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Cell Reports Jun 2024In addition to its role in vision, light also serves non-image-forming visual functions. Despite clinical evidence suggesting the antipruritic effects of bright light...
In addition to its role in vision, light also serves non-image-forming visual functions. Despite clinical evidence suggesting the antipruritic effects of bright light treatment, the circuit mechanisms underlying the effects of light on itch-related behaviors remain poorly understood. In this study, we demonstrate that bright light treatment reduces itch-related behaviors in mice through a visual circuit related to the lateral parabrachial nucleus (LPBN). Specifically, a subset of retinal ganglion cells (RGCs) innervates GABAergic neurons in the ventral lateral geniculate nucleus and intergeniculate leaflet (vLGN/IGL), which subsequently inhibit CaMKIIα neurons in the LPBN. Activation of both the vLGN/IGL-projecting RGCs and the vLGN/IGL-to-LPBN projections is sufficient to reduce itch-related behaviors induced by various pruritogens. Importantly, we demonstrate that the antipruritic effects of bright light treatment rely on the activation of the retina-vLGN/IGL-LPBN pathway. Collectively, our findings elucidate a visual circuit related to the LPBN that underlies the antipruritic effects of bright light treatment.
Topics: Animals; Mice; Parabrachial Nucleus; Pruritus; Light; Retinal Ganglion Cells; Visual Pathways; Mice, Inbred C57BL; Male; Antipruritics; GABAergic Neurons; Behavior, Animal; Calcium-Calmodulin-Dependent Protein Kinase Type 2
PubMed: 38865246
DOI: 10.1016/j.celrep.2024.114356 -
Neuroscience Bulletin Aug 2023The nucleus tractus solitarii (NTS) is one of the morphologically and functionally defined centers that engage in the autonomic regulation of cardiovascular activity....
The nucleus tractus solitarii (NTS) is one of the morphologically and functionally defined centers that engage in the autonomic regulation of cardiovascular activity. Phenotypically-characterized NTS neurons have been implicated in the differential regulation of blood pressure (BP). Here, we investigated whether phenylethanolamine N-methyltransferase (PNMT)-expressing NTS (NTS) neurons contribute to the control of BP. We demonstrate that photostimulation of NTS neurons has variable effects on BP. A depressor response was produced during optogenetic stimulation of NTS neurons projecting to the paraventricular nucleus of the hypothalamus, lateral parabrachial nucleus, and caudal ventrolateral medulla. Conversely, photostimulation of NTS neurons projecting to the rostral ventrolateral medulla produced a robust pressor response and bradycardia. In addition, genetic ablation of both NTS neurons and those projecting to the rostral ventrolateral medulla impaired the arterial baroreflex. Overall, we revealed the neuronal phenotype- and circuit-specific mechanisms underlying the contribution of NTS neurons to the regulation of BP.
Topics: Solitary Nucleus; Blood Pressure; Phenylethanolamine N-Methyltransferase; Neurons; Paraventricular Hypothalamic Nucleus
PubMed: 36588135
DOI: 10.1007/s12264-022-01008-3 -
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 -
Current Neuropharmacology 2024The basal ganglia have the key function of directing our behavior in the context of events from our environment and/or our internal state. This function relies on... (Review)
Review
The basal ganglia have the key function of directing our behavior in the context of events from our environment and/or our internal state. This function relies on afferents targeting the main input structures of the basal ganglia, entering bids for action selection at the level of the striatum or signals for behavioral interruption at the level of the subthalamic nucleus, with behavioral reselection facilitated by dopamine signaling. Numerous experiments have studied action selection in relation to inputs from the cerebral cortex. However, less is known about the anatomical and functional link between the basal ganglia and the brainstem. In this review, we describe how brainstem structures also project to the main input structures of the basal ganglia, namely the striatum, the subthalamic nucleus and midbrain dopaminergic neurons, in the context of approach and avoidance (including escape from threat), two fundamental, mutually exclusive behavioral choices in an animal's repertoire in which the brainstem is strongly involved. We focus on three particularly well-described loci involved in approach and avoidance, namely the superior colliculus, the parabrachial nucleus and the periaqueductal grey nucleus. We consider what is known about how these structures are related to the basal ganglia, focusing on their projections toward the striatum, dopaminergic neurons and subthalamic nucleus, and explore the functional consequences of those interactions.
Topics: Animals; Basal Ganglia; Brain Stem; Avoidance Learning; Humans; Neural Pathways; Escape Reaction; Dopaminergic Neurons
PubMed: 37594168
DOI: 10.2174/1570159X21666230818154903 -
Zoological Research May 2024Painful stimuli elicit first-line reflexive defensive reactions and, in many cases, also evoke second-line recuperative behaviors, the latter of which reflects the...
Painful stimuli elicit first-line reflexive defensive reactions and, in many cases, also evoke second-line recuperative behaviors, the latter of which reflects the sensing of tissue damage and the alleviation of suffering. The lateral parabrachial nucleus (lPBN), composed of external- (elPBN), dorsal- (dlPBN), and central/superior-subnuclei (jointly referred to as slPBN), receives sensory inputs from spinal projection neurons and plays important roles in processing affective information from external threats and body integrity disruption. However, the organizational rules of lPBN neurons that provoke diverse behaviors in response to different painful stimuli from cutaneous and deep tissues remain unclear. In this study, we used region-specific neuronal depletion or silencing approaches combined with a battery of behavioral assays to show that slPBN neurons expressing substance P receptor ( ) (lPBN ) are crucial for driving pain-associated self-care behaviors evoked by sustained noxious thermal and mechanical stimuli applied to skin or bone/muscle, while elPBN neurons are dispensable for driving such reactions. Notably, lPBN neurons are specifically required for forming sustained somatic pain-induced negative teaching signals and aversive memory but are not necessary for fear-learning or escape behaviors elicited by external threats. Lastly, both lPBN and elPBN neurons contribute to chemical irritant-induced nocifensive reactions. Our results reveal the functional organization of parabrachial substrates that drive distinct behavioral outcomes in response to sustained pain versus external danger under physiological conditions.
Topics: Animals; Parabrachial Nucleus; Mice; Nociception; Neurons; Pain; Male; Behavior, Animal
PubMed: 38766746
DOI: 10.24272/j.issn.2095-8137.2023.412 -
Nature Communications May 2024About half of the neurons in the parabrachial nucleus (PB) that are activated by CO are located in the external lateral (el) subnucleus, express calcitonin gene-related...
About half of the neurons in the parabrachial nucleus (PB) that are activated by CO are located in the external lateral (el) subnucleus, express calcitonin gene-related peptide (CGRP), and cause forebrain arousal. We report here, in male mice, that most of the remaining CO-responsive neurons in the adjacent central lateral (PBcl) and Kölliker-Fuse (KF) PB subnuclei express the transcription factor FoxP2 and many of these neurons project to respiratory sites in the medulla. PBcl neurons show increased intracellular calcium during wakefulness and REM sleep and in response to elevated CO during NREM sleep. Photo-activation of the PBcl neurons increases respiration, whereas either photo-inhibition of PBcl or genetic deletion of PB/KF neurons reduces the respiratory response to CO stimulation without preventing awakening. Thus, augmenting the PBcl/KF response to CO in patients with sleep apnea in combination with inhibition of the PBel neurons may avoid hypoventilation and minimize EEG arousals.
Topics: Animals; Hypercapnia; Neurons; Male; Parabrachial Nucleus; Forkhead Transcription Factors; Mice; Carbon Dioxide; Wakefulness; Respiration; Mice, Inbred C57BL; Calcitonin Gene-Related Peptide; Sleep, REM; Repressor Proteins
PubMed: 38796568
DOI: 10.1038/s41467-024-48773-5 -
Regulation of vagally-evoked respiratory responses by the lateral parabrachial nucleus in the mouse.Respiratory Physiology & Neurobiology Oct 2023Vagal sensory inputs to the brainstem can alter breathing through the modulation of pontomedullary respiratory circuits. In this study, we set out to investigate the...
Vagal sensory inputs to the brainstem can alter breathing through the modulation of pontomedullary respiratory circuits. In this study, we set out to investigate the localised effects of modulating lateral parabrachial nucleus (LPB) activity on vagally-evoked changes in breathing pattern. In isoflurane-anaesthetised and instrumented mice, electrical stimulation of the vagus nerve (eVNS) produced stimulation frequency-dependent changes in diaphragm electromyograph (dEMG) activity with an evoked tachypnoea and apnoea at low and high stimulation frequencies, respectively. Muscimol microinjections into the LPB significantly attenuated eVNS-evoked respiratory rate responses. Notably, muscimol injections reaching the caudal LPB, previously unrecognised for respiratory modulation, potently modulated eVNS-evoked apnoea, whilst muscimol injections reaching the intermediate LPB selectively modulated the eVNS-evoked tachypnoea. The effects of muscimol on eVNS-evoked breathing rate changes occurred without altering basal eupneic breathing. These results highlight novel roles for the LPB in regulating vagally-evoked respiratory reflexes.
Topics: Animals; Mice; Respiratory Rate; Apnea; Muscimol; Parabrachial Nucleus; Tachypnea
PubMed: 37597796
DOI: 10.1016/j.resp.2023.104141 -
Journal of Oral Biosciences Jun 2024The trigeminal spinal subnucleus caudalis (Sp5C), also known as the medullary dorsal horn, receives orofacial somatosensory inputs, particularly nociceptive inputs, from... (Review)
Review
BACKGROUND
The trigeminal spinal subnucleus caudalis (Sp5C), also known as the medullary dorsal horn, receives orofacial somatosensory inputs, particularly nociceptive inputs, from the trigeminal nerve. In the Sp5C, excitatory and inhibitory neurons, glutamatergic and GABAergic/glycinergic neurons, respectively, form the local circuits. The axons of the glutamatergic neurons in lamina I ascend toward the thalamic and parabrachial nuclei, and this projection is the main pathway of orofacial nociception. Additionally, the axons of the higher brain regions, including the locus coeruleus, dorsal raphe, and cerebral cortex, are sent to the Sp5C.
HIGHLIGHT
Among these descending projections, this review focuses on the functional profiles of the corticotrigeminal projections to the Sp5C, along with their anatomical aspects. The primary and secondary somatosensory and insular cortices are of particular interest.
CONCLUSION
Corticotrigeminal projections from the somatosensory cortex to the Sp5C play a suppressive role in nociceptive information processing, whereas recent studies have demonstrated a facilitative role of the insular cortex in nociceptive information processing at the Sp5C level.
Topics: Nociception; Cerebral Cortex; Humans; Animals; Trigeminal Caudal Nucleus; Somatosensory Cortex; Neural Pathways; Trigeminal Nucleus, Spinal; Facial Pain
PubMed: 38734177
DOI: 10.1016/j.job.2024.05.004 -
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 -
BioRxiv : the Preprint Server For... Nov 2023Itch is a protective sensation that drives scratching. Although specific cell types have been proposed to underlie itch, the neural circuit basis for itch remains...
Itch is a protective sensation that drives scratching. Although specific cell types have been proposed to underlie itch, the neural circuit basis for itch remains unclear. Here, we used two-photon Ca imaging of the dorsal horn to visualize the neuronal populations that are activated by itch-inducing agents. We identify a convergent population of spinal neurons that is defined by the expression of GRPR. Moreover, we discover that itch is conveyed to the brain via GRPR-expressing spinal output neurons that target the lateral parabrachial nucleus. Further, we show that nalfurafine, a clinically effective kappa opioid receptor agonist, relieves itch by inhibiting GRPR spinoparabrachial neurons. Finally, we demonstrate that a subset of GRPR spinal neurons show persistent, cell-intrinsic Ca oscillations. These experiments provide the first population-level view of the spinal neurons that respond to pruritic stimuli, pinpoint the output neurons that convey itch to the brain, and identify the cellular target of kappa opioid receptor agonists for the inhibition of itch.
PubMed: 37873278
DOI: 10.1101/2023.09.29.560205