Region-specific Effects Research Articles

Thalamic Roles in Conscious Perception Revealed by Low-Intensity Focused Ultrasound Neuromodulation.

The neural basis of conscious perception remains incompletely understood. While cortical mechanisms of conscious content have been extensively investigated, the role of subcortical structures, including the thalamus, remains less explored. We aim to elucidate the causal contributions of different thalamic regions to conscious perception using transcranial low-intensity focused ultrasound (LIFU) neuromodulation. We hypothesize that modulating different thalamic regions would result in distinct perceptual outcomes. We apply LIFU in human volunteers to investigate region-specific and sonication parameter-dependent effects. We target anterior (transmodal-dominant) and posterior (unimodal-dominant) thalamic regions, further divided into ventral and dorsal regions, while participants perform a near-threshold visual perception task. Task performance is evaluated using Signal Detection Theory metrics. We find that the high duty cycle stimulation of the ventral anterior thalamus enhanced object recognition sensitivity. We also observe a general (i.e., region-independent) effect of LIFU on decision bias (i.e., a tendency toward a particular response) and object categorization accuracy. Specifically, high duty cycle stimulation decreases categorization accuracy, whereas low duty cycle shifts decision bias towards a more conservative stance. In conclusion, our results provide causal insight into the functional organization of the thalamus in shaping human visual experience and highlight the unique role of the transmodal-dominant ventral anterior thalamus.

Natural forest regeneration is projected to reduce local temperatures

Forest regeneration is a crucial strategy for mitigating and adapting to global warming. Yet its precise impact on local climate remains uncertain, a factor that complicates decision-making when it comes to prioritizing investments. Here, we developed global maps illustrating how natural forest regeneration influences key local climate drivers—land surface temperature (LST), albedo, and evapotranspiration—using models fitted at a 1-km spatial resolution with a random forest classifier. We found that natural forest regeneration can alter annual mean LST by 0.01 °C, −0.59 °C, −0.50 °C, and −2.03 °C in Boreal, Mediterranean, Temperate, and Tropical regions, respectively. These variations underscore the region-specific effects of forest regeneration. Importantly, natural forest regeneration reduces LST across 64% of 1 billion hectares and 75% of 148 million hectares of potentially restorable land under different scenarios. These findings improve understanding of how forest regeneration can help regulate local climate, supporting climate adaptation efforts.

Classical psychedelics’ action on brain monoaminergic systems

The study of the mechanism of action of classical psychedelics has gained significant interest due to their clinical potential in the treatment of several psychiatric conditions, including major depressive and anxiety disorders. These drugs bind 5-hydroxytryptamine receptors (5-HTR) including 5-HT1AR, 5-HT2AR, 5-HT2BR, and/or 5-HT2CR, as well as other targets. 5-HTRs regulate the activity of ascending monoaminergic neurons, a mechanism primarily involved in the action of classical antidepressant drugs, antipsychotics, and drugs of abuse. Sparse neurochemical data have been produced on the control of monoaminergic neuron activity in response to classical psychedelics. Here we review the available data in order to determine whether classical psychedelics have specific neurochemical effects on serotonergic, dopaminergic, and noradrenergic neurons. The data show that these drugs have disparate effects on each monoaminergic system, demonstrating a complex response with state-dependent and region-specific effects. For instance, several psychedelics inhibit the firing of serotonergic neurons, although this is not necessarily associated with a decrease in serotonin release in all regions. Noradrenergic neuron spontaneous activity also appears to be inhibited by psychedelics, also not necessarily associated with a decrease in noradrenaline release in all regions. Psychedelics influence on dopaminergic systems is also complex as the above-mentioned 5-HTRs may have opposing effects on dopaminergic neuron activity, in a state-dependent manner. There is an apparent lack of clear neuronal signature induced by psychedelics on monoaminergic neuron activity despite specific recurrent mechanisms. This review provides a current summary of the action of psychedelics on monoamine neuromodulators serotonin, dopamine and noradrenaline, compiling reoccurring and contradictory findings demonstrating that a monoamine signature of psychedelics, if applicable, would be state- and region-dependant.

Early brain neuroinflammatory and metabolic changes identified by dual tracer microPET imaging in mice with acute liver injury.

Acute liver injury (ALI) that progresses into acute liver failure (ALF) is a life-threatening condition with an increasing incidence and associated costs. Acetaminophen (N-acetyl-p-aminophenol, APAP) overdosing is among the leading causes of ALI and ALF in the Northern Hemisphere. Brain dysfunction defined as hepatic encephalopathy is one of the main diagnostic criteria for ALF. While neuroinflammation and brain metabolic alterations significantly contribute to hepatic encephalopathy, their evaluation at early stages of ALI remained challenging. To provide insights, we utilized post-mortem analysis and non-invasive brain micro positron emission tomography (microPET) imaging of mice with APAP-induced ALI. Male C57BL/6 mice were treated with vehicle or APAP (600 mg/kg, i.p.). Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), liver damage (using H&E staining), hepatic and serum IL-6 levels, and hippocampal IBA1 (using immunolabeling) were evaluated at 24h and 48h. Vehicle and APAP treated animals also underwent microPET imaging utilizing a dual tracer approach, including [ 11 C]-peripheral benzodiazepine receptor ([ 11 C]PBR28) to assess microglia/astrocyte activation and [ 18 F]-fluoro-2-deoxy-2-D-glucose ([ 18 F]FDG) to assess energy metabolism. Brain images were pre-processed and evaluated using conjunction and individual tracer uptake analysis. APAP-induced ALI and hepatic and systemic inflammation were detected at 24h and 48h by significantly elevated serum ALT and AST levels, hepatocellular damage, and increased hepatic and serum IL-6 levels. In parallel, increased microglial numbers, indicative for neuroinflammation were observed in the hippocampus of APAP-treated mice. MicroPET imaging revealed overlapping increases in [ 11 C]PBR28 and [ 18 F]FDG uptake in the hippocampus, thalamus, and habenular nucleus indicating microglial/astroglial activation and increased energy metabolism in APAP-treated mice (vs. vehicle-treated mice) at 24h. Similar significant increases were also found in the hypothalamus, thalamus, and cerebellum at 48h. The individual tracer uptake analyses (APAP vs vehicle) at 24h and 48h confirmed increases in these brain areas and indicated additional tracer- and region-specific effects including hippocampal alterations. Peripheral manifestations of APAP-induced ALI in mice are associated with brain neuroinflammatory and metabolic alterations at relatively early stages of disease progression, which can be non-invasively evaluated using microPET imaging and conjunction analysis. These findings support further PET-based investigations of brain function in ALI/ALF that may inform timely therapeutic interventions.

Region-specific protective effects of monomethyl fumarate in cerebellar and hippocampal organotypic slice cultures following oxygen-glucose deprivation.

To date, apart from moderate hypothermia, there are almost no adequate interventions available for neuroprotection in cases of brain damage due to cardiac arrest. Affected persons often have severe limitations in their quality of life. The aim of this study was to investigate protective properties of the active compound of dimethyl fumarate, monomethyl fumarate (MMF), on distinct regions of the central nervous system after ischemic events. Dimethyl fumarate is an already established drug in neurology with known anti-inflammatory and antioxidant properties. In this study, we chose organotypic slice cultures of rat cerebellum and hippocampus as an ex vivo model. To simulate cardiac arrest and return of spontaneous circulation we performed oxygen-glucose-deprivation (OGD) followed by treatments with different concentrations of MMF (1-30 μM in cerebellum and 5-30 μM in hippocampus). Immunofluorescence staining with propidium iodide (PI) and 4',6-diamidine-2-phenylindole (DAPI) was performed to analyze PI/DAPI ratio after imaging with a spinning disc confocal microscope. In the statistical analysis, the relative cell death of the different groups was compared. In both, the cerebellum and hippocampus, the MMF-treated group showed a significantly lower PI/DAPI ratio compared to the non-treated group after OGD. Thus, we showed for the first time that both cerebellar and hippocampal slice cultures treated with MMF after OGD are significantly less affected by cell death.

Sex-dependent astrocyte reactivity: Unveiling chronic stress-induced morphological changes across multiple brain regions

Chronic stress is a major precursor to various neuropsychiatric disorders and is linked with increased inflammation in the brain. However, the bidirectional association between inflammation and chronic stress has yet to be fully understood. Astrocytes are one of the key inflammatory regulators in the brain, and the morphological change in reactive astrocytes serves as an important indicator of inflammation. In this study, we evaluated the sex-specific astrocyte response to chronic stress or systemic inflammation in key brain regions associated with mood disorders. We conducted the unpredictable chronic mild stress (UCMS) paradigm to model chronic stress, or lipopolysaccharide (LPS) injection to model systemic inflammation. To evaluate stress-induced morphological changes in astrocyte complexity, we measured GFAP fluorescent intensity for astrocyte expression, branch bifurcation by quantifying branch points and terminal points, branch arborization by conducting Sholl analysis, and calculated the ramification index. Our analysis indicated that chronic stress-induced morphological changes in astrocytes in all brain regions investigated. The effects of chronic stress were region and sex specific. Notably, females had greater stress or inflammation-induced astrocyte activation in the hypothalamus (HYPO), CA1, CA3, and amygdala (AMY) than males. These findings indicate that chronic stress induces astrocyte activation that may drive sex and region-specific effects in females, potentially contributing to sex-dependent mechanisms of disease.

Associations between the neighbourhood food environment and food and drink purchasing in England during lockdown: A repeated cross-sectional analysis.

Evidence for the effect of neighbourhood food environment (NFE) exposures on diet in the UK is mixed, potentially due to exposure misclassification. This study used the first national COVID-19 lockdown in England as an opportunity to isolate the independent effects of the NFE exposure on food and drink purchasing, and assessed whether these varied by region. Transaction-level purchasing data for food and drink items for at-home (1,221 households) and out-of-home consumption (171 individuals) were available from the GB Kantar Fast Moving Consumer Goods Panel for London and the North of England. The study period included 23rd March to 10th May 2020 ('lockdown'), and the same period in 2019 for comparison. NFE exposures included food outlet density and proximity, and NFE composition within a 1 km network buffer around the home. Associations were estimated for both years separately, adjusted for individual and household characteristics, population density and area deprivation. Interaction terms between region and exposures were explored. There were no consistent patterns of association between NFE exposures and food and drink purchasing in either time period. In 2019, there was some evidence for a 1.4% decrease in energy purchased from ultra-processed foods for each additional 500 m in the distance to the nearest OOH outlet (IR 0.986, 95% CI 0.977 to 0.995, p = 0.020). In 2020, there was some evidence for a 1.8% reduction in total take-home energy for each additional chain supermarket per km2 in the neighbourhood (IR 0.982, 95% CI 0.969, 0.995, p = 0.045). Region-specific effects were observed in 2019 only. Findings suggest that the differences in exposure to the NFE may not explain differences in the patterns or healthiness of grocery purchasing. Observed pre-pandemic region-specific effects allude to the importance of geographical context when designing research and policy. Future research may assess associations for those who relied on their NFE during lockdown.

Time- and Region-specific Effect of Vortioxetine on Central LPS-induced Transcriptional Regulation of NLRP3 Inflammasome.

Inflammasome overactivation, multiprotein complexes that trigger inflammatory responses, plays a critical role in Major Depressive Disorder (MDD) pathogenesis and treatment responses. Indeed, different antidepressants alleviate depression-related behaviours by specifically counteracting the NLRP3 inflammasome signalling pathway. The immunomodulatory effects of vortioxetine (VTX), a multimodal antidepressant with cognitive benefits, were recently revealed to counter memory impairment induced by a peripheral lipopolysaccharide (LPS) injection 24 hours (h) postchallenge. The potential link between VTX and NLRP3, along with other inflammasomes, remains unexplored. Hence, adult C57BL/6J male mice (n = 73) were fed with a standard or VTX-enriched diet (600 mg/kg of food, 28 days), injected with LPS (830 μg/kg) or saline, and sacrificed 6/24 h post-LPS. At these time-points, transcriptional effects of LPS and VTX's on NLRP3, NLRP1, NLRC4, AIM2 (inflammasomes), ASC and CASP1 (related subunits) and NEK7 mediator (NLRP3 regulator) were assessed in dorsal and ventral hippocampal subregions, frontal-prefrontal cortex and hypothalamus, brain regions serving behavioural-cognitive functions impaired in MDD. Varied expression patterns of inflammasomes were revealed, with long-term NLRP3 and ASC transcriptional changes observed in response to LPS. It was discovered that VTX counteracted the LPS-mediated NLRP3 and ASC upregulation in memory-related brain areas like the dorsal hippocampus at 24 h time-point, potentially via regulating NEK7 expression. No VTX-mediated transcriptional effects were observed on other inflammasomes, reinforcing a potentially specific modulation on the NLRP3 inflammasome signalling pathway. Thus, a novel VTX's molecular mechanism in modulating the NLRP3 inflammasome in a time- and area-specific manner in the brain was highlighted, with significant clinical implications in treating depression and cognitive impairments.</p>.

Regional-specific changes in rat brain BDNF in a model of methamphetamine abuse

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays key roles in neuronal protection and synaptic plasticity. Changes in BDNF are associated with various pathological conditions, including methamphetamine (meth) addiction, although the effects of meth on BDNF expression are not always consistent. We have previously demonstrated region-specific effects of a chronic meth regime on BDNF methylation and expression in the rat brain. This study aims to determine the effect of chronic meth administration on the expression of BDNF protein using immunohistochemistry in the rat frontal cortex and hippocampus. Novel object recognition (NOR) as a measure of cognitive function was also determined. Male Sprague Dawley rats were administered a chronic escalating dose (0.1–4 mg/kg over 14 days) (ED) of meth or vehicle; a subgroup of animals receiving meth were also given an acute “binge” (4x6mg) dose on the final day before NOR testing. The results showed that hippocampal CA1 BDNF protein was significantly increased by 72 % above control values in the ED-binge rats, while other hippocampal regions and frontal cortex were not significantly affected. Meth-administered animals also demonstrated deficits in NOR after 24 h delay. No significant effect of the additional binge dose on BDNF protein or NOR findings was apparent. This finding is consistent with our previous results of reduced DNA methylation and increased expression of the BDNF gene in this region. The hippocampal BDNF increase may reflect an initial increase in a protective factor produced in response to elevated glutamate release resulting in neurodegenerative excitotoxicity.

Neurochemical Anatomy of Cushing's Syndrome.

The neurochemical anatomy underlying Cushing's syndrome is examined for regional brain metabolism as well as neurotransmitter levels and receptor binding of biogenic amines and amino acids. Preliminary studies generally indicate that glucose uptake, blood flow, and activation on fMRI scans decreased in neocortical areas and increased in subcortical areas of patients with Cushing's syndrome or disease. Glucocorticoid-mediated increases in hippocampal metabolism occurred despite in vitro evidence of glucocorticoid-induced decreases in glucose uptake or consumption, indicating that in vivo increases are the result of indirect, compensatory, or preliminary responses. In animal studies, glucocorticoid administration decreased 5HT levels and 5HT1A receptor binding in several brain regions while adrenalectomy increased such binding. Region-specific effects were also obtained in regard to the dopaminergic system, with predominant actions of glucocorticoid-induced potentiation of reuptake blockers and releasing agents. More in-depth neuroanatomical analyses are warranted of these and amino acid-related neurotransmission.

Region-specific Effects of Transcranial Direct Current Stimulation Over Posterior Parietal Cortex and Cerebellum on Standing Postural Displacement After Prism Adaptation

Prism adaptation (PA) induces the after-effects of adapted tasks and transfers after-effects of non-adapted tasks, in which PA with pointing movements transfers to postural displacement during eyes-closed standing. However, the neural mechanisms underlying the transfer of PA after-effects on standing postural displacement remain unclear. The present study investigated the region-specific effects of transcranial direct current stimulation (tDCS) over the posterior parietal cortex (PPC) and cerebellum during prism exposure (PE) on standing postural displacement in healthy adults. Forty-two healthy young adults were grouped into pointing during PE with cathodal tDCS over the right PPC, anodal tDCS over the right cerebellum, and sham tDCS groups. They received 20 min of tDCS, during which they pointed to the visual targets while wearing prism lenses with a leftward visual shift (30 diopters) for 15 min. During the early PE, the pointing errors in the cerebellum group were significantly displaced more accurately toward the targets than those in the PPC group. However, after leftward PE, all groups had similar rightward displacements of the straight-ahead pointing with eyes closed. The PPC group only exhibited significant rightward center-of-pressure displacement during eyes-closed standing with feet-closed after leftward PE. The perception of longitudinal body axis rotation, as an indicator of the subjective body vertical axis, did not differ significantly between the pre- and post-evaluations in all groups. These results show that the PPC during PE could make an important neural contribution to inducing transfer of PA after-effect on standing postural displacement.

Prenatal ethanol and cannabis exposure have sex- and region-specific effects on somatostatin and neuropeptide Y interneurons in the rat hippocampus.

Cannabis is increasingly being legalized and socially accepted around the world and is often used with alcohol in social settings. We recently showed that in utero exposure to both substances can alter the density of parvalbumin-expressing interneurons in the hippocampus. Here we investigate the effects of in utero alcohol and cannabis exposure, alone or in combination, on somatostatin- and neuropeptide Y-positive (NPY) interneurons. These are separate classes of interneurons important for network synchrony and inhibition in the hippocampus. A 2 (Ethanol, Air) × 2 (tetrahydrocannabinol [THC], Vehicle) design was used to expose pregnant Sprague-Dawley rats to either ethanol or air, in addition to either THC or the inhalant vehicle solution, during gestational days 5-20. Immunohistochemistry for somatostatin- and NPY-positive interneurons was performed in 50 μm tissue sections obtained at postnatal day 70. Exposure to THC in utero had region-specific and sex-specific effects on the density of somatostatin-positive interneurons in the adult rat hippocampus. A female-specific decrease in NPY interneuron cell density was observed in the CA1 region following THC exposure. Combined exposure to alcohol and THC reduced NPY neurons selectively in the ventral dentate gyrus hippocampal subfield. However, overall, co-exposure to alcohol and cannabis had neither additive nor synergistic effects on interneuron populations in other areas of the hippocampus. These results illustrate how alcohol and cannabis exposure in utero may affect hippocampal function by altering inhibitory processes in a sex-specific manner.

Hyperoxia and regional cerebral blood flow: Do brain regions respond differently to high-oxygen gas?

Background: Delivery of oxygen-rich gas (hyperoxia) is used to treat medical emergencies as well as to prevent adverse outcomes in certain occupations that are subjected to extreme environmental conditions. While useful for mitigating acute health risks, hyperoxia has been linked to health decrements including systemic vasoconstriction, increased oxidative stress, worsened neurological outcomes, and increased mortality. Notably, hyperoxia has been found to decrease global cerebral blood flow (CBF) in humans by as much as 37%. Reductions in CBF are associated with increased risk of stroke and cognitive impairment- both of which present heterogeneously. To our knowledge, only one study has explored hyperoxia’s effect on regional CBF and there appeared to be a differential response between regions, but no between-region analysis was performed. If a differential response between regions can be identified, these regions could be monitored more closely for signs of dysfunction or dysregulation. We hypothesized that brain lobes and regions will exhibit a non-uniform reduction in CBF when given 100% oxygen (O2). Methods: Healthy, young adults (n= 15; 7 F; 22 ± 4 yr; BMI: 22 ± 2) were studied after an 8-hour fast and 24-hour abstinence from caffeine, exercise, or alcohol. Women were studied on days 1-5 of their menstrual cycle and not taking any hormonal contraception. Subjects completed a single magnetic resonance imaging (MRI, 3 Tesla) visit. Arterial spin labeling (ASL) MRI quantified microvascular CBF in six lobes and their 71 subregions during normoxia and again after ~10 min steady-state hyperoxia. Hyperoxia was achieved by breathing 100% O2 with supplemental carbon dioxide (CO2) to maintain end-tidal CO2 (ETCO2). The CAT12 toolbox extension for Statistical Parametric Mapping (SPM12) was used to process ASL data. CBF (mL/100g/min) was analyzed as absolute change (Δ), and relative change (%Δ). Two-factor and one-factor repeated measures ANOVA were performed to detect significant main effects and region-condition interactions. A Tukey test was used for post-hoc analysis and pairwise comparisons. Significance was set to P≤0.05. Results: Results are mean ± SD. Heart rate (HR) and ETCO2 remained similar from normoxia to hyperoxia, but mean arterial pressure (MAP) increased by 5 ± 6 mmHg ( P=0.013). Hyperoxia reduced CBF in all anatomical lobes (Occipital; Parietal; Frontal; Temporal; Brainstem/Cerebellum; Subcortical [ P≤0.001]), but the relative decrease was not different between lobes ( P=0.522; range= 18 ± 12% to 21 ± 9%). When examining CBF between 71 smaller brain regions, hyperoxia reduced blood flow in all regions ( P≤0.001; range= 15 ± 13% to 25 ± 13%); ANOVA indicated a region-specific effect ( P≤0.001), however post-hoc analysis did not identify which regions displayed different levels of hypoxic vasoconstriction. Conclusion: These are the first data to systematically examine the regional effects of hyperoxia on CBF. Contrary to our hypothesis, the microvascular CBF reduction to hyperoxia appears uniform across anatomical brain lobes. However, regional analysis indicated that there may be a differential microvascular vasoconstrictor response to hyperoxia between some functional regions of the brain. Funding: NIH R01 HL150361. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

480 Effect of Chronic DBS on Ventral Capsule Ventral Striatum-Specific Circadian Rhythm in Refractory Obsessive-Compulsive Disorder

INTRODUCTION: Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) improves symptoms in ∼66% of patients with treatment-resistant obsessive-compulsive disorder (OCD). However, a common adverse effect of VC/VS DBS is hypomania, marked by decreased need for sleep and increased risk-taking behaviors. Modern DBS devices have enabled 24-hour collection of neural data, allowing for tracking of circadian rhythms reflected by VC/VS local field potentials (LFPs). METHODS: We implanted six patients with treatment-resistant OCD with a DBS device configured for constant VC/VS stimulation and recording. Spectral power in the 9 ± 2.5 Hz band was estimated onboard the device every 10 minutes for a median of 249 days (range 77-608). We assessed the rhythmicity of power in this spectral band by fitting 7-day retrospective rolling windows of per-day normalized LFP power to cosine functions using least-squared regression. Output metrics included acrophase (time of peak activity), amplitude, and fit significance. We quantified trends in acrophase over time using Pearson correlation. RESULTS: All six patients demonstrated consistent 24-hour cyclic LFP activity bilaterally. Two of the six had diurnal peaks which shifted significantly earlier across the study period. The remaining four patients had nocturnal peaks, all shifting significantly later over time. Notably, a patient in the latter group experienced three days of hypomania after DBS initiation associated with circadian disruptions even after clinical symptom resolution. Only after clinical DBS adjustment 2 weeks later did circadian rhythm rapidly return to pre-hypomanic levels. CONCLUSIONS: Study patients demonstrated evolving circadian VC/VS LFP activity across the course of DBS therapy, usually independent of cyclic whole-brain activity (i.e. sleep). Conversely, disruptions to these circadian patterns, as observed here during hypomania, may serve as biomarkers of region-specific stimulation side effects.

Reflections on Labour Productivity of the Sri Lanka Transport Board: An Analysis of Patterns and Evolution

The predominant reliance on buses, particularly by low-income commuters, has made the bus transportation industry one of the most pivotal contributors to the domestic economy. Therefore, as the single largest public bus transportation service provider in Sri Lanka, SLTB’s ability to generate higher volumes of output by employing fewer inputs is increasingly crucial. However, SLTB is a state-owned enterprise that has been criticised for its inefficient factor productivity for a long time. Such allegations against the leading transport service provider of the country would raise serious economic concerns. Thus, this study attempted to examine SLTB’s labour productivity in its physical dimensions as reflected through the elasticity of output on labour inputs to determine the underlying causes for any inefficiency in the utilisation of labour in the organisation. The scale and evolution of elasticities of output of SLTB’s operations on labour inputs between 2011 and 2019 were subject to econometric scrutiny in this study. The results of the study revealed that the SLTB’s elasticity of output on labour inputs has been negative at the overall national level. However, a favourable evolution of the elasticity of output on labour could be observed over the years. The results also revealed the presence of significant differences in region-specific effects on the elasticity of output on labour inputs compared to the national level, indicating that different regions have different labour productivity levels.

Ammoniagenic Action of Valproate without Signs of Hepatic Dysfunction in Rats: Possible Causes and Supporting Evidence.

(1) Background: Valproic acid (VPA) is one of the frequently prescribed antiepileptic drugs and is generally considered well tolerated. However, VPA neurologic adverse effects in the absence of liver failure are fairly common, suggesting that in the mechanism for the development of VPA-induced encephalopathy, much more is involved than merely the exposure to hyperammonemia (HA) caused by liver insufficiency to perform detoxification. Taking into account the importance of the relationship between an impaired brain energy metabolism and elevated ammonia production, and based on the ability of VPA to interfere with neuronal oxidative pathways, the current study intended to investigate a potential regional ammoniagenic effect of VPA on rats' brains by determining activities of the enzymes responsible for ammonia production and neutralization. (2) Methods: Rats received a single intraperitoneal injection of VPA (50, 100, 250, 500 mg/kg). Plasma, the neocortex, the cerebellum, and the hippocampus were collected at 30 min after injection. The levels of ammonia, urea, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were measured in blood plasma. The activities of glutaminase and glutamate dehydrogenase (GDH) in mitochondria and the activities of AMP deaminase (AMPD), adenosine deaminase (ADA), and glutamine synthetase (GS) in cytosolic fractions isolated from rat brain regions were measured. Ammonia, ALT, and AST values were determined in the mitochondrial and cytosolic fractions. (3) Results: Multi-dose VPA treatment did not significantly affect the plasma levels of ammonia and urea or the ALT and AST liver enzymes. Significant dose-independent increases in the accumulation of ammonia were found only in the cytosol from the cerebellum and there was a strong correlation between the ammonia level and the ADA activity in this brain structure. A significant decrease in the AMPD and AST activities was observed, while the ALT activity was unaffected. Only the highest VPA dose (500 mg/kg) was associated with significantly less activity of GS compared to the control in all studied brain structures. In the mitochondria of all studied brain structures, VPA caused a dose-independent increases in ammonia levels, a high concentration of which was strongly and positively correlated with the increased GDH and ALT activity, while glutaminase activity remained unchanged, and AST activity significantly decreased compared to the control in all studied brain structures. (4) Conclusions: This study highlights the rat brain region-specific ammoniagenic effects of VPA, which may manifest themselves in the absence of hyperammonemia. Further research should analyze how the responsiveness of the different brain regions may vary in VPA-treated animals that exhibit compromised energy metabolism, leading to increased ammoniagenesis.

The herbal preparation, STW5-II, reduces proximal gastric tone and stimulates antral pressures in healthy humans.

The herbal preparation, STW5-II, improves upper gastrointestinal symptoms, including abdominal fullness, early satiation, and epigastric pain, in patients with functional dyspepsia, and in preclinical models decreases fundic tone and increases antral contractility. The effects of STW5-II on esophago-gastric junction pressure, proximal gastric tone and antropyloroduodenal pressures, disturbances of which may contribute to symptoms associated with disorders of gut-brain interaction, including functional dyspepsia, in humans, have, hitherto, not been evaluated. STW5-II or placebo (matched for color, aroma, and alcohol content) were each administered orally, at the recommended dose (20 drops), to healthy male and female volunteers (age: 27 ± 1 years) in a double-blind, randomized fashion, on two separate occasions, separated by 3-7 days, to evaluate effects on (i) esophago-gastric junction pressures following a standardized meal using solid-state high-resolution manometry (part 1, n = 16), (ii) proximal gastric volume using a barostat (part 2, n = 16), and (iii) antropyloroduodenal pressures assessed by high-resolution manometry (part 3, n = 18), for 120 min (part 1) or 180 min (parts 2, 3). STW5-II increased maximum intrabag volume (ml; STW5-II: 340 ± 38, placebo: 251 ± 30; p = 0.007) and intrabag volume between t = 120 and 180 min (p = 0.011), and the motility index of antral pressure waves between t = 60 and 120 min (p = 0.032), but had no effect on esophago-gastric junction, pyloric, or duodenal pressures. STW5-II has marked region-specific effects on gastric motility in humans, which may contribute to its therapeutic efficacy in functional dyspepsia.

Meta-modeling the effects of anodal left prefrontal transcranial direct current stimulation on working memory performance

Abstract Numerous studies have demonstrated the beneficial effects of anodal prefrontal transcranial direct current stimulation (tDCS) on working memory. However, a large variability exists in the applied tDCS parameters and working memory outcome measures. Using a meta-modeling approach, we investigated the relationship between tDCS electric fields in the left prefrontal cortex and improvements in working memory performance. Using this approach, a vector of outcome measures is correlated with the tDCS-related electric fields across several studies. These performance-electric field correlations (PEC) are calculated for each spatial location of the grey matter. Extracting 354 data points from 67 studies, we compared the spatial maps of tDCS effects on I) working memory accuracy and speed (regardless of working memory type and time of assessment), II) verbal and visuospatial working memory (regardless of performance measurement and time of assessment), and III) performance during and after stimulation (regardless of performance measurement and working memory type). We found that accuracy improves when anodal tDCS is applied to inferior frontal regions (Brodmann area 47) while working memory speed benefits from stimulation to dorsolateral and anterior prefrontal areas (Brodmann areas 9/10). Furthermore, the beneficial effects of left prefrontal tDCS are exclusive to verbal working memory, with no improvements in visuospatial working memory. We also observed region-specific effects only for task performance during, but not after, stimulation. The results of this study elucidate the causal involvement of prefrontal regions in working memory and can help guide tDCS placement for therapeutic application in disorders that involve working memory deficits.

Glucocorticoid receptor antagonist CORT113176 attenuates motor and neuropathological symptoms of Huntington's disease in R6/2 mice

Huntington's Disease (HD) is a progressive neurodegenerative disease caused by a mutation in the huntingtin gene. The mutation leads to a toxic gain of function of the mutant huntingtin (mHtt) protein resulting in cellular malfunction, aberrant huntingtin aggregation and eventually neuronal cell death. Patients with HD show impaired motor functions and cognitive decline. Elevated levels of glucocorticoids have been found in HD patients and in HD mouse models, and there is a positive correlation between increased glucocorticoid levels and the progression of HD. Therefore, antagonism of the glucocorticoid receptor (GR) may be an interesting strategy for the treatment of HD. In this study, we evaluated the efficacy of the selective GR antagonist CORT113176 in the commonly used R6/2 mouse model. In male mice, CORT113176 treatment significantly delayed the loss of grip strength, the development of hindlimb clasping, gait abnormalities, and the occurrence of epileptic seizures. CORT113176 treatment delayed loss of DARPP-32 immunoreactivity in the dorsolateral striatum. It also restored HD-related parameters including astrocyte markers in both the dorsolateral striatum and the hippocampus, and microglia markers in the hippocampus. This suggests that CORT113176 has both cell-type and brain region-specific effects. CORT113176 delayed the formation of mHtt aggregates in the striatum and the hippocampus. In female mice, we did not observe major effects of CORT113176 treatment on HD-related symptoms, with the exception of the anti-epileptic effects. We conclude that CORT113176 effectively delays several key symptoms related to the HD phenotype in male R6/2 mice and believe that GR antagonism may be a possible treatment option.

Protein arginine methyltransferase 1 is required for the maintenance of adult small intestinal and colonic epithelial cell homeostasis.

The vertebrate adult intestinal epithelium has a high self-renewal rate driven by intestinal stem cells (ISCs) in the crypts, which play central roles in maintaining intestinal integrity and homeostasis. However, the underlying mechanisms remain elusive. Here we showed that protein arginine methyltransferase 1 (PRMT1), a major arginine methyltransferase that can also function as a transcription co-activator, was highly expressed in the proliferating cells of adult mouse intestinal crypts. Intestinal epithelium-specific knockout of PRMT1, which ablates PRMT1 gene starting during embryogenesis, caused distinct, region-specific effects on small intestine and colon: increasing and decreasing the goblet cell number in the small intestinal and colonic crypts, respectively, leading to elongation of the crypts in small intestine but not colon, while increasing crypt cell proliferation in both regions. We further generated a tamoxifen-inducible intestinal epithelium-specific PRMT1 knockout mouse model and found that tamoxifen-induced knockout of PRMT1 in the adult mice resulted in the same region-specific intestinal phenotypes. Thus, our studies have for the first time revealed that the epigenetic enzyme PRMT1 has distinct, region-specific roles in the maintenance of intestinal epithelial architecture and homeostasis, although PRMT1 may influence intestinal development.