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Journal of Diabetes Investigation Mar 2024The report by Adriaenssens et al. in JCI Insight 22 May 2023 explored the role and property of the neurons that express glucose-dependent insulinotropic polypeptide...
The report by Adriaenssens et al. in JCI Insight 22 May 2023 explored the role and property of the neurons that express glucose-dependent insulinotropic polypeptide receptor (GIPR) in the brainstem and hypothalamus. The chemogenetic activation of the brainstem GIPR neurons and that of the hypothalamic GIPR neurons showed different feeding and behavior responses. The brainstem GIPR neurons projected to the paraventricular hypothalamus and lateral parabrachial nucleus. Fluorescent-labeled, stabilized peptide GIPR agonist (GIPRA), peripherally injected, localized to the area postrema, nucleus tractus solitarius, median eminence and arcuate hypothalamus. This report showed the role of brainstem GIPR neurons in receiving GIPRA to drive the neural circuit to reduce feeding and bodyweight. In this commentary, distinct and possible cooperative roles of the hypothalamic and the brainstem GIPR pathways will also be discussed.
Topics: Humans; Hypothalamus; Receptors, Gastrointestinal Hormone; Brain Stem; Neurons
PubMed: 38140849
DOI: 10.1111/jdi.14130 -
Frontiers in Neural Circuits 2023Appropriately responding to various sensory signals in the environment is essential for animal survival. Accordingly, animal behaviors are closely related to external...
Appropriately responding to various sensory signals in the environment is essential for animal survival. Accordingly, animal behaviors are closely related to external and internal states, which include the positive and negative emotional values of sensory signals triggered by environmental factors. While the lateral parabrachial nucleus (LPB) plays a key role in nociception and supports negative valences, it also transmits signals including positive valences. However, the downstream neuronal mechanisms of positive and negative valences have not been fully explored. In the present study, we investigated the ventral tegmental area (VTA) as a projection target for LPB neurons. Optogenetic activation of LPB-VTA terminals in male mice elicits positive reinforcement in an operant task and induces both avoidance and attraction in a place-conditioning task. Inhibition of glutamic acid decarboxylase (GAD) 65-expressing cells in the VTA promotes avoidance behavior induced by photoactivation of the LPB-VTA pathway. These findings indicate that the LPB-VTA pathway is one of the LPB outputs for the transmission of positive and negative valence signals, at least in part, with GABAergic modification in VTA.
Topics: Mice; Male; Animals; Ventral Tegmental Area; Parabrachial Nucleus; Neurons; Reinforcement, Psychology; Avoidance Learning
PubMed: 38094239
DOI: 10.3389/fncir.2023.1273322 -
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 -
Neuroscience Jan 2024The paraventricular nucleus of the thalamus (PVT) sends dense projections to the shell of the nucleus accumbens (NAcSh), dorsolateral region of the bed nucleus of the...
The paraventricular nucleus of the thalamus (PVT) sends dense projections to the shell of the nucleus accumbens (NAcSh), dorsolateral region of the bed nucleus of the stria terminalis (BSTDL) and the lateral region of central nucleus of the amygdala (CeL). Projection specific modulation of these pathways has been shown to regulate appetitive and aversive behavioral responses. The present investigation applied an intersectional monosynaptic rabies tracing approach to quantify the brain-wide sources of afferent input to PVT neurons that primarily project to the NAcSh, BSTDL and CeL. The results demonstrate that these projection neurons receive monosynaptic input from similar brain regions. The prefrontal cortex and the ventral subiculum of the hippocampus were major sources of input to the PVT projection neurons. In addition, the lateral septal nucleus, thalamic reticular nucleus and the hypothalamic medial preoptic area, dorsomedial, ventromedial, and arcuate nuclei were sources of input. The subfornical organ, parasubthalamic nucleus, periaqueductal gray matter, lateral parabrachial nucleus, and nucleus of the solitary tract were consistent but lesser sources of input. This input-output relationship is consistent with recent observations that PVT neurons have axons that bifurcate extensively to divergently innervate the NAcSh, BSTDL and CeL.
Topics: Nucleus Accumbens; Central Amygdaloid Nucleus; Paraventricular Hypothalamic Nucleus; Hypothalamus; Neurons; Neural Pathways
PubMed: 38056620
DOI: 10.1016/j.neuroscience.2023.11.033 -
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 -
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 -
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