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The Journal of Neuroscience : the... Jul 2023The amygdala plays a key role in the processing of itch and pain signals as well as emotion. A previous study revealed that the central nucleus of the amygdala...
The amygdala plays a key role in the processing of itch and pain signals as well as emotion. A previous study revealed that the central nucleus of the amygdala (CeA)-parabrachial nucleus (PBN) pathway is involved in pain regulation. The same pathway might also control itch. To test this possibility, prodynorphin (Pdyn)-Cre mice were used to optogenetically manipulate Pdyn CeA-to-PBN projections. We found that optogenetic stimulation of Pdyn amygdala neurons or Pdyn CeA-to-PBN projections inhibited histamine-evoked and chloroquine-evoked scratching. The number of Fos-positive neurons in the PBN increased following intradermal injection of chloroquine. Optogenetic stimulation of Pdyn CeA-to-PBN projections suppressed the increase in Fos expression in the PBN. Optogenetic stimulation of Pdyn CeA-to-PBN projections increased thermal and mechanical thresholds without affecting anxiety-like behavior. These results highlight the importance of dynorphinergic projections from the central amygdala to the parabrachial nucleus in the regulation of itch signaling. The central nucleus of the amygdala (CeA)-parabrachial nucleus (PBN) pathway regulates pain signaling. Using prodynorphin (Pdyn)-cre mice, we investigated the role of Pdyn CeA-to-PBN projections in itch. Optogenetic stimulation of Pdyn CeA-to-PBN projections inhibited pruritogen-evoked scratching and neuronal activity (c-Fos expression) in the PBN. Together, dynorphinergic projections from the central amygdala to the parabrachial nucleus are important for regulating itch information.
Topics: Mice; Animals; Parabrachial Nucleus; Central Amygdaloid Nucleus; Pain; Neurons; Pruritus; Chloroquine
PubMed: 37399333
DOI: 10.1523/JNEUROSCI.0726-23.2023 -
BioRxiv : the Preprint Server For... Jun 2023The Kölliker-Fuse nucleus (KF), which is part of the parabrachial complex, participates in the generation of eupnea under resting conditions and the control of active...
UNLABELLED
The Kölliker-Fuse nucleus (KF), which is part of the parabrachial complex, participates in the generation of eupnea under resting conditions and the control of active abdominal expiration when increased ventilation is required. Moreover, dysfunctions in KF neuronal activity are believed to play a role in the emergence of respiratory abnormalities seen in Rett syndrome (RTT), a progressive neurodevelopmental disorder associated with an irregular breathing pattern and frequent apneas. Relatively little is known, however, about the intrinsic dynamics of neurons within the KF and how their synaptic connections affect breathing pattern control and contribute to breathing irregularities. In this study, we use a reduced computational model to consider several dynamical regimes of KF activity paired with different input sources to determine which combinations are compatible with known experimental observations. We further build on these findings to identify possible interactions between the KF and other components of the respiratory neural circuitry. Specifically, we present two models that both simulate eupneic as well as RTT-like breathing phenotypes. Using nullcline analysis, we identify the types of inhibitory inputs to the KF leading to RTT-like respiratory patterns and suggest possible KF local circuit organizations. When the identified properties are present, the two models also exhibit quantal acceleration of late-expiratory activity, a hallmark of active expiration featuring forced exhalation, with increasing inhibition to KF, as reported experimentally. Hence, these models instantiate plausible hypotheses about possible KF dynamics and forms of local network interactions, thus providing a general framework as well as specific predictions for future experimental testing.
KEY POINTS
The Kölliker-Fuse nucleus (KF), a part of the parabrachial complex, is involved in regulating normal breathing and controlling active abdominal expiration during increased ventilation. Dysfunction in KF neuronal activity is thought to contribute to respiratory abnormalities seen in Rett syndrome (RTT). This study utilizes computational modeling to explore different dynamical regimes of KF activity and their compatibility with experimental observations. By analyzing different model configurations, the study identifies inhibitory inputs to the KF that lead to RTT-like respiratory patterns and proposes potential KF local circuit organizations. Two models are presented that simulate both normal breathing and RTT-like breathing patterns. These models provide plausible hypotheses and specific predictions for future experimental investigations, offering a general framework for understanding KF dynamics and potential network interactions.
PubMed: 37398197
DOI: 10.1101/2023.06.15.545086 -
Brain Research Bulletin Sep 2023The nucleus tractus solitarii (NTS) is the primary central station that integrates visceral afferent information and regulates respiratory, gastrointestinal,...
The nucleus tractus solitarii (NTS) is the primary central station that integrates visceral afferent information and regulates respiratory, gastrointestinal, cardiovascular, and other physiological functions. Leptin receptor b (LepRb)-expressing neurons of the NTS (NTS neurons) are implicated in central respiration regulation, respiratory facilitation, and respiratory drive enhancement. Furthermore, LepRb dysfunction is involved in obesity, insulin resistance, and sleep-disordered breathing. However, the monosynaptic inputs and outputs of NTS neurons in whole-brain mapping remain to be elucidated. Therefore, the exploration of its whole-brain connection system may provide strong support for comprehensively understanding the physiological and pathological functions of NTS neurons. In the present study, we used a cell type-specific, modified rabies virus and adeno-associated virus with the Cre-loxp system to map monosynaptic inputs and outputs of NTS neurons in LepRb-Cre mice. The results showed that NTS neurons received inputs from 48 nuclei in the whole brain from five brain regions, including especially the medulla. We found that NTS neurons received inputs from nuclei associated with respiration, such as the pre-Bötzinger complex, ambiguus nucleus, and parabrachial nucleus. Interestingly, some brain areas related to cardiovascular regulation-i.e., the ventrolateral periaqueductal gray and locus coeruleus-also sent a small number of inputs to NTS neurons. In addition, anterograde tracing results demonstrated that NTS neurons sent efferent projections to 15 nuclei, including the dorsomedial hypothalamic nucleus and arcuate hypothalamic nucleus, which are involved in regulation of energy metabolism and feeding behaviors. Quantitative statistical analysis revealed that the inputs of the whole brain to NTS neurons were significantly greater than the outputs. Our study comprehensively revealed neuronal connections of NTS neurons in the whole brain and provided a neuroanatomical basis for further research on physiological and pathological functions of NTS neurons.
Topics: Mice; Animals; Solitary Nucleus; Receptors, Leptin; Neurons; Brain Mapping; Obesity
PubMed: 37348822
DOI: 10.1016/j.brainresbull.2023.110693 -
Sheng Li Xue Bao : [Acta Physiologica... Jun 2023Pain is a multi-dimensional emotional experience, and pain sensation and pain emotion are the two main components. As for pain, previous studies only focused on a...
Pain is a multi-dimensional emotional experience, and pain sensation and pain emotion are the two main components. As for pain, previous studies only focused on a certain link of the pain transmission pathway or a certain key brain region, and there is a lack of evidence that connectivity of brain regions is involved in pain or pain regulation in the overall state. The establishment of new experimental tools and techniques has brought light to the study of neural pathways of pain sensation and pain emotion. In this paper, the structure and functional basis of the neural pathways involved in the formation of pain sensation and the regulation of pain emotion in the nervous system above the spinal cord level, including thalamus, amygdala, midbrain periaqueductal gray (PAG), parabrachial nucleus (PB) and medial prefrontal cortex (mPFC), are reviewed in recent years, providing clues for the in-depth study of pain.
Topics: Humans; Pain; Neural Pathways; Periaqueductal Gray; Brain; Spinal Cord; Magnetic Resonance Imaging
PubMed: 37340655
DOI: No ID Found -
Sheng Li Xue Bao : [Acta Physiologica... Jun 2023To explore the changes of cold sensitivity after exposure to acute hypoxia and its mechanisms, Sprague-Dawley rats were divided into normoxia control group (21% O, 25...
To explore the changes of cold sensitivity after exposure to acute hypoxia and its mechanisms, Sprague-Dawley rats were divided into normoxia control group (21% O, 25 °C), 10% O hypoxia group (10% O, 25 °C), 7% O hypoxia group (7% O, 25 °C), normoxia cold group (21% O, 10 °C) and hypoxia cold group (7% O, 10 °C). Cold foot withdrawal latency and preference temperature of each group were measured, skin temperatures were estimated using an infrared thermographic imaging camera, body core temperature was recorded by wireless telemetry system, immunohistochemical staining was used to detect the expression of c-Fos in the lateral parabrachial nucleus (LPB). The results showed that acute hypoxia significantly prolonged the latency of cold foot withdrawal and significantly enhanced the intensity of cold stimulation for foot withdrawal, and the rats under hypoxia preferred cold temperature. Cold exposure (10 °C) for 1 h significantly enhanced the expression of c-Fos in LPB of rats in normoxia, while hypoxia inhibited cold-induced c-Fos expression. Acute hypoxia significantly increased the skin temperature of feet and tails, decreased the skin temperature of interscapular region, and decreased the body core temperature of rats. These results indicate that acute hypoxia can significantly blunt cold sensitivity through the inhibition of LPB, suggesting actively keeping warm measures should be taken at the early stage after ascent to high altitude to prevent the upper respiratory infection and acute mountain sickness.
Topics: Rats; Animals; Rats, Sprague-Dawley; Parabrachial Nucleus; Temperature; Cold Temperature; Hypoxia; Proto-Oncogene Proteins c-fos
PubMed: 37340644
DOI: No ID Found -
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 -
A subthalamo-parabrachial glutamatergic pathway is involved in stress-induced self-grooming in mice.Acta Pharmacologica Sinica Nov 2023Excessive self-grooming is an important behavioral phenotype of the stress response in rodents. Elucidating the neural circuit that regulates stress-induced...
Excessive self-grooming is an important behavioral phenotype of the stress response in rodents. Elucidating the neural circuit that regulates stress-induced self-grooming may suggest potential treatment to prevent maladaptation to stress that is implicated in emotional disorders. Stimulation of the subthalamic nucleus (STN) has been found to induce strong self-grooming. In this study we investigated the role of the STN and a related neural circuit in mouse stress-related self-grooming. Body-restraint and foot-shock stress-induced self-grooming models were established in mice. We showed that both body restraint and foot shock markedly increased the expression of c-Fos in neurons in the STN and lateral parabrachial nucleus (LPB). Consistent with this, the activity of STN neurons and LPB glutamatergic (Glu) neurons, as assessed with fiber photometry recording, was dramatically elevated during self-grooming in the stressed mice. Using whole-cell patch-clamp recordings in parasagittal brain slices, we identified a monosynaptic projection from STN neurons to LPB Glu neurons that regulates stress-induced self-grooming in mice. Enhanced self-grooming induced by optogenetic activation of the STN-LPB Glu pathway was attenuated by treatment with fluoxetine (18 mg·kg·d, p.o., for 2 weeks) or in the presence of a cage mate. Furthermore, optogenetic inhibition of the STN-LPB pathway attenuated stress-related but not natural self-grooming. Taken together, these results suggest that the STN-LPB pathway regulates the acute stress response and is a potential target for intervention in stress-related emotional disorders.
Topics: Mice; Animals; Grooming; Subthalamic Nucleus; Neurons
PubMed: 37322164
DOI: 10.1038/s41401-023-01114-6 -
The Journal of Headache and Pain Jun 2023Repeat mild traumatic brain injuries (RmTBI) result in substantial burden to the public health system given their association with chronic post-injury pathologies, such...
Repeat mild traumatic brain injuries (RmTBI) result in substantial burden to the public health system given their association with chronic post-injury pathologies, such as chronic pain and post-traumatic headache. Although this may relate to dysfunctional descending pain modulation (DPM), it is uncertain what mechanisms drive changes within this pathway. One possibility is altered orexinergic system functioning, as orexin is a potent anti-nociceptive neuromodulator. Orexin is exclusively produced by the lateral hypothalamus (LH) and receives excitatory innervation from the lateral parabrachial nucleus (lPBN). Therefore, we used neuronal tract-tracing to investigate the relationship between RmTBI and connectivity between lPBN and the LH, as well as orexinergic projections to a key site within the DPM, the periaqueductal gray (PAG). Prior to injury induction, retrograde and anterograde tract-tracing surgery was performed on 70 young-adult male Sprague Dawley rats, targeting the lPBN and PAG. Rodents were then randomly assigned to receive RmTBIs or sham injuries before undergoing testing for anxiety-like behaviour and nociceptive sensitivity. Immunohistochemical analysis identified distinct and co-localized orexin and tract-tracing cell bodies and projections within the LH. The RmTBI group exhibited altered nociception and reduced anxiety as well as a loss of orexin cell bodies and a reduction of hypothalamic projections to the ventrolateral nucleus of the PAG. However, there was no significant effect of injury on neuronal connectivity between the lPBN and orexinergic cell bodies within the LH. Our identification of structural losses and the resulting physiological changes in the orexinergic system following RmTBI begins to clarify acute post-injury mechanistic changes that drive may drive the development of post-traumatic headache and the chronification of pain.
Topics: Male; Rats; Animals; Rats, Sprague-Dawley; Orexins; Post-Traumatic Headache; Nociception; Brain Concussion; Chronic Pain
PubMed: 37316796
DOI: 10.1186/s10194-023-01608-y -
ELife Jun 2023Opioids depress breathing by inhibition of interconnected respiratory nuclei in the pons and medulla. Mu opioid receptor (MOR) agonists directly hyperpolarize a...
Opioids depress breathing by inhibition of interconnected respiratory nuclei in the pons and medulla. Mu opioid receptor (MOR) agonists directly hyperpolarize a population of neurons in the dorsolateral pons, particularly the Kölliker-Fuse (KF) nucleus, that are key mediators of opioid-induced respiratory depression. However, the projection target and synaptic connections of MOR-expressing KF neurons are unknown. Here, we used retrograde labeling and brain slice electrophysiology to determine that MOR-expressing KF neurons project to respiratory nuclei in the ventrolateral medulla, including the preBötzinger complex (preBötC) and rostral ventral respiratory group (rVRG). These medullary-projecting, MOR-expressing dorsolateral pontine neurons express FoxP2 and are distinct from calcitonin gene-related peptide-expressing lateral parabrachial neurons. Furthermore, dorsolateral pontine neurons release glutamate onto excitatory preBötC and rVRG neurons via monosynaptic projections, which is inhibited by presynaptic opioid receptors. Surprisingly, the majority of excitatory preBötC and rVRG neurons receiving MOR-sensitive glutamatergic synaptic input from the dorsolateral pons are themselves hyperpolarized by opioids, suggesting a selective opioid-sensitive circuit from the KF to the ventrolateral medulla. Opioids inhibit this excitatory pontomedullary respiratory circuit by three distinct mechanisms-somatodendritic MORs on dorsolateral pontine and ventrolateral medullary neurons and presynaptic MORs on dorsolateral pontine neuron terminals in the ventrolateral medulla-all of which could contribute to opioid-induced respiratory depression.
Topics: Analgesics, Opioid; Medulla Oblongata; Neurons; Pons; Respiration
PubMed: 37314062
DOI: 10.7554/eLife.81119 -
Neuron Aug 2023The central nervous system regulates systemic immune responses by integrating the physiological and behavioral constraints faced by an individual. Corticosterone (CS),...
The central nervous system regulates systemic immune responses by integrating the physiological and behavioral constraints faced by an individual. Corticosterone (CS), the release of which is controlled in the hypothalamus by the paraventricular nucleus (PVN), is a potent negative regulator of immune responses. Using the mouse model, we report that the parabrachial nucleus (PB), an important hub linking interoceptive afferent information to autonomic and behavioral responses, also integrates the pro-inflammatory cytokine IL-1β signal to induce the CS response. A subpopulation of PB neurons, directly projecting to the PVN and receiving inputs from the vagal complex (VC), responds to IL-1β to drive the CS response. Pharmacogenetic reactivation of these IL-1β-activated PB neurons is sufficient to induce CS-mediated systemic immunosuppression. Our findings demonstrate an efficient brainstem-encoded modality for the central sensing of cytokines and the regulation of systemic immune responses.
Topics: Animals; Mice; Cytokines; Corticosterone; Feedback; Parabrachial Nucleus; Hypothalamus; Paraventricular Hypothalamic Nucleus
PubMed: 37279750
DOI: 10.1016/j.neuron.2023.05.009