-
Kyle D Fink,
Julien Rossignol,
Andrew T Crane,
Kendra K Davis,
Angela M Bavar,
Nicholas W Dekorver,
Steven A Lowrance,
Mark P Reilly, Michael I Sandstrom,
Stephan von Hörsten,
Laurent Lescaudron,
Gary L Dunbar
[show abstract]
[hide abstract]
ABSTRACT: Huntington's disease (HD) is a neurodegenerative disorder in humans caused by an expansion of a CAG trinucleotide repeat that produces choreic movements, which are preceded by cognitive deficits. The HD transgenic rat (tgHD), which contains the human HD mutation with a 51 CAG repeat allele, exhibits motor deficits that begin when these rats are 12 months of age. However, there are no reports of cognitive dysfunction occurring prior to this. To assess whether cognitive dysfunction might precede motor deficits in tgHD rats, one group of 9-month-old male rats with homozygotic mutated genes and one group of wild-type (WT) rats underwent three testing phases in a unique Spatial Operant Reversal Test (SORT) paradigm, as well as assessment of spontaneous motor activity. After testing, morphological and histological examination of the brains were made. Results indicated that tgHD rats acquired the cued-response (Phase 1) portion of the SORT, but made significantly more errors during the reversal (Phase 2) and during the pseudorandomized reversals (Phase 3) portion of the study, when compared to WT rats. Analysis of the data using mathematical principles of reinforcement revealed no memory, motor, or motivational deficits. These results indicate that early cognitive dysfunction, as measured by the SORT, occur prior to motor deficits, gross anatomical changes, or cell loss in the tgHD rat with 51 CAG repeats, and suggest that this protocol could provide a useful screen for therapeutic studies.
Behavioral Neuroscience 06/2012; 126(3):479-87. · 2.62 Impact Factor
-
02/2012; , ISBN: 978-953-307-953-0
-
[show abstract]
[hide abstract]
ABSTRACT: The purpose of this study was to evaluate the therapeutic effects of the transplantation of bone-marrow mesenchymal stem cells (MSCs), genetically engineered to over-express brain-derived neurotrophic factor (BDNF) or nerve growth factor (NGF) on motor deficits and neurodegeneration in YAC 128 transgenic mice. MSCs, harvested from mouse femurs, were genetically engineered to over-express BDNF and/or NGF and these cells, or the vehicle solution, were injected into the striata of four-month old YAC 128 transgenic and wild-type mice. Assessments of motor ability on the rotarod and the severity of clasping were made one day prior to transplantation and once monthly, thereafter, to determine the effects of the transplanted cells on motor function. The mice were sacrificed at 13-months of age for immunohistological examination. All YAC 128 mice receiving transplants had reduced clasping, relative to vehicle-treated YAC 128 mice, while YAC 128 mice that were transplanted with MSCs which were genetically engineered to over-express BDNF, had the longest latencies on the rotarod and the least amount of neuronal loss within the striatum of the YAC 128 mice. These results indicate that intrastriatal transplantation of MSCs that over-express BDNF may create an environment within the striatum that slows neurodegenerative processes and provides behavioral sparing in the YAC 128 mouse model of HD. Further research on the long-term safety and efficacy of this approach is needed before its potential clinical utility can be comprehensively assessed.
Behavioural brain research 12/2010; 214(2):193-200. · 3.22 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disorder in which loss of dopaminergic (DA) neurons (>50%) in the substantia nigra (SN) precedes most of the overt motor symptoms, making early diagnosis and treatment interventions difficult. Because PD has been associated with free radicals generated by nitric oxide, this study tested whether treatments of 7-nitroindazole (7NI), a nitric-oxide-synthase inhibitor, could reduce cognitive deficits that often emerge before overt motor symptoms in a presymptomatic rat model of PD. Rats were given intraperitoneal injections of 50 mg/kg 7NI (or vehicle) just before receiving bilateral, intrastriatal injections of the DA-toxin, 6-hydroxydopamine (6-OHDA). The rats were then given a battery of motor tasks, and their learning ability was assessed using a spatial reversal task in a water-T maze. Results indicate that 7NI treatments attenuate 6-OHDA-induced spatial learning deficits and protect against DA cell loss in the SN, suggesting that 7NI may have potential as an early, presymptomatic pharmacotherapy for PD.
Experimental and Clinical Psychopharmacology 04/2008; 16(2):178-89. · 2.58 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The purpose of this study was to test the potential therapeutic effects of the substituted pyrimidine, KP544, which has been shown to amplify the effects of nerve growth factor in vitro, on motor deficits in the R6/2 transgenic mouse model of Huntington's disease (HD).
Young, female R6/2 mice were given daily oral intubation of either 10 mg/kg KP544 or vehicle (0.5% methylcellulose) at 6 weeks of age and tested from postnatal weeks 8 through 12 on a battery of motor tasks, including assessments of clasping (drawing of the limbs to the torso when suspended by the tail), motor coordination on the rotarod, and spontaneous motor activity in the open-field. Following testing, the mice were sacrificed and the brains were sectioned and stained with cresyl violet for histological examination.
KP544 treatment decreased balance deficits on the rotarod task, reduced clasping, delayed the onset of hypoactivity, and reduced enlargement of the lateral ventricles in R6/2 mice.
These results suggest that KP544 can reduce motor deficits and anatomical alterations in R6/2 mice. Further research into the use of KP544 as a potential pharmacotherapy HD is warranted.
Restorative neurology and neuroscience 02/2007; 25(5-6):485-92. · 2.51 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A physiological increase in extracellular ascorbate (AA), an antioxidant vitamin found throughout the striatum, elevates extracellular glutamate (GLU). To determine the role of behavioral arousal in this interaction, microdialysis was used to measure striatal GLU efflux in rats tested in either a lights-off or lights-on condition while reverse dialysis either maintained the concentration of AA at 250 microM or increased it to 1000 microM to approximate endogenous changes.
When lights were off, both locomotion and GLU increased regardless of AA dose. In contrast, animals in the lights-on condition were behaviorally inactive, and infusion of 1000, but not 250, microM AA significantly increased extracellular GLU. Interestingly, when ambient light returned to the lights-off group, 1000 microM prolonged the GLU increase relative to the 250 microM group.
Our results not only support evidence that elevated striatal AA increases extracellular GLU but also indicate that this effect depends on behavioral state and the corresponding level of endogenous GLU release.
BMC Neuroscience 02/2007; 8:32. · 3.04 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The interest in using neurotrophic factors as potential treatments for neurodegenerative disorders, such as Huntington's disease, has grown in the past decade. A major impediment for the clinical utility of neurotrophic factors is their inability to cross the blood-brain barrier in therapeutically significant amounts. Although several novel mechanisms for delivering exogenous neurotrophins to the brain have been developed, most of them involve invasive procedures or present significant risks. One approach to circumventing these problems is using therapeutic agents that can be administered systemically and have the ability to enhance the activity of neurotrophic factors. This review highlights the use of gangliosides, substituted pyrimidines, and mesenchymal stem cells as neurotrophic enhancers that have significant therapeutic potential while avoiding the pitfalls of delivering exogenous neurotrophic factors through the blood-brain barrier. The review focuses on the potential of these neurotrophic enhancers for treating the behavioral deficits in rodent models of Huntington's disease.
Behavioral and Cognitive Neuroscience Reviews 07/2006; 5(2):63-79.
-
[show abstract]
[hide abstract]
ABSTRACT: To determine if extracellular ascorbate, which may increase by several hundred micromolar in striatum during behavioral activation, directly alters glutamate transmission, we monitored striatal glutamate transients evoked by electrical stimulation of cerebral cortex in anesthetized rats tested with varying concentrations of ascorbate (0, 50, 200, and 500 microM) by reverse dialysis. Capillary electrophoresis coupled with laser-induced fluorescence detection was used to analyze dialysates collected at 3-s intervals. Ascorbate elevated striatal glutamate in a concentration-dependent fashion. Addition of 500 microM ascorbate not only more than doubled basal glutamate levels relative to the ascorbate-free condition, but significantly increased both the magnitude of the electrically evoked glutamate response as well as its subsequent return to baseline. In fact, the time required to return to within 10% of the pre-stimulation baseline increased by >100s. Reverse dialysis of iso-ascorbate, in contrast, had no effect on stimulation-evoked glutamate release arguing against an antioxidant effect. It appears, therefore, that the level of extracellular ascorbate plays a critical role in regulating corticostriatal glutamate transmission.
Neuroscience Letters 04/2005; 378(3):166-70. · 2.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The behavioral and neurochemical effects of striatal DA depletions were investigated in rats lesioned as weanlings (Day 27) or as adults (250-300 g). Administration of 6-OHDA into the medial forebrain bundle resulted in comparably large (> or = 95%) depletions of tissue levels of DA in both age groups. As expected, rats depleted of DA as adults exhibited marked deficits in motoric behavior and body weight regulation that persisted for the 8 days of postsurgical observation. In contrast, rats depleted of DA as weanlings were spared from such deficits, and their behavior closely resembled that of age-matched controls. Microdialysis studies revealed dialysate levels of striatal DA that paralleled these age-dependent behavioral differences. At a time when age-related behavioral differences were still quite pronounced (5-6 days postsurgery), basal DA levels were reduced by 80% of control values in rats lesioned as adults whereas basal DA levels in rats lesioned as weanlings were unchanged relative to their controls. Finally, adults depleted of striatal DA as weanlings were no more sensitive to the movement-impairing effects of intrastriatal sulpiride (3.0 or 10.0 micrograms/hemisphere) infusions than were control rats. These data suggest that weanlings compensate for large, but incomplete, denervation of striatal DA with markedly enhanced release and turnover from residual terminals. This developmental plasticity may prevent the occurrence of behavioral deficits soon after the lesion and also the supersensitivity to the challenging effects of DA antagonists as animals grow into adulthood.
Developmental Psychobiology 12/2003; 43(4):373-83. · 2.98 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Single-unit activity in the striatum of unrestrained, conscious rats was characterized by extracellular recording in combination with iontophoresis. To avoid the confounding effect of motor-related changes in firing rate, measurements were restricted to periods when animals were at quiet rest. Recording electrodes were lowered stepwise through 4.0 mm of anterior striatum in 36 equal ventral movements of 111 microm to assess the ratio of spontaneously active vs. silent neurons. Spontaneous activity was assessed at each step followed by iontophoretic glutamate (GLU) application to expose silent neurons. Eleven such experimental sessions resulted in a total of 100 spontaneously active and 264 silent neurons, indicating that without overt movement the large majority (72.7%) of striatal cells are silent. Spontaneously active neurons, moreover, discharged at low rates (4.85 +/- 0.85 spikes/s). In separate experiments, both the AMPA/kainate (CNQX: 6-cyano-2,3-dihydroxy-7-nitro-quinoxaline disodium salt) and NMDA (AP5: D-(-)-2-amino-5-phosphonovaleric acid) GLU-receptor antagonists blocked the activity of most spontaneously active (83% CNQX, 69% AP5), and GLU-stimulated silent (68% CNQX, 98% AP5) units. Collectively, our results are consistent with an overall low level of striatal activity in the absence of strong excitatory input. When neuronal activity is initiated, however, it appears that both NMDA and AMPA/kainate receptors are critical for maintaining continuous impulse activity.
Synapse 03/2003; 47(2):91-100. · 2.94 Impact Factor
