ResearchPad - neostriatum https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Diffusion MRI reveals in vivo and non-invasively changes in astrocyte function induced by an aquaporin-4 inhibitor]]> https://www.researchpad.co/article/elastic_article_14694 The Glymphatic System (GS) has been proposed as a mechanism to clear brain tissue from waste. Its dysfunction might lead to several brain pathologies, including the Alzheimer’s disease. A key component of the GS and brain tissue water circulation is the astrocyte which is regulated by acquaporin-4 (AQP4), a membrane-bound water channel on the astrocytic end-feet. Here we investigated the potential of diffusion MRI to monitor astrocyte activity in a mouse brain model through the inhibition of AQP4 channels with TGN-020. Upon TGN-020 injection, we observed a significant decrease in the Sindex, a diffusion marker of tissue microstructure, and a significant increase of the water diffusion coefficient (sADC) in cerebral cortex and hippocampus compared to saline injection. These results indicate the suitability of diffusion MRI to monitor astrocytic activity in vivo and non-invasively.

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<![CDATA[Bilateral Parkinson’s disease model rats exhibit hyperalgesia to subcutaneous formalin administration into the vibrissa pad]]> https://www.researchpad.co/article/Nc1e56242-0f9e-4dec-b14c-0acf3482ec2d

We bilaterally injected 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle of rats and developed bilateral Parkinson’s disease (PD) model rats in order to experimentally investigate the neural mechanisms underlying the alteration of nociception in the orofacial region of patients with PD. We explored the effects of dopamine depletion on nociception by investigating behavioral responses (face rubbing) triggered by subcutaneous administration of formalin into the vibrissa pad. We also assessed the number of c-Fos–immunoreactive (c-Fos-IR) cells in the superficial layers of the trigeminal spinal subnucleus caudalis (Vc). Subcutaneous formalin administration evoked a two-phase increase in face rubbing. We observed the first increase 0–5 min after formalin administration (first phase) and the second increase 10–60 min after administration (second phase). The number of face rubbing behaviors of 6OHDA–injected rats did not significantly change compared with saline–injected rats in both phases. Significant increase of c-Fos-IR cells in the Vc was found in 6-OHDA–injected rats after formalin administration compared with those in saline–injected rats after formalin administration. We also assessed expression of c-Fos-IR cells in the paraventricular nucleus (PVN), and significant decrease of c-Fos-IR cells in the PVN of 6-OHDA–injected rats was found. Taken together, these findings suggest that bilateral dopaminergic denervation evoked by 6-OHDA administration causes hyperalgesia in the trigeminal region and the PVN may be involved in the hyperalgesia.

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<![CDATA[Brief communication: β-cell function influences dopamine receptor availability]]> https://www.researchpad.co/article/5c8c1952d5eed0c484b4d3f2

We aim to identify physiologic regulators of dopamine (DA) signaling in obesity but previously did not find a compelling relationship with insulin sensitivity measured by oral-minimal model (OMM) and DA subtype 2 and 3 receptor (D2/3R) binding potential (BPND). Reduced disposition index (DI), a β-cell function metric that can also be calculated by OMM, was shown to predict a negative reward behavior that occurs in states of lower endogenous DA. We hypothesized that reduced DI would occur with higher D2/3R BPND, reflecting lower endogenous DA. Participants completed PET scanning, with a displaceable radioligand to measure D2/3R BPND, and a 5-hour oral glucose tolerance test to measure DI by OMM. We studied 26 age-similar females without (n = 8) and with obesity (n = 18) (22 vs 39 kg/m2). Reduced DI predicted increased striatal D2/3R BPND independent of BMI. By accounting for β-cell function, we were able to determine that the state of insulin and glucose metabolism is pertinent to striatal D2/3R BPND in obesity.

Clinical Trial Registration Number: NCT00802204

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<![CDATA[Disrupted reinforcement learning during post-error slowing in ADHD]]> https://www.researchpad.co/article/5c76fe43d5eed0c484e5b7bb

ADHD is associated with altered dopamine regulated reinforcement learning on prediction errors. Despite evidence of categorically altered error processing in ADHD, neuroimaging advances have largely investigated models of normal reinforcement learning in greater detail. Further, although reinforcement leaning critically relies on ventral striatum exerting error magnitude related thresholding influences on substantia nigra (SN) and dorsal striatum, these thresholding influences have never been identified with neuroimaging. To identify such thresholding influences, we propose that error magnitude related activities must first be separated from opposite activities in overlapping neural regions during error detection. Here we separate error detection from magnitude related adjustment (post-error slowing) during inhibition errors in the stop signal task in typically developing (TD) and ADHD adolescents using fMRI. In TD, we predicted that: 1) deactivation of dorsal striatum on error detection interrupts ongoing processing, and should be proportional to right frontoparietal response phase activity that has been observed in the SST; 2) deactivation of ventral striatum on post-error slowing exerts thresholding influences on, and should be proportional to activity in dorsal striatum. In ADHD, we predicted that ventral striatum would instead correlate with heightened amygdala responses to errors. We found deactivation of dorsal striatum on error detection correlated with response-phase activity in both groups. In TD, post-error slowing deactivation of ventral striatum correlated with activation of dorsal striatum. In ADHD, ventral striatum correlated with heightened amygdala activity. Further, heightened activities in locus coeruleus (norepinephrine), raphe nucleus (serotonin) and medial septal nuclei (acetylcholine), which all compete for control of DA, and are altered in ADHD, exhibited altered correlations with SN. All correlations in TD were replicated in healthy adults. Results in TD are consistent with dopamine regulated reinforcement learning on post-error slowing. In ADHD, results are consistent with heightened activities in the amygdala and non-dopaminergic neurotransmitter nuclei preventing reinforcement learning.

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<![CDATA[A neural hallmark of auditory implicit learning is altered in older adults]]> https://www.researchpad.co/article/5c5b5256d5eed0c4842bc694

Temporal regularities in the environment are often learned implicitly. In an auditory target-detection paradigm using EEG, Jongsma and colleagues (2006) showed that the neural response to these implicit regularities results in a reduction of the P3-N2 complex. Here, we utilized the same paradigm, this time in both young and old participants, to determine if this EEG signature of implicit learning was altered with age. Behaviorally, both groups of participants showed similar benefits for the presence of temporal regularity, with faster and more accurate responses given when the auditory targets were presented in a temporally regular vs. random pattern. In the brain, the younger adults showed the expected decrease in amplitude of this complex for regular compared to irregular trials. Older adults, in contrast, showed no difference in the amplitude of the P3-N2 complex between the irregular and regular condition. These data suggest that, although auditory implicit learning may be behaviorally spared in aging, older adults are not using the same neural substrates as younger adults to achieve this.

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<![CDATA[Altered reward processing following an acute social stressor in adolescents]]> https://www.researchpad.co/article/5c390bd4d5eed0c48491e907

Altered reward processing is a transdiagnostic factor implicated in a wide range of psychiatric disorders. While prior animal and adult research has shown that stress contributes to reward dysfunction, less is known about how stress impacts reward processing in youth. Towards addressing this gap, the present study probed neural activation associated with reward processing following an acute stressor. Healthy adolescents (n = 40) completed a clinical assessment, and fMRI data were acquired while participants completed a monetary guessing task under a no-stress condition and then under a stress condition. Based on prior literature, analyses focused on a priori defined regions-of-interest, specifically the striatum (win trials) and dorsal anterior cingulate cortex [dACC] and insula (loss trials). Two main findings emerged. First, reward-related neural activation (i.e., striatum) was blunted in the stress relative to the no-stress condition. Second, the stress condition also contributed to blunted neural response following reward in loss-related regions (i.e., dACC, anterior insula); however, there were no changes in loss sensitivity. These results highlight the importance of conceptualizing neural vulnerability within the presence of stress, as this may clarify risk for mental disorders during a critical period of development.

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<![CDATA[Neurobiology of social reward valuation in adults with a history of anorexia nervosa]]> https://www.researchpad.co/article/5c102907d5eed0c484248db1

Objective

Anorexia nervosa (AN) is a disorder characterized by atypical patterns of reward valuation (e.g. positive valuation of hunger). Atypical reward processing may extend into social domains. If so, such findings would be of prognostic significance as impaired social functioning predicts worse outcome. We explore neural circuits implicated in social reward processing in individuals with a history of AN who are weight-restored relative to controls and examine the effects of illness course on the experience of social value.

Method

20 weight-restored individuals with a history of AN (AN-WR) and 24 healthy control (HC) participants were assessed using fMRI tasks that tapped social reward: smiling faces and full human figures that varied in attractiveness and weight.

Results

AN-WR differed from HC in attractiveness ratings by weight (negatively correlated in AN-WR). While there were no significant differences when viewing smiling faces, viewing full figures resulted in decreased activation in regions implicated in reward valuation (the right caudate) for AN-WR and this region was negatively correlated with a sustained course of the disorder. Exploratory whole brain analyses revealed reduced activation in regions associated with social reward, self-referential processing, and cognitive reappraisal (e.g., medial prefrontal cortex, striatum, and nucleus accumbens) with sustained disorder course.

Discussion

The rewarding value of full body images decreases with a sustained disorder course. This may reflect an extension of atypical reward processing documented in AN-WR, perhaps as a function of starvation dampening visceral motivational signals; the deployment of cognitive strategies that lessen the experience of reward; and/or the nature of the stimuli themselves as provocative of eating disorder symptoms (e.g., thin bodies). These findings did not extend to smiling face stimuli. Advances in technology (e.g., virtual avatars, text messaging) may provide novel means to build relationships, including therapeutic relationships, to support improved social connections without threats to symptom provocation.

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<![CDATA[Neural activity and fundamental learning, motivated by monetary loss and reward, are intact in mild to moderate major depressive disorder]]> https://www.researchpad.co/article/5b6da1a7463d7e4dccc5fae6

Introduction

Reduced motivation is an important symptom of major depression, thought to impair recovery by reducing opportunities for rewarding experiences. We characterized motivation for monetary outcomes in depressed outpatients (N = 39, 22 female) and controls (N = 22, 11 female) in terms of their effectiveness in seeking rewards and avoiding losses. We assessed motivational function during learning of associations between stimuli and actions, as well as when learning was complete. We compared the activity within neural circuits underpinning these behaviors between depressed patients and controls.

Methods

We used a Go/No-Go task that assessed subjects’ abilities in learning to emit or withhold actions to obtain monetary rewards or avoid losses. We derived motivation-relevant parameters of behavior (learning rate, Pavlovian bias, and motivational influence of gains and losses). After learning, participants performed the task during functional magnetic resonance imaging (fMRI). We compared neural activation during anticipation of action emission vs. action inhibition, and for actions performed to obtain rewards compared to actions that avoid losses.

Results

Depressed patients showed a similar Pavlovian bias to controls and were equivalent in terms of withholding action to gain rewards and emitting action to avoid losses, behaviors that conflict with well-described Pavlovian tendencies to approach rewards and avoid losses. Patients were not impaired in overall performance or learning and showed no abnormal neural responses, for example in bilateral midbrain or striatum. We conclude that basic mechanisms subserving motivated learning are thus intact in moderate depression.

Implications

Therapeutically, the intact mechanisms identified here suggest that learning-based interventions may be particularly effective in encouraging recovery. Etiologically, our results suggest that the severe motivational deficits clinically observed in depression are likely to have complex origins, possibly related to an impairment in the representation of future states necessary for long-term planning.

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<![CDATA[Unfolding the Spatial and Temporal Neural Processing of Making Dishonest Choices]]> https://www.researchpad.co/article/5989da88ab0ee8fa60b9cdd5

To understand the neural processing that underpins dishonest behavior in an economic exchange game task, this study employed both functional magnetic resonance imaging (fMRI) and event-related potential (ERP) methodologies to examine the neural conditions of 25 participants while they were making either dishonest or honest choices. It was discovered that dishonest choices, contrary to honest choices, elicited stronger fMRI activations in bilateral striatum and anterior insula. It also induced fluctuations in ERP amplitudes within two time windows, which are 270–30 milliseconds before and 110–290 milliseconds after the response, respectively. Importantly, when making either dishonest or honest choices, human and computer counterparts were associated with distinct fMRI activations in the left insula and different ERP amplitudes at medial and right central sites from 80 milliseconds before to 250 milliseconds after the response. These results support the hypothesis that there would be distinct neural processing during making dishonest decisions, especially when the subject considers the interests of the counterpart. Furthermore, the fMRI and ERP findings, together with ERP source reconstruction, clearly delineate the temporal sequence of the neural processes of a dishonest decision: the striatum is activated before response, then the left insula is involved around the time of response, and finally the thalamus is activated after response.

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<![CDATA[Therapeutic efficacy of AAV8-mediated intrastriatal delivery of human cerebral dopamine neurotrophic factor in 6-OHDA-induced parkinsonian rat models with different disease progression]]> https://www.researchpad.co/article/5989db5fab0ee8fa60be10f0

Parkinson’s disease (PD) is a progressive and age-associated neurodegenerative disorder. Patients at different stages of the disease course have distinguished features, mainly in the number of dopaminergic neurons. Cerebral dopamine neurotrophic factor (CDNF) is a recently discovered neurotrophic factor, being deemed as a hopeful candidate for PD treatment. Here, we evaluated the efficacy of CDNF in protecting dopaminergic function using the 6-OHDA-induced PD rat model suffering from different levels of neuronal loss and the recombinant adeno-associated virus 8 (AAV8) as a carrier for the CDNF gene. The results showed that AAV8-CDNF administration significantly improved the motor function and increased the tyrosine hydroxylase (TH) levels in PD rats with mild lesions (2 weeks post lesion), but it had limited therapeutic effects in rats with severe lesions (5 weeks post lesion). To better improve the recovery of motor function in severely lesioned PD rats, we employed a strategy using the CDNF gene along with the aromatic amino acid decarboxylase (AADC) gene. This combination therapeutic strategy indeed showed an enhanced benefit in restoring the motor function of severely lesioned PD rats by providing the neuroprotective effect of CDNF and dopamine enhancing effect of AADC as expected. This study may provide a basis for future clinical application of CDNF in PD patients at different stages and offer a new alternative strategy of joint use of CDNF and AADC for advanced PD patients in clinical trials.

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<![CDATA[N-terminal Huntingtin Knock-In Mice: Implications of Removing the N-terminal Region of Huntingtin for Therapy]]> https://www.researchpad.co/article/5989da41ab0ee8fa60b8a2db

The Huntington’s disease (HD) protein, huntingtin (HTT), is a large protein consisting of 3144 amino acids and has conserved N-terminal sequences that are followed by a polyglutamine (polyQ) repeat. Loss of Htt is known to cause embryonic lethality in mice, whereas polyQ expansion leads to adult neuronal degeneration. Whether N-terminal HTT is essential for neuronal development or contributes only to late-onset neurodegeneration remains unknown. We established HTT knock-in mice (N160Q-KI) expressing the first 208 amino acids of HTT with 160Q, and they show age-dependent HTT aggregates in the brain and neurological phenotypes. Importantly, the N-terminal mutant HTT also preferentially accumulates in the striatum, the brain region most affected in HD, indicating the importance of N-terminal HTT in selective neuropathology. That said, homozygous N160Q-KI mice are also embryonic lethal, suggesting that N-terminal HTT alone is unable to support embryonic development. Using Htt knockout neurons, we found that loss of Htt selectively affects the survival of developing neuronal cells, but not astrocytes, in culture. This neuronal degeneration could be rescued by a truncated HTT lacking the first 237 amino acids, but not by N-terminal HTT (1–208 amino acids). Also, the rescue effect depends on the region in HTT known to be involved in intracellular trafficking. Thus, the N-terminal HTT region may not be essential for the survival of developing neurons, but when carrying a large polyQ repeat, can cause selective neuropathology. These findings imply a possible therapeutic benefit of removing the N-terminal region of HTT containing the polyQ repeat to treat the neurodegeneration in HD.

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<![CDATA[Characterization of Behavioral, Neuropathological, Brain Metabolic and Key Molecular Changes in zQ175 Knock-In Mouse Model of Huntington’s Disease]]> https://www.researchpad.co/article/5989da9dab0ee8fa60ba48bd

Huntington’s disease (HD) is caused by an expansion of the trinucleotide poly (CAG) tract located in exon 1 of the huntingtin (Htt) gene leading to progressive neurodegeneration in selected brain regions, and associated functional impairments in motor, cognitive, and psychiatric domains. Since the discovery of the gene mutation that causes the disease, mouse models have been developed by different strategies. Recently, a new model, the zQ175 knock-in (KI) line, was developed in an attempt to have the Htt gene in a context and causing a phenotype that more closely mimics HD in humans. The behavioral phenotype was characterized across the independent laboratories and important features reminiscent of human HD are observed in zQ175 mice. In the current study, we characterized the zQ175 model housed in an academic laboratory under reversed dark-light cycle, including motor function, in vivo longitudinal structural MRI imaging for brain volume, MRS for striatal metabolites, neuropathology, as well as a panel of key disease marker proteins in the striatum at different ages. Our results suggest that homozygous zQ175 mice exhibited significant brain atrophy before the motor deficits and brain metabolite changes. Altered striatal medium spiny neuronal marker, postsynaptic marker protein and complement component C1qC also characterized zQ175 mice. Our results confirmed that the zQ175 KI model is valuable in understanding of HD-like pathophysiology and evaluation of potential therapeutics. Our data also provide suggestions to select appropriate outcome measurements in preclinical studies using the zQ175 mice.

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<![CDATA[Progressive Axonal Degeneration of Nigrostriatal Dopaminergic Neurons in Calcium-Independent Phospholipase A2β Knockout Mice]]> https://www.researchpad.co/article/5989dacbab0ee8fa60bb4208

Calcium-independent phospholipase A2β (iPLA2β, PLA2G6) is essential for the remodeling of membrane glycerophospholipids. Mutations in this gene are responsible for autosomal recessive, young onset, L-dopa-responsive parkinsonism (PARK14), suggesting a neurodegenerative condition in the nigrostriatal dopaminergic system in patients with PLA2G6 mutations. We previously observed slowly progressive motor deficits in iPLA2β-knockout (KO) mice. To clarify whether a deficiency of iPLA2β leads to the degeneration of nigrostriatal dopaminergic neurons, we analyzed the striatum of iPLA2β-KO mice. At all clinical stages, nerve terminals in the striatum were immunopositive for tyrosine hydroxylase (TH) and dopamine transporter (DAT) in wild-type (WT) control mice. In iPLA2β-KO mice, focal loss of nerve terminals positive for TH and DAT was found from 56 weeks (early clinical stage), although iPLA2β-KO mice at 56 weeks showed no significant decrease in the number of dopaminergic neurons in the substantia nigra compared with age-matched WT mice, as reported previously. At 100 weeks (late clinical stage), greater decreases in DAT immunoreactivity were observed in the striatum of iPLA2β-KO mice. Moreover, strongly TH-positive structures, presumed to be deformed axons, were observed in the neuropils of the striatum of iPLA2β-KO mice starting at 15 weeks (preclinical stage) and increased with age. These results suggest that the degeneration of dopaminergic neurons occurs mainly in the distal region of axons in iPLA2β-KO mice.

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<![CDATA[Properties of Neurons in External Globus Pallidus Can Support Optimal Action Selection]]> https://www.researchpad.co/article/5989da35ab0ee8fa60b85db5

The external globus pallidus (GPe) is a key nucleus within basal ganglia circuits that are thought to be involved in action selection. A class of computational models assumes that, during action selection, the basal ganglia compute for all actions available in a given context the probabilities that they should be selected. These models suggest that a network of GPe and subthalamic nucleus (STN) neurons computes the normalization term in Bayes’ equation. In order to perform such computation, the GPe needs to send feedback to the STN equal to a particular function of the activity of STN neurons. However, the complex form of this function makes it unlikely that individual GPe neurons, or even a single GPe cell type, could compute it. Here, we demonstrate how this function could be computed within a network containing two types of GABAergic GPe projection neuron, so-called ‘prototypic’ and ‘arkypallidal’ neurons, that have different response properties in vivo and distinct connections. We compare our model predictions with the experimentally-reported connectivity and input-output functions (f-I curves) of the two populations of GPe neurons. We show that, together, these dichotomous cell types fulfil the requirements necessary to compute the function needed for optimal action selection. We conclude that, by virtue of their distinct response properties and connectivities, a network of arkypallidal and prototypic GPe neurons comprises a neural substrate capable of supporting the computation of the posterior probabilities of actions.

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<![CDATA[Specific behavioral and cellular adaptations induced by chronic morphine are reduced by dietary omega-3 polyunsaturated fatty acids]]> https://www.researchpad.co/article/5989db51ab0ee8fa60bdc2af

Opiates, one of the oldest known drugs, are the benchmark for treating pain. Regular opioid exposure also induces euphoria making these compounds addictive and often misused, as shown by the current epidemic of opioid abuse and overdose mortalities. In addition to the effect of opioids on their cognate receptors and signaling cascades, these compounds also induce multiple adaptations at cellular and behavioral levels. As omega-3 polyunsaturated fatty acids (n-3 PUFAs) play a ubiquitous role in behavioral and cellular processes, we proposed that supplemental n-3 PUFAs, enriched in docosahexanoic acid (DHA), could offset these adaptations following chronic opioid exposure. We used an 8 week regimen of n-3 PUFA supplementation followed by 8 days of morphine in the presence of this diet. We first assessed the effect of morphine in different behavioral measures and found that morphine increased anxiety and reduced wheel-running behavior. These effects were reduced by dietary n-3 PUFAs without affecting morphine-induced analgesia or hyperlocomotion, known effects of this opiate acting at mu opioid receptors. At the cellular level we found that morphine reduced striatal DHA content and that this was reversed by supplemental n-3 PUFAs. Chronic morphine also increased glutamatergic plasticity and the proportion of Grin2B-NMDARs in striatal projection neurons. This effect was similarly reversed by supplemental n-3 PUFAs. Gene analysis showed that supplemental PUFAs offset the effect of morphine on genes found in neurons of the dopamine receptor 2 (D2)-enriched indirect pathway but not of genes found in dopamine receptor 1(D1)-enriched direct-pathway neurons. Analysis of the D2 striatal connectome by a retrogradely transported pseudorabies virus showed that n-3 PUFA supplementation reversed the effect of chronic morphine on the innervation of D2 neurons by the dorsomedial prefontal and piriform cortices. Together these changes outline specific behavioral and cellular effects of morphine that can be reduced or reversed by dietary n-3 PUFAs.

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<![CDATA[The Limited Utility of Multiunit Data in Differentiating Neuronal Population Activity]]> https://www.researchpad.co/article/5989dafdab0ee8fa60bc5769

To date, single neuron recordings remain the gold standard for monitoring the activity of neuronal populations. Since obtaining single neuron recordings is not always possible, high frequency or ‘multiunit activity’ (MUA) is often used as a surrogate. Although MUA recordings allow one to monitor the activity of a large number of neurons, they do not allow identification of specific neuronal subtypes, the knowledge of which is often critical for understanding electrophysiological processes. Here, we explored whether prior knowledge of the single unit waveform of specific neuron types is sufficient to permit the use of MUA to monitor and distinguish differential activity of individual neuron types. We used an experimental and modeling approach to determine if components of the MUA can monitor medium spiny neurons (MSNs) and fast-spiking interneurons (FSIs) in the mouse dorsal striatum. We demonstrate that when well-isolated spikes are recorded, the MUA at frequencies greater than 100Hz is correlated with single unit spiking, highly dependent on the waveform of each neuron type, and accurately reflects the timing and spectral signature of each neuron. However, in the absence of well-isolated spikes (the norm in most MUA recordings), the MUA did not typically contain sufficient information to permit accurate prediction of the respective population activity of MSNs and FSIs. Thus, even under ideal conditions for the MUA to reliably predict the moment-to-moment activity of specific local neuronal ensembles, knowledge of the spike waveform of the underlying neuronal populations is necessary, but not sufficient.

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<![CDATA[From Cortical and Subcortical Grey Matter Abnormalities to Neurobehavioral Phenotype of Angelman Syndrome: A Voxel-Based Morphometry Study]]> https://www.researchpad.co/article/5989da07ab0ee8fa60b7615f

Angelman syndrome (AS) is a rare neurogenetic disorder due to loss of expression of maternal ubiquitin-protein ligase E3A (UBE3A) gene. It is characterized by severe developmental delay, speech impairment, movement or balance disorder and typical behavioral uniqueness. Affected individuals show normal magnetic resonance imaging (MRI) findings, although mild dysmyelination may be observed. In this study, we adopted a quantitative MRI analysis with voxel-based morphometry (FSL-VBM) method to investigate disease-related changes in the cortical/subcortical grey matter (GM) structures. Since 2006 to 2013 twenty-six AS patients were assessed by our multidisciplinary team. From those, sixteen AS children with confirmed maternal 15q11-q13 deletions (mean age 7.7 ± 3.6 years) and twenty-one age-matched controls were recruited. The developmental delay and motor dysfunction were assessed using Bayley III and Gross Motor Function Measure (GMFM). Principal component analysis (PCA) was applied to the clinical and neuropsychological datasets. High-resolution T1-weighted images were acquired and FSL-VBM approach was applied to investigate differences in the local GM volume and to correlate clinical and neuropsychological changes in the regional distribution of GM. We found bilateral GM volume loss in AS compared to control children in the striatum, limbic structures, insular and orbitofrontal cortices. Voxel-wise correlation analysis with the principal components of the PCA output revealed a strong relationship with GM volume in the superior parietal lobule and precuneus on the left hemisphere. The anatomical distribution of cortical/subcortical GM changes plausibly related to several clinical features of the disease and may provide an important morphological underpinning for clinical and neurobehavioral symptoms in children with AS.

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<![CDATA[Graphene Functionalized Scaffolds Reduce the Inflammatory Response and Supports Endogenous Neuroblast Migration when Implanted in the Adult Brain]]> https://www.researchpad.co/article/5989db3fab0ee8fa60bd6197

Electroactive materials have been investigated as next-generation neuronal tissue engineering scaffolds to enhance neuronal regeneration and functional recovery after brain injury. Graphene, an emerging neuronal scaffold material with charge transfer properties, has shown promising results for neuronal cell survival and differentiation in vitro. In this in vivo work, electrospun microfiber scaffolds coated with self-assembled colloidal graphene, were implanted into the striatum or into the subventricular zone of adult rats. Microglia and astrocyte activation levels were suppressed with graphene functionalization. In addition, self-assembled graphene implants prevented glial scarring in the brain 7 weeks following implantation. Astrocyte guidance within the scaffold and redirection of neuroblasts from the subventricular zone along the implants was also demonstrated. These findings provide new functional evidence for the potential use of graphene scaffolds as a therapeutic platform to support central nervous system regeneration.

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<![CDATA[Altered Resting-State Functional Connectivity of the Striatum in Parkinson's Disease after Levodopa Administration]]> https://www.researchpad.co/article/5989dabaab0ee8fa60bae2fc

Background

Despite improvement in motor symptoms, the effect of dopaminergic medications on cognition in patients with Parkinson’s disease (PD) is less clear. The purpose of this study was to reveal levodopa-induced acute changes in the functional connectivity of the striatum in patients with PD compared with matched untreated patients and healthy volunteers.

Methods

Twenty-two patients with PD underwent functional magnetic resonance imaging both ON and OFF dopamine-replacement therapy on two consecutive days. Twenty-eight normal aging volunteers also did them without taking in levodopa. Three caudate seeds and two putamen seeds were selected to calculate functional connectivity intensity.

Results

Motor symptoms measured by UPDRS were significantly worse in PD OFF than PD ON. Decreased functional connectivity in PD OFF compared to controls was detected in the following seed regions: dorsal caudate, ventral putamen and dorsal putamen. Increases in connectivity in PD ON compared to controls were found in the primary and supplementary motor areas and the associative prefrontal and parietal regions, while decreases in anterior cingulate, ventromedial prefrontal cortex, and parahippocampal gyrus. For the ventral striatal seeds, decreased connectivity in PD ON compared to PD OFF was found in the ventromedial prefrontal and orbitofrontal regions, dorsolateral prefrontal regions. For the dorsal striatal seeds, increased connectivity in PD ON compared to PD OFF was observed in the primary and secondary motor areas.

Conclusion

Our results suggest that levodopa significantly changes the motor and cognitive networks of the cortico-striatal pathways. This knowledge will lead clinicians to survey a broader range of symptoms in determining optimal therapy.

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<![CDATA[Changes in the miRNA-mRNA Regulatory Network Precede Motor Symptoms in a Mouse Model of Multiple System Atrophy: Clinical Implications]]> https://www.researchpad.co/article/5989d9e3ab0ee8fa60b6a2f1

Multiple system atrophy (MSA) is a fatal rapidly progressive α-synucleinopathy, characterized by α-synuclein accumulation in oligodendrocytes. It is accepted that the pathological α-synuclein accumulation in the brain of MSA patients plays a leading role in the disease process, but little is known about the events in the early stages of the disease. In this study we aimed to define potential roles of the miRNA-mRNA regulatory network in the early pre-motor stages of the disease, i.e., downstream of α-synuclein accumulation in oligodendroglia, as assessed in a transgenic mouse model of MSA. We investigated the expression patterns of miRNAs and their mRNA targets in substantia nigra (SN) and striatum, two brain regions that undergo neurodegeneration at a later stage in the MSA model, by microarray and RNA-seq analysis, respectively. Analysis was performed at a time point when α-synuclein accumulation was already present in oligodendrocytes at neuropathological examination, but no neuronal loss nor deficits of motor function had yet occurred. Our data provide a first evidence for the leading role of gene dysregulation associated with deficits in immune and inflammatory responses in the very early, non-symptomatic disease stages of MSA. While dysfunctional homeostasis and oxidative stress were prominent in SN in the early stages of MSA, in striatum differential gene expression in the non-symptomatic phase was linked to oligodendroglial dysfunction, disturbed protein handling, lipid metabolism, transmembrane transport and altered cell death control, respectively. A large number of putative miRNA-mRNAs interaction partners were identified in relation to the control of these processes in the MSA model. Our results support the role of early changes in the miRNA-mRNA regulatory network in the pathogenesis of MSA preceding the clinical onset of the disease. The findings thus contribute to understanding the disease process and are likely to pave the way towards identifying disease biomarkers for early diagnosis of MSA.

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