Molecular Mechanisms Linking Early Occurring Cognitive Impairment, Stress and Depression (in collaboration with Prof. Albert Pinhasov)
Aging-related cognitive impairment is associated with decline of episodic memory and cognitive function. These signs are also the earliest and perhaps most sensitive marks of emerging Alzheimer's disease (AD) at the preclinical stage. AD, a devastating neurodegenerative disorder of unclear etiology is an age-related, nonreversible brain disorder developing over a period of years and is characterized by memory loss and cognitive degradation. A cross-sectional study of psychiatric symptoms among AD patients demonstrate high rates of depression and showed that it was one of the earliest neuropsychiatric abnormalities to develop. The behavioral disturbances exhibited in neurodegenerative and affective disorders are coupled to changes in the central nervous system and share common molecular mechanisms. These changes differ by their mechanism of action, disease severity, long-term consequences and thereby influence prognosis. It is possible to observe similar symptomatology during different stages of disease development such as memory deficits, reduction in learning abilities and difficulties in adaptation. Moreover, diminishing neurotrophic factors and neuroinflammation observed in depression are associated with the development of AD. It is known that genetic and molecular alterations in the metabolism of acetylcholine and other neurotransmitters cause neurodegenerative alterations resulting in affective disturbances.
In our Laboratory
Findings
Our collaborator, Prof. A. Pinhasov (http://www.ariel.ac.il/research/brain), developed animals with strong dominant (Dom) and submissive (Sub) phenotypes. Sub mice with strong and stable submissive behavior show robust depressive-like phenotype in different behavioral paradigms. Moreover, these animals exhibit strong cognitive deterioration occurring earlier in age, as was found in eight arm radial maze spatial reference memory paradigm and new object recognition non-spatial memory paradigm. Cognitive impairments were found to be accompanied with significant changes in short and long-term synaptic plasticity, different patterns of electroencephalography (EEG). Dramatic difference in mRNA and protein expression profiles were observed between Dom, Sub and wild type (wt) mice. These changes clearly correlated with enhanced expression of synapsin 2b on the presynaptic and GluR1 subunit of AMPA receptors on the post-synaptic level in Sub mice vs wt and Dom counterparts.
Plans
In this research, we focus on study the molecular and functional background underlying aging-related cognitive impairment accompanying depressive-like behavior, which may share pathogenesis with AD. We investigate the link between alteration of the presynaptic synapsin 2b level vs functional and behavioral expression of submissiveness. Further, we investigate which proteins and protein complex may be involved in mediation of synapsin 2b effect on depressive behavior. On the other hand, we also investigate the role of AMPA receptors expression and their different subunit configuration in cognitive impairment and depressive-like behavior. Moreover, utilizing a multidisciplinary approach, we also 1) study the functional and behavioral profile of aging-related cognitive impairments associated with depression and 2) investigate genetic and molecular candidate biomarkers of aging-related cognitive impairments associated with depression.
Projects
All projects will be conducted in collaboration with Prof. Pinhasov
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Elucidation of presynaptic mechanism of early cognitive impairment and depressive-like behavior (Ph.D or Post-Doctoral position, S001)
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Elucidation of postsynaptic mechanism of early cognitive impairment and depressive-like behavior (Ph.D or Post-Doctoral position, S002)
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Identification intracellular signaling pathway responsible for depressive like behavior and cognitive impairments (Ph.D or Post-Doctoral position, S003)
Related References from our Lab
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Gross M, Sheinin A, Nesher E, Tikhonov T, Baranes D, Pinhasov,A, Michaelevski I Early onset of cognitive impairment is associated with altered synaptic plasticity and enhanced hippocampal GluA1 expression in a mouse model of depression Neurobiology of aging. 2015 May;36(5):1938-52. doi: 10.1016/j.neurobiolaging.2015.02.015
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Nesher E, Koman, I, Gross M, Tikhonov T, Bairachnaya M, Gerliz G, Michaelevski I, Yadid G, Pinhasov A. Synapsin IIb as a functional marker of submissive behavior Scientific Reports 2015 May 22; 5:10287. doi: 10.1038/srep10287
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Borovok N, Nesher E, Reichenstein M, Levin Y, Tikhonova T, Pinhasov A and Michaelevski I.& Hippocampal protein expression alteration in depression mice models in naïve vs. stress conditions Molecular and cellular proteomics (Revised version on evaluation, Mol Cell Proteomics)
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Reichenstein M, Nesher E, Borovok N, Levin Y, Tikhonova T, Pinhasov A, Michaelevski I& Protein expression profiles changes in striatum during acquisition of the reference spatial memory (in preparation).