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Optogenetic investigation of GABAergic interneurons in the limbic system during reward and addiction

Final Report Summary - OPTO-REW (Optogenetic investigation of GABAergic interneurons in the limbic system during reward and addiction)

During the period I have established state of the art in vivo optogenetics and electrophysiology to study neuronal subtypes in circuits that regulate reward-related behaviors. I have used genetically modified mice to specifically label interneuron types in striatum and other circuits of the basal ganglia to study their role in regulating microcircuit function and to shape behavior. I have in particular determined the local circuit in striatum and how fast-spiking parvalbumin-expressing GABAergic interneurons regulate the activity of the other neuron type in the local circuit using optogenetics and electrophysiology. I have further studied the basal ganglia circuits that directly control the activity of the serotonin system using genetically modified rabies virus, optogenetics and neuroanatomy.
This work has resulted in publication of two peer-reviewed articles (Neuron and Journal of Neuroscience) that describes this effort.

I have established the infrastructure to study neuron subtype in vivo using a number of state of the art technologies. This approach has proven essential to generate information on how brain circuits are connected and how activity of distinct neuron subtypes directly shapes behavior. My focus has been to elucidate the structure and function of brain circuits that shape motivated behavior, and I have therefore focused on basal ganglia circuits. Following the proposal, my first effort was to study interneuron subtypes in the striatum, to define their unique connectivity pattern and function, in order to ultimately generate new hypotheses on how interneuron subtypes control distinct aspects of reward-related behaviors. This fundamental understanding of the basal ganglia circuit structure and function is also necessary to study the dysfunctional network in mood disorders or psychiatric disorders with reward dysfunction.
I have in the team I formed studied primarily the fast-spiking parvalbumin expressing interneurons and the low-threshold spiking somatostatin expressing interneurons. I have developed methods to label these neuron subtypes using genetically modified mice (specific Cre-expressing mouse lines) and Cre-inducible viral vectors, which has enable us to specifically target these populations. I have also developed and applied optogenetic methods to express light-sensitive proteins (opsins) to control with millisecond precision the activity of these neuron subtypes using light. I have primarily used ChR2 and NpHR for this optogenetic control, but I have recently also studied the circuit using SSFO, Jaws, ArchT, iC1C2 depending on the application. In line with this effort, I also expanded the applicability of optogenetic control from mice to rats through the generation of a transgenic rat model that allows me to control fast-spiking parvalbumin expressing interneurons in the basal ganglia as well as all other brain circuits. This transgenic rat model (PV-Cre BAC transgenic rat) will be a very important complement to the analysis of mouse circuits in terms of understanding the function of the same circuits in two different species and also allows me to study the fast-spiking parvalbumin expressing interneurons in vivo in a more advanced behavioral repertoire. This represents a advancement beyond state of the art in the filed. In addition, during the period I have established the platform to identify connectivity patterns between genetically defined neurons subtypes using a genetically modified rabies virus approach. This complements the approach of electrophysiology and optogenetics and allows for the whole-brain dissection of circuit connectivity.

The IRG Marie Curie support has been essential in integrating my research effort at the Karolinska Institutet and has given me the opportunity to pursue my research and ultimately establish my own research group.