The overall goal of this research plan is to understand the role of the basal ganglia (BG) and superior colliculus(SC) in saccadic eye movement choice and decision-making. This application focuses on developing an in vitrobrain slice model with which we will extend our recent in vivo results and investigate the biophysics of a circuitinvolved in choice and decision-making. This proposal aims to link the properties of neurons and their circuitsto behavior in order to elucidate the role of the SC and the BG in eye-movement related cognitive processes.We have four specific aims; 1) Map response patterns across the SC. Voltage imaging will be used to mapthe spatial patterns of signal spread following electrical stimulation in the superficial SC (sSC) and intermediateSC (iSC).
This aim will provide a basic assessment of the spatial extent of both intra- and inter-laminar circuitrywithin the SC; 2) Evaluate inhibition and excitation in SC activity patterns. In this aim we will test for theexistence of three specific interlaminar pathways: an excitatory pathway arising from the sSC extending to theiSC, an inhibitory pathway arising from the iSC and extending into the sSC and an excitatory pathway arisingfrom the iSC and extending into the sSC. We will use voltage imaging in conjunction with patch clamping tostudy responses to sSC and iSC stimulation, and resolve these responses into contributions mediated byglutamatergic and GABAergic synapses. Experiments with synaptic receptor antagonists will assess the role ofglutamatergic and GABAergic transmission in both intra- and interlaminar circuits; 3) Determine the influenceof BG output on the response pattern across the SC. The experiments of this aim will test the hypothesis thattranslation of visual information from sSC into motor information in iSC is modulated by inhibition from thesubstantia nigra pars reticulata of the BG. We will apply electrical stimulation in the nigra to determine how thenigra modulates SC responses to sSC and iSC stimulation; 4) Map response patterns across the SC inmonkey SC. We will develop an in vitro preparation of the SC using monkey tissue. Experiments as outlined inaims 1 and 2 will be performed. We will test the hypothesis that the underlying circuits in monkey and rodentSC are homologous. Because the BG and its target structures are implicated in many neurological andpsychiatric disease states, the results of our experiments should lead to important insights into the functioningof these circuits and the biophysical mechanisms underlying complex behavioral and cognitive processing inboth health and disease.
A sine qua non of higher mental function is our ability to make decisions. Extreme fluctuations in choice behavior may underlie certain neurological and psychiatric diseases such as schizophrenia, attention deficit disorder, Tourette Syndrome and obsessive compulsive disorder. Eye movement abnormalities are also associated with these cortico-basal ganglia diseases. Therefore, a deeper understanding of the basal ganglia - superior colliculus pathway and circuitry and ultimately their role in higher mental function, may lead to better diagnostics, better ways to assess therapies and should provide important insights into the mechanisms of symptomology in these disease states.
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