IBioBA produced a new contribution to scientific knowledge: a paper was published in the journal Cell Reports on the role of acetylcholine in enhancing synaptic plasticity that helps to understand how memory is produced.
Recently published in the journal Cell Reports, the paper “Cholinergic modulation of dentate gyrus processing through dynamic reconfiguration of inhibitory circuits”, led by Mora Ogando under the direction of Antonia Marin-Burgin, describes the mechanism by which acetylcholine increases synaptic plasticity leading to long term potentiation.
From this study, the team found that in the hippocampus, acetylcholine – a neurotransmitter related to the consolidation of memories, learning, the action of some muscles and the perception of pain – disinhibits, for a moment, the excitatory neurons. This is why it is easier for synaptic plasticity phenomena to occur, which are ultimately what make it possible to form memory. “In other words, what we saw is that the synapses that were just activated when the acetylcholine was released are potentiated and this potentiation remains over time“, says Marin-Burgin.
The central role of the hippocampal dentate gyrus in memory formation
The working group led by Antonia Marin-Burgin has been studying for several years the mechanisms of the ‘gateway’ to the hippocampus: the dentate gyrus. This region, responsible for receiving information from the cortex, plays a fundamental role in memory formation. It is in this key place where neurogenesis occurs, that is, the birth of new neurons – called granule cells (GCs) – in the adult brain, a mechanism that they have been studying for many years in the laboratory.
However, the published paper did not perform experiments on new neurons because during the research process they began to glimpse the effect of cholinergic neuromodulation on mature neurons: the hippocampus receives signals from the septum, a cholinergic region, i.e. it has neurons that release acetylcholine.
“We wondered what happens to the other 95% of neurons, the mature neurons: these neurons are normally tightly controlled by inhibitory neurons, which regulate their activity and prevent processes of exacerbated activity as for example during epilepsy. However, in this study we found that at certain times, such as when acetylcholine is released, this strict inhibitory control is turned off and allows the activity of granule cells to increase in the presence of stimuli, i.e., in the presence of acetylcholine, mature neurons acquire properties similar to those of immature neurons”, explains Mora.
There’s a match!
The research group detected a coincidence: they saw that if a stimulus is received at the same moment in which acetylcholine is released, it is much more likely that the memory of that stimulus is fixed. “So this is important because it is known that acetylcholine is released in situations in which animals are alert, it is a signal to remember what happens at a given moment. And what we saw is a more cellular and synaptic mechanism of how this could occur, well, it happens because there is a disinhibition of the excitatory neurons and this makes the stimuli that arrive at the same moment to be fixed”, expresses Antonia.
In summary: in order to form new memories we need plasticity in the synapses, and this plasticity is favored when there is acetylcholine and there is a mechanism of disinhibition of the excitatory neurons.
The method of study: optogenetics
This work, which took about four years of research and many experiments, was mainly based on molecular, pharmacological and electrophysiological techniques in living brain tissue to observe the microcircuitry of the dentate gyrus. The technique that allowed them to act on such a specific sector of the brain was optogenetics: they used light-activated proteins in the neurons that release acetylcholine. Thus, they measured the activity of different neurons in response to afferent stimuli and studied what changed when they activated the release of acetylcholine by illuminating the brain tissue with blue light. “What we saw was that mature neurons in the dentate gyrus of the hippocampus responded more to strong stimuli and also enhanced their synapses”, says Ogando.
The mechanism discovered by the team, on the modulatory role of acetylcholine in hippocampal activity, which allows increasing its response and enhancing its synapses, is something very novel “and could enable, in the future, the design of more specific drugs”, imagines Antonia. It is interesting to mention that in Alzheimer’s disease, memory formation is altered, and one of the few treatments that exist are drugs related to the increase of acetylcholine. “This work contributes to the understanding of the mechanisms by which acetylcholine can favor memory formation. One might think, then, that stimuli that occur when the brain releases acetylcholine are the most likely to be remembered”, concludes Mora.
The following also participated in the research: Olivia Pedroncini, Noel Federman, Sebastián A. Romano, and Damián Refojo from the IBioBA – CONICET – Max Planck; and Luciano A. Brum and Guillermo M. Lanuza from the Fundación Instituto Leloir – Instituto de Investigaciones Bioquímicas de Buenos Aires – CONICET.
This work is part of the neuroscience research line of IBioBA, which aims to elucidate the development and function of neural circuits involved in behavior based on genetic, molecular, cellular, behavioral and circuit analysis; and specifically belongs to the study area of stimulus processing in the dentate gyrus of the hippocampus. If you want to know more click here.