Abstract: Brain-wide fluctuations in local field potential oscillations reflect emergent network-level signals that mediate behavior. Cracking the code whereby these oscillations coordinate in time and space (spatiotemporal dynamics) to represent complex behaviors would provide fundamental insights into how the brain signals emotional pathology. Using machine learning, we discover a spatiotemporal dynamic network that predicts the emergence of depression-related behavioral dysfunction in mice subjected to chronic social defeat stress. Activity patterns in this network originate in prefrontal cortex and ventral striatum, relay through amygdala and ventral tegmental area, and converge in ventral hippocampus. This network is increased by acute threat, and it is also enhanced in three independent models of depression vulnerability. Finally, we demonstrate that this vulnerability network is biologically distinct from the networks that encode dysfunction after stress. Thus, we reveal a convergent mechanism through which depression vulnerability is mediated in the brain. We also demonstrate a novel strategy for linking mesoscale brain states to emotional behavior.
Cortical circuits in the early visual stream, including primary visual cortex (V1), are necessary for extraction of information from external sensory inputs. These circuits comprise a variety of projection neurons that transmit signals to downstream areas, including cortical and subcortical structures involved in the generation of behavior. A key unanswered question is whether different neuronal populations in V1 encode distinct sensory representations that are "customized" for specific behavioral functions. Here, we combine 2-photon calcium imaging and optogenetic manipulation to demonstrate that a subset of layer 5 neurons that project to the brainstem selectively encode behaviorally-relevant information in a visually-guided classical conditioning task. Activity in corticopontine cells, but not closely intermingled corticostriatal cells, reliably predicts trial-to-trial behavior, and their suppression impairs performance. Our findings reveal functional heterogeneity in microcircuits of the early visual system and indicate the existence of segregated pathways in V1 for the coordination of behavior.
Cortical circuit function is highly flexible, adapting rapidly to changes in environmental context and behavioral demand. Indeed, although the physical components of local circuits remain relatively constant, the precise population of neurons participating in ongoing patterns of activity can vary tremendously from moment to moment. GABAergic interneurons are key mediators of this flexible cortical circuit function. We find that different populations of interneurons are differentially regulated by behavioral states such as arousal and quiescence, contributing to state-dependent changes in visual processing and perceptual performance. We find that inhibitory regulation of GABAergic populations is a critical element of circuit function. In turn, loss or dysregulation of key inhibitory interneurons disrupts the flexible function of cortical circuits and impairs both cortical development and sensory processing in the mature brain. Our recent findings highlight unanticipated roles for sparse but powerful inhibitory populations, such as the VIP cells, and uncover the impact of inhibitory-to-inhibitory interactions in the cortex.
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