Dynamic GABAergic afferent modulation of AgRP neurons

Garfield, Alastair S.; Shah, Bhavik P.; Burgess, Christian R.; Li, Monica M.; Li, Chia; Steger, Jennifer S.; Madara, Joseph C.; Campbell, John N.; Kroeger, Daniel; Scammell, Thomas E.; Tannous, Bakhos A.; Myers, Martin G.; Andermann, Mark L.; Krashes, Michael J.; Lowell, Bradford B.

doi:10.1038/nn.4392

Cited by 177 publications

(222 citation statements)

References 35 publications

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“…To assess the generality of these presystemic changes in VP pp neuron activity across hyperosmolar contexts and across ingestive behaviors, we used fiber photometry to monitor the aggregate calcium activity of populations of VP pp neurons in freely moving mice (Figure 2A; see Garfield et al, 2016, and Experimental Procedures). Experiments were conducted in the home-cage, and mice were habituated to drinking from a water bowl that was placed in the cage midway through each session.…”

Section: Resultsmentioning

confidence: 99%

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Bidirectional Anticipation of Future Osmotic Challenges by Vasopressin Neurons

Mandelblat-Cerf

Kim

Burgess

et al. 2017

Neuron

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SUMMARY Ingestion of water and food are major hypo- and hyperosmotic challenges. To protect the body from osmotic stress, posterior pituitary-projecting, vasopressin-secreting neurons (VPpp neurons) counter osmotic perturbations by altering their release of vasopressin, which controls renal water excretion. Vasopressin levels begin to fall within minutes of water consumption, even prior to changes in blood osmolality. To ascertain the precise temporal dynamics by which water or food ingestion affect VPpp neuron activity, we directly recorded the spiking and calcium activity of genetically defined VPpp neurons. In states of elevated osmolality, water availability rapidly decreased VPpp neuron activity within seconds, beginning prior to water ingestion, upon presentation of water-predicting cues. In contrast, food availability following food restriction rapidly increased VPpp neuron activity within seconds, but only following feeding onset. These rapid and distinct changes in activity during drinking and feeding suggest diverse neural mechanisms underlying anticipatory regulation of VPpp neurons.

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Section: Resultsmentioning

confidence: 99%

“…Here, using optetrode electrophysiology and fiber photometry in awake mice (see Cohen et al, 2012; Garfield et al, 2016), we demonstrate diverse anticipatory changes in activity of genetically defined VP pp neurons within seconds prior to and following the onset of ingestive behaviors.…”

Section: Introductionmentioning

confidence: 93%

Bidirectional Anticipation of Future Osmotic Challenges by Vasopressin Neurons

Mandelblat-Cerf

Kim

Burgess

et al. 2017

Neuron

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“…We used male mice only. Sample sizes were chosen to reliably measure experimental parameters while keeping with standards in the relevant fields 19,28,44,45 , and remaining in compliance with ethical guidelines to minimize the number of animals used. Experiments did not involve experimenter-blinding, but randomization was used with respect to trial order and data collection.…”

Section: Methodsmentioning

confidence: 99%

Homeostatic circuits selectively gate food cue responses in insular cortex

Livneh

Ramesh

Burgess

et al. 2017

Nature

282

293

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Physiological needs bias perception and attention to relevant sensory cues. This process is ‘hijacked’ by drug addiction, causing cue-induced cravings and relapse. Similarly, its dysregulation contributes to failed diets, obesity, and eating disorders. Neuroimaging studies in humans have implicated insular cortex in these phenomena. However, it remains unclear how ‘cognitive’ cortical representations of motivationally relevant cues are biased by subcortical circuits that drive specific motivational states. Here we develop a microprism-based cellular imaging approach to monitor visual cue responses in the insular cortex of behaving mice across hunger states. Insular cortex neurons demonstrate food- cue-biased responses that are abolished during satiety. Unexpectedly, while multiple satiety-related visceral signals converge in insular cortex, chemogenetic activation of hypothalamic ‘hunger neurons’ (expressing agouti-related peptide (AgRP)) bypasses these signals to restore hunger-like response patterns in insular cortex. Circuit mapping and pathway-specific manipulations uncover a pathway from AgRP neurons to insular cortex via the paraventricular thalamus and basolateral amygdala. These results reveal a neural basis for state-specific biased processing of motivationally relevant cues.

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“…9l). Since some LepR-expressing neurons in the ventral DMH (vDMH) are GABAergic 10 and monosynaptically innervate AgRP neurons 30 (Extended Data Fig. 9m, n), we injected AAV-FLEX-hM4Di-mCherry into the vDMH of Vgat-IRES-Cre::Npy-hrGFP mice to specifically transduce GABAergic neurons in this nucleus (vGAT vDMH neurons, Fig.…”

Section: Mainmentioning

confidence: 99%

Genetic identification of leptin neural circuits in energy and glucose homeostases

Bartolome

Low

et al. 2018

Nature

226

216

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Leptin, a hormone produced in white adipose tissue, acts in the brain to communicate fuel status, suppress appetite following a meal, promote energy expenditure, and maintain blood glucose stability1,2. Dysregulations of leptin or its receptors (LepR) result in severe obesity and diabetes3–5. Although intensive studies on leptin have transformed obesity and diabetes research2,6, clinical applications of the molecule are still limited7 which, at least in part, is due to the complexity and our incomplete understanding of the underlying neural circuits. The hypothalamic neurons expressing agouti-related peptide (AgRP) and proopiomelanocortin (POMC) were posited as the first-order leptin-responsive neurons. Selective deletion of LepR in these neurons with Cre-loxP system, however, failed to or marginally recapitulated obesity and diabetes in LepR-deficient Leprdb/db mice, suggesting that AgRP or POMC neurons are not directly required8–10. The primary neural targets for leptin are thus still unclear. Here, we conduct a systematic, unbiased survey of leptin-responsive neurons in streptozotocin (STZ)-induced diabetic mice and exploit CRISPR/Cas9-mediated genetic ablation of LepR in vivo. Unexpectedly, we find that AgRP neurons but not POMC neurons integrate the primary action of leptin to regulate both energy balance and glucose homeostasis. Leptin deficiency disinhibits AgRP neurons, and their chemogenetic inhibition reverses both diabetic hyperphagia and hyperglycemia. In sharp contrast with prior studies, we show that CRISPR-mediated deletion of LepR in AgRP neurons causes severe obesity and diabetes, fatefully replicating the phenotype of Leprdb/db mice. We also uncover divergent mechanisms underlying leptin’s acute and chronic inhibition of AgRP neurons (i.e., presynaptic potentiation of GABAergic neurotransmission and postsynaptic activation of ATP-sensitive potassium channels, respectively). Our findings provide the framework underlying the neurobiological mechanisms of leptin and associated metabolic disorders.

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Dynamic GABAergic afferent modulation of AgRP neurons

Cited by 177 publications

References 35 publications

Bidirectional Anticipation of Future Osmotic Challenges by Vasopressin Neurons

Bidirectional Anticipation of Future Osmotic Challenges by Vasopressin Neurons

Homeostatic circuits selectively gate food cue responses in insular cortex

Genetic identification of leptin neural circuits in energy and glucose homeostases

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