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BioRxiv : the Preprint Server For... May 2023Infections with defined Herpesviruses, such as Pseudorabies virus (PRV) and Varicella zoster virus (VZV) can cause neuropathic itch, referred to as "mad itch" in...
Infections with defined Herpesviruses, such as Pseudorabies virus (PRV) and Varicella zoster virus (VZV) can cause neuropathic itch, referred to as "mad itch" in multiple species. The underlying mechanisms involved in neuropathic "mad itch" are poorly understood. Here, we show that PRV infections hijack the RNA helicase DDX3X in sensory neurons to facilitate anterograde transport of the virus along axons. PRV induces re-localization of DDX3X from the cell body to the axons which ultimately leads to death of the infected sensory neurons. Inducible genetic ablation of in sensory neurons results in neuronal death and "mad itch" in mice. This neuropathic "mad itch" is propagated through activation of the opioid system making the animals "addicted to itch". Moreover, we show that PRV co-opts and diverts T cell development in the thymus via a sensory neuron-IL-6-hypothalamus-corticosterone stress pathway. Our data reveal how PRV, through regulation of DDX3X in sensory neurons, travels along axons and triggers neuropathic itch and immune deviations to initiate pathophysiological programs which facilitate its spread to enhance infectivity.
PubMed: 37214906
DOI: 10.1101/2023.05.09.539956 -
Scientific Reports Jun 2022The habenula is a complex neuronal population integrated in a pivotal functional position into the vertebrate limbic system. Its main afference is the stria medullaris...
The habenula is a complex neuronal population integrated in a pivotal functional position into the vertebrate limbic system. Its main afference is the stria medullaris and its main efference the fasciculus retroflexus. This neuronal complex is composed by two main components, the medial and lateral habenula. Transcriptomic and single cell RNAseq studies have unveiled the morphological complexity of both components. The aim of our work was to analyze the relation between the origin of the axonal fibers and their final distribution in the habenula. We analyzed 754 tracing experiments from Mouse Brain Connectivity Atlas, Allen Brain Map databases, and selected 12 neuronal populations projecting into the habenular territory. Our analysis demonstrated that the projections into the medial habenula discriminate between the different subnuclei and are generally originated in the septal territory. The innervation of the lateral habenula displayed instead a less restricted distribution from preoptic, terminal hypothalamic and peduncular nuclei. Only the lateral oval subnucleus of the lateral habenula presented a specific innervation from the dorsal entopeduncular nucleus. Our results unveiled the necessity of novel sorts of behavioral experiments to dissect the different functions associated with the habenular complex and their correlation with the distinct neuronal populations that generate them.
Topics: Animals; Habenula; Hypothalamus; Mesencephalon; Mice; Neurons; Transcriptome
PubMed: 35710872
DOI: 10.1038/s41598-022-14328-1 -
Endocrine, Metabolic & Immune Disorders... 2020The Renin-Angiotensin-Aldosterone System (RAAS) plays a major role in the regulation of cardiovascular functions, water and electrolytic balance, and hormonal responses.... (Review)
Review
OBJECTIVE
The Renin-Angiotensin-Aldosterone System (RAAS) plays a major role in the regulation of cardiovascular functions, water and electrolytic balance, and hormonal responses. We perform a review of the literature, aiming at providing the current concepts regarding the angiotensin interaction with the immune system in the brain and the related implications for cardiovascular and neuroendocrine responses.
METHODS
Appropriate keywords and MeSH terms were identified and searched in Pubmed. Finally, references of original articles and reviews were examined.
RESULTS
Angiotensin II (ANG II), beside stimulating aldosterone, vasopressin and CRH-ACTH release, sodium and water retention, thirst, and sympathetic nerve activity, exerts its effects on the immune system via the Angiotensin Type 1 Receptor (AT 1R) that is located in the brain, pituitary, adrenal gland, and kidney. Several actions are triggered by the binding of circulating ANG II to AT 1R into the circumventricular organs that lack the Blood-Brain-Barrier (BBB). Furthermore, the BBB becomes permeable during chronic hypertension thereby ANG II may also access brain nuclei controlling cardiovascular functions. Subfornical organ, organum vasculosum lamina terminalis, area postrema, paraventricular nucleus, septal nuclei, amygdala, nucleus of the solitary tract and retroventral lateral medulla oblongata are the brain structures that mediate the actions of ANG II since they are provided with a high concentration of AT 1R. ANG II induces also T-lymphocyte activation and vascular infiltration of leukocytes and, moreover, oxidative stress stimulating inflammatory responses via inhibition of endothelial progenitor cells and stimulation of inflammatory and microglial cells facilitating the development of hypertension.
CONCLUSION
Besides the well-known mechanisms by which RAAS activation can lead to the development of hypertension, the interactions between ANG II and the immune system at the brain level can play a significant role.
Topics: Animals; Arterial Pressure; Brain; Cardiovascular System; Drinking; Humans; Hypertension; Immune System; Neuroimmunomodulation; Neurosecretory Systems; Oxidative Stress; Renin-Angiotensin System; Signal Transduction; Water-Electrolyte Balance
PubMed: 31237219
DOI: 10.2174/1871530319666190617160934 -
Circulation Feb 2022The pathogenic missense variant p.G125R in TBX5 (T-box transcription factor 5) causes Holt-Oram syndrome (also known as hand-heart syndrome) and early onset of atrial...
BACKGROUND
The pathogenic missense variant p.G125R in TBX5 (T-box transcription factor 5) causes Holt-Oram syndrome (also known as hand-heart syndrome) and early onset of atrial fibrillation. Revealing how an altered key developmental transcription factor modulates cardiac physiology in vivo will provide unique insights into the mechanisms underlying atrial fibrillation in these patients.
METHODS
We analyzed ECGs of an extended family pedigree of Holt-Oram syndrome patients. Next, we introduced the TBX5-p.G125R variant in the mouse genome () and performed electrophysiologic analyses (ECG, optical mapping, patch clamp, intracellular calcium measurements), transcriptomics (single-nuclei and tissue RNA sequencing), and epigenetic profiling (assay for transposase-accessible chromatin using sequencing, H3K27ac [histone H3 lysine 27 acetylation] CUT&RUN [cleavage under targets and release under nuclease sequencing]).
RESULTS
We discovered high incidence of atrial extra systoles and atrioventricular conduction disturbances in Holt-Oram syndrome patients. mice were morphologically unaffected and displayed variable RR intervals, atrial extra systoles, and susceptibility to atrial fibrillation, reminiscent of TBX5-p.G125R patients. Atrial conduction velocity was not affected but systolic and diastolic intracellular calcium concentrations were decreased and action potentials were prolonged in isolated cardiomyocytes of mice compared with controls. Transcriptional profiling of atria revealed the most profound transcriptional changes in cardiomyocytes versus other cell types, and identified over a thousand coding and noncoding transcripts that were differentially expressed. Epigenetic profiling uncovered thousands of TBX5-p.G125R-sensitive, putative regulatory elements (including enhancers) that gained accessibility in atrial cardiomyocytes. The majority of sites with increased accessibility were occupied by Tbx5. The small group of sites with reduced accessibility was enriched for DNA-binding motifs of members of the SP (specificity protein) and KLF (Krüppel-like factor) families of transcription factors. These data show that Tbx5-p.G125R induces changes in regulatory element activity, alters transcriptional regulation, and changes cardiomyocyte behavior, possibly caused by altered DNA binding and cooperativity properties.
CONCLUSIONS
Our data reveal that a disease-causing missense variant in TBX5 induces profound changes in the atrial transcriptional regulatory network and epigenetic state in vivo, leading to arrhythmia reminiscent of those seen in human TBX5-p.G125R variant carriers.
Topics: Abnormalities, Multiple; Amino Acid Substitution; Animals; Atrial Fibrillation; Female; Gene Expression Regulation; Heart Atria; Heart Defects, Congenital; Heart Septal Defects, Atrial; Heterozygote; Humans; Lower Extremity Deformities, Congenital; Male; Mice; Mice, Mutant Strains; Mutation, Missense; Pedigree; T-Box Domain Proteins; Upper Extremity Deformities, Congenital
PubMed: 35113653
DOI: 10.1161/CIRCULATIONAHA.121.054347 -
Journal of Affective Disorders Aug 2023Anxiety disorder is one of the most prevalent psychiatric disorders. Intriguingly, dysfunction of the central histaminergic system, which is recognized as a general...
BACKGROUND
Anxiety disorder is one of the most prevalent psychiatric disorders. Intriguingly, dysfunction of the central histaminergic system, which is recognized as a general regulator for whole-brain activity, may result in anxiety, suggesting an involvement of the central histaminergic signaling in the modulation of anxiety. However, the neural mechanisms involved have not been fully identified.
METHODS
Here, we examined the effect of histaminergic signaling in the bed nucleus of the stria terminalis (BNST) on anxiety-like behaviors both in normal and acute restraint stressed male rats by using anterograde tracing, immunofluorescence, qPCR, neuropharmacology, molecular manipulation and behavioral tests.
RESULTS
We found that histaminergic neurons in the hypothalamus send direct projections to the BNST, which forms a part of the circuitry involved in stress and anxiety. Infusion of histamine into the BNST produced anxiogenic effect. Moreover, histamine H1 and H2 receptors are expressed and distributed in the BNST neurons. Blockade of histamine H1 or H2 receptors in the BNST did not affect anxiety-like behaviors in normal rats, but ameliorated anxiogenic effect induced by acute restraint stress. Furthermore, knockdown of H1 or H2 receptors in the BNST induced anxiolytic effect in acute restraint stressed rats, which confirmed the pharmacological results.
LIMITATIONS
A single dose of histamine receptor antagonist was used.
CONCLUSIONS
Together, these findings demonstrate a novel mechanism for the central histaminergic system in the regulation of anxiety, and suggest that inhibition of histamine receptors may be a useful strategy for treating anxiety disorder.
Topics: Rats; Male; Animals; Septal Nuclei; Histamine; Receptors, Histamine H2; Anxiety; Anxiety Disorders
PubMed: 37201895
DOI: 10.1016/j.jad.2023.05.035 -
Frontiers in Neural Circuits 2021The Medial Septum and diagonal Band of Broca (MSDB) was initially studied for its role in locomotion. However, the last several decades were focussed on its intriguing... (Review)
Review
The Medial Septum and diagonal Band of Broca (MSDB) was initially studied for its role in locomotion. However, the last several decades were focussed on its intriguing function in theta rhythm generation. Early studies relied on electrical stimulation, lesions and pharmacological manipulation, and reported an inconclusive picture regarding the role of the MSDB circuits. Recent studies using more specific methodologies have started to elucidate the differential role of the MSDB's specific cell populations in controlling both theta rhythm and behaviour. In particular, a novel theory is emerging showing that different MSDB's cell populations project to different brain regions and control distinct aspects of behaviour. While the majority of these behaviours involve movement, increasing evidence suggests that MSDB-related networks govern the motivational aspect of actions, rather than locomotion . Here, we review the literature that links MSDB, theta activity, and locomotion and propose open questions, future directions, and methods that could be employed to elucidate the diverse roles of the MSDB-associated networks.
Topics: Animals; Diagonal Band of Broca; GABA Agonists; Humans; Locomotion; Motivation; Movement; Nerve Net; Septal Nuclei; Sodium Channel Blockers; Theta Rhythm
PubMed: 34366795
DOI: 10.3389/fncir.2021.699798 -
Neuroscience and Biobehavioral Reviews Mar 2023We suggest that to understand complex behaviors associated with fear and anxiety, we need to understand brain processes at the collective, network level. But what should... (Review)
Review
We suggest that to understand complex behaviors associated with fear and anxiety, we need to understand brain processes at the collective, network level. But what should be the type and spatial scale of the targeted circuits/networks? Not only are multi-region interactions essential-including complex reciprocal interactions, loops, and other types of arrangement-but it is profitable to characterize circuits spanning the entire neuroaxis. In particular, it is productive to conceptualize the circuits contributing to fear/anxiety as embedded into large-scale connectional systems. We discuss circuits involving the basolateral amygdala that contribute to aversive conditioning and fear extinction. In addition, we highlight the importance of the extended amygdala (central nucleus of the amygdala and bed nucleus of the stria terminalis) cortical-subcortical loop, which allows large swaths of cortex and subcortex to influence fear and anxiety. In this manner, fear/anxiety can be understood not only based on traditional "descending" mechanisms involving the hypothalamus and brainstem, but in terms of a considerably broader reentrant organization.
Topics: Humans; Fear; Extinction, Psychological; Anxiety; Brain; Anxiety Disorders; Septal Nuclei
PubMed: 36634832
DOI: 10.1016/j.neubiorev.2023.105039 -
Handbook of Clinical Neurology 2021The bed nucleus of the stria terminalis (BNST) is a compact but neurophenotypically complex structure in the ventral forebrain that is structurally and functionally... (Review)
Review
The bed nucleus of the stria terminalis (BNST) is a compact but neurophenotypically complex structure in the ventral forebrain that is structurally and functionally linked to other limbic structures, including the amygdala nuclear complex, hypothalamic nuclei, hippocampus, and related midbrain structures, to participate in a wide range of functions, especially emotion, emotional learning, stress-related responses, and sexual behaviors. From a variety of sensory inputs, the BNST acts as a node for signal integration and coordination for information relay to downstream central neuroendocrine and autonomic centers for appropriate homeostatic physiological and behavioral responses. In contrast to the role of the amygdala in fear, the BNST has gained wide interest from work suggesting that it has main roles in mediating sustained responses to diffuse, unpredictable and/or long-duration threats that are typically associated with anxiety-related responses. Further, some BNST subregions are highly sexually dimorphic which appear contributory to the differential stress and social interactive behaviors, including reproductive responses, between males and females. Notably, maladaptive BNST neuroplasticity and function have been implicated in chronic pain, depression, anxiety-related abnormalities, and other psychopathologies including posttraumatic stress disorders. The BNST circuits are predominantly GABAergic-the glutaminergic neurons represent a minor population-but the complexity of the system results from an overlay of diverse neuropeptide coexpression in these neurons. More than a dozen neuropeptides may be differentially coexpressed in BNST neurons, and from variable G protein-coupled receptor signaling, may inhibit or activate downstream circuit activities. The mechanisms and roles of these peptides in modulating intrinsic BNST neurocircuit signaling and BNST long-distance target cell projections are still not well understood. Nevertheless, an understanding of some of the principal players may allow assembly of the circuit interactions.
Topics: Amygdala; Anxiety; Corticotropin-Releasing Hormone; Female; Humans; Male; Neuronal Plasticity; Septal Nuclei
PubMed: 34225977
DOI: 10.1016/B978-0-12-819975-6.00025-X -
AJNR. American Journal of Neuroradiology Oct 2019The internal cerebral vein begins at the foramen of Monro by the union of the thalamostriate and the anterior septal veins. The lateral direct vein is its other major...
BACKGROUND AND PURPOSE
The internal cerebral vein begins at the foramen of Monro by the union of the thalamostriate and the anterior septal veins. The lateral direct vein is its other major tributary. Numerous researchers have reported differences in internal cerebral vein branching patterns but did not classify them. Hence, the objectives of this study were to evaluate the anatomy of the internal cerebral vein and its primary tributaries and classify them depending on their course patterns using CTA.
MATERIALS AND METHODS
Head CTAs of 250 patients were evaluated in this study, in which we identified the number and termination of the anterior septal vein and the lateral direct vein. The course of the lateral direct vein and its influence on the number of thalamostriate veins and their diameters and courses were assessed. The anterior septal vein-internal cerebral vein junctions and their locations in relation to the foramen of Monro also were evaluated.
RESULTS
We classified internal cerebral vein branching patterns into 4 types depending on the presence of an extra vessel draining the striatum. Most commonly, the internal cerebral vein continued further as 1 thalamostriate vein (77%). The lateral direct veins were identified in 22% of the hemispheres, and usually they terminated at the middle third of the internal cerebral vein (65.45%). The most common location of the anterior septal vein-internal cerebral vein junction was anterior (57.20%), with the anterior septal vein terminating at the venous angle.
CONCLUSIONS
Detailed knowledge of the anatomy of the deep cerebral veins is of great importance in neuroradiology and neurosurgery because iatrogenic injury to the veins may result in basal nuclei infarcts. A classification of internal cerebral vein branching patterns may aid clinicians in planning approaches to the third and lateral ventricles.
Topics: Adult; Aged; Aged, 80 and over; Cerebral Veins; Computed Tomography Angiography; Female; Humans; Male; Middle Aged; Retrospective Studies
PubMed: 31488502
DOI: 10.3174/ajnr.A6200 -
The Journal of Neuroscience : the... Oct 2020When extreme, anxiety-a state of distress and arousal prototypically evoked by uncertain danger-can be debilitating. Uncertain anticipation is a shared feature of...
When extreme, anxiety-a state of distress and arousal prototypically evoked by uncertain danger-can be debilitating. Uncertain anticipation is a shared feature of situations that elicit signs and symptoms of anxiety across psychiatric disorders, species, and assays. Despite the profound significance of anxiety for human health and wellbeing, the neurobiology of uncertain-threat anticipation remains unsettled. Leveraging a paradigm adapted from animal research and optimized for fMRI signal decomposition, we examined the neural circuits engaged during the anticipation of temporally uncertain and certain threat in 99 men and women. Results revealed that the neural systems recruited by uncertain and certain threat anticipation are anatomically colocalized in frontocortical regions, extended amygdala, and periaqueductal gray. Comparison of the threat conditions demonstrated that this circuitry can be fractionated, with frontocortical regions showing relatively stronger engagement during the anticipation of uncertain threat, and the extended amygdala showing the reverse pattern. Although there is widespread agreement that the bed nucleus of the stria terminalis and dorsal amygdala-the two major subdivisions of the extended amygdala-play a critical role in orchestrating adaptive responses to potential danger, their precise contributions to human anxiety have remained contentious. Follow-up analyses demonstrated that these regions show statistically indistinguishable responses to temporally uncertain and certain threat anticipation. These observations provide a framework for conceptualizing anxiety and fear, for understanding the functional neuroanatomy of threat anticipation in humans, and for accelerating the development of more effective intervention strategies for pathological anxiety. Anxiety-an emotion prototypically associated with the anticipation of uncertain harm-has profound significance for public health, yet the underlying neurobiology remains unclear. Leveraging a novel neuroimaging paradigm in a relatively large sample, we identify a core circuit responsive to both uncertain and certain threat anticipation, and show that this circuitry can be fractionated into subdivisions with a bias for one kind of threat or the other. The extended amygdala occupies center stage in neuropsychiatric models of anxiety, but its functional architecture has remained contentious. Here we demonstrate that its major subdivisions show statistically indistinguishable responses to temporally uncertain and certain threat. Collectively, these observations indicate the need to revise how we think about the neurobiology of anxiety and fear.
Topics: Amygdala; Anticipation, Psychological; Anxiety Disorders; Brain Mapping; Electric Stimulation; Fear; Female; Frontal Lobe; Galvanic Skin Response; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Neural Pathways; Periaqueductal Gray; Photic Stimulation; Prospective Studies; Septal Nuclei; Uncertainty; Young Adult
PubMed: 32958570
DOI: 10.1523/JNEUROSCI.0704-20.2020