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The hippocampus, the prefrontal cortex, and the ventral striatum form interconnected neural circuits that may underlie aspects of spatial cognition and memory. In the present series of experiments, we investigated functional interactions between these areas in rats during the performance of delayed and nondelayed spatially cued radial-arm maze tasks. The twophase delayed task consisted of a training phase that provided rats with information about where food would be located on the maze 30 min later during a test phase. The single-phase nondelayed task was identical to the test phase of the delayed task, but in the absence of a training phase rats lacked previous knowledge of the location of food on the maze. Transient inactivation of the ventral CA1/subiculum (vSub) by a bilateral injection of lidocaine disrupted performance on both tasks. Lidocaine injections into the vSub on one side of the brain and the prefrontal cortex on the other transiently disconnected these two brain regions and significantly impaired foraging during the delayed task but not the nondelayed task. Transient disconnections between the vSub and the nucleus accumbens produced the opposite effect, disrupting foraging during the nondelayed task but not during the delayed task. These data suggest that serial transmission of information between the vSub and the prefrontal cortex is required when trial-unique, short-term memory is used to guide prospective search behavior. In contrast, exploratory goal-directed locomotion in a novel situation not requiring previously acquired information about the location of food is dependent on serial transmission between the hippocampus and the nucleus accumbens. These results indicate that different aspects of spatially mediated behavior are subserved by separate, distributed limbiccortical-striatal networks.

We have produced yeast artificial chromosome (YAC) transgenic mice expressing normal (YAC18) and mutant (YAC46 and YAC72) huntingtin (htt) in a developmental and tissue-specific manner identical to that observed in Huntington's disease (HD). YAC46 and YAC72 mice show early electrophysiological abnormalities, indicating cytoplasmic dysfunction prior to observed nuclear inclusions or neurodegeneration. By 12 months of age, YAC72 mice have a selective degeneration of medium spiny neurons in the lateral striatum associated with the translocation of N-terminal htt fragments to the nucleus. Neurodegeneration can be present in the absence of macro- or microaggregates, clearly showing that aggregates are not essential to initiation of neuronal death. These mice demonstrate that initial neuronal cytoplasmic toxicity is followed by cleavage of htt, nuclear translocation of htt N-terminal fragments, and selective neurodegeneration.

Huntington's disease (HD) is an incurable neuropsychiatric disease associated with CAG repeat expansion within a widely expressed gene that causes selective neuronal death. To understand its normal function, we have created a targeted disruption in exon 5 of Hdh (Hdhex5), the murine homolog of the HD gene. Homozygotes die before embryonic day 8.5, initiate gastrulation, but do not proceed to the formation of somites or to organogenesis. Mice heterozygous for the Hdhex5 mutation display increased motor activity and cognitive deficits. Neuropathological assessment of two heterozygous mice shows significant neuronal loss in the subthalamic nucleus. These studies show that the HD gene is essential for postimplantation development and that it may play an important role in normal functioning of the basal ganglia.