Dopamine D2 Receptor Modulates Exercise Related Effect on Cortical Excitation/Inhibition and Motor Skill Acquisition.

Exercise is known to benefit motor skill learning in health and neurological disease. Evidence from brain stimulation, genotyping, and Parkinson's disease studies converge to suggest that the dopamine D2 receptor, and shifts in the cortical excitation and inhibition (E:I) balance, are prime candidates for the drivers of exercise-enhanced motor learning. However, causal evidence using experimental pharmacological challenge is lacking. We hypothesized that the modulatory effect of the dopamine D2 receptor on exercise-induced changes in the E:I balance would determine the magnitude of motor skill acquisition. To test this, we measured exercise-induced changes in excitation and inhibition using paired-pulse transcranial magnetic stimulation (TMS) in 22 healthy female and male humans, and then had participants learn a novel motor skill-the sequential visual isometric pinch task (SVIPT). We examined the effect of D2 receptor blockade (800 mg sulpiride) on these measures within a randomized, double-blind, placebo-controlled design. Our key result was that motor skill acquisition was driven by an interaction between the D2 receptor and E:I balance. Specifically, poorer skill learning was related to an attenuated shift in the E:I balance in the sulpiride condition, whereas this interaction was not evident in placebo. Our results demonstrate that exercise-primed motor skill acquisition is causally influenced by D2 receptor activity on motor cortical circuits.

Cortico-cortical connectivity is influenced by levodopa in tremor-dominant Parkinson's disease.

Resting tremor is the most common presenting motor symptom in Parkinson's disease (PD). The supplementary motor area (SMA) is a main target of the basal-ganglia-thalamo-cortical circuit and has direct, facilitatory connections with the primary motor cortex (M1), which is important for the execution of voluntary movement. Dopamine potentially modulates SMA and M1 activity, and both regions have been implicated in resting tremor. This study investigated SMA-M1 connectivity in individuals with PD ON and OFF dopamine medication, and whether SMA-M1 connectivity is implicated in resting tremor. Dual-site transcranial magnetic stimulation was used to measure SMA-M1 connectivity in PD participants ON and OFF levodopa. Resting tremor was measured using electromyography and accelerometry. Stimulating SMA inhibited M1 excitability OFF levodopa, and facilitated M1 excitability ON levodopa. ON medication, SMA-M1 facilitation was significantly associated with smaller tremor than SMA-M1 inhibition. The current findings contribute to our understanding of the neural networks involved in PD which are altered by levodopa medication and provide a neurophysiological basis for the development of interventions to treat resting tremor.

Effects of Catecholaminergic and Transcranial Direct Current Stimulation on Response Inhibition.

BACKGROUND: The principle of gain control determines the efficiency of neuronal processing and can be enhanced with pharmacological or brain stimulation methods. It is a key factor for cognitive control, but the degree of how much gain control may be enhanced underlies a physical limit. METHODS: To investigate whether methylphenidate (MPH) and transcranial direct current stimulation (tDCS) share common underlying mechanisms and cognitive effects, we administered MPH and anodal tDCS (atDCS) over the right inferior frontal gyrus both separately and combined, while healthy adult participants (n = 104) performed a response selection and inhibition task. The recorded EEG data were analyzed with a focus on theta band activity, and source estimation analyses were conducted. RESULTS: The behavioral data show that MPH and atDCS revealed interactive effects on the ability to inhibit responses. Both MPH and atDCS modulated task-related theta oscillations in the supplementary motor area when applied separately, making a common underlying mechanism likely. When both stimulation methods were combined, there was no doubling of effects in the supplementary motor area but a shift to inferior frontal areas in the cortical network responsible for theta-driven processing. CONCLUSIONS: The results indicate that both MPH and atDCS likely share a common underlying neuronal mechanism, and interestingly, they demonstrate interactive effects when combined, which are most likely due to the physical limitations of gain control increases. The current study provides critical groundwork for future combined applications of MPH and non-invasive brain stimulation.

Cobalt protoporphyrin modulates antioxidant enzyme activity in the hypothalamus and motor cortex of female rats.

Cobalt protoporphyrin (CoPP) is a synthetic heme analog that has been observed to reduce food intake and promote sustained weight loss. While the precise mechanisms responsible for these effects remain elusive, earlier research has hinted at the potential involvement of nitric oxide synthase in the hypothalamus. This study aimed to delve into CoPP's impact on the activities of crucial antioxidant enzymes: superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST) across seven distinct brain regions (hippocampus, hypothalamus, prefrontal cortex, motor cortex, striatum, midbrain, and cerebellum), as well as in the liver and kidneys. Female Wistar rats weighing 180 to 200 grams received a single subcutaneous dose of 25 µmol/kg CoPP. After six days, brain tissue was extracted to assess the activities of antioxidant enzymes and quantify malondialdehyde levels. Our findings confirm that CoPP administration triggers the characteristic effects of decreased food intake and reduced body weight. Moreover, it led to an increase in SOD activity in the hypothalamus, a pivotal brain region associated with food intake regulation. Notably, CoPP-treated rats exhibited elevated enzymatic activity of catalase, GR, and GST in the motor cortex without concurrent signs of heightened oxidative stress. These results underscore a strong connection between the antioxidant system and food intake regulation. They also emphasize the need for further investigation into the roles of antioxidant enzymes in modulating food intake and the ensuing weight loss, using CoPP as a valuable research tool.

Interhemispheric differences of pyramidal cells in the primary motor cortices of schizophrenia patients investigated postmortem.

Motor disturbances are observed in schizophrenia patients, but the neuroanatomical background is unknown. Our aim was to investigate the pyramidal cells of the primary motor cortex (BA 4) in both hemispheres of postmortem control and schizophrenia subjects-8 subjects in each group-with 2.5-5.5 h postmortem interval. The density and size of the Sternberger monoclonal incorporated antibody 32 (SMI32)-immunostained pyramidal cells in layer 3 and 5 showed no change; however, the proportion of larger pyramidal cells is decreased in layer 5. Giant pyramidal neurons (Betz cells) were investigated distinctively with SMI32- and parvalbumin (PV) immunostainings. In the right hemisphere of schizophrenia subjects, the density of Betz cells was decreased and their PV-immunopositive perisomatic input showed impairment. Part of the Betz cells contained PV in both groups, but the proportion of PV-positive cells has declined with age. The rat model of antipsychotic treatment with haloperidol and olanzapine showed no differences in size and density of SMI32-immunopositive pyramidal cells. Our results suggest that motor impairment of schizophrenia patients may have a morphological basis involving the Betz cells in the right hemisphere. These alterations can have neurodevelopmental and neurodegenerative explanations, but antipsychotic treatment does not explain them.

Recovery of motor function is associated with rescue of glutamate biomarkers in the striatum and motor cortex following treatment with Mucuna pruriens in a murine model of Parkinsons disease.

There is growing interest in the use of natural products for the treatment of Parkinson's disease (PD). Mucuna pruriens has been used in the treatment of humans with PD. The goal of this study was to determine if daily oral treatment with an extract of Mucuna pruriens, starting after the MPTP-induced loss of nigrostriatal dopamine in male mice, would result in recovery/restoration of motor function, tyrosine hydroxylase (TH) protein expression in the nigrostriatal pathway, or glutamate biomarkers in both the striatum and motor cortex. Following MPTP administration, resulting in an 80 % loss of striatal TH, treatment with Mucuna pruriens failed to rescue either striatal TH or the dopamine transporter back to the control levels, but there was restoration of gait/motor function. There was an MPTP-induced loss of TH-labeled neurons in the substantia nigra pars compacta and in the number of striatal dendritic spines, both of which failed to be recovered following treatment with Mucuna pruriens. This Mucuna pruriens-induced locomotor recovery following MPTP was associated with restoration of two striatal glutamate transporter proteins, GLAST (EAAT1) and EAAC1 (EAAT3), and the vesicular glutamate transporter 2 (Vglut2) within the motor cortex. Post-MPTP treatment with Mucuna pruriens, results in locomotor improvement that is associated with recovery of striatal and motor cortex glutamate transporters but is independent of nigrostriatal TH restoration.

Inhibition of VEGFR-2 by SU5416 increases neonatally glutamate-induced neuronal damage in the cerebral motor cortex and hippocampus.

Vascular endothelial growth factor (VEGF) exerts neuroprotective or proinflammatory effects, depending on what VEGF forms (A-E), receptor types (VEGFR1-3), and intracellular signaling pathways are involved. Neonatal monosodium glutamate (MSG) treatment triggers neuronal death by excitotoxicity, which is commonly involved in different neurological disorders, including neurodegenerative diseases. This study was designed to evaluate the effects of VEGFR-2 inhibition on neuronal damage triggered by excitotoxicity in the cerebral motor cortex (CMC) and hippocampus (Hp) after neonatal MSG treatment. MSG was administered at a dose of 4 g/kg of body weight (b.w.) subcutaneously on postnatal days (PD) 1, 3, 5, and 7, whereas the VEGFR-2 inhibitor SU5416 was administered at a dose of 10 mg/kg b.w. subcutaneously on PD 5 and 7, 30 min before the MSG treatment. Neuronal damage was assessed using hematoxylin and eosin staining, fluoro-Jade staining, and TUNEL assay. Additionally, western blot assays for some proteins of the VEGF-A/VEGFR-2 signaling pathway (VEGF-A, VEGFR-2, PI3K, Akt, and iNOS) were carried out. All assays were performed on PD 6, 8, 10, and 14. Inhibition of VEGFR-2 signaling by SU5416 increases the neuronal damage induced by neonatal MSG treatment in both the CMC and Hp. Moreover, neonatal MSG treatment increased the expression levels of the studied VEGF-A/VEGFR-2 signaling pathway proteins, particularly in the CMC. We conclude that VEGF-A/VEGFR-2 signaling pathway activation could be part of the neuroprotective mechanisms that attempt to compensate for neuronal damage induced by neonatal MSG treatment and possibly also in other conditions involving excitotoxicity.

Mechanism of Intermittent Theta-Burst Stimulation in Synaptic Pathology in the Prefrontal Cortex in an Antidepressant-Resistant Depression Rat Model.

Intermittent theta-burst stimulation (iTBS), a form of repetitive transcranial magnetic stimulation, is considered a potential therapy for treatment-resistant depression. The synaptic mechanism of iTBS has long been known to be an effective method to induce long-term potentiation (LTP)-like plasticity in humans. However, there is limited evidence as to whether the antidepressant effect of iTBS is associated with change in synaptic function in the prefrontal cortex (PFC) in preclinical study. Hence, we applied an antidepressant (i.e., fluoxetine)-resistant depression rat model induced by severe foot-shocks to investigate the antidepressant efficacy of iTBS in the synaptic pathology. The results showed that iTBS treatment improved not only the impaired LTP, but also the aberrant long-term depression in the PFC of antidepressant-resistant depression model rats. Moreover, the mechanism of LTP improvement by iTBS involved downstream molecules of brain-derived neurotrophic factor, while the mechanism of long-term depression improvement by iTBS involved downstream molecules of proBDNF. The aberrant spine morphology was also improved by iTBS treatment. This study demonstrated that the mechanism of the iTBS paradigm is complex and may regulate not only excitatory but also inhibitory synaptic effects in the PFC.

Cortical Control of Subthalamic Neuronal Activity through the Hyperdirect and Indirect Pathways in Monkeys.

The subthalamic nucleus (STN) plays a key role in the control of voluntary movements and basal ganglia disorders, such as Parkinson's disease and hemiballismus. The STN receives glutamatergic inputs directly from the cerebral cortex via the cortico-STN hyperdirect pathway and GABAergic inputs from the external segment of the globus pallidus (GPe) via the cortico-striato-GPe-STN indirect pathway. The STN then drives the internal segment of the globus pallidus, which is the output nucleus of the basal ganglia. Thus, clarifying how STN neuronal activity is controlled by the two inputs is crucial. Cortical stimulation evokes early excitation and late excitation in STN neurons, intervened by a short gap. Here, to examine the origin of each component of this biphasic response, we recorded neuronal activity in the STN, combined with electrical stimulation of the motor cortices and local drug application in two male monkeys (Macaca fuscata) in the awake state. Local application of glutamate receptor antagonists, a mixture of an AMPA/kainate receptor antagonist and an NMDA receptor antagonist, into the vicinity of recorded STN neurons specifically diminished early excitation. Blockade of the striatum (putamen) or GPe with local injection of a GABAA receptor agonist, muscimol, diminished late excitation in the STN. Blockade of striato-GPe transmission with local injection of a GABAA receptor antagonist, gabazine, into the GPe also abolished late excitation. These results indicate that cortically evoked early and late excitation in the STN is mediated by the cortico-STN glutamatergic hyperdirect and the cortico-striato-GPe-STN indirect pathways, respectively.SIGNIFICANCE STATEMENT Here we show that the subthalamic nucleus (STN), an input station of the basal ganglia, receives cortical inputs through the cortico-STN hyperdirect and cortico-striato-external pallido-STN indirect pathways. This knowledge is important for understanding not only the normal functions of the STN, but also the pathophysiology of STN-related disorders and therapy targeting the STN. Lesions or application of high-frequency stimulation in the STN ameliorates parkinsonian symptoms. These procedures could affect all components in the STN, such as afferent inputs through the hyperdirect and indirect pathways, and STN neuronal activity. If we can understand which component is most affected by such procedures, we may be able to identify more effective manipulation targets or methods to treat Parkinson's disease.

A comparison of GABA-ergic (propofol) and non-GABA-ergic (dexmedetomidine) sedation on visual and motor cortical oscillations, using magnetoencephalography.

Studying changes in cortical oscillations can help elucidate the mechanistic link between receptor physiology and the clinical effects of anaesthetic drugs. Propofol, a GABA-ergic drug produces divergent effects on visual cortical activity: increasing induced gamma-band responses (GBR) while decreasing evoked responses. Dexmedetomidine, an α2- adrenergic agonist, differs from GABA-ergic sedatives both mechanistically and clinically as it allows easy arousability from deep sedation with less cognitive side-effects. Here we use magnetoencephalography (MEG) to characterize and compare the effects of GABA-ergic (propofol) and non-GABA-ergic (dexmedetomidine) sedation, on visual and motor cortical oscillations. Sixteen male participants received target-controlled infusions of propofol and dexmedetomidine, producing mild-sedation, in a placebo-controlled, cross-over study. MEG data was collected during a combined visuomotor task. The key findings were that propofol significantly enhanced visual stimulus induced GBR (44% increase in amplitude) while dexmedetomidine decreased it (40%). Propofol also decreased the amplitudes of the Mv100 (visual M100) (27%) and Mv150 (52%) visual evoked fields (VEF), whilst dexmedetomidine had no effect on these. During the motor task, neither drug had any significant effect on movement related gamma synchrony (MRGS), movement related beta de-synchronisation (MRBD) or Mm100 (movement-related M100) movement-related evoked fields (MEF), although dexmedetomidine slowed the Mm300. Dexmedetomidine increased (92%) post-movement beta synchronisation/rebound (PMBR) power while propofol reduced it (70%, statistically non- significant). Overall, dexmedetomidine and propofol, at equi-sedative doses, produce contrasting effects on visual induced GBR, VEF, PMBR and MEF. These findings provide a mechanistic link between the known receptor physiology of these sedative drugs with their known clinical effects and may be used to explore mechanisms of other anaesthetic drugs on human consciousness.

Muscarinic receptor blockade causes postcontraction enhancement in corticospinal excitability following maximal contractions.

Although synaptic transmission in motor pathways can be regulated by neuromodulators, such as acetylcholine, few studies have examined how cholinergic activity affects cortical and spinal motor circuits following muscle contractions of varying intensities. This was a human, double-blinded, placebo-controlled, crossover study. Participants attended two sessions where they were administered either a placebo or 25 mg of promethazine. Electromyography of the abductor digiti minimi (ADM) was measured for all conditions. Motor evoked potentials (MEPs) were obtained via motor cortical transcranial magnetic stimulation (TMS), and F waves were obtained via ulnar nerve electrical stimulation. MEPs and F waves were examined: 1) when the muscle was at rest; 2) after the muscle had been active; and 3) after the muscle had been fatigued. MEPs were unaffected by muscarinic receptor blockade when measurements were recorded from resting muscle or following a 50% isometric maximal voluntary contraction (MVC). However, muscarinic receptor blockade increased MEP area following a 10-s MVC (P = 0.019) and following a fatiguing 60-s MVC (P = 0.040). F wave area and persistence were not affected by promethazine for any muscle contraction condition. Corticospinal excitability was influenced by cholinergic effects when voluntary drive to the muscle was high. Given that spinal motoneurone excitability remained unaffected, it is likely that cholinergic effects are influential within the motor cortex during strong muscle contractions. Future research should evaluate how cholinergic effects alter the relationship between subcortical structures and the motor cortex, as well as brainstem neuromodulatory pathways and spinal motoneurons.NEW & NOTEWORTHY The relationship between motor function and cholinergic circuitry in the central nervous system is complex. Although many studies have approached this issue at the cellular level, few studies have examined cholinergic mechanisms in humans performing muscle contractions. This study demonstrates that blockade of muscarinic acetylcholine receptors enhances motor evoked potentials (elicited with transcranial magnetic stimulation) following strong muscle contractions, but not weak muscle contractions.

Human corticospinal-motoneuronal output is reduced with 5-HT2 receptor antagonism.

Animal models indicate that serotonin (5-HT) release onto motoneurons facilitates motor output, particularly during strong motor activities. However, evidence for 5-HT effects during human movement are limited. This study examined how antagonism of the 5-HT2 receptor, which is a 5-HT receptor that promotes motoneuron excitability, affects human movement. Ten healthy participants (24.2 ± 1.9 yr) ingested 8 mg of cyproheptadine (competitive 5-HT2 antagonist) in a double-blinded, placebo-controlled, repeated-measures design. Transcranial magnetic stimulation (TMS) of the motor cortex was used to elicit motor evoked potentials (MEPs) from biceps brachii. First, stimulus-response curves (90%-160% active motor threshold) were obtained during very weak elbow flexions (10% of maximal). Second, to determine if 5-HT effects are scaled to the intensity of muscle contraction, TMS at a fixed intensity was applied during elbow flexions of 20%, 40%, 60%, 80%, and 100% of maximal. Cyproheptadine reduced the size of MEPs across the stimulus-response curves (P = 0.045). Notably, MEP amplitude was 22.3% smaller for the cyproheptadine condition for the strongest TMS intensity. In addition, cyproheptadine reduced maximal torque (P = 0.045), lengthened the biceps silent period during maximal elbow flexions (P = 0.037), and reduced superimposed twitch amplitude during moderate-intensity elbow flexions (P = 0.035). This study presents novel evidence that 5-HT2 receptors influence corticospinal-motoneuronal output, which was particularly evident when a large number of descending inputs to motoneurons were active. Although it is likely that antagonism of 5-HT2 receptors reduces motoneuron gain to ionotropic inputs, supraspinal mechanisms may have also contributed to the study findings.NEW & NOTEWORTHY Voluntary contractions and responses to magnetic stimulation of the motor cortex are dependent on serotonin activity in the central nervous system. 5-HT2 antagonism decreased evoked potential size to high-intensity stimulation, and reduced torque and lengthened inhibitory silent periods during maximal contractions. We provide novel evidence that 5-HT2 receptors are involved in muscle activation, where 5-HT effects are strongest when a large number of descending inputs activate motoneurons.

Early decreases in cortical mid-gamma peaks coincide with the onset of motor deficits and precede exaggerated beta build-up in rat models for Parkinson's disease.

Evidence suggests that exaggerated beta range local field potentials (LFP) in basal ganglia-thalamocortical circuits constitute an important biomarker for feedback for deep brain stimulation in Parkinson's disease patients, although the role of this phenomenon in triggering parkinsonian motor symptoms remains unclear. A useful model for probing the causal role of motor circuit LFP synchronization in motor dysfunction is the unilateral dopamine cell-lesioned rat, which shows dramatic motor deficits walking contralaterally to the lesion but can walk steadily ipsilaterally on a circular treadmill. Within hours after 6-OHDA injection, rats show marked deficits in ipsilateral walking with early loss of significant motor cortex (MCx) LFP peaks in the mid-gamma 41-45 Hz range in the lesioned hemisphere; both effects were reversed by dopamine agonist administration. Increases in MCx and substantia nigra pars reticulata (SNpr) coherence and LFP power in the 29-40 Hz range emerged more gradually over 7 days, although without further progression of walking deficits. Twice-daily chronic dopamine antagonist treatment induced rapid onset of catalepsy and also reduced MCx 41-45 Hz LFP activity at 1 h, with increases in MCx and SNpr 29-40 Hz power/coherence emerging over 7 days, as assessed during periods of walking before the morning treatments. Thus, increases in high beta power in these parkinsonian models emerge gradually and are not linearly correlated with motor deficits. Earlier changes in cortical circuits, reflected in the rapid decreases in MCx LFP mid-gamma LFP activity, may contribute to evolving plasticity supporting increased beta range synchronized activity in basal ganglia-thalamocortical circuits after loss of dopamine receptor stimulation.

Alleviation of Huntington pathology in mice by oral administration of food additive glyceryl tribenzoate.

Huntington's disease (HD) is a neurodegenerative disorder characterized by accumulation of mutant huntingtin protein and significant loss of neurons in striatum and cortex. Along with motor difficulties, the HD patients also manifest anxiety and loss of cognition. Unfortunately, the clinically approved drugs only offer symptomatic relief and are not free from side effects. This study underlines the importance of glyceryl tribenzoate (GTB), an FDA-approved food flavoring ingredient, in alleviating HD pathology in transgenic N171-82Q mouse model. Oral administration of GTB significantly reduced mutant huntingtin level in striatum, motor cortex as well as hippocampus and increased the integrity of viable neurons. Furthermore, we found the presence of sodium benzoate (NaB), a FDA-approved drug for urea cycle disorders and glycine encephalopathy, in the brain of GTB-fed HD mice. Accordingly, NaB administration also markedly decreased huntingtin level in striatum and cortex. Glial activation is found to coincide with neuronal death in affected regions of HD brains. Interestingly, both GTB and NaB treatment suppressed activation of glial cells and inflammation in the brain. Finally, neuroprotective effect of GTB and NaB resulted in improved motor performance of HD mice. Collectively, these results suggest that GTB and NaB may be repurposed for HD.

Dopaminergic denervation impairs cortical motor and associative/limbic information processing through the basal ganglia and its modulation by the CB1 receptor.

The basal ganglia (BG) are involved in cognitive/motivational functions in addition to movement control. Thus, BG segregated circuits, the sensorimotor (SM) and medial prefrontal (mPF) circuits, process different functional domains, such as motor and cognitive/motivational behaviours, respectively. With a high presence in the BG, the CB1 cannabinoid receptor modulates BG circuits. Furthermore, dopamine (DA), one of the principal neurotransmitters in the BG, also plays a key role in circuit functionality. Taking into account the interaction between DA and the endocannabinoid system at the BG level, we investigated the functioning of BG circuits and their modulation by the CB1 receptor under DA-depleted conditions. We performed single-unit extracellular recordings of substantia nigra pars reticulata (SNr) neurons with simultaneous cortical stimulation in sham and 6-hydroxydopamine (6-OHDA)-lesioned rats, together with immunohistochemical assays. We showed that DA loss alters cortico-nigral information processing in both circuits, with a predominant transmission through the hyperdirect pathway in the SM circuit and an increased transmission through the direct pathway in the mPF circuit. Moreover, although DA denervation does not change CB1 receptor density, it impairs its functionality, leading to a lack of modulation. These data highlight an abnormal transfer of information through the associative/limbic domains after DA denervation that may be related to the non-motor symptoms manifested by Parkinson's disease patients.

Differential effects of the cell cycle inhibitor, olomoucine, on functional recovery and on responses of peri-infarct microglia and astrocytes following photothrombotic stroke in rats.

BACKGROUND: Following stroke, changes in neuronal connectivity in tissue surrounding the infarct play an important role in both spontaneous recovery of neurological function and in treatment-induced improvements in function. Microglia and astrocytes influence this process through direct interactions with the neurons and as major determinants of the local tissue environment. Subpopulations of peri-infarct glia proliferate early after stroke providing a possible target to modify recovery. Treatment with cell cycle inhibitors can reduce infarct volume and improve functional recovery. However, it is not known whether these inhibitors can influence neurological function or alter the responses of peri-infarct glia without reducing infarction. The present study aimed to address these issues by testing the effects of the cell cycle inhibitor, olomoucine, on recovery and peri-infarct changes following photothrombotic stroke. METHODS: Stroke was induced by photothrombosis in the forelimb sensorimotor cortex in Sprague-Dawley rats. Olomoucine was administered at 1 h and 24 h after stroke induction. Forelimb function was monitored up to 29 days. The effects of olomoucine on glial cell responses in peri-infarct tissue were evaluated using immunohistochemistry and Western blotting. RESULTS: Olomoucine treatment did not significantly affect maximal infarct volume. Recovery of the affected forelimb on a placing test was impaired in olomoucine-treated rats, whereas recovery in a skilled reaching test was substantially improved. Olomoucine treatment produced small changes in aspects of Iba1 immunolabelling and in the number of CD68-positive cells in cerebral cortex but did not selectively modify responses in peri-infarct tissue. The content of the astrocytic protein, vimentin, was reduced by 30% in the region of the lesion in olomoucine-treated rats. CONCLUSIONS: Olomoucine treatment modified functional recovery in the absence of significant changes in infarct volume. The effects on recovery were markedly test dependent, adding to evidence that skilled tasks requiring specific training and general measures of motor function can be differentially modified by some interventions. The altered recovery was not associated with specific changes in key responses of peri-infarct microglia, even though these cells were considered a likely target for early olomoucine treatment. Changes detected in peri-infarct reactive astrogliosis could contribute to the altered patterns of functional recovery.

Dosage-Dependent Impact of Acute Serotonin Enhancement on Transcranial Direct Current Stimulation Effects.

BACKGROUND: The serotonergic system has an important impact on basic physiological and higher brain functions. Acute and chronic enhancement of serotonin levels via selective serotonin reuptake inhibitor administration impacts neuroplasticity in humans, as shown by its effects on cortical excitability alterations induced by non-invasive brain stimulation, including transcranial direct current stimulation (tDCS). Nevertheless, the interaction between serotonin activation and neuroplasticity is not fully understood, particularly considering dose-dependent effects. Our goal was to explore dosage-dependent effects of acute serotonin enhancement on stimulation-induced plasticity in healthy individuals. METHODS: Twelve healthy adults participated in 7 sessions conducted in a crossover, partially double-blinded, randomized, and sham-controlled study design. Anodal and cathodal tDCS was applied to the motor cortex under selective serotonin reuptake inhibitor (20 mg/40 mg citalopram) or placebo medication. Motor cortex excitability was monitored by single-pulse transcranial magnetic stimulation. RESULTS: Under placebo medication, anodal tDCS enhanced, and cathodal tDCS reduced, excitability for approximately 60-120 minutes after the intervention. Citalopram enhanced and prolonged the facilitation induced by anodal tDCS regardless of the dosage while turning cathodal tDCS-induced excitability diminution into facilitation. For the latter, prolonged effects were observed when 40 mg was administrated. CONCLUSIONS: Acute serotonin enhancement modulates tDCS after-effects and has largely similar modulatory effects on motor cortex neuroplasticity regardless of the specific dosage. A minor dosage-dependent effect was observed only for cathodal tDCS. The present findings support the concept of boosting the neuroplastic effects of anodal tDCS by serotonergic enhancement, a potential clinical approach for the treatment of neurological and psychiatric disorders.

Cortical inhibition, facilitation and plasticity in late-life depression: effects of venlafaxine pharmacotherapy.

BACKGROUND: Late-life depression is often associated with non-response or relapse following conventional antidepressant treatment. The pathophysiology of late-life depression likely involves a complex interplay between aging and depression, and may include abnormalities in cortical inhibition and plasticity. However, the extent to which these cortical processes are modifiable by antidepressant pharmacotherapy is unknown. METHODS: Sixty-eight patients with late-life depression received 12 weeks of treatment with open-label venlafaxine, a serotonin-norepinephrine reuptake inhibitor (≤ 300 mg/d). We combined transcranial magnetic stimulation of the left motor cortex with electromyography recordings from the right hand to measure cortical inhibition using contralateral cortical silent period and paired-pulse short-interval intracortical inhibition paradigms; cortical facilitation using a paired-pulse intracortical facilitation paradigm; and short-term cortical plasticity using a paired associative stimulation paradigm. All measures were collected at baseline, 1 week into treatment (n = 23) and after approximately 12 weeks of treatment. RESULTS: Venlafaxine did not significantly alter cortical inhibition, facilitation or plasticity after 1 or 12 weeks of treatment. Improvements in depressive symptoms during treatment were not associated with changes in cortical physiology. LIMITATIONS: The results presented here are specific to the motor cortex. Future work should investigate whether these findings extend to cortical areas more closely associated with depression, such as the dorsolateral prefrontal cortex. CONCLUSION: These findings suggest that antidepressant treatment with venlafaxine does not exert meaningful changes in motor cortical inhibition or plasticity in late-life depression. The absence of changes in motor cortical physiology, alongside improvements in depressive symptoms, suggests that age-related changes may play a role in previously identified abnormalities in motor cortical processes in latelife depression, and that venlafaxine treatment does not target these abnormalities.

Behavioural impairments after exposure of neonatal mice to propofol are accompanied by reductions in neuronal activity in cortical circuitry.

BACKGROUND: Both animal and retrospective human studies have linked extended and repeated general anaesthesia during early development with cognitive and behavioural deficits later in life. However, the neuronal circuit mechanisms underlying this anaesthesia-induced behavioural impairment are poorly understood. METHODS: Neonatal mice were administered one or three doses of propofol, a commonly used i.v. general anaesthetic, over Postnatal days 7-11. Control mice received Intralipid® vehicle injections. At 4 months of age, the mice were subjected to a series of behavioural tests, including motor learning. During the process of motor learning, calcium activity of pyramidal neurones and three classes of inhibitory interneurones in the primary motor cortex were examined in vivo using two-photon microscopy. RESULTS: Repeated, but not a single, exposure of neonatal mice to propofol i.p. caused motor learning impairment in adulthood, which was accompanied by a reduction of pyramidal neurone number and activity in the motor cortex. The activity of local inhibitory interneurone networks was also altered: somatostatin-expressing and parvalbumin-expressing interneurones were hypoactive, whereas vasoactive intestinal peptide-expressing interneurones were hyperactive when the mice were performing a motor learning task. Administration of low-dose pentylenetetrazol to attenuate γ-aminobutyric acid A receptor-mediated inhibition or CX546 to potentiate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-subtype glutamate receptor function during emergence from anaesthesia ameliorated neuronal dysfunction in the cortex and prevented long-term behavioural deficits. CONCLUSIONS: Repeated exposure of neonatal mice to propofol anaesthesia during early development causes cortical circuit dysfunction and behavioural impairments in later life. Potentiation of neuronal activity during recovery from anaesthesia reduces these adverse effects of early-life anaesthesia.

Enhancing Plasticity Mechanisms in the Mouse Motor Cortex by Anodal Transcranial Direct-Current Stimulation: The Contribution of Nitric Oxide Signaling.

Consistent body of evidence shows that transcranial direct-current stimulation (tDCS) over the primary motor cortex (M1) facilitates motor learning and promotes recovery after stroke. However, the knowledge of molecular mechanisms behind tDCS effects needs to be deepened for a more rational use of this technique in clinical settings. Here we characterized the effects of anodal tDCS of M1, focusing on its impact on glutamatergic synaptic transmission and plasticity. Mice subjected to tDCS displayed increased long-term potentiation (LTP) and enhanced basal synaptic transmission at layer II/III horizontal connections. They performed better than sham-stimulated mice in the single-pellet reaching task and exhibited increased forelimb strength. Dendritic spine density of layer II/III pyramidal neurons was also increased by tDCS. At molecular level, tDCS enhanced: 1) BDNF expression, 2) phosphorylation of CREB, CaMKII, and GluA1, and 3) S-nitrosylation of GluA1 and HDAC2. Blockade of nitric oxide synthesis by L-NAME prevented the tDCS-induced enhancement of GluA1 phosphorylation at Ser831 and BDNF levels, as well as of miniature excitatory postsynaptic current (mEPSC) frequency, LTP and reaching performance. Collectively, these findings demonstrate that anodal tDCS engages plasticity mechanisms in the M1 and highlight a role for nitric oxide (NO) as a novel mediator of tDCS effects.