Bipolar disorder is one of the most common neuropsychiatric disorders, yet the biochemical alterations that contribute to the disease onset and progression remain unknown. While cyclic depressive and manic/hypomanic mood states are requisite for bipolar disorder diagnosis, the majority of bipolar disorder subjects also exhibit a constellation of cognitive and executive function impairments. The magnitude of cognitive impairment is among the best predictors of the severity of day-to-day functional impairment in individual bipolar disorder patients. Studies have consistently identified dysfunction of the prefrontal cortex (PFC) in the etiology of bipolar disorder cognitive impairments, and recent work suggests that a reduction in the density of dendritic spines on pyramidal neurons contributes to this regional hypofunction. Nevertheless, the biochemical mechanisms that potentially contribute to bipolar disorder PFC disruption remain unknown. Our preliminary data identify a loss of activity in the Akt kinase and its downstream target, the mTOR kinase, in a specific subset of bipolar disorder subjects. The overarching hypothesis guiding this proposal is that reduced Akt signaling in the PFC impedes local synaptic structural and functional plasticity thereby attenuating the normal recruitment of other brain regions directly innervated by the PFC during cognitive processing. Using viral-mediated gene transfer we will overexpress dominant-negative Akt (DN-Akt) in the PFC of mice to reproduce the aberrant Akt activity we identified in bipolar disorder subjects. We will then determine if this impaired ability to engage Akt in the PFC is sufficient to cause alterations in synaptic structural and functional plasticity. Further, using a transgenic model that allows for the permanent tracking of neurons transiently activated during behavioral tasks, we will determine if Akt disruption attenuates PFC neuronal engagement during cognitive processing in freely behaving mice (Aim 1). Complex behaviors such as cognition are invariably the product of dynamic regulations in functional connectivity between multiple brain regions. Using a combination of viral-mediated gene transfer and circuit tracing, we will manipulate the expression of DN-Akt in specific projections between the PFC and other brain regions involved in experiential processing, and assess the resulting effects on regional engagement and cognition. This approach will help identify possible brain circuits (rather than just brain regions) that contribute to the effects of disrupted Akt activity on pathological cognitive impairment (Aim 2). If our hypothesis are correct, these studies will implicate aberrant Akt activity in the PFC in contributing to four core clinical and pathological bipolar disorder-relevant features, including: 1) cognitive dysfunction, 2) impaired neuronal PFC synaptic plasticity, 3) aberrant engagement/recruitment of PFC neural populations, and 4) altered functional connectivity between the PFC and other forebrain regions.

Public Health Relevance

Bipolar disorder is among the most common neuropsychiatric conditions and is characterized by cyclic manic and depressive mood states, a constellation of cognitive deficits, and loss of synaptic connectivity. Understanding the mechanisms that give rise to bipolar disorder cognitive and synaptic impairments is of great interest as these impairments are among the best predictors of the magnitude of functional impairment in individual bipolar disorder subjects, and because there are currently no established treatment regimens for alleviating these cognitive symptoms. Our studies identify altered activity of a key biochemical signaling pathway in a major brain cognitive control center, the prefrontal cortex, in a subset of bipolar disorder subjects, and our proposed studies will determine if these identified biochemical alterations cause dysfunction of prefrontal cortical neurons and concomitant bipolar disorder-relevant cognitive phenotypes.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Rossi, Andrew
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University of Wisconsin Madison
Schools of Veterinary Medicine
United States
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