The role of attenuated astrocyte activation in infantile neuronal Ceroid Lipofuscinosis

Infantile neuronal ceroid lipofuscinosis (INCL) is an inherited neurodegenerative disorder affecting the CNS during infancy. INCL is caused by mutations in the CLN1 gene that leads to a deficiency in the lysosomal hydrolase, palmitoyl protein thioesterase (PPT1). A murine model of INCL, the PPT1(−/−) mouse, is an accurate phenocopy of the human disease. The first pathological change observed in the PPT1(−/−) brain is regional areas of GFAP upregulation, which predicts future areas of neurodegeneration. We hypothesized that preventing GFAP upregulation in reactive astrocytes will alter the CNS disease. To test this hypothesis, we generated mice simultaneously carrying null mutations in the GFAP, Vimentin, and PPT1 genes (GFAP(−/−)Vimentin(−/−)PPT1(−/−)). Although the clinical and pathological features of the GFAP(−/−)Vim(−/−)PPT1(−/−) mice are similar to INCL, the disease appears earlier and progresses more rapidly. One mechanism underlying this accelerated phenotype is a profound neuroinflammatory response within the CNS. Thus, our data identify a protective role for intermediate filament upregulation during astrocyte activation in INCL, a model of chronic neurodegeneration

Building Resilience in a Major City Evacuation Plan Using Simulation Modeling

This study provides data on the optimal staff, materials, space, and time resources required to operate a regional hub reception center, a “short-term facility with the goal to process and transport displaced survivors (evacuees) to temporary or permanent shelters following a catastrophic incident,” (Regional Catastrophic Planning Team, 2012). The facility will process approximately 20,000 evacuees over its entire seven-day duration following a disaster to assist in community resilience. The study was performed using a model created using the computer simulation software, AnyLogic. The results of the study demonstrated that the goals set forth by the Illinois-Indiana-Wisconsin Regional Catastrophic Planning Team could be improved upon and that the largest contributing factor to optimizing the RHRC is finding the optimal number of total staff members to operate the facility

Diabetes in sub-Saharan Africa – from policy to practice to progress: targeting the existing gaps for future care for diabetes

The global prevalence and impact of diabetes has increased dramatically, particularly in sub-Saharan Africa. This region faces unique challenges in combating the disease including lack of funding for noncommunicable diseases, lack of availability of studies and guidelines specific to the population, lack of availability of medications, differences in urban and rural patients, and inequity between public and private sector health care. Because of these challenges, diabetes has a greater impact on morbidity and mortality related to the disease in sub-Saharan Africa than any other region in the world. In order to address these unacceptably poor trends, contextualized strategies for the prevention, identification, management, and financing of diabetes care within this population must be developed. This narrative review provides insights into the policy landscape, epidemiology, pathophysiology, care protocols, medication availability, and health care systems to give readers a comprehensive summary of many factors in these domains as they pertain to diabetes in sub-Saharan Africa. In addition to providing a review of the current evidence available in these domains, potential solutions to address the major gaps in care will be proposed to reverse the negative trends seen with diabetes in sub-Saharan Africa

The role of reinforcement and contextual cues in the acquisition and expression of motor memories

Each day we interact with a wide variety objects, from using our computer, to driving a car or preparing a cup of coffee. We can complete the actions necessary to use these objects with little to no error or relearning from the last time we completed the same task. As the phrase ‘just like riding a bicycle’ implies, once learned, certain actions can always be called upon, regardless of how infrequently we execute them. In the following chapters, we focus on the initial learning of goal-directed motor commands, investigating how people first learn to interact with a novel object and what memory they retain from this interaction. First, we investigated what cues serve as indicators that a particular set of motor commands should be retained for future recall. Our results suggested that decreases in reinforcement signaled participants of a change in the dynamics of the tool, allowing participants to separate and retain multiple motor memories for use of the same tool. From these experiments, we determined that reinforcement of actions also served as a critical cue to recall upon these motor memories. When reinforcement of the current motor commands was withheld, participants switched their actions and recalled previous motor training. We next investigated if the retention of a particular set of motor commands was specific to the tool on which these commands were learned. Here, we found that when participants encountered a new tool similar to the one they had used for training, they relied upon their memory of the trained tool, and generalized some of their previous learning. We then asked if the contents of motor memory were stable or if modifications occurred with continued training. The results of these experiments suggested that with sufficient time away from practice, motor memories become more efficient and we begin to minimize energetic inefficiencies in our movements. Finally, we revisited the idea of reinforcement and action selection. We found that patients diagnosed with Parkinson’s Disease (PD), were less sensitive to a lack of reinforcement, which in turn lead to less motor exploration in these patients as compared to healthy controls. Thesis advisor: Dr. Reza Shadmehr ([email protected]) Thesis committee: Drs Reza Shadmehr, Amy Bastian and Jeffrey Ellenboge

Reactive astrogliosis in the era of single-cell transcriptomics

Reactive astrogliosis is a reaction of astrocytes to disturbed homeostasis in the central nervous system (CNS), accompanied by changes in astrocyte numbers, morphology, and function. Reactive astrocytes are important in the onset and progression of many neuropathologies, such as neurotrauma, stroke, and neurodegenerative diseases. Single-cell transcriptomics has revealed remarkable heterogeneity of reactive astrocytes, indicating their multifaceted functions in a whole spectrum of neuropathologies, with important temporal and spatial resolution, both in the brain and in the spinal cord. Interestingly, transcriptomic signatures of reactive astrocytes partially overlap between neurological diseases, suggesting shared and unique gene expression patterns in response to individual neuropathologies. In the era of single-cell transcriptomics, the number of new datasets steeply increases, and they often benefit from comparisons and integration with previously published work. Here, we provide an overview of reactive astrocyte populations defined by single-cell or single-nucleus transcriptomics across multiple neuropathologies, attempting to facilitate the search for relevant reference points and to improve the interpretability of new datasets containing cells with signatures of reactive astrocytes

Astrocyte activation and reactive gliosis : A new target in stroke?

Stroke is an acute insult to the central nervous system (CNS) that triggers a sequence of responses in the acute, subacute as well as later stages, with prominent involvement of astrocytes. Astrocyte activation and reactive gliosis in the acute stage of stroke limit the tissue damage and contribute to the restoration of homeostasis. Astrocytes also control many aspects of neural plasticity that is the basis for functional recovery. Here, we discuss the concept of intermediate filaments (nanofilaments) and the complement system as two handles on the astrocyte responses to injury that both present attractive opportunities for novel treatment strategies modulating astrocyte functions and reactive gliosis.Peer reviewe

Defining cell populations with single-cell gene expression profiling: correlations and identification of astrocyte subpopulations

Single-cell gene expression levels show substantial variations among cells in seemingly homogenous populations. Astrocytes perform many control and regulatory functions in the central nervous system. In contrast to neurons, we have limited knowledge about functional diversity of astrocytes and its molecular basis. To study astrocyte heterogeneity and stem/progenitor cell properties of astrocytes, we used single-cell gene expression profiling in primary mouse astrocytes and dissociated mouse neurosphere cells. The transcript number variability for astrocytes showed lognormal features and revealed that cells in primary cultures to a large extent co-express markers of astrocytes and neural stem/progenitor cells. We show how subpopulations of cells can be identified at single-cell level using unsupervised algorithms and that gene correlations can be used to identify differences in activity of important transcriptional pathways. We identified two subpopulations of astrocytes with distinct gene expression profiles. One had an expression profile very similar to that of neurosphere cells, whereas the other showed characteristics of activated astrocytes in vivo