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BioRxiv : the Preprint Server For... Jun 2024Osteoarthritis (OA) represents a significant pain challenge globally, as current treatments are limited and come with substantial and adverse side effects. Voltage-gated...
Osteoarthritis (OA) represents a significant pain challenge globally, as current treatments are limited and come with substantial and adverse side effects. Voltage-gated calcium channels have proved to be pharmacologically effective targets, with multiple FDA-approved Ca2.2 modulators available for the treatment of pain. Although effective, drugs targeting Ca2.2 are complicated by the same obstacles facing other pain therapeutics-invasive routes of administration, narrow therapeutic windows, side effects, and addiction potential. We have identified a key regulator of Ca2.2 channels, collapsing response mediator protein 2 (CRMP2), that allows us to indirectly regulate Ca2.2 expression and function. We developed a peptidomimetic modulator of CRMP2, CBD3063, that effectively reverses neuropathic and inflammatory pain without negative side effects by reducing membrane expression of Ca2.2. Using a rodent model of OA, we demonstrate the intraperitoneal administration of CBD3063 alleviates both evoked and non-evoked behavioral hallmarks of OA pain. Further, we reveal that CBD3063 reduces OA-induced increased neural activity in the parabrachial nucleus, a key supraspinal site modulating the pain experience. Together, these studies suggest CBD3063 is an effective analgesic for OA pain.
PubMed: 38895294
DOI: 10.1101/2024.06.05.596514 -
Frontiers in Endocrinology 2024Food intake behavior is under the tight control of the central nervous system. Most studies to date focus on the contribution of neurons to this behavior. However,...
Food intake behavior is under the tight control of the central nervous system. Most studies to date focus on the contribution of neurons to this behavior. However, although previously overlooked, astrocytes have recently been implicated to play a key role in feeding control. Most of the recent literature has focused on astrocytic contribution in the hypothalamus or the dorsal vagal complex. The contribution of astrocytes located in the lateral parabrachial nucleus (lPBN) to feeding behavior control remains poorly understood. Thus, here, we first investigated whether activation of lPBN astrocytes affects feeding behavior in male and female rats using chemogenetic activation. Astrocytic activation in the lPBN led to profound anorexia in both sexes, under both feeding schedule and after a fasting challenge. Astrocytes have a key contribution to glutamate homeostasis and can themselves release glutamate. Moreover, lPBN glutamate signaling is a key contributor to potent anorexia, which can be induced by lPBN activation. Thus, here, we determined whether glutamate signaling is necessary for lPBN astrocyte activation-induced anorexia, and found that pharmacological N-methyl D-aspartate (NMDA) receptor blockade attenuated the food intake reduction resulting from lPBN astrocyte activation. Since astrocytes have been shown to contribute to feeding control by modulating the feeding effect of peripheral feeding signals, we further investigated whether lPBN astrocyte activation is capable of modulating the anorexic effect of the gut/brain hormone, glucagon like peptide -1, as well as the orexigenic effect of the stomach hormone - ghrelin, and found that the feeding effect of both signals is modulated by lPBN astrocytic activation. Lastly, we found that lPBN astrocyte activation-induced anorexia is affected by a diet-induced obesity challenge, in a sex-divergent manner. Collectively, current findings uncover a novel role for lPBN astrocytes in feeding behavior control.
Topics: Animals; Astrocytes; Male; Female; Rats; Eating; Parabrachial Nucleus; Anorexia; Feeding Behavior; Rats, Sprague-Dawley; Glutamic Acid; Receptors, N-Methyl-D-Aspartate
PubMed: 38887265
DOI: 10.3389/fendo.2024.1389589 -
CNS Neuroscience & Therapeutics Jun 2024Phenylethanolamine N-methyltransferase (PNMT)-expressing neurons in the nucleus tractus solitarii (NTS) contribute to the regulation of autonomic functions. However, the...
OBJECTIVE
Phenylethanolamine N-methyltransferase (PNMT)-expressing neurons in the nucleus tractus solitarii (NTS) contribute to the regulation of autonomic functions. However, the neural circuits linking these neurons to other brain regions remain unclear. This study aims to investigate the connectivity mechanisms of the PNMT-expressing neurons in the NTS (NTS neurons).
METHODS
The methodologies employed in this study included a modified rabies virus-based retrograde neural tracing technique, conventional viral anterograde tracing, and immunohistochemical staining procedures.
RESULTS
A total of 43 upstream nuclei projecting to NTS neurons were identified, spanning several key brain regions including the medulla oblongata, pons, midbrain, cerebellum, diencephalon, and telencephalon. Notably, dense projections to the NTS neurons were observed from the central amygdaloid nucleus, paraventricular nucleus of the hypothalamus, area postrema, and the gigantocellular reticular nucleus. In contrast, the ventrolateral medulla, lateral parabrachial nucleus, and lateral hypothalamic area were identified as the primary destinations for axon terminals originating from NTS neurons. Additionally, reciprocal projections were evident among 21 nuclei, primarily situated within the medulla oblongata.
CONCLUSION
Our research findings demonstrate that NTS neurons form extensive connections with numerous nuclei, emphasizing their essential role in the homeostatic regulation of vital autonomic functions.
Topics: Animals; Phenylethanolamine N-Methyltransferase; Solitary Nucleus; Neurons; Male; Efferent Pathways; Afferent Pathways; Rats, Sprague-Dawley; Brain Mapping; Rats
PubMed: 38887205
DOI: 10.1111/cns.14808 -
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.
PubMed: 38865246
DOI: 10.1016/j.celrep.2024.114356 -
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 -
Brain Sciences Apr 2024Fibromyalgia syndrome (FM) is a chronic pain condition that affects a significant portion of the population; yet, this condition is still poorly understood. Prior...
Fibromyalgia syndrome (FM) is a chronic pain condition that affects a significant portion of the population; yet, this condition is still poorly understood. Prior research has suggested that individuals with FM display a heightened sensitivity to pain and signs of autonomic dysfunction. Recent advances in functional MRI analysis methods to model blood-oxygenation-level-dependent (BOLD) responses across networks of regions, and structural and physiological modeling (SAPM) have shown the potential to provide more detailed information about altered neural activity than was previously possible. Therefore, this study aimed to apply novel analysis methods to investigate altered neural processes underlying pain sensitivity in FM in functional magnetic resonance imaging (fMRI) data from the brainstem and spinal cord. Prior fMRI studies have shown evidence of functional differences in fibromyalgia (FM) within brain regions associated with pain's motivational aspects, as well as differences in neural activity related to pain regulation, arousal, and autonomic homeostatic regulation within the brainstem and spinal cord regions. We, therefore, hypothesized that nociceptive processing is altered in FM compared to healthy controls (HCs) in the brainstem and spinal cord areas linked to autonomic function and descending pain regulation, including the parabrachial nuclei (PBN) and nucleus tractus solitarius (NTS). We expected that new details of this altered neural signaling would be revealed with SAPM. The results provide new evidence of altered neural signaling in FM related to arousal and autonomic homeostatic regulation. This further advances our understanding of the altered neural processing that occurs in women with FM.
PubMed: 38790429
DOI: 10.3390/brainsci14050450 -
Theranostics 2024Methamphetamine (METH) withdrawal anxiety symptom and relapse have been significant challenges for clinical practice, however, the underlying neuronal basis remains...
Methamphetamine (METH) withdrawal anxiety symptom and relapse have been significant challenges for clinical practice, however, the underlying neuronal basis remains unclear. Our recent research has identified a specific subpopulation of choline acetyltransferase (ChAT) neurons localized in the external lateral portion of parabrachial nucleus (eLPB), which modulates METH primed-reinstatement of conditioned place preference (CPP). Here, the anatomical structures and functional roles of eLPB projections in METH withdrawal anxiety and primed reinstatement were further explored. In the present study, a multifaceted approach was employed to dissect the LPB projections in male mice, including anterograde and retrograde tracing, acetylcholine (Ach) indicator combined with fiber photometry recording, photogenetic and chemogenetic regulation, as well as electrophysiological recording. METH withdrawal anxiety-like behaviors and METH-primed reinstatement of conditioned place preference (CPP) were assessed in male mice. We identified that eLPB send projections to PKCδ-positive (PKCδ) neurons in lateral portion of central nucleus of amygdala (lCeA) and oval portion of bed nucleus of the stria terminalis (ovBNST), forming eLPB-lCeA and eLPB-ovBNST pathways. At least in part, the eLPB neurons positively innervate lCeA neurons and ovBNST neurons through regulating synaptic elements of presynaptic Ach release and postsynaptic nicotinic acetylcholine receptors (nAChRs). METH withdrawal anxiety and METH-primed reinstatement of CPP respectively recruit eLPB-lCeA pathway and eLPB-ovBNST pathway in male mice. Our findings put new insights into the complex neural networks, especially focusing on the eLPB projections. The eLPB is a critical node in the neural networks governing METH withdrawal anxiety and primed-reinstatement of CPP through its projections to the lCeA and ovBNST, respectively.
Topics: Animals; Methamphetamine; Male; Mice; Substance Withdrawal Syndrome; Anxiety; Mice, Inbred C57BL; Neurons; Choline O-Acetyltransferase; Septal Nuclei; Behavior, Animal
PubMed: 38773977
DOI: 10.7150/thno.95383 -
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 -
BioRxiv : the Preprint Server For... May 2024The parabrachial nucleus (PB), located in the dorsolateral pons, contains primarily glutamatergic neurons which regulate responses to a variety of interoceptive and...
The parabrachial nucleus (PB), located in the dorsolateral pons, contains primarily glutamatergic neurons which regulate responses to a variety of interoceptive and cutaneous sensory signals. The lateral PB subpopulation expressing the gene which produces the neuropeptide calcitonin gene-related peptide (CGRP) relays signals related to threatening stimuli such as hypercarbia, pain, and nausea, yet the afferents to these neurons are only partially understood. We mapped the afferent projections to the lateral part of the PB in mice using conventional cholera toxin B subunit (CTb) retrograde tracing, and then used conditional rabies virus retrograde tracing to map monosynaptic inputs specifically targeting the PB neurons. Using vesicular GABA (vGAT) and glutamate (vGLUT2) transporter reporter mice, we found that lateral PB neurons receive GABAergic afferents from regions such as the lateral part of the central nucleus of the amygdala, lateral dorsal subnucleus of the bed nucleus of the stria terminalis, substantia innominata, and the ventrolateral periaqueductal gray. Additionally, they receive glutamatergic afferents from the infralimbic and insular cortex, paraventricular nucleus, parasubthalamic nucleus, trigeminal complex, medullary reticular nucleus, and nucleus of the solitary tract. Using anterograde tracing and confocal microscopy, we then identified close axonal appositions between these afferents and PB neurons. Finally, we used channelrhodopsin-assisted circuit mapping to test whether some of these inputs directly synapse upon the PB neurons. These findings provide a comprehensive neuroanatomical framework for understanding the afferent projections regulating the PB neurons.
PubMed: 38766214
DOI: 10.1101/2024.05.07.593004 -
BioRxiv : the Preprint Server For... May 2024Obese subjects often exhibit hypersomnia accompanied by severe sleep fragmentation, while emerging evidence suggests that poor sleep quality promotes overeating and...
Obese subjects often exhibit hypersomnia accompanied by severe sleep fragmentation, while emerging evidence suggests that poor sleep quality promotes overeating and exacerbates diet-induced obesity (DIO). However, the neural circuit and signaling mechanism underlying the reciprocal control of appetite and sleep is yet not elucidated. Here, we report a neural circuit where prokineticin receptor 2 (PROKR2)-expressing neurons within the parabrachial nucleus (PBN) of the brainstem received direct projections from neuropeptide Y receptor Y2 (NPY2R)-expressing neurons within the lateral preoptic area (LPO) of the hypothalamus. The RNA-Seq results revealed in the PBN is the most regulated GPCR signaling gene that is responsible for comorbidity of obesity and sleep dysfunction. Furthermore, those NPY2R neurons are minimally active during NREM sleep and maximally active during wakefulness and REM sleep. Activation of the NPY2R →PBN circuit or the postsynaptic PROKR2 neurons suppressed feeding of a high-fat diet and abrogated morbid sleep patterns in DIO mice. Further studies showed that genetic ablation of the PROKR2 signaling within PROKR2 neurons alleviated the hyperphagia and weight gain, and restored sleep dysfunction in DIO mice. We further discovered pterostilbene, a plant-derived stilbenoid, is a powerful anti-obesity and sleep-improving agent, robustly suppressed hyperphagia and promoted reconstruction of a healthier sleep architecture, thereby leading to significant weight loss. Collectively, our results unveil a neural mechanism for the reciprocal control of appetite and sleep, through which pterostilbene, along with a class of similarly structured compounds, may be developed as effective therapeutics for tackling obesity and sleep disorders.
PubMed: 38746393
DOI: 10.1101/2024.04.30.591948