Validations of apomorphine-induced BOLD activation correlations in hemiparkinsonian rhesus macaques.

Identification of Parkinson's disease at the earliest possible stage of the disease may provide the best opportunity for the use of disease modifying treatments. However, diagnosing the disease during the pre-symptomatic period remains an unmet goal. To that end, we used pharmacological MRI (phMRI) to assess the function of the cortico-basal ganglia circuit in a non-human primate model of dopamine deficiency to determine the possible relationships between phMRI signals with behavioral, neurochemical, and histological measurements. Animals with unilateral treatments with the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), that expressed stable, long-term hemiparkinsonism were challenged with the dopaminergic receptor agonist, apomorphine, and structure-specific phMRI blood oxygen level-dependent (BOLD) activation responses were measured. Behavioral, histopathological, and neurochemical measurements were obtained and correlated with phMRI activation of structures of the cortico-basal ganglia system. Greater phMRI activations in the basal ganglia and cortex were associated with slower movement speed, decreased daytime activity, or more pronounced parkinsonian features. Animals showed decreased stimulus-evoked dopamine release in the putamen and substantia nigra pars compacta and lower basal glutamate levels in the motor cortex on the MPTP-lesioned hemisphere compared to the contralateral hemisphere. The altered neurochemistry was significantly correlated with phMRI signals in the motor cortex and putamen. Finally, greater phMRI activations in the caudate nucleus correlated with fewer tyrosine hydroxylase-positive (TH+) nigral cells and decreased TH+ fiber density in the putamen. These results reveal the correlation of phMRI signals with the severity of the motor deficits and pathophysiological changes in the cortico-basal ganglia circuit.

Cortical glutamate levels decrease in a non-human primate model of dopamine deficiency.

While Parkinson's disease is the result of dopaminergic dysfunction of the nigrostriatal system, the clinical manifestations of Parkinson's disease are brought about by alterations in multiple neural components, including cortical areas. We examined how 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration affected extracellular cortical glutamate levels by comparing glutamate levels in normal and MPTP-lesioned nonhuman primates (Macaca mulatta). Extracellular glutamate levels were measured using glutamate microelectrode biosensors. Unilateral MPTP-administration rendered the animals with hemiparkinsonian symptoms, including dopaminergic deficiencies in the substantia nigra and the premotor and motor cortices, and with statistically significant decreases in basal glutamate levels in the primary motor cortex on the side ipsilateral to the MPTP-lesion. These results suggest that the functional changes of the glutamatergic system, especially in the motor cortex, in models of Parkinson's disease could provide important insights into the mechanisms of this disease.

GFP fluorescence reports Period 1 circadian gene regulation in the mammalian biological clock.

Endogenous cyclic activation of a specific set of genes, including Period 1 (Per1), drive circadian rhythms in the suprachiasmatic nucleus (SCN), a biological clock nucleus of the brain. We have produced transgenic mice in which a degradable form of recombinant jellyfish green fluorescent protein (GFP) is driven by the mouse Period 1 (mPer1) gene promoter. GFP protein is expressed in the circadian neural structures of the retina and SCN. Fluorescent signals are resolved at the level of individual neurons. mPer1-driven GFP fluorescence intensity reports light-induction and circadian rhythmicity in SCN neurons. This circadian reporter transgene captures the gene expression dynamics of living biological clock neurons and ensembles, providing a novel view of this brain function.

Serotonin modulates glutamate responses in isolated suprachiasmatic nucleus neurons.

Two input pathways to the suprachiasmatic nucleus (SCN) of the hypothalamus are the glutamatergic retinohypothalamic tract and the serotonergic afferent from the midbrain raphe nucleus. To determine whether these two temporal signaling pathways can converge at the cellular level, we have investigated the effects of serotonin on glutamate-induced calcium responses of individual SCN neurons isolated in cell culture. Dispersed cultures were formed from the SCN of neonatal rats. The calcium indicator Fura-2 acetoxymethyl ester was used to assess the changes in [Ca(2+)](i) by recording the 340-nm/380-nm excitation ratio. Application of glutamate (5 microM) to the culture caused a rapid (within 10 s) increase in the fluorescence ratio of neurons indicating a marked increase in the concentration of intracellular free calcium. However, when 5-hydroxytryptamine (5-HT; 5 microM) was coapplied with glutamate, 31% of neurons showed an overall 61% reduction in the peak of the glutamate-induced calcium increase. Application of the 5-HT(7/1A) receptor agonist, (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin [(+/-)-8-OH-DPAT] (1 microM), also reduced the calcium elevation this time by 80% in 18% of the neurons tested. When the 5-HT(7/2/1C) receptor antagonist, ritanserin (800 nM), was coapplied with serotonin, it blocked modulation of the glutamate responses. Further support for the involvement of the 5-HT(7) receptor was provided by the ability of the adenylate cyclase activator, forskolin (10 microM), and the cAMP analogue, 8-Br cAMP (0.5 mM), to mimic the suppressive effect of serotonin. Blocking spike-mediated cell communication with tetrodotoxin (1 microM) did not prevent the serotonergic suppression of glutamate-induced responses. These results support the hypothesis that the serotonergic modulation of photic entraining signals can occur in SCN neurons.

[Fistulization in xanthogranulomatous pyelonephritis. Presentation of 6 clinical cases and review of the literature]. / Fistulización en la pielonefritis xantogranulomatosa. Presentación de 6 casos clínicos y revisión de la literatura.

Fistulization is an uncommon complication in Xanthogranulomatous Pyelonephritis, but harmful for the adjacent organs. Owing to their rare localization we present 6 cases with scrotal skin, bronchi, colon and spleen fistulization.