Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, leading to various motor and non-motor symptoms. Several cellular and molecular mechanisms such as alpha-synuclein (α-syn) accumulation, mitochondrial dysfunction, oxidative stress, and neuroinflammation are involved in the pathogenesis of this disease. MicroRNAs (miRNAs) play important roles in post-transcriptional gene regulation. They are typically about 21-25 nucleotides in length and are involved in the regulation of gene expression by binding to the messenger RNA (mRNA) molecules. miRNAs like miR-221 play important roles in various biological processes, including development, cell proliferation, differentiation, and apoptosis. miR-221 is also implicated in promoting neuronal survival against oxidative stress and in promoting neurite outgrowth and neuronal differentiation. Additionally, the role of miR-221 in PD has been investigated in several studies. According to the results of this study; 1) miR-221 protects against oxidative stress in 6-hydroxydopamine-induced PC12 cells; 2) miR-221 prevents Bax/caspase-3 signaling activation by stopping Bim; 3) miR-221 has moderate predictive power for PD; 4) miR-221 directly targets PTEN, and PTEN over-expression eliminates the protective action of miR-221 on p-AKT expression in PC12 cells; 5) miRNA-221, by manipulating the Akt signaling pathway, performs in controlling cell viability and apoptosis in PD. This review study suggests that miR-221 has the potential to be used as a clinical biomarker for PD diagnosis and stage assignment.
Millions of people suffer from dopamine-related disorders spanning disturbances in movement, cognition and emotion, often attributed to changes in striatal dopamine function. Understanding how dopamine signaling in the striatum and basal ganglia shapes human behavior is fundamental to advancing the treatment of affected patients. Dopaminergic neurons innervate large scale brain networks and many different roles for dopamine signals have been proposed, such as invigoration of movement and tracking of reward contingencies. The canonical circuit architecture of cortico-striatal loops sparks the question, whether dopamine signals in the basal ganglia serve an overarching computational principle which could provide new insights into symptom generation in psychiatry to neurology. Here, we review the perspective that dopamine could bidirectionally control neural population dynamics, increasing, or decreasing their strength and likelihood to reoccur in the future, a process previously termed neural reinforcement. We outline how the basal ganglia pathways could drive strengthening and weakening of circuit dynamics and discuss the implication of this hypothesis on the understanding of motor signs of Parkinson’s disease (PD), the most frequent dopaminergic disorder. We propose that loss of dopamine in PD may lead to a pathological brain state where repetition of neural activity leads to weakening and instability, possibly explanatory for the fact that movement in PD deteriorates with repetition, as defined by the sequence effect or decrement of movement. Finally, we speculate on how therapeutic interventions such as deep brain stimulation (DBS) may be able to reinstate reinforcement signals and thereby improve treatment strategies of PD in the future.
Astrocytes, glial cells in the central nervous system, perform a multitude of homeostatic functions and are in constant bidirectional communication with neuronal cells, a concept named the tripartite synapse, however their role in the dopamine homeostasis remains unexplored. The aim of this study was to clarify the pharmacological and molecular characteristics of dopamine transport in cultured cortical astrocytes of adult rats. In addition, we were interested in the expression of mRNA of dopamine transporters as well as dopamine receptors D1 and D2 and in the effect of dopaminergic drugs on the expression of these transporters and receptors. We have found that astrocytes possess both Na+-dependent and Na+-independent transporters. Uptake of radiolabelled dopamine was time-, temperature- and concentration-dependent and was inhibited by decynium-22, a plasma membrane monoamine transporter inhibitor, tricyclic antidepressants desipramine and nortriptyline, both inhibitors of the norepinephrine transporter. Results of transporter mRNA expression indicate that the main transporters involved in cortical astrocyte dopamine uptake are the norepinephrine transporter and plasma membrane monoamine transporter. Both dopamine receptor subtypes were identified in cortical astrocyte cultures. 24-hour treatment of astrocyte cultures with apomorphine, a D1/D2 agonist, induced upregulation of D1 receptor, norepinephrine transporter and plasma membrane monoamine transporter, whereas the latter was downregulated by haloperidol and L-DOPA. Astrocytes take up dopamine by multiple transporters and express dopamine receptors, which are sensitive to dopaminergic drugs. The findings of this study could open a promising area of research for the fine-tuning of existing therapeutic strategies.
Sepsis is a life-threatening organ dysfunction that results from dysregulated host response to infection. Multiple organ system dysfunction syndromes are prevalent among septic patients and are essential hallmarks of sepsis diagnosis. These syndromes involve failure of the pulmonary, hepatic, circulatory, renal, gastrointestinal and central nervous systems. Neurological dysfunction is part of this syndrome and has gained research attention recently . Sepsis induces neuroinflammation, BBB disruption, cerebral hypoxia, neuronal mitochondrial dysfunction and cell death causing sepsis-associated encephalopathy (SAE). These pathological consequences lead to short- and long-term neurobehavioral deficits. Till now there is no specific treatment that directly improves SAE and its associated behavioral impairments. In this review, we discuss the underlying mechanisms of sepsis-induced brain injury with a focus on the latest progress regarding neuroprotective eﬀects of SIRT1 (silent mating type information regulation-2 homologue-1). SIRT1 is an NAD+-dependent class III protein deacetylase. It is able to modulate multiple downstream signals (including NF-κB, HMGB, AMPK, PGC1α and FoxO) which are involved in the development of SAE by its deacetylation activity. There are multiple recent studies showing the neuroprotective eﬀects of SIRT1 in neuroinﬂammation related diseases. The proposed neuroprotective action of SIRT1 is meant to bring a promising therapeutic strategy for managing SAE and ameliorating its related behavioural deficits.
Psychopathy is characterized by glibness and superficial charm, as well as a lack of empathy, guilt, and remorse, and is often accompanied by antisocial behavior. The cerebral bases of this syndrome have been mostly studied in violent subjects or those with a criminal history. However, the antisocial component of psychopathy is not central to its conceptualization and, in fact, psychopathic traits are present in well-adjusted, non-criminal individuals within the general population. Interestingly, certain psychopathy characteristics appear to be particularly pronounced in some groups or professions. Importantly, as these so-called adaptive or successful psychopaths do not show antisocial tendencies or have significant psychiatric comorbidities, they may represent an ideal population to study this trait. Here we investigated such a group, specifically elite female judo athletes, and compared them to matched non-athletes. Participants completed psychopathy, anger, perspective-taking and empathic concern questionnaires and underwent structural magnetic resonance imaging (MRI). Grey matter density (GMD) was computed using voxel-based morphometry from the T1-weighted images. Athletes scored significantly higher in primary psychopathy and anger, and lower in empathy and perspective taking. They also exhibited smaller GMD in the right Temporal Pole, left Occipital Cortex, and left Amygdala/Hippocampus. GMD values for the latter cluster significantly correlated with primary psychopathy scores across both groups. These results confirm and extend previous findings to a little-studied population and provide support for the conceptualization of psychopathy as a dimensional personality trait which, not only is not necessarily associated with antisocial behavior, but may potentially have adaptive value.
Many clinical and research efforts aim to develop antidepressant drugs for those suffering from major depressive disorder (MDD). Yet even today, the available treatments are suboptimal and unpredictable, with a significant proportion of patients enduring multiple drug attempts and adverse side effects before a successful response; and for many patients, no response at all. Thus, a clearer understanding of the mechanisms underlying MDD is necessary. In the “Brain Development and Disease” class of our Master’s program in Cognitive Sciences, we ask students to collect data about the expression of a gene whose altered expression and/or function is related to a brain disorder. The students’ final exam assignment consists of writing a research article in which the collected data are discussed in relation to the relevant disorder. In the course of one of these assignments, we identified the FKBP5 gene as a key player uniting two major hypotheses of MDD pathogenesis and treatment response. FKBP5 controls biological processes including immunoregulation and glucocorticoid function, both of which are separately implicated in the development and prognosis of MDD. Gene expression analyses from the human, non-human primate, and mouse Allen Brain Atlases revealed that FKBP5 is expressed in brain regions involved in MDD, particularly at ages susceptible to early-life stressors. Data re-analysis from published studies confirmed that FKBP5 expression is upregulated in relevant brain regions in human MDD and preclinical mouse models of MDD. Our experience shows that classes engaging students in data collection and analysis projects may effectively result in novel data-driven hypotheses.
Consciousness is one of final questions for humans to tackle in neuroscience. Due to the lack of understanding of the basic brain network and mechanisms of functions, our knowledge of consciousness remains at the theoretical level. Recent studies using brain imaging in humans and modern neuroscience techniques in animal studies reveal a basic brain network for consciousness. The projection from the thalamus to different cortical regions form a network of activities to maintain consciousness in human and animals. These feedback and feedforward circuits maintain the consciousness even in certain brain injury conditions. Proteins and ion channels that contribute to these circuit neural activities are targets for drugs and manipulations that affect consciousness, such as anesthetic agents. Synaptic plasticity that trains synapses during learning and information recall, modify circuits and contribute to a high level of consciousness in certain populations.
Early life adversities alter the development of a still maturing nervous system and can have long-term consequences on its function at adult age. This include nociceptive circuits that are critical to shape an adaptive pain response to protect our organism from potentially damaging insults. As such, adult rats with a history of neonatal maternal separation (NMS) display a visceral and somatic nociceptive hypersensitivity and inefficient analgesic responses to stress. In this study, we have characterized the consequences of NMS on wide dynamic range neurons (WDR) in the spinal cord of anesthetized adult rat during the nociceptive processing of hot and cold noxious information. We found that WDR neurons of NMS rats display an excessive coding of mechanical and thermal information applied at the rat hindpaws. This nicely explains the hypernociceptive behaviors seen after noxious mechanical, cold and hot peripheral stimulation. A peripheral change in the expression of molecular transducers for these stimuli (i.e. TRPV1, TRPM8, TRPA1) does not seem to account for this general hyperexcitability. Instead, a decreased chloride-mediated inhibitory tone on WDR neurons may play a role as indicated by the abnormal elevated of the type 1 Na-K-Cl cotransporter transcripts. Altogether, we propose that long-term consequences of NMS is associated with a reduced spinal cord inhibition favoring the expression of pain hypersensitivity. We cannot exclude that this phenomenon is also present at supraspinal sites as other NMS-associated symptoms include also excessive anxiety and impaired sociability.
Functional connectivity (FC) indicates the interdependencies between brain signals recorded from spatially distinct locations in different frequency bands, which is modulated by cognitive tasks and is known to change with aging and cognitive disorders. Recently, the power of narrow-band gamma oscillations induced by visual gratings has been shown to reduce with both healthy aging and in subjects with mild cognitive impairment (MCI). However, the impact of aging/MCI on stimulus-induced gamma FC has not been well studied. We recorded electroencephalogram (EEG) from a large cohort (N=229) of elderly subjects (>49 years) while they viewed large cartesian gratings to induce gamma oscillations and studied changes in alpha and gamma FC with healthy aging (N=218) and MCI (N=11). Surprisingly, we found that aging and disease changed power and FC in different ways. With healthy aging, alpha power did not change but FC decreased significantly. MCI reduced gamma but not alpha FC significantly compared with age and gender matched controls, even when power was matched between the two groups. Overall, our results show distinct effects of aging and disease on EEG power and FC, suggesting different mechanisms underlying aging and cognitive disorders.
Expression of the immediate early gene Arc/Arg3.1 (Arc), a key mediator of synaptic plasticity, is enhanced by neural activity and then reduced by proteasome-dependent degradation. We have previously shown that disruption of Arc degradation, in an Arc knock-in mouse (ArcKR), where the predominant Arc ubiquitination sites were mutated, reduced the threshold to induce, and also enhanced, the strength of Group I metabotropic glutamate receptor-mediated long-term depression (DHPG-LTD). Here we have investigated if ArcKR expression changes long-term potentiation (LTP) in CA1 area of the hippocampus. As previously reported, there was no change in basal synaptic transmission at Schaffer collateral/commissural-CA1 (SC-CA1) synapses in ArcKR versus wild-type (WT) mice. There was however a significant increase in the amplitude of synaptically-induced (with low frequency paired-pulse stimulation) LTD in ArcKR mice. Theta burst stimulation-evoked LTP at SC-CA1 synapses was significantly reduced in ArcKR versus WT mice (after 2 hours). Group 1 mGluR priming of LTP was abolished in ArckR mice, which could also potentially contribute to a depression of LTP. Although high frequency-stimulation (HFS)-induced LTP was not significantly different in ArcKR compared to WT mice (after 1 hour) there was a phenotype in environmentally enriched mice, with the ratio of LTP to short-term potentiation (STP) significantly reduced in ArcKR mice. These findings support the hypothesis that Arc ubiquitination supports the induction and expression of LTP, likely via limiting Arc-dependent removal of AMPA receptors at synapses.
Limited axon regeneration following peripheral nerve injury may be related to activation of the lysosomal protease, asparaginyl endopeptidase (AEP, δ-secretase), and its degradation of the microtubule associated protein, Tau. Activity of AEP was increased at the site of sciatic nerve transection and repair but blocked in mice treated systemically with a specific AEP inhibitor, compound 11 (CP11). Treatments with CP11 enhanced axon regeneration in vivo. Amplitudes of compound muscle action potentials recorded four weeks after nerve transection and repair and two weeks after daily treatments with CP11 were double those of vehicle-treated mice. At that time after injury, axons of significantly more motor and sensory neurons had regenerated successfully and reinnervated the tibialis anterior and gastrocnemius muscles in CP11-treated mice than vehicle-treated controls. In cultured adult dorsal root ganglion neurons derived from wild type mice that were treated in vitro for 24 hours with CP11, neurites were nearly 50% longer than in vehicle-treated controls, and similar to neurite lengths in cultures treated with the TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF). Combined treatment with CP11 and 7,8-DHF did not enhance outgrowth more than treatments with either one alone. Enhanced neurite outgrowth produced by CP11 was found also in the presence of the TrkB inhibitor, ANA-12, indicating that the enhancement was independent of TrkB signaling. Longer neurites were found after CP11 treatment in both TrkB+ and TrkB- neurons. Delta secretase inhibition by CP11 is a treatment for peripheral nerve injury with great potential.
Parkinson’s disease is a neurodegenerative disorder characterized by the progressive dysfunction and loss of dopamine (DA) neurons of the substantia nigra pars compacta (SNc). Several pathways of programmed cell death are likely to play a role in DA neuron death, such as apoptosis, necrosis, pyroptosis, ferroptosis as well as cell death associated with proteasomal and mitochondrial dysfunction. A better understanding of the molecular mechanisms underlying DA neuron death could inform the design of drugs that promote neuron survival. Necroptosis is a recently characterized regulated cell death mechanism that exhibits morphological features common to both apoptosis and necrosis. It requires activation of an intracellular pathway involving receptor-interacting protein 1 (RIP1) and its kinase (RIP1 kinase, RIPK1), receptor-interacting protein 3 (RIP3) and its kinase (RIP3 kinase, RIPK3), and mixed lineage kinase domain like pseudokinase (MLKL). The potential involvement of this programmed cell death pathway in the pathogenesis of PD has been studied by analyzing the biomarkers for necroptosis, such as the levels and oligomerization of pRIPK3 and pMLKL, in several PD preclinical models and in PD human tissue. While there is evidence that other types of cell death also have a role in DA neuron death, most studies support the hypothesis that this cell death mechanism is activated in PD tissues. Thus drugs that prevent or reduce necroptosis may provide neuroprotection for PD. In this review, we summarize the findings from these studies. We also discuss how manipulating necroptosis might open a novel therapeutic approach to reduce neuronal degeneration in PD.
It is generally accepted that Cyclooxygenase-2 (COX-2) is activated to cause inflammation. However, COX-2 is also constitutively expressed at the postsynaptic dendrites and excitatory terminals of the cortical and spinal cord neurons. Although some evidence suggests that COX-2 release during neuronal signaling may be pivotal for regulating the function of memory, the significance of constitutively expressed COX-2 in neuron is still unclear. This research aims to discover the role of COX-2 in memory beyond neuroinflammation and to determine whether the inhibition of COX-2 can cause cognitive dysfunction by influencing dendritic plasticity and its underlying mechanism. The cognitive ability was assessed by novel object recognition task (NORT) and Morris water maze (MWM) test. Immunofluorescence, Golgi-cox staining were used to observe dendritic synaptic. Gamma oscillation in hippocampus CA1 was performed by Tetrode in-vivo recording. Prostaglandins were measured by HPLC/mass spectrometry. We observed the expressions of cyclic adenosine monophosphate (cAMP)/ brain-derived neurotrophic factor (BDNF) pathway proteins in hippocampus and N2a cells by Elisa and western blot. We found COX-2 gene knockout (KO) could significantly impact the learning and memory ability; reduce the expression of postsynaptic density protein 95 (PSD95) in the neuron; cause synaptic disorder; influence gamma oscillation and reduce the expression prostaglandin (PG) E2, cAMP, phosphorylated protein kinase A (p-PKA), phosphorylated cAMP response element binding protein (p-CREB) and BDNF in the hippocampus. It suggested COX-2 might play a critical role in learning, regulating synaptic plasticity and gamma oscillation in the hippocampus CA1 by regulating COX-2/BDNF signaling pathway.
Alcohol abuse is not only responsible for 5.3% of the total deaths in the world, but also has a substantial impact on neurological and memory disabilities throughout the population. One extensively studied brain area involved in cognitive functions is the hippocampus. Evidence in several rodent models has shown that ethanol produces cognitive impairment in hippocampal-dependent tasks and that the damage is varied according to the stage of development at which the rodent was exposed to ethanol and the dose. To the authors’ knowledge, there is a biomarker for cognitive processes in the hippocampus that has not been evaluated in association with memory impairment by alcohol administration. This biomarker is called Sharp Wave Ripples which are synchronous neuronal population events that are well known to be involved in memory consolidation. Methodologies for facilitation or automatic identification of ripples and their analysis have been reported for a wider bandwidth than Sharp Wave Ripples. This review is focused on communicating the state-of-the art about the relationship between alcohol, memory consolidation and ripple activity as well as the use of the main methodologies to identify SWRs automatically.
Combining magnetic resonance imaging (MRI) data from multi-site studies is a popular approach for constructing larger datasets to greatly enhance the reliability and reproducibility of neuroscience research. However, the scanner/site variability is a significant confound that complicates the interpretation of the results, so effective and complete removal of the scanner/site variability is necessary to realize the full advantages of pooling multi-site datasets. Independent component analysis (ICA) and general linear model (GLM) based harmonization methods are the two primary methods used to eliminate scanner/site-related effects. Unfortunately, there are challenges with both ICA-based and GLM-based harmonization methods to remove site effects completely when the signals of interest and scanner/site-related variables are correlated, which may occur in neuroscience studies. In this study, we propose an effective and powerful harmonization strategy that implements dual-projection (DP) theory based on ICA to remove the scanner/site-related effects more completely. This method can separate the signal effects correlated with site variables from the identified site-related effects for removal without losing signals of interest. Both simulations and vivo structural MRI datasets, including a dataset from Autism Brain Imaging Data Exchange II and a traveling subject dataset from the Strategic Research Program for Brain Sciences, were used to test the performance of DP-based ICA harmonization method. Results show that DP-based ICA harmonization has superior performance for removing site effects and enhancing the sensitivity to detect signal of interest as compared with GLM-based and conventional ICA harmonization methods.
Multimodal studies evaluating associations between specific for Parkinson’s disease (PD) neuroimaging and neurophysiological biomarkers in revealing executive dysfunction mechanisms are scarce and needed to be validated. Hence, our study aimed to evaluate associations between electroencephalographic power spectral density (PSD-EEG), striatal [18F]Fluorodopa uptake and neuropsychological testing parameters in PD. Additional aim was to estimate PD diagnostic accuracy of the PSD-EEG parameters. We compared resting PSD-EEG, striatal [18F]Fluorodopa uptake ratio with positron emission computed tomography ([18F]FDOPA PET/CT), and neuropsychological test outcomes between PD patients and healthy controls, and then calculated correlations among these outcomes. Additionally we estimated PD diagnostic sensitivity and specificity (with the receiver operating characteristic curves) of the PSD-EEG parameters in reference to the gold diagnostic standard of the striatal [18F]FDOPA PET/CT uptake ratio.PD patients exhibited (i) increased power of the EEG theta and lower-alpha bands in the frontal lobe areas, (ii) decreased putaminal and caudate nuclei [18F]FDOPA PET/CT uptake ratios and (iii) longer performance times of part A and B of the Trail Making Test (TMT-A and TMT-B). Most of the PSD-EEG parameters negatively correlated with striatal [18F]FDOPA PET/CT uptake ratios and positively correlated with TMT-A and TMT-B. Furthermore, [18F]FDOPA PET/CT uptake ratios positively correlated with TMT-A and TMT-B. Theta and lower-alpha bands PSD-EEG were found to have high diagnostic accuracy. Our findings showed that slowing of EEG waves in the frontal lobe was correlated with striatal dopaminergic deficiency and executive dysfunction in mild PD patients, and appears to be a promising biomarker of PD-related executive dysfunction.
The dopaminergic system is implicated in the pathophysiology of migraine. However, the underlying mechanisms remain unclear. We explored the effects and mechanisms of dopaminergic system modulation in the in-vivo and in-vitro rat models of migraine. Dopaminergic agonist apomorphine, D2 receptor antagonists metoclopramide and haloperidol, and 5-HT3 receptor antagonist ondansetron alone and together were tested in nitroglycerin-induced migraine model, in vivo. Likewise, the combinations of drugs were also tested on basal CGRP release in-vitro hemiskull preparations. Mechanical allodynia was tested by von-Frey filaments. CGRP concentrations in trigeminovascular structures and in-vitro superfusates, and c-Fos levels in brainstem were determined by ELISA. Meningeal-mast cells were evaluated with toluidine-blue staining. Apomorphine further enhanced nitroglycerin-induced mechanical allodynia, brainstem c-fos expression, trigeminal ganglion and brainstem CGRP concentrations, and meningeal mast cell degranulation, in vivo. Haloperidol completely antagonised all apomorphine-induced effects and also alleviated changes induced by nitroglycerin without apomorphine. Metoclopramide and ondansetron partially attenuated apomorphine- or nitroglycerin-induced effects. A combination of haloperidol and ondansetron decreased basal CGRP release, in-vitro, while the other administrations were ineffective. Apomorphine-mediated dopaminergic activation exacerbated nitroglycerin-stimulated migraine pain by further enchancing c-fos expression, CGRP release and mast cell degranulation in strategical structures associated with migraine pain. Metoclopramide partially attenuated the effects of apomorphine, most likely because it is also a 5-HT3 receptor antagonist. Haloperidol with pure D2 receptor antagonism feature appears to be more effective than metoclopramide in reducing migraine-related parameters in dopaminergic activation- and/or NTG-induced migrane like conditions.