Noradrenaline is released throughout the forebrain from locus coeruleus (LC) projections in close temporal proximity to emotional and goal-directed events. To examine interactive influences of these ...processes on LC neuronal activity, we used a task where Pavlovian and operant processes vary and can be easily identified. We recorded 69 single LC neurons from two monkeys performing a task where cues indicate the progression through schedules of one, two, or three operant trials. Pavlovian responses and phasic LC activations occur following the appearance of conditioned visual cues (54/69 neurons), especially those at the beginning of new schedules, whether the current trial will be rewarded (single trial schedule) or not (2 or 3 trial schedules), and after visual imperative signals eliciting the operant response (64/69 neurons), whether the current trial will be rewarded or not. The modulation of LC responses seems to be relatively independent of attention or motivation, because the responses do not covary with operant performance in the task. The magnitude of LC responses across the schedules varied in close relation to the intensity of Pavlovian behavior but these responses were also modulated by operant processes. Our conclusion is that LC activation occurs when task-relevant stimuli evoke a conditioned instinctive (Pavlovian) response, with the strength of the activation also being modulated by goal-directed processes. Thus locus coeruleus neurons broadcast information about stimulus-elicited primitive and goal-directed behaviors to forebrain structures important for executive functions and emotions.
The arcuate nucleus of the hypothalamus (ARH) is a critical component of the forebrain pathways that regulate energy homeostasis, and it plays a particularly important role in relaying leptin signal ...to other part of the hypothalamus. However, until recently, little was known about the development of these critical pathways. Recent work investigating the development of leptin-sensitive hypothalamic pathways suggests possible developmental mechanisms that may contribute to obesity later in life. Anatomic findings indicate that ARH circuits are structurally and functionally immature until the third week of postnatal life in mice. Recent data also suggest that leptin is required for normal development of ARH pathways and that this developmental activity of leptin is restricted to a neonatal window of maximum sensitivity that corresponds to a period of elevated leptin secretion. Thus, leptin may function to organize formation of hypothalamic circuitry in much the same way that sex steroids act on sexually dimorphic circuits. Perturbations in perinatal nutrition that alter leptin levels may, therefore, have enduring consequences for the formation and function of circuits regulating food intake and body weight.
In rats selectively bred to develop diet-induced obesity (DIO) 3 wk of postweaning exercise reduces weight and adipose regain for 10 wk after exercise cessation, despite intake of 31% fat high-energy ...(HE) diet. To test the hypothesis that this effect is due to increased central leptin sensitivity, 4-wk-old DIO rats were fed the HE diet and left sedentary (Sed), exercised for 3 wk, and then remained sedentary for 10 additional weeks (Ex/Sed) or continued exercise for a full 13 wk (Ex). After 3 wk, leptin (5 mg/kg ip) induced a 36% decrease in 24-h food intake in Ex rats, while Sed rats had no change in 24-h intake. Ex rats also had 23% more leptin-induced phospho-STAT3 (pSTAT3)-expressing neurons in the arcuate nucleus (ARC) and 95% and 68% higher (125)I-labeled leptin receptor binding in the ventromedial and dorsomedial nuclei than did Sed rats, respectively. At 7 wk after onset, leptin decreased 24-h intake by 20% in Ex and 24% in Ex/Sed rats without altering Sed intake. After a total of 13 wk, compared with Sed rats, Ex and Ex/Sed rats had 58% and 38% less fat, respectively, but leptin failed to decrease food intake in any group. Nevertheless, Ex, but not Ex/Sed rats, still had 32% more ARC leptin-induced pSTAT3-expressing neurons than Sed rats. These data suggest that brief postweaning exercise in DIO rats that are inherently leptin resistant causes a sustained resistance to obesity on HE diet, which is, in part, due to increased central leptin sensitivity.
Selectively bred diet-induced obese (DIO) rats become obese on a high-fat diet and are leptin resistant before becoming obese. Compared with diet-resistant (DR) neonates, DIO neonates have impaired ...leptin-dependent arcuate (ARC) neuropeptide Y/agouti-related peptide (NPY/AgRP) and α-melanocyte-stimulating hormone (α-MSH; from proopiomelanocortin (POMC) neurons) axon outgrowth to the paraventricular nucleus (PVN). Using phosphorylation of STAT3 (pSTAT3) as a surrogate, we show that reduced DIO ARC leptin signaling develops by postnatal day 7 (P7) and is reduced within POMC but not NPY/AgRP neurons. Since amylin increases leptin signaling in adult rats, we treated DIO neonates with amylin during postnatal hypothalamic development and assessed leptin signaling, leptin-dependent ARC-PVN pathway development, and metabolic changes. DIO neonates treated with amylin from P0-6 and from P0-16 increased ARC leptin signaling and both AgRP and α-MSH ARC-PVN pathway development, but increased only POMC neuron number. Despite ARC-PVN pathway correction, P0-16 amylin-induced reductions in body weight did not persist beyond treatment cessation. Since amylin enhances adult DIO ARC signaling via an IL-6-dependent mechanism, we assessed ARC-PVN pathway competency in IL-6 knockout mice and found that the AgRP, but not the α-MSH, ARC-PVN pathway was reduced. These results suggest that both leptin and amylin are important neurotrophic factors for the postnatal development of the ARC-PVN pathway. Amylin might act as a direct neurotrophic factor in DIO rats to enhance both the number of POMC neurons and their α-MSH ARC-PVN pathway development. This suggests important and selective roles for amylin during ARC hypothalamic development.
The area postrema (AP) and the nucleus of the solitary tract (NTS) are important hindbrain centers involved in the control of energy homeostasis. The AP mediates the anorectic action and the ...inhibitory effect on gastric emptying induced by the pancreatic hormone amylin. Amylin's target cells in the AP project to the NTS, an integrative relay center for enteroceptive signals. Perinatal hormonal and metabolic factors influence brain development. A postnatal surge of the adipocyte-derived hormone leptin represents a developmental signal for the maturation of projections between hypothalamic nuclei controlling energy balance. Amylin appears to promote neurogenesis in the AP in adult rats. Here, we examined whether amylin and leptin are required for the development of projections from the AP to the NTS in postnatal and adult mice by conducting neuronal tracing studies with DiI in amylin- (IAPP
) and leptin-deficient (ob/ob) mice. Compared to wild-type littermates, postnatal (P10) and adult (P60) IAPP
mice showed a significantly reduced density of AP-NTS projections. While AP projections were also reduced in postnatal (P14) ob/ob mice, AP-NTS fiber density did not differ between adult ob/ob and wild-type animals. Our findings suggest a crucial function of amylin for the maturation of neuronal brainstem pathways controlling energy balance and gastrointestinal function. The impaired postnatal development of neuronal AP-NTS projections in ob/ob mice appears to be compensated in this experimental model during later brain maturation. It remains to be elucidated whether an amylin- and leptin-dependent modulation in neuronal development translates into altered AP/NTS-mediated functions.
Motivational deficits are pervasive in psychiatric and neurological disorders but their assessment and treatment remain inadequate. Pessiglione et al. present a computational approach that consists ...of phenotyping patients' behaviour in tests of motivation. Computational phenotypes may provide mechanistic insights at both cognitive and neural levels, and guide therapeutic intervention.
Abstract
Motivation deficits, such as apathy, are pervasive in both neurological and psychiatric diseases. Even when they are not the core symptom, they reduce quality of life, compromise functional outcome and increase the burden for caregivers. They are currently assessed with clinical scales that do not give any mechanistic insight susceptible to guide therapeutic intervention. Here, we present another approach that consists of phenotyping the behaviour of patients in motivation tests, using computational models. These formal models impose a precise and operational definition of motivation that is embedded in decision theory. Motivation can be defined as the function that orients and activates the behaviour according to two attributes: a content (the goal) and a quantity (the goal value). Decision theory offers a way to quantify motivation, as the cost that patients would accept to endure in order to get the benefit of achieving their goal. We then review basic and clinical studies that have investigated the trade-off between the expected cost entailed by potential actions and the expected benefit associated with potential rewards. These studies have shown that the trade-off between effort and reward involves specific cortical, subcortical and neuromodulatory systems, such that it may be shifted in particular clinical conditions, and reinstated by appropriate treatments. Finally, we emphasize the promises of computational phenotyping for clinical purposes. Ideally, there would be a one-to-one mapping between specific neural components and distinct computational variables and processes of the decision model. Thus, fitting computational models to patients' behaviour would allow inferring of the dysfunctional mechanism in both cognitive terms (e.g. hyposensitivity to reward) and neural terms (e.g. lack of dopamine). This computational approach may therefore not only give insight into the motivation deficit but also help personalize treatment.
The ventromedial nucleus of the hypothalamus (VMH) is a critical component of the forebrain pathways that regulate energy homeostasis. It also plays an important role in the metabolic response to ...fasting. However, the mechanisms contributing to these physiological processes remain elusive. Autophagy is an evolutionarily conserved mechanism that maintains cellular homeostasis by turning over cellular components and providing nutrients to the cells during starvation. Here, we investigated the importance of the autophagy-related gene Atg7 in Sf1-expressing neurons of the VMH in control and fasted conditions.
We generated Sf1-Cre; Atg7loxP/loxP mice and examined their metabolic and cellular response to fasting.
Fasting induces autophagy in the VMH, and mice lacking Atg7 in Sf1-expressing neurons display altered leptin sensitivity and impaired energy expenditure regulation in response to fasting. Moreover, loss of Atg7 in Sf1 neurons causes alterations in the central response to fasting. Furthermore, alterations in mitochondria morphology and activity are observed in mutant mice.
Together, these data show that autophagy is nutritionally regulated in VMH neurons and that VMH autophagy participates in the control of energy homeostasis during fasting.
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•Fasting induces autophagy in the ventromedial nucleus of the hypothalamus.•Genetic loss of Atg7 in the VMH impairs metabolic response to fasting.•Mice lacking Atg7 in the VMH display impaired mitochondria morphology and activity.
Litter size is a biological variable that strongly influences adult physiology in rodents. Despite evidence from previous decades and recent studies highlighting its major impact on metabolism, ...information about litter size is currently underreported in the scientific literature. Here, we urge that this important biological variable should be explicitly stated in research articles.
Below, we briefly describe the scientific evidence supporting the impact of litter size on adult physiology and outline a series of recommendations and guidelines to be implemented by investigators, funding agencies, editors in scientific journals, and animal suppliers to fill this important gap.
•In rodents, litter size is a variable that strongly influences adult physiology.•Information about litter size is underreported in the scientific literature.•Major efforts must be made to explicitly report this information to the scientific community.•We provide suggestions and tools for reporting litter size in scientific articles.
The melanocortin system is a critical component of the forebrain and hindbrain regulatory systems involved in energy balance. This system is composed of pro-opiomelanocortin (POMC) neurons that act, ...in part, through the melanocortin-4 receptor (MC4R). Although the importance of the melanocortin system in controlling feeding has been established for two decades, the understanding of the developmental substrates underlying POMC and MC4R neuron development and function has just begun to emerge. The formation of the melanocortin system involves several discrete developmental steps that include the birth and fate specification of POMC- and MC4R-containing neurons and the extension and guidance of POMC axons to their MC4R-expressing target nuclei. Each of these developmental processes appears to require specific sets of genes and developmental cues that include perinatal hormones. Recent evidence has also highlighted the importance of perinatal nutrition in controlling the ultimate architecture of the melanocortin system.
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