Fronto-insular network in cognitive-affective interactions during decision-making

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ABSTRACT Alzheimer’s Disease (AD) is one of the most prevalent age-related neurodegenerative disorders with devastating effects on a broad range of brain functions from memory to decision making. While it is well known that AD impairs cognitive functions, neuropsychiatric symptoms are common in those at risk of or with AD and predict the incidence of cognitive impairment. Human brain imaging studies have highlighted a network of brain regions, particularly the medial prefrontal cortex (mPFC), the anterior insular cortex (aIC), and midbrain dopamine (DA) regions, as the potential interface between cognitive and affective processing. Furthermore, comparative neuroanatomy and developmental genetics have identified in mice brain regions evolutionarily related to human mPFC, aIC, and DA regions. The overall objective of our parent grant (R01MH127737) is to elucidate the fronto-insular circuit mechanisms underlying cognitive-affective interactions during flexible decision-making and the impact of stress on such mechanisms in mice. Frontal cortical association areas typically show early appearance of amyloid pathology during AD progression. However, how amyloid pathology impacts long-range cortical projections mediating cognitive-affective interactions during decision-making has not been investigated. This administrative supplement extends our mechanistic investigation of fronto-insular network in cognitive-affective interactions during decision-making to mouse genetic models of AD. We hypothesize that the balanced neural communication in mPFC-aIC-DA circuits is progressively impaired by amyloidosis, leading to the impairment of cognitive flexibility. Using amyloidosis mice (APP/PS1 and 5xFAD), we propose two aims. Aim 1 determines how amyloidosis affects mPFC-aIC connectivity and function; Aim 2 defines the impact of amyloidosis on DA modulation of mPFC and aIC function. With preliminary data obtained through this supplement, we will apply for NIA funding to further investigate the mechanistic links among progressive changes in neural activity, synaptic morphology, and amyloid pathology in fronto-insular circuits in AD mouse models, and to explore fronto-insular circuit modulation paradigms to protect against the pathological progression and cognitive decline associated with AD.