The molecular processes that underlie learning and memory were discovered
Researchers have now discovered the intracellular signal mechanism through which ACh controls aversive Learning, an important screening procedure for AD medication.
Research has shown that donepezil activates the signal cascade to prevent unfavorable learning. These findings suggest that the signaling cascade could contain pharmacological targets.
Unpleasant learning is possible with the help of acetylcholine, a neuromodulator. It is possible to quickly train the senses to become more comfortable with unpleasant smells, tastes, and touches. These learning-related tasks are performed by cells known as D2R+MSNs (D2R+MSNs), found in the NAC. After negative learning experiences, ACh levels in the NAc rise.
Research has shown that ACh stimulates D2R/MSNs via the muscarinic receptor M1R (M1R). This activates the protein kinase C signaling mole, which is then stimulated in response to earlier research.
However, it is not clear how ACh influences aversive learning. This has hampered the development of AD treatments that target ACh intracellular signaling.
Researchers from Fujita Health University’s Prof. Kozo Kaibuchi published a study that explains the molecular mechanisms behind ACh learning, memory and learning.
This has not been done since the discovery of the cholinergic hypothesis in AD 45 years ago. Our research also revealed the intracellular mechanism and effects donepezil had on learning and memory. Yukie Yamashi (assistant professor and principal author of the study), says that this discovery opens up new AD treatments.
Phosphorylation is a process that facilitates molecular signaling cascades. This is where cellular kinases attach phosphate groups to specific substrate molecules. Professor Kozo Kaibuchi developed and disseminated a method called Kinase-oriented Proteomic Analysis that was used by the research team.
The study team was able to confirm ACh’s ability to stimulate PKC through the observation of phosphorylation events following ACh binding ex vivo to M1Rs in animals with striatal/NAc cut. Next came the phosphoproteomic research. It identified 116 possible PKC substrates, which included “bPIX,” which activates small GTPase Rac.
“We discovered that PKC activated bPIX after ACh. This activated a downstream target of Rac, PAK, and made it active. Using passive avoidance tests in mice, we next investigated the role of the discovered ACh-M1R-PKC-Rac-b-PIX-PAK cascade in aversive learning and aversion memory “Dr. Yamahashi explains. The researchers also discovered that donepezil triggers this cascade in order to increase negative learning.
Dr. Yamahashi says this is the first study to show intracellular donepezil processes that control learning and memory.
These results are consistent with a study published by Prof. Kaibuchi in the Journal of Neurochemistry. Dr. Md. published the study for the first time. Omar Faruk has received the Mark A. Smith Award from the International Society for Neurochemistry.
According to a study, KCNQ2, a voltage-gated sodium channel, was implicated in unfavorable learning. PKC phosphorylates KCNQ2’s threonine 217 directly. This phosphorylation site was thought to modulate its channel activity. The NAc phosphorylation event was also increased by the administration of donepezil.
Scientists discovered that M1R–PKC–b-PIX–PAK was involved in associative learning and recognition memory. This is significant because it provides a platform to screen for new AD medicines.
Our phosphoproteomic data revealed many other PKC substrates including postsynaptic scaffold protein and presynaptic protein, which are registered in a database called KinaseAssociated Neural PHOsphossignaling. We remained focused on bPIX and elucidating the M1RPKC-PAK pathway (KANPHOS).
Dr. Yamahashi says that they are only looking at the tip end of an iceberg when it comes to the future prospects for their research.
The latest news about memory, learning
Acetylcholine is essential for memory and learning. Donepezil, a cholinesterase inhibitor, increases brain acetylcholine. This lowers the chance of Alzheimer’s disease (AD)-associated learning disabilities.
Acetylcholine (M1R) activates the D2-expressing medium spiny neuron (D2R -MSNs) of the striatal/nucleus incumbents dopamine receptor D2-expressing dopamine receiver. These neurons control unpleasant learning via the muscarinic receptors. It is not clear how acetylcholine promotes learning beyond the M1Rs.
We discovered that mouse striatal/nucleus PKC (acetylcholine-stimulated protein kinase C) was activated. Our initial kinaseoriented phosphoproteomic investigation identified 116 potential PKC substrates. This included b–PIX, a Rac1 activater. Acetylcholine activated Rac1-activated kinase p21 through activating bPIX phosphorylation. (PAK).
In mice, D2R/MSNs triggered the M1R/PKC/PAK pathway by activating aversive stimuli. Cre-Flex controlled PAK mutations in D2R/MSNs. This controlled aversive learning, as well as dendritic structure and plasticity. Donepezil promoted PAK activity in the CA1 and accumbal areas of the D2R–MSNs of the hippocampus. This increased D2R–MSN-mediated learning.
These results show that acetylcholine activates M1R-PKC-b-PIX-Rac1-PAK signalling for unpleasant learning in D2R-MSNs and suggest the cascade’s therapeutic potential for AD since aversive learning is utilised to assess prospective AD treatments.
