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Nature Communications Mar 2024The "dorsal pons", or "dorsal pontine tegmentum" (dPnTg), is part of the brainstem. It is a complex, densely packed region whose nuclei are involved in regulating many...
The "dorsal pons", or "dorsal pontine tegmentum" (dPnTg), is part of the brainstem. It is a complex, densely packed region whose nuclei are involved in regulating many vital functions. Notable among them are the parabrachial nucleus, the Kölliker Fuse, the Barrington nucleus, the locus coeruleus, and the dorsal, laterodorsal, and ventral tegmental nuclei. In this study, we applied single-nucleus RNA-seq (snRNA-seq) to resolve neuronal subtypes based on their unique transcriptional profiles and then used multiplexed error robust fluorescence in situ hybridization (MERFISH) to map them spatially. We sampled ~1 million cells across the dPnTg and defined the spatial distribution of over 120 neuronal subtypes. Our analysis identified an unpredicted high transcriptional diversity in this region and pinpointed the unique marker genes of many neuronal subtypes. We also demonstrated that many neuronal subtypes are transcriptionally similar between humans and mice, enhancing this study's translational value. Finally, we developed a freely accessible, GPU and CPU-powered dashboard ( http://harvard.heavy.ai:6273/ ) that combines interactive visual analytics and hardware-accelerated SQL into a data science framework to allow the scientific community to query and gain insights into the data.
Topics: Humans; Animals; Mice; In Situ Hybridization, Fluorescence; Pontine Tegmentum; Brain Stem; Locus Coeruleus; Parabrachial Nucleus; Ascomycota
PubMed: 38438345
DOI: 10.1038/s41467-024-45907-7 -
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... Oct 2019The parabrachial nucleus (PBN) has long been recognized as a sensory relay receiving an array of interoceptive and exteroceptive inputs relevant to taste and ingestive... (Review)
Review
The parabrachial nucleus (PBN) has long been recognized as a sensory relay receiving an array of interoceptive and exteroceptive inputs relevant to taste and ingestive behavior, pain, and multiple aspects of autonomic control, including respiration, blood pressure, water balance, and thermoregulation. Outputs are known to be similarly widespread and complex. How sensory information is handled in PBN and used to inform different outputs to maintain homeostasis and promote survival is only now being elucidated. With a focus on taste and ingestive behaviors, pain, and thermoregulation, this review is intended to provide a context for analysis of PBN circuits involved in aversion and avoidance, and consider how information of various modalities, interoceptive and exteroceptive, is processed within PBN and transmitted to distinct targets to signal challenge, and to engage appropriate behavioral and physiological responses to maintain homeostasis.
Topics: Animals; Body Temperature Regulation; Humans; Neural Pathways; Neurons; Nociception; Pain; Parabrachial Nucleus; Taste
PubMed: 31619491
DOI: 10.1523/JNEUROSCI.1162-19.2019 -
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 -
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 -
Sleep Medicine Jan 2024The basal forebrain (BF) and the medial septum (MS) respectively drive neuronal activity of cerebral cortex and hippocampus (HPC) in sleep-wake cycle. Our previous...
INTRODUCTION
The basal forebrain (BF) and the medial septum (MS) respectively drive neuronal activity of cerebral cortex and hippocampus (HPC) in sleep-wake cycle. Our previous studies of lesions and neuronal circuit tracing have shown that the pontine parabrachial nucleus (PB) projections to the BF and MS may be a key circuit for cortical and HPC arousal.
AIMS
This study aims to demonstrate that PB projections to the BF and MS activate the cerebral cortex and HPC.
RESULTS
By using chemogenetic stimulation of the BF, the PB-BF and the PB-MS pathway combined with electroencephalogram (EEG) Fast Fourier Transformation (FFT) analysis in rats, we demonstrated that chemogenetic stimulation of the BF or PB neurons projecting to the BF activated the cerebral cortex while chemogenetic stimulation of the MS or PB neurons projecting to the MS activated HPC activity, in sleep and wake state. These stimulations did not significantly alter sleep-wake amounts.
CONCLUSIONS
Our results support that PB projections to the BF and MS specifically regulating cortical and HPC activity.
Topics: Rats; Animals; Wakefulness; Parabrachial Nucleus; Basal Forebrain; Arousal; Electroencephalography; Hippocampus
PubMed: 37984017
DOI: 10.1016/j.sleep.2023.10.032 -
Brain : a Journal of Neurology Apr 2021Deep brain stimulation (DBS) of the subthalamic nucleus, pallidum, and thalamus is an established therapy for various movement disorders. Limbic targets have also been...
Deep brain stimulation (DBS) of the subthalamic nucleus, pallidum, and thalamus is an established therapy for various movement disorders. Limbic targets have also been increasingly explored for their application to neuropsychiatric and cognitive disorders. The brainstem constitutes another DBS substrate, although the existing literature on the indications for and the effects of brainstem stimulation remains comparatively sparse. The objective of this review was to provide a comprehensive overview of the pertinent anatomy, indications, and reported stimulation-induced acute and long-term effects of existing white and grey matter brainstem DBS targets. We systematically searched the published literature, reviewing clinical trial articles pertaining to DBS brainstem targets. Overall, 164 studies describing brainstem DBS were identified. These studies encompassed 10 discrete structures: periaqueductal/periventricular grey (n = 63), pedunculopontine nucleus (n = 48), ventral tegmental area (n = 22), substantia nigra (n = 9), mesencephalic reticular formation (n = 7), medial forebrain bundle (n = 8), superior cerebellar peduncles (n = 3), red nucleus (n = 3), parabrachial complex (n = 2), and locus coeruleus (n = 1). Indications for brainstem DBS varied widely and included central neuropathic pain, axial symptoms of movement disorders, headache, depression, and vegetative state. The most promising results for brainstem DBS have come from targeting the pedunculopontine nucleus for relief of axial motor deficits, periaqueductal/periventricular grey for the management of central neuropathic pain, and ventral tegmental area for treatment of cluster headaches. Brainstem DBS has also acutely elicited numerous motor, limbic, and autonomic effects. Further work involving larger, controlled trials is necessary to better establish the therapeutic potential of DBS in this complex area.
Topics: Brain Stem; Deep Brain Stimulation; Humans
PubMed: 33313788
DOI: 10.1093/brain/awaa374 -
Proceedings of the National Academy of... Oct 2023Travel can induce motion sickness (MS) in susceptible individuals. MS is an evolutionary conserved mechanism caused by mismatches between motion-related sensory...
Travel can induce motion sickness (MS) in susceptible individuals. MS is an evolutionary conserved mechanism caused by mismatches between motion-related sensory information and past visual and motion memory, triggering a malaise accompanied by hypolocomotion, hypothermia, hypophagia, and nausea. Vestibular nuclei (VN) are critical for the processing of movement input from the inner ear. Motion-induced activation of VN neurons recapitulates MS-related signs. However, the genetic identity of VN neurons mediating MS-related autonomic and aversive responses remains unknown. Here, we identify a central role of cholecystokinin (CCK)-expressing VN neurons in motion-induced malaise. Moreover, we show that CCK VN inputs onto the parabrachial nucleus activate -expressing neurons and are sufficient to establish avoidance to novel food, which is prevented by CCK-A receptor antagonism. These observations provide greater insight into the neurobiological regulation of MS by identifying the neural substrates of MS and providing potential targets for treatment.
Topics: Animals; Mice; Motion Sickness; Movement; Neurons; Vestibular Nuclei; Vestibule, Labyrinth
PubMed: 37847729
DOI: 10.1073/pnas.2304933120 -
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 -
Brain and Nerve = Shinkei Kenkyu No... Mar 2022Epileptic activity that involves the central autonomic system, including the insular lobe, medial prefrontal cortex, amygdala, hypothalamus, periaqueductal gray,...
Epileptic activity that involves the central autonomic system, including the insular lobe, medial prefrontal cortex, amygdala, hypothalamus, periaqueductal gray, parabrachial complex, nucleus tractus solitarius, and ventrolateral medulla results in seizures with various autonomic manifestations. Some autonomic manifestations suggest localization and lateralization of epileptic foci. The autonomic nervous system modulates cerebral activity under physiological and pathological conditions. Vagus nerve stimulation (VNS) has attracted much attention for treatment of various neurological and psychiatric disorders and is an established palliative care strategy for patients with medically intractable epilepsy. Clinical and experimental studies suggest that VNS stabilizes cerebral cortical activity and inhibits abnormal excitability via pathways including upward vagus nerve conduction, nucleus tractus solitarius, and the thalamus, which consequently produces an anti-epileptic effect.
Topics: Autonomic Nervous System; Cerebral Cortex; Epilepsy; Humans; Medulla Oblongata; Thalamus; Vagus Nerve
PubMed: 35260526
DOI: 10.11477/mf.1416202023