Sleep deprivation is harmful and can even cause death through unknown means. Many things go wrong in sleep deprived animals so it appears difficult to pinpoint a specific detrimental event. We show that sleep deprived flies, and mice, accumulate reactive oxygen species (ROS) and experience oxidative stress - in their intestines. Clearing ROS allows normal survival in the complete absence of sleep. Our data provide the first direct link between sleep deprivation-induced death and a specific physiological change, and offer an explanation for why this state is essential for survival. In the second part of my talk, I will describe how the brain decides (on a molecular and circuit level) if mating is appropriate in a given situation, and how it motivates the animals to engage in a courtship ritual.
The concept of gene-environment interactions, wherein genetic predisposition shapes one’s response to particular environmental exposures, is widely recognized in a variety of neurological disorders, but poorly understood. In particular, how are environmental exposures conveyed to genes, and how do they confer lasting effects on brain and behavior? The microbiota is well positioned at this intersection, as its composition and function are dependent on genetic background and shaped by environmental factors, including infection, diet and drug treatments. Moreover, changes in the microbiota have lasting effects on health and disease. For example, several diet-induced phenotypes are sufficiently mediated by changes in the gut microbiota; symptoms of atherosclerosis in response to a carnitine-rich diet, malnutrition in response to the Malawian diet and obesity in response to the “Western” diet are each recapitulated by transplanting the diet-induced microbiota into mice that are fed standard chow. Here we explore the effects of dietary alterations in the context of genetic susceptibility to neural dysfunction, using the ketogenic diet and epilepsy as a model system. We find that the microbiota is both necessary and sufficient for the anti-seizure effects of the ketogenic diet across two mouse models for refractory epilepsy and further explore molecular and cellular mechanisms underlying microbial modulation of neuronal activity.
Mitochondrial movement is tightly controlled by the cell to balance energy homeostasis and reduce oxidative stress. The anterograde transport of mitochondria in neurons is mediated by a motor-adaptor complex that includes Miro, milton, and kinesin-1 heavy chain (KHC). Miro is incorporated into the outer mitochondrial membrane (OMM) and anchors mitochondria to microtubules via milton and KHC. Miro situates at a critical nexus to relay multiple cytosolic signals to influence mitochondrial motility. We and others have shown that Miro is removed from the OMM of depolarized mitochondria to the cytosol for proteasome degradation prior to mitophagy, and this Miro removal is primed by PINK1/Parkin-meditated phosphorylation and ubiquitination and LRRK2 interaction. Mutations in LRRK2, PINK1, or Parkin cause familial Parkinson’s disease (PD). We have found a unifying cellular defect in removing Miro from damaged mitochondria in skin fibroblasts or induced pluripotent stem cell (iPSC)-derived neurons, not only from PD patients harboring mutations in LRRK2, PINK1, or Parkin, but also from PD patients with other mutations or no known mutations. Miro is stabilized and remains on damaged mitochondria for longer than normal, prolonging active transport and delaying the onset of mitophagy. This defect renders vulnerable neurons to accumulate damaged mitochondria, causing energy shortage and oxidative stress, and consequently leading to neurodegeneration. We have also found novel factors coming from the inside of the mitochondria that stabilize Miro on the OMM. These factors are sensitized by mitochondrial metabolism and aging in Drosophila. Thus, molecular regulations of Miro may underlie mitochondrial responses to cellular signals and stresses in health and disease.
Thesis Defense Seminar
Thesis Defense Seminar
Huntington’s disease (HD) is the most common inherited neurodegenerative disorder, and is characterized by early and most dramatic loss of neurons in the caudate and putamen as well as a debilitating triad of cognitive, motor, and psychiatric symptoms. The huntingtin gene was first linked to HD over twenty years ago, yet to date there is neither a precise molecular explanation for the cell loss that is seen in human patients, nor a curative therapeutic. In my talk, I will describe our efforts over the last few years to advance our understanding of the mechanistic basis of HD. We have combined the use of cell type-specific gene expression profiling with in vivo genetic screening to reveal transcriptional pathways perturbed by mutant Huntingtin protein, as well as the genes that help neurons survive in HD.
Thesis Defense Seminar
The Datta lab studies how information from the outside world is detected, encoded in the brain, and transformed into meaningful behavioral outputs. We address this problem by characterizing the olfactory system, the sensory modality used by most animals to interact with their environment. Here, we describe a novel molecular and circuit mechanism that underlies odor perception, one that may be specialized for the detecting and processing of odors with innate meaning. We also describe recent experiments using a combination of volumetric population imaging in awake mice and behavioral analysis to explore odor codes in piriform cortex, the main cortical center devoted to olfaction in the mammalian brain; these experiments identify an invariant representation for odor space in cortex, thereby suggesting mechanisms through which the olfactory system can link chemically-related odors to similar behaviors and perceptual qualities both within and across individuals.