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BioRxiv : the Preprint Server For... Jan 2023In addition to its canonical function in protecting from pathogens, the immune system can also promote behavioural alterations . The scope and mechanisms of behavioural...
In addition to its canonical function in protecting from pathogens, the immune system can also promote behavioural alterations . The scope and mechanisms of behavioural modifications by the immune system are not yet well understood. Using a mouse food allergy model, here we show that allergic sensitization drives antigen-specific behavioural aversion. Allergen ingestion activates brain areas involved in the response to aversive stimuli, including the nucleus of tractus solitarius, parabrachial nucleus, and central amygdala. Food aversion requires IgE antibodies and mast cells but precedes the development of gut allergic inflammation. The ability of allergen-specific IgE and mast cells to promote aversion requires leukotrienes and growth and differentiation factor 15 (GDF15). In addition to allergen-induced aversion, we find that lipopolysaccharide-induced inflammation also resulted in IgE-dependent aversive behaviour. These findings thus point to antigen-specific behavioural modifications that likely evolved to promote niche selection to avoid unfavourable environments.
PubMed: 36712030
DOI: 10.1101/2023.01.19.524823 -
Journal of Neurophysiology Feb 2023The parabrachial nucleus (PB) in the upper brainstem receives interoceptive information and sends a massive output projection directly to the cerebral cortex. Its...
The parabrachial nucleus (PB) in the upper brainstem receives interoceptive information and sends a massive output projection directly to the cerebral cortex. Its glutamatergic axons primarily target the midinsular cortex, and we have proposed that this PB-insular projection promotes arousal. Here, we test whether stimulating this projection causes wakefulness. We combined optogenetics and video-electroencephalography (vEEG) in mice to test this hypothesis by stimulating PB axons in the insular cortex. Stimulating this projection did not alter the cortical EEG or awaken mice. Also, despite a tendency toward aversion, PB-insular stimulation did not significantly alter real-time place preference (RTPP). These results are not consistent with the hypothesis that the direct PB-insular projection is part of the ascending arousal system. A brainstem region critical for wakefulness overlaps the medial parabrachial nucleus (PB) and has functional and direct axonal connectivity with the insular cortex. In this study, we hypothesized that this direct projection from the PB to the insular cortex promotes arousal. However, photostimulating PB axons in the insular cortex did not alter the cortical EEG or awaken mice. This information constrains the possible circuit connections through which brainstem neurons may sustain arousal.
Topics: Mice; Animals; Cerebral Cortex; Brain Stem; Electroencephalography; Arousal; Wakefulness
PubMed: 36542422
DOI: 10.1152/jn.00318.2022 -
Nature Communications Feb 2023Breathing is regulated automatically by neural circuits in the medulla to maintain homeostasis, but breathing is also modified by behavior and emotion. Mice have rapid...
Breathing is regulated automatically by neural circuits in the medulla to maintain homeostasis, but breathing is also modified by behavior and emotion. Mice have rapid breathing patterns that are unique to the awake state and distinct from those driven by automatic reflexes. Activation of medullary neurons that control automatic breathing does not reproduce these rapid breathing patterns. By manipulating transcriptionally defined neurons in the parabrachial nucleus, we identify a subset of neurons that express the Tac1, but not Calca, gene that exerts potent and precise conditional control of breathing in the awake, but not anesthetized, state via projections to the ventral intermediate reticular zone of the medulla. Activating these neurons drives breathing to frequencies that match the physiological maximum through mechanisms that differ from those that underlie the automatic control of breathing. We postulate that this circuit is important for the integration of breathing with state-dependent behaviors and emotions.
Topics: Mice; Animals; Neurons; Respiration; Medulla Oblongata
PubMed: 36810601
DOI: 10.1038/s41467-023-36603-z -
The Journal of Pain Aug 2022The lateral parabrachial nucleus (LPBN) plays an important role in the processing and establishment of pain aversion. It receives direct input from the superficial...
The lateral parabrachial nucleus (LPBN) plays an important role in the processing and establishment of pain aversion. It receives direct input from the superficial dorsal horn and forms reciprocal connections with the periaqueductal grey matter (PAG), which is critical for adaptive behaviour and the modulation of pain processing. Here, using in situ hybridization and optogenetics combined with in vitro electrophysiology, we characterized the spinal- and PAG-LPBN circuits of rats. We found spinoparabrachial projections to be strictly glutamatergic, while PAG neurons send glutamatergic and GABAergic projections to the LPBN. We next investigated the effects of drugs with anti-aversive and/or anti-nociceptive properties on these synapses: The µ-opioid receptor agonist DAMGO (10 µM) reduced spinal and PAG synaptic inputs onto LPBN neurons, and the excitability of LPBN neurons receiving these inputs. The benzodiazepine receptor agonist diazepam (5 µM) strongly enhanced GABAergic action at inhibitory PAG-LPBN synapses. The cannabinoid receptor agonist WIN 55,212-2 (5 µM) led to a reduction in inhibitory and excitatory PAG-LPBN synaptic transmission, without affecting excitatory spinoparabrachial synaptic transmission. Our study reveals that opioid, cannabinoid and benzodiazepine receptor agonists differentially affect distinct LPBN synapses. These findings may support the efforts to develop pinpointed therapies for pain patients. PERSPECTIVE: The LPBN is an important brain region for the control of pain aversion versus recuperation, and as such constitutes a promising target for developing new strategies for pain management. We show that clinically-relevant drugs have complex and pathway-specific effects on LPBN processing of putative nociceptive and aversive inputs.
Topics: Analgesics, Opioid; Animals; Pain; Parabrachial Nucleus; Periaqueductal Gray; Rats; Rats, Sprague-Dawley; Receptors, GABA-A
PubMed: 35339662
DOI: 10.1016/j.jpain.2022.03.234 -
Nature Communications Mar 2024The "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 the unique marker genes of many neuronal subtypes. 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.
Topics: Humans; Animals; Mice; In Situ Hybridization, Fluorescence; Pontine Tegmentum; Brain Stem; Locus Coeruleus; Parabrachial Nucleus; Ascomycota
PubMed: 38438345
DOI: 10.1038/s41467-024-45907-7 -
CNS Neuroscience & Therapeutics Nov 2023Neuropathic pain after spinal cord injury (SCI) remains a common and thorny problem, influencing the life quality severely. This study aimed to elucidate the...
Neuropathic pain following spinal cord hemisection induced by the reorganization in primary somatosensory cortex and regulated by neuronal activity of lateral parabrachial nucleus.
AIMS
Neuropathic pain after spinal cord injury (SCI) remains a common and thorny problem, influencing the life quality severely. This study aimed to elucidate the reorganization of the primary sensory cortex (S1) and the regulatory mechanism of the lateral parabrachial nucleus (lPBN) in the presence of allodynia or hyperalgesia after left spinal cord hemisection injury (LHS).
METHODS
Through behavioral tests, we first identified mechanical allodynia and thermal hyperalgesia following LHS. We then applied two-photon microscopy to observe calcium activity in S1 during mechanical or thermal stimulation and long-term spontaneous calcium activity after LHS. By slice patch clamp recording, the electrophysiological characteristics of neurons in lPBN were explored. Finally, exploiting chemogenetic activation or inhibition of the neurons in lPBN, allodynia or hyperalgesia was regulated.
RESULTS
The calcium activity in left S1 was increased during mechanical stimulation of right hind limb and thermal stimulation of tail, whereas in right S1 it was increased only with thermal stimulation of tail. The spontaneous calcium activity in right S1 changed more dramatically than that in left S1 after LHS. The lPBN was also activated after LHS, and exploiting chemogenetic activation or inhibition of the neurons in lPBN could induce or alleviate allodynia and hyperalgesia in central neuropathic pain.
CONCLUSION
The neuronal activity changes in S1 are closely related to limb pain, which has accurate anatomical correspondence. After LHS, the spontaneously increased functional connectivity of calcium transient in left S1 is likely causing the mechanical allodynia in right hind limb and increased neuronal activity in bilateral S1 may induce thermal hyperalgesia in tail. This state of allodynia and hyperalgesia can be regulated by lPBN.
Topics: Humans; Hyperalgesia; Parabrachial Nucleus; Calcium; Somatosensory Cortex; Spinal Cord; Neuralgia; Neurons; Spinal Cord Injuries
PubMed: 37170721
DOI: 10.1111/cns.14258 -
Behavioural Brain Research Jan 2015Serotonin has been implicated in the control of satiety for almost four decades. Historically, the insight that the appetite suppressant effect of fenfluramine is linked... (Review)
Review
Serotonin has been implicated in the control of satiety for almost four decades. Historically, the insight that the appetite suppressant effect of fenfluramine is linked to serotonin has stimulated interest in and research into the role of this neurotransmitter in satiety. Various rodent models, including transgenic models, have been developed to identify the involved 5-HT receptor subtypes. This approach also required the availability of receptor ligands of different selectivity, and behavioural techniques had to be developed simultaneously which allow differentiating between unspecific pharmacological effects of these ligands and 'true' satiation and satiety. Currently, 5-HT1B, 5-HT2C and 5-HT6 receptors have been identified to mediate serotonergic satiety in different ways. The recently approved anti-obesity drug lorcaserin is a 5-HT2C receptor agonist. In brain, both hypothalamic (arcuate nucleus, paraventricular nucleus) and extrahypothalamic sites (parabrachial nucleus, nucleus of the solitary tract) have been identified to mediate the serotonergic control of satiety. Serotonin interacts within the hypothalamus with endogenous orexigenic (Neuropeptide Y/Agouti related protein) and anorectic (α-melanocyte stimulating hormone) peptides. In the nucleus of the solitary tract serotonin integrates peripheral satiety signals. Here, the 5-HT3, but possibly also the 5-HT2C receptor play a role. It has been found that 5-HT acts in concert with such peripheral signals as cholecystokinin and leptin. Despite the recent advances of our knowledge, many of the complex interactions between 5-HT and other satiety factors are not fully understood yet. Further progress in research will also advance the development of new serotonergic anti-obesity drugs.
Topics: Animals; Eating; Feeding Behavior; Humans; Obesity; Receptors, Serotonin; Satiety Response; Serotonin
PubMed: 25217810
DOI: 10.1016/j.bbr.2014.08.065 -
Frontiers in Psychiatry 2023In humans and animals, exposure to changes in internal or external environments causes acute stress, which changes sleep and enhances neurochemical, neuroendocrine, and...
In humans and animals, exposure to changes in internal or external environments causes acute stress, which changes sleep and enhances neurochemical, neuroendocrine, and sympathetic activities. Repeated stress responses play an essential role in the pathogenesis of psychiatric diseases and sleep disorders. However, the underlying mechanism of sleep changes and anxiety disorders in response to acute stress is not well established. In the current study, the effects of restraint stress (RS) on anxiety and sleep-wake cycles in mice were investigated. We found that after RS, the mice showed anxiety-like behavior after RS manipulation and increased the amounts of both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep in the dark period. The increase in sleep time was mainly due to the increased number of episodes of NREM and REM sleep during the dark period. In addition, the mice showed an elevation of the EEG power spectrum of both NREM and REM sleep 2 h after RS manipulation. There was a significant reduction in the EEG power spectrum of both NREM and REM sleep during the darkperiod in the RS condition. The expression of the c-Fos protein was significantly increased in the parabrachial nucleus, bed nucleus of the stria terminalis, central amygdala, and paraventricular hypothalamus by RS manipulation. Altogether, the findings from the present study indicated that neural circuits from the parabrachial nucleus might regulate anxiety and sleep responses to acute stress, and suggest a potential therapeutic target for RS induced anxiety and sleep alterations.
PubMed: 37124267
DOI: 10.3389/fpsyt.2023.1090420 -
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 -
The Journal of Neuroscience : the... Oct 2019The parabrachial nucleus (PBN) has long been recognized as a sensory relay receiving an array of interoceptive and exteroceptive inputs relevant to taste and ingestive... (Review)
Review
The parabrachial nucleus (PBN) has long been recognized as a sensory relay receiving an array of interoceptive and exteroceptive inputs relevant to taste and ingestive behavior, pain, and multiple aspects of autonomic control, including respiration, blood pressure, water balance, and thermoregulation. Outputs are known to be similarly widespread and complex. How sensory information is handled in PBN and used to inform different outputs to maintain homeostasis and promote survival is only now being elucidated. With a focus on taste and ingestive behaviors, pain, and thermoregulation, this review is intended to provide a context for analysis of PBN circuits involved in aversion and avoidance, and consider how information of various modalities, interoceptive and exteroceptive, is processed within PBN and transmitted to distinct targets to signal challenge, and to engage appropriate behavioral and physiological responses to maintain homeostasis.
Topics: Animals; Body Temperature Regulation; Humans; Neural Pathways; Neurons; Nociception; Pain; Parabrachial Nucleus; Taste
PubMed: 31619491
DOI: 10.1523/JNEUROSCI.1162-19.2019