Mice Studies Shed Light on Serotonin and Memory

Memory regulation in humans and animal models is regulated by the serotonin 2C receptor in the brain, according to research from Baylor College of Medicine, the University of Cambridge in the United Kingdom, and affiliated institutions.

The results, which were published in the journal Science Advances, offer fresh perspectives on the elements that affect both healthy memory and memory-related disorders like Alzheimer's disease. The scientists also propose innovative treatment approaches.

Serotonin, a compound produced by neurons in the midbrain, acts as a neurotransmitter, passing messages between brain cells. Serotonin-producing neurons reach out to multiple brain regions including the hippocampus, a region essential for short- and long-term memory.”

Dr. Yong Xu, Co-Corresponding Author and Professor, Department of Pediatrics – Nutrition, Baylor College of Medicine

Dr. Yong Xu is also the Associate Director for Basic Sciences at the USDA/ARS Children’s Nutrition Research Center at Baylor.

Serotonin binds to receptors on the surface of brain cells to send signals that instruct the receiving cell to perform a specific action. The Xu lab, which specializes in basic and genetic animal studies, and the human genetics lab of co-corresponding author Dr. I. Sadaf Farooqi, a Professor of metabolism and medicine at the University of Cambridge, investigated the function of serotonin 2C receptors in memory in both human and animal models. Serotonin 2C receptors are widely distributed in the brain’s ventral hippocampal CA1 region (vCA1).

We had previously identified five individuals carrying variants of the serotonin 2C receptor gene (HTR2C) that produce defective forms of the receptor. People with these rare variants showed significant deficits on memory questionnaires. These findings led us to investigate the association between HTR2C variants and memory deficits in animal models.”

Dr. I. Sadaf Farooqi, Professor, Department of Metabolism and Medicine, University of Cambridge

The group manipulated mice's genetic makeup to resemble human mutation. When these mice were subjected to behavioral tests to assess memory, the researchers discovered that, in comparison to the unmodified mice, both male and female mice with the non-functional gene had lower memory recall.

When we combined the human data and the mouse data, we found compelling evidence connecting non-functional mutations of the serotonin receptor 2C with memory deficits in humans.”

Dr. Yong Xu, Co-Corresponding Author and Professor, Department of Pediatrics – Nutrition, Baylor College of Medicine

The group was able to learn more about how the receptor modulates memory thanks to the animal models. They found a brain circuit that starts in the midbrain, which is home to neurons that produce serotonin. The vCA1 region, which has a large number of serotonin 2C receptors, is where these neurons project.

Xu said, “When neurons in the midbrain reaching out to neurons in the vCA1 region release serotonin, the neurotransmitter binds to its receptor signaling these cells to make changes that help the brain consolidate memories.”

Crucially, the researchers also discovered that an Alzheimer's disease-related mouse model exhibits impairments to this serotonin-associated neural circuit.

Xu said, “The neural circuit in the Alzheimer’s disease animal model cannot release sufficient serotonin into the vCA1 region that would need to bind to its receptor in the downstream neurons to signal the changes required to consolidate a memory.”

By giving a serotonin analog, such as lorcaserin, which selectively activates the serotonin 2C receptor in these cells, one can circumvent this serotonin deficiency and directly activate the downstream serotonin receptor.

Xu said, “We tested this strategy in our animal model and were excited to find that the animals treated with the serotonin analog improved their memory. We hope our findings encourage further studies to evaluate the value of serotonin analogs in the treatment of Alzheimer’s disease.”

Source:
Journal reference:

Liu, H., et al. (2024) Neural circuits expressing the serotonin 2C receptor regulate memory in mice and humans. Science Advances. doi.org/10.1126/sciadv.adl2675

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