2009 Research Awards
Proteomics of the peripheral and central auditory system during maturation
PI: Raphael Pinaud, Ph.D.
Co-Investigator: Anne Luebke, Ph.D.
Hearing loss affects humans of various ages, from birth to older adulthood, and with various degrees of severity, ranging from mild deficits in hearing thresholds to deafness. To explore potential avenues for the amelioration or restoration of dysfunctional hearing, it is central to elucidate how hearing loss impacts the anatomical and functional organization of the auditory system. In this project we will uncover the molecular scripts that guide the normal development of peripheral and central auditory circuits. In addition, we will study how genetic mutations that lead to hearing deficits impact these cellular programs in the vertebrate cochlea and brain. This research is expected to reveal key processes involved in the development and function of the peripheral and central auditory system, and may expose potential cellular substrates that can be targeted for therapeutic strategies aimed at recovering hearing function.
Novel Retinal Circuits in the primate brain
PI: Liz Romanski, Ph.D.
Co-Investigator: William Merigan, Ph.D.
In this proposal we will refine and extend our knowledge of basic anatomical pathways that bring visual information to specific subcortical targets. In Aim 1 we will determine whether there are subcortical pathways that provide visual information to the amygdala in an analogous manner that subcortical auditory regions have been shown to project directly to the amygdala. These direct visual pathways to the amygdala have been suggested to play a role in rapid face recognition, fear responses, phobias and post traumatic stress disorder. In Aim 2 we will investigate the possibility that single retinal ganglion cells might project to more than one subcortical visual target. This would provide a unique opportunity for the retina to simultaneously influence the neuronal activity of diverse brain systems. For these experiments we will place retrograde tracers into several retinal targets and then characterize double-labeled ganglion cells in the retina. This research is of particular importance because recent work suggests that many visual capacities survive complete damage to the most prominent and better understood visual pathways. Both aims address a major focus of the Schmitt program, the Senses and Behavior by examining how less understood visual pathways contribute to essential visually guided behaviors. Results of this study will make possible NIH applications from both investigators to pursue the behavioral role of the identified bifurcating pathways.
The role of inflammation in epilepsy
PI: John Olschowka, Ph.D.
Co-Investigators: Robert Gross, M.D., Ph.D.; Kerry O'Banion, M.D., Ph.D.
Inflammation is known to participate in the mediation of a growing number of acute and chronic neurological disorders. Unfortunately, the involvement of inflammation in the pathogenesis of epilepsy and seizure induced brain damage has only recently been appreciated. Inflammatory processes, including disruption of the blood-brain barrier, activation of microglia and astrocytes, and production of pro-inflammatory cytokines have been described in both human epilepsy patients and in animal models. Systemic inflammation (sepsis, arthritis, chemotherapy, and many others) leads to increased susceptibility and severity of seizures. Anti-inflammatory treatments (steroids, anti-TNFα, IL-1ra) reduce the likelihood of seizures in both humans and in animal models. Recently we observed constant seizure activity in mice whose brains were irradiated 6 months prior to EEG recording. While we have described both acute and chronic inflammation after brain irradiation, irradiation is generally considered safe for the treatment of CNS tumors. However, the seizures we observed suggests that minor CNS inflammation may have important clinical consequences. This proposal seeks to acquire EEG recording technology for use in three pilot experiments designed to test the hypothesis that inflammation leads to increased neuronal excitability and seizures. In the first study, we will attempt to replicate our observation of seizures following brain irradiation. Following irradiation, EEGs will be recorded in a time course study extending up to 6 months. At the time of sacrifice, the brains will be collected for both molecular and immunohistochemical analyses of endothelial and glial cell activation, immune cell infiltration, and evidence of neuronal seizures. This time course study seeks to determine whether the acute inflammatory response is sufficient to generate seizures or whether development of chronic inflammation is required. In our second pilot study, we will examine the role of chemotherapyinduced inflammation of the brain. Following baseline EEG recording, animals will be treated with 5-fluorouracil (5-FU), a drug reported to affect spatial learning as well as induce seizures. Animals will be recorded and the tissue analyzed similar to the first study. The final pilot study will examine the role of peripheral inflammation on seizure activity. Following baseline EEG recording, animals will be given the proinflammatory cytokine HMGB1 over 3 days (to replicate sepsis) and then recorded. The molecular & immunohistochemical analysis of inflammation will follow. Collectively, these studies will begin to determine the roles of acute vs. chronic and CNS vs. peripheral inflammation on seizure activity. These results may lead to better and/or safer treatments for epilepsy and CNS tumors.
Neural Mechanisms of visual working memory in humans and non-human primates
PI: Duje Tadin, Ph.D.
Co-Investigator: Tania Pasternak, Ph.D.
Our actions and decisions are often based on sensory cues that are not continuously available. For example, when driving, we are able to check a blind spot while continuing to accelerate because we are guided by past visual input. This ability to briefly store and manipulate sensory information is referred to as sensory working memory and has been one of the key research questions in both cognitive and systems neuroscience. Much of what we know about the neural mechanisms underlying visual working memory has been provided by animal studies. Less is known, however, about how these results generalize to working memory processes in humans. Here, we propose a series of multidisciplinary and cross-species studies that will examine, in parallel, the functional role of the visual and prefrontal cortex in sensory working memory for both human and monkey subjects. This will allow us to determine the degree to which monkey results generalize to working memory processes in humans.
Encoding prior knowledge for probabilistic decision making in neural circuits
PI: Jin Jeong, Ph.D.
Mentors: Raphael Pinaud, Ph.D.; Ania Majewska, Ph.D.
In order for us to be able to see our surroundings, information from the eyes must be routed to the correct area of the brain, the visual cortex. This information travels through many neurons which are connected to each other to form orderly networks. The precise wiring of neurons in these networks is crucial for our brain to correctly interpret the signals coming from the eyes. How such precise connections can form between neurons separated by large areas is still not well understood. The development of connections in the visual system is thought to progress in two stages – an “initial period” where connections form more or less randomly, and a refinement period where electrical activity elicited by visual cues leads to a precise connectivity by eliminating spurious connections. This second phase is crucial for the development of proper brain function. While a lot of work has focused on how visual activity affects the responses of neurons, very little is known about the molecular pathways that implement such changes in neuronal responses. Additionally, the majority of molecular studies of activity-dependent changes in neuronal function have focused on the molecular changes that occur within the neurons themselves. It is now becoming increasingly clear that the molecular structure of the extracellular matrix surrounding neurons is critical in modulating the refinement of neuronal circuitry. The changes in the extracellular milieu elicited by visual activity, however, are completely unknown. In my work I will use proteomics approaches to examine the extracellular matrix in animals that have undergone manipulations of vision. This will allow me to identify, for the first time, important molecular elements in the extracellular matrix that control neuronal function. This work will shed light not only on the molecular underpinnings of the refinement of visual circuitry, but is likely to illuminate many different forms of nervous system remodeling and give insight into how this process goes awry in neurodevelopmental disorders such as autism.