"Where" and "how" memories are encoded in a nervous system is one of the most challenging and also the most fascinating endeavor in biological research. We aim to investigate the role of neurons, glia and the extracellular matrix in learning and memory processes. It is hypothesized that sensory cues are linked in the brain for making associations and forming long-term memories. Formation of long-term memories between sensory cues requires the participation of molecular switches, such as the NMDAR receptor, a voltage-gated glutamate receptor, that is predominantly located in the postsynaptic membrane. A few years ago, we discovered that primary motor cortex NMDA receptor is necessary for associative learning and memory formation (Hasan et al., Nat Commun 4:2258, 2013). This study demonstrated for the first time that certain forms of memories are formed in the cortex, with possible help from the hippocampus. How hippocampal-cortical and corticocortical circuits prints memories in the brain is an open question. Mechanistically, for multimodal processing, integration of converging synaptic input onto the different dendritic compartments (apical and basal dendrites) engaging both local and distant neuronal circuits is hypothesized to generate a physical substrate of a memory representation or a memory engram. In order to reveal a memory engram, it is imperative to first identify which synaptic connections in different parts of the brain are needed in learning and memory processes (acquisition, consolidation, storage and retrieval). For this purpose, we have developed and applied novel genetic tools based on recombinant adeno-associated viruses (Dogbevia et., Mol Ther Nucleic Acids. 5:e309, 2016) to inducibly and reversibly block synaptic output and synaptic plasticity before learning and after memory consolidation. For identifying cells that are engaged in learning and memory processes, we have developed a method to permanently tag neurons (and possibly glial cells) that are activated during the learning and the consolidation phases. This is a powerful method for activity and genetic manipulation of the identified circuits (neurons and glia) and the extracellular matrix, and will help to tease apart the role of different physical brain components in the learning and memory processes. We are also pursuing projects for high-resolution connectivity mapping the memory circuits. Clearly, a better understanding of learning and memory processes is bound to facilitate the development of novel therapeutic approaches to treat (or even cure) various memory-related brain dysfunctions, such as mental dementia, amnesia and the Alzheimer's disease.
Life & Medical Sciences
- Biosciences & Health