Die Theorie der relativen Aktivität - Wie das Striatum Bewegungen kontrolliert
Experimentelle und theoretische Netzwerk-Neurowissenschaften
Molekulare und zelluläre Neurologie und Neuropathologie
Zusammenfassung der Projektergebnisse
The ability to translate sensory experiences into action is critical to survival: a deficit in this process is a hallmark of many neuropsychiatric disease states including depression, autism, and schizophrenia. Despite its importance in health and disease, we know remarkably little about how we assign meaning to and use sensory stimuli to guide actions. In this project, we aimed at studying the brain circuits involved in transforming sensory stimuli into appropriate actions. Specifically, we focused on the local neural circuitry of the striatum, a brain area that has long been hypothesized to play a major role in sensory-motor transformation. We employed a combination of optical imaging methods, including 2-Photon calcium imaging and fiber-photometry, to analyze the activity of neurons as well as the release of neuromodulators in the striatum in mice that performed a simple sensory-transformation task. In addition, we employed optogenetic activation and inhibition experiments to test the effect of direct manipulation of neurons in the striatum on behavior. In particular, we focused on the question of whether the two major cell types in the striatum, the direct and indirect Spiny Projection Neurons (dSPNs & iSPNs) are differentially involved in translating sensory stimuli into the activation or suppression of specific movements during an auditory guided Go/NoGo task. Our initial hypothesis was that dSPNs which are anatomically connected in a way that supports the initiation of movements, might be preferentially activated by Go sounds, and that iSPNs which are connected in a way that supports the suppression of movements, might be preferentially activated by No-Go sounds. We also hypothesized that the activity patterns of both dSPNs and iSPNs in the striatum would change over the course of learning. Finally, we predicted that optogenetic activation of dSPNs should lead to the initiation of movements in the task, while optogenetic activation of iSPNs should lead to the suppression of movements. While this project is far from being concluded, we overcame substantial technical difficulties and were able to test most of these predictions over the course of the funding period: 1. Contrary to our initial hypothesis, we did not observe differences in the activation of dSPNs and iSPNs by Go vs. No-Go sounds. Surprisingly, this was despite the fact that our optogenetic experiments confirmed the hypothesis that dSPNs are capable of and necessary to produce movements in the task and iSPNs are capable of and necessary to suppress movements in the task. 2. We observed an increase in sound-evoked responses in both dSPNs and iSPNs over the course of learning in our fiber-photometry recordings, which measure the aggregated activity of inputs and outputs of large numbers of neurons in a particular area. However, we did not observe any learning dependent changes when we restricted our analysis to individually recorded dSPNs or iSPNs in our 2-Photon experiments during the same task. Taken together, this suggests that the particular input-output computations in the striatum during sensory-motor transformation are more complex than we initially hypothesized. In an attempt to solve this puzzle, we performed additional experiments to test whether these results might be different across different striatal subregions and how the release of neuromodulators like dopamine and acetylcholine influences the activity of dSPNs and iSPNs during the task. These experiments are currently ongoing.
