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Cerebral Cortex (New York, N.Y. : 1991) Jul 2020The parabrachial nucleus (PB) in the upper brain stem tegmentum includes several neuronal subpopulations with a wide variety of connections and functions. A...
The parabrachial nucleus (PB) in the upper brain stem tegmentum includes several neuronal subpopulations with a wide variety of connections and functions. A subpopulation of PB neurons projects axons directly to the cerebral cortex, and limbic areas of the cerebral cortex send a return projection directly to the PB. We used retrograde and Cre-dependent anterograde tracing to identify genetic markers and characterize this PB-cortical interconnectivity in mice. Cortical projections originate from glutamatergic PB neurons that contain Lmx1b (81%), estrogen receptor alpha (26%), and Satb2 (20%), plus mRNA for the neuropeptides cholecystokinin (Cck, 48%) and calcitonin gene-related peptide (Calca, 13%), with minimal contribution from FoxP2+ PB neurons (2%). Axons from the PB produce an extensive terminal field in an unmyelinated region of the insular cortex, extending caudally into the entorhinal cortex, and arcing rostrally through the dorsolateral prefrontal cortex, with a secondary terminal field in the medial prefrontal cortex. In return, layer 5 neurons in the insular cortex and other prefrontal areas, along with a dense cluster of cells dorsal to the claustrum, send a descending projection to subregions of the PB that contain cortically projecting neurons. This information forms the neuroanatomical basis for testing PB-cortical interconnectivity in arousal and interoception.
Topics: Animals; Cerebral Cortex; Female; Male; Mice; Mice, Inbred C57BL; Neural Pathways; Parabrachial Nucleus
PubMed: 32383444
DOI: 10.1093/cercor/bhaa072 -
Physiological Reports Jun 2018Fluid satiation, or quenching of thirst, is a critical homeostatic signal to stop drinking; however, its underlying neurocircuitry is not well characterized.... (Review)
Review
Fluid satiation, or quenching of thirst, is a critical homeostatic signal to stop drinking; however, its underlying neurocircuitry is not well characterized. Cutting-edge genetically encoded tools and techniques are now enabling researchers to pinpoint discrete neuronal populations that control fluid satiation, revealing that hindbrain regions, such as the nucleus of the solitary tract, area postrema, and parabrachial nucleus, primarily inhibit fluid intake. By contrast, forebrain regions such as the lamina terminalis, primarily stimulate thirst and fluid intake. One intriguing aspect of fluid satiation is that thirst is quenched tens of minutes before water reaches the circulation, and the amount of water ingested is accurately calibrated to match physiological needs. This suggests that 'preabsorptive' inputs from the oropharyngeal regions, esophagus or upper gastrointestinal tract anticipate the amount of fluid required to restore fluid homeostasis, and provide rapid signals to terminate drinking once this amount has been consumed. It is likely that preabsorptive signals are carried via the vagal nerve to the hindbrain. In this review, we explore our current understanding of the fluid satiation neurocircuitry, its inputs and outputs, and its interconnections within the brain, with a focus on recent studies of the hindbrain, particularly the parabrachial nucleus.
Topics: Brain; Brain Mapping; Drinking; Homeostasis; Humans; Neural Pathways; Prosencephalon; Rhombencephalon; Satiation; Thirst
PubMed: 29932494
DOI: 10.14814/phy2.13744 -
Neuropharmacology Oct 2021Our understanding of the role of the parabrachial nucleus (PBN) has evolved as technology has advanced, in part due to cell-specific studies and complex behavioral... (Review)
Review
Our understanding of the role of the parabrachial nucleus (PBN) has evolved as technology has advanced, in part due to cell-specific studies and complex behavioral assays. This is reflected in the heterogeneous neuronal populations within the PBN to the extended amygdala (EA) circuits which encompass the bed nucleus of the stria terminalis (BNST) and central amygdala (CeA) circuitry, as they differentially modulate aspects of behavior in response to diverse threat-like contexts necessary for survival. Here we review how the PBN→CeA and PBN→BNST pathways differentially modulate fear-like behavior, innate and conditioned, through unique changes in neurotransmission in response to stress-inducing contexts. Furthermore, we hypothesize how in specific instances the PBN→CeA and PBN→BNST circuits are redundant and in part intertwined with their respective reciprocal projections. By deconstructing the interoceptive and exteroceptive components of affect- and stress related behavioral paradigms, evidence suggests that the PBN→CeA circuit modulates innate response to physical stimuli and fear conditioning. Conversely, the PBN→BNST circuit modulates distress-like stress in unpredictable contexts. Thereby, the PBN provides a pathway for alarming interoceptive and exteroceptive stimuli to be processed and relayed to the EA to induce stress-relevant affect. Additionally, we provide a framework for future studies to detail the cell-type specific intricacies of PBN→EA circuits in mediating behavioral responses to threats, and the relevance of the PBN in drug-use as it relates to threat and negative reinforcement. This article is part of the special Issue on 'Neurocircuitry Modulating Drug and Alcohol Abuse'.
Topics: Affect; Amygdala; Animals; Fear; Humans; Parabrachial Nucleus; Septal Nuclei; Stress, Psychological
PubMed: 34461068
DOI: 10.1016/j.neuropharm.2021.108757 -
Neuroscience Bulletin Apr 2023The parabrachial nucleus (PBN) integrates interoceptive and exteroceptive information to control various behavioral and physiological processes including breathing,...
The parabrachial nucleus (PBN) integrates interoceptive and exteroceptive information to control various behavioral and physiological processes including breathing, emotion, and sleep/wake regulation through the neural circuits that connect to the forebrain and the brainstem. However, the precise identity and function of distinct PBN subpopulations are still largely unknown. Here, we leveraged molecular characterization, retrograde tracing, optogenetics, chemogenetics, and electrocortical recording approaches to identify a small subpopulation of neurotensin-expressing neurons in the PBN that largely project to the emotional control regions in the forebrain, rather than the medulla. Their activation induces freezing and anxiety-like behaviors, which in turn result in tachypnea. In addition, optogenetic and chemogenetic manipulations of these neurons revealed their function in promoting wakefulness and maintaining sleep architecture. We propose that these neurons comprise a PBN subpopulation with specific gene expression, connectivity, and function, which play essential roles in behavioral and physiological regulation.
Topics: Parabrachial Nucleus; Wakefulness; Neurons; Emotions; Sleep
PubMed: 36522525
DOI: 10.1007/s12264-022-00994-8 -
Neuron Jan 2022Humans and animals alike perform behaviors-like putting on a sweater or building a warm nest-to regulate body temperature. In this issue of Neuron, Jung et al. (2022)...
Humans and animals alike perform behaviors-like putting on a sweater or building a warm nest-to regulate body temperature. In this issue of Neuron, Jung et al. (2022) reveal a parabrachial nucleus-to-lateral hypothalamus circuit that regulates thermoregulatory behavior, a circuit distinct from that which governs motivated feeding behavior.
Topics: Animals; Body Temperature Regulation; Feeding Behavior; Hunger; Hypothalamic Area, Lateral; Neurons
PubMed: 35051361
DOI: 10.1016/j.neuron.2021.12.030 -
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 -
The Journal of Neuroscience : the... Jul 2023Thermoregulatory behavior in homeothermic animals is an innate behavior to defend body core temperature from environmental thermal challenges in coordination with...
Thermoregulatory behavior in homeothermic animals is an innate behavior to defend body core temperature from environmental thermal challenges in coordination with autonomous thermoregulatory responses. In contrast to the progress in understanding the central mechanisms of autonomous thermoregulation, those of behavioral thermoregulation remain poorly understood. We have previously shown that the lateral parabrachial nucleus (LPB) mediates cutaneous thermosensory afferent signaling for thermoregulation. To understand the thermosensory neural network for behavioral thermoregulation, in the present study, we investigated the roles of ascending thermosensory pathways from the LPB in avoidance behavior from innocuous heat and cold in male rats. Neuronal tracing revealed two segregated groups of LPB neurons projecting to the median preoptic nucleus (MnPO), a thermoregulatory center (LPB→MnPO neurons), and those projecting to the central amygdaloid nucleus (CeA), a limbic emotion center (LPB→CeA neurons). While LPB→MnPO neurons include separate subgroups activated by heat or cold exposure of rats, LPB→CeA neurons were only activated by cold exposure. By selectively inhibiting LPB→MnPO or LPB→CeA neurons using tetanus toxin light chain or chemogenetic or optogenetic techniques, we found that LPB→MnPO transmission mediates heat avoidance, whereas LPB→CeA transmission contributes to cold avoidance. electrophysiological experiments showed that skin cooling-evoked thermogenesis in brown adipose tissue requires not only LPB→MnPO neurons but also LPB→CeA neurons, providing a novel insight into the central mechanism of autonomous thermoregulation. Our findings reveal an important framework of central thermosensory afferent pathways to coordinate behavioral and autonomous thermoregulation and to generate the emotions of thermal comfort and discomfort that drive thermoregulatory behavior. Coordination of behavioral and autonomous thermoregulation is important for maintaining thermal homeostasis in homeothermic animals. However, the central mechanism of thermoregulatory behaviors remains poorly understood. We have previously shown that the lateral parabrachial nucleus (LPB) mediates ascending thermosensory signaling that drives thermoregulatory behavior. In this study, we found that one pathway from the LPB to the median preoptic nucleus mediates heat avoidance, whereas the other pathway from the LPB to the central amygdaloid nucleus is required for cold avoidance. Surprisingly, both pathways are required for skin cooling-evoked thermogenesis in brown adipose tissue, an autonomous thermoregulatory response. This study provides a central thermosensory network that coordinates behavioral and autonomous thermoregulation and generates thermal comfort and discomfort that drive thermoregulatory behavior.
Topics: Male; Rats; Animals; Parabrachial Nucleus; Body Temperature Regulation; Skin; Cold Temperature; Afferent Pathways; Neural Pathways
PubMed: 37339876
DOI: 10.1523/JNEUROSCI.0643-23.2023 -
Proceedings of the National Academy of... Feb 2021The TGFβ cytokine family member, GDF-15, reduces food intake and body weight and represents a potential treatment for obesity. Because the brainstem-restricted...
The TGFβ cytokine family member, GDF-15, reduces food intake and body weight and represents a potential treatment for obesity. Because the brainstem-restricted expression pattern of its receptor, GDNF Family Receptor α-like (GFRAL), presents an exciting opportunity to understand mechanisms of action for area postrema neurons in food intake; we generated and conditional mice to visualize and manipulate GFRAL neurons. We found infection or pathophysiologic states (rather than meal ingestion) stimulate GFRAL neurons. TRAP-Seq analysis of GFRAL neurons revealed their expression of a wide range of neurotransmitters and neuropeptides. Artificially activating -expressing neurons inhibited feeding, decreased gastric emptying, and promoted a conditioned taste aversion (CTA). GFRAL neurons most strongly innervate the parabrachial nucleus (PBN), where they target CGRP-expressing (CGRP) neurons. Silencing CGRP neurons abrogated the aversive and anorexic effects of GDF-15. These findings suggest that GFRAL neurons link non-meal-associated pathophysiologic signals to suppress nutrient uptake and absorption.
Topics: Animals; Avoidance Learning; Body Weight; Eating; Feeding Behavior; Female; Glial Cell Line-Derived Neurotrophic Factor Receptors; Growth Differentiation Factor 15; Male; Mice; Neurons; Parabrachial Nucleus; Rats; Rats, Long-Evans
PubMed: 33593916
DOI: 10.1073/pnas.2021357118 -
Cell Reports Aug 2022Perception of threats is essential for survival. Previous findings suggest that parallel pathways independently relay innate threat signals from different sensory...
Perception of threats is essential for survival. Previous findings suggest that parallel pathways independently relay innate threat signals from different sensory modalities to multiple brain areas, such as the midbrain and hypothalamus, for immediate avoidance. Yet little is known about whether and how multi-sensory innate threat cues are integrated and conveyed from each sensory modality to the amygdala, a critical brain area for threat perception and learning. Here, we report that neurons expressing calcitonin gene-related peptide (CGRP) in the parvocellular subparafascicular nucleus in the thalamus and external lateral parabrachial nucleus in the brainstem respond to multi-sensory threat cues from various sensory modalities and relay negative valence to the lateral and central amygdala, respectively. Both CGRP populations and their amygdala projections are required for multi-sensory threat perception and aversive memory formation. The identification of unified innate threat pathways may provide insights into developing therapeutic candidates for innate fear-related disorders.
Topics: Calcitonin Gene-Related Peptide; Central Amygdaloid Nucleus; Cues; Parabrachial Nucleus; Thalamus
PubMed: 35977501
DOI: 10.1016/j.celrep.2022.111222 -
Cell Metabolism May 2016Campos et al. (2016) identify a role for CGRP neurons in the external lateral parabrachial nucleus in regulating meal size in response to vagal or hormonal stimuli....
Campos et al. (2016) identify a role for CGRP neurons in the external lateral parabrachial nucleus in regulating meal size in response to vagal or hormonal stimuli. This area may also have a broader role as a "house alarm" that can alter ongoing behaviors in response to noxious visceral inputs.
Topics: Animals; Calcitonin Gene-Related Peptide; Humans; Mice; Neurons; Parabrachial Nucleus
PubMed: 27166934
DOI: 10.1016/j.cmet.2016.04.021