The nucleus accumbens (NAc) and the dynorphinergic system are widely implicated in motivated behaviors. Prior studies have shown that activation of the dynorphin-kappa opioid receptor (KOR) system ...leads to aversive, dysphoria-like behavior. However, the endogenous sources of dynorphin in these circuits remain unknown. We investigated whether dynorphinergic neuronal firing in the NAc is sufficient to induce aversive behaviors. We found that photostimulation of dynorphinergic cells in the ventral NAc shell elicits robust conditioned and real-time aversive behavior via KOR activation, and in contrast, photostimulation of dorsal NAc shell dynorphin cells induced a KOR-mediated place preference and was positively reinforcing. These results show previously unknown discrete subregions of dynorphin-containing cells in the NAc shell that selectively drive opposing behaviors. Understanding the discrete regional specificity by which NAc dynorphinerigic cells regulate preference and aversion provides insight into motivated behaviors that are dysregulated in stress, reward, and psychiatric disease.
•Optogenetic excitation of nucleus accumbens dynorphin cells elicits dynorphin release•Discrete accumbens shell dynorphinergic populations drive either aversion or reward•These two nucleus accumbens subregions can be bi-directionally controlled•Both aversive and rewarding behaviors require kappa opioid receptors
Al-Hasani et al. show that dynorphin is necessary to drive opposing motivational states within subregions of the nucleus accumbens shell. Dynorphinergic neurons in the ventral shell drive aversion whereas in the dorsal shell they drive preference and reward seeking.
DREADDs are chemogenetic tools widely used to remotely control cellular signaling, neuronal activity, and behavior. Here we used a structure-based approach to develop a new Gi-coupled DREADD using ...the kappa-opioid receptor as a template (KORD) that is activated by the pharmacologically inert ligand salvinorin B (SALB). Activation of virally expressed KORD in several neuronal contexts robustly attenuated neuronal activity and modified behaviors. Additionally, co-expression of the KORD and the Gq-coupled M3-DREADD within the same neuronal population facilitated the sequential and bidirectional remote control of behavior. The availability of DREADDs activated by different ligands provides enhanced opportunities for investigating diverse physiological systems using multiplexed chemogenetic actuators.
•Structure-guided approach for κ-opioid receptor (KOR)-DREADD (KORD) design•KORD is selectively activated by salvinorin B, and not by endogenous opioids•KORD robustly silenced multiple neuronal subtypes•Inhibitory KORD combined with excitatory hM3Dq for multiplexed behavioral control
The κ-opioid receptor (KOR) was used as a template to generate a novel inhibitory DREADD (KORD), which is activated by salvinorin B and insensitive to endogenous opioid peptides. Sequential activation of the inhibitory KOR-DREADD and an excitatory M3-DREADD facilitated the bidirectional, multiplexed modulation of behavior.
Agouti-related peptide (AgRP) neurons of the hypothalamus release a fast transmitter (GABA) in addition to neuropeptides (neuropeptide Y NPY and Agouti-related peptide AgRP). This raises questions as ...to their respective functions. The acute activation of AgRP neurons robustly promotes food intake, while central injections of AgRP, NPY, or GABA agonist results in the marked escalation of food consumption with temporal variance. Given the orexigenic capability of all three of these neuroactive substances in conjunction with their coexpression in AgRP neurons, we looked to unravel their relative temporal role in driving food intake. After the acute stimulation of AgRP neurons with DREADD technology, we found that either GABA or NPY is required for the rapid stimulation of feeding, and the neuropeptide AgRP, through action on MC4 receptors, is sufficient to induce feeding over a delayed yet prolonged period. These studies help to elucidate the neurochemical mechanisms of AgRP neurons in controlling temporally distinct phases of eating.
•GABA, NPY, and AgRP via MC4Rs are required for DREADD-stimulation-mediated feeding•Loss of each individual mediator does not impair feeding, suggesting redundancy•GABA or NPY is required for the rapid stimulation of feeding•AgRP via MC4R signaling is sufficient for the delayed chronic feeding response
The melanocortin system provides a conceptual blueprint for the central control of energetic state. Defined by four principal molecular components--two antagonistically acting ligands and two cognate ...receptors--this phylogenetically conserved system serves as a prototype for hierarchical energy balance regulation. Over the last decade the application of conditional genetic techniques has facilitated the neuroanatomical dissection of the melanocortinergic network and identified the specific neural substrates and circuits that underscore the regulation of feeding behavior, energy expenditure, glucose homeostasis and autonomic outflow. In this regard, the melanocortin-4 receptor is a critical coordinator of mammalian energy homeostasis and body weight. Drawing on recent advances in neuroscience and genetic technologies, we consider the structure and function of the melanocortin-4 receptor circuitry and its role in energy homeostasis.
Behavioral choice is ubiquitous in the animal kingdom and is central to goal-oriented behavior. Hypothalamic Agouti-related peptide (AgRP) neurons are critical regulators of appetite. Hungry animals, ...bombarded by multiple sensory stimuli, are known to modify their behavior during times of caloric need, rapidly adapting to a consistently changing environment. Utilizing ARCAgRP neurons as an entry point, we analyzed the hierarchical position of hunger related to rival drive states. Employing a battery of behavioral assays, we found that hunger significantly increases its capacity to suppress competing motivational systems, such as thirst, anxiety-related behavior, innate fear, and social interactions, often only when food is accessible. Furthermore, real-time monitoring of ARCAgRP activity revealed time-locked responses to conspecific investigation in addition to food presentation, further establishing that, even at the level of ARCAgRP neurons, choices are remarkably flexible computations, integrating internal state, external factors, and anticipated yield.
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•ARCAgRP activation directs biased caloric consumption•ARCAgRP stimulation suppresses anxiety-like behavior depending on food location•ARCAgRP activation competes with innate motivational drives•ARCAgRP neural activity responds to food and conspecifics
Burnett et al. investigate the competitive influence of physiological and simulated hunger state on orthogonal motivated behaviors, revealing that a subset of hypothalamic neurons respond to initial investigative contact with a conspecific in addition to food cues.
Satiety-promoting neurons of the hindbrain have long been known for their role in meal termination. An innovative new study now reveals how different hindbrain cell types mediate appetite on distinct ...timescales.
Satiety-promoting neurons of the hindbrain have long been known for their role in meal termination. An innovative new study now reveals how different hindbrain cell types mediate appetite on distinct timescales.
Neural regulation of energy expenditure is incompletely understood. By genetically disrupting GABAergic transmission in a cell-specific fashion, and by combining this with selective pharmacogenetic ...activation and optogenetic mapping techniques, we have uncovered an arcuate-based circuit that selectively drives energy expenditure. Specifically, mice lacking synaptic GABA release from RIP-Cre neurons have reduced energy expenditure, become obese and are extremely sensitive to high-fat diet-induced obesity, the latter due to defective diet-induced thermogenesis. Leptin’s ability to stimulate thermogenesis, but not to reduce feeding, is markedly attenuated. Acute, selective activation of arcuate GABAergic RIP-Cre neurons, which monosynaptically innervate PVH neurons projecting to the NTS, rapidly stimulates brown fat and increases energy expenditure but does not affect feeding. Importantly, this response is dependent upon GABA release from RIP-Cre neurons. Thus, GABAergic RIP-Cre neurons in the arcuate selectively drive energy expenditure, contribute to leptin’s stimulatory effect on thermogenesis, and protect against diet-induced obesity.
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▸ Synaptic release of GABA but not glutamate from RIP-Cre neurons prevents obesity ▸ RIP-Cre neurons in the arcuate stimulate energy expenditure by releasing GABA ▸ RIP-Cre neurons mediate leptin action on energy expenditure but not on feeding ▸ Arcuate RIP-Cre neurons directly inhibit NTS-projecting PVH neurons
A neuronal circuit involving GABAergic neurons in the arcuate nucleus of the hypothalamus stimulates energy expenditure by regulating brown fat activity, preventing obesity without affecting feeding.
Labile memory is thought to be held in the brain as persistent neural network activity 1–4. However, it is not known how biologically relevant memory circuits are organized and operate. Labile and ...persistent appetitive memory in Drosophila requires output after training from the α′β′ subset of mushroom body (MB) neurons and from a pair of modulatory dorsal paired medial (DPM) neurons 5–9. DPM neurons innervate the entire MB lobe region and appear to be pre- and postsynaptic to the MB 7, 8, consistent with a recurrent network model. Here we identify a role after training for synaptic output from the GABAergic anterior paired lateral (APL) neurons 10, 11. Blocking synaptic output from APL neurons after training disrupts labile memory but does not affect long-term memory. APL neurons contact DPM neurons most densely in the α′β′ lobes, although their processes are intertwined and contact throughout all of the lobes. Furthermore, APL contacts MB neurons in the α′ lobe but makes little direct contact with those in the distal α lobe. We propose that APL neurons provide widespread inhibition to stabilize and maintain synaptic specificity of a labile memory trace in a recurrent DPM and MB α′β′ neuron circuit.
► Output from inhibitory APL neurons is required after training for labile memory ► APL neuron output is dispensable for memory consolidation ► APL neurons contact DPM neurons and make zonal contact with MB neurons ► We propose that these inhibitory neurons maintain network specificity of labile memory
Asprosin is a recently discovered fasting-induced hormone that promotes hepatic glucose production. Here we demonstrate that asprosin in the circulation crosses the blood-brain barrier and directly ...activates orexigenic AgRP
neurons via a cAMP-dependent pathway. This signaling results in inhibition of downstream anorexigenic proopiomelanocortin (POMC)-positive neurons in a GABA-dependent manner, which then leads to appetite stimulation and a drive to accumulate adiposity and body weight. In humans, a genetic deficiency in asprosin causes a syndrome characterized by low appetite and extreme leanness; this is phenocopied by mice carrying similar mutations and can be fully rescued by asprosin. Furthermore, we found that obese humans and mice had pathologically elevated concentrations of circulating asprosin, and neutralization of asprosin in the blood with a monoclonal antibody reduced appetite and body weight in obese mice, in addition to improving their glycemic profile. Thus, in addition to performing a glucogenic function, asprosin is a centrally acting orexigenic hormone that is a potential therapeutic target in the treatment of both obesity and diabetes.
Understanding the neural framework behind appetite control is fundamental to developing effective therapies to combat the obesity epidemic. The paraventricular hypothalamus (PVH) is critical for ...appetite regulation, yet, the real-time, physiological response properties of PVH neurons to nutrients are unknown. Using a combination of fiber photometry, electrophysiology, immunohistochemistry, and neural manipulation strategies, we determined the population dynamics of four molecularly delineated PVH subsets implicated in feeding behavior: glucagon-like peptide 1 receptor (PVHGlp1r), melanocortin-4 receptor (PVHMc4r), oxytocin (PVHOxt), and corticotropin-releasing hormone (PVHCrh). We identified both calorie- and state-dependent sustained activity increases and decreases in PVHGlp1r and PVHCrh populations, respectively, while observing transient bulk changes of PVHMc4r, but no response in PVHOxt, neurons to food. Furthermore, we highlight the role of PVHGlp1r neurons in orchestrating acute feeding behavior, independent of the anti-obesity drug liraglutide, and demonstrate the indispensability of PVHGlp1r and PVHMc4r, but not PVHOxt or PVHCrh neurons, in body weight maintenance.
•Caloric restoration induces differential activity in the paraventricular hypothalamus•Sensory detection of food rapidly regulates PVHGlp1r and PVHCrh subpopulations•Stimulation of PVHGlp1r neurons bidirectionally orchestrates feeding behavior•Chronic perturbation of PVHGlp1r or PVHMc4r populations induces obesity
The hypothalamic paraventricular nucleus has long been implicated in appetite regulation. Li et al. employ a multidisciplinary approach to investigate the physiological response properties of genetically labeled neural populations in this structure to food. They highlight neurons marked by glucagon-like peptide 1 receptor that respond acutely to calories and regulate energy homeostasis.
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