Aging is associated with declining function across a broad spectrum of behavioral and biological measures. This component of the program project will pursue a combination of behavioral and neurophysiological studies aimed at characterizing the nature and range of alterations in neuronal representations associated with aging:
Specific Aim 1 : Extending on findings of the previous funding period, we will examine the development of new hippocampal spatial representations when animals are presented with a novel environment. Our previous studies indicated that CAS neurons selectively are hyperactive and are """"""""rigid"""""""" in that they retrieve old representations rather than form new ones when experiencing a novel environment. These studies will examine the relationship between hyperactivity and rigidity of CAS cells and memory performance, and will examine the effects of putative memory enhancing drugs on hippocampal network activity.
Specific Aim 2 : Exploiting recent findings of hippocampal neuronal activity patterns closely associated with memory performance in young animals, we will characterize the nature of performance-related abnormalities in hippocampal representation associated with aging. These studies will determine whether trial-by-trial memory errors in a T-maze spatial delayed alternation task are associated with compromised stability of hippocampal spatial representations, retrieval of inappropriate memory representations, or failure to encode or retrieve trial specific representations. These studies will also examine the effects of putative memory enhancing drugs on memory-related neural activity patterns.
Specific Aim 3 : We will use recently developed protocol for distinguishing """"""""recollection"""""""" and """"""""familiarity"""""""" components of recognition memory to examine the nature of age-related cognitive deficits in our rodent model. We will also compare performance related activation of areas of the prefrontal cortex and hippocampal region in encoding and retrieval and loss of functions in these areas associated with aging. These studies will also examine the effects of putative memory enhancing drugs on component processes in recognition memory in aged rats. Each of these experiments is designed to test specific hypotheses about the nature of age-related cognitive decline and to identify and characterize pharmacological agents as targets of potential therapeutic value. Furthermore, comparisons of the results among these experiments, and with findings from the other projects, will identify features of cognitive aging and effects of therapeutic agents that are common or distinct across a range of behavioral tasks.
|Haberman, Rebecca P; Branch, Audrey; Gallagher, Michela (2017) Targeting Neural Hyperactivity as a Treatment to Stem Progression of Late-Onset Alzheimer's Disease. Neurotherapeutics 14:662-676|
|Haberman, Rebecca P; Koh, Ming Teng; Gallagher, Michela (2017) Heightened cortical excitability in aged rodents with memory impairment. Neurobiol Aging 54:144-151|
|Posada-Duque, Rafael Andrés; Ramirez, Omar; Härtel, Steffen et al. (2017) CDK5 downregulation enhances synaptic plasticity. Cell Mol Life Sci 74:153-172|
|Gu, Yu; Tran, Trinh; Murase, Sachiko et al. (2016) Neuregulin-Dependent Regulation of Fast-Spiking Interneuron Excitability Controls the Timing of the Critical Period. J Neurosci 36:10285-10295|
|Wang, Hui; Ardiles, Alvaro O; Yang, Sunggu et al. (2016) Metabotropic Glutamate Receptors Induce a Form of LTP Controlled by Translation and Arc Signaling in the Hippocampus. J Neurosci 36:1723-9|
|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|
|Gallagher, Michela; Burwell, Rebecca; Burchinal, Margaret (2015) Severity of spatial learning impairment in aging: Development of a learning index for performance in the Morris water maze. Behav Neurosci 129:540-8|
|Tomás Pereira, Inês; Gallagher, Michela; Rapp, Peter R (2015) Head west or left, east or right: interactions between memory systems in neurocognitive aging. Neurobiol Aging 36:3067-3078|
|Mayse, Jeffrey D; Nelson, Geoffrey M; Avila, Irene et al. (2015) Basal forebrain neuronal inhibition enables rapid behavioral stopping. Nat Neurosci 18:1501-8|
|Castellano, James F; Fletcher, Bonnie R; Patzke, Holger et al. (2014) Reassessing the effects of histone deacetylase inhibitors on hippocampal memory and cognitive aging. Hippocampus 24:1006-16|
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