Structures of the brain's limbic system are critically important for processes of attention, memory and cognition, and for the etiology of cognitive and behavioral disturbances such as schizophrenia and attention deficit disorder. Yet, knowledge of the specific malfunctions that bring about attentional and mnemonic disturbance has been elusive. This project approaches these issues, beginning with two fundamental premises. First, an understanding of the etiology of attentional and mnemonic disturbance will require a basic understanding of the involved brain mechanisms in production and control of these processes. Second, individual brain areas do not influence attention and memory in isolation. Instead, these processes emerge from the interactions of neurons in multiple brain areas that form functional circuits. This project continues an extensive programmatic analysis of the interactions of hippocampal, cingulate cortical, limbic diencephalic, amygdalar and striatal neurons involved in mediation of discriminative instrumental learning. The interactions are studied by recording the activity of neurons simultaneously in multiple brain sites during learning in rabbits. Selective circuit lesions and neurochemical manipulations experimentally alter attention- and memory-relevant information flow in the circuits. Recent discoveries set the stage for major advances concerning the documentation of specific learning relevant brain pathways and circuit interactions. The new data demonstrate that contextual information from medial temporal lobe structures (entorhinal cortex, hippocampal formation) modulates distinct associative processes of various other limbic circuit modules to which it is projected. The proposed studies test the following hypotheses, stimulated by these results. Neural transmission (signaling) identifying the learning context, projected from dorsal subiculum, enhances associative attention in cingulate cortex in response to nonsalient, significant cues. Context signaling from entorhinal cortex reduces cingulate cortical associative attention during extinction, however, cingulate cortical attention is preserved during extinction in a novel context. Context-signaling from entorhinal cortex via the ventral subiculum to the nucleus accumbens suppresses behavioral responding during extinction in the presence of novel contextual stimuli. Context signaling from subiculum to the limbic diencephalon induces context-specific topographic retrieval patterns of cue elicited cingulothalamic activation. Disruption of these patterns will impair memory by increasing pro-, and retroactive interference. Flow from entorhinal cortex to amygdala is required to initiate learning-relevant plasticity subserving many or all of the aforementioned effects.
