CHARACTERIZATION OF PERFORANT PATH LESIONS IN RODENT MODELS OF MEMORYAND ATTENTION

Early stage Alzheimer's disease (AD) pathology is associated with neur odegeneration of systems within the temporal cortex, e.g. the entorhin al cortex, perforant pathway and hippocampus. The perforant pathway pr ovides the major neuronal input to the hippocampus from the entorhinal cortex and thus relays multimodal sensory information derived from co rtical zones into the hippocampus. The earliest symptoms of AD include cognitive impairments, e.g. deficits in short-term memory and attenti on. Consequently we have investigated the effect of bilateral knife cu t lesions to the perforant path on cognition in rats using models meas uring primarily short-term memory (operant delayed match to position t ask), attention (serial five-choice reaction time task) and spatial le arning (Morris water maze). Rats receiving bilateral perforant path le sions showed normal neurological function and a mild hyperactivity. Th e lesion produced little effect on attention assessed using the five-c hoice task. In contrast, animals with equivalent lesions showed a robu st delay-dependent deficit in the delayed match to position task. Spat ial learning in the water maze task was also severely impaired. The de lay-dependent deficit in the match to position task was not reversed b y tacrine (3 mg/kg) pretreatment. The present data support a selective impairment of cognitive function following perforant path lesions tha t was confined to mnemonic rather than attentional processing. These f indings complement primate and human studies identifying a critical ro le of the perforant pathway and associated temporal lobe structures in declarative memory. Degeneration of the perforant pathway is likely t o contribute to the mnemonic deficits characteristic of early AD. The failure of tacrine to ameliorate these deficits may be relevant to an emerging clinical literature suggesting that cholinomimetic therapies improve attentional rather than mnemonic function in AD.