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Journal of Translational Medicine Dec 2023Attentional deficits are among the most common pain-induced cognitive disorders. Pain disrupts attention and may excessively occupy attentional resources in pathological...
BACKGROUND
Attentional deficits are among the most common pain-induced cognitive disorders. Pain disrupts attention and may excessively occupy attentional resources in pathological states, leading to daily function impairment and increased disability. However, the neural circuit mechanisms by which pain disrupts attention are incompletely understood.
METHODS
We used a three-choice serial reaction time task (3CSRTT) to construct a sustained-attention task model in male C57BL/6J mice. Formalin or complete Freund's adjuvant was injected into a paw to establish an inflammatory pain model. We measured changes in 3CSRTT performance in the two inflammatory pain models, and investigated the neural circuit mechanisms of pain-induced attentional deficits.
RESULTS
Acute inflammatory pain impaired 3CSRTT performance, while chronic inflammatory pain had no effect. Either inhibition of the ascending pain pathway by blockade of the conduction of nociceptive signals in the sciatic nerve using the local anesthetic lidocaine or chemogenetic inhibition of Ca/calmodulin-dependent protein kinase IIα (CaMKIIα) neurons in the lateral parabrachial nucleus (LPBN) attenuated the acute inflammatory pain-induced impairment of 3CSRTT performance, while chemogenetic activation of CaMKIIα neurons in the LPBN disrupted the 3CSRTT. Furthermore, the activity of CaMKIIα neurons in the LPBN was significantly lower on Day 2 after complete Freund's adjuvant injection than on the day of injection, which correlated with the recovery of 3CSRTT performance during chronic inflammatory pain.
CONCLUSIONS
Activation of excitatory neurons in the LPBN is a mechanism by which acute inflammatory pain disrupts sustained attention. This finding has implications for the treatment of pain and its cognitive comorbidities.
Topics: Mice; Animals; Male; Parabrachial Nucleus; Freund's Adjuvant; Mice, Inbred C57BL; Neurons; Chronic Pain; Attention
PubMed: 38072957
DOI: 10.1186/s12967-023-04583-9 -
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 -
The Journal of Pain Sep 2023Opioids are powerful analgesics commonly used in pain management. However, opioids can induce complex neuroadaptations, including synaptic plasticity, that ultimately...
Opioids are powerful analgesics commonly used in pain management. However, opioids can induce complex neuroadaptations, including synaptic plasticity, that ultimately drive severe side effects, such as pain hypersensitivity and strong aversion during prolonged administration or upon drug withdrawal, even following a single, brief administration. The lateral parabrachial nucleus (LPBN) in the brainstem plays a key role in pain and emotional processing; yet, the effects of opioids on synaptic plasticity in this area remain unexplored. Using patch-clamp recordings in acute brainstem slices from male and female Sprague Dawley rats, we demonstrate a concentration-dependent, bimodal effect of opioids on excitatory synaptic transmission in the LPBN. While a lower concentration of DAMGO (0.5 µM) induced a long-term depression of synaptic strength (low-DAMGO LTD), abrupt termination of a higher concentration (10 µM) induced a long-term potentiation (high-DAMGO LTP) in a subpopulation of cells. LTD involved a metabotropic glutamate receptor (mGluR)-dependent mechanism; in contrast, LTP required astrocytes and N-methyl-D-aspartate receptor (NMDAR) activation. Selective optogenetic activation of spinal and periaqueductal gray matter (PAG) inputs to the LPBN revealed that, while LTD was expressed at all parabrachial synapses tested, LTP was restricted to spino-parabrachial synapses. Thus, we uncovered previously unknown forms of opioid-induced long-term plasticity in the parabrachial nucleus that potentially modulate some adverse effects of opioids. PERSPECTIVE: We found a previously unrecognized site of opioid-induced plasticity in the lateral parabrachial nucleus, a key region for pain and emotional processing. Unraveling opioid-induced adaptations in parabrachial function might facilitate the identification of new therapeutic measures for addressing adverse effects of opioid discontinuation such as hyperalgesia and aversion.
Topics: Rats; Male; Female; Animals; Analgesics, Opioid; Rats, Sprague-Dawley; Pain Clinics; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Neuronal Plasticity; Brain Stem; Pain
PubMed: 37150382
DOI: 10.1016/j.jpain.2023.05.001 -
The Journal of Neuroscience : the... Jul 2023Thermoregulatory behavior in homeothermic animals is an innate behavior to defend body core temperature from environmental thermal challenges in coordination with...
Thermoregulatory behavior in homeothermic animals is an innate behavior to defend body core temperature from environmental thermal challenges in coordination with autonomous thermoregulatory responses. In contrast to the progress in understanding the central mechanisms of autonomous thermoregulation, those of behavioral thermoregulation remain poorly understood. We have previously shown that the lateral parabrachial nucleus (LPB) mediates cutaneous thermosensory afferent signaling for thermoregulation. To understand the thermosensory neural network for behavioral thermoregulation, in the present study, we investigated the roles of ascending thermosensory pathways from the LPB in avoidance behavior from innocuous heat and cold in male rats. Neuronal tracing revealed two segregated groups of LPB neurons projecting to the median preoptic nucleus (MnPO), a thermoregulatory center (LPB→MnPO neurons), and those projecting to the central amygdaloid nucleus (CeA), a limbic emotion center (LPB→CeA neurons). While LPB→MnPO neurons include separate subgroups activated by heat or cold exposure of rats, LPB→CeA neurons were only activated by cold exposure. By selectively inhibiting LPB→MnPO or LPB→CeA neurons using tetanus toxin light chain or chemogenetic or optogenetic techniques, we found that LPB→MnPO transmission mediates heat avoidance, whereas LPB→CeA transmission contributes to cold avoidance. electrophysiological experiments showed that skin cooling-evoked thermogenesis in brown adipose tissue requires not only LPB→MnPO neurons but also LPB→CeA neurons, providing a novel insight into the central mechanism of autonomous thermoregulation. Our findings reveal an important framework of central thermosensory afferent pathways to coordinate behavioral and autonomous thermoregulation and to generate the emotions of thermal comfort and discomfort that drive thermoregulatory behavior. Coordination of behavioral and autonomous thermoregulation is important for maintaining thermal homeostasis in homeothermic animals. However, the central mechanism of thermoregulatory behaviors remains poorly understood. We have previously shown that the lateral parabrachial nucleus (LPB) mediates ascending thermosensory signaling that drives thermoregulatory behavior. In this study, we found that one pathway from the LPB to the median preoptic nucleus mediates heat avoidance, whereas the other pathway from the LPB to the central amygdaloid nucleus is required for cold avoidance. Surprisingly, both pathways are required for skin cooling-evoked thermogenesis in brown adipose tissue, an autonomous thermoregulatory response. This study provides a central thermosensory network that coordinates behavioral and autonomous thermoregulation and generates thermal comfort and discomfort that drive thermoregulatory behavior.
Topics: Male; Rats; Animals; Parabrachial Nucleus; Body Temperature Regulation; Skin; Cold Temperature; Afferent Pathways; Neural Pathways
PubMed: 37339876
DOI: 10.1523/JNEUROSCI.0643-23.2023 -
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 -
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 -
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 -
CNS Neuroscience & Therapeutics Feb 2024Autonomic dysfunction with central autonomic network (CAN) damage occurs frequently after intracerebral hemorrhage (ICH) and contributes to a series of adverse outcomes.... (Review)
Review
AIMS
Autonomic dysfunction with central autonomic network (CAN) damage occurs frequently after intracerebral hemorrhage (ICH) and contributes to a series of adverse outcomes. This review aims to provide insight and convenience for future clinical practice and research on autonomic dysfunction in ICH patients.
DISCUSSION
We summarize the autonomic dysfunction in ICH from the aspects of potential mechanisms, clinical significance, assessment, and treatment strategies. The CAN structures mainly include insular cortex, anterior cingulate cortex, amygdala, hypothalamus, nucleus of the solitary tract, ventrolateral medulla, dorsal motor nucleus of the vagus, nucleus ambiguus, parabrachial nucleus, and periaqueductal gray. Autonomic dysfunction after ICH is closely associated with neurological functional outcomes, cardiac complications, blood pressure fluctuation, immunosuppression and infection, thermoregulatory dysfunction, hyperglycemia, digestive dysfunction, and urogenital disturbances. Heart rate variability, baroreflex sensitivity, skin sympathetic nerve activity, sympathetic skin response, and plasma catecholamine concentration can be used to assess the autonomic functional activities after ICH. Risk stratification of patients according to autonomic functional activities, and development of intervention approaches based on the restoration of sympathetic-parasympathetic balance, would potentially improve clinical outcomes in ICH patients.
CONCLUSION
The review systematically summarizes the evidence of autonomic dysfunction and its association with clinical outcomes in ICH patients, proposing that targeting autonomic dysfunction could be potentially investigated to improve the clinical outcomes.
Topics: Humans; Autonomic Nervous System; Sympathetic Nervous System; Autonomic Nervous System Diseases; Vagus Nerve; Cerebral Hemorrhage; Heart Rate
PubMed: 38372446
DOI: 10.1111/cns.14544 -
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 -
Addiction Biology Feb 2024Adolescent alcohol use is a strong predictor for the subsequent development of alcohol use disorders later in life. Additionally, adolescence is a critical period for...
Adolescent alcohol use is a strong predictor for the subsequent development of alcohol use disorders later in life. Additionally, adolescence is a critical period for the onset of affective disorders, which can contribute to problematic drinking behaviours and relapse, particularly in females. Previous studies from our laboratory have shown that exposure to adolescent intermittent ethanol (AIE) vapour alters glutamatergic transmission in the bed nucleus of the stria terminalis (BNST) and, when combined with adult stress, elicits sex-specific changes in glutamatergic plasticity and negative affect-like behaviours in mice. Building on these findings, the current work investigated whether BNST stimulation could substitute for stress exposure to increase the latency to consume a palatable food in a novel context (hyponeophagia) and promote social avoidance in adult mice with AIE history. Given the dense connections between the BNST and the parabrachial nucleus (PBN), a region involved in mediating threat assessment and feeding behaviours, we hypothesized that increased negative affect-like behaviours would be associated with PBN activation. Our results revealed that the chemogenetic stimulation of the dorsolateral BNST induced hyponeophagia in females with AIE history, but not in female controls or males of either group. Social interaction remained unaffected in both sexes. Notably, this behavioural phenotype was associated with higher activation of calcitonin gene-related peptide and dynorphin cells in the PBN. These findings provide new insights into the neurobiological mechanisms underlying the development of negative affect in females and highlight the potential involvement of the BNST-PBN circuitry in regulating emotional responses to alcohol-related stimuli.
Topics: Male; Mice; Female; Animals; Parabrachial Nucleus; Alcoholism; Septal Nuclei; Ethanol
PubMed: 38380710
DOI: 10.1111/adb.13366