Yaşlanmanın farelerde zamanlama ve karar verme üzerine etkisi: Davranışsal, hesaplamalı ve nörobiyolojik yaklaşımlar

The aim of this thesis was to investigate age-related alterations in interval timing and decision-making at the levels of behavioral output and latent variables along with their neurobiological correlates in mice. In the first experiment (Chapter 2), age-related alterations in interval timing behavior and its neurobiological correlates were investigated in young, adult, and old mice using dual peak interval procedure. Behavioral outputs were evaluated to make inferences regarding the source of variability in timing behavior within the framework of Scalar Expectancy Theory. In the second experiment (Chapter 3), in addition to age-related changes in interval timing ability, how probabilistic information is integrated into temporal decisions was investigated in young and old mice using the switch paradigm. In the third experiment (Chapter 4), we expanded the scope of our study to include perceptual decisions and investigated how latent variables of simple perceptual decision process changes with aging and the neurobiological correlates of these age-related changes in young, adult and old mice using a brightness discrimination task we adapted for mice. In both first and second experiments, we found that the core timing ability of old mice was intact; however, they exhibited a pronounced deficit in the termination of an ongoing timed response. In the first experiment, we also found that the acquisition of response termination was delayed and the contribution of threshold variance relative to clock/memory variance was higher in old mice. In the second experiment, the observed deficit disappeared when mice were supposed to adopt a switch strategy from a low probability short option to a high probability long option as opposed to switching from a high probability short option to a low probability long option. Consequently, we suggest that such a deficit is due to age-dependent changes in the decisional component of interval timing. Decrements in both dopaminergic (VTA & SNc) and cholinergic (MS/DB complex) neuron counts and dopaminergic axon terminal densities (DLS & DMS) were evident in old mice (Experiment 1). From all these neurobiological measures the number of dopaminergic neurons in VTA and the number of cholinergic neurons in MS/DB complex were negatively correlated with the time of response termination and the acquisition of response termination, respectively, which pointed at the role of dopaminergic and cholinergic functions in the observed age-dependent alterations in timing behavior. In the third experiment, we found that brightness discrimination accuracy was lower in old mice with no difference in response times. Modeling of the decision outputs within the framework of the Hierarchical Drift Diffusion Model revealed that observed accuracy difference was due to a decrease in the quality of evidence integration (i.e., drift rate) during the decision-making process suggesting slowing down of information processing in aging in the domain of perceptual decision-making. The quality of evidence integration was positively correlated with mesocortical (number of dopaminergic neurons in VTA) and nigrostriatal (density of dopaminergic axon terminals in DMS) dopaminergic function. Overall, the results of these three experiments suggest that a healthy aging process is characterized by different deficits (i.e. decision component vs. information processing speed) in different cognitive domains (i.e. interval timing vs. decision-making) despite their overlapping neurobiological correlates. Taken together, these results constitute a comprehensive characterization of a healthy cognitive aging process in the mouse model based on timing and choice behavior, latent variables that underlie these behaviors, and their neurobiological correlates. Our results highlight the translational value of animal models of cognitive aging.