Interdisciplinary Research Projects

AMPA-mediated excitotoxicity in Batten disease

PIs:

• David Pearce, Ph.D. (Center for Aging & Devel. Biol.)
• Robert Gross (Neurology)
• Kovacs Attila (Center for Aging &Devel. Biol.)

Many brain diseases have disruptions in what are called circuits. These circuits form the basis for the many cells in the brain communicating with each other and controlling multiple functions such coordination, memory and emotion. Thus, when there are disruptions in these circuits these processes may manifest abnormalities such as loss of balance, memory loss or confusion and anxiety, respectively. These circuits communicate using small molecules called neurotransmitters. Disruption in the way cells in the brain react to these neurotransmitters is one way a disruption in the brain is evident. The project “AMPA-mediated excitotoxicity in Batten disease”explores how brain cells from a mouse model for Batten disease may respond to the neurotransmitter glutamate. Batten disease is a fatal neurodegenerative disease of childhood. An unfortunate aspect of this disease are epileptic seizures. The proposed studies aim to understand the alterations that could underlie how seizures are manifest through a disruption of the circuitry that responds to glutamate. Overall, it is hoped that this better understanding of seizures in Batten disease could lead to better treatment of the associated seizures.

Sensorimotor integration in Parkinson’s disease

PIs:

• Martha Gdowski (Neurobiology & Anatomy)
• Jason Schwalb (Neurosurgery)
• Greg Gdowski (Neurobiology & Anatomy)
• David Loiselle (Neurology)
• Jon Mink (Neurology)

Parkinson’s Disease (PD) is a degenerative neurological disorder characterized by progressive deterioration of brain function. Public figures such as Michael J. Fox, Janet Reno, and Pope John Paul II have increased awareness of the debilitating nature of PD, in part because some of the most overt aspects of PD become manifest as voluntary movement deficits. The effects of PD dramatically impact activities of daily living and have thus driven the development of medical technologies such as deep brain stimulation (DBS). Although DBS has significantly improved voluntary movement for many PD patients, several studies of PD patients suggest that movement deficits involve more than just having the desire to move but not being able to; cognitive processes involved in deciding when and how to move are also impaired. The goal of this proposal is to collect behavioral data from control subjects and PD patients through a custom Multisensory Integration and Motor Planning Assessment (MIMPA) that is used in ongoing monkey studies in our laboratory. These data will be used to address key questions about the ability of PD patients to incorporate multisensory cues to guide voluntary movements and will be compared with neuronal responses recorded from monkeys performing the same tasks in a set of parallel studies.

HMGB1-induced inflammation in response to traumatic brain injury

PI: Stephanos Kyrkanides, Assoc. Prof., Dentistry

Co-PI: M. Kerry O’Banion, Assoc. Prof., Neurobio. & Anatomy

The purpose of our investigation is to study the effects of arthritis on the brain using mice. As the aging population increases and arthritis presents in 80% of humans over the age of 65, it becomes very important to understand the effects of arthritis outside the joints. Studies like the present one will allow us to better understand the connection of arthritis with the brain and evaluate whether arthritis plays a role in the development of diseases such as Alzheimers.

Development of transgenic models to modulate neuronal CGRP/AM receptor function

PIs:

• John Olschowka (Neurobiology &Anatomy)
• Jeff Bazarian (Neurology)
• Sean Hurley (Neurobiology &Anatomy)

The focus of this research proposal is to determine the role of the late-appearing cytokine, high-mobility group B1 protein (HMGB1), in the secondary inflammatory response seen following traumatic brain injury. We will also ascertain the role of the presumed HMGB1 receptor, receptor for advanced glycation end-products (RAGE), in this inflammatory process using RAGE knockout mice. HMGB1 is a newly recognized cytokine that appears to play a major role in sepsis, necrosis-induced inflammation, and delayed inflammatory processes. Unlike the pro-inflammatory cytokines TNFa and IL-1ß, HMGB1 is not rapidly expressed, but peaks 18-24 hours following injury or infection. It is released from macrophage/monocytic cells and presumably from microglia. Acting via the RAGE receptor, it induces expression of cytokines, chemokines, adhesion molecules, metalloproteinases, etc. as well as inducing itself. A single report suggests HMGB1 is upregulated following traumatic brain injury (TBI). Another suggests it induces fever, anorexia and sickness behavior. Beyond these reports, nothing is known regarding HMGB1 function in the CNS. We propose four experiments to begin to determine the role of HMGB1. First, using stereotaxic surgery, we will inject recombinant HMGB1 into the striatum and then analyze the inflammatory response using immunohistochemical, stereological, ELISA an real-time RT-PCR techniques. Secondly, we will examine the role of HMGB1 in a model of CNS trauma using a controlled cortical impact (CCI) model. We will determine whether HMGB1 is induced during CNS injury. Third, we will determine if the presumed receptor of HMGB1, the RAGE receptor, is required for its pro-inflammatory actions.

Again we will examine the use the CCI model in RAGE knockout mice. Finally, we will attempt to inhibit the actions of HMGB1 by two means: anti-HMGB1 antibodies or application of recombinant HMGB1 A box protein. The HMGB1 A box protein, a 79 amino acid fragment of the intact protein, appears to inhibit binding of HGMB1 to its receptor and thus acts as an antagonist. The findings of these studies may have implications in the treatment of TBI, stroke, and spinal cord injury.

Effect of visual training on motion perseption after N1 damage in humans

PIs:

• Krystel Huxlin (Ophthalmology)
• Scott Burgin (Neurology)
• Deborah Friedman (Neurology)
• Mary Hayhoe (Brain &Cognitive Sciences)

Currently, there are no widely accepted, rehabilitative treatments for patients suffering from blindness induced by damage to primary visual cortex. Our approach to date has differed from previous attempts at such rehabilitation by concentrating on retraining of a specific visual modality (in our case, motion perception) and by requiring the visual system to perform relatively complex processing for this modality. Visual motion perception is important for the correct evaluation of and action upon our dynamic visual environment, and it is devastated by damage to primary visual cortex. Our work in adult cats with extrastriate cortical damage has shown that it is possible to induce recovery of visual motion perception with intensive motion discrimination retraining in the blind field. This prompted us to ask whether such recovery could be elicited following primary visual cortex damage in humans. By building on preliminary results which show that complex motion discrimination retraining can be used to improve visual motion thresholds in such patients, the proposed experiments will:

1. assess the relative efficacy of different retraining stimuli and tasks for eliciting recovery of visual motion perception; and
2. measure the generalizability of training-induced improvements in visual motion perception to stimulus and task dimensions other than those used during retraining.

In answering this second question, we have begun using virtual reality to determine whether psychophysically-measured improvements in visual motion perception translate into improved usage of visual motion information in complex, naturalistic environments. Results from the proposed experiments will provide novel insight into how visual motion information is detected, processed and acted upon by patients with V1 lesions and by normal, age-matched controls. They will also provide much needed information about the relative effectiveness of different retraining stimuli and tasks in eliciting improvements in visual motion perception, both in V1 patients and in normal subjects. All in all, our results should serve as an important basis for designing and evaluating principled, customized rehabilitation procedures, which maximize visual recovery following visual cortical damage in adult humans.

Again we will examine the use the CCI model in RAGE knockout mice. Finally, we will attempt to inhibit the actions of HMGB1 by two means: anti-HMGB1 antibodies or application of recombinant HMGB1 A box protein. The HMGB1 A box protein, a 79 amino acid fragment of the intact protein, appears to inhibit binding of HGMB1 to its receptor and thus acts as an antagonist. The findings of these studies may have implications in the treatment of TBI, stroke, and spinal cord injury.

Post-Doctoral Awards

Wei-Ji Ma

Mentors:

• Alex Pouget
• Daphne Bavelier

This is a one-year project which will bridge the research of two laboratories in the Department of Brain and Cognitive Sciences, those of Daphne Bavelier and Alexandre Pouget. This collaboration will bring together expertise in human psychophysics of visual learning (Bavelier) with expertise in computational neuroscience (Pouget). The central objectives are:

1. To design a neural learning rule which:
1. Can account for human improvements in performance during learning of a basic visual feature, based on a biologically realistic structure of the neural input data
2. Has a plausible biological implementation
2. To test the validity of this rule with new psychophysical experiments. We will explore in particular how subjects’ performance generalizes across tasks of varying difficulty, and how the dynamics of learning changes with feedback.