Understanding how information is processed within neuronal networks requires knowledge of how neurons use cellular and molecular mechanisms to transform information communicated by synapses. Defects in the communication between synapses are thought to be at the heart of the memory deficits associated with neuropathological disorders such as Alzheimer’s disease and autism. Therefore, elucidating the properties of synapses and their ability to adapt the strength of such communication is fundamental to our understanding of brain function, learning, and memory storage under normal and pathological conditions.
Using advanced optical techniques to monitor and manipulate synaptic signaling in thin dendrites, somata and presynaptic boutons, we hope to identify new cellular mechanisms that define computational rules within cerebellar microcircuits. The crystalline cytoarchitecture of the cerebellum makes it ideal for studying the mechanisms influencing microcircuit computations. Because the cerebellum integrates various sensory inputs in order to fine-tune motor movements, the mechanisms and rules of multi-sensory computations identified from proposed experiments are likely to be relevant for microcircuit function throughout the brain.
Although the cytoarchitecture and synaptic connections within the cerebellar cortex are well known, surprisingly little is known about how this microcircuit uses its molecular, cellular, and anatomical properties to dynamically process sensory information. Our previous publications and preliminary data (see below) have identified novel cellular mechanisms influencing information flow within the cerebellum, and form the basis of experiments proposed here. Using a multi-disciplinary team of physicists and biologists (as well collaborators specializing in computational neuroscience), we will combine state-of-the-art optical techniques (conventional confocal and 2-photon imaging), holographic photolysis, smart scanning (x, y and z dimensions), and superresolution imaging to study the cellular and molecular underpinnings of microcircuit computations.
(A) Distance dependence of short-term facilitation. 2P-images of a cerebellar stellate cell (SC) loaded with Alexa 594. (B) Normalized EPSP train stimulating somatic and dendritic synapses. (C) Summary plot ofshort-term facilitation (n = 9 cells). (D) Sublinear dendritic
integration across synapses demonstrated by glutamate uncaging. 2P-imagesof a SC with uncaging locations (red circles). Photoysis-evoked EPSPs in response to increasing number of stimulated synapses (5 spots, 5 mm apart). Bottom traces show the linear sum expected from individual responses. (E) Sublinear input-output function for this cell. Figure adapted from Abrahamsson et al. /Neuron/2012.