Allen E. Butt, Ph.D. - US grants

The proposed research tests the hypothesis that learning to discriminate between vibratory stimuli will produce synaptic plasticity in the somatosensory cortex of rats and that this plasticity will critically depend on the cholinergic modulation of NMDA channels. In the first experiment, rats will be trained to lick a spout for sugar-water in response to the presentation of one of two different vibratory stimuli applied to an individual whisker. While the rat is learning this discrimination, electrophysiological recordings will be made from single neurons within the vibrissae representation of the somatosensory cortex. The evolution in the responsiveness of those neurons to the training stimuli will be monitored and will subsequently be related to discrimination performance. It is hypothesized that the response of somatosensory cortical neurons to the reinforced stimulus will become enhanced and the response to the nonreinforced stimulus to become suppressed during discrimination learning. In the second experiment, prior to discrimination training and single unit recording, rats will receive systemic injections of the cholinergic agonist BIBN-99 or the antagonist atropine. It is hypothesized that cholinergic facilitation will enhance learning-induced changes in somatosensory cortical neurons and improve acquisition in the discrimination task; conversely, it is hypothesized that cholinergic suppression will block learning-induced synaptic plasticity and impair acquisition in the discrimination task. In the third experiment, prior to discrimination training and single unit recording, rats will receive systemic injections of the NMDA antagonist MK-801. It is hypothesized that NMDA receptor blockade, like cholinergic suppression, will prevent the emergence of learning-induced synaptic plasticity and will impair acquisition in the discrimination task. Results from these experiments will provide unique evidence directly linking the cholinergic system to memory formation and synaptic plasticity, and in turn will help to illuminate the relationship between memory loss and cholinergic hypofunction in Alzheimer's disease.

The proposed experiments involve the use of in vivo microdialysis and high-performance liquid chromotography/electrochemical detection techniques to measure the amount of the neurotransmitter acetylcholirie (ACh) released from the corticopetal projections of the nucleus basalis magnocellularis into primary auditory (A1) and visual (V1) cortices in the rat brain during various Pavlovian associative learning paradigms. The specific aims of these experiments are (1) to demonstrate the relationship between ACh release in task-relevant sensory cortices and the strength of conditioned responding to modality-specific sensory stimuli, (2) to provide evidence for the existence of a differential, regionally-specific pattern of ACh release (as opposed to a generalized, global pattern of release), where the greatest levels of ACh are released in task-relevant sensory cortices during associative learning, and (3) to determine whether manipulating demands on attentional processing of conditioned stimuli causes increases or decreases in the amount of ACh released in the sensory cortex corresponding to the affected conditioned stimulus. These goals will be achieved through a series of three experiments where ACh release will be simultaneously measured in A1 and V1, and where conditioned appetitive approach behavior will be quantified in a classical conditioning paradigm (Experiment 1), an incremental attentional processing paradigm (Experiment 2), or in a blocking paradigm (Experiment 3). Developing this novel model of selective attention and associative learning will provide important insight into the brain mechanisms involved in attention, in cortical synaptic plasticity, and in memory formation itself. Furthermore, results from these experiments will contribute to ongoing research in diverse areas of medicine and neuroscience, ranging from the study of Alzheimer's disease (characterized by cortical ACh deficiency and memory impairments) to reorganization of cortical function following peripheral nerve injury (where such reorganization depends on cortical ACh).