Marcussenanthony8065

Cardiovascular cells show the activity of the TERT subunit of telomerase, an enzyme that prevents telomere shortening. It turns out that disrupting the activity of this enzyme can also contribute to the formation of cardiovascular diseases. Measurements of telomere length according to the "blood-muscle" model may help in the future to assess the risk of cardiovascular complications in people undergoing cardiological procedures, as well as to assess the effectiveness of some drugs.d-Serine plays an important role in modulating N-methyl-d-aspartate receptor (NMDAR) neurotransmission in the mammalian brain by binding to the receptor's glycine modulatory site (GMS). The cytosolic enzyme serine racemase (SR) converts L-serine to d-serine, while the peroxisomal enzyme d-amino acid oxidase (DAAO) catalyzes the breakdown of d-serine. Although it is important to understand how the activities of SR and DAAO regulate d-serine levels, very little is known about the mechanisms that regulate the expression of SR and DAAO. In this study, we investigated whether the different centrally active drugs affect the expression of SR and DAAO in adult mouse brain. We found that the NMDAR antagonist, MK801, and cocaine, psychotropic drugs that both augment glutamate release, reduce the expression of SR and DAAO. This regulation is brain region selective, and in the case of cocaine, is reversed in part byα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX). However, d-serine and antipsychotics do not regulate SR and DAAO protein levels. In a genetic model of SR disruption, we found that DAAO expression was unaltered in SR conditional knockout mice, in which tissue d-serine content remains fairly stable despite marked reduction in SR expression. This study reveals a new mechanism by which AMPAR activity could regulate NMDAR function via d-serine availability.The identity of sensory neurons innervating the heart tissue and the extent of information reported to the brain via these neurons are poorly understood. #link# In order to evaluate the multidimensional distribution and abundance of the cardiac spinal and vagal afferents, we assessed the retrograde labeling efficiency of various tracers, and mapped the cardiac afferents qualitatively and quantitatively at the bilateral nodose ganglia (NGs) and dorsal root ganglia (DRGs). From the five different retrograde tracers evaluated, Di-8-ANEPPQ yielded reproducibly the highest labeling efficiency of cardiac afferents. We demonstrated specific cardiac afferents at NGs and C4 to T11 DRG segments. Next, the 2D reconstruction of the tissue sections and 3D imaging of the whole NGs and DRGs revealed homogeneous and bilateral distribution of cardiac afferents. The quantitative analyses of the labeled cardiac afferents demonstrated approximately 5-6% of the soma in NGs that were equally distributed bilaterally. The neuronal character of Di-8-ANEPPQ labeled cells were validated by coimmunostaning with pan-neuronal marker Tuj-1. In addition, the cell diameters of labeled cardiac sensory neurons were found smaller than 20 μm, implying the nociceptor phenotype confirmed by co-labeling with TRPV1 and Di-8-ANEPPQ. Importantly, co-labeling with two distinct tracers Di-8-ANEPPQ and WGA-647 demonstrated exclusively the same cardiac afferents in DRGs and NGs, validating our findings. Collectively, our findings revealed the cardiac afferents in NGs bilaterally and DRGs with the highest labeling efficiency reported, spatial distribution and quantitation at both 2D and 3D levels, furthering our understanding of this novel neuron population.Pain is a common symptom in patients with opioid use disorder (OUD), which increases synthetic and illicit synthetic opioid abuse and even fatalities due to opioid overdose. Many FDA-approved drugs are available for the treatment of OUD, however, the use of these medications is limited, mainly due to the development of various side effects. Active vaccination is a new therapeutic approach but the resulting antibodies may compromise the use and efficiency of opioid and non-opioid drugs. In this study, we evaluated whether the antibodies produced by the morphine/heroin vaccine (M-TT) would alter the antinociceptive effects of opioid and non-opioid drugs. Female Balb-c mice were immunized with the M-TT vaccine. link2 A solid-phase antibody-capture ELISA was used for monitoring antibody titer responses after each booster dose in vaccinated animals, followed by tail-flick testing. This study found that the M-TT vaccine did not affect the antinociception induced by different doses of morphine or the ability of non-opioid and synthetic opioid drugs to decrease thermal pain. Moreover, the combination of vaccination and naloxone increased the time-course of morphine antagonism relative to either vaccination or naloxone alone. These results suggest that the antibody titers generated by the M-TT vaccine 1) are capable of reducing morphine-induced antinociception and 2) are selective enough not to alter antinociception induced by non-opioid or synthetic drugs. These characteristics support its potential as a treatment agent for patients with symptoms of pain comorbid to OUD.Cognitive dysfunction has been reported in patients with carbon monoxide (CO) poisoning. However, the underpinning mechanism remained unclear. This study examined dopamine transporter (DAT) and metabolite ratios concurrently and their relationships with cognitive dysfunction in CO poisoning. Eighteen suicide attempters with charcoal burning which results in CO poisoning and 18 age- and gender- matched normal controls were recruited. A battery of cognitive assessments including attention, memory, and executive function was administered. Each participant received one single photon emission computed tomography with 99mTc-TRODAT for measuring striatal DAT availability and proton magnetic resonance spectroscopy to determine N-acetyl aspartate/creatine (NAA/Cr), choline-containing compounds/creatine (Cho/Cr) and myo-inositol/creatine (mI/Cr) in the left parietal white matter and mid-occipital gray matter (OGM). LMK-235 had significant impairments in memory and executive function. Compared to normal, CO poisoning patients had lower striatal DAT availability, lower NAA/Cr levels in both regions and higher Cho/Cr levels in both regions. link3 In CO poisoning patients, the altered left striatal DAT availability and Cho/Cr level in OGM were significantly associated with executive dysfunction in the expected directions. Moreover, there was a significant interaction between these two imaging indices on their relationships with executive dysfunction and combination of them could adequately predict executive dysfunction in more CO poisoning cases than either alone. The current results suggested that both alterations in DAT availability and metabolite ratios might play crucial roles in executive dysfunction in CO poisoning. This research also highlights the importance of multimodal imaging approaches for studying neurotoxicity effects.Anxiety disorders are highly prevalent across the lifespan, although diagnoses peak early in adolescence. As a method for inhibiting fear, safety signals have the potential to augment conventional treatments for anxiety. However, the ability to acquire and use safety signals during adolescence remains unclear. Moreover, the impact of stress on safety learning has received surprisingly little attention given that stress is a major factor preceding anxiety onset. In this study, mice were trained in a discriminative conditioning protocol to facilitate safety learning and were tested for fear inhibition using a conditioned safety signal. Next, independent groups of mice were exposed to chronic unpredictable stress (CUS) conditions between postnatal day 22 and 28, followed by tests for anxiety-like phenotypes or fear inhibition using a safety signal, performed either 24 h or five weeks following CUS. Pre-adolescent CUS reduced weight in adolescence and this effect endured into adulthood. CUS also increased specific anxiety-like behaviors in adolescence that were unique from the increase in anxiety observed in adulthood. Despite increased anxiety-like behaviors, adolescents were able to learn about and effectively use safety signals to inhibit fear. In contrast, adults that experienced CUS showed a subtle increase in anxiety but had impaired safety signal learning and usage. Together, these findings indicate that pre-adolescent stress has immediate and enduring effects on anxiety-like behaviors but impairs the capacity for conditioned inhibition only following incubation.Cannabinoid receptor type 1 (CB1R) is the most abundant cannabinoid receptor in central nervous system. Clinical studies and animal models have shown that the attenuation of endocannabinoid system signaling correlates with the development of psychiatric disorders such as anxiety, depression and schizophrenia. In the present work, multiple behavioral tests were performed to evaluate behaviors related to anxiety and depression in CB1R+/- and CB1R-/-. CB1R+/- mice had anxiety-related behavior similar to wild type (CB1R+/+) mice, whereas CB1R-/- mice displayed an anxious-like phenotype, which indicates that lower expression of CB1R is sufficient to maintain the neural circuits modulating anxiety. In addition, CB1R-/- mice exhibited alterations in risk assessment and less exploration, locomotion, grooming, body weight and appetite. These phenotypic characteristics observed in CB1R-/- mice could be associated with symptoms observed in human psychiatric disorders such as depression. A better knowledge of the neuromodulatory role of CB1R may contribute to understand scope and limitations of the development of medical treatments.Cannabinoid receptor type 1 (CB1R) is widely distributed in the substantia nigra pars reticulata (SNpr). However, the role of CB1R at the SNpr level in threatening situations is poorly understood. We investigated the role of CB1R in the SNpr on the expression of fear responses in mice confronted with urutu-cruzeiro pit vipers. First, a bidirectional neurotracer was injected into the SNpr; then, immunostaining of the vesicular GABA transporter was conducted at the levels of the striatum (CPu) and deep layers of the superior colliculus (dlSC). In addition, CB1R immunostaining and GABA labelling were performed in the SNpr. Using a prey-versus-snake paradigm, mice were pretreated with the CB1R antagonist AM251 (100 pmol) and treated with the endocannabinoid anandamide (AEA, 5 pmol) in the SNpr, followed by bicuculline (40 ng) in the dlSC, and were then confronted with a snake. Bidirectional neural tract tracers associated with immunofluorescence showed the GABAergic striatonigral disinhibitory and nigrotectal inhibitory pathways. Furthermore, we showed that CB1R labelling was restricted to axonal fibres surrounding SNpr GABAergic cells. We also demonstrated a decrease in the defensive behaviours of mice treated with AEA in the SNpr, but this effect was blocked by pre-treatment with AM251 in this structure. Taken together, our results show that the panicolytic consequences of the AEA enhancement in the SNpr are signalled by CB1R, suggesting that CB1R localised in axon terminals of CPu GABAergic neurons in the SNpr modulates the activity of the nigrotectal GABAergic pathway during the expression of defensive behaviours in threatening situations.