A high fat, sugar, and salt Western diet induces motor-muscular and sensory dysfunctions and neurodegeneration in mice during aging: Ameliorative action of metformin.

AIMS: To explore the novel linkage between a Western diet combining high saturated fat, sugar, and salt (HFSS) and neurological dysfunctions during aging as well as Metformin intervention, we assessed cerebral cortex abnormalities associated with sensory and motor dysfunctions and cellular and molecular insights in brains using HFSS-fed mice during aging. We also explored the effect of Metformin treatment on these mice. METHODS: C57BL/6 mice were fed with HFSS and treated with metformin from 20 to 22 months of age, resembling human aging from 56 to 68 years of age (an entry phase of the aged portion of lifespan). RESULTS: The motor and sensory cortexes in mice during aging after HFSS diet showed: (A) decreased motor-muscular and sensory functions; (B) reduced inflammation-resolving Arg-1+ microglia; (C) increased inflammatory iNOs+ microglia and TNFα levels; (D) enhanced abundance of amyloid-ß peptide and of phosphorylated Tau. Metformin attenuated these changes. CONCLUSION: A HFSS-combined diet caused motor-muscular and sensory dysfunctions, neuroinflammation, and neurodegeneration, whereas metformin counteracted these effects. Our findings show neuroinflammatory consequences of a HFSS diet in aging. Metformin curbs the HFSS-related neuroinflammation eliciting neuroprotection.

An Exercise Mimetic Approach to Reduce Poststroke Deconditioning and Enhance Stroke Recovery.

Evidence supports early rehabilitation after stroke to limit disability. However, stroke survivors are typically sedentary and experience significant cardiovascular and muscular deconditioning. Despite growing consensus that preclinical and clinical stroke recovery research should be aligned, there have been few attempts to incorporate cardiovascular and skeletal muscle deconditioning into animal models of stroke. Here, we demonstrate in rats that a hindlimb sensorimotor cortex stroke results in both cardiovascular and skeletal muscle deconditioning and impairments in gait akin to those observed in humans. To reduce poststroke behavioral, cardiovascular, and skeletal muscle perturbations, we then used a combinatorial intervention consisting of aerobic and resistance exercise in conjunction with administration of resveratrol (RESV), a drug with exercise mimetic properties. A combination of aerobic and resistance exercise mitigated decreases in cardiovascular fitness and attenuated skeletal muscle abnormalities. RESV, beginning 24 hours poststroke, reduced acute hindlimb impairments, improved recovery in hindlimb function, increased vascular density in the perilesional cortex, and attenuated skeletal muscle fiber changes. Early RESV treatment and aerobic and resistance exercise independently provided poststroke benefits, at a time when individuals are rapidly becoming deconditioned as a result of inactivity. Although no additive effects were observed in these experiments, this approach represents a promising strategy to reduce poststroke behavioral impairments and minimize deconditioning. As such, this treatment regime has potential for enabling patients to engage in more intensive rehabilitation at an earlier time following stroke when mechanisms of neuroplasticity are most prevalent.

Levodopa-Induced Dyskinesia in Parkinson Disease Specifically Associates With Dopaminergic Depletion in Sensorimotor-Related Functional Subregions of the Striatum.

PURPOSE: To determine whether the development of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) specifically relates to dopaminergic depletion in sensorimotor-related subregions of the striatum. METHODS: Our primary study sample consisted of 185 locally recruited PD patients, of which 73 (40%) developed LID. Retrospective 123I-FP-CIT SPECT data were used to quantify the specific dopamine transporter (DAT) binding ratio within distinct functionally defined striatal subregions related to limbic, executive, and sensorimotor systems. Regional DAT levels were contrasted between patients who developed LID (PD + LID) and those who did not (PD-LID) using analysis of covariance models controlled for demographic and clinical features. For validation of the findings and assessment of the evolution of LID-associated DAT changes from an early disease stage, we also studied serial 123I-FP-CIT SPECT data from 343 de novo PD patients enrolled in the Parkinson Progression Marker's Initiative using mixed linear model analysis. RESULTS: Compared with PD-LID, DAT level reductions in PD + LID patients were most pronounced in the sensorimotor striatal subregion (F = 5.99, P = 0.016) and also significant in the executive-related subregion (F = 5.30, P = 0.023). In the Parkinson Progression Marker's Initiative cohort, DAT levels in PD + LID (n = 161, 47%) were only significantly reduced compared with PD-LID in the sensorimotor striatal subregion (t = -2.05, P = 0.041), and this difference was already present at baseline and remained largely constant over time. CONCLUSION: Measuring DAT depletion in functionally defined sensorimotor-related striatal regions of interest may provide a more sensitive tool to detect LID-associated dopaminergic changes at an early disease stage and could improve individual prognosis of this common clinical complication in PD.

Higher-order sensorimotor circuit of the brain's global network supports human consciousness.

Consciousness is a mental characteristic of the human mind, whose exact neural features remain unclear. We aimed to identify the critical nodes within the brain's global functional network that support consciousness. To that end, we collected a large fMRI resting state dataset with subjects in at least one of the following three consciousness states: preserved (including the healthy awake state, and patients with a brain injury history (BI) that is fully conscious), reduced (including the N1-sleep state, and minimally conscious state), and lost (including the N3-sleep state, anesthesia, and unresponsive wakefulness state). We also included a unique dataset of subjects in rapid eye movement sleep state (REM-sleep) to test for the presence of consciousness with minimum movements and sensory input. To identify critical nodes, i.e., hubs, within the brain's global functional network, we used a graph-theoretical measure of degree centrality conjoined with ROI-based functional connectivity. Using these methods, we identified various higher-order sensory and motor regions including the supplementary motor area, bilateral supramarginal gyrus (part of inferior parietal lobule), supragenual/dorsal anterior cingulate cortex, and left middle temporal gyrus, that could be important hubs whose degree centrality was significantly reduced when consciousness was reduced or absent. Additionally, we identified a sensorimotor circuit, in which the functional connectivity among these regions was significantly correlated with levels of consciousness across the different groups, and remained present in the REM-sleep group. Taken together, we demonstrated that regions forming a higher-order sensorimotor integration circuit are involved in supporting consciousness within the brain's global functional network. That offers novel and more mechanism-guided treatment targets for disorders of consciousness.

Does paternal methamphetamine exposure affect the behavior of rat offspring during development and in adulthood?

Methamphetamine (MA) is one of the most abused psychostimulants in the Czech Republic and worldwide. Previous studies have demonstrated the adverse effects of maternal drug abuse. However, the father's contribution as a parent and donor of the half genetic information is unclear. The present study aimed to examine the effect of paternal MA exposure on behavioral development and locomotor activity in rat offspring. MA was administrated subcutaneously for 30 days at a dose of 5 mg/kg to adult male rats. The impact of paternal MA exposure on rat pups was investigated using behavioral tests during development and locomotor activity tests in adulthood. Prior to testing, adult offspring were exposed to an acute challenge dose of MA (1 mg/kg) to examine the possible sensitizing effect of the paternal treatment. Our results found no significant differences in behavioral development or locomotor activity in adulthood of offspring linked to paternal MA application. These results differ from the effects induced by maternal MA application. Further, our results demonstrated a significant increase in locomotor activity on the Laboras test after acute MA application. When comparing sex differences, females showed more activity than males in adulthood, whereas males were more active during development.

The effects of a spaceflight analog with elevated CO2 on sensorimotor adaptation.

Aboard the International Space Station (ISS), astronauts must adapt to altered vestibular and somatosensory inputs due to microgravity. Sensorimotor adaptation on Earth is often studied with a task that introduces visuomotor conflict. Retention of the adaptation process, known as savings, can be measured when subjects are exposed to the same adaptive task multiple times. It is unclear how adaptation demands found on the ISS might interfere with the ability to adapt to other sensory conflict at the same time. In the present study, we investigated the impact of 30 days' head-down tilt bed rest combined with elevated carbon dioxide (HDBR + CO2) as a spaceflight analog on sensorimotor adaptation. Eleven subjects used a joystick to move a cursor to targets presented on a computer screen under veridical cursor feedback and 45° rotated feedback. During this NASA campaign, five individuals presented with optic disk edema, a sign of spaceflight-associated neuro-ocular syndrome (SANS). Thus, we also performed post hoc exploratory analyses between subgroups who did and did not show signs of SANS. HDBR + CO2 had some impact on sensorimotor adaptation, with a lack of savings across the whole group. SANS individuals showed larger, more persistent after-effects, suggesting a shift from relying on cognitive to more implicit processing of adaptive behaviors. Overall, these findings suggest that HDBR + CO2 alters the way in which individuals engage in sensorimotor processing. These findings have important implications for missions and mission training, which require individuals to adapt to altered sensory inputs over long periods in space.NEW & NOTEWORTHY This is the first bed rest campaign examining sensorimotor adaptation and savings in response to the combined effect of HDBR + CO2 and to observe signs of spaceflight-associated neuro-ocular syndrome (SANS) in HDBR participants. Our findings suggest that HDBR + CO2 alters the way that individuals engage in sensorimotor processing. Individuals who developed signs of SANS seem to rely more on implicit rather than cognitive processing of adaptive behaviors than subjects who did not present signs of SANS.

Bexarotene normalizes chemotherapy-induced myelin decompaction and reverses cognitive and sensorimotor deficits in mice.

Frequently reported neurotoxic sequelae of cancer treatment include cognitive deficits and sensorimotor abnormalities that have long-lasting negative effects on the quality of life of an increasing number of cancer survivors. The underlying mechanisms are not fully understood and there is no effective treatment. We show here that cisplatin treatment of mice not only caused cognitive dysfunction but also impaired sensorimotor function. These functional deficits are associated with reduced myelin density and complexity in the cingulate and sensorimotor cortex. At the ultrastructural level, myelin abnormalities were characterized by decompaction. We used this model to examine the effect of bexarotene, an agonist of the RXR-family of nuclear receptors. Administration of only five daily doses of bexarotene after completion of cisplatin treatment was sufficient to normalize myelin density and fiber coherency and to restore myelin compaction in cingulate and sensorimotor cortex. Functionally, bexarotene normalized performance of cisplatin-treated mice in tests for cognitive and sensorimotor function. RNAseq analysis identified the TR/RXR pathway as one of the top canonical pathways activated by administration of bexarotene to cisplatin-treated mice. Bexarotene also activated neuregulin and netrin pathways that are implicated in myelin formation/maintenance, synaptic function and axonal guidance. In conclusion, short term treatment with bexarotene is sufficient to reverse the adverse effects of cisplatin on white matter structure, cognitive function, and sensorimotor performance. These encouraging findings warrant further studies into potential clinical translation and the underlying mechanisms of bexarotene for chemobrain.

Changes in Neuronal Density of the Sensorimotor Cortex and Neurodevelopmental Behaviour in Neonatal Mice with Kaolin-Induced Hydrocephalus.

INTRODUCTION: Hydrocephalus is a disorder in which the circulation of cerebrospinal fluid is altered in a manner that leads to its accumulation in the ventricles and subarachnoid space. Its impact on the neuronal density and networks in the overlying cerebral cortex in a time-dependent neonatal hydrocephalic process is largely unknown. We hypothesize that hydrocephalus will affect the cytoarchitecture of the cerebral cortical mantle of neonatal hydrocephalic mice, which will in turn modify sensorimotor processing and neurobehaviour. OBJECTIVE: The purpose of this study is to probe the effect of hydrocephalus on 3 developmental milestones (surface righting reflex, cliff avoidance reflex, and negative geotaxis) and on cortical neuronal densities in neonatal hydrocephalic mice. METHODS: Hydrocephalus was induced in 1-day-old mice by intracisternal injection of sterile kaolin suspension. The pups were tested for reflex development and sensorimotor ability using surface righting reflex (PND 5, 7, and 9), cliff avoidance (PND 6), and negative geotaxis (PND 10 and 12) prior to their sacrifice on PND 7, 14, and 21. Neuronal density and cortical thickness in the sensorimotor cortex were evaluated using atlas-based segmentation of the neocortex and boundary definition in 4-µm paraffin-embedded histological sections with hematoxylin and eosin as well as cresyl violet stains. RESULTS: Surface righting and cliff avoidance activities were significantly impaired in hydrocephalic pups but no statistically significant difference was observed in negative geotaxis in both experimental and control pups. The neuronal density of the sensorimotor cortex was significantly higher in hydrocephalic mice than in age-matched controls on PND 14 and 21 (373.20 ± 21.54 × 10-6 µm2 vs. 157.70 ± 21.88 × 10-6 µm2; 230.0 ± 44.1 × 10-6 µm2 vs. 129.60 ± 3.72 × 10-6 µm2, respectively; p < 0.05). This was accompanied by reduction in the cortical thickness (µm) in the hydrocephalic mice on PND 7 (2,409 ± 43.37 vs. 3,752 ± 65.74, p < 0.05), PND 14 (2,035 ± 322.10 vs. 4,273 ± 67.26, p < 0.05), and PND 21 (1,676 ± 33.90 vs. 4,945 ± 81.79, p < 0.05) compared to controls. CONCLUSION: In this murine model of neonatal hydrocephalus, the quantitative changes in the cortical neuronal population may play a role in the observed changes in neurobehavioural findings.

Prolonged prophylactic effects of gabapentin on status epilepticus-induced neocortical injury.

Long-term consequences of status epilepticus (SE) occur in a significant proportion of those who survive the acute episode. We developed an in vivo model of acute focal neocortical SE (FSE) to study long-term effects on local cortical structure and function and potential strategies to mitigate adverse consequences of SE. An acute 2 h episode of FSE was induced in anesthetized mice by epidural application of gabazine +4-aminopyridine over sensorimotor neocortex. Ten and 30 days later, the morphological and functional consequences of this single episode of FSE were studied using immunocytochemical and electrophysiological techniques. Results, focused on cortical layer V, showed astrogliosis, microgliosis, decreased neuronal density, and increased excitatory synapses, along with increased immunoreactivity for thrombospondin 2 (TSP2) and α2δ-1 proteins. In addition, neocortical slices, obtained from the area of prior focal seizure activity, showed abnormal epileptiform burst discharges along with increases in the frequency of miniature and spontaneous excitatory postsynaptic currents in layer V pyramidal cells, together with decreases in both parvalbumin immunoreactivity (PV-IR) and the frequency of miniature inhibitory postsynaptic currents in layer V pyramidal cells. Treatment with an approved drug, gabapentin (GBP) (ip 100 mg/kg/day 3×/day for 7 days following the FSE episode), prevented the gliosis, the enhanced TSP2- and α2δ-1- IR and the increased excitatory synaptic density in the affected neocortex. This model provides an approach for assessing adverse effects of FSE on neocortical structure and function and potential prophylactic treatments.

DPP-4 inhibitor reduces striatal microglial deramification after sensorimotor cortex injury induced by external force impact.

Dipeptidyl peptidase-4 inhibitors (or gliptins), a class of antidiabetic drugs, have recently been shown to have protective actions in the central nervous system. Their cellular and molecular mechanisms responsible for these effects are largely unknown. In the present study, two structurally different gliptins, sitagliptin and vildagliptin, were examined for their therapeutic actions in a controlled cortical impact (CCI) model of moderate traumatic brain injury (TBI) in mice. Early post-CCI treatment with sitagliptin, but not vildagliptin, significantly reduced body asymmetry, locomotor hyperactivity, and brain lesion volume. Sitagliptin attenuated post-CCI microglial deramification in the ipsilateral dorsolateral (DL) striatum, while vildagliptin had no effect. Sitagliptin also reduced striatal expression of galectin-3 and monocyte chemoattractant protein 1(MCP-1), and increased the cortical and striatal levels of the anti-inflammatory cytokine IL-10 on the ipsilateral side. These data support a differential protective effect of sitagliptin against TBI, possibly mediated by an anti-inflammatory effect in striatum to preserve connective network. Both sitagliptin and vildagliptin produced similar increases of active glucagon-like peptide-1 (GLP-1) in blood and brain. Increasing active GLP-1 may not be the sole molecular mechanisms for the neurotherapeutic effect of sitagliptin in TBI.

Behavioral Flexibility in Alcohol-Drinking Monkeys: The Morning After.

BACKGROUND: Heavy alcohol drinking has aspects of inflexible behavior. This study addressed the consequences of chronic alcohol drinking on cognitive and sensory-motor domains of behavioral flexibility in rhesus monkeys. METHODS: Behavioral flexibility was assessed in 12 monkeys (n = 9, ethanol [EtOH] drinkers) with a set-shifting visual discrimination procedure before alcohol self-administration and while maintaining consumption of 1.5 g/kg/d EtOH. Task performance was assessed in the morning after ~18 hours of drinking 1.5 g/kg, and 1 hour before the next day's drinking session began. The first 10 set-shifting sessions had the original (preethanol) test parameters and were used to determine retention of preethanol performance. Then, an effect of sensory-motor challenge (60% reduction in the size of the discriminative stimuli) on performance was assessed during 10 additional sessions. RESULTS: There were no average group-dependent differences in the performance between control and EtOH groups at the preethanol time-point. The daily consumption of 1.5 g/kg/d produced binge alcohol intakes in 7 of 9 monkeys (blood EtOH concentration [BEC ≥ 80 mg/dl]). Chronic daily intakes of 1.5 g/kg had no effect on retention of the task in the sober state. However, when challenged with a reduction in the size of the stimuli, daily 1.5 g/kg EtOH resulted in a decrement in performance due to an increase in the number of errors. CONCLUSIONS: Rhesus monkeys consuming 1.5 g/kg alcohol daily perform equally as could as control monkeys in retention of a well-learned cognitive task. However, this pattern of daily alcohol intake robustly decreased the ability to flexibly adjust behavior when confronted with novel changes to perceptual stimuli.

Electrophysiological resting state networks of predominantly akinetic-rigid Parkinson patients: Effects of dopamine therapy.

Parkinson's disease (PD) causes both motor and non-motor symptoms, which can partially be reversed by dopamine therapy. These symptoms as well as the effect of dopamine may be explained by distinct alterations in whole-brain architecture. We used functional connectivity (FC) and in particular resting state network (RSN) analysis to identify such whole-brain alterations in a frequency-specific manner. In addition, we hypothesized that standard dopaminergic medication would have a normalizing effect on these whole brain alterations. We recorded resting-state EEGs of 19 PD patients in the medical OFF and ON states, and of 12 healthy age-matched controls. The PD patients were either of akinetic-rigid or mixed subtype. We extracted RSNs with independent component analysis in the source space for five frequency bands. Within the sensorimotor network (SMN) the supplementary motor area (SMA) showed decreased FC in the OFF state compared to healthy controls. This finding was reversed after dopamine administration. Furthermore, in the OFF state no stable SMN beta component could be identified. The default mode network showed alterations due to PD independent of the medication state. The visual network was altered in the OFF state, and reinstated to a pattern similar to healthy controls by medication. In conclusion, PD causes distinct RSN alterations, which are partly reversed after levodopa administration. The changes within the SMN are of particular interest, because they broaden the pathophysiological understanding of PD. Our results identify the SMA as a central network hub affected in PD and a crucial effector of dopamine therapy.

Endocannabinoid degradation inhibitors ameliorate neuronal and synaptic alterations following traumatic brain injury.

Our previous work showed that lateral fluid percussion injury to the sensorimotor cortex (SMC) of anesthetized rats increased neuronal synaptic hyperexcitability in layer 5 (L5) neurons in ex vivo brain slices 10 days postinjury. Furthermore, endocannabinoid (EC) degradation inhibition via intraperitoneal JZL184 injection 30 min postinjury attenuated synaptic hyperexcitability. This study tested the hypothesis that traumatic brain injury (TBI) induces synaptic and intrinsic neuronal alterations of L5 SMC pyramidal neurons and that these alterations are significantly attenuated by in vivo post-TBI treatment with EC degradation inhibitors. We tested the effects of systemically administered EC degradation enzyme inhibitors (JZL184, MJN110, URB597, or JZL195) with differential selectivity for fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on electrophysiological parameters in SMC neurons of TBI- and sham-treated rats 10 days post-TBI. We recorded intrinsic neuronal properties, including resting membrane voltage, input resistance, spike threshold, spiking responses to current input, voltage "sag" (rebound response to hyperpolarization-activated inward current), and burst firing. We also measured the frequency and amplitude of spontaneous excitatory postsynaptic currents. We then used the aggregate parameter sets (intrinsic + synaptic properties) to apply a machine learning classification algorithm to quantitatively compare neural population responses from each experimental group. Collectively, our electrophysiological and computational results indicate that sham neurons are the most distinguishable from TBI neurons. Administration of EC degradation inhibitors post-TBI exerted varying degrees of rescue, approximating the neuronal phenotype of sham neurons, with neurons from TBI/JZL195 (a dual MAGL/FAAH inhibitor) being most similar to neurons from sham rats.NEW & NOTEWORTHY This study elucidates neuronal properties altered by traumatic brain injury (TBI) in layer 5 of sensorimotor cortex, which may be implicated in post-TBI circuit dysfunction. We compared effects of systemic administration of four different endocannabinoid degradation inhibitors within a clinically relevant window postinjury. Electrophysiological measures and using a machine learning classification algorithm collectively suggest that pharmacological inhibitors targeting both monoacylglycerol lipase and fatty acid amide hydrolase (e.g., JZL195) may be most efficacious in attenuating TBI-induced neuronal dysfunction at site of injury.

Effect of tadalafil and nitric oxide agonist sodium nitroprusside on penicillin-induced epileptiform activity.

Objective: Comorbidity of erectile dysfunction (ED) and epilepsy is not rare. Tadalafil is widely used in the treatment of ED and shows its effect by increasing nitric oxide (NO) level. Previous studies demonstrated that ED treatment drugs increased epileptiform activity in clinical studies and various experimental epilepsy models. Therefore, it is important to know whether an ED treatment drug has proconvulsion or anticonvulsant properties. This study was designed to demonstrate the effect of tadalafil and NO agonist sodium nitroprusside during penicillin-induced seizures in rats. The experimental penicillin epilepsy model is preferred in clinical studies of partial epilepsy.Methods: A single dose of penicillin (500 units) intracortical (i.c.) injection into the left sensorimotor cortex induced epileptiform activity. In the first set of experiments, tadalafil (20 mg/kg/intraperitoneal [i.p.]) and sodium nitroprusside (50 µg/intracerebroventricular [µg/i.c.v]) were administered 30 min after penicillin injection.In the second set of experiments, tadalafil (i.p) was administered 30 min after penicillin injection and sodium nitroprusside was administered simultaneously with the tadalafil injection.Results: Tadalafil, sodium nitroprusside and tadalafil+sodium nitroprusside groups decreased the frequency and amplitude of epileptiform activity in rats. Spike frequency of all groups decreased significantly 10 min after the administration and this decrease continued for 180 min. The mean amplitude of epileptiform activity significantly decreased 120 min after penicillin application in tadalafil or sodium nitroprusside applications. But this decrease was observed 110 min after tadalafil+sodium nitroprusside combined application.Conclusion: Data from the present study indicate that tadalafil has an anticonvulsion effect against penicillin-induced epileptiform activity in rats.

Intranasal oxytocin enhances EEG mu rhythm desynchronization during execution and observation of social action: An exploratory study.

Intranasal administration of oxytocin (OT) has been found to facilitate prosocial behaviors, emotion recognition and cooperation between individuals. Recent electroencephalography (EEG) investigations have reported enhanced mu rhythm (alpha: 8-13 Hz; beta: 15-25 Hz) desynchronization during the observation of biological motion and stimuli probing social synchrony after the administration of intranasal OT. This hormone may therefore target a network of cortical circuits involved in higher cognitive functions, including the mirror neuron system (MNS). Here, in a double-blind, placebo-controlled, between-subjects exploratory study, we investigated whether intranasal OT modulates the cortical activity from sensorimotor areas during the observation and the execution of social and non-social grasping actions. Participants underwent EEG testing after receiving a single dose (24 IU) of either intranasal OT or placebo. Results revealed an enhancement of alpha - but not beta - desynchronization during observation and execution of social grasps, especially over central and parietal electrodes, in participants who received OT (OT group). No differences between the social and non-social condition were found in the control group (CTRL group). Moreover, we found a significant difference over the cortical central-parietal region between the OT and CTRL group only within the social condition. These results suggest a possible action of intranasal OT on sensorimotor circuits involved in social perception and action understanding, which might contribute to facilitate the prosocial effects typically reported by behavioral studies.

JNK-IN-8, a c-Jun N-terminal kinase inhibitor, improves functional recovery through suppressing neuroinflammation in ischemic stroke.

C-Jun N-terminal kinase (JNK) is a pivotal MAPK (mitogen-activated protein kinase), which activated by ischemia brain injury and plays a fairly crucial function in cerebral ischemic injury. Emerging studies demonstrated that JNK-IN-8 (a JNK inhibitor with high specificity) regulates traumatic brain injury through controlling neuronal apoptosis and inflammation. However, the function of JNK-IN-8 in ischemic stroke and the mechanisms underlying of JNK-IN-8 about neuroprotection are not well understood. In this work, male rats were treated with JNK-IN-8 after transient middle cerebral artery occlusion, and then the modified improved neurological function score (mNSS), the foot-fault test (FFT), interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α) levels were assessed. We found that JNK-IN-8-treated rats with MCAO exerted an observable melioration in space learning as tested by the improved mNSS, and showed sensorimotor functional recovery as measured by the FFT. JNK-IN-8 also played anti-inflammatory roles as indicated through decreased activation of microglia and decreased IL-6, IL-1ß, and TNF-α expression. Furthermore, JNK-IN-8 suppressed the activation of JNK and nuclear factor-κB (NF-κB) signaling as indicated by the decreased level of phosphorylated-JNK and p65. All data demonstrate that JNK-IN-8 inhibits neuroinflammation and improved neurological function by inhibiting JNK/NF-κB and is a promising agent for the prevention of ischemic brain injury.

Putative Trace-Amine Associated Receptor 5 (TAAR5) Agonist α-NETA Increases Electrocorticogram Gamma-Rhythm in Freely Moving Rats.

Cortical gamma rhythm is involved in transmission of information (communication) between brain areas that are believed to be involved in the pathogenesis of cognitive dysfunctions. Trace amines represent a group of endogenous biogenic amines that are known to be involved in modulation of function of classical monoamines, such as dopamine. To evaluate potential modulatory influence of a specific receptor for trace amines Trace Amine-Associated Receptor 5 (TAAR5) on the dopamine system, we used HPLC measurements of dopamine and its metabolites in the mouse striatum following administration of the putative TAAR5 agonist α-NETA. Administration of α-NETA caused significant modulation of dopaminergic system as evidenced by an altered dopamine turnover rate in the striatum. Then, to evaluate potential modulatory influence of TAAR5 on the rat brain gamma rhythm, we investigated the changes of electrocorticogram (ECoG) spectral power in the gamma-frequency range (40-50 Hz) following administration of the putative TAAR5 agonist α-NETA. In addition, we analyzed the changes of spatial synchronization of gamma oscillations of rat ECoG by multichannel recording. Significant complex changes were observed in the ECoG spectrum, including an increase in the spectral power in the ranges of delta (1 Hz), theta (7 Hz), and gamma rhythms (40-50 Hz) after the introduction of α-NETA. Furthermore, a decrease in the spatial synchronization of gamma oscillations of 40-50 Hz and its increase for theta oscillations of 7 Hz were detected after the introduction of α-NETA. In conclusion, putative TAAR5 agonist α-NETA can modulate striatal dopamine transmission and cause significant alterations of gamma rhythm of brain activity in a manner consistent with schizophrenia-related deficits described in humans and experimental animals. These observations suggest a role of TAAR5 in the modulation of cognitive functions affected in brain pathologies.

Subchronic use of rivastigmine increases procognitive flexibility across multimodal behavioral tasks in healthy male rats.

Rivastigmine (RVT) is a reversible inhibitor of cholinesterase approved worldwide for the treatment of cognitive dysfunctions, especially in Alzheimer's disease. Most previous pre-clinical studies have examined the effects of RVT treatment in a wide variety of pathological research models. Nonetheless, the effects of this drug on sensorimotor gating, memory, and learning tasks in healthy subjects remains unclear. In this study, we investigate the procognitive effects of RVT treatment in healthy rats through sensorimotor gating evaluations (measured as prepulse inhibition of the acoustic startle reflex), active avoidance learning, and spatial memory learning in a radial maze. There is an increase in the amplitude of the startle reflex in RVT-treated rats compared to the control groups, whereas the latency remained constant. Sensorimotor gating values were also incremented compared to those values from controls. In active avoidance, rats treated with RVT learned faster to successfully perform the task compared to controls, but afterwards all groups exhibited virtually identical results. During the sessions in the radial maze, RVT-treated rats committed fewer errors in both the working and reference memory compared to controls. All in all, our results support the hypothesis that RVT treatment may entail procognitive effects in healthy subjects.

Low-dose perampanel improves refractory cortical myoclonus by the dispersed and suppressed paroxysmal depolarization shifts in the sensorimotor cortex.

OBJECTIVE: To elucidate the effects of perampanel (PER) on refractory cortical myoclonus for dose, etiology and somatosensory-evoked potential (SEP) findings. METHODS: We examined 18 epilepsy patients with seizure and cortical myoclonus. Based on data accumulated before and after PER treatment, correlations among clinical scores in myoclonus and activities of daily life (ADL); early cortical components of SEP; and PER blood concentration, were analyzed. RESULTS: PER (mean dose: 3.2 ±â€¯2.1 mg/day) significantly improved seizures, myoclonus and ADL and significantly decreased the amplitude of and prolonged latency of giant SEP components. The degree of P25 and N33 prolongations (23.8 ±â€¯1.6 to 24.7 ±â€¯1.7 ms and 32.1 ±â€¯4.0 to 33.7 ±â€¯3.4 ms) were significantly correlated with improved ADL score (p = 0.019 and p = 0.025) and blood PER concentration (p = 0.011 and p = 0.025), respectively. CONCLUSIONS: Low-dose PER markedly improved myoclonus and ADL in patients with refractory cortical myoclonus. Our results suggest that SEP, particularly P25 latency, can be used as a potential biomarker for assessing the objective effects of PER on intractable cortical myoclonus. SIGNIFICANCE: In this study, PER lessened the degree of synchronized discharges in the postsynaptic neurons in the primary motor cortex.

Delta-9-THC exposure during zebra finch sensorimotor vocal learning increases cocaine reinforcement in adulthood.

Zebra finches are songbirds that learn vocal patterns during a sensitive period of development that approximates adolescence. Exposure of these animals to a cannabinoid agonist during their period of sensorimotor vocal learning alters song patterns produced in adulthood. Thus, songbirds have unique value in studying developmental effects of drug exposure on a naturally learned behavior. A missing feature of this animal model has been a method to study drug reinforcement of behavior. To address this gap we have adapted place conditioning methods, used previously to determine that singing behavior is rewarding, to study cocaine reinforcement of behavior. We have found that cocaine dose-dependently reinforces both place conditioning and aversion at potencies consistent with those observed in mammalian species. Use of this place conditioning method has allowed us to determine that, when administered during periods of sensorimotor vocal learning, delta-9-THC, but not nicotine persistently increases sensitivity to cocaine through adulthood. Establishment of this method significantly expands the songbird drug exposure model, and holds promise for better appreciation of mechanisms important to sensorimotor learning that is dependent upon successful progress through sensitive periods of CNS development.