ABSTRACT
BACKGROUND: Parkinson's disease (PD) is characterized by Lewy body and neurite pathology associated with dopamine terminal dysfunction. Clinically, it is associated with motor slowing, rigidity, and tremor. Postural instability and pain are also features. Physical exercise benefits PD patients - possibly by promoting neuroplasticity including synaptic regeneration. OBJECTIVES: In a parkinsonian rat model, we test the hypotheses that exercise: (a) increases synaptic density and reduces neuroinflammation and (b) lowers the nociceptive threshold by increasing µ-opioid receptor expression. METHODS: Brain autoradiography was performed on rats unilaterally injected with either 6-hydroxydopamine (6-OHDA) or saline and subjected to treadmill exercise over 5 weeks. [3H]UCB-J was used to measure synaptic vesicle glycoprotein 2A (SV2A) density. Dopamine D2/3 receptor and µ-opioid receptor availability were assessed with [3H]Raclopride and [3H]DAMGO, respectively, while neuroinflammation was detected with the 18kDA translocator protein (TSPO) marker [3H]PK11195. The nociceptive threshold was determined prior to and throughout the exercise protocol. RESULTS: We confirmed a dopaminegic deficit with increased striatal [3H]Raclopride D2/3 receptor availability and reduced nigral tyrosine hydroxylase immunoreactivity in the ipsilateral hemisphere of all 6-OHDA-injected rats. Sedentary rats lesioned with 6-OHDA showed significant reduction of ipsilateral striatal and substantia nigra [3H]UCB-J binding while [3H]PK11195 showed increased ipsilateral striatal neuroinflammation. Lesioned rats who exercised had higher levels of ipsilateral striatal [3H]UCB-J binding and lower levels of neuroinflammation compared to sedentary lesioned rats. Striatal 6-OHDA injections reduced thalamic µ-opioid receptor availability but subsequent exercise restored binding. Exercise also raised thalamic and hippocampal SV2A synaptic density in 6-OHDA lesioned rats, accompanied by a rise in nociceptive threshold. CONCLUSION: These data suggest that treadmill exercise protects nigral and striatal synaptic integrity in a rat lesion model of PD - possibly by promoting compensatory mechanisms. Exercise was also associated with reduced neuroinflammation post lesioning and altered opioid transmission resulting in an increased nociceptive threshold.
Subject(s)
Brain/metabolism , Parkinsonian Disorders/metabolism , Parkinsonian Disorders/therapy , Physical Conditioning, Animal/physiology , Synapses/metabolism , Animals , Brain/drug effects , Exercise Test/methods , Male , Oxidopamine/toxicity , Parkinsonian Disorders/chemically induced , Physical Conditioning, Animal/methods , Rats , Rats, Wistar , Synapses/drug effectsABSTRACT
The aim of this study was to investigate whether the previously reported effect of chronic restraint stress (CRS) on hippocampal neuron morphology and spine density is paralleled by a similar change in the expression levels of synaptic scaffolding proteins. Adult male Wistar rats were subjected either to CRS (6 h/day) for 21 days or to control conditions. The resulting brains were divided and one hemisphere was impregnated with Golgi-Cox before coronal sectioning and autometallographic development. Neurons from CA1, CA3b, CA3c, and dentate gyrus (DG) area were reconstructed and subjected to Sholl analysis and spine density estimation. The contralateral hippocampus was used for quantitative real-time polymerase chain reaction and protein analysis of genes associated with spine density and morphology (the synaptic scaffolding proteins: Spinophilin, Homer1-3, and Shank1-3). In the CA3c area, CRS decreased the number of apical dendrites and their total length, whereas CA1 and DG spine density were significantly increased. Analysis of the contralateral hippocampal homogenate displayed an increased gene expression of Spinophilin, Homer1, Shank1, and Shank2 and increased protein expression of Spinophilin and Homer1 in the CRS animals. In conclusion, CRS influences hippocampal neuroplasticity by modulation of dendrite branching pattern and spine density paralleled by increased expression levels of synaptic scaffolding proteins.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Dendritic Spines/pathology , Guanylate Kinases/metabolism , Hippocampus/cytology , Neuronal Plasticity/physiology , Stress, Physiological , Animals , Dentate Gyrus/cytology , Male , Rats , Rats, Wistar , Real-Time Polymerase Chain ReactionABSTRACT
Pathogenic stimuli induce alterations in the morphology of microglial cells. We analysed changes in lectin-stained cells on the 1st, 3rd, 7th or 14th day after transient global ischemia. Three areas differing in the degree of microglial reaction were selected for analysis: the upper cerebral cortex, the hippocampal CA1 area, and the hilus of the dentate gyrus. Nine morphological parameters, including fractal dimension, lacunarity, self-similarity range, solidity, convexity and form factor were determined. Then the resultant data were processed using principal component analysis (PCA). We found that the two first principal components together explained more than 73% of the observed variability, and may be sufficient both to describe the morphological diversity of the cells, and to determine the dynamics and direction of the changes. In both hippocampal areas, the transformation to hypertrophied and phagocytic cells was observed, but changes in the hilus were faster than in the CA1. In contrast, in the cortex, a microglial reaction was characterised by an increase in the complexity of processes. The results presented show that the quantitative morphological analysis can be an effective tool in research on the reactive behaviour of microglia and, particularly, in the detection of small and early changes in the cells.
