Neuroscience
-
Iron homeostasis is essential for the integrity of brain monoaminergic functions and its deregulation might be involved in neurological movement disorders such as the restless legs syndrome (RLS). Although iron metabolism breakdown concomitantly appears with monoaminergic system dysfunction in iron-deficient rodents and in RLS patients, the direct consequences of peripheral iron deficiency in the central nervous system (CNS) of non-human primates have received little attention. Here, we evaluated the peripheral iron-depletion impact on brain monoamine levels in macaque monkeys. ⋯ Additionally, striatal extracellular DA, DOPAC and 5-HIAA levels evaluated by in vivo microdialysis showed a substantial increase, suggesting an overall increase in both DA and 5-HT tones. Finally, a trending increase in general locomotor activity, measured by actimetry, was observed in the most serum iron-depleted macaques. Taken together, our data are compatible with an increase in nigrostriatal DAergic function in the event of iron deficiency and point to a specific alteration of the 5-HT/DA interaction in the CNS that is possibly involved in the etiology of RLS.
-
Chronic delivery of neuropeptides in the brain is a useful experimental approach to study their long-term effects on various biological parameters. In this work, we tested albumin-alginate microparticles, as a potential delivery system, to study if continuous release in the hypothalamus of α-melanocyte-stimulating hormone (α-MSH), an anorexigenic neuropeptide, may result in a long-term decrease in food intake and body weight. The 2-week release of α-MSH from peptide-loaded particles was confirmed by an in vitro assay. ⋯ Food intake was significantly decreased for 3 days in rats receiving α-MSH-loaded particles and it was not followed by the feeding rebound effect which appears after food restriction. The presence of α-MSH-loaded particles in the hypothalamus was confirmed by immunohistochemistry. In conclusion, our study validates albumin-alginate microparticles as a new carrier system for long-term delivery of neuropeptides in the brain and demonstrates that chronic delivery of α-MSH in the hypothalamus results in a prolonged suppression of food intake and a decrease of body weight gain in rats.
-
Post-mitotic neurons are particularly susceptible to DNA double-strand breaks during their relatively long lifespan. Here, we report the anatomical distribution and subcellular localization of a molecule first identified as a DNA damage checkpoint protein. Immunocytochemical analysis of 53BP1 showed that this nuclear molecule is widely expressed in adult human and rat brains. ⋯ Notably, 53BP1 is only expressed in neuronal cells as the DNA damage checkpoint protein was virtually absent from glial cells. Finally, we found that human neural progenitors showed a differential index of DNA fragmentation at different stages of cellular differentiation. These data provide additional and important anatomical findings for the distribution and phenotype of DNA double-strand breaks in the mammalian brain, and suggest that DNA fragmentation is a spontaneous event routinely occurring in neural progenitors and adult neurons.
-
Previously, we demonstrated that group II metabotropic glutamate receptors (mGluRs) reduce glutamate release from thalamocortical synapses during early postnatal development (P7-11). To further examine the role of group II mGluRs in the modulation of somatosensory circuitry, we determined whether group II mGluRs continue to modulate thalamocortical synapses until adulthood and whether these receptors also modulate intra-cortical synapses in the barrel cortex. To address these issues, we examined the effect of the group II mGluR agonists on thalamocortical excitatory postsynaptic currents (EPSCs) and intra-barrel EPSCs in slices from animals of different ages (P7-53). ⋯ Similar to the thalamocortical synapses, the group II mGluR modulation of intra-barrel excitatory synapses declined with development. In young adult animals (P30-50), group II mGluR stimulation had little effect on intra-barrel EPSCs but did hyperpolarize the neurons. Together our results demonstrate that group II mGluRs modulate barrel cortex circuitry by presynaptic and postsynaptic mechanisms depending on the source of the synapse and that this modulation declines with development.
-
We have previously reported that presynaptic dysfunction and cognitive decline have been found in lipoprotein lipase (LPL) deficient mice, but the mechanism remains to be elucidated. Accumulating evidence supported that α-synuclein (α-syn) and ubiquitin C-terminal hydrolase L1 (UCHL1) are required for normal synaptic and cognitive function. In this study, we found that α-syn aggregated and the expression of UCHL1 decreased in the brain of LPL deficient mice. ⋯ Reverse changes were found in cultured cells overexpressing LPL. Furthermore, deficiency of LPL increased ubiquitination of α-syn. These results indicated that aggregation of α-syn and reduction of UCHL1 expression in LPL-deficient mice may affect synaptic function.