Final Report Summary - NEURODYNAMICS (Inhibition and neuromodulation in oscillation and synchrony) Cognition is a collective term for complex but sophisticated mental processes such as attention, learning, social interaction, decision making and other executive functions. For normal brain function, these higher-order brain functions need to be aptly regulated and controlled. The loss of cognitive control is intricately related to pathological states such as schizophrenia, depression, attention deficit hyperactive disorder and addiction. A large body of work indicates cognitive control is dependent on the integrity of local neural synchrony mediated by interneuron networks and actuated by the balance of different neuromodulators. Theta oscillations (4-12 Hz) are the most prominent oscillatory activity observed in the hippocampus (HPC) – an area heavily implicated in learning and memory. Given the prominence of theta oscillations in the HPC, many cognitive functions have been attributed to be dependent on rhythmic modulation of HPC principal cells that project to elsewhere in the brain. Principal cells in medial prefrontal cortex (mPFC) have been shown to be entrained by ongoing HPC theta oscillations during decision making dependent on working memory. Further work has suggested that inhibitory neurons containing parvalbumin (PV) in mPFC may play a major role in the theta coherence observed between mPFC and HPC. However, it is unclear if PV neurons are causally involved in directing HPC theta entrainment of mPFC and how this control is achieved.The main purposes of this proposal was to 1) combine optical stimulation and neurophysiological recordings into one integrated probe drive for implantation in rodents; 2) provide causal evidence that prefrontal (mPFC) parvalbumin-containing (PV) inhibitory neurons are responsible for coordinating prefrontal-hippocampal (mPFC-HPC) oscillation and synchrony and; 3) examine the role of dopamine action on mPFC-HPC interactions.To achieve the research goals a novel recording/stimulation system (assembled into a microdrive) has been constructed and utilized to independently target mPFC and HPC with high-density tetrode recordings and optic fibers for optogenetic stimulation. A fully automated figure-of-eight maze was designed and custom built for probing of HPC-mPFC theta coupling in a spatial working memory task. Optogenetic tools were targeted to mPFC PV interneurons using the classical Cre/loxP strategy with transgenic mice and adeno-associated viruses, and mPFC PV neurons were bi-directionally modulated (silenced and activated, respectively) through optogenetics at the task phase where mPFC-HPC interaction are know to occur at theta and gamma frequencies. Importantly, a stabilized step-function opsin (SSFO) was used for activation, conveying subthreshold depolarization and increased spiking in a physiological manner in response to synaptic input. More than 1000 single units were recorded from mPRC and HPC and manually spike sorted and analysis demonstrated that most units have task and location-relative activities. Optogenetic manipulations during task performance identified a subset of putative mPFC PV neurons that increased or decreased their spiking activities consistent with the type of opsin activated, and related changes in spiking activities of putative principle neurons in the local circuitry were also observed. However, the overall excitation-inhibition balance was maintained as suggested by statistically non-significant firing rate distribution across the population of recorded neurons. This lack of overall change in the rate code was consistent with the lack of change in choice accuracy in the spatial working memory task. Further, phase entrainment across theta and low gamma was not modified by bi-directional optogenetic modulation of mPFC PV interneurons. In summary, from the currently available data we conclude that mPFC interneurons control the gain of mPFC activity not its timing in relation to local and HPC rhythmic activities.
