INVESTIGATIONS OF THE ROLE OF THE TRANSCRIPTION FACTOR CREB IN MEMORY FORMATION, AND INTERACTIONS BETWEEN THE HIPPOCAMPUS AND THE STRIATUM MEMORY SYSTEMS
Description
Extensive research in both humans and animals has identified and isolated distinct brain regions essential for different types of memory, supporting the notion of multiple memory systems (MMS). The hippocampus and the striatum are the two systems that have been studied widely and are the focus of our studies. Research involving lesion and pharmacologic manipulations on both memory systems show strong evidence for independence. However, recent evidence suggests that both memory systems can interact as well. Though evidence point also in favor interactions, the mechanisms under which these systems interact are unknown. The experiments in this dissertation primarily focused on understanding how these two systems operate in a normally functioning brain. Two methods were used to investigate our notions: 1) Behavioral experiment measured cellular changes in the levels of phosphorylated CREB (pCREB) in the regions of interest (ROI) 2) Somatic experiments measured changes in the behavior following manipulation of CREB selectively in the ROI. Overall, these experiments demonstrate CREB as a critical neuronal marker that can be used in both interventions. Behavioral intervention experiment showed evidence as a plasticity related changes in the levels of pCREB that suggested both the hippocampus and the striatum might act in a competitive manner, bidirectionally. The somatic intervention experiments used lentiviral (LV) vectors and showed evidence that LV CREB manipulations are suitable for chronic stable expression and can be used to investigate multiple tasks following a single manipulation. LV mutant CREB in the hippocampus impaired memory across two different hippocampus-dependent tasks and demonstrated that CREB is critical for long term memory. Overexpression of wild type CREB in the striatum enhanced striatal memory, but also showed evidence for hippocampus competition and cooperation. Similarly, CREB overexpressed in the hippocampus of young and middle-aged rats demonstrate that CREB might be a rate limiting factor in young, but not in the middle-aged rats.