Basal forebrain regulation of default mode and task-on functional network activity: translational modeling of psychiatric disorders

Va Boston Health Care System, Boston MA

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Abstract

OBJECTIVE: Cognitive deficits are a major determinant of the long-term disability associated with severe neuropsychiatric disorders, including schizophrenia (Sz). The antipsychotic medications currently available do not satisfactorily address Sz-related cognitive symptoms. Normal brain and cognitive function require networks of distributed brain regions to maintain stable, yet flexible communication. The focus of this study is the default mode network (DMN), which is a brain-wide functional network that is generally associated with introspective processes and is conserved across mammalian species. Suppression of DMN activity is important to allow Task-On associated network when subjects are performing tasks that require interaction with the environment. Impaired DMN suppression has been observed in Sz patients and is associated with psychopathology, particularly cognitive impairments. Recent evidence suggests the basal forebrain (BF) represents an important DMN node and may play a central role in the regulation of DMN activity. Deficits in functional network dynamics have been suggested to be related to perturbations in the balance of cortical excitatory and inhibitory neurotransmission (E/I Balance). Our published findings show that optogenetic stimulation of BF parvalbumin neurons (BF-PV) alters cortical E/I balance, eliciting an elevation in spontaneous cortical gamma band activity (>30 Hz, GBA), and behavioral phenotypes that resemble psychosis. Through our proposed work, we will illuminate the mechanisms behind subcortical modulation of DMN versus the Task-On network activity and inform novel therapeutics to restore impaired network connectivity in psychiatric disorders affecting Veterans. RESEARCH DESIGN: The Overall Hypothesis postulates that long range inhibitory GABAergic BF-PV output from the BF fine tunes cortical E/I balance and that this process is critical for efficient suppression of DMN activity that is needed for the transition to a predominance of Task-On network activity required for cognitive performance. Aim 1 will confirm that local BF GBA is associated with GBA throughout the DMN and will characterize the cortical regions associated with DMN-like neural oscillations in mice. Aim 2 will build upon these findings by examining how transitions between DMN and Task-On network function is regulated by BF, specifically BF-PV neurons, during operant tasks targeting both attentional and executive function domains of cognition. Finally, Aim 3 will utilize cutting-edge fiber photometric techniques to directly assess the ability of BF-PV neurons to influence cortical E/I balance across a range of behavioral contexts. Further, these aims will examine DMN activity, and its regulation via BF, in two translationally relevant mouse models of Sz that mimic the neurochemical changes of the human Sz brain (i.e., 2 models of glutamatergic NMDA receptor hypofunction). Finally, optogenetic modulation of BF-PV neurons will be used to probe both E/I balance and DMN network function, and to mitigate Sz-like patterns of brain activity and function in the mouse Sz models. METHODOLOGY: Here we will utilize an innovative multimodal state of the art, approach to directly examine how basal forebrain modulation of cortical disinhibition helps to regulate functional network activity relevant to cognition. Multi-site electrophysiological measures and fiber photometry will be used in to help validate a novel preclinical model to define circuit-level explanations to better understand the physiologic basis of DMN and its interaction with other functional networks such as the Task-On network, and for abnormalities in functional network activity (elevated DMN activity) and cognitive symptoms associated severe neuropsychiatric disorders. IMPACT/SIGNIFICANCE: These experiments will provide a better understanding of aspects of coordinated neural activity that are important for cognition. Further, it will characterize a subcortical pathway capable of modulating E/I balance and interrogate this pathway as a novel therapeutic target to rescue impairments in psychiatric disorders. This work is novel and will provide valuable insight into the pathogenesis behind a variety of neuropsychiatric disorders, and lay groundwork for the development of therapeutics for effective treatment.