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Neuroscience Jan 2024The lateral parabrachial nucleus (LPBN) is known to play a key role in relaying noxious information from the spinal cord to the brain. Different LPBN efferent mediate...
The lateral parabrachial nucleus (LPBN) is known to play a key role in relaying noxious information from the spinal cord to the brain. Different LPBN efferent mediate different aspects of the nocifensive response. However, the function of the LPBN → lateral hypothalamus (LH) circuit in response to noxious stimuli has remained unknown. Here, we show that LPBN → LH circuit is activated by noxious stimuli. Interestingly, either activation or inhibition of this circuit induced analgesia. Optogenetic activation of LPBN afferents in the LH elicited spontaneous jumping and induced place aversion. Optogenetic inhibition inhibited jumping behavior to noxious heat. Ablation of LH glutamatergic neurons could abolish light-evoked analgesia and jumping behavior. Our study revealed a role for the LPBN → LH pathway in nocifensive behaviors.
Topics: Humans; Hypothalamic Area, Lateral; Parabrachial Nucleus; Pain; Brain; Neurons
PubMed: 38036057
DOI: 10.1016/j.neuroscience.2023.11.020 -
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 -
BioRxiv : the Preprint Server For... Nov 2023The "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 many neuronal subtypes' unique marker genes. 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.
PubMed: 38014113
DOI: 10.1101/2023.09.18.558047 -
Synapse (New York, N.Y.) Jan 2024Dopamine (DA) is involved in stress and stress-related illnesses, including many psychiatric disorders. Corticotropin-releasing factor (CRF) plays a role in stress...
Dopamine (DA) is involved in stress and stress-related illnesses, including many psychiatric disorders. Corticotropin-releasing factor (CRF) plays a role in stress responses and targets the ventral midbrain DA system, which is composed of DA and non-DA cells, and divided into specific subregions. Although CRF inputs to the midline A10 nuclei ("classic VTA") are known, in monkeys, CRF-containing terminals are also highly enriched in the expanded A10 parabrachial pigmented nucleus (PBP) and in the A8 retrorubral field subregions. We characterized CRF-labeled synaptic terminals on DA (tyrosine hydroxylase, TH+) and non-DA (TH-) cell types in the PBP and A8 regions using immunoreactive electron microscopy (EM) in male and female macaques. CRF labeling was present mostly in axon terminals, which mainly contacted TH-negative dendrites in both subregions. Most CRF-positive terminals had symmetric profiles. In both PBP and A8, CRF symmetric (putative inhibitory) synapses onto TH-negative dendrites were significantly greater than asymmetric (putative excitatory) profiles. This overall pattern was similar in males and females, despite shifts in the size of these effects between regions depending on sex. Because stress and gonadal hormone shifts can influence CRF expression, we also did hormonal assays over a 6-month time period and found little variability in basal cortisol across similarly housed animals at the same age. Together our findings suggest that at baseline, CRF-positive synaptic terminals in the primate PBP and A8 are poised to regulate DA indirectly through synaptic contacts onto non-DA neurons.
Topics: Humans; Animals; Male; Female; Dopamine; Corticotropin-Releasing Hormone; Macaca; Presynaptic Terminals; Tyrosine 3-Monooxygenase; Piperidones; Benzeneacetamides
PubMed: 37996987
DOI: 10.1002/syn.22284 -
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 -
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 -
Nature Neuroscience Nov 2023In addition to its motor functions, the cerebellum is involved in emotional regulation, anxiety and affect. We found that suppressing the firing of cerebellar Purkinje...
In addition to its motor functions, the cerebellum is involved in emotional regulation, anxiety and affect. We found that suppressing the firing of cerebellar Purkinje cells (PCs) rapidly excites forebrain areas that contribute to such functions (including the amygdala, basal forebrain and septum), but that the classic cerebellar outputs, the deep cerebellar nuclei, do not directly project there. We show that PCs directly inhibit parabrachial nuclei (PBN) neurons that project to numerous forebrain regions. Suppressing the PC-PBN pathway influences many regions in the forebrain and is aversive. Molecular profiling shows that PCs directly inhibit numerous types of PBN neurons that control diverse behaviors that are not involved in motor control. Therefore, the PC-PBN pathway allows the cerebellum to directly regulate activity in the forebrain, and may be an important substrate for cerebellar disorders arising from damage to the posterior vermis.
Topics: Purkinje Cells; Parabrachial Nucleus; Cerebellum; Prosencephalon; Neurons
PubMed: 37919612
DOI: 10.1038/s41593-023-01462-w -
BioRxiv : the Preprint Server For... Oct 2023The transition from acute to chronic pain involves maladaptive plasticity in central nociceptive pathways. Growing evidence suggests that changes within the parabrachial...
The transition from acute to chronic pain involves maladaptive plasticity in central nociceptive pathways. Growing evidence suggests that changes within the parabrachial nucleus (PBN), an important component of the spino-parabrachio-amygdaloid pain pathway, are key contributors to the development and maintenance of chronic pain. In animal models of chronic pain, PBN neurons become sensitive to normally innocuous stimuli and responses to noxious stimuli become amplified and more often produce after-discharges that outlast the stimulus. Using slice electrophysiology and two mouse models of neuropathic pain, sciatic cuff and chronic constriction of the infraorbital nerve (CCI-ION), we find that changes in the firing properties of PBN neurons and a shift in inhibitory synaptic transmission may underlie this phenomenon. Compared to PBN neurons from shams, a larger proportion of PBN neurons from mice with a sciatic cuff were spontaneously active at rest, and these same neurons showed increased excitability relative to shams. In contrast, quiescent PBN neurons from cuff mice were less excitable than those from shams. Despite an increase in excitability in a subset of PBN neurons, the presence of after-discharges frequently observed were largely absent in both injury models. However, GABA-mediated presynaptic inhibition of GABAergic terminals is enhanced in PBN neurons after CCIION. These data suggest that the amplified activity of PBN neurons observed in rodent models of chronic pain arise through a combination of changes in firing properties and network excitability.
PubMed: 37905065
DOI: 10.1101/2023.10.11.561891 -
Brain Sciences Oct 2023Accumulated evidence has demonstrated that the gut microbiome can contribute to pain modulation through the microbiome-gut-brain axis. Various relevant microbiome... (Review)
Review
Accumulated evidence has demonstrated that the gut microbiome can contribute to pain modulation through the microbiome-gut-brain axis. Various relevant microbiome metabolites in the gut are involved in the regulation of pain signaling in the central nervous system. In this review, we summarize recent advances in gut-brain interactions by which the microbiome metabolites modulate pain, with a focus on orofacial pain, and we further discuss the role of gut-brain crosstalk in the central mechanisms of orofacial pain whereby the gut microbiome modulates orofacial pain via the vagus nerve-mediated direct pathway and the gut metabolites/molecules-mediated indirect pathway. The direct and indirect pathways both contribute to the central regulation of orofacial pain through different brain structures (such as the nucleus tractus solitarius and the parabrachial nucleus) and signaling transmission across the blood-brain barrier, respectively. Understanding the gut microbiome-regulated pain mechanisms in the brain could help us to develop non-opioid novel therapies for orofacial pain.
PubMed: 37891825
DOI: 10.3390/brainsci13101456 -
Biological Psychiatry Global Open... Oct 2023The neuropeptide PACAP (pituitary adenylate cyclase-activating polypeptide) is a master regulator of central and peripheral stress responses, yet it is not clear how...
BACKGROUND
The neuropeptide PACAP (pituitary adenylate cyclase-activating polypeptide) is a master regulator of central and peripheral stress responses, yet it is not clear how PACAP projections throughout the brain execute endocrine and behavioral stress responses.
METHODS
We used AAV (adeno-associated virus) neuronal tracing, an acute restraint stress (ARS) paradigm, and intersectional genetics, in C57BL/6 mice, to identify PACAP-containing circuits controlling stress-induced behavior and endocrine activation.
RESULTS
PACAP deletion from forebrain excitatory neurons, including a projection directly from medial prefrontal cortex to hypothalamus, impairs c-fos activation and corticotropin-releasing hormone (CRH) messenger RNA elevation in the paraventricular nucleus after 2 hours of restraint, without affecting ARS-induced hypophagia, or c-fos elevation in nonhypothalamic brain. Elimination of PACAP within projections from lateral parabrachial nucleus to extended amygdala, on the other hand, attenuates ARS-induced hypophagia, along with extended amygdala fos induction, without affecting ARS-induced CRH messenger RNA elevation in the paraventricular nucleus. PACAP projections to extended amygdala terminate at protein kinase C delta type (PKCδ) neurons in both the central amygdala and the oval bed nucleus of the stria terminalis. Silencing of PKCδ neurons in the central amygdala, but not in the oval bed nucleus of the stria terminalis, attenuates ARS-induced hypophagia. Experiments were carried out in mice of both sexes with ≥ 3 per group.
CONCLUSIONS
A frontocortical descending PACAP projection controls paraventricular nucleus CRH messenger RNA production to maintain hypothalamic-pituitary-adrenal axis activation and regulate the endocrine response to stress. An ascending PACAPergic projection from the external lateral parabrachial nucleus to PKCδ neurons in the central amygdala regulates behavioral responses to stress. Defining two separate limbs of the acute stress response provides broader insight into the specific brain circuitry engaged by the psychogenic stress response.
PubMed: 37881538
DOI: 10.1016/j.bpsgos.2023.04.001