. The ability to make effective decisions is critical for managing finances, health care, and other activities of daily living necessary to maintain personal independence. Decision making is altered in both normal aging and in Alzheimer's disease (AD), albeit in different ways. Specifically, healthy older adults tend to make less impulsive and risky choices compared to young adults, whereas AD is associated with greater impulsivity and maladaptive risk taking relative to age-matched healthy controls. While distinct, these decision biases associated with aging and AD can both be maladaptive and have significant implications for life quality. Optimizing decision making could broadly benefit functional outcomes and promote independent living among older adults; however, development of interventions is currently hindered by a poor understanding of the neural mechanisms underlying maladaptive decision making in aging and AD. To begin to address this gap in knowledge, our labs have shown that aged rats, which lack overt AD pathology, exhibit reductions in impulsive and risky choice in a manner similar to that observed in aged humans. Moreover, preliminary data suggest that these age differences in decision making are mediated by the basolateral amygdala (BLA). The BLA is implicated in affective processing and is highly interconnected within decision-making circuits. Using in vivo optogenetic approaches in both young and aged rats, we have identified multiple, temporally distinct contributions of BLA to both impulsive and risky choice and shown these contributions of BLA to decision making change with age. The long-term goal of this research program is to determine the mechanisms by which decision making is altered in aging and AD. The immediate objective is to determine the effects of aging and early tau pathology on BLA function and its role in decision making. Our overarching hypothesis is that aging and tau pathology disrupt adaptive decision making through alterations in BLA excitatory and inhibitory dynamics.
Aim 1 will determine how optogenetic activation and inhibition of BLA at discrete stages of the decision process influence aged rats' decision making. Parallel biochemical assays will evaluate the influence of age on BLA synaptic and excitatory/inhibitory signaling proteins in conjunction with decision making behavior.
Aim 2 will address similar questions in conjunction with a virally-mediated approach that induces medial temporal lobe tau pathology in a manner that is anatomically relevant to early stage AD.
Aim 3 will use optogenetic approaches to determine how aging alters the contributions of distinct BLA efferent circuits to decision making, and will use cellular electrophysiology to evaluate effects of aging on anatomically defined subsets of BLA efferent neurons. Completion of these experiments will reveal at the biochemical, cellular, and systems level how the BLA is influenced by aging and tau pathology, as well as how such alterations contribute to maladaptive decision making. The information will be significant because it will provide foundational knowledge that is critical for development of novel interventions to maximize decision quality in both normal aging and AD.
Effective decision making is critical for navigating everyday situations, for long-term health, and for financial and personal well-being. The proposed research is relevant to public health because it seeks to identify neurobiological mechanisms that underlie maladaptive alterations in decision making resulting from both normal aging and Alzheimer's disease. This contribution will be significant because discovering neural mechanisms of maladaptive decision making in aging will reveal targets for interventions to promote improved cognition at advanced ages.
