Researchers have made a breakthrough in understanding memory loss due to repeated head impacts, as often experienced by athletes. The study reveals that memory problems following head trauma in mice are linked to the inadequate reactivation of neurons involved in memory formation. By using lasers to activate specific memory neurons, researchers successfully reversed amnesia in mice, opening new avenues for treating cognitive impairments in humans caused by repeated head impacts.
Repeated exposure to head impacts during an athletic career, even without causing overt concussions, has been linked to cognitive problems such as memory impairments and an increased risk of neurodegenerative diseases such as chronic traumatic encephalopathy (CTE).
Common activities in contact sports, such as heading a soccer ball or the head movements in sports such as bobsledding and Formula 1, generate these subconcussive impacts that, over time, can result in persistent cognitive symptoms. Researchers have found that, on average, college football players receive 21 head impacts per week, with defensive ends receiving 41 head impacts per week.
While there is evidence linking these brain injuries to proteins such as amyloid and tau (which are found in dementia), the relationship between these injuries and cognitive dysfunction is not yet fully understood.
To explore these mechanisms, studies using animal models, such as mice, have been essential. These studies demonstrate that repeated impacts can cause physiological changes in the brain, specifically in the hippocampus (a region linked to memory), resulting in memory and learning deficits, even without visible damage to brain structures.
Researchers at Georgetown University Medical Center have discovered that these changes are mediated by synaptic adaptations, changes in the connections between neurons, especially in response to the neurotransmitter glutamate.
Recent experiments, published in the Journal of Neuroscience, have shown that treating mice with NMDA glutamate receptor antagonists prevented these synaptic changes and, consequently, prevented the memory deficits caused by impacts. However, treatments to reverse the damage in people who already suffer from these deficits have not yet been developed.
Another important concept is the “memory engram,” which refers to the specific changes in synapses and neurons that store memory. In more advanced experiments, scientists have used transgenic mice that can visualize and manipulate these memory engrams.
In the new study, scientists gave two groups of mice a new memory by training them on a test they had never seen before. One group was exposed to a high frequency of lightheaded impacts for a week (similar to exposure to contact sports in people), and one group was a control group that received no impacts. The impacted mice were unable to recall the new memory a week later.
However, by using techniques such as optogenetics, which involves directly activating neurons with a specific type of laser, researchers were able to temporarily reactivate memories that had been “lost.”
Optogenetics and High-Frequency Head Impact (HFHI). E) Confocal microscope images of the dentate gyrus engram of Shaw (uninjured, left) and HFHI (right) mice. Green, neurons that were active in memory acquisition; magenta, neurons that were active in memory retrieval; blue, nuclei of all cells. F) The number of green neurons in the dentate gyrus is similar between sham and HFHI mice. G) The number of magenta neurons in the dentate gyrus is similar between sham and HFHI mice. H) The percentage of overlapping green/magenta neurons is significantly reduced in HFHI mice compared with sham controls. F (females) and M (males). doi.org/10.1523/JNEUROSCI.1560-23.2024
This finding suggests that cognitive impairment after such repeated impacts can be reversed by stimulating synaptic plasticity, opening promising avenues for future treatments aimed at restoring cognitive function in individuals affected by repetitive head trauma.
This work shows that chronic cognitive impairment after HFHI is a result of deficiencies in synaptic plasticity rather than a loss in neuronal infrastructure and that we can restore a forgotten memory in the amnesic brain by stimulating the memory engram.
Targeting synaptic plasticity may have therapeutic potential for treating memory impairments caused by repetitive head impacts.
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Amnesia after Repeated Head Impact Is Caused by Impaired Synaptic Plasticity in the Memory Engram
Daniel P. Chapman, Sarah D. Power, Stefano Vicini, Tomás J. Ryan, and Mark P. Burns
Journal of Neuroscience. 2024. doi.org/10.1523/JNEUROSCI.1560-23.2024
Abstract:
Subconcussive head impacts are associated with the development of acute and chronic cognitive deficits. We recently reported that high-frequency head impact (HFHI) causes chronic cognitive deficits in mice through synaptic changes. To better understand the mechanisms underlying HFHI-induced memory decline, we used TRAP2/Ai32 transgenic mice to enable visualization and manipulation of memory engrams. We labeled the fear memory engram in male and female mice exposed to an aversive experience and subjected them to sham or HFHI. Upon subsequent exposure to natural memory recall cues, sham, but not HFHI, mice successfully retrieved fearful memories. In sham mice the hippocampal engram neurons exhibited synaptic plasticity, evident in amplified AMPA: NMDA ratio, enhanced AMPA-weighted tau, and increased dendritic spine volume compared with nonengram neurons. In contrast, although HFHI mice retained a comparable number of hippocampal engram neurons, these neurons did not undergo synaptic plasticity. This lack of plasticity coincided with impaired activation of the engram network, leading to retrograde amnesia in HFHI mice. We validated that the memory deficits induced by HFHI stem from synaptic plasticity impairments by artificially activating the engram using optogenetics and found that stimulated memory recall was identical in both sham and HFHI mice. Our work shows that chronic cognitive impairment after HFHI is a result of deficiencies in synaptic plasticity instead of a loss in neuronal infrastructure, and we can reinstate a forgotten memory in the amnestic brain by stimulating the memory engram. Targeting synaptic plasticity may have therapeutic potential for treating memory impairments caused by repeated head impacts.
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