BackgroundRecent studies designed to identify the mechanism by which retinal horizontal cells communicate with cones have implicated two processes. According to one account, horizontal cell hyperpolarization induces an increase in pH within the synaptic cleft that activates the calcium current (Ca2+-current) in cones, enhancing transmitter release. An alternative account suggests that horizontal cell hyperpolarization increases the Ca2+-current to promote transmitter release through a hemichannel-mediated ephaptic mechanism.Methodology/Principal FindingsTo distinguish between these mechanisms, we interfered with the pH regulating systems in the retina and studied the effects on the feedback responses of cones and horizontal cells. We found that the pH buffers HEPES and Tris partially inhibit feedback responses in cones and horizontal cells and lead to intracellular acidification of neurons. Application of 25 mM acetate, which does not change the extracellular pH buffer capacity, does lead to both intracellular acidification and inhibition of feedback. Because intracellular acidification is known to inhibit hemichannels, the key experiment used to test the pH hypothesis, i.e. increasing the extracellular pH buffer capacity, does not discriminate between a pH-based feedback system and a hemichannel-mediated feedback system. To test the pH hypothesis in a manner independent of artificial pH-buffer systems, we studied the effect of interfering with the endogenous pH buffer, the bicarbonate/carbonic anhydrase system. Inhibition of carbonic anhydrase allowed for large changes in pH in the synaptic cleft of bipolar cell terminals and cone terminals, but the predicted enhancement of the cone feedback responses, according to the pH-hypothesis, was not observed. These experiments thus failed to support a proton mediated feedback mechanism. The alternative hypothesis, the hemichannel-mediated ephaptic feedback mechanism, was therefore studied experimentally, and its feasibility was buttressed by means of a quantitative computer model of the cone/horizontal cell synapse.ConclusionWe conclude that the data presented in this paper offers further support for physiologically relevant ephaptic interactions in the retina.

The literature dealing with the behavioral effects produced by lesions of the septum, frontal cortical areas, and the hippocampus is reviewed. It is concluded that the dorsomedial septum, the dorsolateral frontal cortex (and homologous structures), and the dorsal hippocampus form a nodal point within a larger neuronal system that is involved in response regulation. A model describing the response regulatory processes mediated by this frontal cortical-limbic system is proposed. Motor programs are written in frontal cortex and temporarily stored in hippocampus. Feedback stimuli derived from response initiation and maintenance are compared against the stored hippocampal motor program. If the feedback information matches with the expected outcomes dictated by the motor program, the response sequence is terminated. If comparator deviations arise, the frontal cortical areas are signaled of error and a new motor program is written. Hippocampal theta activity is postulated to be a correlate of comparator activation and feedback analysis.

The retina can function under a variety of adaptation conditions and stimulus paradigms. To adapt to these various conditions, modifications in the phototransduction cascade and at the synaptic and network levels occur. In this paper, we focus on the properties and function of a gain control mechanism in the cone synapse. We show that horizontal cells, in addition to inhibiting cones via a "lateral inhibitory pathway," also modulate the synaptic gain of the photoreceptor via a "lateral gain control mechanism." The combination of lateral inhibition and lateral gain control generates a highly efficient transformation. Horizontal cells estimate the mean activity of cones. This mean activity is subtracted from the actual activity of the center cone and amplified by the lateral gain modulation system, ensuring that the deviation of the activity of a cone from the mean activity of the surrounding cones is transmitted to the inner retina with high fidelity.

The hypothesis of this article is that the interactions between the prefrontal cortex and the hippocampus play a critical role in the modulation of goal-directed self-action and the strengthening of episodic memories. We describe various theories that model a comparator function for the hippocampus, and then elaborate the empirical evidence that supports these theories. One theory which describes a prefrontal-hippocampal comparator for voluntary action is emphasized. Action plans are essential for successful goal-directed behavior, and are elaborated by the prefrontal cortex. When an action plan is initiated, the prefrontal cortex transmits an efference copy (or corollary discharge) to the hippocampus where it is stored as a working memory for the action plan (which includes the expected outcomes of the action plan). The hippocampus then serves as a response intention-response outcome working memory comparator. Hippocampal comparator function is enabled by the hippocampal theta rhythm allowing the hippocampus to compare expected action outcomes to actual action outcomes. If the expected and actual outcomes match, the hippocampus transmits a signal to prefrontal cortex which strengthens or consolidates the action plan. If a mismatch occurs, the hippocampus transmits an error signal to the prefrontal cortex which facilitates a reformulation of the action plan, fostering behavioral flexibility and memory updating. The corollary discharge provides the self-referential component to the episodic memory, affording the personal and subjective experience of what behavior was carried out, when it was carried out, and in what context (where) it occurred. Such a perspective can be applied to episodic memory in humans, and episodic-like memory in non-human animal species.