Genes & Memory: Signaling Networks Evoking Gene Expression Responsible for Formation of Memory
Long-term memory formation is related to multiple signal transduction pathways, delivering information from synapses to the neuron nucleus to alter gene expression pattern, cAMP-PKA-CREB pathway is one of the most widely studied signaling network. However, multiplicity of structural and functional changes occurring during long-term memory formation, e.g. late LTP, synapse consolidation, new synapse formations and de novo protein synthesis, cannot be explained only via limited number of signaling mechanisms. Hence, this project is design to determine the key regulatory proteins involved in signal transduction from synapses towards the nucleus during the memory formation process.
AKT & LTP: Non-canonical Pathway of the Membrane-tethered AKT1 Kinase in LTP Expression Regulation
The Serine/Threonine kinase AKT/PKB is involved in neuronal cell development, axonal growth and synaptic plasticity. Previous studies revealed a critical role of AKT in long-term plasticity and dendritic architecture. Multiple upstream activators of AKT signaling have an essential role in neuronal plasticity and memory formation. Particularly, BDNF-dependent AKT phosphorylation in hippocampus correlates with spatial memory formation, whereas in the amygdala AKT phosphorylation is associated with long-term potentiation (LTP) and fear conditioning. AKT is a connecting link in the PI3K-mTORC pathway, associated with late phase LTP (L-LTP). PI3K activity is necessary for spinogenesis, persistence of L-LTP, protein synthesis and AMPA receptor (AMPAR) insertion during the L-LTP. Activation of the PI3K/AKT/GSK3 pathway increases synaptogenesis and spinogenesis and enhances learning formation. Phospho-AKT in tandem with APPL1 is involved in spine formation. APPL1 increases the amount of active AKT in spines and synapses, and modulates AKT activity. A crucial role in regulation of L-LTP and long-term memory was demonstrated for AKT downstream effector, mTORC1, a key regulator of protein de novo synthesis. In contrast to L-LTP, evidences for the role of AKT signaling in regulation of early phase LTP (eLTP) are scarce. AKT phosphorylation time-course correlates with expression of eLTP. Scavenging of PIP3, an essential factor of AKT activation, blocks eLTP. Moreover, PI3K affects induction, expression and maintenance of eLTP. Phosphorylation of GSK-3β during LTP by the AKT inhibits long-term depression (LTD). In the NMDAR-dependent LTD, PP1 dephosphorylates and caspase-3 cleaves AKT, activating GSK3β, which sustains LTD. Hence, GSK3β is involved in downregulation of AMPARs. In contrast, a very recent finding supporting this idea shows that AKT downstream effector, PIP5K2A regulates GluR1 expression. Several other studies indicate the importance of PI3K and AKT in AMPARs upregulation.
ABL in Synapses: Abelson Kinase Family in Regulation of Synpatic Activity and Plasticity
Abelson (Abl) non-receptor tyrosine kinases act in the cytoplasm to coordinate remodeling of actin microfilaments in response to appropriate stimuli. The Abl kinase family contains Abl-1 and Abl-2 (Arg- Abl related gene) proteins, which play multiple roles in the CNS, including neurulation and neurite outgrowth. Abl was shown to localize in the synaptic compartment on both sides of the synaptic cleft, at presynapses and dendrite spines, being particularly prominent at post-synaptic densities (PSD).
In the hippocampus, Abl-1 modulates neurotransmitter release at Schaffer collateral–CA1 synapses, inhibits NMDA receptors downstream to the PDGFb receptor and co-localizes with PSD95, regulating its clustering by tyrosine phosphorylation. Abl kinases modulate short-term synaptic plasticity, while Rin1, an upstream regulator of Abl-1, affects long-term synaptic plasticity and impairs conditioned fear extinction. Moreover, Rin1-null mice showed normal long-term depression, but enhanced depotentiation, which was impaired by introduction of an Abl kinase inhibitor. Loss of Abl-interactor (Abi), involved in Abl kinase signaling, leads to abnormal dendritic spine morphology and density, as well as a severe deficit in short- and long-term memory. Furthermore, Abl was shown to be involved in the pathogenesis of Alzheimer's disease (AD): subcellular distribution of Abl kinases in the hippocampus was shown to be altered in AD patients, while amyloid Ab-peptide and reactive oxygen species were both shown to activate Abl kinase. Moreover, the Abl kinase inhibitor, STI571 (Imatinib), prevents Abl/p73 signaling pathway- related apoptosis, microtubule associated Tau protein hyper-phosphorylation and was found to decrease the production of amyloid species by inhibiting gamma-cleavage of the amyloid precursor protein's C-terminal fragment (APP-CTF).
Stress & Cognition: 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.
Terahertz & Folding: Non-Ionizing Electromagnetic Radiation Impact on Protein Misfolding and Neurodegenerative Diseases
Terahertz (THz or TH) band is non-ionizing electromagnetic radiation (NIER) lying between microwave and infrared rays wavelengths. TH radiation is useful in medical diagnostics, petrochemical, aerospace industries, security and scientific research. In medical field, TH radiation sensitivity to the molecular properties of biological tissue, from cell hydration to conformation states of important biomolecules, has spurred development of new TH-based approaches to cancer diagnosis. TH pulsed imaging was demonstrated to succeed in detection of breast cancer, melanoma and basal cell skin carcinoma. The first in vivo trials of TH imaging as an intra-operative tool during cancer surgery are currently underway. The TH spectral region of 0.1-10 THz NIER has been demonstrated to have a great potential as diagnostic and treatment tool in different fields of medicine. On the physical level, energy delivered by TH waves induces atoms’ vibrations, incapable to degrade biomacromolecules, such as nucleic acids and proteins. However, theoretical research suggests that picosecond TH pulses may enhance hydrogen bonds vibrations leading to openings between the DNA strands, subsequently triggering an increase in the multiple tumor suppressor proteins levels, ceasing cell-cycle progression. This strategy could be beneficial in ceasing of tumorogenesis and subsequently in cancer therapy. Moreover, TH waves exhibit a potential affecting protein folding dynamics, deterioration of which is the major hallmark of a wide range of diseases, particularly of the most neurodegenerative diseases.
Quantum Brain: Quantum Model of Memory and Neural Information Processing
This project is at its initial phase of development. This is completely alternative view of understanding of information processing and storage by the neural system. This approach dismisses classical understanding of information processing inferred from computational sciences to neuroscience. It creates a new idea of the neural system activity, as energetic “fingerprints” impressed “the information”. According to this new logic the information flow in the neural system as perturbations in the miniature electric fields (nanofields) energetic state , generating “information elementary particles”, infotrons, as brain analogs of “computer bits”, while the properties of the infotron can be described by a wave function. The new perception relies on postulates (P), new term definitions and two central hypotheses: