Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2 model of Parkinson's disease.

Several studies have revealed that midbrain dopamine (DA) neurons, even within a single neuroanatomical area, display heterogeneous properties. In parallel, studies using single cell profiling techniques have begun to cluster DA neurons into subtypes based on their molecular signatures. Recent work has shown that molecularly defined DA subtypes within the substantia nigra (SNc) display distinctive anatomic and functional properties, and differential vulnerability in Parkinson's disease (PD).

Left common carotid artery to left innominate vein arteriovenous fistula after transvenous laser lead extraction.

Transvenous lead extraction (TLE) is used for lead infection, lead debulking, venous recanalization and device upgrades. Lead extraction is performed using specialized tools including locking stylets, mechanical or rotating sheaths, femoral snares or laser sheaths. The most feared complications associated with lead extraction are bleeding, vascular tear, cardiac avulsion and tamponade.

Sox6 expression distinguishes dorsally and ventrally biased dopamine neurons in the substantia nigra with distinctive properties and embryonic origins.

Dopamine (DA) neurons in the ventral tier of the substantia nigra pars compacta (SNc) degenerate prominently in Parkinson's disease, while those in the dorsal tier are relatively spared. Defining the molecular, functional, and developmental characteristics of each SNc tier is crucial to understand their distinct susceptibility. We demonstrate that Sox6 expression distinguishes ventrally and dorsally biased DA neuron populations in the SNc.

VGluT2 Expression in Dopamine Neurons Contributes to Postlesional Striatal Reinnervation.

A subset of adult ventral tegmental area dopamine (DA) neurons expresses vesicular glutamate transporter 2 (VGluT2) and releases glutamate as a second neurotransmitter in the striatum, while only few adult substantia nigra DA neurons have this capacity. Recent work showed that cellular stress created by neurotoxins such as MPTP and 6-hydroxydopamine can upregulate VGluT2 in surviving DA neurons, suggesting the possibility of a role in cell survival, although a high level of overexpression could be toxic to DA neurons. Here we examined the level of VGluT2 upregulation in response to neurotoxins and its impact on postlesional plasticity.

PRISM: A Progenitor-Restricted Intersectional Fate Mapping Approach Redefines Forebrain Lineages.

Lineage tracing aims to identify the progeny of a defined population of dividing progenitor cells, a daunting task in the developing central nervous system where thousands of cell types are generated. In mice, lineage analysis has been accomplished using Cre recombinase to indelibly label a defined progenitor population and its progeny. However, the interpretation of historical recombination events is hampered by the fact that driver genes are often expressed in both progenitors and postmitotic cells.

Classification of Midbrain Dopamine Neurons Using Single-Cell Gene Expression Profiling Approaches.

Dysfunctional dopamine (DA) signaling has been associated with a broad spectrum of neuropsychiatric disorders, prompting investigations into how midbrain DA neuron heterogeneity may underpin this variety of behavioral symptoms. Emerging literature indeed points to functional heterogeneity even within anatomically defined DA clusters. Recognizing the need for a systematic classification scheme, several groups have used single-cell profiling to catalog DA neurons based on their gene expression profiles.

Immunogenicity and safety of a quadrivalent plant-derived virus like particle influenza vaccine candidate-Two randomized Phase II clinical trials in 18 to 49 and ≥50 years old adults.

Background: New influenza vaccines eliciting more effective protection are needed, particularly for the elderly who paid a large and disproportional toll of hospitalization and dead during seasonal influenza epidemics. Low (≤15 μg/strain) doses of a new plant-derived virus-like-particle (VLP) vaccine candidate have been shown to induce humoral and cellular responses against both homologous and heterologous strains in healthy adults 18-64 years of age. The two clinical trials reported here addressed the safety and immunogenicity of higher doses (≥15 μg/strain) of quadrivalent VLP candidate vaccine on 18-49 years old and ≥50 years old subjects.

Dopamine neuron glutamate cotransmission evokes a delayed excitation in lateral dorsal striatal cholinergic interneurons.

Unlabelled: Dopamine neurons have different synaptic actions in the ventral and dorsal striatum (dStr), but whether this heterogeneity extends to dStr subregions has not been addressed. We have found that optogenetic activation of dStr dopamine neuron terminals in mouse brain slices pauses the firing of cholinergic interneurons in both the medial and lateral subregions, while in the lateral subregion the pause is shorter due to a subsequent excitation. This excitation is mediated mainly by metabotropic glutamate receptor 1 (mGluR1) and partially by dopamine D1-like receptors coupled to transient receptor potential channel 3 and 7.

Humoral and cell-mediated immune responses to H5N1 plant-made virus-like particle vaccine are differentially impacted by alum and GLA-SE adjuvants in a Phase 2 clinical trial.

The hemagglutinination inhibition (HI) response remains the gold standard used for the licensure of influenza vaccines. However, cell-mediated immunity (CMI) deserves more attention, especially when evaluating H5N1 influenza vaccines that tend to induce poor HI response. In this study, we measured the humoral response (HI) and CMI (flow cytometry) during a Phase II dose-ranging clinical trial (NCT01991561).

Blunted mGluR Activation Disinhibits Striatopallidal Transmission in Parkinsonian Mice.

The prevailing circuit model predicts that hyperactivity of the striatopallidal pathway and subsequently increased inhibition of external globus pallidus (GPe) neurons lead to the hypokinetic symptoms of Parkinson's disease (PD). It is believed that hyperactivity of the striatopallidal pathway is due to inactivity of dopamine receptors on the somatodendritic membrane of striatopallidal neurons, but the exact cellular underpinnings remain unclear. In this study, we show that mouse GPe astrocytes critically control ambient glutamate level, which in turn gates striatopallidal transmission via the activation of presynaptic metabotropic glutamate receptors.

Disentangling neural cell diversity using single-cell transcriptomics.

Cellular specialization is particularly prominent in mammalian nervous systems, which are composed of millions to billions of neurons that appear in thousands of different 'flavors' and contribute to a variety of functions. Even in a single brain region, individual neurons differ greatly in their morphology, connectivity and electrophysiological properties. Systematic classification of all mammalian neurons is a key goal towards deconstructing the nervous system into its basic components.

A plant-derived quadrivalent virus like particle influenza vaccine induces cross-reactive antibody and T cell response in healthy adults.

Recent issues regarding efficacy of influenza vaccines have re-emphasized the need of new approaches to face this major public health issue. In a phase 1-2 clinical trial, healthy adults received one intramuscular dose of a seasonal influenza plant-based quadrivalent virus-like particle (QVLP) vaccine or placebo. The hemagglutination inhibition (HI) titers met all the European licensure criteria for the type A influenza strains at the 3μg/strain dose and for all four strains at the higher dosages 21days after immunization.

Molecular heterogeneity of midbrain dopaminergic neurons--Moving toward single cell resolution.

Since their discovery, midbrain dopamine (DA) neurons have been researched extensively, in part because of their diverse functions and involvement in various neuropsychiatric disorders. Over the last few decades, reports have emerged that midbrain DA neurons were not a homogeneous group, but that DA neurons located in distinct anatomical locations within the midbrain had distinctive properties in terms of physiology, function, and vulnerability. Accordingly, several studies focused on identifying heterogeneous gene expression across DA neuron clusters.

Excessive Wnt/beta-catenin signaling promotes midbrain floor plate neurogenesis, but results in vacillating dopamine progenitors.

The floor plate (FP), a ventral midline structure of the developing neural tube, has differential neurogenic capabilities along the anterior-posterior axis. The midbrain FP, unlike the hindbrain and spinal cord floor plate, is highly neurogenic and produces midbrain dopaminergic (mDA) neurons. Canonical Wnt/beta-catenin signaling, at least in part, is thought to account for the difference in neurogenic capability.

Defining midbrain dopaminergic neuron diversity by single-cell gene expression profiling.

Effective approaches to neuropsychiatric disorders require detailed understanding of the cellular composition and circuitry of the complex mammalian brain. Here, we present a paradigm for deconstructing the diversity of neurons defined by a specific neurotransmitter using a microfluidic dynamic array to simultaneously evaluate the expression of 96 genes in single neurons. With this approach, we successfully identified multiple molecularly distinct dopamine neuron subtypes and localized them in the adult mouse brain.

Influenza virus-like particle vaccines made in Nicotiana benthamiana elicit durable, poly-functional and cross-reactive T cell responses to influenza HA antigens.

Cell-mediated immunity plays a major role in long-lived, cross-reactive protection against influenza virus. We measured long-term poly-functional and cross-reactive T cell responses to influenza hemagglutinin (HA) elicited by a new plant-made Virus-Like Particle (VLP) vaccine targeting either H1N1 A/California/7/09 (H1) or H5N1 A/Indonesia/5/05 (H5). In two independent clinical trials, we characterized the CD4(+) and CD8(+) T cell homotypic and heterotypic responses 6 months after different vaccination regimens.

Enkephalin knockdown in the basolateral amygdala reproduces vulnerable anxiety-like responses to chronic unpredictable stress.

The endogenous enkephalins (ENKs) are potential candidates participating in the naturally occurring variations in coping styles and determining the individual capacities for adaptation during chronic stress exposure. Here we demonstrate that there is a large variance in individual behavioral, as well as in physiological outcomes, in a population of Sprague-Dawley rats subjected to 3 weeks of chronic unpredictable stress (CUS). Separation of resilient and vulnerable subpopulations reveals specific long-term neuroadaptation in the ENKergic brain circuits.

Enkephalin downregulation in the nucleus accumbens underlies chronic stress-induced anhedonia.

Restraint and immobilization have been extensively used to study habituation of the neuroendocrine response to a repeated stressor, but behavioral consequences of this stress regimen remain largely uncharacterized. In this study, we used sucrose preference and the elevated-plus maze to probe behavioral alterations resulting from 14 days of restraint in rats. We observed a decrease in sucrose preference in stressed animals, particularly in a subgroup of individuals, but no alteration in anxiety behaviors (as measured in the elevated-plus maze) four days following the last restraint.

Enkephalin knockdown in the central amygdala nucleus reduces unconditioned fear and anxiety.

The endogenous opioid enkephalins (ENK) are highly expressed in the central nucleus of the amygdaloid complex (CeA) where several lines of evidence point to a potential role in the modulation of fear and anxiety. In this study, we aimed to assess the role of CeA ENK using local injections of a lentiviral vector expressing a short hairpin RNA (shRNA) targeting ENK in Sprague-Dawley rats. We injected this vector in the CeA and a 56% downregulation of ENK mRNA was observed in animals when compared with scrambled shRNA animals.

β-Lactoglobulin tablets as a suitable vehicle for protection and intestinal delivery of probiotic bacteria.

The use of succinylated β-lactoglobulin as a novel functional tablet excipient for the protection of probiotic bacteria against the adverse gastric conditions and their delivery in the intestine was studied. Tablets were produced by direct compression of a dry mixture of Bifidobacterium longum HA-135 and the tested excipient. The results showed that tablets made of native β-lg did not ensure cell survival while grafting carboxylic acid groups on the protein revealed to be an innovative method to create a gastroresistant matrix that could allow the survival of up to 10(8)CFU and 10(7)CFU after 1h and 2h gastric incubation, respectively.

A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura.

Migraine with aura is a common, debilitating, recurrent headache disorder associated with transient and reversible focal neurological symptoms. A role has been suggested for the two-pore domain (K2P) potassium channel, TWIK-related spinal cord potassium channel (TRESK, encoded by KCNK18), in pain pathways and general anaesthesia. We therefore examined whether TRESK is involved in migraine by screening the KCNK18 gene in subjects diagnosed with migraine.

Cysteamine, the molecule used to treat cystinosis, potentiates the antimalarial efficacy of artemisinin.

Malaria continues to be a major threat to global health. Artemisinin combination therapy (ACT) is the recommended treatment for clinical malaria; however, recent reports of parasite resistance to artemisinin in certain areas where malaria is endemic have stressed the need for developing more efficacious ACT. We report that cysteamine (Cys), the aminothiol used to treat nephropathic cystinosis in humans, strongly potentiates the efficacy of artemisinin against the Plasmodium parasite in vivo.

Neuroanatomical characterization of endogenous opioids in the bed nucleus of the stria terminalis.

Numerous neuroanatomical data indicate that the bed nucleus of the stria terminalis (BST) provides an interface between cortical and amygdaloid neurons, and effector neurons modulating motor, autonomic and neuroendocrine responses. Distinct divisions of the BST may be involved in stress response, homeostatic regulation, nociception, and motivated behaviors. Endogenous opioid peptides and receptors are expressed in the BST, but their exact distribution is poorly characterized.