Optogenetic dissection of the developing prefrontal-hippocampal circuitry that gates mnemonic and executive maturation

• Applicants: Dr. Michael Denker; Professorin Dr. Ileana L. Hanganu-Opatz; Professor Dr. Peter Hegemann; Professor Dr. Thomas Oertner
• Subject Area: Cognitive, Systems and Behavioural Neurobiology
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 237833830

Processing and integration of information within neuronal networks accounts for mnemonic and executive abilities. The relevance of these functional interactions is exemplified in the case of the prefrontal cortex (PFC) and hippocampus (HP). Entrainment of both areas in oscillatory rhythms ensures the spatiotemporal orchestration of neuronal activity and enables information transfer and storage. The oscillatory coupling within prefrontal-hippocampal networks emerges during early neonatal development, with discontinuous theta activity in the HP driving the local gamma-band synchrony in the PFC via axonal projections. However, the cellular elements critically underlying the functional communication within developing prefrontal-hippocampal networks and the net impact of early network entrainment on the later cognitive abilities remain unknown. The present project aims at elucidating these issues within a collaborative effort of a troika by combining the engineering of new optogenetic tools and development of analytic approaches with in vivo and in vitro electrophysiology as well as behavioral investigation. Fast light-activation and silencing of different neuronal subtypes will be achieved at two different wavelengths after delivering by region-specific in utero electroporation newly designed push-pull tandem constructs that contain mutated channelrhodopsins and inhibitory ion pumps. Recordings of the local field potential (LFP) and multiple unit activity (MUA) in the neonatal PFC and HP using optoelectrodes in vivo followed by synchrony analysis at the spike and population levels will determine the neuronal subtypes (key neurons) critically causing prefrontal network oscillations in different frequency bands and the cellular mechanisms of prefrontal-hippocampal communication during early development. To ascertain the long-term functional and behavioral readout of light-activation/silencing of key neurons, optogenetic tools for extended depolarization and hyperpolarization will be designed by Two Component Optogenetic (TCO) and activated during defined periods of development. Their impact on the oscillatory entrainment and directed interactions within prefrontal-hippocampal networks will be assessed by in vivo extracellular recordings from freely-moving pups during accomplishment of cognitive tasks. The results of these investigations will yield novel insights into the causal relationships between early neuronal activity and correct wiring of developing networks underlying cognitive processing at adulthood.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1665: Resolving and Manipulating Neuronal Networks in the Mammalian Brain - From Correlative to Causal Analysis
• Major Instrumentation: Electrophysiology and light-stimulation set-up
• Instrumentation Group: 3440 Elektrophysiologische Meßsysteme (außer 300-309 und 340-343)