Optical tools to probe neural circuits in the echolocating bat

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PROJECT SUMMARY/ABSTRACT: A major goal in neuroscience is to dissect the neural circuits that support complex behaviors. Comparative approaches are fundamental to the success of this goal, to separate species specializations from general principles, and to understand the brain in light of its evolved functions. The optical tools that have revolutionized circuit neuroscience in rodents must be expanded to investigate a broad range of species. Here, we propose to develop technologies to map out bottom‐up and top‐down sensory circuits in the echolocating bat, an animal that has been an important tool for furthering our understanding how the brain operates under natural conditions. The bat uses active sensing for its goal directed hunting behaviors to adapt its sonar signal design to search, track and intercept targets in the 3D environment. Here, we will optimize molecular and optical tools to determine how bottom‐up and top‐down circuits control both long‐time scale behavioral mode switching and short time‐scale behavioral adaptation. With these efforts we will also enable a wide‐range of new experiments that exploit molecular tools for circuit dissection in the echolocating bat. Initially, our focus will be on the midbrain superior colliculus (SC). The SC is critical for stimulus selection in humans and other animals, as well as for converting sensory information about the relative location of an object into motor commands for orienting. In the bat, the SC is adapted for acoustic orienting, and is therefore important to the animal's natural target search, tracking, and interception behaviors. The SC is an integrative hub receiving bottom‐up sensory input from the inferior colliculus (IC) and top‐down projections from the auditory cortex (AC). In past studies, we found that neurons in the bat SC select for natural sounds over artificial stimuli. We then pioneered recordings from the SC of behaving bats and found dynamic sensory and motor coding when behavior was adapted to track and select targets. In our proposed work, we will test the hypothesis that the IC‐AC‐SC circuit is critical for both switching between behavioral modes (e.g. search, tracking, and interception), as well as fine‐scale motor adjustments based upon sensory feedback within a behavioral mode. This type of circuit dissection requires the use of optical tools that are currently unavailable in the bat and whose development is the focus of this R34. Specifically, we propose the development of calcium imaging techniques to assay broad circuit activation, and optogenetics for cell‐specific manipulations of circuit‐level activity. To pursue these lines of investigation, we first established the feasibility of different viral tools to target cell types and circuits in the bat. We are now using our optimized AAV system to validate the applicability of two‐photon calcium imaging for monitoring neural networks in bats, with a longer‐term goal of showing how optogenetics can be used to make causal inferences about the role of different circuit components in behavioral mode switching and adaptive behavioral control. Finally, we will develop the tools to enable the use of wireless, battery free optogenetic stimulation devices to alter circuit properties in bats engaged in natural behaviors in the real, 3D environment. Through these efforts, we will be well positioned to subsequently pursue a Targeted Brain Circuits Projects R01 to dissect neural circuits supporting adaptive sensorimotor behaviors through comparative studies of rodents and bats.