Changes in cortical and striatal neurons predict behavioral and electrophysiological abnormalities in a transgenic murine model of Huntington's disease.

Neurons in Huntington's disease exhibit selective morphological and subcellular alterations in the striatum and cortex. The link between these neuronal changes and behavioral abnormalities is unclear. We investigated relationships between essential neuronal changes that predict motor impairment and possible involvement of the corticostriatal pathway in developing behavioral phenotypes. We therefore generated heterozygote mice expressing the N-terminal one-third of huntingtin with normal (CT18) or expanded (HD46, HD100) glutamine repeats. The HD mice exhibited motor deficits between 3 and 10 months. The age of onset depended on an expanded polyglutamine length; phenotype severity correlated with increasing age. Neuronal changes in the striatum (nuclear inclusions) preceded the onset of phenotype, whereas cortical changes, especially the accumulation of huntingtin in the nucleus and cytoplasm and the appearance of dysmorphic dendrites, predicted the onset and severity of behavioral deficits. Striatal neurons in the HD mice displayed altered responses to cortical stimulation and to activation by the excitotoxic agent NMDA. Application of NMDA increased intracellular Ca(2+) levels in HD100 neurons compared with wild-type neurons. Results suggest that motor deficits in Huntington's disease arise from cumulative morphological and physiological changes in neurons that impair corticostriatal circuitry.

Leptin, corticotropin-releasing hormone (CRH), and neuropeptide Y (NPY)in free-ranging pregnant bats.

Leptin, the product of the obese gene first identified in mice, restores fertility in obese mice, and accelerates puberty in mice. We hypothesized that leptin's putative role in reproduction may extend to pregnancy and lactation. Leptin levels were determined in Myotis lucifugus, the little brown bat, a free-ranging mammal with a seasonal breeding cycle. The present study shows that plasma levels of leptin progressively rise during pregnancy, supporting a potential role for leptin in the maintenancy of pregnancy. In contrast, leptin was significantly lower during lactation, a time when most mammals, including bats, demonstrate reduced fertility. In addition to its possible roles in reproduction, leptin appears important in regulation of energy balance. M. lucifugus spontaneously fasts for up to 16 h each day during the active season, which allowed us to test the hypothesis that acute fasting was associated with decreased leptin. Leptin was significantly lower in fasted (lactating) bats, compared to those that recently returned from nightly foraging. Although postprandial lactating bats had a significantly higher fat index than fasted bats, plasma leptin and body fat were not significantly correlated, and were only weakly correlated (r2 = 0.26) when both pregnant and lactating females were included in the analysis. Similar changes during pregnancy, lactation, and the daily feeding cycle were observed in the hypothalamic neuropeptide, corticotropin-releasing hormone (CRH), which is believed to play an important role in energy balance and reproduction. By contrast, neuropeptide Y (NPY) increased during pregnancy but did not change during fasting. These results suggest that leptin's putative role in reproduction may extend to pregnancy and lactation, and that spontaneous, acute fasting results in decreased circulating levels of leptin in M. lucifugus.