The treatment of disorders such as deficiencies in the ability to form new memories and impaired spatial memory presents a major unmet medical need of particular importance to aged individuals, and animal models for normal aging offer a window on potential therapeutic approaches. Studies of aging in rodents have revealed that structural and functional changes occur in the hippocampus, a structure critical for the encoding and retrieval of memory, that correlate with memory deficits. The research described in this application builds upon the phenomenon that the animal?s physical location is encoded by hippocampal pyramidal cells (HPCs), such that firing rates for HPCs correlate with location in physical space. Such neurons are referred to as place cells. Aging induced spatial memory impairments (ASMI) are characterized by (1) poor performance during hippocampus-dependent spatial learning and memory tasks, and (2) deficits in remapping of place fields upon introduction into a novel environment. Place fields are thought to represent elements of a cognitive map of the environment or representations of places where significant events occur within episodic memories. The proposed research is aimed at understanding the network mechanisms that accompany place field representations in adult and ASMI rats that may be modulated via pharmacological and genetic methods to enhance cognitive performance. alpha5GABA{A}Rs are located primarily in the hippocampus and their genetic deletion or pharmacological inhibition enhances learning and memory in rodent models. We were struck by the observation that ASMI rats exhibit a reduction in alpha5 subunit-containing gamma-aminobutyric acid type A receptor (alpha5GABA{A}R) mRNA expression in the hippocampus along with significant hyperactivity of CA3 pyramidal neurons, raising the possibility that age-induced adaptive changes such as these may underlie the observed cognitive impairments. In this application chronically implanted multi-unit high density electrodes will be used to measure the effects of (1) systemically administered TB21007, an alpha5GABA{A}R preferring negative modulator that acts as a cognitive enhancer in normal adult rat, and (2) bilaterally administered AAV2 viral vectors that regulate alpha5 subunit levels on HPC firing rates and place field remapping in awake, freely behaving normal adult and ASMI rats. These experiments will determine whether alpha5GABA{A}Rs differentially alter HPC firing rates in the CA1 and CA3 subregions and whether age-related changes in neural activity affect hippocampal-specific place field representations (as reflected in their ability to carry out pattern separation and completion). In addition, we will test whether an alpha5GABAAR-preferring negative modulator and specific AAV2 viral vectors that regulate alpha5 subunit levels enhance cognitive performance in adult and/or ASMI animals. These studies will begin a molecular dissection of place field remapping, contribute to a deeper understanding of the role of HPC activity in age-related cognitive decline, and provide the basis for establishing a systems-level approach to evaluate pharmacological strategies for treatment of cognitive deficits associated with normal aging.
In the United States, there were 37.3 million people 65 years or older in 2006, representing about one in every eight Americans, and by 2030 this group is expected to grow to become 20% of the population. Aging is accompanied by a decline in memory and this impairment has been associated with changes in the function of the hippocampus, a brain region important for memory in humans and animals. The work put forth in this training program is one of the first of its kind to train a doctoral student in multiple research domains that will enable her as a young independent scientist to take cutting edge technologies and apply them together to uncover the molecular substrate for a therapeutic strategy for cognitive deficits associated with normal aging.
| Robitsek, Jonathan; Ratner, Marcia H; Stewart, Tara et al. (2015) Combined administration of levetiracetam and valproic acid attenuates age-related hyperactivity of CA3 place cells, reduces place field area, and increases spatial information content in aged rat hippocampus. Hippocampus 25:1541-55 |
