Levels In Prefrontal Cortex Research Articles

Trigonelline as an anticonvulsant agent: mechanistic insights into NMDA receptor expression and oxidative stress balance

Glutamatergic neurotransmission and oxidative stress are involved in the pathophysiology of seizures. Some anticonvulsants exert their effects through modulation of these pathways. Trigonelline (TRG) has been shown to possess various pharmacological effects like neuroprotection. Therefore, this study was performed to determine TRG’s anticonvulsant effects, focusing on its potential effects on N-methyl-D-aspartate (NMDA) receptors, a type of glutamate receptor, and oxidative stress state in the prefrontal cortex (PFC) in PTZ-induced seizure in mice. Seventy-two male mice were randomly divided into nine groups. The groups included mice that received normal saline, TRG at doses of 10, 50, and 100 mg/kg, diazepam, NMDA (an agonist), ketamine (an antagonist), the effective dose of TRG with NMDA, as well as sub-effective dose of TRG with ketamine, respectively. All agents were administrated intraperitoneally 60 min before induction of seizures by PTZ. Latency to seizure, total antioxidant capacity (TAC), and malondialdehyde (MDA) levels in serum and PFC were measured. Furthermore, the gene expression of NR2A and NR2B, subunits of NMDA receptors, was measured in the PFC. TRG administration increased the latency to seizure onset and enhanced TAC while reducing MDA levels in both the PFC and serum. TRG also decreased the gene expression of NR2B in the PFC. Unexpectedly, the findings revealed that the concurrent administration of ketamine amplified, whereas NMDA mitigated, the impact of TRG on latency to seizure. Furthermore, NMDA diminished the positive effects of TRG on antioxidant capacity and oxidative stress, while ketamine amplified these beneficial effects, indicating a complex interaction between TRG and NMDA receptor modulation. In the gene expression of NMDA receptors, results showed that ketamine significantly decreased the gene expression of NR2B when co-administrated with a sub-effective dose of TRG. It was found that, at least partially, the anticonvulsant effect of TRG in PTZ-induced seizures in male mice was mediated by the attenuation of glutamatergic neurotransmission as well as the reduction of oxidative stress.

Vagus Nerve Stimulation (VNS) Modulates Synaptic Plasticity in the Infralimbic Cortex via Trk-B Receptor Activation to Reduce Drug-Seeking in Male Rats.

Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces relapse. Vagus nerve stimulation (VNS) has previously been shown to enhance extinction learning and reduce drug-seeking. Here we determined the effects of VNS-mediated release of brain-derived neurotrophic factor (BDNF) on extinction and cue-induced reinstatement in male rats trained to self-administer cocaine. Pairing 10 d of extinction training with VNS facilitated extinction and reduced drug-seeking behavior during reinstatement. Rats that received a single extinction session with VNS showed elevated BDNF levels in the medial PFC as determined via an enzyme-linked immunosorbent assay. Systemic blockade of tropomyosin receptor kinase B (TrkB) receptors during extinction, via the TrkB antagonist ANA-12, decreased the effects of VNS on extinction and reinstatement. Whole-cell recordings in brain slices showed that cocaine self-administration induced alterations in the ratio of AMPA and NMDA receptor-mediated currents in Layer 5 pyramidal neurons of the infralimbic cortex (IL). Pairing extinction with VNS reversed cocaine-induced changes in glutamatergic transmission by enhancing AMPAR currents, and this effect was blocked by ANA-12. Our study suggests that VNS consolidates the extinction of drug-seeking behavior by reversing drug-induced changes in synaptic AMPA receptors in the IL, and this effect is abolished by blocking TrkB receptors during extinction, highlighting a potential mechanism for the therapeutic effects of VNS in addiction.

Long-term administration of omeprazole in mice: a study of behavior, inflammatory, and oxidative stress alterations with focus on central nervous system.

Chronic use of omeprazole has been linked to central effects alongside with the global concern of increasing appearance of neuropsychiatric disorders. This study aimed to identifying behavioral, inflammatory, and oxidative stress alterations after long-term administration of omeprazole. C57BL/6 mice were divided in groups: OME and Sham, each received either solutions of omeprazole or vehicle, administered for 28 days by gavage. Results observed in the omeprazole-treated mice: Decrease in the crossing parameter in the open field, no change in the motor performance assessed by rotarod, an immobility time reduction in the forced swimming test, improved percentage of correct alternances in the Ymaze and an exploration time of the novel object reduction in the novel object recognition. Furthermore, a reduced weight gain and hippocampal weight were observed. There was an increase in the cytokine IL1-β levels in both prefrontal cortex (PFC) and serum, whereas TNF-α increased only in the PFC. Nitrite levels increased in the hippocampus (HP) and PFC, while malondialdehyde (MDA) and glutathione (GSH) levels decreased. These findings suggest that omeprazole improves depressive-like behavior and working memory, likely through the increase in nitrite and reduction in MDA levels in PFC and HP, whereas, the impairment of the recognition memory is more likely to be related to the reduced hippocampal weight. The diminished weight gain might be associated with the IL-1β increased levels in the peripheral blood. Altogether, omeprazole showed to have the potential to impact at central level and inflammatory and oxidative parameters might exert a role between it.

Long Mu Qing Xin mixture improves behavioral performance in spontaneously hypertensive rats (SHR/NCrl) by upregulating catecholamine neurotransmitters in prefrontal cortex and striatum via DRD1/cAMP/PKA-CREB signaling pathway.

Attention deficit hyperactivity disorder (ADHD), a prevalent neurodevelopmental disorder in children, can be effectively alleviated by the herbal preparation Long Mu Qing Xin Mixture (LMQXM), but its mechanism has not been fully elucidated. To scrutinize the potential pharmacological mechanisms by which LMQXM improves behavior in spontaneously hypertensive rats (SHR/NCrl). The SHR/NCrl rats were randomly stratified into the model (SHR) group, the methylphenidate hydrochloride (MPH) group, and groups subjected to varying dosages of LMQXM into the medium dose (MD) group with a clinically effective dose, the low dose (LD) group with 0.5 times the clinically effective dose, and high dose (HD) group with 2 times the clinically effective dose. Furthermore, the WKY/NCrl rats constituted the control group. The evaluation of behavior involved the open field test and the Morris water maze test. HPLC, LC-MS, ELISA, immunohistochemistry, Western blot, and RT-qPCR were utilized to scrutinize the catecholamine neurotransmitter content and the expression of proteins and genes associated with the dopamine receptor D1 (DRD1)/cAMP/protein kinase A (PKA)-cAMP response element-binding (CREB) pathway in prefrontal cortex (PFC) and striatum. MPH and LMQXM ameliorated hyperactivity and learning and memory deficits of SHR/NCrl rats. Among them, LMQXM-MD and MPH also upregulated dopamine (DA), norepinephrine (NE), adenylate cyclase (AC) and cAMP levels, and the expression of proteins and genes associated with the DRD1/cAMP/PKA-CREB pathway in PFC and striatum of SHR/NCrl rats. PFC and striatum DA levels were also upregulated in the LMQXM-LD group as well as the striatum DA levels in the LMQXM-HD group, but there were no statistically significant differences in their NE levels compared to the SHR group. LMQXM-LD and LMQXM-HD also upregulated some DRD1/cAMP/PKA-CREB pathway-related proteins and gene expression, but the effects were discernibly disparate in PFC and striatum. Upon comprehensive analysis, LMQXM-MD appeared to be the most effective dose. Our study tentatively suggests that LMQXM may rectify hyperactivity and learning and memory deficits of SHR/NCrl rats by elevating catecholamine neurotransmitters in the PFC and striatum. This effect may be attributed to the potential activation of the DRD1/cAMP/PKA-CREB signaling pathway, which appears to achieve an optimal response at moderate doses.

Effects of repeated binge intake of the pyrovalerone cathinone derivative 3,4-methylenedioxypyrovalerone on prefrontal cytokine levels in rats - a preliminary study.

Drugs of abuse activate neuroimmune signaling in addiction-related regions of the brain, including the prefrontal cortex (PFC) which mediates executive control, attention, and behavioral inhibition. Traditional psychostimulants including methamphetamine and cocaine are known to induce PFC inflammation, yet the effects of synthetic cathinone derivatives are largely unexplored. In this study, we examined the ability of repeated binge-like intake of the pyrovalerone cathinone derivative 3,4-methylenedioxypyrovalerone (MDPV) to alter cytokine profiles in the PFC. Male and female rats were allowed to intravenously self-administer MDPV (0.05 mg/kg/infusion) or saline as a control under conditions of prolonged binge-like access, consisting of three 96 h periods of drug access interspersed with 72 h of forced abstinence. Three weeks following cessation of drug availability, PFC cytokine levels were assessed using antibody arrays. Employing the unsupervised clustering and regression analysis tool CytoMod, a single module of co-signaling cytokines associated with MDPV intake regardless of sex was identified. With regards to specific cytokines, MDPV intake was positively associated with PFC levels of VCAM-1/CD106 and negatively associated with levels of Flt-3 ligand. These findings indicate that prolonged MDPV intake causes changes in PFC cytokine levels that persist into abstinence; however, the functional ramifications of these changes remain to be fully elucidated.

Chemogenetic activation of locus coeruleus neurons ameliorates the severity of multiple sclerosis

BackgroundMost current disease-modifying therapies approved for multiple sclerosis (MS) are immunomodulatory drugs that counteract the aberrant activity of the immune system. Hence, new pharmacological interventions that drive anti-inflammatory activity and neuroprotection would represent interesting alternative therapeutic approaches or complementary strategies to treat progressive forms of MS. There is evidence of reduced noradrenaline levels and alterations to locus coeruleus (LC) noradrenergic neurons in MS patients, as well as in animal models of this disease, potentially factors contributing to the pathophysiology. Drugs that enhance noradrenaline appear to have some beneficial effects in MS, suggesting their potential to dampen the underlying pathology and disease progression.MethodsTherefore, we explored the consequences of chronic LC noradrenergic neurons activation by chemogenetics in experimental autoimmune encephalomyelitis (EAE) mice, the most widely used experimental model of MS. LC activation from the onset or the peak of motor symptoms was explored as two different therapeutic approaches, assessing the motor and non-motor behavioral changes as EAE progresses, and studying demyelination, inflammation and glial activation in the spinal cord and cerebral cortex during the chronic phase of EAE.ResultsLC activation from the onset of motor symptoms markedly alleviated the motor deficits in EAE mice, as well as their anxiety-like behavior and sickness, in conjunction with reduced demyelination and perivascular infiltration in the spinal cord and glial activation in the spinal cord and prefrontal cortex (PFC). When animals exhibited severe paralysis, LC activation produced a modest alleviation of EAE motor symptoms and it enhanced animal well-being, in association with an improvement of the EAE pathology at the spinal cord and PFC level. Interestingly, the reduced dopamine beta-hydroxylase expression associated with EAE in the spinal cord and PFC was reversed through chemogenetic LC activation.ConclusionTherefore, clear anti-inflammatory and neuroprotective effects were produced by the selective activation of LC noradrenergic neurons in EAE mice, having greater benefits when LC activation commenced earlier. Overall, these data suggest noradrenergic LC neurons may be targets to potentially alleviate some of the motor and non-motor symptoms in MS.

Ethnicity-dependent effect of rs1799971 polymorphism on OPRM1 expression in the postmortem brain and responsiveness to antipsychotics

Schizophrenia is associated with aberration of inhibitory neurons. Although the mu-opioid receptor (MOR) is an essential modulator of inhibitory neurons, the effect of rs1799971 polymorphism in the MOR gene on risk of schizophrenia is controversial. Moreover, the disturbance of opioids systems in patients with schizophrenia has not been fully examined. We firstly conducted preliminary meta-analyses integrating Asian and European populations separately over 12,000 subjects to assess the effect of rs1799971 on risk of schizophrenia. Based on the above result, we also investigated the effect on the expression levels of MOR mRNA in the prefrontal cortex (PFC) and caudate nucleus of 41 postmortem brains. In addition, we determined whether these levels were related to antemortem schizophrenia symptoms and pharmacotherapeutic effects. The rs1799971 G-allele reduced the risk of schizophrenia in Asian populations (OR: 0.56, 95%CI: 0.32–0.98, p = 0.042) but increased it in European populations (OR: 1.66, 95%CI: 1.08–2.56, p = 0.022). It decreased MOR mRNA levels in PFC in the Japanese population (p = 0.031). Increased MOR mRNA level in PFC correlated with higher total score of antemortem schizophrenia symptoms (p = 0.017). Furthermore, the pharmacotherapeutic effect of first-generation antipsychotics was higher for genotype AA than AG/GG of rs1799971 (p = 0.036). The rs1799971 affects risk of schizophrenia and MOR mRNA expression and the effect varies according to ethnicity. Overexpression of MOR might induce severe schizophrenia symptoms. Therefore, MOR modulation may be the key clue for treating antipsychotics-resistant schizophrenia, and genotyping rs1799971 may provide a better pharmacotherapeutic strategy.

Gestational stress decreases postpartum mitochondrial respiration in the prefrontal cortex of female rats

Postpartum depression (PPD) is a major psychiatric complication of childbirth, affecting up to 20% of mothers, yet remains understudied. Mitochondria, dynamic organelles crucial for cell homeostasis and energy production, share links with many of the proposed mechanisms underlying PPD pathology. Brain mitochondrial function is affected by stress, a major risk factor for development of PPD, and is linked to anxiety-like and social behaviors. Considering the importance of mitochondria in regulating brain function and behavior, we hypothesized that mitochondrial dysfunction is associated with behavioral alterations in a chronic stress-induced rat model of PPD. Using a validated and translationally relevant chronic mild unpredictable stress paradigm during late gestation, we induced PPD-relevant behaviors in adult postpartum Wistar rats. In the mid-postpartum, we measured mitochondrial function in the prefrontal cortex (PFC) and nucleus accumbens (NAc) using high-resolution respirometry. We then measured protein expression of mitochondrial complex proteins and 4-hydroxynonenal (a marker of oxidative stress), and Th1/Th2 cytokine levels in PFC and plasma. We report novel findings that gestational stress decreased mitochondrial function in the PFC, but not the NAc of postpartum dams. However, in groups controlling for the effects of either stress or parity alone, no differences in mitochondrial respiration measured in either brain regions were observed compared to nulliparous controls. This decrease in PFC mitochondrial function in stressed dams was accompanied by negative behavioral consequences in the postpartum, complex-I specific deficits in protein expression, and increased Tumor Necrosis Factor alpha cytokine levels in plasma and PFC. Overall, we report an association between PFC mitochondrial respiration, PPD-relevant behaviors, and inflammation following gestational stress, highlighting a potential role for mitochondrial function in postpartum health.

Prefrontal oxygenation is quantified with time-resolved near-infrared spectroscopy: Effect of sex on baseline oxygenation and the response during exercise.

Using time-resolved near-infrared spectroscopy that enables quantitative analysis of optical properties and oxygenation in cerebral tissues and thereby subject-to-subject comparisons in the variables, this study examined the influence of sex on baseline optical properties and oxygenation in the prefrontal cortex (PFC) and the responses during cycling exercise. Absolute levels of oxygenated- and deoxygenated-hemoglobin concentration (Oxy-Hb and Deoxy-Hb) in bilateral PFC were measured at rest and during unilateral cycling at low- and moderate-intensity in young participants (8 women and 10 men). Unilateral cycling was utilized to evaluate no lateralization of the prefrontal oxygenation responses during exercise. Baseline optical properties of bilateral PFC, defined optical pathlength and reduced scattering coefficient, and their responses during cycling were not different between the sexes. Baseline absolute Oxy-Hb of bilateral PFC was significantly lower in women (37 ± 3 μM) than in men (47 ± 7 μM), whereas absolute Deoxy-Hb revealed no sex-related difference. The absolute Oxy-Hb levels in bilateral PFC during low- and moderate-intensity cycling were also lower in women. However, no sex difference was observed when using changes against the baseline levels to normalize baseline differences. No laterality-related differences were observed in the changes in prefrontal Oxy-Hb and Deoxy-Hb during unilateral cycling. Ascertaining no sex-related difference in optical properties of the PFC, the current findings suggest that baseline absolute level of oxygenation in the PFC is lower in women than in men, likely due to lower oxygen supply rather than higher oxygen utilization, and that prefrontal oxygenation responds similarly during exercise independently of sex.

Depressive-like Behavior Is Accompanied by Prefrontal Cortical Innate Immune Fatigue and Dendritic Spine Losses after HIV-1 Tat and Morphine Exposure.

Opioid use disorder (OUD) and HIV are comorbid epidemics that can increase depression. HIV and the viral protein Tat can directly induce neuronal injury within reward and emotionality brain circuitry, including the prefrontal cortex (PFC). Such damage involves both excitotoxic mechanisms and more indirect pathways through neuroinflammation, both of which can be worsened by opioid co-exposure. To assess whether excitotoxicity and/or neuroinflammation might drive depressive behaviors in persons infected with HIV (PWH) and those who use opioids, male mice were exposed to HIV-1 Tat for eight weeks, given escalating doses of morphine during the last two weeks, and assessed for depressive-like behavior. Tat expression decreased sucrose consumption and adaptability, whereas morphine administration increased chow consumption and exacerbated Tat-induced decreases in nesting and burrowing-activities associated with well-being. Across all treatment groups, depressive-like behavior correlated with increased proinflammatory cytokines in the PFC. Nevertheless, supporting the theory that innate immune responses adapt to chronic Tat exposure, most proinflammatory cytokines were unaffected by Tat or morphine. Further, Tat increased PFC levels of the anti-inflammatory cytokine IL-10, which were exacerbated by morphine administration. Tat, but not morphine, decreased dendritic spine density on layer V pyramidal neurons in the anterior cingulate. Together, our findings suggest that HIV-1 Tat and morphine differentially induce depressive-like behaviors associated with increased neuroinflammation, synaptic losses, and immune fatigue within the PFC.

Protective Effect of Nimodipine Against Valproic-acid Induced Biochemical and Behavioral Phenotypes of Autism.

Present study was designed to investigate behavioral and biochemical role of nimodipine in prenatal valproic acid (Pre-VPA) induced autism in rats. Valproic acid was utilized to induce autistic phenotypes in Wistar rats. The rats were assessed for social behavior. Hippocampus and prefrontal cortex (PFC) were utilized for various biochemical assessments, whereas cerebellum was used to assess blood brain barrier (BBB) permeability. Pre-VPA rats showed reduction social interaction. Pre-VPA administration were decreased PFC levels of interleukin- 10 (IL-10), and glutathione along with hippocampus cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF). Also, the animals have shown increase in PFC levels of IL-6, tumor necrosis factor-α, thiobarbituric acid reactive substance, Evans blue leakage and water content. Nimodipine countered Pre-VPA administered reduction in social interaction, CREB, BDNF, inflammation, oxidative stress, BBB permeability. Pre-VPA has induced autistic phenotype, which were attenuated by nimodipine in rats. Nimodipine and other calcium channel blockers should further investigate to check the management of autism.

The 5-HT1A receptor biased agonist, NLX-204, shows rapid-acting antidepressant-like properties and neurochemical changes in two mouse models of depression

Activation of cortical serotonin 5-HT1A receptors may be a promising strategy to achieve rapid-acting antidepressant (RAAD) activity. NLX-204 is a selective 5-HT1A receptor biased agonist that, in naïve mice, robustly decreases immobility in the forced swim test (FST), and preferentially phosphorylates extracellular signal-regulated kinase (ERK1/2), involved in antidepressant activity. Here, we evaluated the properties of NLX-204 in two mouse models of depression. Male CD-1 mice were subjected to unpredictable chronic mild stress (UCMS) for 4-weeks or to repeated corticosterone (CORT, 20 mg/kg s.c./day) for 3-weeks before receiving acute administration of NLX-204 (2 mg/kg, p.o.). Depressive-like behavior was assessed in the FST, anhedonia-like behavior in the sucrose preference test (SPT) and locomotor activity was also recorded. Phosphorylation of ERK1/2 (pERK1/2) and cAMP response binding element (pCREB) were measured ex vivo in hippocampus and prefrontal cortex (PFC). UCMS or CORT treatment increased immobility in the FST, elicited a sucrose preference deficit, and decreased pERK1/2 and pCREB levels in PFC and hippocampus. NLX-204 reduced depressive-like behavior in the FST in CORT and UCMS mice, and normalized sucrose preference in CORT mice, suggesting anti-anhedonic activity. NLX-204 increased pERK1/2 levels in PFC of UCMS mice. NLX-204 also increased pCREB levels in PFC of CORT mice. These data suggest that NLX-204 has RAAD-like properties not only in naïve mice, but also in mice in a “depressive-like” state, and that these involve changes in PFC and hippocampal pERK1/2 and pCREB levels. These data provide additional evidence that activation of 5-HT1A receptors by selective biased agonists, such as NLX-204, may constitute a promising RAAD strategy.

Effect Of Tai Chi Participation On Prefrontal Cortex Activation During Precision Fitting Task

PURPOSE: The purpose of this study was to investigate the group effects on balance performance and prefrontal cortex (PFC) activation level when performing fitting task among Tai Chi (TC), older (OG), and young (YG) groups. METHODS: TC (67.5 ± 3.6 yrs), OG (66.9 ± 3.4 yrs) and YG (19.5 ± 0.6 yrs) were recruited. Each participant performed four different fitting tasks: (1) close-large (CL), (2) close-small (CS), (3) far-large (FL), and (4) far-small (FS) conditions. The order of opening size was random, but the distance was following from close to far conditions. Each task was required to repeat five times. Meanwhile, the center of pressure (CoP) was recorded by the force plate (2000 Hz, Kistler 9285BA), as well as the oxygenation levels of the PFC were recorded by the fNIRS device (50 Hz, Brite 24). Two three-way mixed models of ANOVA with repeated measure were used to examine the group, distance, and size effects on CoP measures and PFC activation, respectively. RESULTS: There was no significant group difference on time to complete. In the CL condition, TC and YG showed significantly smaller average CoP velocity (TC: 28.1 ± 11.4, YG: 26.6 ± 10.8, & OG: 42.8 ± 13.5 mm/s) in the Medial-Lateral (ML) direction than OG (p < .05). Additionally, in the CS condition, YG also presented smaller average CoP velocity than OG in the Anterior-Posterior (AP) direction (YG: 52.7 ± 17.0, & OG: 77.0 ± 30.1 mm/s) (p < .05). In the FS condition, YG exhibited smaller average CoP velocity than OG in the AP (YG: 43.1 ± 16.6, & OG: 61.8 ± 13.0 mm/s) and ML (YG: 27.0 ± 12.4, & OG: 61.8 ± 13.0 mm/s) directions (p < .05). In the FL and FS conditions, OG had significant larger activation levels in the right/left dorsolateral PFC (YG: 0.8 ± 0.9/0.3 ± 0.6, & OG: 1.8 ± 1.3/1.2 ± 0.8 μm), left dorsomedial PFC (YG: 0.3 ± 1.0, & OG: 1.0 ± 1.4 μm), and left ventrolateral PFC (YG: 0.5 ± 1.1, & OG: 1.9 ± 1.1 μm) than YG (p < .05). In addition, OG also had a higher activation level in the right dorsolateral PFC (TC: 0.8 ± 1.1 μm) than TC (p < .05). CONCLUSION: In the far condition, healthy older adults presented an alternative control strategy using additional PFC activation in fitting task compared to young adults. However, Tai Chi group adopted similar control strategy with young adults, thereby can be considered as a feasible intervention approach to reduce falling risks.

Effect of Mentone® on depression- and anxiety-like profiles and regional brain neurochemistry in the adolescent Wistar Kyoto rat, a putative model of endogenous depression

Objectives: Antidepressants, when prescribed to treat adolescent depression tend to induce adverse effects, including suicidal tendencies. This is because the adolescent brain circuitry is still maturing and is therefore extremely vulnerable. As such, the search is on for compounds for use in complementary/alternative medicine. Polyherbal formulations are widely used as therapeutic alternatives for the treatment of depression. Such formulations and plant extracts are being studied in adult rodent models using standard pharmacological parameters, but not much emphasis has been given to testing the same in adolescents and endogenous animal models of depression. Therefore, the present study was focused on testing out the effect of the polyherbal formulation Mentone® on depression- and anxiety-like profiles and brain neurochemistry in the adolescent Wistar Kyoto rat (WKY), a putative model of endogenous and treatment-resistant depression (TRD). Materials and Methods: Mentone®, a polyherbal formulation comprising of four different plant species: Centella asiatica (Brahmi), Evolvulus alsinoides (Shankapushpi), Tinospora cordifolia (Guduchi), and Glycyrrhiza glabra (Yashtimadhu) was tested at two (18 and 36 mg/kg body weight) doses from the post-natal day (pnd) 25 to pnd 42 using standard neurobehavioral paradigms. Vehicular controls were intubated with saline and positive controls with 10 mg/kg body weight of conventional antidepressant, Fluoxetine. From pnd 35 onwards, animals were tested on a battery of tests, including sucrose preference, novel open field, elevated plus maze, and forced swim or Porsolt’s learned helplessness test. On pnd 42, animals were sacrificed and brain regional tissues such as the Prefrontal cortex (PFC), Striatum (Str), Nucleus Accumbens (NAc), and Hippocampus were microdissected out and subjected to reverse phase HPLC for the separation and quantification of monoamines: Norepinephrine (NE), dopamine (DA), serotonin (5-HT) and their metabolites, 3,4-Dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) in reference to external standards. Results: Mentone® reversed anhedonia by increasing sucrose consumption in Mentone®-treated as compared to Fluoxetine-treated groups. However, there was no effect on anxiety-related parameters in the novel open field or elevated plus-maze. Mentone® exhibited significant anti-depressant-like effects as indicated by its ability to reduce swim stress-induced immobility in Porsolt’s behavioural despair test with a concomitant increase in climbing or struggling behaviour, signifying reversal of depressive-like symptomatology. HPLC-based separation and quantification of brain regional levels of monoamines and their metabolites revealed increased DA levels in NAc and Str in treated groups with decreased levels of metabolite DOPAC in Mentone®-treated groups indicating increased DA tone. Significantly reduced 5-HT metabolite 5-HIAA levels in both PFC and Str is indicative of increased 5-HT tone in both Mentone®- and Fluoxetine-treated groups. NE was variably affected. Conclusion: While no anxiolytic effects and differential neurochemical effects were observed in brain regional areas in relation to Mentone® and Fluoxetine treatment, anhedonia and forced swim test, which are gold-standard tests for assessing depressive-like profiles indicated an effect of Mentone® that was on par with Fluoxetine. Thus, studies on such Ayurvedic formulations would enable a teasing out or differentiation between anxiolytic-like and depressive-like symptomatology and could constitute a source that holds promise in the development of complementary/alternative therapies for the treatment of depression in general and TRD in particular.

Temporal changes in cortical oxygenation in the motor-related areas and bilateral prefrontal cortex based on exercise intensity and respiratory metabolism during incremental exercise in male subjects: A near-Infrared spectroscopy study.

A recent study has reported that prefrontal cortex (PFC) activity during incremental exercise may be related to exercise termination on exhaustion. However, few studies have focused on motor-related areas during incremental exercise. This study investigated changes in the oxygenation of the PFC and motor-related areas using near-infrared spectroscopy during incremental exercise. Moreover, we analyzed the effect of exercise termination on changes in cortical oxygenation based on exercise intensity and respiratory metabolism. Sixteen healthy young male patients participated in this study. After a 4-min rest and 4-min warm-up period, incremental exercise was started at an incremental load corresponding to 20 W/min. Oxyhemoglobin (O2Hb), deoxyhemoglobin (HHb), and total hemoglobin (THb) in the bilateral PFC, supplementary motor area, and primary motor cortex were measured. We evaluated changes in oxygenation in each cortex before and after the anaerobic threshold (AT) and respiratory compensation point to identify changes due to respiratory metabolism. O2Hb and THb increased from moderate intensity or after AT to maximal exercise, and HHb increased slowly compared to O2Hb and THb; these changes in hemoglobin levels were consistent in all cortical areas we measured. However, the increase in each hemoglobin level in the bilateral PFC during incremental exercise was faster than that in motor-related areas. Moreover, changes in cortical oxygenation in the right PFC were faster than those in the left PFC. These results suggest changes based on differences in neural activity due to the cortical area.

Changes in Nitric oxide Levels in Basal Forebrain during Sedation with Dexmedetomidine and Sevoflurane

BackgroundPerioperative and critical care settings frequently require periods of prolonged sedation but the effect of sedation on sleep homeostasis is not completely understood. In the ongoing studies in our laboratory, continuous 8 h sedation with dexmedetomidine (DEX) was shown to increase wakefulness (WAKE), decrease slow‐wave sleep (SWS), and nearly eliminate rapid eye movement sleep (REMS) in the post‐sedation period [1]. In contrast, continuous 8 h sedation with sevoflurane (SEVO) did not affect the time spent in WAKE or SWS, but increased REMS in the post‐sedation period [1]. Past studies have shown nitric oxide (NO) in basal forebrain (BF) to be a key modulator of sleep homeostasis. Specifically, NO concentration in BF has been shown to increase with sleep pressure (e.g., during sleep deprivation) and decrease with the reduced sleep need (e.g., during recovery from sleep deprivation). To determine the effect of sedation produced by DEX or SEVO on sleep homeostasis, as inferred from changes in NO levels in BF, we quantified the changes in NO concentration before, during, and after sedation with DEX and SEVO.MethodsAdult male Sprague Dawley rats (N=4 male) were surgically prepared to record electroencephalogram (EEG) and electromyogram and intravenous delivery of DEX via a chronic catheter in jugular vein. In addition, an open flow microperfusion guide cannula was implanted into BF (N=2) or prefrontal cortex (N=2) for collection of perfusates for NO analysis. Prefrontal cortex (PFC) was used as an anatomical control for BF. After at least 15 days of post‐surgical recovery, rats were connected to the EEG recording system and a sampling insert was lowered into BF or PFC to route the perfusate samples directly into a high‐performance liquid chromatograph for online analysis of nitrite and nitrate levels, which are collectively termed as NOx and are considered a surrogate for endogenous NO concentration. The EEG and NOx were recorded during 2 h baseline wake condition, 8 h of sedation with either DEX (0.5‐0.7ug/kg/min) or SEVO (1.5‐3.0%), and 2 h post‐sedation period. Each rat was administered with DEX or SEVO in a counter‐balanced manner and with a washout period of at least 7 days.ResultsThe NOx levels in BF decreased during sedation with DEX (mean ± standard deviation: 0.52 μM ± 0.31 during baseline vs 0.08 μM ± 0.01 during DEX) and SEVO (mean ± standard deviation: 1.58 μM ± 0.16 during baseline vs 0.72 μM ± 0.07 during SEVO). The NOx levels in PFC during sedation with DEX stayed about at the same level as observed during baseline state (2.40 μM ± 1.39 during baseline vs. 3.01 μM ± 0.16 during DEX), but the NOx levels in PFC decreased during sedation with SEVO (1.45 μM ± 1.23 during baseline vs 0.37 μM ± 0.18 during SEVO).ConclusionAlthough these are preliminary data, the decrease in NOx levels in BF after sedation with DEX and SEVO suggest a reduced sleep pressure and is supportive of the changes in sleep homeostasis as described in our previous report.References Parkar A, Liu T, Fryzel A, Groenhout T, Mashour GA and Pal D (2020) Effect of prolonged sedation with dexmedetomidine, midazolam, propofol, or sevoflurane on sleep homeostasis in rat. J Neurosurgical Anesthesiology, Vol 32, No 4, Page 403, Abstract no SNACC‐387.

Remediate Effect of Ryanodine Receptor Antagonist in Valproic-Acid Induced Autism

Autism spectrum disorder (ASD) mainly diagnosed with social behavioral problems, lack of communication, social interaction, and repetitive behavior along with cognitive dysfunction. Ryanodine receptors are involved in various neurological and behavioral impairments in different conditions. The role of Ryanodine receptors has not been explored in experimental ASD. The present study explicates the role of ryanodine receptor antagonist; ruthenium red (RR) in prenatal valproic acid (Pre-VPA) administered experimental ASD phenotypes. Three chamber social behavior, Y-Maze were utilized to assess social interaction, spontaneous alteration, respectively. Hippocampus and Prefrontal cortex (PFC) were utilized for various biochemical assessments, whereas cerebellum was used for assessments of blood brain barrier (BBB) permeability. Pre-VPA rats showed reduction in spontaneous alteration, social interaction. Pre-VPA administration were decreased PFC levels of IL-10, and GSH along with hippocampus cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF). Also, the animals have shown increase in PFC levels of IL-6, TNF-α, TBARS, Evans blue leakage and water content. Daily administration of R Red considerably diminished Pre-VPA administered reduction in spontaneous alteration, social interaction, CREB, BDNF and increase in inflammation, oxidative stress, BBB permeability. Conclusively, Pre-VPA has induced autistic phenotype, which were attenuated by ryanodine receptor antagonist. Ryanodine receptor antagonists may further test for their pharmacological effects in ASD phenotypes.

Involvement of oxidative pathways and BDNF in the antidepressant effect of carvedilol in a depression model induced by chronic unpredictable stress.

Depression is a severe psychiatric disorder with oxidative imbalance and neurotrophic deficits as underlying mechanisms. Based on the antioxidant effects of carvedilol (CARV), here, we aimed to evaluate CARV's effects against depression induced by the chronic unpredictable stress (CUS) model. Female Swiss mice were submitted to the CUS protocol for 21days. Between days 15 and 22, the animals received CARV (5 or 10mg/kg) or desvenlafaxine (DVS 10mg/kg) orally. On the 22nd day, mice were subjected to behavioral tests to evaluate locomotion, depressive-like behavior (tail suspension test), motivation/self-care with the splash test (ST), social interaction, and working memory Y-maze test. The prefrontal cortex (PFC) and hippocampus were dissected to evaluate alterations of oxidative and brain-derived neurotrophic factor (BDNF). The CUS model reduced locomotion and increased grooming latency, while it reduced the number of groomings in the ST. Both doses of CARV and DVS reverted these alterations. In addition, DVS and CARV reversed CUS model-induced working memory and social interaction deficits. The CUS model decreased hippocampal reduced glutathione (GSH), while DVS and CARV increased GSH in the PFC (CARV5) and hippocampus (CARV5 and 10). The CUS model increased nitrite and malondialdehyde (MDA) concentrations in both areas. All treatments reversed nitrite alterations, while CARV10 changed MDA levels in PFC and all treatments in the hippocampus. The CUS model reduced BDNF levels. CARV10 increased BDNF in the PFC, while both doses of CARV increased hippocampal levels of this neurotrophin. CARV presents antidepressant-like effects comparable to those observed with DVS. In addition, it has an antioxidant effect and is capable of increasing BDNF brain concentrations. Further studies are needed to elucidate the mechanisms involved in the antidepressant effect of CARV.

Identification of Molecular Markers of Clozapine Action in Ketamine-Induced Cognitive Impairment: A GPCR Signaling PathwayFinder Study.

Background: Cognitive disorders associated with schizophrenia are closely linked to prefrontal cortex (PFC) dysfunction. Administration of the non-competitive NMDA receptor antagonist ketamine (KET) induces cognitive impairment in animals, producing effects similar to those observed in schizophrenic patients. In a previous study, we showed that KET (20 mg/kg) induces cognitive deficits in mice and that administration of clozapine (CLZ) reverses this effect. To identify biochemical mechanisms related to CLZ actions in the context of KET-induced impairment, we performed a biochemical analysis using the same experimental paradigm—acute and sub-chronic administration of these drugs (0.3 and 1 mg/kg). Methods: Since the effect of CLZ mainly depends on G-protein-related receptors, we used the Signaling PathwayFinder Kit to identify 84 genes involved in GPCR-related signal transduction and then verified the genes that were statistically significantly different on a larger group of mice using RT-PCR and Western blot analyses after the administration of acute and sub-chronic drugs. Results: Of the 84 genes involved in GPCR-related signal transduction, the expression of six, βarrestin1, βarrestin2, galanin receptor 2 (GalR2), dopamine receptor 2 (DRD2), metabotropic glutamate receptor 1 (mGluR1), and metabotropic glutamate receptor 5 (mGluR5), was significantly altered. Since these genes affect the levels of other signaling proteins, e.g., extracellular signal-regulated kinase 1/2 (ERK1/2), G protein-coupled receptor kinase 2 (Grk2), and G protein-gated inwardly rectifying potassium 3 (Girk3), we determined their levels in PFC using Western blot. Most of the observed changes occurred after acute treatment with 0.3 mg/kg CLZ. We showed that acute treatment with CLZ at a lower dose significantly increased βarrestin1 and ERK1/2. KET treatment induced the upregulation of βarrestin1. Joint administration of these drugs had no effect on the βarrestin1 level. Conclusion: The screening kit we used to study the expression of GPCR-related signal transduction allowed us to select several important genes affected by CLZ. However, the obtained data do not explain the mechanism of action of CLZ that is responsible for reversing KET-induced cognitive impairment.

Epigenetic treatment of behavioral and physiological deficits in a tauopathy mouse model.

Epigenetic abnormality is implicated in neurodegenerative diseases associated with cognitive deficits, such as Alzheimer's disease (AD). A common feature of AD is the accumulation of neurofibrillary tangles composed of hyperphosphorylated tau. Transgenic mice expressing mutant P301S human tau protein develop AD‐like progressive tau pathology and cognitive impairment. Here, we show that the euchromatic histone‐lysine N‐methyltransferase 2 (EHMT2) is significantly elevated in the prefrontal cortex (PFC) of P301S Tau mice (5–7 months old), leading to the increased repressive histone mark, H3K9me2, which is reversed by treatment with the selective EHMT inhibitor UNC0642. Behavioral assays show that UNC0642 treatment induces the robust rescue of spatial and recognition memory deficits in P301S Tau mice. Concomitantly, the diminished PFC neuronal excitability and glutamatergic synaptic transmission in P301S Tau mice are also normalized by UNC0642 treatment. In addition, EHMT inhibition dramatically attenuates the hyperphosphorylated tau level in PFC of P301S Tau mice. Transcriptomic analysis reveals that UNC0642 treatment of P301S Tau mice has normalized a number of dysregulated genes in PFC, which are enriched in cytoskeleton and extracellular matrix organization, ion channels and transporters, receptor signaling, and stress responses. Together, these data suggest that targeting histone methylation enzymes to adjust gene expression could be used to treat cognitive and synaptic deficits in neurodegenerative diseases linked to tauopathies.