Investigating the Age-Dependent Impact of Lactate Dehydrogenase on Cognition in Flies and Mice
Abstract
Lactate is a carbohydrate breakdown product typically produced in astrocytes, a type of glial cell, and transported to neurons within the brain. This type of metabolic coupling is commonly referred to as the astrocyte neuron lactate shuttle (ANLS). While numerous studies have shown that the ANLS is involved in cognition in mammals few have taken into consideration sex differences, changes with age, or evolutionary conservation in invertebrates. Lactate metabolism is controlled by the enzymatic interconversion of pyruvate and lactate in a reaction catalyzed by lactate dehydrogenase (LDH). In this thesis I examined cognitive changes across lifespan affected by genetic manipulation of LDH in invertebrate and mammalian animal models, Drosophila melanogaster (flies) and mice, respectively. In male flies, I upregulated or downregulated the expression of dLdh, a gene encoding the only fly LDH isoform, specifically in adult neurons or glia. Transgenic dLdh flies were tested for survival, long-term memory, and brain metabolite changes. Memory deficits were detected only in aged flies with neuronal or glial dLdh downregulation and flies with neuronal dLdh upregulation. In addition, survival in flies was reduced by neuronal or glial dLdh upregulation, and neuronal dLdh downregulation. These results suggest lactate metabolism in the brain of flies impacts memory and survival in a cell-type and age-dependent manner. In mice, I knocked out or induced expression of Ldha, an LDH isoform biased towards lactate production, in neurons of adult male and female brains. Transgenic Ldha mice were tested for locomotor, anxiety-like, and cognitive behaviours using six different paradigms. Short-term memory requiring high pattern separation was increased in female mice with neuronal Ldha upregulation at young age or neuronal Ldha knockout at old age. Furthermore, I found neuronal Ldha expression was cognitively detrimental in aged mice and impacted cognition differently in young mice depending on cognition test type and sex. These results suggest that ANLS-related neuronal lactate metabolism impacts various aspects of cognition in a manner that shifts with age and sex. Altogether, my findings highlight conserved functions of age-related lactate involvement in maintenance of cognitive processing, and uncovered sex-dependent effects of neuronal lactate production on task-specific cognition in mice.