Rebekah Coleman Evans, Ph.D. - US grants

DESCRIPTION (provided by applicant): Long term plasticity is essential for the proper function of the striatum. It occurs on a timescale of tens of minutes and putatively underlies habit formation and learning. The delicate balance between long term potentiation and long term depression is important for correct motor and cognitive function and is disrupted in striatal based diseases such as Parkinson's Disease (Calabresi et al., 2007). Many molecules are necessary for long term plasticity, but exactly where they need to be active is not well established. Cyclic AMP dependent protein kinase (PKA) is one such molecule. Long term potentiation (LTP) of striatal synapses requires active PKA, but PKA is not randomly located within a neuron. PKA is localized to specific areas of the neuron by A-kinase anchoring proteins (AKAPs). This study investigates where PKA must be active for cortico- striatal LTP to occur. Using electrophysiology, pharmacology, and transgenic mice, I will test whether PKA needs to be anchored pre- or post-synaptically, and whether it needs to be concentrated close to its phosphorylation targets or close to the source of cAMP. I will also investigate the role of one particular AKAP, AKAP150, which has been implicated in striatal learning tasks, but whose role in cortico-striatal plasticity is unknown (Weisenhaus et al., 2010). An in-depth analysis of PKA anchoring in the striatum is an essential step in understanding the intracellular signaling cascades that underlie striatal plasticity. A complete understanding of these pathways will guide research to novel drug targets that address both the motor and the cognitive deficits of Parkinson's Disease. PUBLIC HEALTH RELEVANCE: The correct balance between the strengthening and weakening of neuronal pathways is essential for proper brain function. A disruption of this balance in the dorsal striatum may be the cause of motor and cognitive deficits associated with Parkinson's Disease. This project will examine specific mechanisms underlying the strengthening of dorsal striatum pathways and will yield information helpful for establishing new drug targets and evaluating current treatments for Parkinson's Disease.

This project addresses coronal mass ejections (CMEs) which are violent expulsions of plasma from the Sun that contribute to space weather. It is vital to understand how these eruptions happen and how they propagate towards Earth in order to accurately predict their behavior. The current fleet of solar and space observatories provides unprecedented temporal and spatial coverage of the surface magnetic field, extreme ultraviolet (EUV) and X-ray coronal structures. In this study, data-constrained simulations of CME initiation and propagation will be performed starting from realistic initial conditions for the magnetic field and plasma of an active region that contains a flux rope on the verge of eruption. These simulations will provide a unique opportunity to investigate the processes behind the eruption and early development of CMEs.
The project has the following science objectives: 1) Develop models of CME initiation that are highly constrained by observations in order to study the early development phases of CMEs; 2) Constrain CME properties near the Sun (kinetics, morphology, shock and compression region parameters) based on the flux rope properties and the ambient coronal field, and 3) Reproduce the observed three-part and two-front structure of CMEs and their in situ properties using data-constrained magnetohydrodynamic (MHD) simulations.
Data-constrained non-linear force-free field (NLFFF) models of observed erupting active regions will be used as initial conditions to the Space Weather Modeling Framework (SWMF) global MHD code. The initial conditions on the active region and flux rope plasma will also be constrained by data using recently developed analysis techniques. These tools will be used to propagate more realistic CMEs to 1AU. The properties of the simulated CMEs (direction, velocity, acceleration, morphology, and shock-driving capability) will be compared with all available observations (coronal EUV and X-ray, white-light and in situ data).

The initiation and maintenance of organized movement through the basal ganglia is strongly influenced by its feed-forward and feedback inhibitory architecture. The substantia nigra pars compacta (SNc) and pedunculopontine nucleus (PPN) contribute to the overall output of the basal ganglia. Neurons in both structures degenerate in Parkinson's Disease, resulting in impaired motion. While treatments such as deep brain stimulation in the PPN (Snijders et al., 2016), and the implantation of stem cells into the SNc (Sonntag et al., 2018) have both met with variable success, their potential efficacy is constrained by a fundamental lack of knowledge about the circuitry of these two nuclei. The research proposed here will generate new insights into the function of inhibitory circuitry in these two nuclei and represents the first step toward a full understanding of the local and extended basal ganglia circuits which control organized motion. My long-term goal is to develop an independent research program focused on identifying cellular and network interactions that underlie basal ganglia control of motion. The overall objective of this K99/R00 application is to determine the extent to which local functional connectivity between genetically-defined subpopulations modulates basal ganglia output. My central hypothesis is that inhibition onto SNc and PPN neurons sculpts basal ganglia output by modulating excitatory gain. This hypothesis is based on preliminary two-photon uncaging, calcium imaging, optogenetic experiments, morphological reconstructions, and computational modeling. The rationale for this research is that once the circuit connectivity of the PPN and SNc is functionally mapped, we can begin to define the connections by which the basal ganglia select actions and control coordinated motion. To achieve my overall objective, I will work with my mentor, Dr. Zayd Khaliq and co-mentor, Dr. Chris McBain to learn and implement multi-channel optogenetic techniques and the simultaneous use of spatially-specific optogenetics with two photon glutamate uncaging and calcium imaging. These new techniques, in combination with my computational modeling and electrophysiological experience will allow me to complete my specific aims. During the mentored phase, I will complete aims 1 by performing functional tests of inhibitory inputs onto SNc dopamine neurons, including a comparison of the strength and location of inhibition from the striatal patch (striosome) compartments and the striatal matrix. In aim 2, I will test the functional consequences of dendrite-specific inhibition on the excitatory gain of SNc dopamine neurons. During the independent phase, I will utilize the same techniques to investigate the inhibitory circuitry of the PPN. In aim 3, I will perform functional tests of inhibitory inputs to the glutamatergic neurons of the PPN which have been identified with rabies tracing. In aim 4, I will define the intrinsic and genetic characteristics of a projection-defined subpopulation of PPN neurons. The proposed activities will generate fundamental knowledge about basal ganglia circuitry and will provide training in advanced two-photon and optogenetic techniques to compliment my current expertise in computational modeling and electrophysiology.