiposity of mice fed a high-fat diet for 28 days (2); acute treatment with the ACE-inhibitor captopril on gene expression of inflammatory markers in mice fed a high-fat diet (HFD); and (3) short-term (2 days) and chronic (28 days) treatment of ACE-inhibition on energy expenditure (EE) and energy balance in mice fed HFD ad libitum (AL), as well as receiving HFD limited to the amount of calories eaten by controls (pair-fed (PF) group). Body weight, food intake, adiposity and plasma leptin were lower in ACE inhibitor or ARB-treated groups over 28 days compared with HFD untreated mice. Short-term treatment with captopril led to increased EE relative to the level in the PF group. After 28 days, EE was lower in both captopril-treated and PF mice compared with AL, but the effect was greater in the captopril-treated group. Adiponectin was elevated in captopril-treated mice, but not in PF mice, after both 2 and 28 days. Additionally, acute RAS blockade in HFD-fed mice reduced mRNA expression for MCP-1, IL-6, TLR4, and leptin in adipose tissue relative to values in untreated groups. These data demonstrate that ACE inhibition and angiotensin receptor blockade reduce food intake to produce weight loss and suggest that the anti-inflammatory effects of ACE inhibition may be independent of weight loss.

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