Plasticity of GABA(A) receptor-mediated neurotransmission in the nucleus accumbens of alcohol-dependent rats.

Chronic alcohol exposure-induced changes in reinforcement mechanisms and motivational state are thought to contribute to the development of cravings and relapse during protracted withdrawal. The nucleus accumbens (NAcc) is a key structure of the mesolimbic dopaminergic reward system and plays an important role in mediating alcohol-seeking behaviors. Here we describe the long-lasting alterations of γ-aminobutyric acid type A receptors (GABA(A)Rs) of medium spiny neurons (MSNs) in the NAcc after chronic intermittent ethanol (CIE) treatment, a rat model of alcohol dependence. CIE treatment and withdrawal (>40 days) produced decreases in the ethanol and Ro15-4513 potentiation of extrasynaptic GABA(A)Rs, which mediate the picrotoxin-sensitive tonic current (I(tonic)), while potentiation of synaptic receptors, which give rise to miniature inhibitory postsynaptic currents (mIPSCs), was increased. Diazepam sensitivity of both I(tonic) and mIPSCs was decreased by CIE treatment. The average magnitude of I(tonic) was unchanged, but mIPSC amplitude and frequency decreased and mIPSC rise time increased after CIE treatment. Rise-time histograms revealed decreased frequency of fast-rising mIPSCs after CIE treatment, consistent with possible decreases in somatic GABAergic synapses in MSNs from CIE rats. However, unbiased stereological analysis of NeuN-stained NAcc neurons did not detect any decreases in NAcc volume, neuronal numbers, or neuronal cell body volume. Western blot analysis of surface subunit levels revealed selective decreases in α1 and δ and increases in α4, α5, and γ2 GABA(A)R subunits after CIE treatment and withdrawal. Similar, but reversible, alterations occurred after a single ethanol dose (5 g/kg). These data reveal CIE-induced long-lasting neuroadaptations in the NAcc GABAergic neurotransmission.

Neuroprotective effects and mechanisms of exercise in a chronic mouse model of Parkinson's disease with moderate neurodegeneration.

The protective impact of exercise on neurodegenerative processes has not been confirmed, and the mechanisms underlying the benefit of exercise have not been determined in human Parkinson's disease or in chronic animal disease models. This research examined the long-term neurological, behavioral, and mechanistic consequences of endurance exercise in experimental chronic parkinsonism. We used a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease with moderate neurodegeneration and examined the effects of treadmill exercise on movement and balance coordination, changes in dopamine neuron biomarkers, mitochondrial functions, and neurotrophic factor activities in the nigrostriatal system. The exercise results were compared with those of the control and sedentary chronic parkinsonian animals. After 18 weeks of exercise training in the chronic parkinsonian mice, we observed a significant deterrence in the loss of neuronal dopamine-producing cells and other functional indicators. The impaired movement and balance incoordination in the chronic parkinsonian mice were also markedly reduced following exercise. Mechanistic investigations revealed that the neuronal and behavioral recovery produced by exercise in the chronic parkinsonian mice was associated with an improved mitochondrial function and an increase in the brain region-specific levels of brain-derived and glial cell line-derived neurotrophic factors. Our findings indicate that exercise not only produces neuronal and mitochondrial protection, it also boosts nigrostriatal neurotrophic factor levels in the chronic parkinsonian mice with moderate neurodegeneration. Therefore, modifying lifestyle with increased exercise activity would be a non-pharmacological neuroprotective approach for averting neurodegenerative processes, as demonstrated in experimental chronic parkinsonism.

Involvement of TRPC channels in CCL2-mediated neuroprotection against tat toxicity.

Chemokine (C-C motif) ligand 2 (CCL2), also known as monocyte chemoattractant protein-1, plays a critical role in leukocyte recruitment and activation. In the present study, we identify an additional role for CCL2 that of neuroprotection against HIV-1 transactivator protein (Tat) toxicity in rat primary midbrain neurons. Furthermore, we report the involvement of transient receptor potential canonical (TRPC) channels in CCL2-mediated neuroprotection. TRPC are Ca(2+)-permeable, nonselective cation channels with a variety of physiological functions. Blockage of TRPC channels resulted in suppression of both CCL2-mediated neuroprotection and intracellular Ca(2+) elevations. Parallel but distinct extracellular signal-regulated kinase (ERK)/cAMP response element-binding protein (CREB) and Akt/nuclear factor kappaB (NF-kappaB) pathways were involved in the CCL2-mediated neuroprotection. Blocking TRPC channels and specific downregulation of TRPC channels 1 and 5 resulted in suppression of CCL2-induced ERK/CREB activation but not Akt/NF-kappaB activation. In vivo relevance of these findings was further corroborated in wild-type and CCR2 knock-out mice. In the wild-type but not CCR2 knock-out mice, exogenous CCL2 exerted neuroprotection against intrastriatal injection of HIV-1 Tat. These findings clearly demonstrate a novel role of TRPC channels in the protection of neurons against Tat through the CCL2/CCR2 axis.

Effects of endurance exercise on ventral tegmental area neurons in the chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid-treated mice.

Loss of dopaminergic neurons in the substantia nigra (A9 cells) and ventral tegmental area (VTA) (A10 cells) has been reported in Parkinson's disease with reference to causing motor and non-motor deficits, although clinical and laboratory animal studies on the degeneration of VTA neurons are less emphasized comparative to the degeneration of substantia nigra neurons. In the present study, we examined the VTA dopaminergic neurons in a chronic mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid at a level showing moderate neurodegeneration and studied the impact of endurance exercise on VTA neurons in this model. In comparison to the normal control animals, the chronic mouse model of Parkinson's disease with moderate neurodegeneration demonstrated a significant reduction of VTA neurons (52% loss), when these animals were kept sedentary throughout the study. Morphologically, the VTA dopaminergic neurons in this model displayed a decrease in cell volume and showed irregular or disparaging axonal and dendritic projections. When the chronic Parkinsonian mice were exercised on a motorized rodent treadmill up to 15m/min, 40 min/day, 5 days/week for 10 and 18 weeks, the total number of VTA dopaminergic neurons were significantly higher than the sedentary Parkinsonian animals. Especially noted with the 18-week exercised Parkinsonian mice, the number of VTA neurons returned to normal range and the cells were densely populated and displayed distinctive axons and dendritic arborization. These results demonstrate that prolonged exercise training is neuroprotective to the dopaminergic neurons in the VTA of the chronic mouse model of Parkinson's disease with moderate neurodegeneration.

Reduced numbers of dopamine neurons in the substantia nigra pars compacta and ventral tegmental area of rats fed an n-3 polyunsaturated fatty acid-deficient diet: a stereological study.

Inadequate dietary n-3 polyunsaturated fatty acid (PUFA) content is associated with altered function of the CNS dopamine systems. In this study, the effects of dietary n-3 PUFA content were determined on dopamine cell number and morphology. Adult (postnatal day 70), male, Long-Evans rats were raised from conception on diets containing adequate (control) or negligible n-3 PUFAs. The number and morphology of tyrosine hydroxylase-positive cells in the substantia nigra pars compacta and ventral tegmental area were determined stereologically. The number of tyrosine hydroxylase-positive cells in rats fed the n-3 PUFA-deficient diet was 33.9% lower in the substantia nigra pars compacta and 33.7% lower in the ventral tegmental area than in those fed the control diet (P<0.05); however, the volume of tyrosine hydroxylase-positive cell bodies was not different between diet groups in either brain region. Rats fed the n-3 PUFA-deficient diet also exhibited dendritic depletion and isolation of tyrosine hydroxylase-positive cells compared to rats fed the control diet, which had clustering of tyrosine hydroxylase-positive cells and extensive dendritic arborization. These findings support a role for n-3 PUFAs in the survival of dopamine neurons and suggest that altered dopamine cell number, as well as function, contributes to the behavioral effects observed in rats raised on n-3 PUFA-deficient diets.

Endurance exercise improves function in individuals with Parkinson's disease: A meta-analysis.

Current evidence has shown that exercise can reduce symptoms of Parkinson's disease (PD). However, previous studies indicated mixed results, possibly because of variability in terms of the nature of the exercise interventions. The purpose of this study was to perform a metaanalysis of current evidence from endurance exercise intervention studies for effects on the United Parkinson's Disease Rating Scale (UPDRS) in individuals with PD. A systematic literature search in six electronic databases was performed and two independent reviewers screened the title and abstract of 1106 records captured by the initial search. Inclusion criteria for full-text review were (A) peer-reviewed English-language publications, (B) randomized controlled trials that compared an endurance exercise intervention group to a non-exercising control group, and (C) an outcome measure which included the UPDRS total score or section III (motor) subscore. From the title/abstract screening, the same independent reviewers assessed 245 full-text articles for eligibility. Of the fulltext articles reviewed 7 articles were included in our meta-analysis, 238 were excluded for the following reasons: 147 did not meet endurance exercise criteria, 53 were review/systematic reviews, 34 were conference abstracts or posters, 2 were editorial or commentary, 1 was a study protocol, and 1 was unpublished. The d index was used to calculate the difference between means of different groups within individual studies, and a weighting factor or w was used to calculate the effect size across studies. Overall, d index was found to be -0.32 with 95% confidence interval, CI (-0.09, -0.56) found to be statistically significant indicating a positive effect of endurance exercise in UPDRS scores. In conclusion, this meta-analysis supports integrating endurance exercise training, as defined by ACSM, into treatment of PD.

Analyzing course objectives: assessing critical thinking in the pharmacy curriculum.

Assessment of critical thinking objectives in a pharmacy program curriculum is an important part of program assessment. This study measures the proportion of cognitive learning objectives at various levels of Bloom's taxonomy throughout the required curriculum using the stated objectives in course syllabi (the explicit curriculum). In one entry level doctor of pharmacy program, 54.90% of cognitive objectives identified critical thinking outcomes using the rubric of Bloom's level 3 or higher as an indicator of critical thinking. In this program, there was a similar percent of critical thinking objectives in each of the first three years, but the final year of the curriculum had a higher percent of critical thinking objectives than each of the first three years (p = 0.0018, Kruskal-Wallis test). The increase in critical thinking in the final year suggests that the explicit expectations in the syllabi are weighted toward a higher percent of critical thinking objectives during clinical rotations. The methods described in the study may serve as tools for a curriculum committee or program assessment team to compare critical thinking in the curriculum at different points in time, and may assist in curricular mapping efforts. These methods may complement studies measuring the implicit curriculum (that which the faculty actually teach, which may not be stated in the explicit curriculum.).

Neuroscience Literacy: "Brain Tells" as Signals of Brain Dysfunction Affecting Daily Life.

The structures and circuits of the central and the peripheral nervous systems provide the basis for thinking, speaking, experiencing sensations, and performing perceptual and motor activities in daily life. Healthy people experience normal functioning without giving brain functions a second thought, while dysfunction of the neural circuits may lead to marked impairments in cognition, communication, sensory awareness, and performing perceptual and motor tasks. Neuroscience literacy provides the knowledge to associate the deficits observed in patients with the underlying deficits in the structures and circuits of the nervous system. The purpose of this paper is to begin the conversation in this area via a neuroscience literacy model of "Brain Tells," defined as stereotypical or observable behaviors often associated with brain dysfunction. Occupational therapists and other allied health professionals should be alert for the signs of "Brain Tells" that may be early warning signs of brain pathology. We also suggest that neuroscience literacy be emphasized in training provided to public safety workers, teachers, caregivers, and health care professionals at all levels.

Altered nucleolar morphology in substantia nigra dopamine neurons following 6-hydroxydopamine lesion in rats.

The nucleolus, the site of ribosomal ribonucleic acid (rRNA) transcription and assembly, is an important player in the cellular response to stress. Altered nucleolar function and morphology, including decreased nucleolar volume, has been observed in Parkinson's disease; thus the nucleolus represents a potential indicator of neurodegeneration in the disease. This study determined the effects of a partial unilateral intrastriatal 6-hydroxydopamine (6-OHDA) lesion, which models the dopaminergic loss found in Parkinson's disease, on the nucleoli of dopaminergic cells in the substantia nigra pars compacta (SNpc). Adult male Long-Evans rats underwent unilateral intrastriatal infusion of 6-OHDA (12.5µg). Lesions were verified by amphetamine-stimulated rotation 7 days later, and rats were euthanized 14 days after infusion. Coronal sections (50µm) were stained for tyrosine hydroxylase-silver nucleolar (TH-AgNOR) stain using MultiBrain Technology (NeuroScience Associates), which resulted in clearly defined nucleoli and neuronal outlines. Stereological methods were used to compare dopaminergic morphology between lesioned and intact hemispheres in each rat. In cells exhibiting a definable nucleolus, nucleolar volume was decreased by 16% on the ipsilateral side. The ipsilateral SNpc also exhibited an 18% decrease in SNpc planimetric volume, a 46% decrease in total TH-positive neuron number, and an 11% decrease in neuronal body volume (all P<0.05 by paired t-test). These findings suggest that the 6-OHDA lesion alters nucleolar morphology and that these changes are similar to those occurring in Parkinson's disease.

A novel use of combined tyrosine hydroxylase and silver nucleolar staining to determine the effects of a unilateral intrastriatal 6-hydroxydopamine lesion in the substantia nigra: a stereological study.

Neurotoxic lesions of the nigrostriatal pathway model the deficits found in Parkinson's disease. This study used stereology and a novel staining method to examine the effects of a partial unilateral striatal 6-hydroxydopamine (6-OHDA) lesion on substantia nigra pars compacta (SNpc) dopamine neuron number and morphology in rats. Adult male Long-Evans rats were subjected to unilateral lesion of the SNpc by intrastriatal microinjection of 6-OHDA (12.5 µg). Lesions were verified by d-amphetamine-stimulated rotation (2.5 mg/kg, sc) by force-plate rotometry 7 days post-surgery. Seven days after rotation testing, rats were euthanized, and brains were prepared for either histology (n=12) or determination of striatal dopamine content by HPLC-EC (n=20). Brains prepared for histology were stained for tyrosine hydroxylase (TH) combined with a silver nucleolar (AgNOR) stain using a modified protocol developed for stereological assessment. The AgNOR counterstain allowed for precise definition of the nucleolus of the cells, facilitating both counting and qualitative morphometry of TH-positive neurons. Stereological quantitation determined a 54% decrease in TH-positive neuron number (P<0.01), and a 14% decrease in neuron volume (P<0.05) on the lesioned side. Striatal dopamine concentration was decreased by 92% (P<0.01), suggesting that striatal dopamine analysis may overestimate the numbers of SNpc neurons lost. These findings demonstrate that combined use of TH and AgNOR staining provides improved characterization of 6-OHDA-induced pathology. Furthermore, the data suggest that decreased neuronal volume as well as number contributes to the functional deficits observed after unilateral intrastriatal 6-OHDA lesion.

Effects of corticosteroids on functional recovery and neuron survival after facial nerve injury in mice.

OBJECTIVES: To assess the effects of corticosteroid administration on functional recovery and cell survival in the facial motor nucleus (FMN) following crush injury in adult and juvenile mice and to evaluate the relationship between functional recovery and facial motoneuron survival. METHODS: A prospective blinded analysis of functional recovery and cell survival in the FMN after crush injury in juvenile and adult mice was carried out. All mice underwent a unilateral facial nerve crush injury and received 7 doses of daily injections. Adults received normal saline or low-dose or high-dose corticosteroid treatment. Juveniles received either normal saline or low-dose corticosteroid treatment. Whisker function was monitored to assess functional recovery. Stereologic analysis was performed to determine neuron and glial survival in the FMN following recovery. RESULTS: Following facial nerve injury, all adult mice recovered fully, while juvenile mice recovered slower and incompletely. This corresponded to a significantly greater neuron loss in the FMN of juveniles compared with adults. Corticosteroid treatment slowed functional recovery in adult mice. This corresponded with significantly greater neuron loss in the FMN in corticosteroid-treated mice. In juvenile mice, corticosteroid treatment showed a trend, which was significant at several time points, toward a more robust functional recovery compared with controls. CONCLUSIONS: Corticosteroid treatment slows functional recovery and impairs neuron survival following facial nerve crush injury in adult mice. The degree of motor neuron survival corresponds with functional status. In juvenile mice, crush injury results in overall poor functional recovery and profound cell loss in the FMN. With low-dose corticosteroid treatment, there is a significantly enhanced functional recovery after injury in these mice (P < .05).

Current clinical practices in stroke rehabilitation: regional pilot survey.

This study was aimed at understanding the current physical and occupational therapy practices in stroke rehabilitation in the Midwest. The insights gained from this pilot study will be used in a future study aimed at understanding stroke rehabilitation practices across the nation. Researchers and clinicians in the field of stroke rehabilitation were interviewed, and past studies in the literature were analyzed. Through these activities, we developed a 37-item questionnaire that was sent to occupational and physical therapists practicing in Kansas and Missouri who focus on the care of people who have had a stroke (n = 320). A total of 107 respondents returned a com pleted questionnaire, which gives a response rate of about 36%. The majority of respondents had more than 12 years of experience treating patients with stroke. Consensus of 70% or more was found for 80% of the items. The preferred approaches for the rehabilitation of people who have had a stroke are the Bobath and Brunnstrom methods, which are being used by 93% and 85% of the physical and occupational therapists, respectively. Even though some variability existed in certain parts of the survey, in general clinicians agreed on different treatment approaches in issues dealing with muscle tone, weakness, and limited range of motion in stroke rehabilitation. Some newer treatment approaches that have been proven to be effective are practiced only by a minority of clinicians. The uncertainty among clinicians in some sections of the survey reveals that more evidence on clinical approaches is needed to ensure efficacious treatments.