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Melatonin receptor expression exhibits profound developmental changes through poorly understood mechanisms. In mammals, a current model suggests that pubertal reactivation of gonadotrophin-releasing hormone (GnRH) secretion down-regulates MT1 melatonin receptors in pituitary gonadotroph cells, via the induction of early growth response factor-1 (EGR-1). Here we have examined this model by testing the hypotheses that inhibition of Mt1 expression by GnRH occurs directly in gonadotroph cells, can be reversed in adulthood by blockade of GnRH receptors, and requires EGR-1. We first confirmed the endogenous expression of Mt1 mRNA in the αT3-1 gonadotroph cell line. Stimulation of these cells with a GnRH agonist resulted in a rapid increase of Egr-1 mRNA expression, which peaked after 30–60 minutes, and a more prolonged elevation of nuclear EGR-1 immunoreactivity. Moreover, the GnRH agonist significantly decreased Mt1 mRNA. We then treated adult male rats with the GnRH antagonist cetrorelix or saline. After 4 weeks of daily injections, cetrorelix significantly reduced serum LH concentration and testis weight, with histological analysis confirming absence of spermatogenesis. Despite the successful inhibition of GnRH signalling, pituitary Mt1 expression was unchanged. Next we studied the proximal region of the rat Mt1 promoter. Consistent with previous work, over-expression of the transcription factor PITX-1 increased Mt1-luciferase reporter activity; this effect was dependent on the presence of consensus PITX-1 promoter binding regions. Over-expression of EGR-1 inhibited PITX-1-stimulated activity, even following mutation of the consensus EGR-1 binding site. Finally, we studied Egr1−/− mice and observed no difference in pituitary Mt1 expression between Egr1−/− and wild-type litter mates. This work demonstrates that GnRH receptor activation directly down-regulates Mt1 expression in gonadotroph cells. However, pituitary Mt1 expression in adults is unaltered by blockade of GnRH signalling or absence of EGR-1. Our data therefore suggest that melatonin receptor regulation by GnRH is not reversible in adulthood and doesn't require EGR-1. [ABSTRACT FROM AUTHOR]

Cognitive decline precedes motor symptoms in Huntington disease (HD). A transgenic rat model for HD carrying only 51 CAG repeats recapitulates the late-onset HD phenotype. Here, we assessed prefrontostriatal function in this model through both behavioral and electrophysiological assays. Behavioral examination consisted in a temporal bisection task within a supra-second range (2 vs.8 s), which is thought to involve prefrontostriatal networks. In two independent experiments, the behavioral analysis revealed poorer temporal sensitivity as early as 4 months of age, well before detection of overt motor deficits. At a later symptomatic age, animals were impaired in their temporal discriminative behavior. In vivo recording of field potentials in the dorsomedial striatum evoked by stimulation of the prelimbic cortex were studied in 4- to 5-month-old rats. Input/output curves, paired-pulse function, and plasticity induced by theta-burst stimulation (TBS) were assessed. Results showed an altered plasticity, with higher paired-pulse facilitation, enhanced short-term depression, as well as stronger long-term potentiation after TBS in homozygous transgenic rats. Results from the heterozygous animals mostly fell between wild-type and homozygous transgenic rats. Our results suggest that normal plasticity in prefrontostriatal circuits may be necessary for reliable and precise timing behavior. Furthermore, the present study provides the first behavioral and electrophysiological evidence of a presymptomatic alteration of prefrontostriatal processing in an animal model for Huntington disease and suggests that supra-second timing may be the earliest cognitive dysfunction in HD. [ABSTRACT FROM AUTHOR]

The present study investigated temporal perception in a Huntington disease transgenic rat model using a temporal bisection procedure. After initial discrimination training in which animals learned to press one lever after a 2-s tone duration, and the other lever after a 8-s tone duration for food reward, the bisection procedure was implemented in which intermediate durations with no available reinforcement were interspersed with trials with the anchor durations. Bisection tests were repeated in a longitudinal design from 4 to 8 months of age. The results showed that response latencies evolved from a monotonic step-function to an inverted U-shaped function with repeated testing, a precursor of non-responding on trials with intermediate durations. We inferred that temporal sensitivity and incentive motivation combined to control the transformation of the bisection task from a two-choice task at the outset of testing to a three-choice task with repeated testing. Changes in the structure of the task and/or continued training were accompanied by improvement in temporal sensitivity. In sum, the present data highlight the possible joint roles of temporal and non-temporal factors in the temporal bisection task, and suggested that non-temporal factors may compensate for deficits in temporal processing.