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PARTNERS IN RESEARCH: CNDR || IOA || UDALL || Penn ADC
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2010 ADCC Pilot Research Grants

This year, the Penn ADCC awarded two Pilot Research Grants of $50,000 each to the following Penn faculty members. The grants begin July 1, 2009.

Thomas A. Jongens, PhD

"Testing for Calcium Dysregulation in a New Fly AD Model"

Abstract:

We have developed a new Drosophila model for Alzheimer's Disease that is based on haplo-insufficiency for the Drosophila presenilin (psn) gene (see background and significance). In studying this psn-het model, we have found age dependent deficits in learning and memory that can be rescued by treatment with mGluR antagonists, or by genetic reduction of the inositol-triphosphate receptor calcium release channel (InsP3R) pathway. Since the observed rescue occurs through pathways that should reduce intracellular calcium levels, they provide support for a growing body of literature that suggests that sustained disruption of intracellular Ca2+ signaling processes may play an early proximal, and perhaps central, role in the pathogenesis of AD. Therefore our goal as outlined in this proposal is to develop and examine calcium regulation in cells derived from our fly model to determine if the observed age onset cognitive deficits and the rescue of these defects correlates with detectable changes in calcium regulation. If successful our studies will provide evidence that directly links calcium dysregulation due to mutation of the presenilin gene, to the occurrence of age onset cognitive deficits. They will also indicate that correction of this dysregulation is a potential route to take to ameliorate at least some aspects of Alzheimer's disease.

Specific Aim 1. To establish whole brain and primary cell based systems to measure Ca2+ regulation in neurons derived from control and psn-het flies.

Specific Aim 2. To validate that the pharmacological and genetic approaches that rescue the age onset cognitive deficits of psn-hets also reduce resting intracellular Ca2+ levels and/or Ca2+ release by the InsP3-receptor.

David A. Wolk, MD

"Exploration of Episodic Memory Enhancement in Aging with Transcranial Direct Current Stimulation"

Abstract:

Normal aging is associated with decline in a number of cognitive functions. Episodic memory – our memory for life’s prior events and experiences – is particularly affected by the aging process. A reduced ability to learn and remember new information has an obvious impact on functional capacity and is a common source of frustration in older people. In conjunction with medial temporal structures (e.g. hippocampus), several neocortical regions appear to support this form of memory. In particular, the prefrontal cortex (PFC) and lateral parietal lobe have been consistently linked to memory success. Converging evidence from a variety of methodologies has suggested that functional changes in the PFC play a major role in cognitive decline with aging, but a more specific understanding of the neural mechanisms underlying this dysfunction is lacking. While some functional imaging studies have reported reductions in PFC recruitment in elderly relative to young subjects, a number of studies have also reported paradoxical increases in activation. There is great debate in the field as to whether they reflect compensatory activity in pursuit of task goals, or inefficient/nonselective recruitment that may actually have a deleterious effect on task performance. 

Brain stimulation techniques, which can produce ‘virtual lesions,’ offer an exciting potential avenue for addressing these issues and more directly testing the necessity of brain regions involved in cognitive functions. Transcranial direct current stimulation (tDCS) involves the application of a low level direct current to the scalp, which by depolarizing (cathodal stimulation) or hyperpolarizing (anodal stimulation) the underlying tissue modulates the likelihood that neurons will fire. As such, in addition to producing virtual lesions, tDCS can also be used to enhance activity in a brain region.

Given these properties, tDCS may be used to more directly test hypotheses regarding alterations in neural recruitment with aging and possibly enhance memory performance. In the present project, we propose to use this technique to assess the functional significance of altered recruitment patterns in elderly subjects during both memory encoding (study) and retrieval (test). Two main questions will be addressed: First, does excitatory stimulation (anodal) of hypo-recruited regions enhance memory performance in aging; second, do regions of hyper-recruitment represent neural compensation or inefficiency/non-selective recruitment. 

A greater understanding of the neural basis of cognitive aging is critical to the development of ameliorative strategies to improve function. It is hoped that the current work will provide preliminary data for further work and funding applications using this technique. In addition to addressing issues of cognitive neuroscience, the potential cognitive enhancing effects of tDCS offer the possibility of therapeutic interventions in aging and AD.