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Muscle contractions release chemical signals that promote brain network development

Chemical signals from contracting muscles can influence the growth of brain networks, according to new research published in Neuroscience.

Eric W Dolan, PsyPost, Jun 2, 2023

The study highlights the importance of physical activity to mental health, and the findings could also help contribute to the development of more effective treatments for cognitive disorders such as Alzheimer's disease.

Previous studies had shown that exercise has significant benefits for cognitive health, even when initiated at late stages in life. Exercise has been associated with long-term changes in the hippocampus, a brain region crucial for learning and memory, including increased neurogenesis, synaptogenesis, and enlarged volume.

However, the specific mechanisms through which exercise produces these changes in the hippocampus were not well understood. By uncovering these mechanisms, the authors behind the new study aim to develop exercise-based treatments for cognitive pathologies that affect the hippocampus, such as Alzheimer's disease, stress, depression, anxiety, and normal aging.

"I was initially drawn to this topic due to my fascination with the intricacies of the human brain and mind," explained study author Ki Yun Lee, a PhD candidate in the Department of Mechanical Science and Engineering at University of Illinois at Urbana-Champaign.

"The fact that many principles I regularly encounter, such as those in machine learning and deep learning, originate from the remarkable workings of the brain further piqued my interest. With substantial portions of the brain still remaining unexplored, I was eager to delve into its complexities and gain insights by reverse engineering its processes."

"Specifically, I wanted to understand the brain's interactive nature with the environment during periods of activity. Consequently, studying the effects of exercise on the brain became a captivating starting point in my journey to unravel the mysteries of the brain and mind."

To investigate the interactions between contracting muscle cells and hippocampal cells, the researchers used an in vitro approach. They isolated muscle cells from mice and cultured them in the lab. When these muscle cells matured, they spontaneously started contracting, releasing compounds into the culture medium. The researchers collected the conditioned media containing these compounds and applied it to primary cultures of hippocampal cells, which included neurons and astrocytes.

Astrocytes are a type of glial cell, which are non-neuronal cells that provide support and functionality to neurons in the brain and spinal cord. Astrocytes are the most abundant type of glial cell in the central nervous system.

The study aimed to determine whether the conditioned media from contracting muscle cells influenced the function and maturation of hippocampal neuronal networks. Additionally, the researchers wanted to investigate the role of astrocytes in transmitting the signals from muscle contractions to the activity of hippocampal neuronal networks.

The researchers employed various techniques, such as immunofluorescent and calcium imaging to assess cell growth and multi-electrode arrays to record neuronal electrical activity, to examine the effects of the chemical signals on the hippocampal cells.

The findings of the study suggest that muscle contractions release factors that can directly influence hippocampal cells involved in cognition. Lee and his colleagues observed that exposure to these chemical signals resulted in the more rapid maturation of the hippocampal neuronal network.

Specifically, the hippocampal neurons exposed to these chemical signals showed increased synapse development and synchronous neuronal activity, indicating a more mature and organized network. The proliferation of astrocytes, a type of glial cell, increased 4.4-fold and the proliferation of neurons increased 1.4-fold.

"The study's findings, when considered alongside existing research, provide compelling evidence that exercise benefits not only physical health but also cognitive health," Lee told PsyPost. "The results indicate that chemical signals released by contracting muscles play a significant role in promoting the development of hippocampal neurons, which are essential for learning, memory, and the formation of neural networks."

"Additionally, the study highlights the critical involvement of astrocytes, the supportive cells of neurons, in mediating the impact of exercise on neuronal activity. This suggests that maintaining a balance between neurons and astrocytes is crucial for optimal brain function."

"These findings emphasize the importance of adopting a holistic approach to brain health, considering not only the well-being of neurons but also the supportive role of astrocytes," Lee explained. "By incorporating lifestyle factors such as balanced diet and exercise, individuals can potentially optimize their brain function and overall well-being."

To understand the role of astrocytes in the increased spike rate observed in response to the chemical signals, the researchers conducted an experiment using primary hippocampal cell cultures with reduced astrocyte populations. They found that astrocytes played a critical role in mediating the effects of exercise by regulating neuronal activity and preventing excessive excitability.

"I was particularly surprised by the significant role of astrocytes as regulators of neuronal activity, which had previously been overlooked. In our in vitro cell cultures, when we removed astrocytes, we observed the neurons became hyperexcitable," Lee said.

"However, this hyperexcitability was effectively mediated when we reintroduced either astrocytes themselves or the chemical factors released by astrocytes. This finding has opened up exciting new possibilities for further exploration, understanding, and potential treatment of neurological disorders, such as epilepsy, where hyperexcitability of neurons is a primary factor."

In future studies, the researchers plan to explore the communication between muscle cells and hippocampal cells in more detail. They also want to identify the specific substances released by contracting muscles that have an impact on the growth and maturation of hippocampal neurons. This information could be used to develop treatments that replicate the cognitive benefits of exercise even without physical activity.

"While this in vitro study has the advantage of isolating and investigating specific components of the body, such as muscles, it is important to acknowledge a major distinction between the in vitro model and the whole organism," Lee told PsyPost. "In the brain, astrocytes form the blood-brain barrier, which acts as a selective filter for substances from the blood that can reach neurons. However, in the in vitro model, there is no blood-brain barrier, allowing muscle factors to directly influence neurons.

"Despite this disparity, our in vitro model demonstrated that astrocytes responded more significantly to muscle signals compared to neurons, indicating a role consistent with that of the blood-brain barrier. Furthermore, the model successfully reproduced key phenomena observed in the whole organism, including neurogenesis, synaptogenesis, and astrogliogenesis (- genesis means formation). These findings suggest that both the in vitro model and the whole organism likely operate through a similar underlying mechanism."

Understanding how muscle contractions affect the growth and regulation of hippocampal neurons could lead to better exercise-based treatments for cognitive disorders like Alzheimer's disease.

"I would like to mention that our research into the effects of chemical cues from contracting muscle cells on neurons and astrocytes has yielded valuable insights into the intricate workings of the brain," Lee said. "As we move forward, we are expanding our study to incorporate an engineering perspective. While I am unable to share specific details at this time, one area of investigation involves exploring the mechanical cues that impact neurons during exercise, and our preliminary results appear to be supportive."

"Additionally, we are conducting a promising study to analyze the electrical activity of neurons during exercise. The patterns of neuronal excitement we observe can bear resemblance to dynamic systems found in nature, such as volcanoes and earthquakes."

The study, "Astrocyte-mediated Transduction of Muscle Fiber Contractions Synchronizes Hippocampal Neuronal Network Development", was authored by Ki Yun Lee, Justin S. Rhodes, and M. Taher A. Saif.

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