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    • br Genetic rescue of GluR A dependent spatial

    2022-07-21


    Genetic rescue of GluR-A-dependent spatial working memory Spatial working memory performance in GluR-A−/− mice can be restored by the forebrain-specific mtor inhibitors of GluR-A subunits labeled with green-fluorescent protein (GFP) on an otherwise GluR-A knockout background (Schmitt et al., 2005). This genetic rescue was under the control of the αCaMKII promoter and was especially pronounced in the CA1 subfield of the dorsal subregion of the hippocampus. The level of performance of the rescued mice on the spatial working memory component of the radial maze and during non-matching to place on the T-maze (Fig. 5) was intermediate between the performance of the wild-type controls and the full GluR-A knockout mice. Importantly, GFP-GluR-A expression also resulted in a significant rescue of hippocampal field LTP (Mack et al., 2001). Again the mtor inhibitors level of LTP in the rescued animals was intermediate between the wild-type and GluR-A−/− mice, thus further strengthening the correlation between this form of hippocampal synaptic plasticity and a rapid, flexible form of information processing that underlies spatial working memory performance.
    GluR-A and performance on conditional learning tasks In a separate series of experiments, the trial-specific conditional information was provided by floor inserts placed in the start arm of the maze (Schmitt et al., 2004a). For example, for a given mouse, when there was a white perspex floor insert in the start arm of the maze then the animal had to go to the left goal arm for a food reward (Fig. 6, left-hand side). When there was a black, wire mesh floor insert in the start arm of the maze then the mouse had to go to the right goal arm to get its food reward (Murray and Ridley, 1999). Mice with hippocampal lesions found this task insoluble (Fig. 6). They remained at chance levels of performance throughout testing. When wild-type and GluR-A−/− mice were compared on this conditional task, there was also a complete impairment in the knockout animals, resembling that seen in the lesioned mice (Fig. 6). Thus, GluR-A−/− mice also found the task insoluble. Importantly, in a second experiment we found that if the floor inserts extended throughout the entire maze, including not only the start arm but also both of the goal arms (see Fig. 6, right-hand side), then both mice with hippocampal lesions and GluR-A−/− mice were perfectly able to acquire the task (Fig. 6). The same learning rules applied, but now the relevant floor insert was also present at the location where the animal received the reward. Separate groups of mice were trained on this version of the task. For these animals there was no spatio-temporal discontiguity between the floor insert and the place where the animal was rewarded. Under these conditions there was no impairment in either lesioned or knockout mice. Both hippocampal-lesioned and GluR-A−/− mice acquired this task as well as their respective control groups. Taken together, these results show that hippocampal GluR-A is essential when the animal is required to bridge a spatio-temporal discontiguity between the conditional cue and the place where the reward is experienced (Rawlins, 1985). In other words, hippocampal GluR-A is required when the appropriate spatial response is selected rapidly and flexibly on the basis of a cue representation that is retrieved from recent, short-term memory.
    Non-spatial hippocampus-dependent tasks The deficit in GluR-A−/− mice is not solely restricted to tasks in which the animal is required to make a spatial response. There is increasing evidence that the hippocampus may be important for the temporal encoding of non-spatial, as well as spatial, information (Meck et al., 1984; Young and McNaughton, 2000; Fortin et al., 2002; Kesner et al., 2002). For example, mice or rats with hippocampal lesions are impaired on a non-spatial, operant differential reinforcement of low rates of responding (DRL) task (Clark and Isaacson, 1965; Jarrard and Becker, 1977; Johnson et al., 1977; Boitano et al., 1980; Sinden et al., 1986; Reisel et al., 2005). In this task, animals are trained in an operant chamber to press a lever to obtain a food reward. They are then required to wait a prescribed period of time before pressing the lever again to obtain subsequent food rewards. If the animal responds prematurely during this time period, then the animal is not rewarded and the timer resets to zero. This task therefore requires the animal to switch between withholding and making a response contingent upon the elapse of some minimum period of time (the DRL requirement) since the last response.