Copper deficiency elicits glial and neuronal response typical of neurodegenerative disorders.

Dysregulation of copper homeostasis has been associated with neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and prion diseases. The investigation of the role of abnormal copper level in the development of neuropathological damage is essential for the understanding of pathogenetic mechanisms of these neurodegenerative disorders. Using a mouse model of perinatally induced copper deficiency, the present study analysed the response of neuronal and glial cells to copper deficiency from infancy to young adult age. In mice born and maintained after weaning on copper-deficient diet, copper measurements indicated that at 6-8 weeks the copper levels in the brain were decreased by about 80% with respect to controls. In the brain of copper-deficient mice, microglial and astrocytic activation was observed, mostly in the cerebral cortex and thalamus. In addition, small vacuolated globoid cells confined to the subgranular zone of the dentate gyrus were found in the third postnatal week, and larger vacuolar profiles, identified as neuronal vacuoles, were observed in layer V of the cortex after the fourth week. The spatial distribution and temporal onset of vacuolation appeared to be unrelated to those of activated microglia and astrocytes. Nitrotyrosine-positivity was found to reflect the distribution of vacuoles in the cortex. The specific histopathological features here reported, as well as the severity of neurological deficits observed in this murine model of copper deficiency, strongly suggest that some hallmarks of neurodegenerative disorders could be mediated by multifactorial pathogenetic mechanisms that include copper dysregulation.

BDNF and trkB mRNAs oscillate in rat brain during the light-dark cycle.

In this study, we investigated whether in basal conditions the different functional states occurring during a 24-h cycle are reflected by the expression of brain-derived neurotrophic factor (BDNF) and its receptor, trkB, in rat cerebral cortex and hippocampus. Using semiquantitative RT-PCR assay, the levels of both BDNF and trkB mRNAs were found to undergo significant variation in a 24-h period. The strongest variation was detected in the hippocampus, where the ratio between maximum and minimum levels was about 3.5 and 17.5 for BDNF and trkB, respectively. These findings provide the first evidence that, in the absence of any experimental manipulation, the expression of a neurotrophin and its receptor undergoes diurnal oscillation, possibly related to the physiological variations of the activity level.

Differential expression pattern of jun B and c-jun in the rat brain during the 24-h cycle.

Data from a previous report [3] demonstrated that the proto-oncogene c-fos mRNA expression undergoes basally a circadian fluctuation in the rat brain. The present study was designed to verify by means of Northern blot hybridization the eventual occurrence of a spontaneous oscillation in the expression of other two proto-oncogenes, jun B and c-jun, during 24 h. Rats were either entrained to a light-dark photoperiod or maintained under constant darkness or light. During the dark period, as well as the subjective night, the jun B mRNA levels in the cerebral cortex and striatum were 4-6 times higher than in the light hours or subjective day. No consistent oscillation was found in the c-jun mRNA expression during 24 h in any of the examined brain regions. These results suggest the possibility of different interactions of the c-fos, jun B and c-jun gene products throughout a 24-h period in discrete brain regions.

Environmental stimuli modulate the circadian rhythm of [3H-methyl]thymidine incorporation into brain DNA of male rats.

A circadian rhythm of DNA synthesis is present in most organs of adult mammals, with peak levels (acrophase) generally in the rest period. We have recently reported that in the rat brain the acrophase of the rhythm of thymidine incorporation into DNA occurs on the contrary during the active period. To determine whether the brain waking activity was exerting a modulatory action we measured the circadian rhythm of incorporation in the brain and kidney of young adult male rats housed in conditions of sensory and social enrichment or impoverishment for four days. Biochemical and autoradiographic data show that the brain rhythm persists in the enriched condition, but is abolished in the impoverished condition. On the other hand, the rhythm of incorporation in the kidney is maintained in both conditions. These results suggest that the permanence of the brain oscillation is selectively dependent on the complexity of the sensory and social stimulation.

Paradoxical sleep deprivation of the mother enhances DNA synthesis in fetal rat brain: autoradiographic and biochemical evidence.

Pregnant rats were deprived of paradoxical sleep for 3 days starting on the 18th gestational day. The condition of PS-D was imposed by confinement on a small platform surrounded by water or by daily injections of clomipramine. Four hours before the killing rats received a s.c. injection of [3H]-thymidine. The amount of radioactive DNA determined by autoradiography in several regions of fetal brain was found to be markedly increased under both experimental conditions in comparison with the control fetal brain. Considerably more limited effects were observed in kidney. Comparable changes of lower magnitude were obtained by comparing the specific radioactivity of DNA samples purified by chlorophorm extraction and digestion with RNase and proteinase K. The results fully confirm our previous data obtained under similar experimental conditions but based on the analysis of an acid-washed DNA fraction.