Research in the CNSL focuses on the regulation and function of a major component of the brain’s attention systems, the cortical cholinergic input system. We are specifically interested in understanding what cognitive processes are mediated via fast or “transient” cholinergic signals, and how we can use this knowledge to enhance and restore cognition in healthy subjects and patients, respectively.

Our research utilizes a wide range or neuroscientific methods, including sophisticated electrochemical techniques to monitor synaptic signaling in performing rodents, optogenetic methods and DREADDs to control different aspects of cortical cholinergic activity and cortico-striatal glutamatergic signaling, and genetic approaches to vary the capacity of cholinergic neurons to sustain elevated levels of neurotransmission.

We conduct parallel and converging research in rodents and humans, to validate and expand our conclusions from animal models, and to determine the relevance of our basic research in animals for human cognition and cognitive disorders. The Table below summarizes our basic and translational research projects and it illustrates the parallel strategies of research in rodents and humans.

Our research on the neuronal and cognitive impact of expressing genetic variations of the neuronal choline transporter (CHT) exemplifies our translational research strategy. We found that humans expressing a subcapacity variant of the CHT (I89V) exhibit distinct and robust attentional vulnerabilities, and their (right) frontal cortex does not activate during attentional performance. In mice expressing the CHT Val89 variant, choline import into the synapse is attenuated, and this results in a reduced capacity for sustaining elevated levels of cholinergic signaling as required, for example, during attentional performance. Together, our research in humans and rodents demonstrates the cognitive impact of such a variant and reveals the neuronal mechanisms via which the variant CHT influences behavior and cognition.  See Research for more details.