Identity and Function of Neurons Receiving Bottom-Up or Top-Down Inputs in the Adult and Developing V1

About This Grant

PROJECT SUMMARY/ABSTRACT Our brain generates sensory perceptions by integrating externally (bottom-up) and internally (top-down) driven representations of the world. The bottom-up pathways provide information originating from the sensory periphery about the physical properties of the stimulus. The top-down pathways provide inferential or predictive information about the nature of the stimulus based on its context and on the organism’s experience. Imbalances between the bottom-up or top-down driven representations result in profound perceptual abnormalities, leading to various psychiatric disorders. However, the mechanisms that enable our brain to establish and maintain a balanced integration of bottom-up and top-down information streams during sensory processing is unknown. Specifically, the mammalian sensory cortices are composed of a diverse array of neuronal types classified by their transcriptomes. It is unclear which types receive inputs from the bottom-up, top-down, or both sensory streams. Additionally, while sensory neurons exhibit varying responses to the same stimuli depending on the context within which the stimuli are presented, it remains unclear whether this variability is influenced by how these neurons are integrated in the bottom-up and top-down pathways. Furthermore, the timeline for when bottom-up and top- down integration matures is largely unknown, as is the impact of experience on this developmental trajectory. I propose to address these questions using the mouse primary visual cortex (V1) as a model system. V1 receives visual information that ascends from the eyes through the dorsolateral geniculate nucleus of the thalamus (dLGN) and descends from higher-order visual areas, including the lateral posterior (LP) nucleus and cortical higher visual areas (HVAs). I hypothesize that V1 neurons receiving bottom-up or top-down inputs from the dLGN, LP or HVAs represent largely distinct transcriptomic categories with distinct laminar profiles and response properties to visual stimuli. Furthermore, I hypothesize that visual experience is necessary for the development of bottom- up and top-down integration in V1. To test these hypotheses, I will implement a combination of a newly developed anterograde transsynaptic tracing technique, spatial transcriptomics and in vivo two-photon imaging to carry out the following experiments. In the K99 phase, I will first determine the molecular identities of neurons receiving bottom-up or top-down inputs in the adult mouse V1. I will then characterize the response properties of adult V1 neurons in relation to the origins of inputs they receive and to their molecular identities (K99 + R00). In the R00 phase, I will determine the developmental time course and the role of visual experience in the development of bottom-up and top-down integration in V1. These experiments will allow us to provide the first mapping of the two major streams of visual information, the bottom-up and the top-down, to V1 onto molecularly defined neuronal types. We will also reveal, for the first time, the logic of neuronal responses to sensory stimuli in relation to the two major pathways that impinge on these neurons. Furthermore, we will uncover fundamental principles of the development of bottom-up and top-down integration in V1.