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JCI Insight Mar 2020Semaglutide, a glucagon-like peptide 1 (GLP-1) analog, induces weight loss, lowers glucose levels, and reduces cardiovascular risk in patients with diabetes. Mechanistic...
Semaglutide, a glucagon-like peptide 1 (GLP-1) analog, induces weight loss, lowers glucose levels, and reduces cardiovascular risk in patients with diabetes. Mechanistic preclinical studies suggest weight loss is mediated through GLP-1 receptors (GLP-1Rs) in the brain. The findings presented here show that semaglutide modulated food preference, reduced food intake, and caused weight loss without decreasing energy expenditure. Semaglutide directly accessed the brainstem, septal nucleus, and hypothalamus but did not cross the blood-brain barrier; it interacted with the brain through the circumventricular organs and several select sites adjacent to the ventricles. Semaglutide induced central c-Fos activation in 10 brain areas, including hindbrain areas directly targeted by semaglutide, and secondary areas without direct GLP-1R interaction, such as the lateral parabrachial nucleus. Automated analysis of semaglutide access, c-Fos activity, GLP-1R distribution, and brain connectivity revealed that activation may involve meal termination controlled by neurons in the lateral parabrachial nucleus. Transcriptomic analysis of microdissected brain areas from semaglutide-treated rats showed upregulation of prolactin-releasing hormone and tyrosine hydroxylase in the area postrema. We suggest semaglutide lowers body weight by direct interaction with diverse GLP-1R populations and by directly and indirectly affecting the activity of neural pathways involved in food intake, reward, and energy expenditure.
Topics: Animals; Body Weight; Brain; Eating; Energy Metabolism; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Mice; Neural Pathways; Rats
PubMed: 32213703
DOI: 10.1172/jci.insight.133429 -
Cell Nov 2022After ingestion of toxin-contaminated food, the brain initiates a series of defensive responses (e.g., nausea, retching, and vomiting). How the brain detects ingested...
After ingestion of toxin-contaminated food, the brain initiates a series of defensive responses (e.g., nausea, retching, and vomiting). How the brain detects ingested toxin and coordinates diverse defensive responses remains poorly understood. Here, we developed a mouse-based paradigm to study defensive responses induced by bacterial toxins. Using this paradigm, we identified a set of molecularly defined gut-to-brain and brain circuits that jointly mediate toxin-induced defensive responses. The gut-to-brain circuit consists of a subset of Htr3a+ vagal sensory neurons that transmit toxin-related signals from intestinal enterochromaffin cells to Tac1+ neurons in the dorsal vagal complex (DVC). Tac1+ DVC neurons drive retching-like behavior and conditioned flavor avoidance via divergent projections to the rostral ventral respiratory group and lateral parabrachial nucleus, respectively. Manipulating these circuits also interferes with defensive responses induced by the chemotherapeutic drug doxorubicin. These results suggest that food poisoning and chemotherapy recruit similar circuit modules to initiate defensive responses.
Topics: Animals; Mice; Neurons; Neurons, Afferent; Parabrachial Nucleus; Vagus Nerve; Brain-Gut Axis
PubMed: 36323317
DOI: 10.1016/j.cell.2022.10.001 -
Trends in Neurosciences May 2018The parabrachial nucleus (PBN), which is located in the pons and is dissected by one of the major cerebellar output tracks, is known to relay sensory information... (Review)
Review
The parabrachial nucleus (PBN), which is located in the pons and is dissected by one of the major cerebellar output tracks, is known to relay sensory information (visceral malaise, taste, temperature, pain, itch) to forebrain structures including the thalamus, hypothalamus, and extended amygdala. The availability of mouse lines expressing Cre recombinase selectively in subsets of PBN neurons and viruses for Cre-dependent gene expression is beginning to reveal the connectivity and functions of PBN component neurons. This review focuses on PBN neurons expressing calcitonin gene-related peptide (CGRP) that play a major role in regulating appetite and transmitting real or potential threat signals to the extended amygdala. The functions of other specific PBN neuronal populations are also discussed. This review aims to encourage investigation of the numerous unanswered questions that are becoming accessible.
Topics: Animals; Calcitonin Gene-Related Peptide; Humans; Neurons; Parabrachial Nucleus
PubMed: 29703377
DOI: 10.1016/j.tins.2018.03.007 -
Neuron Feb 2021Nausea, the unpleasant sensation of visceral malaise, remains a mysterious process. The area postrema is implicated in some nausea responses and is anatomically...
Nausea, the unpleasant sensation of visceral malaise, remains a mysterious process. The area postrema is implicated in some nausea responses and is anatomically privileged to detect blood-borne signals. To investigate nausea mechanisms, we built an area postrema cell atlas through single-nucleus RNA sequencing, revealing a few neuron types. Using mouse genetic tools for cell-specific manipulation, we discovered excitatory neurons that induce nausea-related behaviors, with one neuron type mediating aversion imposed by multiple poisons. Nausea-associated responses to agonists of identified area postrema receptors were observed and suppressed by targeted cell ablation and/or gene knockout. Anatomical mapping revealed a distributed network of long-range excitatory but not inhibitory projections with subtype-specific patterning. These studies reveal the basic organization of area postrema nausea circuitry and provide a framework toward understanding and therapeutically controlling nausea.
Topics: Animals; Area Postrema; Behavior, Animal; Calcitonin Receptor-Like Protein; Glucagon-Like Peptide-1 Receptor; Mice; Mice, Knockout; Nausea; Neurons
PubMed: 33278342
DOI: 10.1016/j.neuron.2020.11.010 -
American Journal of Physiology.... May 2016Glucagon-like peptide-1 (GLP-1) is currently one of the most promising biological systems for the development of effective obesity pharmacotherapies. Long-acting GLP-1... (Review)
Review
Glucagon-like peptide-1 (GLP-1) is currently one of the most promising biological systems for the development of effective obesity pharmacotherapies. Long-acting GLP-1 analogs potently reduce food intake and body weight, and recent discoveries reveal that peripheral administration of these drugs reduces food intake largely through humoral pathways involving direct action on brain GLP-1 receptors (GLP-1R). Thus, it is of critical importance to understand the neural systems through which GLP-1 and long-acting GLP-1 analogs reduce food intake and body weight. In this review, we discuss several neural, physiological, cellular and molecular, as well as behavioral mechanisms through which peripheral and central GLP-1R signaling reduces feeding. Particular attention is devoted to discussion regarding the numerous neural substrates through which GLP-1 and GLP-1 analogs act to reduce food intake and body weight, including various hypothalamic nuclei (arcuate nucleus of the hypothalamus, periventricular hypothalamus, lateral hypothalamic area), hindbrain nuclei (parabrachial nucleus, medial nucleus tractus solitarius), hippocampus (ventral subregion; vHP), and nuclei embedded within the mesolimbic reward circuitry [ventral tegmental area (VTA) and nucleus accumbens (NAc)]. In some of these nuclei [VTA, NAc, and vHP], GLP-1R activation reduces food intake and body weight without concomitant nausea responses, suggesting that targeting these specific pathways may be of particular interest for future obesity pharmacotherapy. The widely distributed neural systems through which GLP-1 and GLP-1 analogs act to reduce body weight highlight the complexity of the neural systems regulating energy balance, as well as the challenges for developing effective obesity pharmacotherapies that reduce feeding without producing parallel negative side effects.
Topics: Brain; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Weight Loss
PubMed: 27030669
DOI: 10.1152/ajpregu.00520.2015 -
Nature Communications Nov 2020The lateral parabrachial nucleus (LPBN) is known to relay noxious information to the amygdala for processing affective responses. However, it is unclear whether the LPBN...
The lateral parabrachial nucleus (LPBN) is known to relay noxious information to the amygdala for processing affective responses. However, it is unclear whether the LPBN actively processes neuropathic pain characterized by persistent hyperalgesia with aversive emotional responses. Here we report that neuropathic pain-like hypersensitivity induced by common peroneal nerve (CPN) ligation increases nociceptive stimulation-induced responses in glutamatergic LPBN neurons. Optogenetic activation of GABAergic LPBN neurons does not affect basal nociception, but alleviates neuropathic pain-like behavior. Optogenetic activation of glutamatergic or inhibition of GABAergic LPBN neurons induces neuropathic pain-like behavior in naïve mice. Inhibition of glutamatergic LPBN neurons alleviates both basal nociception and neuropathic pain-like hypersensitivity. Repetitive pharmacogenetic activation of glutamatergic or GABAergic LPBN neurons respectively mimics or prevents the development of CPN ligation-induced neuropathic pain-like hypersensitivity. These findings indicate that a delicate balance between excitatory and inhibitory LPBN neuronal activity governs the development and maintenance of neuropathic pain.
Topics: Animals; Disease Models, Animal; Excitatory Amino Acid Agonists; Excitatory Postsynaptic Potentials; GABA Agonists; Glutamic Acid; Humans; Hyperalgesia; Inhibitory Postsynaptic Potentials; Male; Mice; Mice, Transgenic; Neural Pathways; Neuralgia; Neurons; Nociception; Optogenetics; Parabrachial Nucleus; Peroneal Nerve; Stereotaxic Techniques; gamma-Aminobutyric Acid
PubMed: 33239627
DOI: 10.1038/s41467-020-19767-w -
ELife Nov 2022The parabrachial nucleus (PBN) is a major hub that receives sensory information from both internal and external environments. Specific populations of PBN neurons are...
The parabrachial nucleus (PBN) is a major hub that receives sensory information from both internal and external environments. Specific populations of PBN neurons are involved in behaviors including food and water intake, nociceptive responses, breathing regulation, as well as learning and responding appropriately to threatening stimuli. However, it is unclear how many PBN neuron populations exist and how different behaviors may be encoded by unique signaling molecules or receptors. Here we provide a repository of data on the molecular identity, spatial location, and projection patterns of dozens of PBN neuron subclusters. Using single-cell RNA sequencing, we identified 21 subclusters of neurons in the PBN and neighboring regions. Multiplexed in situ hybridization showed many of these subclusters are enriched within specific PBN subregions with scattered cells in several other regions. We also provide detailed visualization of the axonal projections from 21 Cre-driver lines of mice. These results are all publicly available for download and provide a foundation for further interrogation of PBN functions and connections.
Topics: Animals; Mice; Parabrachial Nucleus; Neurons; Axons
PubMed: 36317965
DOI: 10.7554/eLife.81868 -
Neural Plasticity 2022Chronic pain patients often develop mental disorders, and anxiety disorders are common. We hypothesize that the comorbid anxiety results from an imbalance between the... (Review)
Review
Chronic pain patients often develop mental disorders, and anxiety disorders are common. We hypothesize that the comorbid anxiety results from an imbalance between the reward and antireward system due to persistent pain, which leads to the dysfunction of the pain and anxiety regulatory system. In this review, we will focus on changes in neuroplasticity, especially in neural circuits, during chronic pain and anxiety as observed in animal studies. Several neural circuits within specific regions of the brain, including the nucleus accumbens, lateral habenular, parabrachial nucleus, medial septum, anterior cingulate cortex, amygdala, hippocampus, medial prefrontal cortex, and bed nucleus of the stria terminalis, will be discussed based on novel findings after chemogenetic or optogenetic manipulation. We believe that these animal studies provide novel insights into human conditions and can guide clinical practice.
Topics: Animals; Anxiety; Anxiety Disorders; Brain; Chronic Pain; Comorbidity; Humans
PubMed: 35211169
DOI: 10.1155/2022/4217593 -
Nature Neuroscience Mar 2023Poor sleep is associated with the risk of developing chronic pain, but how sleep contributes to pain chronicity remains unclear. Here we show that following peripheral...
Poor sleep is associated with the risk of developing chronic pain, but how sleep contributes to pain chronicity remains unclear. Here we show that following peripheral nerve injury, cholinergic neurons in the anterior nucleus basalis (aNB) of the basal forebrain are increasingly active during nonrapid eye movement (NREM) sleep in a mouse model of neuropathic pain. These neurons directly activate vasoactive intestinal polypeptide-expressing interneurons in the primary somatosensory cortex (S1), causing disinhibition of pyramidal neurons and allodynia. The hyperactivity of aNB neurons is caused by the increased inputs from the parabrachial nucleus (PB) driven by the injured peripheral afferents. Inhibition of this pathway during NREM sleep, but not wakefulness, corrects neuronal hyperactivation and alleviates pain. Our results reveal that the PB-aNB-S1 pathway during sleep is critical for the generation and maintenance of chronic pain. Inhibiting this pathway during the sleep phase could be important for treating neuropathic pain.
Topics: Animals; Mice; Chronic Pain; Sleep; Sleep, Slow-Wave; Neuralgia; Cholinergic Neurons
PubMed: 36690899
DOI: 10.1038/s41593-022-01250-y -
Nutrients Jan 2023Body sodium (Na) levels must be maintained within a narrow range for the correct functioning of the organism (Na homeostasis). Na disorders include not only elevated... (Review)
Review
Body sodium (Na) levels must be maintained within a narrow range for the correct functioning of the organism (Na homeostasis). Na disorders include not only elevated levels of this solute (hypernatremia), as in diabetes insipidus, but also reduced levels (hyponatremia), as in cerebral salt wasting syndrome. The balance in body Na levels therefore requires a delicate equilibrium to be maintained between the ingestion and excretion of Na. Salt (NaCl) intake is processed by receptors in the tongue and digestive system, which transmit the information to the nucleus of the solitary tract via a neural pathway (chorda tympani/vagus nerves) and to circumventricular organs, including the subfornical organ and area postrema, via a humoral pathway (blood/cerebrospinal fluid). Circuits are formed that stimulate or inhibit homeostatic Na intake involving participation of the parabrachial nucleus, pre-locus coeruleus, medial tuberomammillary nuclei, median eminence, paraventricular and supraoptic nuclei, and other structures with reward properties such as the bed nucleus of the stria terminalis, central amygdala, and ventral tegmental area. Finally, the kidney uses neural signals (e.g., renal sympathetic nerves) and vascular (e.g., renal perfusion pressure) and humoral (e.g., renin-angiotensin-aldosterone system, cardiac natriuretic peptides, antidiuretic hormone, and oxytocin) factors to promote Na excretion or retention and thereby maintain extracellular fluid volume. All these intake and excretion processes are modulated by chemical messengers, many of which (e.g., aldosterone, angiotensin II, and oxytocin) have effects that are coordinated at peripheral and central level to ensure Na homeostasis.
Topics: Sodium; Oxytocin; Homeostasis; Kidney; Angiotensin II
PubMed: 36678265
DOI: 10.3390/nu15020395