40Hz Sensory Stimulation Improves Cognition in Down Syndrome Mice
40Hz sensory stimulation boosts cognition, hippocampal activity and neurogenesis in a mouse model of Down syndrome.
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Researchers at the Picower Institute for Learning and Memory and the Alana Down Syndrome Center at the Massachusetts Institute of Technology (MIT) have demonstrated that daily exposure to 40Hz sensory stimulation improves cognition, enhances circuit connectivity and promotes neurogenesis in a mouse model of Down syndrome. The study, published in PLOS ONE, utilized genetically engineered mice that reflect key aspects of the human condition.
Neurogenesis
Neurogenesis is the biological process by which new neurons are formed in the brain. This process is essential for learning, memory and brain repair.
The research focuses on Gamma Entrainment Using Sensory Stimulation (GENUS), a method that exposes subjects to synchronized light and sound pulses at a frequency of 40Hz. Although these findings are encouraging, the authors emphasized that further research is necessary to determine the translational potential for humans. A small-scale human study is already underway at MIT.
Cognitive improvements linked to hippocampal changes
The research team, led by postdoctoral associate Md Rezaul Islam and former graduate student Brennan Jackson, used the Ts65Dn mouse model of Down syndrome. Over a three-week period, the mice received one hour of combined light and sound stimulation daily. Following treatment, the mice showed improvements in three different short-term memory tasks.
Because these tasks are known to involve the hippocampus, the researchers examined neural activity in this brain region. Mice exposed to GENUS displayed higher levels of activity indicators compared to untreated controls. To explore the underlying mechanisms, the team conducted single-cell RNA sequencing on hippocampal tissue, analyzing gene expression profiles across nearly 16,000 individual cells.
The analysis revealed that genes involved in synapse formation and organization were more actively expressed in treated mice. Additional histological examinations confirmed that treated mice had a greater number of synapses in the dentate gyrus, a subregion of the hippocampus critical for memory and learning.
Synapse
A synapse is a structure that permits a neuron to pass an electrical or chemical signal to another neuron or target cell, facilitating communication within the nervous system.
Hippocampus
The hippocampus is a brain region located within the temporal lobe that plays a major role in learning, memory and spatial navigation.
Increased neurogenesis linked to gene expression changes
Beyond examining individual gene changes, the researchers analyzed patterns of coordinated gene expression, identifying several modules associated with synaptic development. A key finding was the upregulation of TCF4, a transcription factor critical for promoting neurogenesis. Treated mice exhibited improved TCF4 expression, correlating with higher rates of new neuron generation in the dentate gyrus.
TCF4
TCF4 (Transcription Factor 4) is a protein that helps regulate the expression of genes necessary for neuronal development and neurogenesis.
“In this study, we found that GENUS enhances the percentage of Reln+ neurons in hippocampus of a mouse model of Down syndrome, suggesting that GENUS may promote cognitive resilience,” said Islam.
While these observations are correlational, the researchers suggest that enhanced neurogenesis may contribute to the observed cognitive improvements. This study is the first to link GENUS with increased neurogenesis in the brain.
Broader effects on aging and Alzheimer’s-related pathology
The researchers also found that GENUS appeared to mitigate some molecular signatures of brain aging and Alzheimer’s disease in the Down syndrome mouse model. A cluster of genes typically downregulated during aging and Alzheimer’s remained more active in stimulated mice.
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Additionally, the study noted a higher retention of Reelin-expressing neurons in the hippocampus of treated mice. These neurons are often lost in Alzheimer's disease and are associated with cognitive resilience. As individuals with Down syndrome have a high lifetime risk of developing Alzheimer’s disease, this finding is particularly relevant.
Limitations and future directions
While the results are promising, the authors caution that several limitations exist. The Ts65Dn mouse model does not fully replicate human Down syndrome, and only male mice were used. Furthermore, the cognitive tests assessed only short-term memory, and changes in other critical brain regions, such as the prefrontal cortex, were not investigated.
Future research will need to validate these findings in human studies and explore the effects of GENUS across a broader range of cognitive domains and brain structures.
Reference: Islam MR, Jackson B, Naomi MT, et al. Multisensory gamma stimulation enhances adult neurogenesis and improves cognitive function in male mice with Down Syndrome. PLoS One. 2025;20(4):e0317428. doi: 10.1371/journal.pone.0317428
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