Interim-Chair, Department of Neurobiology and Anatomy
Nina and Michael Zilkha Distinguished Chair in Neurodegenerative Disease Research, Neurodegenerative Disease Research
Formation and Impairment of Memory
Research in my laboratory aims to delineate the biochemical and molecular changes that are critical for memory formation. Experimental and clinical studies performed by a number of investigators have established that short-term memory (memories lasting for minutes-to-hours) depends on post-translation modification (e.g. phosphorylation) of proteins within neurons, whereas long-term memory (memories lasting for days-to-weeks, and in some cases, a lifetime) requires de novo protein synthesis and morphological changes. Using a multi-disciplinary approach, we disrupt or augment specific biochemical events within the hippocampus and other brain regions to determine the aspect of memory altered as a result of these manipulations.
Working memory (memories that last for seconds) is critical for holding information “online” in order to guide goal-directed behavior. Working memory is required for decision making and coherent thought processes, and is often impaired as a result of normal aging, and diseases such as Parkinson’s, Alzheimer’s, schizophrenia and traumatic brain injury (TBI). It is not well understood if the biochemical and molecular mechanisms that are required for short-term memory formation also play a role in working memory. Research in our laboratory has demonstrated that while short-term memory requires protein kinase-mediated phosphorylation of cellular substrate proteins (e.g. channels, transcription factors), these activities in prefrontal cortex neurons impair working memory. Interestingly, prefrontal protein phosphatase activity, vis a vis calcineurin, appears to be critical for this temporary form of memory. One of our ongoing projects is to identify the substrate proteins that are dephosphorylated during working memory with the goal of developing agents that can be used to treat working memory impairments.
TBI can profoundly alter memory formation that can markedly compromise day-to-day activities and quality of life. These impairments can occur in the absence of overt brain damage such as is seen in persons sustaining a concussion. Interestingly, our research has shown that the cellular and molecular mechanisms of memory impairments are not static, but evolve over time. This suggests that a pharmacological treatment that is effective in the acute stage of injury, is unlikely to work in the chronic stage of injury. The long-term goal of our research is to identify potential targets for therapeutic interventions to alleviate the memory disorders triggered by TBI.
- Rozas NS, Redell JB, Pita-Almenar JD, Mckenna J 3rd, Moore AN, Gambello MJ, Dash PK. Intrahippocampal glutamine administration inhibits mTORC1 signaling and impairs long-term memory. Learn Mem. 22:239-46, 2015.
- Gibb SL, Zhao Y, Potter D, Hylin MJ, Bruhn R, Baimukanova G, Zhao J, Xue H, Abdel-Mohsen M, Pillai SK, Moore AN, Johnson EM, Cox CS Jr, Dash PK, Pati S. TIMP3 Attenuates the Loss of Neural Stem Cells, Mature Neurons and Neurocognitive Dysfunction in Traumatic Brain Injury. Stem Cells, Epub ahead of print 2015.
- Dash PK, Hylin MJ, Hood KN, Orsi A, Zhao J, Redell JB, Tsvetkov AS and Moore AN. Inhibition of eIF2α phosphatase reduces tissue damage and improves learning and memory following traumatic brain injury. J Neurotrauma 32:1608-20, 2015.
- Kobori N, Moore AN and Dash PK. Altered regulation of protein kinase a activity in the medial prefrontal cortex of normal and brain-injured animals actively engaged in a working memory task. J. Neurotrauma 32:139-48, 2014.
- Hylin MJ, Orsi SA, Rozas NS, Hill JK, Zhao J, Redell JB, Moore AN and Dash PK. Repeated mild closed head injury impairs short-term visuospatial memory and complex learning. J Neurotrauma 30:716-726, 2013.
- Hylin MJ, Orsi SA, Moore AN and Dash PK. Disruption of perineuronal net impairs fear conditioning. Learning and Memory 20:267-273, 2013.
- Hylin MJ, Orsi SA, Zhao J, Bockhorst KH, Perez AL, Moore AN and Dash PK. Behavioral and histopathological alterations resulting from mild fluid percussion injury. J Neurotrauma 30(9):702-15, 2013.
- Reith MR, McKenna J, Wu H, Hashmi S, Cho S-H, Dash PK and Gambello MJ. Loss of Tsc2 in purkinje cells is associated with autistic-like behavior in a mouse model of tuberous sclerosis complex. Neurobiology of Disease 51:93-103, 2012.
- Menge T, Zhao Y, Zhao J, Wataha K, Gerber M, Zhang J, Letourneau P, Redell J, Shen L, Wang J, Peng Z, Kozar R, Cox CS, Khakoo AY, Holcomb JB, Dash PK and Pati S. Mesenchymal stem cells regulate blood brain barrier integrity in traumatic brain injury through production of the soluble factor TIMP3. Science Trans. Med. 4:161ra150, 2012.
- Dash PK, Johnson D, Clark J, Orsi SA, Zhang M, Zhao J, Grill RJ, Moore AN, Pati S. Involvement of the Glycogen Synthase Kinase-3 Signaling Pathway in TBI Pathology and Neurocognitive Outcome. PLoS One. 6(9):e24648, 2011.