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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 -
Journal of Neurochemistry Dec 2023Chemogenetic activation of oxytocin receptor-expressing neurons in the parabrachial nucleus (Oxtr neurons) acts as a satiation signal for water. In this research, we...
Chemogenetic activation of oxytocin receptor-expressing neurons in the parabrachial nucleus (Oxtr neurons) acts as a satiation signal for water. In this research, we investigated the effect of activating Oxtr neurons on satiation for different types of fluids. Chemogenetic activation of Oxtr neurons in male and female transgenic Oxtr mice robustly suppressed the rapid, initial (15-min) intake of several solutions after dehydration: water, sucrose, ethanol and saccharin, but only slightly decreased intake of Ensure®, a highly caloric solution (1 kcal/mL; containing 3.72 g protein, 3.27 g fat, 13.42 g carbohydrates, and 1.01 g dietary fibre per 100 mL). Oxtr neuron activation also suppressed cumulative, longer-term (2-h) intake of lower caloric, less palatable solutions, but not highly caloric, palatable solutions. These results suggest that Oxtr neurons predominantly control initial fluid-satiation responses after rehydration, but not longer-term intake of highly caloric, palatable solutions. The suppression of fluid intake was not because of anxiogenesis, but because Oxtr neuron activation decreased anxiety-like behaviour. To investigate the role of different PBN subdivisions on the intake of different solutions, we examined FOS as a proxy marker of PBN neuron activation. Different PBN subdivisions were activated by different solutions: the dorsolateral PBN similarly by all fluids; the external lateral PBN by caloric but not non-caloric solutions; and the central lateral PBN primarily by highly palatable solutions, suggesting PBN subdivisions regulate different aspects of fluid intake. To explore the possible mechanisms underlying the minimal suppression of Ensure® after Oxtr neuron activation, we demonstrated in in vitro slice recordings that the feeding-associated agouti-related peptide (AgRP) inhibited Oxtr neuron firing in a concentration-related manner, suggesting possible inhibition by feeding-related neurocircuitry of fluid satiation neurocircuitry. Overall, this research suggests that although palatable beverages like sucrose- and ethanol-containing beverages activate fluid satiation signals encoded by Oxtr neurons, these neurons can be inhibited by hunger-related signals (agouti-related peptide, AgRP), which may explain why these fluids are often consumed in excess of what is required for fluid satiation.
Topics: Mice; Male; Female; Animals; Parabrachial Nucleus; Agouti-Related Protein; Satiation; Water; Sucrose; Ethanol
PubMed: 37855271
DOI: 10.1111/jnc.15991 -
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 -
BMC Anesthesiology Oct 2023While the mechanism of general anesthesia has been extensively studied, the underlying neural circuitry has yet to be fully understood. The parabrachial nucleus (PBN)...
While the mechanism of general anesthesia has been extensively studied, the underlying neural circuitry has yet to be fully understood. The parabrachial nucleus (PBN) plays a crucial role in modulating wakefulness and promoting arousal from general anesthesia. However, the specific role of PBN projections in the process of general anesthesia remains unclear. In this study, we bilaterally injected AAV-associated viruses encoding excitatory or inhibitory optogenetic probes into the PBN and implanted optical fibers in the LH or BF area. After four weeks, we optogenetically activated or inhibited the PBN-LH and PBN-BF pathways under 1.5 vol% isoflurane. We calculated the time it took for anesthesia induction and emergence, simultaneously monitoring changes in the burst-suppression ratio using electroencephalogram recording. Our findings indicate that optogenetic activation of the PBN-LH and PBN-BF projections plays a significant role in promoting both cortical and behavioral emergence from isoflurane inhalation, without significantly affecting the induction time. Conversely, photoinhibition of these pathways prolonged the recovery time, with no notable difference observed during the induction phase.In summary, our results demonstrate that the PBN-LH and PBN-BF pathways are crucial for promoting arousal from isoflurane general anesthesia, but do not have a pronounced impact on the induction phase.
Topics: Mice; Animals; Isoflurane; Anesthetics, Inhalation; Hypothalamic Area, Lateral; Basal Forebrain; Optogenetics; Parabrachial Nucleus; Anesthesia, General
PubMed: 37784027
DOI: 10.1186/s12871-023-02294-8 -
The Journal of Neuroscience : the... Nov 2023The parabrachial nucleus (PBN) interfaces between taste and feeding systems and is also an important hub for relaying distress information and threats. Despite that the...
The parabrachial nucleus (PBN) interfaces between taste and feeding systems and is also an important hub for relaying distress information and threats. Despite that the PBN sends projections to the ventral tegmental area (VTA), a heterogeneous brain region that regulates motivational behaviors, the function of the PBN-to-VTA connection remains elusive. Here, by using male mice in several behavioral paradigms, we discover that VTA-projecting PBN neurons are significantly engaged in contextual fear, restraint or mild stress but not palatable feeding, visceral malaise, or thermal pain. These results suggest that the PBN-to-VTA input may relay negative emotions under threat. Consistent with this notion, optogenetic activation of PBN-to-VTA glutamatergic input results in aversion, which is sufficient to override palatable feeding. Moreover, in a palatable food-reinforced operant task, we demonstrate that transient optogenetic activation of PBN-to-VTA input during food reward retrieval disengages instrumental food-seeking behaviors but spares learned action-outcome association. By using an activity-dependent targeting approach, we show that VTA DA neurons are disengaged by the PBN afferent activation, implicating that VTA non-DA neurons may mediate PBN afferent regulation. We further show that optogenetic activation of VTA neurons functionally recruited by the PBN input results in aversion, dampens palatable feeding, and disengages palatable food self-administration behavior. Finally, we demonstrate that transient activation of VTA glutamatergic, but not GABAergic, neurons recapitulates the negative regulation of the PBN input on food self-administration behavior. Together, we reveal that the PBN-to-VTA input conveys negative affect, likely through VTA glutamatergic neurons, to disengage instrumental food-seeking behaviors. The PBN receives multiple inputs and thus is well positioned to route information of various modalities to engage different downstream circuits to attend or respond accordingly. We demonstrate that the PBN-to-VTA input conveys negative affect and then triggers adaptive prioritized responses to address pertinent needs by withholding ongoing behaviors, such as palatable food seeking or intake shown in the present study. It has evolutionary significance because preparing to cope with stressful situations or threats takes priority over food seeking to promote survival. Knowing how appropriate adaptive responses are generated will provide new insights into circuitry mechanisms of various coping behaviors to changing environmental stimuli.
Topics: Mice; Male; Animals; Ventral Tegmental Area; Parabrachial Nucleus; Food; GABAergic Neurons; Emotions; Reward
PubMed: 37684032
DOI: 10.1523/JNEUROSCI.2114-22.2023 -
Reviews in the Neurosciences Feb 2024Breathing is a natural daily action that one cannot do without, and it sensitively and intensely changes under various situations. What if this essential act of... (Review)
Review
Breathing is a natural daily action that one cannot do without, and it sensitively and intensely changes under various situations. What if this essential act of breathing can impact our overall well-being? Recent studies have demonstrated that breathing oscillations couple with higher brain functions, i.e., perception, motor actions, and cognition. Moreover, the timing of breathing, a phase transition from exhalation to inhalation, modulates specific cortical activity and accuracy in cognitive tasks. To determine possible respiratory roles in attentional and memory processes and functional neural networks, we discussed how breathing interacts with the brain that are measured by electrophysiology and functional neuroimaging: (i) respiration-dependent modulation of mental health and cognition; (ii) respiratory rhythm generation and respiratory pontomedullary networks in the brainstem; (iii) respiration-dependent effects on specific brainstem regions and functional neural networks (e.g., glutamatergic PreBötzinger complex neurons, GABAergic parafacial neurons, adrenergic C1 neurons, parabrachial nucleus, locus coeruleus, temporoparietal junction, default-mode network, ventral attention network, and cingulo-opercular salience network); and (iv) a potential application of breathing manipulation in mental health care. These outlines and considerations of "brain-breath" interactions lead to a better understanding of the interoceptive and cognitive mechanisms that underlie brain-body interactions in health conditions and in stress-related and neuropsychiatric disorders.
Topics: Humans; Brain; Respiration; Brain Stem; Memory; Cognition
PubMed: 37651646
DOI: 10.1515/revneuro-2023-0062 -
BioRxiv : the Preprint Server For... Aug 2023In the brain, connectivity determines function. Neurons in the parabrachial nucleus (PB) relay diverse information to widespread brain regions, but the connections and...
In the brain, connectivity determines function. Neurons in the parabrachial nucleus (PB) relay diverse information to widespread brain regions, but the connections and functions of PB neurons that express (neuropeptide S) remain mysterious. Here, we use Cre-dependent anterograde tracing and whole-brain analysis to map their output connections. While many other PB neurons project ascending axons through the central tegmental tract, NPS axons reach the forebrain via distinct periventricular and ventral pathways. Along the periventricular pathway, NPS axons target the tectal longitudinal column and periaqueductal gray then continue rostrally to target the paraventricular nucleus of the thalamus. Along the ventral pathway, NPS axons blanket much of the hypothalamus but avoid the ventromedial and mammillary nuclei. They also project prominently to the ventral bed nucleus of the stria terminalis, A13 cell group, and magnocellular subparafasciular nucleus. In the hindbrain, NPS axons have fewer descending projections, targeting primarily the superior salivatory nucleus, nucleus of the lateral lemniscus, and periolivary region. Combined with what is known about NPS and its receptor, the output pattern of -expressing neurons in the PB region predicts a role in threat response and circadian behavior.
PubMed: 37645772
DOI: 10.1101/2023.08.13.553140 -
Biology Aug 2023Hypertension, a leading cause of death, was investigated in this study to understand the role of specific brain regions in regulating blood pressure. The lateral...
INTRODUCTION
Hypertension, a leading cause of death, was investigated in this study to understand the role of specific brain regions in regulating blood pressure. The lateral parabrachial nucleus (LPBN), Kolliker-fuse nucleus (KF), and periductal grey matter (PAG) were examined for their involvement in hypertension.
METHODS
Lentiviral vectors were used to alter the activity of these brain regions in hypertensive rats. Over a 75-day period, blood pressure, heart rate, reflex responses, and heart rate variability were measured.
RESULTS
Decreasing the activity in the LPBN resulted in a reduced sympathetic outflow, lowering the blood pressure and heart rate. In the KF, the sympathetic activity decreased and chemoreflex variation was attenuated, without affecting the blood pressure. Silencing the PAG had no significant impact on blood pressure or sympathetic tone, but decreased cardiac baroreflex gain.
DISCUSSION
These findings highlight the significant role of the LPBN in hypertension-related sympathetic activation. Additionally, LPBN and KF neurons appear to activate mechanisms that control respiration and sympathetic outflow during chemoreceptor activation.
CONCLUSIONS
The study provided insights into the contribution of the midbrain and pontine regions to neurogenic hypertension and offers potential avenues for future genetic interventions and developing novel treatment approaches.
PubMed: 37627036
DOI: 10.3390/biology12081153 -
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 -
Nature Communications Aug 2023Thermal homeostasis is vital for mammals and is controlled by brain neurocircuits. Yet, the neural pathways responsible for cold defense regulation are still unclear....
Thermal homeostasis is vital for mammals and is controlled by brain neurocircuits. Yet, the neural pathways responsible for cold defense regulation are still unclear. Here, we found that a pathway from the lateral parabrachial nucleus (LPB) to the dorsomedial hypothalamus (DMH), which runs parallel to the canonical LPB to preoptic area (POA) pathway, is also crucial for cold defense. Together, these pathways make an equivalent and cumulative contribution, forming a parallel circuit. Specifically, activation of the LPB → DMH pathway induced strong cold-defense responses, including increases in thermogenesis of brown adipose tissue (BAT), muscle shivering, heart rate, and locomotion. Further, we identified somatostatin neurons in the LPB that target DMH to promote BAT thermogenesis. Therefore, we reveal a parallel circuit governing cold defense in mice, which enables resilience to hypothermia and provides a scalable and robust network in heat production, reshaping our understanding of neural circuit regulation of homeostatic behaviors.
Topics: Mice; Animals; Thermogenesis; Preoptic Area; Neural Pathways; Homeostasis; Hypothermia; Adipose Tissue, Brown; Cold Temperature; Mammals
PubMed: 37582782
DOI: 10.1038/s41467-023-40504-6