Doctor of Philosophy
Cumming, Robert C.
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.
Summary for Lay Audience
Brain cells work together to fuel processes required for cognition such as learning and memory. In the brain, astrocytes are a type of glial cell which breakdown sugar into lactate, which is then used as a fuel for neurons. This process is known as the astrocyte neuron lactate shuttle (ANLS). Past studies have shown that the ANLS helps cognition in mammals, such as mice and humans. However, the relationship between the ANLS and cognition has not been well studied in females, elderly animals, or non-mammals, such as flies. The ANLS is modified by manipulating levels of a protein which functions to produce lactate, lactate dehydrogenase (LDH). In this thesis, I genetically altered LDH in certain cells in fly and mouse brains then tested their cognitive ability across age. In flies, I increased or decreased their only LDH gene, dLdh, in neurons or glia. Using male flies, I found that only old flies with altered dLdh had memory impairments. Less dLdh in either neurons or glia was bad for memory, while more dLdh in neurons also resulted in worse memory. These results suggest that old flies make memories using lactate metabolism in brain cells differently. In mice, there are multiple forms of LDH, with one version, LDHA, that mostly acts to produce lactate. I genetically manipulated neurons in the brain of male and female mice to either make more or less LDHA as adults. To test mouse memory, I used a multitude or different types of tests. In a test requiring mice to learn to discriminate one spatial pattern from another similar spatial pattern I found that modifying LDHA production in neurons caused only females to have increased memory. Moreover, induction of LDHA increased memory only in young mice, yet inactivation of LDHA only led to memory increase in old mice. I also found neuronal LDHA was problematic for cognition in old mice and had different effects in young mice depending on their sex. Altogether, I have demonstrated that lactate metabolism impacts memory predominately in both old mammals and non-mammals and discovered that males and females respond differently to altered levels of neuronal lactate metabolism.
Frame, Ariel Khaya, "Investigating the Age-Dependent Impact of Lactate Dehydrogenase on Cognition in Flies and Mice" (2023). Electronic Thesis and Dissertation Repository. 9441.
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