Midbrain Dopamine Neurons Defined by TrpV1 Modulate Psychomotor Behavior

Dopamine (DA) neurons of the ventral tegmental area (VTA) continue to gain attention as far more heterogeneous than previously realized. Within the medial aspect of the VTA, the unexpected presence of TrpV1 mRNA has been identified. TrpV1 encodes the Transient Receptor Potential cation channel subfamily V member 1, TRPV1, also known as the capsaicin receptor, well recognized for its role in heat and pain processing by peripheral neurons. In contrast, the brain distribution of TrpV1 has been debated. Here, we hypothesized that the TrpV1+ identity defines a distinct subpopulation of VTA DA neurons. To explore these brain TrpV1+ neurons, histological analyses and Cre-driven mouse genetics were employed. TrpV1 mRNA was most strongly detected at the perinatal stage forming a band of scattered neurons throughout the medial VTA, reaching into the posterior hypothalamus. Within the VTA, the majority of TrpV1 co-localized with both Tyrosine hydroxylase (Th) and Vesicular monoamine transporter 2 (Vmat2), confirming a DA phenotype. However, TrpV1 also co-localized substantially with Vesicular glutamate transporter 2 (Vglut2), representing the capacity for glutamate (GLU) release. These TrpV1+/Th+/Vglut2+/Vmat2+ neurons thus constitute a molecularly and anatomically distinct subpopulation of DA-GLU co-releasing neurons. To assess behavioral impact, a TrpV1Cre-driven strategy targeting the Vmat2 gene in mice was implemented. This manipulation was sufficient to alter psychomotor behavior induced by amphetamine. The acute effect of the drug was accentuated above control levels, suggesting super-sensitivity in the drug-na ve state resembling a “pre-sensitized” phenotype. However, no progressive increase with repeated injections was observed. This study identifies a distinct TrpV1+ VTA subpopulation as a critical modulatory component in responsiveness to amphetamine. Moreover, expression of the gene encoding TRPV1 in selected VTA neurons opens up for new possibilities in pharmacological intervention of this heterogeneous, but clinically important, brain area.

Gabra5LHA Mediate Astrocytic GABA-induced Obesity via Decreasing Energy Expenditure

The lateral hypothalamic area (LHA) regulates food intake and energy expenditure. Although LHA neurons innervate adipose tissues, the identity of neurons that regulate fat is undefined. Here we identify that Gabra5-positive neurons in LHA (Gabra5LHA) polysynaptically project to brown and white adipose tissues in the periphery. Gabra5LHA are a distinct subpopulation of GABAergic neurons and show decreased pacemaker firing in diet-induced obesity (DIO) mouse model. Gene silencing of Gabra5 in LHA decreases weight gain, whereas chemogenetic inhibition of LHA suppresses energy expenditure and increases weight gain. In DIO mouse model, Gabra5LHA are tonically inhibited by nearby reactive astrocytes releasing GABA, which is synthesized by MAOB. Administration of a MAOB inhibitor, KDS2010 reduces weight gain significantly without affecting food intake, which is recapitulated by gene-silencing of astrocytic MAOB in LHA. We propose that firing of Gabra5LHA facilitates energy expenditure and selective inhibition of astrocytic GABA is a molecular target for treating obesity.

Dysfunctions, Molecular Mechanisms, and Therapeutic Strategies of Regulatory T Cells in Rheumatoid Arthritis

Regulatory T cells (Tregs) represent a distinct subpopulation of CD4+ T lymphocytes that promote immune tolerance and maintain immune system homeostasis. The dysfunction of Tregs is tightly associated with rheumatoid arthritis (RA). Although the complex pathogenic processes of RA remain unclear, studies on Tregs in RA have achieved substantial progress not only in fundamental research but also in clinical application. This review discusses the current knowledge of the characterizations, functions, and molecular mechanisms of Tregs in the pathogenesis of RA, and potential therapies for these disorders are also involved.

Distinctive genetic structure and selection patterns in Plasmodium vivax from South Asia and East Africa

Despite the high burden of Plasmodium vivax malaria in South Asian countries, the genetic diversity of circulating parasite populations is not well described. Determinants of antimalarial drug susceptibility for P. vivax in the region have not been characterised. Our genomic analysis of global P. vivax (n = 558) establishes South Asian isolates (n = 92) as a distinct subpopulation, which shares ancestry with some East African and South East Asian parasites. Signals of positive selection are linked to drug resistance-associated loci including pvkelch10, pvmrp1, pvdhfr and pvdhps, and two loci linked to P. vivax invasion of reticulocytes, pvrbp1a and pvrbp1b. Significant identity-by-descent was found in extended chromosome regions common to P. vivax from India and Ethiopia, including the pvdbp gene associated with Duffy blood group binding. Our investigation provides new understanding of global P. vivax population structure and genomic diversity, and genetic evidence of recent directional selection in this important human pathogen.

Scn1a-GFP transgenic mouse revealed Nav1.1 expression in neocortical pyramidal tract projection neurons

Expressions of voltage-gated sodium channels Nav1.1 and Nav1.2, encoded by SCN1A and SCN2A genes, respectively, have been reported to be mutually exclusive in most brain regions. In adult neocortex, Nav1.1 is dominant in inhibitory neurons while Nav1.2 is dominant in excitatory neurons. Although a distinct subpopulation of neocortical excitatory neurons was also reported to express Nav1.1, their nature has been uncharacterized. By using newly-generated transgenic mouse lines expressing Scn1a promoter-driven green fluorescent protein (GFP), here we confirm mutually-exclusive expressions of Nav1.1 and Nav1.2, absence of Nav1.1 in hippocampal excitatory neurons, and further show that among neocortical excitatory neurons Nav1.1 is expressed in pyramidal tract and a subpopulation of cortico-cortical while Nav1.2 in cortico-striatal, cortico-thalamic and a distinct subpopulation of cortico-cortical projection neurons. These observations now contribute to the elucidation of pathological neural circuits for epilepsies and neurodevelopmental disorders caused by SCN1A and SCN2A mutations including sudden death in Dravet syndrome.

The Significance of Targeting Poly (ADP-Ribose) Polymerase-1 in Pancreatic Cancer for Providing a New Therapeutic Paradigm

Genome-wide studies focusing on elucidating the effects on cancer progression have enabled the consequent identification of a distinct subpopulation of pancreatic cancer cells with unstable genomic characteristics. Based on this background, deleterious changes by poly (adenosine diphosphate (ADP)-ribose) polymerase-1 (PARP)-1 have been concentrated in oncology. One of the critical functions of PARP-1 is the response to DNA damage, which plays a pivotal role in DNA repair in cancers. PARP-1 also has widespread functions that are essential for the survival and growth of cancer cells. It regulates oxidative stress in mitochondria through the regulation of superoxide and oxidation. PARP-1 is in charge of regulating mitosis, which is a crucial role in tumorigenesis and remodels histones and chromatin enzymes related to transcriptional regulation, causing alterations in epigenetic markers and chromatin structure. Given the significance of these processes, it can be understood that these processes in cancer cells are at the frontline of the pathogenetic changes required for cancer cell survival, and these contributions can result in malignant transformation. Therefore, this review addresses the current molecular biological features for understanding the multifactorial function of PARP-1 in pancreatic cancer related to the aforementioned roles, along with the summary of recent approaches with PARP-1 inhibition in clinical studies targeting pancreatic cancer. This understanding could help to embrace the importance of targeting PARP-1 in the treatment of pancreatic cancer, which may present the potential to find out a variety of research topics that can be both challenged clinically and non-clinically.

The Concept of Pathogenic TH2 Cells: Collegium Internationale Allergologicum Update 2021

T helper (T_H) cells have evolved into distinct subsets that mediate specific immune responses to protect the host against a myriad of infectious and noninfectious challenges. However, if dysregulated, T_H-cell subsets can cause inflammatory disease. Emerging evidence now suggests that human allergic disease is caused by a distinct subpopulation of pathogenic T_H2 cells. Pathogenic T_H2 cells from different type-2-driven diseases share a core phenotype and show overlapping functional attributes. The unique differentiation requirements, activating signals, and metabolic characteristics of pathogenic T_H2 cells are just being discovered. A better knowledge of this particular T_H2 cell population will enable the specific targeting of disease-driving pathways in allergy. In this review, we introduce a rational for classifying T_H cells into distinct subsets, discuss the current knowledge on pathogenic T_H2 cells, and summarize their involvement in allergic diseases.

Absent expansion of pericentral hepatocytes and altered physiology in Axin2CreERT2 mice

Abstract/IntroductionUnderstanding how the liver regenerates is a key biological question. Hepatocytes are the principle regenerative population in the liver. Recently, numerous lineage tracing studies (which apply genetic tagging to a restricted population and track its descendants over time) have reported conflicting results using a variety of hepatocyte based reporting systems in mice1,2. The first significant lineage tracing from a distinct subpopulation of hepatocytes in homeostasis reported hyper-proliferation of self-renewing pericentral hepatocytes with their subsequent expansion across the liver lobule3. This study used a CreERT2 construct knocked into the endogenous Axin2 locus; here termed Axin2CreERT2. Subsequent studies, using either a different pericentral marker (Lgr54) or a different AxinCreERT2 transgene5, did not show lineage tracing. Here we aim to reconcile these discrepancies by re-evaluating lineage tracing in the Axin2CreERT2 knock-in model and explore the physiological consequences of this mutant allele. We were unable to find evidence of expansion of an Axin2CreERT2 labelled population and show that this population, whilst zonated, is spread throughout the lobule rather than being zonally restricted. Finally, we report that this allele results in profound perturbation of the Wnt pathway and physiology in the mouse.