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Frontiers in Neuroscience 2019Obstructive sleep apnea is a sleep and breathing disorder, in which, patients suffer from cycles of atonia of airway dilator muscles during sleep, resulting in airway... (Review)
Review
Obstructive sleep apnea is a sleep and breathing disorder, in which, patients suffer from cycles of atonia of airway dilator muscles during sleep, resulting in airway collapse, followed by brief arousals that help re-establish the airway patency. These repetitive arousals which can occur hundreds of times during the course of a night are the cause of the sleep-disruption, which in turn causes cognitive impairment as well as cardiovascular and metabolic morbidities. To prevent this potential outcome, it is important to target preventing the arousal from sleep while preserving or augmenting the increase in respiratory drive that reinitiates breathing, but will require understanding of the neural circuits that regulate the cortical and respiratory responses to apnea. The parabrachial nucleus (PB) is located in rostral pons. It receives chemosensory information from medullary nuclei that sense increase in CO2 (hypercapnia), decrease in O2 (hypoxia) and mechanosensory inputs from airway negative pressure during apneas. The PB area also exerts powerful control over cortical arousal and respiration, and therefore, is an excellent candidate for mediating the EEG arousal and restoration of the airway during sleep apneas. Using various genetic tools, we dissected the neuronal sub-types responsible for relaying the stimulus for cortical arousal to forebrain arousal circuits. The present review will focus on the circuitries that regulate waking-up from sleep in response to hypercapnia.
PubMed: 31080401
DOI: 10.3389/fnins.2019.00401 -
Nature Communications Jul 2022Both rodents and primates have evolved to orchestrate food intake to maintain thermal homeostasis in coping with ambient temperature challenges. However, the mechanisms...
Both rodents and primates have evolved to orchestrate food intake to maintain thermal homeostasis in coping with ambient temperature challenges. However, the mechanisms underlying temperature-coordinated feeding behavior are rarely reported. Here we find that a non-canonical feeding center, the anteroventral and periventricular portions of medial preoptic area (apMPOA) respond to altered dietary states in mice. Two neighboring but distinct neuronal populations in apMPOA mediate feeding behavior by receiving anatomical inputs from external and dorsal subnuclei of lateral parabrachial nucleus. While both populations are glutamatergic, the arcuate nucleus-projecting neurons in apMPOA can sense low temperature and promote food intake. The other type, the paraventricular hypothalamic nucleus (PVH)-projecting neurons in apMPOA are primarily sensitive to high temperature and suppress food intake. Caspase ablation or chemogenetic inhibition of the apMPOA→PVH pathway can eliminate the temperature dependence of feeding. Further projection-specific RNA sequencing and fluorescence in situ hybridization identify that the two neuronal populations are molecularly marked by galanin receptor and apelin receptor. These findings reveal unrecognized cell populations and circuits of apMPOA that orchestrates feeding behavior against thermal challenges.
Topics: Animals; Arcuate Nucleus of Hypothalamus; Feeding Behavior; In Situ Hybridization, Fluorescence; Mice; Paraventricular Hypothalamic Nucleus; Temperature
PubMed: 35869064
DOI: 10.1038/s41467-022-31917-w -
Anesthesiology Oct 2021Recent studies showed partial reversal of opioid-induced respiratory depression in the pre-Bötzinger complex and the parabrachial nucleus/Kölliker-Fuse complex. The...
BACKGROUND
Recent studies showed partial reversal of opioid-induced respiratory depression in the pre-Bötzinger complex and the parabrachial nucleus/Kölliker-Fuse complex. The hypothesis for this study was that opioid antagonism in the parabrachial nucleus/Kölliker-Fuse complex plus pre-Bötzinger complex completely reverses respiratory depression from clinically relevant opioid concentrations.
METHODS
Experiments were performed in 48 adult, artificially ventilated, decerebrate rabbits. The authors decreased baseline respiratory rate ~50% with intravenous, "analgesic" remifentanil infusion or produced apnea with remifentanil boluses and investigated the reversal with naloxone microinjections (1 mM, 700 nl) into the Kölliker-Fuse nucleus, parabrachial nucleus, and pre-Bötzinger complex. In another group of animals, naloxone was injected only into the pre-Bötzinger complex to determine whether prior parabrachial nucleus/Kölliker-Fuse complex injection impacted the naloxone effect. Last, the µ-opioid receptor agonist [d-Ala,2N-MePhe,4Gly-ol]-enkephalin (100 μM, 700 nl) was injected into the parabrachial nucleus/Kölliker-Fuse complex. The data are presented as medians (25 to 75%).
RESULTS
Remifentanil infusion reduced the respiratory rate from 36 (31 to 40) to 16 (15 to 21) breaths/min. Naloxone microinjections into the bilateral Kölliker-Fuse nucleus, parabrachial nucleus, and pre-Bötzinger complex increased the rate to 17 (16 to 22, n = 19, P = 0.005), 23 (19 to 29, n = 19, P < 0.001), and 25 (22 to 28) breaths/min (n = 11, P < 0.001), respectively. Naloxone injection into the parabrachial nucleus/Kölliker-Fuse complex prevented apnea in 12 of 17 animals, increasing the respiratory rate to 10 (0 to 12) breaths/min (P < 0.001); subsequent pre-Bötzinger complex injection prevented apnea in all animals (13 [10 to 19] breaths/min, n = 12, P = 0.002). Naloxone injection into the pre-Bötzinger complex alone increased the respiratory rate to 21 (15 to 26) breaths/min during analgesic concentrations (n = 10, P = 0.008) but not during apnea (0 [0 to 0] breaths/min, n = 9, P = 0.500). [d-Ala,2N-MePhe,4Gly-ol]-enkephalin injection into the parabrachial nucleus/Kölliker-Fuse complex decreased respiratory rate to 3 (2 to 6) breaths/min.
CONCLUSIONS
Opioid reversal in the parabrachial nucleus/Kölliker-Fuse complex plus pre-Bötzinger complex only partially reversed respiratory depression from analgesic and even less from "apneic" opioid doses. The lack of recovery pointed to opioid-induced depression of respiratory drive that determines the activity of these areas.
Topics: Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Female; Infusions, Intravenous; Kolliker-Fuse Nucleus; Male; Parabrachial Nucleus; Rabbits; Remifentanil; Respiratory Insufficiency
PubMed: 34352068
DOI: 10.1097/ALN.0000000000003886 -
The Journal of Pain Sep 2023Opioids are powerful analgesics commonly used in pain management. However, opioids can induce complex neuroadaptations, including synaptic plasticity, that ultimately...
Opioids are powerful analgesics commonly used in pain management. However, opioids can induce complex neuroadaptations, including synaptic plasticity, that ultimately drive severe side effects, such as pain hypersensitivity and strong aversion during prolonged administration or upon drug withdrawal, even following a single, brief administration. The lateral parabrachial nucleus (LPBN) in the brainstem plays a key role in pain and emotional processing; yet, the effects of opioids on synaptic plasticity in this area remain unexplored. Using patch-clamp recordings in acute brainstem slices from male and female Sprague Dawley rats, we demonstrate a concentration-dependent, bimodal effect of opioids on excitatory synaptic transmission in the LPBN. While a lower concentration of DAMGO (0.5 µM) induced a long-term depression of synaptic strength (low-DAMGO LTD), abrupt termination of a higher concentration (10 µM) induced a long-term potentiation (high-DAMGO LTP) in a subpopulation of cells. LTD involved a metabotropic glutamate receptor (mGluR)-dependent mechanism; in contrast, LTP required astrocytes and N-methyl-D-aspartate receptor (NMDAR) activation. Selective optogenetic activation of spinal and periaqueductal gray matter (PAG) inputs to the LPBN revealed that, while LTD was expressed at all parabrachial synapses tested, LTP was restricted to spino-parabrachial synapses. Thus, we uncovered previously unknown forms of opioid-induced long-term plasticity in the parabrachial nucleus that potentially modulate some adverse effects of opioids. PERSPECTIVE: We found a previously unrecognized site of opioid-induced plasticity in the lateral parabrachial nucleus, a key region for pain and emotional processing. Unraveling opioid-induced adaptations in parabrachial function might facilitate the identification of new therapeutic measures for addressing adverse effects of opioid discontinuation such as hyperalgesia and aversion.
Topics: Rats; Male; Female; Animals; Analgesics, Opioid; Rats, Sprague-Dawley; Pain Clinics; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Neuronal Plasticity; Brain Stem; Pain
PubMed: 37150382
DOI: 10.1016/j.jpain.2023.05.001 -
BioRxiv : the Preprint Server For... Oct 2023Pain that persists beyond the time required for tissue healing and pain that arises in the absence of tissue injury are poorly understood phenomena mediated by...
Pain that persists beyond the time required for tissue healing and pain that arises in the absence of tissue injury are poorly understood phenomena mediated by plasticity within the central nervous system. The parabrachial nucleus (PBN) is a hub that relays aversive sensory information and appears to play a role in nociplasticity. Here, by preventing PBN neurons from releasing neurotransmitter or directly stimulating them we demonstrate that activation of neurons is both necessary for the manifestation of chronic pain after nerve ligation and is sufficient to drive nociplasticity in wild-type mice. Aversive stimuli such as exposure to nitroglycerin, cisplatin, or LiCl can drive nociplasticity in a -neuron-dependent manner. Calcium fluorescence imaging reveals that nitroglycerin activates PBN neurons and potentiates their responses to mechanical stimulation. The activity and excitability of neurons increased for several days after aversive events, but prolonged nociplasticity likely occurs in downstream circuitry.
PubMed: 37961621
DOI: 10.1101/2023.10.26.564223 -
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 -
Brain Structure & Function Sep 2022The paraventricular nucleus of the thalamus (PVT) projects to areas of the forebrain involved in regulating behavior. Homeostatic challenges and salient cues activate...
The paraventricular nucleus of the thalamus (PVT) projects to areas of the forebrain involved in regulating behavior. Homeostatic challenges and salient cues activate the PVT and evidence shows that the PVT regulates appetitive and aversive responses. The brainstem is a source of afferents to the PVT and the present study was done to determine if the lateral parabrachial nucleus (LPB) is a relay for inputs to the PVT. Retrograde tracing experiments with cholera toxin B (CTB) demonstrate that the LPB contains more PVT projecting neurons than other regions of the brainstem including the catecholamine cell groups. The hypothesis that the LPB is a relay for signals to the PVT was assessed using an intersectional monosynaptic rabies tracing approach. Sources of inputs to LPB included the reticular formation; periaqueductal gray (PAG); nucleus cuneiformis; and superior and inferior colliculi. Distinctive clusters of input cells to LPB-PVT projecting neurons were also found in the dorsolateral bed nucleus of the stria terminalis (BSTDL) and the lateral central nucleus of the amygdala (CeL). Anterograde viral tracing demonstrates that LPB-PVT neurons densely innervate all regions of the PVT in addition to providing collateral innervation to the preoptic area, lateral hypothalamus, zona incerta and PAG but not the BSTDL and CeL. The paper discusses the anatomical evidence that suggests that the PVT is part of a network of interconnected neurons involved in arousal, homeostasis, and the regulation of behavioral states with forebrain regions potentially providing descending modulation or gating of signals relayed from the LPB to the PVT.
Topics: Animals; Brain Stem; Midline Thalamic Nuclei; Neurons; Paraventricular Hypothalamic Nucleus; Prosencephalon; Rats; Rats, Sprague-Dawley; Thalamus
PubMed: 35838792
DOI: 10.1007/s00429-022-02534-6