UC Berkeley

The goal of my dissertation is to shed new light on how genetic variation and developmental experiences sculpt cognitive flexibility in young adulthood. My dissertation is intended to inform public health and understanding of human adversity by using mice as a model. However, this work may also contribute to a more established scientific understanding of how an organism’s life experience can interact with development and have profound and persistent effects on expression of the neurobiological and behavioral phenotypes. This interaction between the environment and a developing organism has previously been studied in various fields under different names, as experience dependent plasticity in neuroscience, adaptive developmental plasticity (ADP) in biology, and life history theory in ecology. These three fields do not often interact because they tend to focus on different levels of analysis. Neuroscience tends to focus on the proximate or mechanistic level, while ultimate level questions about evolution are the domain of biology and ecology. By looking at neural systems and examining the effects of genotype and developmental experience, I attempt to forge links between the proximate and ultimate levels of understanding.

At the proximate level, I focus on the role of the striatal dopamine (DA) system in behaviors requiring cognitive flexibility or flexible updating. This critical executive function, responsible for adaptive learning and goal-directed behaviors, has been shown to rely heavily on the DA system. At the ultimate level, I discuss how genetic polymorphisms and phenotypic plasticity allow adaptation to different environmental conditions and how the application of ADP and life history theory may strengthen the interpretation of the changes in behavioral phenotypes and neural functions. Through a similar lens, cognitive flexibility may represent how sensitive an organism is to cues from the environment, with greater sensitivity associated with greater flexibility.

In Chapter 1, I first briefly introduce the framework of ADP by presenting different levels that ADP can act on as well as different models and hypotheses. I also review ideas of life history theory and sensitive periods which interact with ADP and together affect and sculpt developmental trajectories of cognitive, behavioral, and neural functions. I then review the growing literature that demonstrates behavioral and neurobiological variables are sensitive to early life developmental experiences, with a special focus on cognitive function and the striatal DA system. Based on the ADP framework and the neurobiological literature, I develop a model of how experience may have profound effects on the development of striatal DA systems that support learning and decision making.

In Chapter 2, I present data from a mouse model of a common human genetic polymorphism in the brain derived neurotrophic factor (BDNF) gene, Val66Met. In these mice, we find that genotype affects cognitive flexibility in two separate tasks. Met/met mice (homozygous with the mutant allele) showed greater flexibility than the Val/Val controls. I discuss these findings in the context of literature that views this polymorphism as a plasticity allele instead of a risk allele. I also explore how the ADP framework explains why a genetic polymorphism that affects cognitive flexibility might be maintained in a population.

In Chapter 3 and 4, I focus on the impacts of developmental food abundance versus food scarcity on brain and behavior. Food abundance and scarcity are important environmental variables affecting organisms’ survival and are relevant to public health. Food scarcity and unpredictability is known in public health as food insecurity. Currently, this is a growing public health challenge both nationally and globally. For this work, I developed a novel mouse model of food insecurity using a varying schedule of feeding for 20 days during development.

In Chapter 3, I examine the impacts of juvenile-adolescent (Postnatal Day (P)21-40) developmental feeding history on learning, cognitive flexibility, and decision-making in adulthood. I found that adult male mice with different developmental feeding histories (ad libitum or food insecurity treatment) during the juvenile-adolescent period P21-40 exhibited differences in cognitive flexibility, past reward integration, and sensitivity to reward uncertainty when tested after P60. These group effects were not found in females nor in males when the differences in feeding experience and testing were both shifted twenty days later, suggesting a sex difference and a sensitive window for the effects of treatment or testing. I also applied computational modeling to further characterize that behavioral differences in adult males with different P21-40 feeding histories. I found that differences in behavioral performance in the two tasks were due to differences in updating in response to negative outcomes, weighing of past unrewarded history, and sensitivity to different reward probabilities. While I did not see impacts of feeding experience on learning and cognitive flexibility in adult female mice, I did observe effects on adult weight gain in females.

In Chapter 4, I examine the impacts of developmental feeding history on neurobiological measures of DA neurons and DA release in the striatum in brain slices. I found that adult male mice with different developmental feeding histories showed differences in AMPAR/NMDAR-mediated excitatory postsynaptic currents ratios on mesolimbic DA neurons and differences in DA release in the nigrostriatal DA pathways in vitro. In both Chapter 3 and 4, I explore how we may use the ADP framework to explain our results as a predictive adaptive response to the developmental experience of food abundance or scarcity.

Together, my data demonstrate how genes and experience can impact cognitive flexibility and serve as an example of how we can use multiple levels of analyses to understand phenotypic variation. I hope to advance the field of adversity studies by using theoretical and mechanistic models and novel insights to explain how information from the environment can act on neural circuits and in turn alter expression of behavioral phenotypes. Furthermore, my data suggests that the juvenile adolescent period is a potentially significant time for interventions to impact core learning and decision making systems. This last point may have special relevance during the time of the COVID-19 pandemic, as the subsequent economic downturn increases food insecurity.