Project Summary
Cognitive dysfunction results in a diminished quality of life and poorer social and occupational outcomes across
many neuropsychiatric diseases, including addiction, depression, autism, and schizophrenia. Currently,
therapeutic coverage for cognitive dysfunction is severely lacking; remedying this requires a better understanding
of the underlying neural circuitry of cognition. Optimal cognitive function is supported by the stable emergence
of cognitive networks, which are composed of co-activating cortical regions. A cognitive network that consistently
activates across cognitive tasks is the Fronto-Parietal Network (FPN). This network involves co-activation of
prefrontal and more posterior parietal cortices. FPN destabilization occurs in several neuropsychiatric disorders
characterized by dysfunction. Thus, understanding the neural circuit mechanisms allowing for FPN stabilization
stands to fill a major gap in knowledge necessary for devising novel treatment strategies targeting cognitive
dysfunction. The claustrum is a subcortical structure that upon activation synchronizes distant cortical regions.
This is enabled by widespread direct excitatory projections from claustrum to cortex, including FPN cortical
regions. Furthermore, the claustrum is functionally connected to the FPN as assessed by human functional
imaging. Our preliminary data in mice indicates the presence of a functional circuit linking prefrontal cortex to
posterior parietal cortices through the claustrum and that this circuit is capable of stabilizing through potentiation
of synaptic strength at prefrontal-to-claustrum synapses. Thus, we hypothesize that the claustrum adaptively
stabilizes FPN cortical components. To test this novel hypothesis, in Aim 1 we use a combination of viral tract-
tracing, optogenetics, and whole-cell electrophysiology to test the presence and strength of synaptic connectivity
of prefrontal afferents with claustrum projection neurons targeting posterior parietal cortices. In Aim 2, I will
determine the synaptic mechanisms underlying potentiation within the prefrontal-to-claustrum synapse and how
this potentiation drives circuit stabilization. This will be performed using whole-cell patch clamp
electrophysiology, which represents the primary approach for technical training in this proposal. The results of
this study stand to introduce the first candidate circuit mechanism for FPN emergence and, therefore, advance
our knowledge of FPN pathology, and ultimately, cognitive dysfunction. Taken together, this innovative proposal
will provide substantial conceptual and technical training opportunities that are necessary for the PI to ultimately
gain research independence.