The complex changes needed to adapt normal cognitive functions to altered internal and external conditions are achieved mostly via gene regulation, through highly regulated transcriptional and post-transcriptional events.
My research program focuses on the molecular events that underlie the plasticity of the brain in face of stress and neurological insults, bridging the gap between the gross physiological effects, and the molecular and cellular events that underlie them.
Our current research focuses on 3 main projects:
Hormonal regulation of adult neurogenesis in the dentate gyrus.
We aim to determine the environmental and internal cues that control fate choices of stem cells, and the role of gene expression and RNA processing in the translation of those cues to fate decision made by the stem cell. Specifically, we are looking at the effects of stress and steroid hormones on hippocampal neuroprecursor cells, and try to manipulate them using gene delivery methods.
Hormonal regulation of alternative splicing in neuronal and organismal stress responses.
We have previously identified alternative splicing as causally involved in the stress-induced changes in the cholinergic balance. We now intend to study the general role of RNA regulation, and particularly alternative splicing, in the brainÃ•s response to stress.
The molecular mechanisms underlying BBB opening and its consequences.
The central nervous system microenvironment is normally isolated from elements circulating in the blood by the blood-brain-barrier (BBB). Common brain insults are associated with compromise of the BBB. The consequences of BBB compromise and the resultant exposure of the brain to serum components, specifically albumin, were shown recently to induce epileptogenesis. We follow changes in gene expression in the cortex following BBB compromise, during the epilptogenesis time window, and correlate them with electrophysiological measures of pathology to delineate the mechanism underlying this pathology, and identify potential therapeutic targets.
The tools we apply for this research include molecular, cellular and imaging techniques, and through collaborations with other labs we extend these tools to include also behavioral, electrophysiological and high-throughput methods.
Kaufer D., Ogle W.O., Pincus, Z.S., Clark K.L., Nicholas A.C., Dinkel K.M., Dumas T.C., Ferguson D., Lee A.L., Winters, M.A., Sapolsky, R.M. (2004) Restructuring the neuronal stress response with anti-glucocorticoid gene delivery. Nature Neurosci. 7:947-953.
Meshorer, E., Erb, C., Gazit, R., Ben-Arie, N., Pavlovsky, L., Kaufer, D., Friedman, A., and Soreq, H. (2002) Stimulus-induced alternative splicing and modulated neuritic mRNA translocation promote neuronal hypersensitivity. Science 295:508-12.
Tomkins, O., Kaufer, D., Korn, A., Shelef, I., Golan, H., Reichenthal, E., Soreq, H., Friedman, A. (2001) Frequent blood-brain barrier disruption in the human cerebral cortex. Cell Mol Neurobiol 21:675-91
Shohami, E., Kaufer, D., Chen, Y., Cohen, O., Ginzberg, D., Melamed-Book, N., Seidman, S., Yirmiya, R. and Soreq, H. (2000) Antisense prevention of neuronal damages following head injury. J Mol Med 78:228-236
Kaufer, D., Friedman, A., Seidman, S. and Soreq, H. (1998). Acute stress facilitates long-lasting changes in cholinergic gene expression. Nature, 393:373-376
Friedman, A., Kaufer, D., Shemer, J., Hendler, I., Soreq, H. and Tur-Kaspa, I. (1996). Pyridostigmine brain penetration under stress enhances neuronal excitability and induces early immediate transcriptional response. Nature Med. 2:1382-1385