Anna Dobretsova
Research Assistant Professor
Ph.D., University of Arkansas for Medical Sciences
Office: (501) 686-5211
Lab:      (501) 686-5367
Email: dobretsovaanna@uams.edu

The focus of my research is to study pathological processes leading to abnormalities during CNS development, particularly with regard to psychiatric diseases like schizophrenia and major depression. Schizophrenia is a human disease of unknown etiology that affects the integrity of brain function and is associated with inability to process sensory information and hallucinations.  Current hypothesis for schizophrenia suggests that environmental insults in combination with genetic factors may result in the abnormal CNS development and ultimately in the disease.  Mature CNS structures are dynamically established during development, and exhibit complex interactions between neurons and non-neuronal cells.  Oligodendrocytes represent an essential non-neuronal component of CNS by providing trophic support and myelin ensheathing of mature axons, which is required for saltatory conduction of neuronal impulses (very rapid unidirectional propagation of neuron-generated electrical signal to the target).  Myelin composition is characterized by presence of a small set of myelin-specific proteins.  Examination of cortical areas of human post-mortem brains revealed sharp decrease in expression of number of myelin-specific genes by microarray analysis and reduced numbers of myelinating oligodendrocytes by immunohistochemistry in patients diagnosed with schizophrenia, bipolar disorder and major depression.  In addition, changes in myelin structure were detected in schizophrenic patients by magnetic resonance imaging.  Thus, it is becoming evident that impairment of normal CNS myelin constitutes an essential pathogenic component of the psychiatric diseases.  We hypothesize that schizophrenia-like symptoms occur due to the impairment of axon-oligodendrocyte interactions, delayed maturation of oligodendroglia and subsequent production of immature myelin.  In order to understand the mechanisms of myelin pathology in schizophrenia and related disorders it is important to monitor oligodendrocyte differentiation during the impaired CNS development.  For many other myelin-related disorders the use of animal models has been proven successful for understanding mechanisms of pathology in oligodendroglial cells.  There is no animal model that would reproduce all symptoms of schizophrenia.  Drugs of abuse, like PCP, are often used to model certain measurable symptoms of schizophrenia in animals.  Reduction of myelin gene expression was noted in the cortex of adult rats chronically treated with PCP-like drug MK-801.  However, the model that recapitulates an insult to CNS during critical period of development will be more useful to study abnormalities in the formation of myelin.  One model utilizes sub-chronic perinatal PCP administration to developmentally induce schizophrenia-like symptoms in adult rats.  The most prominent manifestation of treated animals is the impaired ability to process sensory information, which can be measured by the decreased inhibition of the acoustic startle reflex by a non-startling stimulus.  Importantly, the same paradigm is regarded as a prominent positive symptom of schizophrenia.  Moreover, perinatally treated animals are responsive to antipsychotic drugs like olanzapine.  We propose to use the developmental PCP rat model to study dynamics of myelination in the brain and to examine the correlation between abnormalities in sensorimotor gating and oligodendrocyte differentiation.

 Representative Publications

Dobretsova A., Kokorina N.A., and Wight P.A. (2004) Potentiation of myelin proteolipid protein (Plp) gene expression is mediated through AP-1-like binding sites. J. Neurochem. 90:1500-1510.

Wight P. A. and Dobretsova A. (2004) Where, when and how much: regulation of myelin proteolipid protein gene expression. Cell. Mol. Life Sci. 61:810-821.

Li S., Moore C.L., Dobretsova A., and Wight P.A. (2002). Myelin proteolipid protein (Plp) intron 1 DNA is required to temporally regulate Plp gene expression in the brain. J. Neurochem. 83:193-201.

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