Parvalbumin-Expressing Neurons As Modulators Of An Integrated Prefrontal Cortex: Relevance To Cognitive Impairments In Neuropsychiatric Disease
Abstract
Gamma rhythms (30 – 100hz) emerge in the prefrontal cortex (PFC) during engagement in cognitive tests of attention, working memory, and task switching. Further, abnormalities in prefrontal gamma synchrony are present during cognitive testing in patients with neuropsychiatric diseases such as schizophrenia. A subset of GABAergic neurons expressing the protein parvalbumin (PVNs), are known to facilitate local gamma synchrony, are abnormal in the PFC of schizophrenia patients, and contribute to various forms of PFC-dependent cognition in rodents.
This thesis aimed to evaluate the role of prefrontal PVNs in cognitive processes relevant to schizophrenia, namely working memory and attention. Mice were tested using touchscreen-based cognitive tasks designed to mirror human paradigms more closely. PVNs were assessed using calcium imaging and manipulated using excitatory and inhibitory optogenetics during cognitive testing. Due to the role of PVNs in gamma band activity, activation was performed at both gamma (30hz) and theta (5hz) frequencies to induce optimal or aberrant local oscillatory activity, respectively.
First, we optimized a touchscreen-based task of working memory and confirmed its dependence on intact mPFC functioning. We further show that perturbing PVN activity outside the gamma range induces deficits in both working memory and attention, and that PVN contributions are strongly modulated by cognitive load. We observed that PVN activity is effectively shaped by learning, differentially recruited depending on task demands, and confers information regarding the outcome of behavioral responses. Finally, we observed reduced prefrontal PVN activity in a mouse model of neuropsychiatric disease that displayed attention deficits. Interestingly, stimulating PVNs at the gamma frequency rescued these impairments.
Our findings indicate the PVNs play a flexible role in PFC-dependent cognition, and aid task performance depending on the unique demands of a given task. Importantly, PVNs do not appear to modulate specific domains of cognition, but underlie the integrated functions of the PFC. This role is tightly associated with gamma band activity, as inhibiting or sub-optimal stimulation of PVNs induced cognitive deficits, while gamma stimulation had pro-cognitive effects. We also show that targeting PVN and restoring PFC gamma synchrony may provide a therapeutic avenue to future treatment options.