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Cell Nov 2022After ingestion of toxin-contaminated food, the brain initiates a series of defensive responses (e.g., nausea, retching, and vomiting). How the brain detects ingested...
After ingestion of toxin-contaminated food, the brain initiates a series of defensive responses (e.g., nausea, retching, and vomiting). How the brain detects ingested toxin and coordinates diverse defensive responses remains poorly understood. Here, we developed a mouse-based paradigm to study defensive responses induced by bacterial toxins. Using this paradigm, we identified a set of molecularly defined gut-to-brain and brain circuits that jointly mediate toxin-induced defensive responses. The gut-to-brain circuit consists of a subset of Htr3a+ vagal sensory neurons that transmit toxin-related signals from intestinal enterochromaffin cells to Tac1+ neurons in the dorsal vagal complex (DVC). Tac1+ DVC neurons drive retching-like behavior and conditioned flavor avoidance via divergent projections to the rostral ventral respiratory group and lateral parabrachial nucleus, respectively. Manipulating these circuits also interferes with defensive responses induced by the chemotherapeutic drug doxorubicin. These results suggest that food poisoning and chemotherapy recruit similar circuit modules to initiate defensive responses.
Topics: Animals; Mice; Neurons; Neurons, Afferent; Parabrachial Nucleus; Vagus Nerve; Brain-Gut Axis
PubMed: 36323317
DOI: 10.1016/j.cell.2022.10.001 -
Neuron Sep 2019Sleep is crucial for our survival, and many diseases are linked to long-term poor sleep quality. Before we can use sleep to enhance our health and performance and...
Sleep is crucial for our survival, and many diseases are linked to long-term poor sleep quality. Before we can use sleep to enhance our health and performance and alleviate diseases associated with poor sleep, a greater understanding of sleep regulation is necessary. We have identified a mutation in the β-adrenergic receptor gene in humans who require fewer hours of sleep than most. In vitro, this mutation leads to decreased protein stability and dampened signaling in response to agonist treatment. In vivo, the mice carrying the same mutation demonstrated short sleep behavior. We found that this receptor is highly expressed in the dorsal pons and that these ADRB1 neurons are active during rapid eye movement (REM) sleep and wakefulness. Activating these neurons can lead to wakefulness, and the activity of these neurons is affected by the mutation. These results highlight the important role of β-adrenergic receptors in sleep/wake regulation.
Topics: Animals; Gene Knock-In Techniques; Humans; Mice; Mutation; Neurons; Pedigree; Pontine Tegmentum; Receptors, Adrenergic, beta-1; Sleep; Sleep Wake Disorders; Sleep, REM; Wakefulness
PubMed: 31473062
DOI: 10.1016/j.neuron.2019.07.026 -
Nature Reviews. Neuroscience Nov 2020The locus coeruleus (LC), or 'blue spot', is a small nucleus located deep in the brainstem that provides the far-reaching noradrenergic neurotransmitter system of the... (Review)
Review
The locus coeruleus (LC), or 'blue spot', is a small nucleus located deep in the brainstem that provides the far-reaching noradrenergic neurotransmitter system of the brain. This phylogenetically conserved nucleus has proved relatively intractable to full characterization, despite more than 60 years of concerted efforts by investigators. Recently, an array of powerful new neuroscience tools have provided unprecedented access to this elusive nucleus, revealing new levels of organization and function. We are currently at the threshold of major discoveries regarding how this tiny brainstem structure exerts such varied and significant influences over brain function and behaviour. All LC neurons receive inputs related to autonomic arousal, but distinct subpopulations of those neurons can encode specific cognitive processes, presumably through more specific inputs from the forebrain areas. This ability, combined with specific patterns of innervation of target areas and heterogeneity in receptor distributions, suggests that activation of the LC has more specific influences on target networks than had initially been imagined.
Topics: Animals; Cognition; Humans; Locus Coeruleus; Neural Pathways; Neuronal Plasticity; Neurons; Nucleus Accumbens
PubMed: 32943779
DOI: 10.1038/s41583-020-0360-9 -
ELife Nov 2022The parabrachial nucleus (PBN) is a major hub that receives sensory information from both internal and external environments. Specific populations of PBN neurons are...
The parabrachial nucleus (PBN) is a major hub that receives sensory information from both internal and external environments. Specific populations of PBN neurons are involved in behaviors including food and water intake, nociceptive responses, breathing regulation, as well as learning and responding appropriately to threatening stimuli. However, it is unclear how many PBN neuron populations exist and how different behaviors may be encoded by unique signaling molecules or receptors. Here we provide a repository of data on the molecular identity, spatial location, and projection patterns of dozens of PBN neuron subclusters. Using single-cell RNA sequencing, we identified 21 subclusters of neurons in the PBN and neighboring regions. Multiplexed in situ hybridization showed many of these subclusters are enriched within specific PBN subregions with scattered cells in several other regions. We also provide detailed visualization of the axonal projections from 21 Cre-driver lines of mice. These results are all publicly available for download and provide a foundation for further interrogation of PBN functions and connections.
Topics: Animals; Mice; Parabrachial Nucleus; Neurons; Axons
PubMed: 36317965
DOI: 10.7554/eLife.81868 -
Neuron Mar 2022Breathing can be heavily influenced by pain or internal emotional states, but the neural circuitry underlying this tight coordination is unknown. Here we report that...
Breathing can be heavily influenced by pain or internal emotional states, but the neural circuitry underlying this tight coordination is unknown. Here we report that Oprm1 (μ-opioid receptor)-expressing neurons in the lateral parabrachial nucleus (PBL) are crucial for coordinating breathing with affective pain in mice. Individual PBL neuronal activity synchronizes with breathing rhythm and responds to noxious stimuli. Manipulating PBL activity directly changes breathing rate, affective pain perception, and anxiety. Furthermore, PBL neurons constitute two distinct subpopulations in a "core-shell" configuration that divergently projects to the forebrain and hindbrain. Through non-overlapping projections to the central amygdala and pre-Bötzinger complex, these two subpopulations differentially regulate breathing, affective pain, and negative emotions. Moreover, these subsets form recurrent excitatory networks through reciprocal glutamatergic projections. Together, our data define the divergent parabrachial opioidergic circuits as a common neural substrate that coordinates breathing with various sensations and behaviors such as pain and emotional processing.
Topics: Animals; Brain Stem; Central Amygdaloid Nucleus; Emotions; Mice; Neural Pathways; Pain; Parabrachial Nucleus
PubMed: 34921781
DOI: 10.1016/j.neuron.2021.11.029 -
Nature Methods Sep 2023Genetically encoded indicators engineered from G-protein-coupled receptors are important tools that enable high-resolution in vivo neuromodulator imaging. Here, we...
Genetically encoded indicators engineered from G-protein-coupled receptors are important tools that enable high-resolution in vivo neuromodulator imaging. Here, we introduce a family of sensitive multicolor norepinephrine (NE) indicators, which includes nLightG (green) and nLightR (red). These tools report endogenous NE release in vitro, ex vivo and in vivo with improved sensitivity, ligand selectivity and kinetics, as well as a distinct pharmacological profile compared with previous state-of-the-art GRAB indicators. Using in vivo multisite fiber photometry recordings of nLightG, we could simultaneously monitor optogenetically evoked NE release in the mouse locus coeruleus and hippocampus. Two-photon imaging of nLightG revealed locomotion and reward-related NE transients in the dorsal CA1 area of the hippocampus. Thus, the sensitive NE indicators introduced here represent an important addition to the current repertoire of indicators and provide the means for a thorough investigation of the NE system.
Topics: Animals; Mice; Norepinephrine; Locus Coeruleus; Hippocampus; Receptors, G-Protein-Coupled
PubMed: 37474807
DOI: 10.1038/s41592-023-01959-z -
Neuron Oct 2022Individual memories are often linked so that the recall of one triggers the recall of another. For example, contextual memories acquired close in time can be linked, and...
Individual memories are often linked so that the recall of one triggers the recall of another. For example, contextual memories acquired close in time can be linked, and this is known to depend on a temporary increase in excitability that drives the overlap between dorsal CA1 (dCA1) hippocampal ensembles that encode the linked memories. Here, we show that locus coeruleus (LC) cells projecting to dCA1 have a key permissive role in contextual memory linking, without affecting contextual memory formation, and that this effect is mediated by dopamine. Additionally, we found that LC-to-dCA1-projecting neurons modulate the excitability of dCA1 neurons and the extent of overlap between dCA1 memory ensembles as well as the stability of coactivity patterns within these ensembles. This discovery of a neuromodulatory system that specifically affects memory linking without affecting memory formation reveals a fundamental separation between the brain mechanisms modulating these two distinct processes.
Topics: Locus Coeruleus; Dopamine; Memory; Hippocampus; Neurons
PubMed: 36041433
DOI: 10.1016/j.neuron.2022.08.001 -
Blood Mar 2022Comparison of treatment strategies in de novo pediatric acute lymphoblastic leukemia (ALL) requires standardized measures of efficacy. Key parameters that define...
Comparison of treatment strategies in de novo pediatric acute lymphoblastic leukemia (ALL) requires standardized measures of efficacy. Key parameters that define disease-related events, including complete remission (CR), treatment failure (TF; not achieving CR), and relapse (loss of CR) require an updated consensus incorporating modern diagnostics. We collected the definitions of CR, TF, and relapse from recent and current pediatric clinical trials for the treatment of ALL, including the key components of response evaluation (timing, anatomic sites, detection methods, and thresholds) and found significant heterogeneity, most notably in the definition of TF. Representatives of the major international ALL clinical trial groups convened to establish consensus definitions. CR should be defined at a time point no earlier than at the end of induction and should include the reduction of blasts below a specific threshold in bone marrow and extramedullary sites, incorporating minimal residual disease (MRD) techniques for marrow evaluations. TF should be defined as failure to achieve CR by a prespecified time point in therapy. Relapse can only be defined in patients who have achieved CR and must include a specific threshold of leukemic cells in the bone marrow confirmed by MRD, the detection of central nervous system leukemia, or documentation of extramedullary disease. Definitions of TF and relapse should harmonize with eligibility criteria for clinical trials in relapsed/refractory ALL. These consensus definitions will enhance the ability to compare outcomes across pediatric ALL trials and facilitate development of future international collaborative trials.
Topics: Child; Consensus; Humans; Neoplasm, Residual; Pons; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Remission Induction; Treatment Failure
PubMed: 34192312
DOI: 10.1182/blood.2021012328 -
Neuron Oct 2022The use of body-focused repetitive behaviors (BFRBs) is conceptualized as a means of coping with stress. However, the neurological mechanism by which repetitive...
The use of body-focused repetitive behaviors (BFRBs) is conceptualized as a means of coping with stress. However, the neurological mechanism by which repetitive behaviors affect anxiety regulation is unclear. Here, we identify that the excitatory somatostatin-positive neurons in the medial paralemniscal nucleus (MPL neurons) in mice promote self-grooming and encode reward. MPL neurons display prominent grooming-related neuronal activity. Loss of function of MPL neurons impairs both self-grooming and post-stress anxiety alleviation. Activation of MPL neurons is rewarding and sufficient to drive reinforcement by activating dopamine (DA) neurons in the ventral tegmental area (VTA) and eliciting dopamine release. The neuropeptide SST facilitates the rewarding impact of MPL neurons. MPL neuron-mediated self-grooming is triggered by the input from the central amygdala (CeA). Our study reveals a dual role of CeA-MPL-VTA circuit in self-grooming and post-stress anxiety regulation and conceptualizes MPL neurons as an interface linking the stress and reward systems in mice.
Topics: Animals; Mice; Grooming; Dopamine; Reward; Ventral Tegmental Area; Dopaminergic Neurons; Pontine Tegmentum; Somatostatin
PubMed: 36070748
DOI: 10.1016/j.neuron.2022.08.010 -
Neuroscience and Biobehavioral Reviews Sep 2023The locus coeruleus (LC) is a small brainstem structure located in the lower pons and is the main source of noradrenaline (NA) in the brain. Via its phasic and tonic... (Review)
Review
The locus coeruleus (LC) is a small brainstem structure located in the lower pons and is the main source of noradrenaline (NA) in the brain. Via its phasic and tonic firing, it modulates cognition and autonomic functions and is involved in the brain's immune response. The extent of degeneration to the LC in healthy ageing remains unclear, however, noradrenergic dysfunction may contribute to the pathogenesis of Alzheimer's (AD) and Parkinson's disease (PD). Despite their differences in progression at later disease stages, the early involvement of the LC may lead to comparable behavioural symptoms such as preclinical sleep problems and neuropsychiatric symptoms as a result of AD and PD pathology. In this review, we draw attention to the mechanisms that underlie LC degeneration in ageing, AD and PD. We aim to motivate future research to investigate how early degeneration of the noradrenergic system may play a pivotal role in the pathogenesis of AD and PD which may also be relevant to other neurodegenerative diseases.
Topics: Humans; Locus Coeruleus; Brain; Brain Stem; Parkinson Disease; Norepinephrine; Alzheimer Disease
PubMed: 37437752
DOI: 10.1016/j.neubiorev.2023.105311