Sensory gating in a computer model of the CA3 neural network of the hippocampus.

We have developed a unique computer model of the CA3 region of the hippocampus that simulates the P50 auditory evoked potential response to repeated stimuli in order to study the neuronal circuits involved in a sensory processing deficit associated with schizophrenia. Our computer model of the CA3 hippocampal network includes recurrent activation from within the CA3 region as well as input from the entorhinal cortex and the medial septal nucleus. We used the model to help us determine if the cortical and septal inputs to the CA3 hippocampus alone are responsible for the gating of auditory evoked activity, or if the strong recurrent activity within the CA3 region contributes to this phenomenon. The model suggests that the medial septal input is critical for normal gating; however, to a large extent the activity of the medial septal input can be replaced by simulated stimulation of the hippocampal neurons by a nicotinic agonist. The model is thus consistent with experimental data that show that nicotine restores gating of the N40 evoked potential in fimbria-fornix lesioned rats and of the P50 evoked potential in schizophrenic patients.

Characterization, scaling, and partial representation of diffuse and discrete input junctions to CA3 hippocampus.

This paper applies a general mathematical system for characterizing and scaling functional connectivity and information flow across the diffuse (EC) and discrete (DG) input junctions to the CA3 hippocampus. Both gross connectivity and coordinated multiunit informational firing patterns are quantitatively characterized in terms of 32 defining parameters interrelated by 17 equations, and then scaled down according to rules for uniformly proportional scaling and for partial representation. The diffuse EC-CA3 junction is shown to be uniformly scalable with realistic representation of both essential spatiotemporal cooperativity and coordinated firing patterns down to populations of a few hundred neurons. Scaling of the discrete DG-CA3 junction can be effected with a two-step process, which necessarily deviates from uniform proportionality but nonetheless produces a valuable and readily interpretable reduced model, also utilizing a few hundred neurons in the receiving population. Partial representation produces a reduced model of only a portion of the full network where each model neuron corresponds directly to a biological neuron. The mathematical analysis illustrated here shows that although omissions and distortions are inescapable in such an application, satisfactorily complete and accurate models the size of pattern modules are possible. Finally, the mathematical characterization of these junctions generates a theory which sees the DG as a definer of the fine structure of embedded traces in the hippocampus and entire coordinated patterns of sequences of 14-cell links in CA3 as triggered by the firing of sequences of individual neurons in DG.

Clearance of exogenous dopamine in rat dorsal striatum and nucleus accumbens: role of metabolism and effects of locally applied uptake inhibitors.

In vivo electrochemistry was used to investigate the mechanisms contributing to the clearance of locally applied dopamine in the dorsal striatum and nucleus accumbens of urethane-anesthetized rats. Chronoamperometric recordings were continuously made at 5 Hz using Nafion-coated carbon fiber electrodes. When a finite amount of dopamine was pressure-ejected at 5-min intervals from a micropipette adjacent to the electrode, transient and reproducible dopamine signals were detected. Substitution of L-alpha-methyldopamine, a substrate for the dopamine transporter but not for monoamine oxidase, for dopamine in the micropipette did not substantially alter the time course of the resulting signals. This indicates that metabolism of locally applied dopamine to 3,4-dihydroxy-phenylacetic acid is not responsible for the decline in the dopamine signal. Similarly, changing the applied oxidation potential from +0.45 to +0.80 V, which allows for detection of 3-methoxytyramine formed from dopamine via catechol-O-methyltransferase, had little effect on signal amplitude or time course. In contrast, lesioning the dopamine terminals with 6-hydroxydopamine, or locally applying the dopamine uptake inhibitors cocaine or nomifensine before pressure ejection of dopamine, significantly increased the amplitude and time course of the dopamine signals in both regions. The effects of cocaine and nomifensine were greater in the nucleus accumbens than in the dorsal striatum. Local application of lidocaine and procaine had no effect on the dopamine signals. Initial attempts at modeling resulted in curves that were in qualitative agreement with our experimental findings. Taken together, these data indicate that (1) uptake of dopamine by the neuronal dopamine transporter, rather than metabolism or diffusion, is the major mechanism for clearing locally applied dopamine from the extracellular milieu of the dorsal striatum and nucleus accumbens, and (2) the nucleus accumbens is more sensitive to the effects of inhibitors of dopamine uptake than is the dorsal striatum.