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2010 Research Awards

CNS Plasticity In Chronic Inflammation

PI: Peter Shrager, Ph.D.
Co-Investigator: Kerry O'Banion, Ph.D.

Inflammation plays a major role in a number of diseases of the central nervous system in which learning and memory are impaired. Most studies utilize experimental systems in which inflammatory mediators are applied acutely and observations are made over a relatively short period. However, in many cases, e.g. Alzheimer’s disease, traumatic brain injury, and Down syndrome, pathological changes occur over an extended period, and it is thus desirable to study a more chronic animal model. The hippocampus is a major region of the brain known to play an essential role in memory formation. Different cell types and pathways are organized in layers, and sections of the hippocampus can be readily prepared that preserve their circuit organization. It has been shown that the synaptic connections between neurons in the hippocampus are strengthened or weakened, depending on the pattern of stimulation applied. This plasticity is considered to be a cellular correlate of the behavioral adaptations seen in memory formation. It is thus possible to study learning and memory at the cellular/molecular level appropriate for the development of new therapies. The key novel component to this study is the use of a mouse that has been genetically engineered to allow the spatially restricted release of an inflammatory mediator, interleukin-1 beta. By introducing this mediator in the hippocampus, it has been possible to induce inflammation that lasts many months. Through the use of electrophysiological techniques, this project will then evaluate resultant changes in synaptic plasticity in the hippocampus. Molecular techniques are also utilized to provide important controls. A second project investigates seizures, common events in several diseases including epilepsy, and also linked to inflammation. The basic experimental approach is similar: recording from hippocampal slices prepared from the brains of mice with chronic inflammation. However, in this case the idea is to see if there are increases in the likelihood of spontaneous activity and epileptiform discharges that are correlates of seizures. The ultimate aim of these studies is to suggest targets for therapies useful in relevant disease states.

Adaptive Properties of Reflective Head Movements Evoked During Whole Body Linear Acceleration

PI: Greg Gdowski, Ph.D.
Co-Investigator: Gary Paige, M.D., Ph.D.

Postural instability occurs when our reflexes produce muscle activity that is insufficient to compensate for movement caused by the body’s inertia. A property of all postural reflexes is that they must be able to plastically scale the muscle activity they produce in order to reduce the possibility of postural instability. More importantly, the CNS must be able to regulate this scaling, otherwise many contexts which biomechanically challenge our reflexes (e.g. wearing a backpack or a helmet) would render these multisensory reflexes ineffective during behaviors like gait, potentially increasing the risk of falling. Despite the significance of this problem, remarkably little is known about how postural reflexes are regulated by the CNS. Animal studies carried out in the Gdowski laboratory were the first to reveal the plastic adaptive properties of postural reflexes in squirrel monkeys. The fundamental goal of the proposed human-subject study is to develop a new parallel research stream in collaboration between the Gdowski and Paige laboratories. The proposed studies draws upon the combined expertise of the Paige and Gdowski laboratories. The Paige laboratory has developed a novel apparatus at the University of Rochester will be used to translate a seated human subject in any direction at moderate accelerations. This system will be used in conjunction with the Gdowski laboratory’s 3-D motion capture system and electromyography system in order to quantify head movement kinematics and to record neck electromyography (EMG) produced during translation. The aim of the project is to quantify how changes in the head’s moment of inertia effect reflexive head movements in human subjects. The kinematics of reflexive head movements and neck electromyography will be recorded while the subject is translated with and without a helmet. Multiple directions of translation will be tested to quantify the directional sensitivity of the reflex in stabilizing the head with respect to the neck. Quantitative comparisons between the each condition (with and without a helmet) and orientation will be carried out to determine differences in the activation of the neck’s musculature and the kinematics of reflexive head movements. Knowledge of these processes and their limits will be the fundamental backbone for developing future rehabilitative strategies that function to restore postural reflexes in aging and labryinthe-deficient individuals.

Social versus Non-social Sensory Integration: Neuronal Mechanisms and Relevance to Autism

PI: Liz Romanski, Ph.D.
Co-Investigator: Laura Silverman, Ph.D.

Autism Spectrum Disorders (ASD) are characterized by significant impairments in social reciprocity and communication. It has been suggested that difficulties in these areas may stem from an underlying problem with sensory integration abilities since people routinely integrate information that they hear with what they see to make sense of what is happening in the world. Studies have suggested that individuals with autism have an impaired ability to match voices with faces, to discriminate the temporal synchrony of audiovisual speech, and to blend auditory and visual speech, but that integration of non-communication stimuli may not be compromised. We hypothesize that sensory integration abilities in children with ASD will differ across social and non-social stimuli. Furthermore, we hypothesize that there will also be differences in the neural signals in a communication relevant brain region, the ventral prefrontal cortex, during the perception and integration of social and non-social audiovisual stimuli. In our first aim we will (1) determine the relationship between social and non-social audiovisual stimuli and audiovisual integration abilities in autism. This will be achieved through a series of behavioral studies in a sample of children and adolescents with high-functioning autism and matched controls. Participants will detect asynchronous audiovisual stimuli as a measure of temporal integration using English speech stimuli, Dutch and Non-word speech stimuli (no communicative meaning, same face, similar biological motion), Bird Song (no meaning, non-human face stimuli, biological motion) and Computer Graphic objects moving with sound (no communication, non-biological motion). Previous research suggests that detection of asynchrony is more accurate for non-social stimuli in participants with ASD than in controls. In our second aim we will (2) determine the neuronal mechanisms underlying the integration of social and non-social audio-visual stimuli. This will be achieved by recording single cells from the ventral prefrontal cortex of non-human primates as they perform a similar sensory integration task as that used in Aim 1. Results will inform us as to how an area that has long been associated with language and communication integrates social and non-social stimuli.

This study directly compares integration of social and non-social stimuli over a broad range of stimuli with built in controls for biological motion and communicative relevance. Thus, it will clarify whether sensory integration problems are universal in autism or whether they are related to communication, motion or the difficulty of experimental tasks. Our results will reveal the neuronal mechanisms which underlie integration of audiovisual stimuli and how changes in synchrony affect neuronal transmission, with hopes to catalyze improved therapies used to treat children with autism.

Technology Development - New Faculty Scholar Award

Neural Mechanisms of Visual Working Memory in Humans and Non-Human Primates

PI: Patricia White, Ph.D.

A major research initiative in neuroscience at the UR is sensory neuromedicine. Among several directions promoted, the most exciting entails regenerative sensory prosthetics. The overall topic includes both biological and artificial forms. Biological prosthetics entail implantable or exogenously modifiable genes, cells, or aggregates to restore structure and function to essential but damaged neural systems. Our prime target resides within an expanding strength in hearing and balance, as witnessed by the Center for Navigation and Communication Science (CNCS)--an NIH-NIDCD supported P30 Core-Center. Specifically, we have targeted sensory regeneration in the inner ear, or hair-cell regeneration. This means utilizing cultured stem/progenitor cells to restore hearing through implantation into damaged cochlea and/or vestibule, or alternatively, inducing existing supporting cells to reenter the cell cycle and effectively become progenitors once again. The latter actually exists in lower animals, and this provides relevant motivation. Evolutionary biology, and in particular related to birds, is important, because these rather advanced war- blooded animals with four-chambered hearts spontaneously regenerate hair cells following complete ablation of them in adult animals. Many birds live long lives (decades), and have evolved this important attribute without perishing from runaway development or cancer. The selective advantage for birds is that they cannot fly without a vestibular (balance) system—a lethal outcome. Further, communication (birdsong) is essential for procreation of future generations. Cracking this challenge in mammals, and ultimately humans, is particularly encouraging given the solution that already exists in other creatures.

Following a national search, a clear lead contender was identified and successfully recruited-- Patricia White. She embodies the most direct match for our interests in a variety of ways, notably providing leading-edge expertise and experience in the field of hair cell regeneration and its promise to revolutionize the interventional treatment of sensorineural hearing loss.

Graduate Student Awards

Development of Therapeutic Strategies for the Treatment of Hearing Loss and Deafness

PI: Miriam Gladstone
Mentors: Robert Frisina, Ph.D., David Borkholder, Ph.D.

According to the NIDCD (National Institute on Deafness and Other Communication Disorders), approximately 17% of adults in America have a hearing deficit. This percentage increases with age, such that at least 47% of adults over 75 years old have some form of hearing loss. This is the third most prevalent chronic public health issue in the United States and therefore development of therapies that could efficiently prevent or treat permanent hearing loss would benefit millions of Americans and help reduce the stress on our US healthcare system.

To this end, the overall aim for this project is to further the development of therapeutic strategies for the treatment of hearing loss and deafness. In order to accomplish this aim, a computational computer model will be developed to determine an optimal set of infusion parameters that will lead to the delivery of a therapeutic agent throughout the cochlea with known concentration. Using mice as an animal model, live micro-Computed Tomography imaging will be used to visualize the real-time infusion of a contrast agent, allowing for direct measurement of spatio-temporal concentrations, and calculation of clearance and inter-compartment communication rates for inclusion in the model. Additionally, auditory testing will be performed while infusing ototoxic agents directly into the inner ear in order to validate the computer model in both the young adult and aged auditory system.

The long term goal of this line of translational research is to develop gene transfer methods via local application of biotherapeutic compounds to preserve hearing, including correction or prevention of hearing loss in the aging auditory system. Through a combination of bioengineering modeling and imaging techniques as well as auditory experiments using a CBA mouse model, optimization of surgical/infusion approaches will yield delivery of a substance throughout the mammalian cochlea with appropriate concentration profiles.