Objective: In this study we use the CAG140 HD mouse model, chosen for its slow progression with motor symptoms emerging at 12 months of age and provide evidence of the benefits of long-term treadmill running. Background: Huntington’s... more
Objective: In this study we use the CAG140 HD mouse model, chosen for its slow progression with motor symptoms emerging at 12 months of age and provide evidence of the benefits of long-term treadmill running. Background: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by progressive decline in cognitive and motor functions with neuropsychiatric disturbances. Defects in the respiratory chain in HD have been observed in early biochemical studies. Severe reduction in the activity of complex II/III and milder reduction of complex IV were found in post mortem samples of the caudate/putamen in HD patients. The cerebral cortex showed minor changes in respiratory chain enzymes. Massive loss of aconitase activity has been found in the caudate (~90%), and putamen (~70%). Nitric oxide is a hydrophobic gas which can cross all biological membranes without mediation of channels or receptors. Nitric oxide is biosynthesized endogenously from L-arginine, nitric oxide synthase (NOS), oxide, and nicotinamide adenine dinucleotide phosphate (NADPH) enzymes. Nitric oxide is membrane permeable and has the ability to diffuse into dopaminergic neurons, thereby allowing NO receptors to be utilized for signaling transduction for intracellular communication. Design/Methods: HD and WT mice of two separate ages (9 and 15 months) ran for 3 months 60 mins per day 5 days a week. Studies include mitochondrial complex activity with isolated brain mitochondria, behavior and motor function tests, and measurements of substrate related to the nitric oxide pathway in brain homogenate. Results: Chronic cardiovascular exercise improved mitochondrial complex activities, motor function, cognition, and elevated nitrite/nitrate and aconitase levels in the brain. Conclusions: We explore a novel hypothesis that elevated nitric oxide stored as nitrosothiols from chronic exercise links mitochondrial brain metabolism and cerebral vasculature through the proposed mechanism of decreasing transglutaminase activity. Disclosure: Dr. Caldwell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with BluePath Solutions. Dr. Cadenas has nothing to disclose.
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l‐Lactate is an energetic and signaling molecule that may be produced through astrocyte‐specific aerobic glycolysis and is elevated in striatal muscle during intensive exercise. l‐Lactate has been shown to promote neurotrophic gene... more
l‐Lactate is an energetic and signaling molecule that may be produced through astrocyte‐specific aerobic glycolysis and is elevated in striatal muscle during intensive exercise. l‐Lactate has been shown to promote neurotrophic gene expression through astrocytes within the hippocampus, however, its role in neuroplasticity within the striatum remains unknown. This study sought to investigate the role of peripheral sources of l‐lactate in promoting astrocyte‐specific gene expression and morphology as well as its role in neuroplasticity within the striatum of healthy animals. Using in vitro primary astrocyte cell culture, administration of l‐lactate increased the expression of the neurotrophic factors Bdnf, Gdnf, Cntf, and the immediate early gene cFos. l‐Lactate's promotion of neurotrophic factor expression was mediated through the lactate receptor HCAR1 since application of the HCAR1 agonist 3,5‐DHBA also increased expression of Bdnf in primary astrocytes. Similar to our previous report demonstrating exercise‐induced changes in astrocytic structure within the striatum, l‐lactate administration to healthy mice led to increased astrocyte morphological complexity as well as astrocyte‐specific neurotrophic expression within the striatum. Our study failed to demonstrate an effect of peripheral l‐lactate on synaptogenesis or motor behavior. Insufficient levels and/or inadequate delivery of l‐lactate through regional cerebral blood flow within the striatum may account for the lack of these benefits. Taken together, these novel findings suggest a potential framework that links peripheral l‐lactate production within muscle and intensive exercise with neuroplasticity of specific brain regions through astrocytic function.
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Administration of the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to C57BL/6 mice targets nigrostriatal dopaminergic neurons, leading to cell death and the depletion of striatal dopamine. After MPTP lesioning in... more
Administration of the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to C57BL/6 mice targets nigrostriatal dopaminergic neurons, leading to cell death and the depletion of striatal dopamine. After MPTP lesioning in young adult mice, surviving nigrostriatal dopaminergic neurons display robust and reproducible return of striatal dopamine weeks to months after injury. Thus, the mouse provides an excellent model with which to investigate the mechanisms underlying neuroplasticity of the nigrostriatal system following neurotoxic injury. The purpose of this study was to analyze proteins and mRNA transcripts of genes involved in dopamine biosynthesis (tyrosine hydroxylase; TH) and uptake (dopamine transporter; DAT) with regard to time course (7-90 days) after MPTP lesioning. Molecular analysis using immunohistochemistry and Western immunoblotting techniques demonstrated an increase in striatal TH by 30-60 days postlesioning that returned to near-control (prelesioned) levels by 60-90 days. In situ hybridization histochemistry indicated that this increase in TH protein might be due in part to increased TH mRNA expression in surviving nigrostriatal dopaminergic neurons. Analysis of TH protein at 7, 30, 60, and 90 days postlesioning with two-dimensional polyacrylamide gel electrophoresis in conjunction with Western immunoblotting revealed altered TH protein isoforms migrating at isoelectric points different from those of the native isoform. In contrast to TH protein, which returned to prelesioned levels by 60 days, DAT protein analysis showed that increased expression of striatal DAT protein did not return to near-prelesion levels until 90 days postlesioning. These results suggest that TH and DAT may differ in their time course of expression in surviving dopaminergic neurons and may play a role in mediating the return of striatal dopamine.
Research Interests: Endocrinology, Neuroscience, Biology, Immunohistochemistry, Medicine, and 15 moreIn Situ Hybridization, Dopamine, Internal Medicine, Mice, Animals, Neurons, Membrane transport proteins, High Pressure Liquid Chromatography, Analysis of Variance, Dopamine Transporter, Neurosciences, dopaminergic, Corpus striatum, Cell count, and MPTP
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Publisher Summary This chapter provides an overview of the nonhuman primate models of Parkinson's disease and experimental therapeutics. The nonhuman primate model serves as an important model for understanding the pathophysiology of... more
Publisher Summary This chapter provides an overview of the nonhuman primate models of Parkinson's disease and experimental therapeutics. The nonhuman primate model serves as an important model for understanding the pathophysiology of the basal ganglia, evaluating new treatment modalities for neurodegenerative disorders affecting this region, especially Parkinson's disease (PD). It provides a valuable tool for discovery of new therapeutic targets that may lead to a cure for PD. The nonhuman primate model generated through either neurotoxicant or surgical lesioning has been most commonly used for experimental therapeutic studies in PD, in particular for identifying new symptomatic strategies primarily targeting the dopaminergic system, as well as those neurotransmitter systems known to modulate dopamine. The model is extremely valuable in providing important insights into the pathophysiology and treatment of levodopa-induced dyskinesia, a disabling complication of long-term levodopa use in PD. This chapter begins with a discussion on assessment of motor behavior in nonhuman primate models of PD. It explains nonmotor features in MPTP-leasioned nonhuman primates in detail. The MPTP-lesioned nonhuman primate model is also reviewed in the chapter. The chapter concludes with a discussion on electrophysiological studies of basal ganglia function in the nonhuman primate model of PD.
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Research Interests: Neuroscience, Psychology, Biology, Membrane Proteins, Medicine, and 15 moreGene expression, In Situ Hybridization, Cerebral Cortex, Animals, Male, Brain injury, Structural Change, Rats, Motor Function, Lesion, Neurosciences, Functional Laterality, Motor activity, Brain injuries, and functional outcome
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Animal models of neurological disorders are critical for determining underlying disease mechanisms and developing new therapeutic modalities. In general, the utility of an animal model for a particular disease is often dependent on how... more
Animal models of neurological disorders are critical for determining underlying disease mechanisms and developing new therapeutic modalities. In general, the utility of an animal model for a particular disease is often dependent on how closely the model replicates all or part of the human condition. In Parkinson’s disease (PD) and related parkinsonian disorders there now exists a variety of animal models, each of which makes a unique contribution to our understanding of the human condition. These models have been derived in a variety of species (pig, nonhuman primate, rodent, and cat) using multiple techniques, including (1) surgical lesioning, (2) pharmacological manipulation, (3) administration of neurotoxicants, and (4) genetic alterations. While these models are not identical to the human condition with respect to behavioral characteristics, brain anatomy, or disease progression, they have provided significant advancements in our understanding of the underlying mechanisms and treatment of movement disorders such as PD.
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Page 1. Chapter 3 Correlates and Analysis of Motor Function in Humans and Animal Models of Parkinson's Disease Alexandra Y. Schang, Beth E. Fisher, Natalie R. Sashkin, Cindy Moore, Lisa B. Dirling, Giselle M. Petzinger, Michael W.... more
Page 1. Chapter 3 Correlates and Analysis of Motor Function in Humans and Animal Models of Parkinson's Disease Alexandra Y. Schang, Beth E. Fisher, Natalie R. Sashkin, Cindy Moore, Lisa B. Dirling, Giselle M. Petzinger, Michael W. Jakowec, and Charles K. Meshul Abstract ...
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The basal ganglia are important modulators of the cognitive and motor benefits of exercise. However, the neural networks underlying these benefits remain poorly understood. Our study systematically analyzed exercise-associated changes in... more
The basal ganglia are important modulators of the cognitive and motor benefits of exercise. However, the neural networks underlying these benefits remain poorly understood. Our study systematically analyzed exercise-associated changes in metabolic connectivity in the cortico-basal ganglia-thalamic network during the performance of a new motor task, with regions-of-interest defined based on mesoscopic domains recently defined in the mouse brain structural connectome. Mice were trained on a motorized treadmill for six weeks or remained sedentary (control), thereafter undergoing [14C]-2-deoxyglucose metabolic brain mapping during wheel walking. Regional cerebral glucose uptake (rCGU) was analyzed in 3-dimensional brains reconstructed from autoradiographic brain sections using statistical parametric mapping. Metabolic connectivity was assessed by calculating inter-regional correlation of rCGU cross-sectionally across subjects within a group. Compared to controls, exercised animals showe...
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Objective Higher volume fraction of perivascular space (PVS) has recently been reported in Parkinson’s disease (PD) and related disorders. Both elevated PVS and altered levels of neurometabolites, assayed by proton magnetic resonance... more
Objective Higher volume fraction of perivascular space (PVS) has recently been reported in Parkinson’s disease (PD) and related disorders. Both elevated PVS and altered levels of neurometabolites, assayed by proton magnetic resonance spectroscopy (MRS), are suspected indicators of neuroinflammation, but no published reports have concurrently examined PVS and MRS neurometabolites. Methods In an exploratory pilot study, we acquired multivoxel 3-T MRS using a semi-Localization by Adiabatic SElective Refocusing (sLASER) pulse-sequence (repetition time/echo time = 2810/60 ms, voxels 10 × 10 × 10 mm3) from a 2D slab sampling bilateral frontal white matter (FWM) and anterior middle cingulate cortex (aMCC). PVS maps obtained from high-resolution (0.8 × 0.8 × 0.8 mm3) T1-weighted MRI were co-registered with MRS. In each MRS voxel, PVS volume and neurometabolite levels were measured. Results Linear regression accounting for age, sex, and BMI found greater PVS volume for higher levels of choli...
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BACKGROUND Physical activity (PA) is known to improve quality of life (QoL) as well as reduce mortality and disease progression in individuals with chronic neurological disorders. However, Latina women are less likely to participate in... more
BACKGROUND Physical activity (PA) is known to improve quality of life (QoL) as well as reduce mortality and disease progression in individuals with chronic neurological disorders. However, Latina women are less likely to participate in recommended levels of PA due to common socioeconomic barriers, including limited resources and access to exercise programs. Therefore, we developed a community-based intervention with activity monitoring and behavioral coaching to target these barriers and facilitate sustained participation in an exercise program promoting PA. OBJECTIVE The aim of this study was to determine the feasibility and efficacy of a community-based intervention to promote PA through self-monitoring via a Fitbit and behavioral coaching among Latina participants with chronic neurological disorders. METHODS We conducted a proof-of-concept study among 21 Spanish-speaking Latina participants recruited from the Los Angeles County and University of Southern California (LAC+USC) neur...
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Alcohol use disorders (AUD) continue to have a staggering impact on individuals and society. Current available therapeutics are few and only produce limited results. This chapter discusses the preclinical investigations of avermectins as... more
Alcohol use disorders (AUD) continue to have a staggering impact on individuals and society. Current available therapeutics are few and only produce limited results. This chapter discusses the preclinical investigations of avermectins as novel AUD treatments. We found that the ability of certain avermectins (e.g., ivermectin, moxidectin) to reduce ethanol intake in mice strongly correlates with their ability to antagonize ethanol inhibition on purinergic P2X4 receptors (P2X4Rs) in vitro. The use of P2X4R knockout animal model confirms that the majority of the antialcohol effect for these avermectins comes from their activity on P2X4Rs. Drug treatments did not cause any signs of overt toxicity, tolerance, or dependence. Overall, our findings support the potential clinical utility of avermectins as a novel group of compounds for the treatment of AUD and that P2X4R can be used as a platform for the continuing development of more effective antialcohol medications.
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BackgroundThe glymphatic system, including the perivascular space (PVS), plays a critical role in brain homeostasis. Although mounting evidence from Alzheimer's disease has supported the potential role of PVS in neurodegenerative... more
BackgroundThe glymphatic system, including the perivascular space (PVS), plays a critical role in brain homeostasis. Although mounting evidence from Alzheimer's disease has supported the potential role of PVS in neurodegenerative disorders, its contribution in Parkinson's disease (PD) has not been fully elucidated. Although idiopathic (IPD) and familial PD (FPD) share similar pathophysiology in terms of protein aggregation, the differential impact of PVS on PD subtypes remains unknown. Our objective was to examine the differences in PVS volume fraction in IPD and FPD compared to healthy controls (HCs) and nonmanifest carriers (NMCs).MethodsA total of 470 individuals were analyzed from the Parkinson's Progression Markers Initiative database, including (1) IPD (n = 179), (2) FPD (LRRK2 [leucine‐rich repeat kinase 2], glucocerebrosidase, or α‐synuclein) (n = 67), (3) NMC (n = 101), and (4) HCs (n = 84). Total PVS volume fraction (%) was compared using parcellation and quant...
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Background: Studies in aging older adults have shown the positive association between cognition and exercise related fitness, particularly cardiorespiratory fitness. These reports have also demonstrated the association of high... more
Background: Studies in aging older adults have shown the positive association between cognition and exercise related fitness, particularly cardiorespiratory fitness. These reports have also demonstrated the association of high cardiorespiratory fitness, as well as other types of fitness, on the reversal of age-related decline in neural network connectivity, highlighting the potential role of fitness on age- and disease-related brain changes. While the clinical benefits of exercise are well-documented in Parkinson’s disease (PD), the extent to which cardiorespiratory fitness (assessed by estimated VO2max testing) or motor skill fitness (assessed by the Physical Performance Test (PPT)) affects neural network connectivity in PD remains to be investigated. The purpose of this study was to explore the hypothesis that higher fitness level is associated with an increase in the intrinsic network connectivity of cognitive networks commonly affected in PD. Methods: In this cross-sectional res...
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BACKGROUND Physical activity is known to improve quality of life as well as reduce mortality and disease progression in individuals with chronic neurological disorders. However, Latinas are less likely to participate in recommended levels... more
BACKGROUND Physical activity is known to improve quality of life as well as reduce mortality and disease progression in individuals with chronic neurological disorders. However, Latinas are less likely to participate in recommended levels of physical activity due to common socioeconomic barriers including limited resources and access to exercise programs. Therefore, we developed a community-based intervention with activity-monitoring and behavioral coaching to target these barriers and facilitate sustained participation in an exercise program promoting physical activity. OBJECTIVE To determine the feasibility and efficacy of a community-based intervention to promote physical activity (PA) through self-monitoring via a Fitbit and behavioral coaching in Latina participants with chronic neurological disorders. METHODS We conducted a proof-of-concept study in 21 Spanish-speaking Latina participants recruited from the Los Angeles County/ University of Southern California (LAC/USC) neurol...
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Purinergic P2X4 receptors (P2X4Rs) are ion channels gated by adenosine‐5′‐triphosphate in the brain. Recent investigations from our laboratory have reported a role for P2X4Rs in regulation of various behaviors including sensorimotor... more
Purinergic P2X4 receptors (P2X4Rs) are ion channels gated by adenosine‐5′‐triphosphate in the brain. Recent investigations from our laboratory have reported a role for P2X4Rs in regulation of various behaviors including sensorimotor gating, emotional responses to acute stressors, motor behavior and drug reward. Amongst these behaviors, our laboratory was greatly interested in the role of P2X4Rs in regulation of sensorimotor gating considering that disruption of this function has major implications in wide spectrum of psychiatric disorders including schizophrenia, bipolar disorder and autism. Sensorimotor gating is the process by which irrelevant stimuli can be filtered out prior to generation of motor output in response to a sensory stimulus. This process allows an individual to efficiently navigate a stimulus‐laden environment with minimum distraction. Positive modulation of P2X4Rs by ivermectin (IVM) induced deficits in prepulse inhibition (PPI) of acoustic startle reflex, which i...
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ObjectiveMild cognitive impairment (MCI) and psychiatric symptoms (anxiety, depression, and apathy) are common in Parkinson's disease (PD). While studies have supported the association between psychiatric symptoms and cognitive... more
ObjectiveMild cognitive impairment (MCI) and psychiatric symptoms (anxiety, depression, and apathy) are common in Parkinson's disease (PD). While studies have supported the association between psychiatric symptoms and cognitive performance in PD, it is unclear if the magnitude of link between psychiatric symptoms and cognitive health is stronger by MCI status. The purpose of this study was to examine the association between cognitive performance and psychiatric symptoms in PD and whether MCI status moderates this association.Methods/DesignParticipants (N = 187) completed a comprehensive neuropsychological assessment that included measures of attention, language, executive function (EF), visuospatial ability, episodic memory, and psychiatric symptoms. Participants were classified as PD‐MCI (N = 73) or PD‐normal cognition (NC; N = 114). Linear regression analyses were conducted to examine the association between psychiatric symptoms and cognitive performance and the moderating eff...
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Neuroimaging, especially functional brain mapping, may provide insights into the distributed involvement of multiple brain regions and loops in disorders classically associated with pathology of a localized region. One example is... more
Neuroimaging, especially functional brain mapping, may provide insights into the distributed involvement of multiple brain regions and loops in disorders classically associated with pathology of a localized region. One example is Huntington's disease (HD), typically classified as a basal ganglia disorder. Here, we report genotypic differences in cerebral perfusion mapping in an HD mouse model characterized by a gene knock-in (KI) of a human exon 1 CAG140 expansion repeat (CAG140 KI mice). Animals were examined at 6 months and compared with wild-type littermates. Regional cerebral blood flow (rCBF) was mapped in the awake, nonrestrained, male mouse at rest using [C]-iodoantipyrine autoradiography and analyzed in three-dimensionally reconstructed brains by statistical parametric mapping. Our results showed significant changes in rCBF between CAG140 KI and WT mice, such that CAG140 KI animals showed hypoperfusion of the basal ganglia motor circuit and hyperperfusion of cerebellar-t...
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A series of compounds, including glycine betaine and proline, known to accumulate in plants during osmotic stress, have been found to function as osmoprotective compounds for bacteria. In fulfilling “Koch’s Postulates” for the biological... more
A series of compounds, including glycine betaine and proline, known to accumulate in plants during osmotic stress, have been found to function as osmoprotective compounds for bacteria. In fulfilling “Koch’s Postulates” for the biological activity of these compounds, they have been found to protect against osmotic stress when added to the growth medium in relatively low concentration, or when synthesized in the cell. Cells may accumulate very high intracellular levels corresponding to the osmolarity of the medium using uptake systems that appear to be osmotically modulated. A proline overproducing mutation conferring osmotic tolerance has been constructed. Molecular cloning of an osmotic tolerance gene has been achieved. A unified concept of osmoregulation in microorganisms, animals and plants is discussed with some possible applications being pointed out.
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Cessation of lactation causes a massive loss of surplus lactotrophs in the rat pituitary gland. The factors and mechanisms involved in this phenomenon have not yet been elucidated. Besides its inhibitory control on prolactin secretion and... more
Cessation of lactation causes a massive loss of surplus lactotrophs in the rat pituitary gland. The factors and mechanisms involved in this phenomenon have not yet been elucidated. Besides its inhibitory control on prolactin secretion and lactotroph proliferation, evidence suggests that dopamine (DA) may be a proapoptotic factor for lactotrophs. We therefore tested the proapoptotic effect of DA on pituitary glands from virgin, lactating, and postlactating rats. By measuring mitochondrial membrane potential loss, caspase-3 activation, and nuclear fragmentation, we show that DA induces apoptosis specifically in lactotrophs from postlactating rats. We then determined that this effect was partly mediated by the DA transporter (DAT) rather than the D2 receptor, as corroborated by the detection of DAT expression exclusively in lactotrophs from postlactating rats. We also observed tyrosine hydroxylase (TH) expression in postlactating lactotrophs that was accompanied by an increase in DA co...
Research Interests: Endocrinology, Lactation, Apoptosis, Biological Sciences, Dopamine, and 15 moreProlactin, Internal Medicine, Female, Animals, Cell Death, Inhibitory Control, Caspase, Apoptose, Pituitary Gland, Rat, Dopamine Transporter, Mitochondrial Membrane Potential, Anterior Pituitary, Gene Expression Regulation, and Medical and Health Sciences
Introduction:Cognitive deficits occur in Parkinson’s disease (PD). Cardiorespiratory fitness (CRF) is associated with better cognitive performance in aging especially in executive function (EF) and memory. The association between CRF and... more
Introduction:Cognitive deficits occur in Parkinson’s disease (PD). Cardiorespiratory fitness (CRF) is associated with better cognitive performance in aging especially in executive function (EF) and memory. The association between CRF and cognitive performance is understudied in people with PD. Brain structures underlying associations also remains unknown. This cross-sectional study examined the associations between CRF and cognitive performance in PD. We also examined associations between CRF and brain structures impacted in PD. Mediation analysis were conducted to examine whether brain structures impacted in PD mediate putative associations between CRF and cognitive performance.Methods:Individuals with PD (N=33) underwent magnetic resonance imaging (MRI), CRF evaluation (estimated VO2max), and neuropsychological assessment. Composite cognitive scores of episodic memory, EF, attention, language, and visuospatial functioning were generated. Structural equation models were constructed to examine whether MRI volume estimates (thalamus and pallidum) mediated associations between CRF and cognitive performance (adjusting for age, education, PD disease duration, sex, MDS-UPDRS motor score, and total intracranial volume).Results:Higher CRF was associated with better episodic memory (Standardized β=0.391; p=0.008), EF (Standardized β=0.324; p=0.025), and visuospatial performance (Standardized β=0.570; p=0.005). Higher CRF was associated with larger thalamic (Standardized β=0.722; p=0.004) and pallidum (Standardized β=0.635; p=0.004) volumes. Thalamic volume mediated the association between higher CRF and better EF (Indirect effect=0.309) and episodic memory (Indirect effect=0.209) performance (p<0.05). The pallidum did not significantly mediate associations between CRF and cognitive outcomes.Conclusion:The thalamus plays an important role in the association between CRF and both EF and episodic memory in PD.
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L-lactate is an energetic and signaling molecule that is key to the metabolic and neuroplastic connection between astrocytes and neurons and may be involved in exercise-induced neuroplasticity. This study sought to explore the role of... more
L-lactate is an energetic and signaling molecule that is key to the metabolic and neuroplastic connection between astrocytes and neurons and may be involved in exercise-induced neuroplasticity. This study sought to explore the role of L-lactate in astrocyte reactivity and neuroplasticity. Using in vitro cultures of primary astrocytes, we show L-lactate increased expression of plasticity-related genes, including neurotrophic factors, Bdnf, Gdnf, Cntf and the immediate early gene cFos. L-lactate’s promotion of neurotrophic factor expression may be mediated in part by the lactate receptor HCAR1 since application of the HCAR1 agonist 3,5-DHBA also increased expression of Bdnf in primary astrocytes. In vivo L-lactate administration to healthy mice caused a similar increase in the expression of plasticity-related genes as well as increased astrocyte morphological complexity in a region-specific manner, with increased astrocytic response found in the striatum but not the ectorhinal cortex,...
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Impaired motor learning in individuals with Parkinson’s disease is often attributed to deficits in executive function, which serves as an important cognitive process supporting motor learning. However, less is known about the role of... more
Impaired motor learning in individuals with Parkinson’s disease is often attributed to deficits in executive function, which serves as an important cognitive process supporting motor learning. However, less is known about the role of other cognitive domains and its association with motor learning in Parkinson’s disease. The objective of this study was to investigate the associations between motor learning and multiple domains of cognitive performance in individuals with Parkinson’s disease. Twenty-nine participants with Parkinson’s disease received comprehensive neuropsychological testing, followed by practice of a bimanual finger sequence task. A retention test of the finger sequence task was completed 24 h later. Hierarchical linear regressions were used to examine the associations between motor learning (acquisition rate and retention) and cognitive performance in five specific cognitive domains, while controlling for age, sex, and years of Parkinson’s disease diagnosis. We found that a higher acquisition rate was associated with better episodic memory, specifically better recall in visual episodic memory, in individuals with Parkinson’s disease. No significant associations were observed between retention and cognitive performance in any domains. The association between motor acquisition and episodic memory indicates an increased dependency on episodic memory as a potential compensatory cognitive strategy used by individuals with Parkinson’s disease during motor learning.
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IS1 is one of the smallest transposable elements found in bacteria (768 bp). It contains eight overlapping open-reading-frames (ORFs) greater than 50 codons, designated insA to insG and insB'. To determine which of the ORFs actually... more
IS1 is one of the smallest transposable elements found in bacteria (768 bp). It contains eight overlapping open-reading-frames (ORFs) greater than 50 codons, designated insA to insG and insB'. To determine which of the ORFs actually code for proteins involved in transposition, we have introduced amber codons into each ORF by site-directed mutagenesis which make neutral changes in the overlapping ORFs. Each mutant IS1 was then tested for its ability to mediate cointegrate formation in Su+ and Su- backgrounds. The mutant elements were also tested for trans-complementation in an IS1-free Salmonella background. Our results show that the products of the insA and insB genes are the only ones essential for cointegrate formation. We suggest that other ORFs may, however, encode accessory proteins.
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Exercise and other forms of physical activity lead to the activation of specific motor and cognitive circuits within the mammalian brain. These activated neuronal circuits are subjected to increased metabolic demand and must respond to... more
Exercise and other forms of physical activity lead to the activation of specific motor and cognitive circuits within the mammalian brain. These activated neuronal circuits are subjected to increased metabolic demand and must respond to transient but significant reduction in available oxygen. The transcription factor hypoxia-inducible factor 1&agr; (HIF-1&agr;) is a regulatory mediator of a wide spectrum of genes involved in metabolism, synaptogenesis, and blood flow. The purpose of this study was to begin to explore the potential relationship between exercise in the form of running on a motorized treadmill and the activation of genes involved in exercise-dependent neuroplasticity to begin to elucidate the underlying molecular mechanisms involved. Mice were subjected to treadmill exercise and striatal tissues analyzed with a commercial microarray designed to identify transcripts whose expression is altered by exposure to hypoxia, a condition occurring in cells under a high metabolic demand. Several candidate genes were identified, and a subset involved in metabolism and angiogenesis were selected to elucidate their temporal and regional patterns of expression with exercise. Transcript analysis included Hif1a (hypoxia-inducible factor 1&agr;), Ldha (lactate dehydrogenase A), Slc2a1 (glucose transporter 1), Slc16a1 (monocarboxylate transporter 1), Slc16a7 (monocarboxylate transporter 2), and Vegf (vascular endothelial growth factor). Overall these results indicate that several genes involved in the elevated metabolic response with exercise are consistent with increased expression of HIF-1&agr; suggesting a regulatory role for HIF-1&agr; in exercise-enhanced neuroplasticity. Furthermore, these increases in gene expression appear regionally specific; occurring with brain regions we have previously shown to be sites for increased cerebral blood flow with activity. Such findings are beginning to lay down a working hypothesis that specific forms of exercise lead to circuit specific neuronal activation and can identify a potentially novel therapeutic approach to target dysfunctional behaviors subserved by such circuitry.
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A paradox is a seemingly absurd or impossible concept, proposition, or theory that is often difficult to understand or explain, sometimes apparently self-contradictory, and yet ultimately correct or true. How is it possible, for example,... more
A paradox is a seemingly absurd or impossible concept, proposition, or theory that is often difficult to understand or explain, sometimes apparently self-contradictory, and yet ultimately correct or true. How is it possible, for example, that oxygen "a toxic environmental poison" could be also indispensable for life (Beckman and Ames Physiol Rev 78(2):547-81, 1998; Stadtman and Berlett Chem Res Toxicol 10(5):485-94, 1997)?: the so-called Oxygen Paradox (Davies and Ursini 1995; Davies Biochem Soc Symp 61:1-31, 1995). How can French people apparently disregard the rule that high dietary intakes of cholesterol and saturated fats (e.g., cheese and paté) will result in an early death from cardiovascular diseases (Renaud and de Lorgeril Lancet 339(8808):1523-6, 1992; Catalgol et al. Front Pharmacol 3:141, 2012; Eisenberg et al. Nat Med 22(12):1428-1438, 2016)?: the so-called, French Paradox. Doubtless, the truth is not a duality and epistemological bias probably generates appare...
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Exercise and physical activity are fundamental components of a lifestyle essential in maintaining a healthy brain. This is primarily due to the fact that the adult brain maintains a high degree of plasticity and activity is essential for... more
Exercise and physical activity are fundamental components of a lifestyle essential in maintaining a healthy brain. This is primarily due to the fact that the adult brain maintains a high degree of plasticity and activity is essential for homeostasis throughout life. Plasticity is not lost even in the context of a neurodegenerative disorder, but could be maladaptive thus promoting disease onset and progression. A major breakthrough in treating brain disorders such as Parkinson's disease is to drive neuroplasticity in a direction to improve motor and cognitive dysfunction. The purpose of this short review is to present the evidence from our laboratories that supports neuroplasticity as a potential therapeutic target in treating brain disorders. We consider that the enhancement of motor recovery in both animal models of dopamine depletion and in patients with Parkinson's disease is optimized when cognitive circuits are engaged; in other words, the brain is engaged in a learning...