Acetylcholine (ACh) is crucial for the attentional modulation of brain circuits. But the question remains: What are the cellular mechanisms by which ACh increases neuronal firing in response to a stimulus? Application of ACh has been shown to paradoxically affect excitatory and inhibitory inputs onto a neuron. It has not been shown if these paradoxical effects are antagonistic or cooperative in affecting neuronal firing. A neural circuit involved with spatial attention and under the influence of cholinergic modulation is the optic tectum (called the superior colliculus in mammalian species). In avian species, the nucleus isthmi pars compacta (Ipc) provides point to point cholinergic connectivity with the optic tectum, and has been suggested to regulate the gain of tectal neurons. The focus of this proposal is to assess the function of ACh on firing in a major output neuron of the optic tectum, the layer 13 Deep Tectal Neuron (DTN). We will determine the effect of ACh on intrinsic and synaptic currents in DTNs using acute slices of the optic tectum and whole cell patch-clamp physiology. Then we will attempt to relate these changes in channel and synapse function to changes in neuronal firing. We will focally apply ACh by pressure injection to characterize the effect of ACh on intrinsic currents in DTNs. We will also characterize the effect of exogenously applied ACh on synaptic currents onto DTNs. Then we will determine the effect of localized, synaptically released ACh on the tectum by stimulating Ipc;connections Ipc and the tectum have been shown to be intact in the acute slice preparation. The long term goal of this line of research is to uncover the mechanisms by which the brain selectively modulates circuits in sensory processing. Correspondingly, ACh is crucial for proper development of sensory circuits and for learning and memory. Also, Alzheimer's disease, Parkinson's disease, and other forms of neurodegenerative disorders are associated with alterations in cholinergic function. Understanding the architecture and mechanisms that are likely to underlie ACh-mediated attention may provide insight into novel therapeutic treatments for these forms of cognitive and neurological impairments.
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