Rod C. Scott, MD, PhD - US grants

DESCRIPTION (provided by applicant): Many children with epilepsy have severe and permanent adverse cognitive, behavioral and quality of life outcomes. However, the relative contributions of seizures, epileptic discharges in the EEG and etiology to those long term outcomes are not usually known. Current treatment strategies emphasize the role of antiepileptic drugs (AEDs) for termination of seizures with the hope that this will also minimize cognitive and behavioral impairments. Unfortunately clinical evidence for better outcomes following AED therapy is disappointing, and may even make cognition worse. If the major determinants of outcome are not seizure related phenomena but rather the underlying brain disorder, then therapeutic approaches which are broader than antiepileptic drug use (e.g.educational programs) may ultimately have major positive impacts on outcomes of childhood epilepsy. We now propose to test the hypothesis that the additional effect of seizures in the context of malformations of cortical development is minor. We further hypothesize that these adverse outcomes are related to abnormalities in brain structure and in the integration of single unit firing with oscillatory activities. Finally, these adverse outcomes will be worsened by AEDs and improved with cognitive training. In an animal model of cortical dysplasia we will investigate the additional impact of early life seizures, during development and in adulthood, on spatial cognition and prefrontal cortex function. We will also investigate the structural and electrophysiological mechanisms underlying those outcomes and evaluate the therapeutic potential of cognitive training.

? DESCRIPTION (provided by applicant): This application requests funding for a NIH sponsored summer research experience (SRE) program for undergraduate students in areas of neuroscience relevant to the mission of the National Institute for Neurological Disease and Stroke (NINDS): stroke, traumatic brain injury, neurodegenerative disease, pain, and epilepsy. We plan to provide, for six students a year, a ten week long hands-on research experience at the laboratory bench, together with opportunities to interact with and observe clinicians in order to foster recognition of the relevance of neuroscience to human health and a commitment to translational research. We have identified pairs of committed basic science and clinical faculty who will co-mentor these students. The mentors conduct research relevant to NINDS in an environment that is well suited for translational research: UVM's university-wide Neuroscience Graduate Program (NGP) has over fifty actively participating faculty members supported by research core facilities that facilitate molecular/cellular investigations (Dr. Sheryl White, PhD, director) and an advanced imaging core (Mr. Todd Clason, director) funded by an NIGMS Center of Biomedical Research Excellence (COBRE) grant. In addition, UVM is unusual in that the clinical facilities at Fletcher Allen Health Care (FAHC) are located adjacent to the undergraduate and medical campuses, which greatly facilitates the interaction of SRE students with their clinical mentors. We have extensive experience in providing a SRE program in basic neuroscience for the past ten years. We therefore have established expertise and the necessary infrastructure required for summer programs, including the recruitment and mentoring of students from under-represented minority backgrounds. The main goal of the current proposal is to secure funding for a highly diverse population of students interested in research related to neurological disease.

PROJECT SUMMARY Temporal lobe epilepsy associated with mesial temporal sclerosis (MTS) is common, frequently difficult to treat medically and therefore many patients have epilepsy surgery. Although temporal lobe resections are often successful at stopping seizures this approach usually fails to improve the commonly identified memory comorbidities and can make those impairments worse. A therapeutic approach in which MTS is modified in a way that reduces epileptic phenomena and leads to an improvement in memory would have a major impact on the quality of life of many patients with MTS. Implantation of interneuron precursors has been shown to reduce seizures and improve cognition. We hypothesize that transplanted interneuron precursors will restore temporal organization of hippocampal pyramidal cells thereby improving abnormalities in rate, temporal and population coding that underpins normal cognitive behavior. In addition they will also minimize hypersynchrony leading to seizure reduction. We propose to study interactions between multiple simultaneously firing hippocampal neurons recorded from CA1 and CA3 bilaterally in awake, freely moving rodents during foraging and during an active place-avoidance task. Systems level changes at the level of rate coding, temporal coding and population coding will be compared between implanted and non-implanted rats. We will use standard and novel analytical tools developed in our laboratories to apply to these data. A detailed systems level understanding of how neural networks need to change in order to improve disease outcomes will guide optimization of cell based therapies and will provide a target for other interventions such as electrical stimulation or optogenetics.

PROJECT SUMMARY The overall goal of this project is to establish the time course for developing abnormalities in hippocampal neural circuit action potential firing dynamics after pilocarpine induced hippocampal injury, determine whether maintenance of normal neuronal firing dynamics prevents epileptogenesis and establish the genetic mechanisms of those effects. Temporal lobe epilepsy (TLE) associated with mesial temporal sclerosis (MTS) is a common form of focal epilepsy in which seizures are difficult to treat and memory impairments are common. These factors enormously diminish the quality of life of people with TLE. MTS/TLE develops after brain injury via pathophysiological processes that take at least weeks to reach the endpoint of seizures and memory impairments. This suggests that there is a window of therapeutic opportunity to minimize adverse outcomes. Epileptogenesis is associated with an enormous number of pathological changes at the levels of gene expression, inflammation, synaptic plasticity, neuronal loss and neuronal reorganization amongst many others. Targeting individual pathogenic mechanisms has had limited success in preventing adverse outcomes in animal models of TLE. Thus, new approaches to preventing epileptogenesis are required. We suggest that the above pathophysiological processes converge to disrupt neural dynamics (the patterns of action potential firing over time). The consequent abnormal activity dependent sculpting of synaptic weights and gene expression iteratively alters the self-organization rules governing the formation of dynamic hippocampal circuits, with the emergence of a maladapted circuit. Brain stimulation to maintain normal dynamics from forming thus represents a novel approach to modifying epileptogenesis. The observation that brain stimulation can minimize seizures and improve cognition outside of stimulation periods in animal models with structural brain abnormalities, including MTS, supports the view that patterns of neural activity can be modified to improve network function. It remains unknown whether stimulation during the process of epileptogenesis reduces the development of maladaptive circuits. We will use optimized stimulation paradigms to perturb hippocampal firing patterns during the post-injury period to maintain normal interictal dynamics and establish whether this improves outcomes and whether gene expression changes provide mechanistic insight that could also be harnessed for therapeutic gain.