Sex-linked behavioural differences in mice expressing a human insulin transgene in the medial habenula.

We previously reported that a human insulin transgene was specifically expressed in the medial habenula of the adult mouse brain, and that this expression was ascribed to the delta-168 transgene. The present study analyses the possible behavioural consequences of this insulin transgene expression using measures of food intake, spontaneous activity, emotional reactivity, learning and extinction performance of an operant task. The delta-168 transgenic mice did not differ from the C57BL/6 control mice as concerns food intake, behaviour in the open field, or emotional response in an elevated plus maze. On the other hand, measures of locomotor activity in a circular corridor revealed a significantly faster decline of spontaneous locomotor activity in male as compared to female delta-168 transgenic mice. Moreover, as compared to female transgenic mice, male transgenic mice exhibited a deficit in the rate of acquisition and an acceleration of the rate of extinction of a bar press response in a Skinner box. In contrast, the behaviour of female transgenic mice did not differ from either male or female C57BL/6 control mice. The results of the present study demonstrate that the behavioural modifications observed in delta-168 transgenic mice are sex-linked and suggest that these behavioural differences result from changes in the interaction (interface) between motivational and motor mechanisms mediated via the striato-habenulo-mesencephalic system.

Differential time courses of c-fos mRNA expression in hippocampal subfields following acquisition and recall testing in mice.

Spatio-temporal patterns of c-fos mRNA expression were studied in the mouse brain following the partial acquisition of an appetitive conditioning task in a Skinner box. We used two experimental situations: during the initial acquisition of the task (acquisition paradigm) and during the retention test (recall paradigm). In both paradigms the in situ hybridization signal was exclusively located in the hippocampal formation and the posterior cingulate cortex. However, the time-dependent pattern of expression was quite different according to the experimental situation: mRNA levels peaked at 90 min post-test in both paradigms but returned to basal (control) level by 180 min in the acquisition group, while in CA3 and DG subfields, high levels of mRNA expression were maintained at 180 min in the recall group. Taken together these results suggest that the IEG c-fos is implicated in the different phases of post-acquisition memory processes and involve a differential spatio-temporal regulation of its expression in hippocampal subfields.

K+ channel openers prevent global ischemia-induced expression of c-fos, c-jun, heat shock protein, and amyloid beta-protein precursor genes and neuronal death in rat hippocampus.

Transient global forebrain ischemia induces in rat brain a large increase of expression of the immediate early genes c-fos and c-jun and of the mRNAs for the 70-kDa heat-shock protein and for the form of the amyloid beta-protein precursor including the Kunitz-type protease-inhibitor domain. At 24 hr after ischemia, this increased expression is particularly observed in regions that are vulnerable to the deleterious effects of ischemia, such as pyramidal cells of the CA1 field in the hippocampus. In an attempt to find conditions which prevent the deleterious effects of ischemia, representatives of three different classes of K+ channel openers, (-)-cromakalim, nicorandil, and pinacidil, were administered both before ischemia and during the reperfusion period. This treatment totally blocked the ischemia-induced expression of the different genes. In addition it markedly protected neuronal cells against degeneration. The mechanism of the neuroprotective effects involves the opening of ATP-sensitive K+ channels since glipizide, a specific blocker of that type of channel, abolished the beneficial effects of K+ channel openers. The various classes of K+ channel openers seem to deserve attention as potential drugs for cerebral ischemia.