Circuit-Based Therapies Rescue Cognitive Dysfunction in Neurological and Psychiatric Diseases

Julia B Kahn, University of Pennsylvania

Abstract

In both neurological and psychiatric diseases, many different structural and functional alterations occur in the brain, making interventions focused on singular mechanisms insufficient to manage the varied, intolerable symptoms. However, these various alterations culminate in the same outcome: inappropriate circuit activity, i.e. the distorted recruitment of principal cells. In these studies, we explored if the aggregate of this aberrant activity could be a therapeutic target in and of itself, without addressing the underlying mechanisms that generate the dysregulation. Hippocampal circuit disruptions are characteristic of neurological and psychiatric diseases, generating disease-related symptoms and making them attractive therapeutic targets. The hippocampus’ modular structure introduces interesting implications for managing symptoms. While structurally similar across the septotemporal axis, individual modules within the hippocampus support different behavioral functions. For example, the dorsal hippocampus critically supports spatial memory, with the dorsal dentate gyrus contributing to spatial discrimination. In temporal lobe epilepsy (TLE), the dentate gyrus undergoes massive alterations, culminating in a hyperactive circuit. In an experimental mouse model of TLE, this hyperactivity compromises spatial discrimination performance. Using either muscarinic or kappa-opioid inhibitory DREADDs in the dorsal dentate, we were able to reduce the epilepsy-associated hyperactivity to rescue spatial discrimination function. Similarly, an experimental mouse model of 22q11.2 deletion syndrome (22q) exhibits a hyperactive ventral CA1, which is a critical circuit for social discrimination performance. 22q mice fail to discriminate novel from familiar conspecifics; however, normalizing ventral hippocampal activity with either inhibitory DREADD restored behavioral performance. Moreover, robustly recruiting the inhibitory DREADDs in either disease model again compromised behavioral performance, indicating that tuning circuit activity to appropriate levels is critical for successful coding. Furthermore, DREADD-induced effects were modularly specific: recruiting dorsally expressed DREADDs did not affect ventral hippocampal-dependent behavioral outcomes and vice-versa. These findings suggest that correcting inappropriate disease-associated circuit tuning is sufficient to restore circuit function, even in the face of significant, unmodified structural changes. Targeting circuit activity in a specific, modular manner may prove an effective translational therapeutic approach.

Subject Area

Neurosciences

Recommended Citation

Kahn, Julia B, "Circuit-Based Therapies Rescue Cognitive Dysfunction in Neurological and Psychiatric Diseases" (2019). Dissertations available from ProQuest. AAI27541120.
https://repository.upenn.edu/dissertations/AAI27541120

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