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Memory, a fundamental tool for our survival, is intimately linked to the way we encode, remember, and respond to external stimuli. Over the past decade, extensive research has focused on memory-coding cells, known as engram cells, and their synaptic connections. Most of this research has focused on excitatory neurons and the neurotransmitter glutamate, emphasizing their interaction between specific brain regions.
To expand the understanding of memory, a research team led by KAANG Bong-Kiun (Seoul National University, Institute of Basic Science) has developed a technology called LCD-eGRASP (local circuit dual-eGRASP) that synapses neural circuits within can label a specific area. brain area. The team applied this new technology to identify the local synaptic connections between inhibitory interneurons and engram cells, shedding light on the role of inhibitory interneurons in memory expression.
The researchers focused on the basolateral amygdala (BLA), an evolutionarily well-conserved brain region in vertebrates known for controlling positive and negative emotions in animals, especially fear. When a fear-related event occurs, neurons that activate at that specific time become engram cells, which encode fear memory. Subsequent activity of these engram cells in the BLA leads to a fear response during the recall of fear memories. The neural structure that allows signal transduction between these engram cells is called synapses, which act as a functional unit of our brain, like individual transistors in semiconductor devices.
Dr. Kaang is one of the leading experts on memory and engrams at the synapse level. In the previous study, his group developed the Dual-eGRASP (Green Fluorescent Protein Reconstruction across Synaptic Partners) technology that can selectively label synapses between engram cells, defined as engram synapses. Dual-eGRASP uses cyan and yellow fluorescence to distinguish synapses formed between presynaptic and postsynaptic non-engram or engram neurons, allowing the identification of four different synaptic combinations simultaneously.
However, this technology has been limited to examining the changes between excitatory neurons and long-range areas of the brain. To overcome this limitation, the researchers further improved Dual-eGRASP to develop LCD-eGRASP, a modified version that can highlight local synaptic connections between neurons in a single area of the brain (Figure 1).
Researchers tested the newly developed LCD-eGRASP in mice. When the fear conditioning paradigm was used to form fear memories, a certain population of inhibitory neurons in the BLA (called somatostatin (SOM) interneurons) were activated during fear memory formation. By applying LCD-eGRASP, the researchers showed that these activated SOM interneurons formed more synapses with the fear engram cells in the BLA.
Furthermore, these specific SOM interneurons showed higher cellular excitability than non-activated SOM interneurons in the neutral context, indicating that the suppression of fear expression occurs through inhibition of fear engram. When the fear memory was recalled, their irritability decreased further. Finally, the artificial activation or inhibition of these activated SOM interneurons resulted in direct and indirect changes in fear memory expression and behavioral responses, suggesting that inhibitory interneurons also play an important role in correct memory recall as part of an engram ensemble.
“We were able to go a step further than the previous study of excitatory engram cells and identify the role of inhibitory interneurons in regulating local brain circuits,” says Dr. Kaang, head of the research team. “This mechanism indicates that fear memories and behaviors are well controlled and appropriately evoked in normal situations based on external stimuli.”
LCD-eGRASP presents new candidates for future research in diseases such as post-traumatic stress disorders, as memory can be controlled by regulating inhibitory interneurons. Dr. Kaang notes: “LCD-eGRASP, which can mark synapses in a local area of the brain, together with Dual-eGRASP, a conventional inter-regional synaptic labeling technology in the brain, will create a core technology in the field of neuroscience.”
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