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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) requiresde novo蛋白质合成和形态变化。使用多学科方法，我们破坏或增强海马和其他大脑区域内的特定生化事件，以确定由于这些操纵而改变的记忆方面。

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钙调神经素似乎对于这种临时记忆形式至关重要。我们正在进行的项目之一是确定在工作记忆过程中被脱磷酸化的底物蛋白，其目的是开发可用于治疗工作记忆障碍的代理。

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.

Publications

Publication Information

  • 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.学习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，Dash PK，Pati S. Timp3衰减率神经干细胞，成熟神经元和神经认知功能障碍的丧失在创伤性脑损伤中。Stem Cells，Epub在2015年印刷之前。
  • 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 Neurotrauma32：1608-20，2015。
  • 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 .创伤32:139-48, 2014年。
  • Hylin MJ，Orsi SA，Rozas NS，Hill JK，Zhao J，Redell JB，Moore An和Dash PK。反复轻度闭合头部受伤会损害短期视觉空间记忆和复杂的学习。J Neurotrauma30:716-726, 2013.
  • Hylin MJ, Orsi SA, Moore AN and Dash PK. Disruption of perineuronal net impairs fear conditioning.Learning and Memory20:267-273, 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 Neurotrauma30(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 Disease51:93 - 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，PatiS。糖原合酶激酶-3信号传导途径的参与在TBI病理学和神经认知结果中。PLoS One. 6(9):e24648, 2011.