September 12th - Molecular Interactions of the Bacterial Actin Cytoskeleton
Until recently, bacteria were believed to lack a cytoskeleton. We now know that many species contain true orthologues of eukaryotic actin, tubulin and even intermediate filaments. The bacterial protein MreB is required for asymmetrical shape, polarity control and chromosome segregation in a wide variety of bacterial species. Its atomic structure and subcellular localization support its role as a bona fide cytoskeletal element. The eukaryotic actin cytoskeleton derives its many cellular functions from the complex interplay of actin-binding proteins with the highly dynamic polymer itself. We are characterizing the biochemical functions and interactions of MreB to determine the means by which this newly appreciated protein carries out its crucial role in cells.
October 13th (Note: Friday Lecture) - Functional Specificity in the Cortex: Selectivity, Experience, & Generality
Selective information processing in the brain. Regions on the surface of the macaque (left) and human (right) brain that respond selectively, as indicated. For both species, the back of the brain is at the left. Brains are not proportionally scaled to each other.
Functional MRI has revealed several cortical regions in the ventral visual pathway in humans that exhibit a striking degree of functional specificity: the fusiform face area (FFA), parahippocampal place area (PPA), and extrastriate body area (EBA). I will briefly review this work and then discuss more recent studies that investigate the specificity, origins, and generality of domain specificity in the cortex. In particular these studies ask i) how specialized is the FFA for faces and what exactly it does with faces?, ii) how do cortical responses to visually presented objects change with experience and is extensive experience ever sufficient to create them?, and iii) are domain specific regions of cortex found only in the visual system, or can they sometimes be found for very abstract high-level cognitive functions as well?
November 14th - The Power of Expectancy, Anxiety, and the Brain
Brain areas activated by aversion: anticipation of and response to aversive compared to neutral pictures.
Our expectations have an impact on our lives in multiple ways, including our perception of external events, our emotional responses to them, and how well we remember them. The impact can be positive in terms of enhancing the pleasant emotions following success or in terms of mitigating the negative emotional consequences following adversity. The impact of expectancy can also be negative, as seen in individuals suffering from anxiety disorders. For them, expectations about possible negative events in the future can result in debilitating levels of worry and distress. Research in my laboratory investigates the brain mechanisms responsible for these expectancy effects. Using both clinical and healthy populations, our research has shown how expectancy modulates neural responses to emotional events and influences perception and subsequent memory of those events.
December 12th - Actin Filaments and Fried Eggs: Cytoskeletal Pathways to Neuritogenesis
A fundamental aspect of neuronal development is the formation of neurites from a spherical cell body. Yet, there is relatively little research on the mechanisms by which neurites are formed. Recently, analysis of mice lacking all three Ena/VASP proteins revealed an important role for this family of proteins in axon tract formation in cortex. Ena/VASP proteins are known to regulate actin filament dynamics and are important for filopodia formation in neurons. By using live cell microscopy and platinum replica electron microscopy we found that Ena/VASP dependent actin bundles that comprise the core of the filopodia were essential for neuritogenesis. These results reveal an unexpected and intriguing role for filopodia in early cortical development.
February 13th - Imaging the Dynamics of the Euprymna scolopes/Vibrio fischeri Model Symbiosis
The symbiotic association between the squid Euprymna scolopes and the luminous bacterium Vibrio fischeri provides a unique opportunity to study both immune and developmental signals associated with the establishment and maintenance of beneficial animal-bacterial interactions. Upon host light-organ infection with V. fischeri, the organ undergoes a 5-d, symbiont-induced morphogenesis involving widespread hemocyte infiltration and apoptosis in complex ciliated epithelial fields, which are associated with facilitating colonization. These symbiont-induced processes eventually lead to the complete regression of these fields. The tetrapeptide fragment of the bacterial surface molecule peptidoglycan, TCT, which causes extensive host tissue damage characteristic of gonorrhea and whooping cough, works synergistically with another bacterial surface molecule, lipopolysaccharide (LPS), to induce light organ development. Construction of an EST database of the host light organ revealed four peptidoglycan-recognition proteins (PGRPs) and three lipopolysaccharide-binding proteins (LBPs). We are characterizing the expression and production of these molecules over the trajectory of early development of the symbiosis. Our studies of the squid-vibrio system rely heavily on microscopy. In addition to SEM and TEM, we extensively use confocal microscopy, as our tissue is three-dimensionally highly complex. Recently, we have begun a collaboration with colleagues at Washington U St Louis using a NanoSIMS (Nano-secondary ion mass spectrometry) imaging system, which is a marriage of TEM and mass spectrometry, to locate non-antigenic molecules associated with host-symbiont communication.
March 13th - Microglia on the Move: The Dynamics of Microglial Mobilization in Injured Brain Tissues
Microglia are brain-resident glial cells that activate and transform into highly mobile phagocytes in response to neuronal injury, infection, or neurodegeneration. Microglia promote clearance of dead and dying cells, thereby helping to limit secondary damage and support recovery after injury. We seek to better understand how microglial activation and mobilization is regulated at a molecular level. In this lecture, I will review studies utilizing confocal and multiphoton time-lapse imaging to explore the dynamics of microglial mobilization following traumatic injury in excised rodent brain tissue slices and in the intact rodent brain in vivo. Recent work using genetically-modified mice is elucidating the roles of extracellular purines and their receptors in modulating the earliest responses of microglia to injury.
April 10th - Mimicking the Blood-Brain Barrier In Vitro and Overcoming it In Vivo
Millions of people worldwide are afflicted with neurological diseases such as Parkinson's disease, Alzheimer's disease, brain cancer, and cerebral AIDS. Although many new drugs are being developed to combat these and other brain diseases, few new treatments have made it to the clinic. The impermeable nature of the brain vasculature, also known as the blood-brain barrier (BBB), is at least partially responsible for the paucity of new brain therapeutics. As examples, approximately 98% of small molecule pharmaceuticals do not enter the brain after intravenous administration, and the BBB prevents nearly all protein and gene medicines from entering the brain. Our research group is therefore focused on developing tools for the analysis of the brain drug delivery process and identifying novel strategies for circumventing this transport barrier. This presentation will detail our recent work regarding the development of cell-based in vitro experimental models that accurately mimic the BBB characteristics observed in vivo. Such models are amenable to drug permeability screening and a priori prediction of brain uptake. In addition, I will discuss our efforts to overcome BBB restrictions on brain drug delivery. To this end, we are mining large antibody libraries to identify antibodies that can target and act as artificial substrates for endogenous receptor-mediated BBB nutrient transport systems. After conjugation to drug payloads that can include small molecules, proteins, or DNA therapeutics, these antibodies have the potential to deliver medicines across the BBB noninvasively.
May 8th - Sleep: A Window on the Brain
Background: The function of sleep remains one of the few unsolved mysteries of biology. In the lecture, I will discuss a novel hypothesis – the synaptic homeostasis hypothesis – which claims that sleep plays a role in the regulation of synaptic weight in the brain. In brief, the hypothesis is as follows: 1. Wakefulness is associated with synaptic potentiation in several cortical circuits; 2. Synaptic potentiation is tied to the homeostatic regulation of slow wave activity; 3. Slow wave activity is associated with synaptic downscaling; 4. Synaptic downscaling is tied to the beneficial effects of sleep on neural function and, indirectly, on performance.
Methods: Evidence for the hypothesis has been obtained using many experimental paradigms, from molecular studies of sleep and wakefulness to neuroimaging studies in humans. Results: The synaptic homeostasis hypothesis can account for several aspects of sleep and its regulation, and several of its specific predictions were confirmed experimentally.
Conclusions: According to the hypothesis, plastic processes occurring during wakefulness result in a net increase in synaptic strength in many brain circuits. The role of sleep is to downscale synaptic strength to a baseline level that is energetically sustainable, makes efficient use of gray matter space, and is beneficial for learning and memory. Thus, sleep is the price we pay for plasticity, and its goal is the homeostatic regulation of the total synaptic weight impinging on neurons. The hypothesis accounts for a large number of experimental facts, makes several specific predictions, and has implications for sleep, neurological, and psychiatric disorders.