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Dopaminergic neurons in the mouse ventral tegmental area signal the difference between received and expected reward, whereas GABAergic neurons signal expected reward. The brain's response to reward The ventral tegmental area (VTA), a part of the brain involved in reward and addiction, contains both dopaminergic and GABAergic signals, but the role of the subpopulations in reward representation and processing is unclear. Using optogenetics to identify dopaminergic and GABAergic neurons, this study characterizes VTA responses to rewarding and aversive stimuli. The two neuronal types are shown to have distinct responses to reward: dopaminergic neurons signal reward prediction errors, whereas GABAergic neurons signal reward expectation. Dopamine has a central role in motivation and reward. Dopaminergic neurons in the ventral tegmental area (VTA) signal the discrepancy between expected and actual rewards (that is, reward prediction error) 1 , 2 , 3 , but how they compute such signals is unknown. We recorded the activity of VTA neurons while mice associated different odour cues with appetitive and aversive outcomes. We found three types of neuron based on responses to odours and outcomes: approximately half of the neurons (type I, 52%) showed phasic excitation after reward-predicting odours and rewards in a manner consistent with reward prediction error coding; the other half of neurons showed persistent activity during the delay between odour and outcome that was modulated positively (type II, 31%) or negatively (type III, 18%) by the value of outcomes. Whereas the activity of type I neurons was sensitive to actual outcomes (that is, when the reward was delivered as expected compared to when it was unexpectedly omitted), the activity of type II and type III neurons was determined predominantly by reward-predicting odours. We ‘tagged’ dopaminergic and GABAergic neurons with the light-sensitive protein channelrhodopsin-2 and identified them based on their responses to optical stimulation while recording. All identified dopaminergic neurons were of type I and all GABAergic neurons were of type II. These results show that VTA GABAergic neurons signal expected reward, a key variable for dopaminergic neurons to calculate reward prediction error.

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.

Touch-evoked dynamic mechanical pain is one of most bothersome and prevalent symptoms in chronic pain patients. Here the authors have genetically identified a population of spinal excitatory neurons that contribute to this form of pain. These cells process information from low-threshold Aβ mechanoreceptors and are part of a morphine-resistant pathway. Mechanical hypersensitivity is a debilitating symptom for millions of chronic pain patients. It exists in distinct forms, including brush-evoked dynamic and filament-evoked punctate hypersensitivities. We reduced dynamic mechanical hypersensitivity induced by nerve injury or inflammation in mice by ablating a group of adult spinal neurons defined by developmental co-expression of VGLUT3 and Lbx1 (VT3 Lbx1 neurons): the mice lost brush-evoked nocifensive responses and conditional place aversion. Electrophysiological recordings show that VT3 Lbx1 neurons form morphine-resistant polysynaptic pathways relaying inputs from low-threshold Aβ mechanoreceptors to lamina I output neurons. The subset of somatostatin-lineage neurons preserved in VT3 Lbx1 -neuron-ablated mice is largely sufficient to mediate morphine-sensitive and morphine-resistant forms of von Frey filament-evoked punctate mechanical hypersensitivity. Furthermore, acute silencing of VT3 Lbx1 neurons attenuated pre-established dynamic mechanical hypersensitivity induced by nerve injury, suggesting that these neurons may be a cellular target for treating this form of neuropathic pain.

Significance Both in rodents and humans, melanocortin-4 receptors (MC4Rs) suppress appetite and prevent obesity. Unfortunately, the underlying neural mechanisms by which MC4Rs regulate food intake are poorly understood. Unraveling these mechanisms may open up avenues for treating obesity. In the present study we have established that MC4Rs on neurons in the paraventricular nucleus of the hypothalamus are both necessary and sufficient for MC4R control of feeding and that these neurons are glutamatergic and not GABAergic and do not express the neuropeptides oxytocin, corticotropin-releasing hormone, prodynorphin, or vasopressin. In addition, we identify downstream projections from these glutamatergic neurons to the lateral parabrachial nucleus, which could mediate the appetite suppressing effects.

Melanocortin 4 receptors (MC4Rs) in the CNS regulate metabolism. Here the authors examine extra-hypothalamic MC4Rs in the autonomic nervous system and find that they contribute to energy and glucose homeostasis. Whether melanocortin 4 receptors (MC4Rs) in extra-hypothalamic neurons, including cholinergic autonomic pre-ganglionic neurons, are required to control energy and glucose homeostasis is unclear. We found that MC4Rs in sympathetic, but not parasympathetic, pre-ganglionic neurons were required to regulate energy expenditure and body weight, including thermogenic responses to diet and cold exposure and 'beiging' of white adipose tissue. Deletion of Mc4r genes in both sympathetic and parasympathetic cholinergic neurons impaired glucose homeostasis.

Previous work has suggested, but not demonstrated directly, a critical role for both glutamatergic and GABAergic neurons of the pontine tegmentum in the regulation of rapid eye movement (REM) sleep. To determine the in vivo roles of these fast-acting neurotransmitters in putative REM pontine circuits, we injected an adeno-associated viral vector expressing Cre recombinase (AAV-Cre) into mice harboring lox-P modified alleles of either the vesicular glutamate transporter 2 (VGLUT2) or vesicular GABA-glycine transporter (VGAT) genes. Our results show that glutamatergic neurons of the sublaterodorsal nucleus (SLD) and glycinergic/GABAergic interneurons of the spinal ventral horn contribute to REM atonia, whereas a separate population of glutamatergic neurons in the caudal laterodorsal tegmental nucleus (cLDT) and SLD are important for REM sleep generation. Our results further suggest that presynaptic GABA release in the cLDT-SLD, ventrolateral periaqueductal gray matter (vlPAG) and lateral pontine tegmentum (LPT) are not critically involved in REM sleep control. These findings reveal the critical and divergent in vivo role of pontine glutamate and spinal cord GABA/glycine in the regulation of REM sleep and atonia and suggest a possible etiological basis for REM sleep behavior disorder (RBD).

Compulsive behavior is a debilitating clinical feature of many forms of neuropsychiatric disease, including Tourette syndrome, obsessive-compulsive spectrum disorders, eating disorders, and autism. Although several studies link striatal dysfunction to compulsivity, the pathophysiology remains poorly understood. Here, we show that both constitutive and induced genetic deletion of the gene encoding the melanocortin 4 receptor (MC4R), as well as pharmacologic inhibition of MC4R signaling, normalize compulsive grooming and striatal electrophysiologic impairments in synapse-associated protein 90/postsynaptic density protein 95-associated protein 3 (SAPAP3)-null mice, a model of human obsessive-compulsive disorder. Unexpectedly, genetic deletion of SAPAP3 restores normal weight and metabolic features of MC4R-null mice, a model of human obesity. Our findings offer insights into the pathophysiology and treatment of both compulsive behavior and eating disorders.

Resumo: O objetivo deste estudo era a aplicação de inteligencia artificial e dispositivos de monitorização na prevenção de crimes de desordem pública e conduta desordeira. O artigo apresenta algumas questoes urgentes e bases científicas para a aplicação da inteligencia artificial e dispositivos de monitorização pública na prevenção de crimes de desordem pública e conduta desordeira no presente e no futuro próximo. o autor utilizou uma combinação de métodos tradicionais de investigação das ciencias científicas sociais e jurídicas, tais como o método de análise jurídica, avaliação jurídica, comparação jurídica e perito para alcançar o objetivo do estudo. Foram recolhidos dados a partir de documentos oficiáis, livros, relatórios independentes, jornais e análises de partes relacionadas. Os resultados mostram que é necessário promover a investigação e aplicação das realizaçoes científicas e tecnológicas, especialmente a aplicação da inteligencia artificial na construção de um grande sistema de base de dados para a gestäo estatal da prevenção do crime, incluindo a prevenção de crimes de desordem pública e conduta desordenada, contribuindo para o desenvolvimento sócio-económico do país rumo â civilização, modernidade e desenvolvimento sustentável para o futuro.

Novel drug targets for sustained reduction in body mass index (BMI) are needed to curb the epidemic of obesity, which affects 650 million individuals worldwide and is a causal driver of cardiovascular and metabolic disease and mortality. Previous studies reported that the Arg95Ter nonsense variant of GPR151, an orphan G protein-coupled receptor, is associated with reduced BMI and reduced risk of Type 2 Diabetes (T2D). Here, we further investigate GPR151 with the Pakistan Genome Resource (PGR), which is one of the largest exome biobanks of human homozygous loss-of-function carriers (knockouts) in the world. Among PGR participants, we identify eleven GPR151 putative loss-of-function (plof) variants, three of which are present at homozygosity (Arg95Ter, Tyr99Ter, and Phe175LeufsTer7), with a cumulative allele frequency of 2.2%. We confirm these alleles in vitro as loss-of-function. We test if GPR151 plof is associated with BMI, T2D, or other metabolic traits and find that GPR151 deficiency in complete human knockouts is not associated with clinically significant differences in these traits. Relative to Gpr151 +/+ mice, Gpr151 -/- animals exhibit no difference in body weight on normal chow and higher body weight on a high-fat diet. Together, our findings indicate that GPR151 antagonism is not a compelling therapeutic approach to treatment of obesity.