Hypothalamic Agrp Neurons Drive Stereotypic Behaviors beyond Feeding

Dietrich, Marcelo O.; Zimmer, Marcelo R.; Bober, Jeremy; Horváth, Tamas L.

doi:10.1016/j.cell.2015.02.024

Cited by 231 publications

(170 citation statements)

References 63 publications

(62 reference statements)

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“…Remarkably, initiating an identical AgRP photostimulation protocol in the home cage, prior to entering the shock-containing arena, drove fed mice to subsequently engage in this sensory discrimination task. This observation expands the set of complex motivated behaviors orchestrated by this remarkably small neuronal population [6–7, 14]. Thus, our findings provide a useful starting point for the investigation of neural circuits downstream of AgRP neurons, which are likely regulated by competing drives, including food seeking and threat avoidance.…”

Section: Discussionmentioning

confidence: 55%

Preemptive Stimulation of AgRP Neurons in Fed Mice Enables Conditioned Food Seeking under Threat

et al. 2016

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Summary The decision to engage in food-seeking behavior depends not only on homeostatic signals related to energy balance [1] but also on the presence of competing motivational drives [2] and learned cues signaling food availability [3]. Agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus (ARC) are critical for homeostatic feeding behavior. Selective ablation or silencing of AgRP neurons causes anorexia [4,6] while selective stimulation in fed mice promotes feeding and learned instrumental actions to obtain food rewards [5–8]. However, it remains unknown whether AgRP neuron stimulation is sufficient to drive food-seeking behavior in the continued presence of a competing motivational drive, such as threat avoidance, or whether it can drive discrimination between learned sensory cues associated with food rewards and other outcomes. Here, we trained mice to perform a sensory discrimination task involving appetitive and aversive visual cues. Food-restricted mice exhibited selective operant responding to food-predicting cues but largely failed to avoid cued shocks by moving onto a safety platform. The opposite was true following re-feeding. Strikingly, AgRP neuron photostimulation did not restore operant responding in fed mice when initiated within the threat-containing arena, but did when initiated in the home cage, prior to arena entry. These data suggest that the choice to pursue certain behaviors and not others (e.g. food seeking vs. shock avoidance) can depend on the temporal primacy of one motivational drive relative to the onset of a competing drive.

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Section: Discussionmentioning

confidence: 55%

Preemptive Stimulation of AgRP Neurons in Fed Mice Enables Conditioned Food Seeking under Threat

et al. 2016

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“…By combining ARC AgRP targeted DREADDs with existing KO mouse models, follow-up studies revealed that NPY or GABA was necessary for the acute effects on ARC AgRP neuron activation, while AgRP was sufficient for long-term effects (Krashes et al 2013). More recent experiments have used hCh2R and DREADDs to further define how ARC AgRP neurons encode a negative balance signal for energy depletion (Betley et al 2015) and how they evoke typified energy seeking behaviors even in the absence of food (Dietrich et al 2015). Together, these studies establish a critical role of AgRP neurons in the regulation of feeding behavior and serve as a model by which to study the role of other genetically defined populations.…”

Section: Analysis Of α-Msh Action In the Cns Using Optogenetics And Cmentioning

confidence: 99%

60 YEARS OF POMC: Regulation of feeding and energy homeostasis by α-MSH

Anderson

Çakır

Carrington

et al. 2016

Journal of Molecular Endocrinology

130

117

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The melanocortin peptides derived from pro-opiomelanocortin (POMC) were originally understood in terms of the biological actions of α-melanocyte-stimulating hormone (α-MSH) on pigmentation and adrenocorticotrophic hormone on adrenocortical glucocorticoid production. However, the discovery of POMC mRNA and melanocortin peptides in the CNS generated activities directed at understanding the direct biological actions of melanocortins in the brain. Ultimately, discovery of unique melanocortin receptors expressed in the CNS, the melanocortin-3 (MC3R) and melanocortin-4 (MC4R) receptors, led to the development of pharmacological tools and genetic models leading to the demonstration that the central melanocortin system plays a critical role in the regulation of energy homeostasis. Indeed, mutations in MC4R are now known to be the most common cause of early onset syndromic obesity, accounting for 2–5% of all cases. This review discusses the history of these discoveries, as well as the latest work attempting to understand the molecular and cellular basis of regulation of feeding and energy homeostasis by the predominant melanocortin peptide in the CNS, α-MSH.

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“…Dietrich et al [214] recently used a chemogenetic approach to demonstrate that activation of AgRP neurons in the absence of food triggers foraging and repetitive behaviors, which are reverted by food consumption. These stereotypic behaviors are coupled with an increased willingness to explore normally fear- or anxiety-provoking environments.…”

Section: Role In Energy Expenditurementioning

confidence: 99%

“…These stereotypic behaviors are coupled with an increased willingness to explore normally fear- or anxiety-provoking environments. These effects are most likely not due to altered melanocortin signaling, since NPY5 receptor signaling is necessary to mediate the repetitive behaviors after AgRP neuron activation [214]. As previously described, inhibiting AgRP activity provides a way to rapidly halt the energy-intensive activity of foraging when food is found [73] .…”

Section: Role In Energy Expenditurementioning

confidence: 99%

The Role of the Melanocortin System in Metabolic Disease: New Developments and Advances

Hill

Faulkner²

2016

Neuroendocrinology

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Obesity is increasing in prevalence across all sectors of society, and with it a constellation of associated ailments including hypertension, type 2 diabetes, and eating disorders. The melanocortin system is a critical neural system underlying the control of body weight and other functions. Deficits in the melanocortin system may promote or exacerbate the comorbidities of obesity. This system has therefore generated great interest as a potential target for treatment of obesity. However, drugs targeting melanocortin receptors are plagued by problematic side effects, including undesirable increases in sympathetic nervous system activity, heart rate, and blood pressure. Circumnavigating this roadblock will require a clearer picture of the precise neural circuits that mediate the functions of melanocortins. Recent, novel experimental approaches have significantly advanced our understanding of these pathways. We here review the latest advances in our understanding of the role of melanocortins in food intake, reward pathways, blood pressure, glucose control, and energy expenditure. The evidence suggests that downstream melanocortin-responsive circuits responsible for different physiological actions do diverge. Ultimately, a more complete understanding of melanocortin pathways and their myriad roles should allow treatments tailored to the mix of metabolic disorders in the individual patient.

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Hypothalamic Agrp Neurons Drive Stereotypic Behaviors beyond Feeding

Cited by 231 publications

References 63 publications

Preemptive Stimulation of AgRP Neurons in Fed Mice Enables Conditioned Food Seeking under Threat

Preemptive Stimulation of AgRP Neurons in Fed Mice Enables Conditioned Food Seeking under Threat

60 YEARS OF POMC: Regulation of feeding and energy homeostasis by α-MSH

The Role of the Melanocortin System in Metabolic Disease: New Developments and Advances

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