Apathy is diagnosed in approximately 70% of patients with dementia, including Alzheimer?s disease (AD). Changes in affective expression and reduced motivation towards daily activities is thought to involve deficits in synaptic communication between mesolimbic dopamine (DA) circuitry and hippocampus of AD patients. Our central hypothesis is that overexpression of ?-amyloid protein (A?) or hyperphosphorylated tau (p-tau) reduces neuronal activity between dorsal hippocampal CA1 (dHC-CA1), nucleus accumbens and the DA-enriched ventral tegmental area (VTA). This is predicted to be linked to reduced reward-seeking and sociability and is rescued by drugs that increase brain DA levels. The proposed research will employ high-field resting state functional magnetic resonance imaging (rsfMRI), network analysis, functional tracer-based MRI (MEMRI), and assessment of non-cognitive (affective) behaviors in A? or p-tau overexpressing mice to clarify the effects of DA drugs on reward and cognitive network activity. We will investigate the functional brain and behavioral responses to two compounds with therapeutic value for apathy and other non-cognitive affective conditions in AD, the DA reuptake inhibitor methylphenidate and the monoamine oxidase B (MAO-B) inhibitor selegiline. To test our central hypothesis, we will: (1) determine how drugs that block DA reuptake or inhibit DA breakdown affect reward-seeking and sociability in A?-expressing TgCRND8 mice and tau-expressing rTg4510 mice (aim 1), (2) investigate how these two drugs alter functional connectivity between mesolimbic and cognitive brain networks of TgCRND8 and rTg4510 mice (aim 2), and (3) determine the effect of these DAergic agents on in vivo calcium-dependent synaptic activity between the VTA and dHC-CA1 of TgCRND8 and rTg4510 mice (aim 3). We will combine cutting edge high field rsfMRI, quantification of network analysis metrics with biomarker- like properties and will apply circuit-specific contrast-based synaptic activity mapping in mice bearing human AD mutations that produce well-defined plaque or tangle pathology. From a public health perspective, the proposed studies will provide new insight on non-cognitive aspects of AD. It will contribute to clarifying the effects of A? or p-tau on functional network activity and on specific dHC-CA1 circuits, and in relation to reward/affective behaviors.
Impaired motivation, reductions in daily activities, and blunted emotional responding to relatives and caregivers are signs of apathy, which is observed in over 70% of cases of dementia of Alzheimer?s type. There is evidence suggesting that during early pre-cognitive stages of Alzheimer?s disease the communication between brain areas involved in reward and memory processing declines, and this can be rescued by medications that elevate dopamine. The objective of this exploratory R21 proposal is to clarify the in vivo mechanism by which this occurs through the testing of mouse models of Alzheimer?s disease, dementia, and tauopathies, for their expression of sociability, reward preferences, and their neural activity between hippocampus and brain reward centers.
