Evoked potentials recorded from rat hippocampus and neocortex demonstrate sequential dependency in a differential tone discrimination task. These potentials reflect retention of the preceding trial sequence via changes in amplitude of the potentials that correlate with the sequence of tone stimuli. These potentials have been shown to be disrupted by systemic injections of delta-9-THC, which suggests that cannabinoid receptors may perform a key role in regulating the memory processes represented by this sequential dependency. Previous studies of sequential dependency demonstrate that the hippocampus integrates prior inputs with the current stimulus to bias discharges of hippocampal neurons. These outputs are directly correlated with a component of the neocortical evoked potential on the same trial, and inversely correlated with the entorhinal cortex-to- hippocampus (perforant path) mediated synaptic potential on the following trial. The anatomic pathways required to provide trial-specific inputs to the hippocampus, as well as sequence-specific outputs from hippocampus to neocortex both pass through the entorhinal cortex. Recent studies have demonstrated that neural circuitry within the etorhinal cortex is capable of differentially """"""""filtering"""""""" inputs to the hippocampus (Jones 1993). Experiments involving evoked potential recording from superficial layers of the entorhinal cortex will be used to determine the role of this area in producing the inverted feedback of the trial sequence information. Two adjacent brain areas may also contribute to processing of the sequential dependency in the hippocampus. The hippocampal outputs via the parasubiculum project onto the cells of origin of the entorhinal (perforant path) projection to the hippocampus. Perirhinal cortical projections to these same superficial entorhinal layers constitute a major target of neocortical afferents to the entorhinal cortex. A combination of recording and selective lesioning of these two brain areas will be used to identify the role o both short and long feedback """"""""loops"""""""" on sequential dependency. Many of the proposed critical sites for processing of trial sequence are also densely populated with cannabinoid receptors. Therefore, the effects of delta-9-THC on evoked potentials and sequential dependencies in the entorhinal cortex and adjacent structures will be examined to determine which connections are most susceptible to disruption by cannabinoids. Local application of cannabinoid analogs to these same specific sites will be used to determine the role of cannabinoid receptors in regulating the normal processing of sequential memories.
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