The SCid, a sensorimotor hub in the midbrain, plays a fundamental role in stimulus-guided behavior as well as spatial attention control. It encodes a topographic map of stimulus priority, i.e., of physical salience + behavioral relevance of stimuli, as well as a map of relative stimulus priority, which, together, form the basis of SCid's role in behavior. However, the contributions of intrinsic inhibitory cell types to the construction of the SCid's priority map and to behavior are not known. Similarly, how SCid's map of relative stimulus priority, which requires long-range competitive inhibition, is constructed, is unclear. Dissecting the logic of local and long-range competitive inhibition in the SCid, as well as their roles in visually guided behavior necessitates the use of cutting edge technologies for the measurement and perturbation of neural circuits in a cell-type specific manner. The central focus of our future planned R01 is to address these questions in freely behaving mice engaged in visual discrimination tasks, as well in rigorous, primate-like visuospatial attention tasks (that we have developed in the lab). In this R34, we propose to acquire and establish the use of two revolutionary technologies that are indispensable to this endeavor.
In Aim 1, using the nVoke system (Inscopix Inc.), we will measure the responses of ensembles of excitatory SCid neurons to visual stimuli in awake, head-fixed mice, without and with optogenetic inactivation of local inhibitory neurons. This unique technology for combined endoscopic calcium imaging and optogenetic perturbation of neurons of different sub-types intermingled within the same brain area will elucidate the role of intrinsic inhibition in the construction of SCid's map of stimulus salience.
In Aim 2, using the Quartet system (Neurescence Inc.), we will measure the responses of ensembles of excitatory SCid neurons to competing visual stimuli in awake head-fixed mice, without and with optogenetic inactivation of a group of parvalbumin-positive GABAergic neurons in the midbrain tegmentum called the periparabigeminal lateral tegmental nucleus (pLTN). This unique technology that permits simultaneous endoscopic calcium imaging and optogenetic perturbation of neurons in distinct brain areas will allow us to test the hypothesis, produced by our recent work in barn owls, that the mammalian pLTN generates the long-range competitive inhibition that is essential for competitive representations in SCid, and for the construction of SCid's map of relative stimulus salience. These two aims, coupled with the novel behavioral paradigms that we have developed in the lab for studying spatial attention and visual discrimination in freely behaving mice, will establish the scientific and methodological foundation necessary to pursue our longer-term goals in the planned R01: (a) to dissect the role of local inhibitory circuits of different sub-types in the construction of SCid's map of stimulus priority, as well as in visually-guided behaviors and spatial attention, and (b) to investigate the role of the GABAergic pLTN in the construction of SCid's map of relative stimulus priority, as well as in distracter suppression, target selection and spatial attention. Results have the potential to reveal fundamental mechanistic insights into intrinsic as well as extrinsic inhibitory circuitry that shape SCid function and mediate its role in behavior.
The superior colliculus (SC), a midbrain structure found in all vertebrates, plays a key role in sensory stimulus-guided behavior and in the control of spatial attention. Here, we investigate in mice in vivo, the role of local inhibitory neurons intrinsic to the SC in shaping the functional properties of excitatory SC neurons, as well as the role of specialized inhibitory neurons extrinsic to the SC in generating competitive inhibition essential for stimulus selection by the SC. To this end, we propose the use cutting-edge technologies that are unique in their ability to permit simultaneous measurement as well as perturbation of the ensemble activity of specific sub-types of neurons deep in the brains (even in freely behaving animals). Results from this work will set the stage for future planned work that will elucidate the roles of local as well as long-range competitive inhibition in stimulus-guided behavior and in the control of spatial attention in freely behaving animals, and inform our understanding of neural mechanisms of attentional dysfunction in psychiatric illnesses.
