Publications
Topographic representation of current and future threats in the nociceptive amygdala. Nature Communications
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Adaptive behaviors arise from an integration of current sensory context and internal representations of past experiences. The central amygdala (CeA) is positioned as a key integrator of cognitive and affective signals, yet it remains unknown whether individual populations simultaneously carry current- and future-state representations. We find that a primary nociceptive population within the CeA of mice, defined by CGRP-receptor (Calcrl) expression, receives topographic sensory information, with spatially defined representations of internal and external stimuli. While Calcrl+ neurons in both the rostral and caudal CeA respond to noxious stimuli, rostral neurons promote locomotor responses to externally sourced threats, while caudal CeA Calcrl+ neurons are activated by internal threats and promote passive coping behaviors and associative valence coding. During associative fear learning, rostral CeA Calcrl+ neurons stably encode noxious stimulus occurrence, while caudal CeA Calcrl+ neurons acquire predictive responses. This arrangement supports valence-aligned representations of current and future threats for the generation of adaptive behaviors.
Optogenetic targeting of mouse vagal afferents using an organ-specific scalable, wireless optoelectronic device. Bio-protocol
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Optogenetics has the potential to transform the study of the peripheral nervous system (PNS), but the complex anatomy of the PNS poses unique challenges for the focused delivery of light to specific tissues. This protocol describes the fabrication of a wireless telemetry system for studying peripheral sensory pathways. Unlike existing wireless approaches, the low-power wireless telemetry offers organ specificity via a sandwiched pre-curved tether, and enables high-throughput analysis of behavioral experiments with a channel isolation strategy. We describe the technical procedures for the construction of these devices, the wireless power transmission (TX) system with antenna coils, and their implementation for in vivo experimental applications. In total, the timeline of the procedure, including device fabrication, implantation, and preparation to begin in vivo experimentation can be completed in ~2-4 weeks. Implementation of these devices allows for chronic (>1 month) wireless optogenetic manipulation of peripheral neural pathways in freely behaving animals navigating homecage environments (up to 8).
Organ-specific, multimodal, wireless optoelectronics for high-throughput phenotyping of peripheral neural pathways. Nature Communications
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The vagus nerve supports diverse autonomic functions and behaviors important for health and survival. To understand how specific components of the vagus contribute to behaviors and long-term physiological effects, it is critical to modulate their activity with anatomical specificity in awake, freely behaving conditions using reliable methods. Here, we introduce an organ-specific scalable, multimodal, wireless optoelectronic device for precise and chronic optogenetic manipulations in vivo. When combined with an advanced, coil-antenna system and a multiplexing strategy for powering 8 individual homecages using a single RF transmitter, the proposed wireless telemetry enables low cost, high-throughput, and precise functional mapping of peripheral neural circuits, including long-term behavioral and physiological measurements. Deployment of these technologies reveals an unexpected role for stomach, non-stretch vagal sensory fibers in suppressing appetite and demonstrates the durability of the miniature wireless device inside harsh gastric conditions.
Taborsky GJ, Morton GJ (2020). CNS control of the endocrine pancreas. Diabetologia
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Increasing evidence suggests that, although pancreatic islets can function autonomously to detect and respond to changes in the circulating glucose level, the brain cooperates with the islet to maintain glycaemic control. Here, we review the role of the central and autonomic nervous systems in the control of the endocrine pancreas, including mechanisms whereby the brain senses circulating blood glucose levels. We also examine whether dysfunction in these systems might contribute to complications of type 1 diabetes and the pathogenesis of type 2 diabetes. Graphical abstract.
Chronic Gq signaling in AgRP neurons does not cause obesity. Proceedings of the National Academy of Sciences
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Maintaining energy homeostasis requires coordinating physiology and behavior both on an acute timescale to adapt to rapid fluctuations in caloric intake and on a chronic timescale to regulate body composition. Hypothalamic agouti-related peptide (AgRP)-expressing neurons are acutely activated by caloric need, and this acute activation promotes increased food intake and decreased energy expenditure. On a longer timescale, AgRP neurons exhibit chronic hyperactivity under conditions of obesity and high dietary fat consumption, likely due to leptin resistance; however, the behavioral and metabolic effects of chronic AgRP neuronal hyperactivity remain unexplored. Here, we use chemogenetics to manipulate Gq signaling in AgRP neurons in mice to explore the hypothesis that chronic activation of AgRP neurons promotes obesity. Inducing chronic Gq signaling in AgRP neurons initially increased food intake and caused dramatic weight gain, in agreement with published data; however, food intake returned to baseline levels within 1 wk, and body weight returned to baseline levels within 60 d. Additionally, we found that, when mice had elevated body weight due to chronic Gq signaling in AgRP neurons, energy expenditure was not altered but adiposity and lipid metabolism were both increased, even under caloric restriction. These findings reveal that the metabolic and behavioral effects of chronic Gq signaling in AgRP neurons are distinct from the previously reported effects of acute Gq signaling and also of leptin insensitivity.
Parabrachial CGRP neurons establish and sustain aversive taste memories. Neuron
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Food aversions develop when the taste of a novel food is associated with sickness, which often occurs after food poisoning or chemotherapy treatment. We identified calcitonin-gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN) as sufficient and necessary for establishing a conditioned taste aversion (CTA). Photoactivating projections from CGRPPBN neurons to either the central nucleus of the amygdala or the bed nucleus of the stria terminalis can also induce robust CTA. CGRPPBN neurons undergo plasticity following CTA, and inactivation of either Arc or Grin1 (genes involved in memory consolidation) prevents establishment of a strong CTA. Calcium imaging reveals that the novel food re-activates CGRPPBN neurons after conditioning. Inhibition of these neurons or inactivation of the Grin1 gene after conditioning attenuates CTA expression. Our results indicate that CGRPPBN neurons not only play a key role for learning food aversions but also contribute to the maintenance and expression of those memories.
Encoding of danger by parabrachial CGRP neurons. Nature
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Animals must respond to various threats to survive. Neurons that express calcitonin gene-related peptide in the parabrachial nucleus (PBN CGRP neurons) relay sensory signals that contribute to satiation and pain-induced fear behaviour, but it is unclear how they encode these distinct processes. Here, by recording calcium transients in vivo from individual neurons in mice, we show that most PBN CGRP neurons are activated by noxious cutaneous (shock, heat, itch) and visceral stimuli (lipopolysaccharide). The same neurons are inhibited during feeding, but become activated during satiation, consistent with evidence that PBN CGRP neurons prevent overeating. PBN CGRP neurons are also activated during consumption of novel foods or by an auditory cue that has previously been paired with electrical footshocks. Correspondingly, silencing of PBN CGRP neurons attenuates the expression of food neophobia and conditioned fear responses. Therefore, in addition to transducing primary sensory danger signals, PBN CGRP neurons promote affective-behavioural states that limit harm in response to potential threats.
Oxytocin-receptor-expressing neurons in the parabrachial nucleus regulate fluid intake. Nature Neuroscience
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Brain regions that regulate fluid satiation are not well characterized, yet are essential for understanding fluid homeostasis. We found that oxytocin-receptor-expressing neurons in the parabrachial nucleus of mice (OxtrPBN neurons) are key regulators of fluid satiation. Chemogenetic activation of OxtrPBN neurons robustly suppressed noncaloric fluid intake, but did not decrease food intake after fasting or salt intake following salt depletion; inactivation increased saline intake after dehydration and hypertonic saline injection. Under physiological conditions, OxtrPBN neurons were activated by fluid satiation and hypertonic saline injection. OxtrPBN neurons were directly innervated by oxytocin neurons in the paraventricular hypothalamus (OxtPVH neurons), which mildly attenuated fluid intake. Activation of neurons in the nucleus of the solitary tract substantially suppressed fluid intake and activated OxtrPBN neurons. Our results suggest that OxtrPBN neurons act as a key node in the fluid satiation neurocircuitry, which acts to decrease water and/or saline intake to prevent or attenuate hypervolemia and hypernatremia.
Cancer-induced anorexia and malaise are mediated by CGRP neurons in the parabrachial nucleus. Nature Neuroscience
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Anorexia is a common manifestation of chronic diseases, including cancer. Here we investigate the contribution to cancer anorexia made by calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN) that transmit anorexic signals. We show that PBN CGRP neurons are activated in mice implanted with Lewis lung carcinoma cells. Inactivation of PBN CGRP neurons before tumor implantation prevents anorexia and loss of lean mass, and their inhibition after symptom onset reverses anorexia. PBN CGRP neurons are also activated in Apcmin/+ mice, which develop intestinal cancer and lose weight despite the absence of reduced food intake. Inactivation of PBN CGRP neurons in Apcmin/+ mice permits hyperphagia that counteracts weight loss, revealing a role for these neurons in a 'nonanorexic' cancer model. We also demonstrate that inactivation of PBN CGRP neurons prevents lethargy, anxiety and malaise associated with cancer. These findings establish PBN CGRP neurons as key mediators of cancer-induced appetite suppression and associated behavioral changes.
Vagal afferent signaling and the integration of direct and indirect controls of food intake. Chapter 11 in ‘Appetite and Food Intake: Central Control’, Review
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In terms of individual survival, feeding arguably is the most important behavior in which animals engage, because all physiological functions, including other behaviors, depend on the energy and nutrients obtained only through food intake. Consequently, control of feeding behavior is of high priority for the brain, the organ of behavior. Indeed, it is tempting to argue that selective pressures driving the evolution of ganglia or brains near the oral opening of the digestive system included efficient detection, pursuit, capture, and ingestion of food. Moreover, the anatomical concentration of sensory inputs in ganglia or brain facilitates network interactions between modalities that represent distinct qualities of food, such as chemical composition (taste) and bulk or mass (gut stretch). The integration of afferent information from disparate peripheral sources is the foundation for control of food intake. For a concise review of nervous system and behavioral evolution see Dethier and Stellar (1964).
Parabrachial CGRP Neurons Control Meal Termination. Cell Metabolism
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The lateral parabrachial nucleus is a conduit for visceral signals that cause anorexia. We previously identified a subset of neurons located in the external lateral parabrachial nucleus (PBel) that express calcitonin gene-related peptide (CGRP) and inhibit feeding when activated by illness mimetics. We report here that in otherwise normal mice, functional inactivation of CGRP neurons markedly increases meal size, with meal frequency being reduced in a compensatory manner, and renders mice insensitive to the anorexic effects of meal-related satiety peptides. Furthermore, CGRP neurons are directly innervated by orexigenic hypothalamic AgRP neurons, and photostimulation of AgRP fibers supplying the PBel delays satiation by inhibiting CGRP neurons, thereby contributing to AgRP-driven hyperphagia. By establishing a role for CGRP neurons in the control of meal termination and as a downstream mediator of feeding elicited by AgRP neurons, these findings identify a node in which hunger and satiety circuits interact to control feeding behavior.
NMDA-type glutamate receptors participate in reduction of food intake following hindbrain melanocortin receptor activation. American Journal of Physiology
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Hindbrain injection of a melanocortin-3/4 receptor agonist, MTII, reduces food intake primarily by reducing meal size. Our previously reported results indicate that N-methyl-D-aspartate-type glutamate receptors (NMDAR) in the nucleus of the solitary tract (NTS) play an important role in the control of meal size and food intake. Therefore, we hypothesized that activation of NTS NMDARs contribute to reduction of food intake in response to fourth ventricle or NTS injection of MTII. We found that coinjection of a competitive NMDAR antagonist (d-CPP-ene) with MTII into the fourth ventricle or directly into the NTS of adult male rats attenuated MTII-induced reduction of food intake. Hindbrain NMDAR antagonism also attenuated MTII-induced ERK1/2 phosphorylation in NTS neurons and prevented synapsin I phosphorylation in central vagal afferent endings, both of which are cellular mechanisms previously shown to participate in hindbrain melanocortinergic reduction of food intake. Together, our results indicate that NMDAR activation significantly contributes to reduction of food intake following hindbrain melanocortin receptor activation, and it participates in melanocortinergic signaling in NTS neural circuits that mediate reduction of food intake.
Central vagal afferent endings mediate reduction of food intake by melanocortin-3/4 receptor agonist. Journal of Neuroscience
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Injection of the melanocortin-3/4 receptor agonist melanotan-II (MTII) into the nucleus of the solitary tract (NTS) produces rapid and sustained reduction of food intake. Melanocortin-4 receptors (MC4Rs) are expressed by vagal afferent endings in the NTS, but it is not known whether these endings participate in MTII-induced reduction of food intake. In experiments described here, we evaluated the contribution of central vagal afferent endings in MTII-induced reduction of food intake. Examination of rat hindbrain sections revealed that neuronal processes expressing immunoreactivity for the endogenous MC4R agonist α-melanoctyte-stimulating hormone course parallel and wrap around anterogradely labeled vagal afferent endings in the NTS and thus are aptly positioned to activate vagal afferent MC4Rs. Furthermore, MTII and endogenous MC4R agonists increased protein kinase A (PKA)-catalyzed phosphorylation of synapsin I in vagal afferent endings, an effect known to increase synaptic strength by enhancing neurotransmitter release in other neural systems. Hindbrain injection of a PKA inhibitor, KT5720, significantly attenuated MTII-induced reduction of food intake and the increase in synapsin I phosphorylation. Finally, unilateral nodose ganglion removal, resulting in degeneration of vagal afferent endings in the ipsilateral NTS, abolished MTII-induced synapsin I phosphorylation ipsilateral to nodose ganglion removal. Moreover, reduction of food intake following MTII injection into the NTS ipsilateral to nodose ganglion removal was significantly attenuated, whereas the response to MTII was not diminished when injected into the contralateral NTS. Altogether, our results suggest that reduction of food intake following hindbrain MC4R activation is mediated by central vagal afferent endings.
Vagal afferent NMDA receptors modulate CCK-induced reduction of food intake through synapsin I phosphorylation in adult male rats. Endocrinology
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Vagal afferent nerve fibers transmit gastrointestinal satiation signals to the brain via synapses in the nucleus of the solitary tract (NTS). Despite their pivotal role in energy homeostasis, little is known about the cellular mechanisms enabling fleeting synaptic events at vagal sensory endings to sustain behavioral changes lasting minutes to hours. Previous reports suggest that the reduction of food intake by the satiation peptide, cholecystokinin (CCK), requires activation of N-methyl-D-aspartate-type glutamate receptors (NMDAR) in the NTS, with subsequent phosphorylation of ERK1/2 (pERK1/2) in NTS vagal afferent terminals. The synaptic vesicle protein synapsin I is phosphorylated by pERK1/2 at serines 62 and 67. This pERK1/2-catalyzed phosphorylation increases synaptic strength by increasing the readily releasable pool of the neurotransmitter. Conversely, dephosphorylation of serines 62 and 67 by calcineurin reduces the size of the readily releasable transmitter pool. Hence, the balance of synapsin I phosphorylation and dephosphorylation can modulate synaptic strength. We postulated that CCK-evoked activation of vagal afferent NMDARs results in pERK1/2-catalyzed phosphorylation of synapsin I in vagal afferent terminals, leading to the suppression of food intake. We found that CCK injection increased the phosphorylation of synapsin I in the NTS and that this increase is abolished after surgical or chemical ablation of vagal afferent fibers. Furthermore, fourth ventricle injection of an NMDAR antagonist or the mitogen-activated ERK kinase inhibitor blocked CCK-induced synapsin I phosphorylation, indicating that synapsin phosphorylation in vagal afferent terminals depends on NMDAR activation and ERK1/2 phosphorylation. Finally, hindbrain inhibition of calcineurin enhanced and prolonged synapsin I phosphorylation and potentiated reduction of food intake by CCK. Our findings are consistent with a mechanism in which NMDAR-dependent phosphorylation of ERK1/2 modulates satiation signals via synapsin I phosphorylation in vagal afferent endings.
CCK-induced reduction of food intake and hindbrain MAPK signaling are mediated by NMDA receptor activation. Endocrinology
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The dorsal vagal complex of the hindbrain, including the nucleus of the solitary tract (NTS), receives neural and humoral afferents that contribute to the process of satiation. The gut peptide, cholecystokinin (CCK), promotes satiation by activating gastrointestinal vagal afferents that synapse in the NTS. Previously, we demonstrated that hindbrain administration of N-methyl-D-aspartate (NMDA)-type glutamate receptor antagonists attenuate reduction of food intake after ip CCK-8 injection, indicating that these receptors play a necessary role in control of food intake by CCK. However, the signaling pathways through which hindbrain NMDA receptors contribute to CCK-induced reduction of food intake have not been investigated. Here we report CCK increases phospho-ERK1/2 in NTS neurons and in identified vagal afferent endings in the NTS. CCK-evoked phospho-ERK1/2 in the NTS was attenuated in rats pretreated with capsaicin and was abolished by systemic injection of a CCK1 receptor antagonist, indicating that phosphorylation of ERK1/2 occurs in and is mediated by gastrointestinal vagal afferents. Fourth ventricle injection of a competitive NMDA receptor antagonist, prevented CCK-induced phosphorylation of ERK1/2 in hindbrain neurons and in vagal afferent endings, as did direct inhibition of MAPK kinase. Finally, fourth ventricle administration of either a MAPK kinase inhibitor or NMDA receptor antagonist prevented the reduction of food intake by CCK. We conclude that activation of NMDA receptors in the hindbrain is necessary for CCK-induced ERK1/2 phosphorylation in the NTS and consequent reduction of food intake.
Reduction of food intake by cholecystokinin requires activation of hindbrain NMDA-type glutamate receptors. American Journal of Physiology
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Intraperitoneal injection of CCK reduces food intake and triggers a behavioral pattern similar to natural satiation. Reduction of food intake by CCK is mediated by vagal afferents that innervate the stomach and small intestine. These afferents synapse in the hindbrain nucleus of the solitary tract (NTS) where gastrointestinal satiation signals are processed. Previously, we demonstrated that intraperitoneal (IP) administration of either competitive or noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists attenuates reduction of food intake by CCK. However, because vagal afferents themselves express NMDA receptors at both central and peripheral endings, our results did not speak to the question of whether NMDA receptors in the brain play an essential role in reduction of feeding by CCK. We hypothesized that activation of NMDA receptors in the NTS is necessary for reduction of food intake by CCK. To test this hypothesis, we measured food intake following IP CCK, subsequent to NMDA receptor antagonist injections into the fourth ventricle, directly into the NTS or subcutaneously. We found that either fourth-ventricle or NTS injection of the noncompetitive NMDA receptor antagonist MK-801 was sufficient to inhibit CCK-induced reduction of feeding, while the same antagonist doses injected subcutaneously did not. Similarly fourth ventricle injection of d-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphoric acid (d-CPPene), a competitive NMDA receptor antagonist, also blocked reduction of food intake following IP CCK. Finally, d-CPPene injected into the fourth ventricle attenuated CCK-induced expression of nuclear c-Fos immunoreactivity in the dorsal vagal complex. We conclude that activation of NMDA receptors in the hindbrain is necessary for the reduction of food intake by CCK. Hindbrain NMDA receptors could comprise a critical avenue for control and modulation of satiation signals to influence food intake and energy balance.
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