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Scientific Reports Jul 2020Anorexia nervosa is a complex eating disorder with genetic, metabolic, and psychosocial underpinnings. Using genome-wide methods, recent studies have associated many...
Anorexia nervosa is a complex eating disorder with genetic, metabolic, and psychosocial underpinnings. Using genome-wide methods, recent studies have associated many genes with the disorder. We characterized these genes by projecting them into reference transcriptomic atlases of the prenatal and adult human brain to determine where these genes are expressed in fine detail. We found that genes from an induced stem cell study of anorexia nervosa cases are expressed at higher levels in the lateral parabrachial nucleus. Although weaker, expression enrichment of the adult lateral parabrachial is also found with genes from independent genetic studies. Candidate causal genes from the largest genetic study of anorexia nervosa to date were enriched for expression in the arcuate nucleus of the hypothalamus. We also found an enrichment of anorexia nervosa associated genes in the adult and fetal raphe and ventral tegmental areas. Motivated by enrichment of these feeding circuits, we tested if these genes respond to fasting in mice hypothalami, which highlighted the differential expression of Rps26 and Dalrd3. This work improves our understanding of the neurobiology of anorexia nervosa by suggesting disturbances in subcortical appetitive circuits.
Topics: Adult; Animals; Anorexia Nervosa; Brain; Exome; Female; Gene Expression Profiling; Genetic Markers; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Hypothalamus; Induced Pluripotent Stem Cells; Male; Mice; Microglia; Oligonucleotide Array Sequence Analysis; Ribosomal Proteins; Transcriptome; tRNA Methyltransferases
PubMed: 32651428
DOI: 10.1038/s41598-020-67692-1 -
Neuron Jan 2022Thermoregulatory behavior is a basic motivated behavior for body temperature homeostasis. Despite its fundamental importance, a forebrain region or defined neural...
Thermoregulatory behavior is a basic motivated behavior for body temperature homeostasis. Despite its fundamental importance, a forebrain region or defined neural population required for this process has yet to be established. Here, we show that Vgat-expressing neurons in the lateral hypothalamus (LH neurons) are required for diverse thermoregulatory behaviors. The population activity of LH neurons is increased during thermoregulatory behavior and bidirectionally encodes thermal punishment and reward (P&R). Although this population also regulates feeding and caloric reward, inhibition of parabrachial inputs selectively impaired thermoregulatory behaviors and encoding of thermal stimulus by LH neurons. Furthermore, two-photon calcium imaging revealed a subpopulation of LH neurons bidirectionally encoding thermal P&R, which is engaged during thermoregulatory behavior, but is largely distinct from caloric reward-encoding LH neurons. Our data establish LH neurons as a required neural substrate for behavioral thermoregulation and point to the key role of the thermal P&R-encoding LH subpopulation in thermoregulatory behavior.
Topics: Body Temperature Regulation; Hypothalamic Area, Lateral; Neurons; Prosencephalon; Reward
PubMed: 34687664
DOI: 10.1016/j.neuron.2021.09.039 -
BioRxiv : the Preprint Server For... May 2023The parabrachial nuclear complex (PBN) is a nexus for aversion, and for the sensory and affective components of pain perception. We have previously shown that, during...
UNLABELLED
The parabrachial nuclear complex (PBN) is a nexus for aversion, and for the sensory and affective components of pain perception. We have previously shown that, during chronic pain, PBN neurons in anesthetized rodents have amplified activity. We report a method to record from PBN neurons of behaving, head-restrained mice, while applying reproducible noxious stimuli. We find that both spontaneous and evoked activity are higher in awake animals, compared to urethane anesthetized mice. Fiber photometry of calcium responses from CGRP-expressing PBN neurons demonstrates that these neurons respond to nociceptive stimuli. In both males and females with neuropathic or inflammatory pain, responses of PBN neurons remain amplified for at least 5 weeks, in parallel with increased pain metrics. We also show that PBN neurons can be rapidly conditioned to respond to innocuous stimuli, after pairing with nociceptive stimuli. Finally, we demonstrate that changes in PBN neuronal activity are correlated with changes in arousal, measured as changes in pupil diameter.
SIGNIFICANCE STATEMENT
The parabrachial complex is a nexus of aversion, including pain. We report a method to record from parabrachial nucleus neurons of behaving mice, while applying reproducible noxious stimuli. This allowed, for the first time, tracking the activity of these neurons over time in animals with neuropathic or inflammatory pain. It also allowed us to show that the activity of these neurons correlates with arousal states, and that these neurons can be conditioned to respond to innocuous stimuli.
PubMed: 36993729
DOI: 10.1101/2023.03.22.533230 -
ELife Mar 2022A new brain circuit that contributes to aversive states, such as fear or anxiety, has been characterized in mice.
A new brain circuit that contributes to aversive states, such as fear or anxiety, has been characterized in mice.
Topics: Affect; Animals; Anxiety; Brain; Emotions; Fear; Mice
PubMed: 35297762
DOI: 10.7554/eLife.77550 -
Peptides Aug 2021Pituitary adenylate cyclase activating polypeptide (PACAP) is a pleiotropic polypeptide that can activate G protein-coupled PAC1, VPAC1, and VPAC2 receptors, and has... (Review)
Review
Pituitary adenylate cyclase activating polypeptide (PACAP) is a pleiotropic polypeptide that can activate G protein-coupled PAC1, VPAC1, and VPAC2 receptors, and has been implicated in stress signaling. PACAP and its receptors are widely distributed throughout the nervous system and other tissues and can have a multitude of effects. Human and animal studies suggest that PACAP plays a role responding to a variety of threats and stressors. Here we review the roles of PACAP in several regions of the central nervous system (CNS) as they relate to several behavioral functions. For example, in the bed nucleus of the stria terminalis (BNST), PACAP is upregulated following chronic stress and may drive anxiety-like behavior. PACAP can also influence both the consolidation and expression of fear memories, as demonstrated by studies in several fear-related areas, such as the amygdala, hippocampus, and prefrontal cortex. PACAP can also mediate the emotional component of pain, as PACAP in the central nucleus of the amygdala (CeA) is able to decrease pain sensitivity thresholds. Outside of the central nervous system, PACAP may drive glucocorticoid release via enhanced hypothalamic-pituitary-adrenal axis activity and may participate in infection-induced stress responses. Together, this suggests that PACAP exerts effects on many stress-related systems and may be an important driver of emotional behavior.
Topics: Animals; Humans; Mental Disorders; Pituitary Adenylate Cyclase-Activating Polypeptide; Stress, Psychological
PubMed: 33865930
DOI: 10.1016/j.peptides.2021.170554 -
ELife May 2022Food intake behavior is regulated by a network of appetite-inducing and appetite-suppressing neuronal populations throughout the brain. The parasubthalamic nucleus...
Food intake behavior is regulated by a network of appetite-inducing and appetite-suppressing neuronal populations throughout the brain. The parasubthalamic nucleus (PSTN), a relatively unexplored population of neurons in the posterior hypothalamus, has been hypothesized to regulate appetite due to its connectivity with other anorexigenic neuronal populations and because these neurons express Fos, a marker of neuronal activation, following a meal. However, the individual cell types that make up the PSTN are not well characterized, nor are their functional roles in food intake behavior. Here, we identify and distinguish between two discrete PSTN subpopulations, those that express tachykinin-1 (PSTN neurons) and those that express corticotropin-releasing hormone (PSTN neurons), and use a panel of genetically encoded tools in mice to show that PSTN neurons play an important role in appetite suppression. Both subpopulations increase activity following a meal and in response to administration of the anorexigenic hormones amylin, cholecystokinin (CCK), and peptide YY (PYY). Interestingly, chemogenetic inhibition of PSTN, but not PSTN neurons, reduces the appetite-suppressing effects of these hormones. Consistently, optogenetic and chemogenetic stimulation of PSTN neurons, but not PSTN neurons, reduces food intake in hungry mice. PSTN and PSTN neurons project to distinct downstream brain regions, and stimulation of PSTN projections to individual anorexigenic populations reduces food consumption. Taken together, these results reveal the functional properties and projection patterns of distinct PSTN cell types and demonstrate an anorexigenic role for PSTN neurons in the hormonal and central regulation of appetite.
Topics: Animals; Appetite; Appetite Regulation; Corticotropin-Releasing Hormone; Eating; Mice; Neurons; Optogenetics
PubMed: 35507386
DOI: 10.7554/eLife.75470 -
Neurobiology of Pain (Cambridge, Mass.) 2021The parabrachial nucleus (PB) is a hub for aversive behaviors, including those related to pain. We have shown that the expression of chronic pain is causally related to...
The parabrachial nucleus (PB) is a hub for aversive behaviors, including those related to pain. We have shown that the expression of chronic pain is causally related to amplified activity of PB neurons, and to changes in synaptic inhibition of these neurons. These findings indicate that regulation of synaptic activity in PB may modulate pain perception and be involved in the pathophysiology of chronic pain. Here, we identify the roles in PB of signaling pathways that modulate synaptic functions. In pharmacologically isolated lateral PB neurons in acute mouse slices we find that baclofen, a GABA receptor agonist, suppresses the frequency of miniature inhibitory and excitatory postsynaptic currents (mIPSCs and mEPSC). Activation of µ-opioid peptide receptors with DAMGO had similar suppressive effects on excitatory and inhibitory synapses, while the κ-opioid peptide receptor agonist U-69593 suppressed mIPSC release but had no consistent effects on mEPSCs. Activation of cannabinoid type 1 receptors with WIN 55,212-2 reduced the frequency of both inhibitory and excitatory synaptic events, while the CB1 receptor inverse agonist AM251 had opposite effects on mIPSC and mEPSC frequencies. AM251 increased the frequency of inhibitory events but led to a reduction in excitatory events through a GABA mediated mechanism. Although none of the treatments produced a consistent effect on mIPSC or mEPSC amplitudes, baclofen and DAMGO both reliably activated a postsynaptic conductance. These results demonstrate that multiple signaling pathways can alter synaptic transmission and neuronal excitability in PB and provide a basis for investigating the contributions of these systems to the development and maintenance of chronic pain.
PubMed: 33364528
DOI: 10.1016/j.ynpai.2020.100057 -
Frontiers in Neuroscience 2023Visceral pain is a complex and heterogeneous pain condition that is often associated with pain-related negative emotional states, including anxiety and depression, and... (Review)
Review
Visceral pain is a complex and heterogeneous pain condition that is often associated with pain-related negative emotional states, including anxiety and depression, and can exert serious effects on a patient's physical and mental health. According to modeling stimulation protocols, the current animal models of visceral pain mainly include the mechanical dilatation model, the ischemic model, and the inflammatory model. Acupuncture can exert analgesic effects by integrating and interacting input signals from acupuncture points and the sites of pain in the central nervous system. The brain nuclei involved in regulating visceral pain mainly include the nucleus of the solitary tract, parabrachial nucleus (PBN), locus coeruleus (LC), rostral ventromedial medulla (RVM), anterior cingulate cortex (ACC), paraventricular nucleus (PVN), and the amygdala. The neural circuits involved are PBN-amygdala, LC-RVM, amygdala-insula, ACC-amygdala, claustrum-ACC, bed nucleus of the stria terminalis-PVN and the PVN-ventral lateral septum circuit. Signals generated by acupuncture can modulate the central structures and interconnected neural circuits of multiple brain regions, including the medulla oblongata, cerebral cortex, thalamus, and hypothalamus. This analgesic process also involves the participation of various neurotransmitters and/or receptors, such as 5-hydroxytryptamine, glutamate, and enkephalin. In addition, acupuncture can regulate visceral pain by influencing functional connections between different brain regions and regulating glucose metabolism. However, there are still some limitations in the research efforts focusing on the specific brain mechanisms associated with the effects of acupuncture on the alleviation of visceral pain. Further animal experiments and clinical studies are now needed to improve our understanding of this area.
PubMed: 38027491
DOI: 10.3389/fnins.2023.1243232 -
Transcriptomics reveals amygdala neuron regulation by fasting and ghrelin thereby promoting feeding.Science Advances May 2023The central amygdala (CeA) consists of numerous genetically defined inhibitory neurons that control defensive and appetitive behaviors including feeding. Transcriptomic...
The central amygdala (CeA) consists of numerous genetically defined inhibitory neurons that control defensive and appetitive behaviors including feeding. Transcriptomic signatures of cell types and their links to function remain poorly understood. Using single-nucleus RNA sequencing, we describe nine CeA cell clusters, of which four are mostly associated with appetitive and two with aversive behaviors. To analyze the activation mechanism of appetitive CeA neurons, we characterized serotonin receptor 2a (Htr2a)-expressing neurons (CeA) that comprise three appetitive clusters and were previously shown to promote feeding. In vivo calcium imaging revealed that CeA neurons are activated by fasting, the hormone ghrelin, and the presence of food. Moreover, these neurons are required for the orexigenic effects of ghrelin. Appetitive CeA neurons responsive to fasting and ghrelin project to the parabrachial nucleus (PBN) causing inhibition of target PBN neurons. These results illustrate how the transcriptomic diversification of CeA neurons relates to fasting and hormone-regulated feeding behavior.
Topics: Transcriptome; Ghrelin; Fasting; Central Amygdaloid Nucleus; Neurons
PubMed: 37224253
DOI: 10.1126/sciadv.adf6521 -
Hormones and Behavior May 2018Endocrine disrupting compounds (EDC) are ubiquitous environmental contaminants that can interact with steroid and nuclear receptors or alter hormone production. Many... (Review)
Review
Endocrine disrupting compounds (EDC) are ubiquitous environmental contaminants that can interact with steroid and nuclear receptors or alter hormone production. Many studies have reported that perinatal exposure to EDC including bisphenol A, PCB, dioxins, and DDT disrupt energy balance, body weight, adiposity, or glucose homeostasis in rodent offspring. However, little information exists on the effects of perinatal EDC exposure on the control of feeding behaviors and meal pattern (size, frequency, duration), which may contribute to their obesogenic properties. Feeding behaviors are controlled centrally through communication between the hindbrain and hypothalamus with inputs from the emotion and reward centers of the brain and modulated by peripheral hormones like ghrelin and leptin. Discrete hypothalamic nuclei (arcuate nucleus, paraventricular nucleus, lateral and dorsomedial hypothalamus, and ventromedial nucleus) project numerous reciprocal neural connections between each other and to other brain regions including the hindbrain (nucleus tractus solitarius and parabrachial nucleus). Most studies on the effects of perinatal EDC exposure examine simple crude food intake over the course of the experiment or for a short period in adult models. In addition, these studies do not examine EDC's impacts on the feeding neurocircuitry of the hypothalamus-hindbrain, the response to peripheral hormones (leptin, ghrelin, cholecystokinin, etc.) after refeeding, or other feeding behavior paradigms. The purpose of this review is to discuss those few studies that report crude food or energy intake after perinatal EDC exposure and to explore the need for deeper investigations in the hypothalamic-hindbrain neurocircuitry and discrete feeding behaviors.
Topics: Animals; Appetite Regulation; Brain; Eating; Endocrine Disruptors; Energy Intake; Feeding Behavior; Female; Humans; Infant Nutritional Physiological Phenomena; Infant, Newborn; Pregnancy; Prenatal Exposure Delayed Effects; Prenatal Nutritional Physiological Phenomena
PubMed: 29107582
DOI: 10.1016/j.yhbeh.2017.10.017