Neurogenesis and Memory: How Exercise Rewires the Brain in Mice

PTSD is a mental health condition that can be triggered by experiencing or witnessing a traumatic event, such as a natural disaster, serious accident, or attack. Globally, approximately 3.9% of the general population suffers from PTSD, which is characterized by intense flashbacks and avoidance behaviors, such as avoiding places or people that remind them of the traumatic event. At present, PTSD is commonly treated with therapy or medications like anti-depressants. However, since many individuals don’t respond well to these treatments, researchers are exploring alternative options.

In a recent study on mice, Assistant Professor Risako Fujikawa from Kyushu University’s Faculty of Pharmaceutical Sciences, along with her former supervisor Professor Paul Frankland from the University of Toronto, and their team, including Adam Ramsaran, investigated how the formation of new neurons, known as neurogenesis, in the hippocampus affects the ability to forget fear memories. The hippocampus is a brain region that plays a crucial role in forming memories associated with specific places.The dentate gyrus, an area in the brain, constantly produces new neurons, a process known as neurogenesis. According to Fujikawa, this process is not only important for forming new memories, but also for forgetting old ones. The integration of new neurons into neural circuits leads to the creation of new connections and the loss of older ones, which can disrupt the ability to recall memories. Researchers wanted to investigate whether this process could help mice forget strong, traumatic memories as well. In their study, mice were given two strong shocks in different settings, which included being shocked after leaving a brightly-lit, white box and entering a dark, ethanol-scented environment.The mice exhibited PTSD-like behaviors after receiving the second shock in a different environment. Even after a month, the mice continued to show fear and hesitation when entering the original dark compartment, indicating an inability to forget the traumatic memory. This fear also extended to other dark compartments, leading to a generalized sense of fear. In addition, the mice showed signs of anxiety by exploring less in open spaces and avoiding the center.

To alleviate these PTSD-like behaviors, the researchers investigated the effects of exercise, which previous studies had shown to increase neurogenesis. The double-shocked mice were then divided into two groups, with one group undergoing exercise.The researchers found that mice with access to a running wheel showed increased numbers of newly-formed neurons in their hippocampi after four weeks, and their PTSD-like behaviors were less severe compared to mice without wheel access who were double-shocked. In addition, mice that were able to exercise before the second shock also showed a prevention of some PTSD-like behaviors. However, the researchers noted that it wasn’t clear whether the effects of exercise were specifically due to hippocampal circuit rewiring by neurogenesis, or if other factors were at play due to the various impacts of exercise on the brain and body.Before conducting the study, the researchers employed two different genetic methods to evaluate the effects of integrating newborn neurons into the hippocampus. Firstly, they utilized optogenetics, a technique that involved introducing light-sensitive proteins to recently formed neurons in the dentate gyrus. This allowed the neurons to be activated by light. The results showed that when blue light was applied to these cells, the new neurons underwent a faster maturation process. After a span of 14 days, the neurons exhibited increased length, more branches, and a quicker integration into the neural circuits of the hippocampus. In the second approach, the research team used genetic modification to eliminate a specific protein in the ne.The scientists used genetic methods to inhibit the activity of a protein that hinders the growth of new neurons, resulting in faster growth and increased integration of neurons into neural circuits. These genetic approaches reduced PTSD-like symptoms in mice and shortened the time it took for them to forget fearful memories. However, the effects were not as strong as those seen with exercise and did not decrease anxiety levels in the mice. Fujikawa suggests that the creation of new neurons and the restructuring of hippocampal circuits may disrupt fearful memories but have less impact on mood or emotions compared to exercise.

The scientists also investigated whether the increased production of new brain cells and remodeling of the hippocampus could also be beneficial in addressing other mental disorders in which memory is a key factor, such as substance use disorders. For individuals struggling with drug addiction, relapse often occurs when cues, such as being in an environment where the drug was previously used, trigger intense cravings.

To conduct their study, the researchers placed mice in a two-room cage. In one room, the mice were given a saline solution, while in the other room, they were given cocaine.When given the choice, the mice preferred the room where they had been given cocaine. However, when the researchers used exercise and genetic methods to enhance neurogenesis and hippocampus re-modeling, the mice no longer showed a preference for the cocaine room, indicating that they had forgotten the connection between the room and the drug. In future studies, Risako aims to discover a drug that can enhance neurogenesis or hippocampus re-modeling, with the goal of testing it as a potential treatment for PTSD and drug dependence. She also emphasizes the need for further research in this area.

Exercise was found to have a significant impact on reducing symptoms of PTSD and drug dependence in mice, according to Risako. Clinical studies in humans also support the effectiveness of exercise in addressing these issues. Risako believes this is the most important finding from their experiments.