Demonstrating the Analytical Potential of a Wearable Microneedle-Based Device for Intradermal CO2 Detection

Monitoring of carbon dioxide (CO2) body levels is crucial under several clinical conditions (e.g., human intensive care and acid–base disorders). To date, painful and risky arterial blood punctures have been performed to obtain discrete CO2 measurements needed in clinical setups. Although noninvasive alternatives have been proposed to assess CO2, these are currently limited to benchtop devices, requiring trained personnel, being tedious, and providing punctual information, among other disadvantages. To the best of our knowledge, the literature and market lack a wearable device for real-time, on-body monitoring of CO2. Accordingly, we have developed a microneedle (MN)-based sensor array, labeled as CO2–MN, comprising a combination of potentiometric pH- and carbonate (CO32–)-selective electrodes together with the reference electrode. The CO2–MN is built on an epidermal patch that allows it to reach the stratum corneum of the skin, measuring pH and CO32– concentrations directly into the interstitial fluid (ISF). The levels for the pH–CO32– tandem are then used to estimate the PCO2 in the ISF. Assessing the response of each individual MN, we found adequate response time (t95 < 5s), sensitivity (50.4 and −24.6 mV dec–1 for pH and CO32–, respectively), and stability (1.6 mV h–1 for pH and 2.1 mV h–1 for CO32–). We validated the intradermal measurements of CO2 at the ex vivo level, using pieces of rat skin, and then, with in vivo assays in anesthetized rats, showing the suitability of the CO2–MN wearable device for on-body measurements. A good correlation between ISF and blood CO2 concentrations was observed, demonstrating the high potential of the developed MN sensing technology as an alternative to blood-based analysis in the near future. Moreover, these results open new horizons in the noninvasive, real-time monitoring of CO2 as well as other clinically relevant gases

Reduced Vglut2/Slc17a6 Gene Expression Levels throughout the Mouse Subthalamic Nucleus Cause Cell Loss and Structural Disorganization Followed by Increased Motor Activity and Decreased Sugar Consumption.

The subthalamic nucleus (STN) plays a central role in motor, cognitive, and affective behavior. Deep brain stimulation (DBS) of the STN is the most common surgical intervention for advanced Parkinson's disease (PD), and STN has lately gained attention as target for DBS in neuropsychiatric disorders, including obsessive compulsive disorder, eating disorders, and addiction. Animal studies using STN-DBS, lesioning, or inactivation of STN neurons have been used extensively alongside clinical studies to unravel the structural organization, circuitry, and function of the STN. Recent studies in rodent STN models have exposed different roles for STN neurons in reward-related functions. We have previously shown that the majority of STN neurons express the vesicular glutamate transporter 2 gene (Vglut2/Slc17a6) and that reduction of Vglut2 mRNA levels within the STN of mice [conditional knockout (cKO)] causes reduced postsynaptic activity and behavioral hyperlocomotion. The cKO mice showed less interest in fatty rewards, which motivated analysis of reward-response. The current results demonstrate decreased sugar consumption and strong rearing behavior, whereas biochemical analyses show altered dopaminergic and peptidergic activity in the striatum. The behavioral alterations were in fact correlated with opposite effects in the dorsal versus the ventral striatum. Significant cell loss and disorganization of the STN structure was identified, which likely accounts for the observed alterations. Rare genetic variants of the human VGLUT2 gene exist, and this study shows that reduced Vglut2/Slc17a6 gene expression levels exclusively within the STN of mice is sufficient to cause strong modifications in both the STN and the mesostriatal dopamine system

Intradermal Glycine Detection with a Wearable Microneedle Biosensor : The First In Vivo Assay

Glycine (GLY) is gaining importance in medical diagnoses due to its relationship with multiple physiological functions. Today, GLY is exclusively analyzed using instrumentation centralized in clinical labs, and a tangible point-of-care tool that gathers real-time data from the patient for effective and fast evaluations is lacking. Relevant clinical advances are expected as soon as the rapid provision of both punctual and continuous measurements is possible. In that context, this work presents a microneedle (MN)-based biosensor for intradermal GLY detection in interstitial fluid (ISF). The MN tip is externally tailored to detect GLY levels through the hydrogen peroxide formed in its reaction with a quinoprotein-based GLY oxidase enzyme. The analytical performance of the MN biosensor indicates a fast response time (< 7 s); acceptable reversibility, reproducibility, and stability; as well as a wide linear range of response (25-600 mu M) that covers the physiological levels of GLY in ISF. The MN biosensor conveniently exhibits high selectivity for GLY over other compounds commonly found in ISF, and the response is not influenced by temperature, pH, or skin insertions. Validated intradermal measurements of GLY were obtained at the in vitro (with pieces of rat skin), ex vivo (on-body tests of euthanized rats) and in vivo (on-body tests of anesthetized rats) levels, demonstrating its ability to produce accurate physiological data. The developed GLY MN biosensor is skin-wearable and provides reliable, real-time intradermal GLY measurements in ISF by means of a minimally invasive approach

Midbrain Gene Screening Identifies a New Mesoaccumbal Glutamatergic Pathway and a Marker for Dopamine Cells Neuroprotected in Parkinson's Disease

The ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) of the midbrain are associated with Parkinson's disease (PD), schizophrenia, mood disorders and addiction. Based on the recently unraveled heterogeneity within the VTA and SNc, where glutamate, GABA and co-releasing neurons have been found to co-exist with the classical dopamine neurons, there is a compelling need for identification of gene expression patterns that represent this heterogeneity and that are of value for development of human therapies. Here, several unique gene expression patterns were identified in the mouse midbrain of which NeuroD6 and Grp were expressed within different dopaminergic subpopulations of the VTA, and TrpV1 within a small heterogeneous population. Optogenetics-coupled in vivo amperometry revealed a previously unknown glutamatergic mesoaccumbal pathway characterized by TrpV1-Cre-expression. Human GRP was strongly detected in non-melanized dopaminergic neurons within the SNc of both control and PD brains, suggesting GRP as a marker for neuroprotected neurons in PD. This study thus unravels markers for distinct subpopulations of neurons within the mouse and human midbrain, defines unique anatomical subregions within the VTA and exposes an entirely new glutamatergic pathway. Finally, both TRPV1 and GRP are implied in midbrain physiology of importance to neurological and neuropsychiatric disorders

Lumateperone-mediated effects on prefrontal glutamatergic receptor-mediated neurotransmission : A dopamine D-1 receptor dependent mechanism

Lumateperone is a novel drug approved for the treatment of schizophrenia in adults and depressive episodes associated with bipolar depression in adults, as monotherapy and as adjunctive therapy with lithium or valproate treatment in the United States. Lumateperone simultaneously modulates key neurotransmitters, such as serotonin, dopamine, and glutamate, implicated in serious mental illness. In patients with schizophrenia, lumateperone was shown to improve positive symptoms along with negative and depressive symptoms, while also enhancing prosocial behavior. Moreover, in patients with bipolar I or II disorder, lumateperone improved depressive symptoms as well. To further understand the mechanisms related to lumateperone's clinical response, the aim of this study was to investigate the effect of lumateperone on dopaminergic-and glutamatergic signaling in the rat medial prefrontal cortex (mPFC). We used the conditioned avoidance response (CAR) test to determine the antipsychotic-like effect of lumateper one, electrophysiology in vitro to study lumateperone's effects on NMDA-and AMPA-induced currents in the mPFC, and the neurochemical techniques microdialysis and amperometry to measure dopamine-and glutamate release in the rat mPFC. Our results demonstrate that lu-mateperone; i) significantly suppressed CAR in rats, indicating an antipsychotic-like effect, ii) facilitated NMDA and AMPA receptor-mediated currents in the mPFC, in a dopamine D-1-dependent manner, and iii) significantly increased dopamine and glutamate release in the rat mPFC. To the extent that these findings can be translated to humans, the ability of lumate-perone to activate these pathways may contribute to its demonstrated effectiveness in safely improving symptoms related to neuropsychiatric disorder including mood alterations. (C) 2022 The Author(s). Published by Elsevier B.V