The brain is extraordinarily complex, not least because its function relies on emergent properties that arise when individual neurons fire together in a coordinated fashion. This exciting project uses cutting-edge techniques to examine how Alzheimer’s pathology can disrupt healthy coordination in brain circuitry even before the loss of significant numbers of circuit neurons and how manipulating sleep may increase its ability to restore criticality, the optimal computational regime underlying complex, adaptive learning, and cognitive function.
Toxic forms of amyloid accumulate in the brain decades before noticeable cognitive symptoms appear. How the brain copes with this growing amyloid burden over time and what ultimately triggers the shift to clinical dysfunction remains unclear. While synaptic loss and the spread of tau tangles from the hippocampus to other brain regions are currently the strongest correlates of cognitive decline, these features are difficult to measure in living patients and do not directly explain how the brain’s networks fail. Brain networks emerge from the coordinated electrical activity of thousands of neurons, forming intricate patterns that govern various aspects of cognitive function, including memory, emotions, and decision-making. Our brains’ networks are remarkably adaptable and also very stable. Since few lost neurons can be replaced, they must remain functional for a lifetime as they continue to encounter and respond to countless new and unpredictable situations. This balance between adaptability and stability is maintained by homeostatic mechanisms operating at the level of individual neurons and across brain networks. Some researchers suggest that the clinical stage of Alzheimer’s disease starts when these homeostatic mechanisms break down.
Dr. Hengen is particularly interested in the role of sleep in this process. Sleep has many beneficial roles for brain health—one of which is to return the brain’s networks to a stable set point after long periods of neuronal activity while awake. Sleep disturbances are reported by Alzheimer’s patients both before and after diagnosis, but whether and how this directly contributes to disease is unclear. Dr. Hengen’s team recently collaborated with Dr. Dave Holtzman to address sleep disturbances in a mouse model of tauopathy (Tau/ApoE4). They performed continuous electrical recordings of neuronal activity in the brains of living mice over many months and found that abnormal tau in these mice negatively impacted a specific metric of a well-balanced network: criticality. Changes in criticality in young tau mice reliably predicted later disease progression. Their preliminary results also showed that the brain’s inability to return to a critical set point is related to changes in sleep, leading them to the questions and experiments posed in this project. Dr. Hengen hypothesizes that when sleep is disrupted, brain networks fail to restore to their optimal set points, accelerating the onset of clinical symptoms.
Dr. Hengen proposed two experimental aims. In the first, he is testing the hypothesis that both tau and amyloid interfere with sleep’s ability to restore brain networks to a healthy set point. The previous electrical recordings they performed in the Tau/ApoE4 mice resulted in an immense amount of data (~ 1 petabyte), and the team has only scratched the surface of potential analyses. Now, they are performing more detailed computational analyses to dissect the role of sleep in restoring network homeostasis across ages in these mice. They are also collecting an entirely new dataset of recordings in an amyloid mouse model (APP-KI) for similar analyses. In the second aim, they are investigating whether improved sleep early in life prevents the loss of criticality and improves behavior and amyloid- and tau-related pathologies. They are treating the tau and amyloid mouse models with a known insomnia drug approved for use in Alzheimer’s patients called suvorexant. They are also depriving mice of sleep early in life using physical methods to keep them awake to see how this impacts network set points and amyloid and tau pathologies. Together, these aims should help identify how sleep affects the brain’s ability to maintain normal cognition during Alzheimer’s disease and test the potential of sleep modulation as a viable strategy for reducing the impact on cognitive function.
In the first year of funding, Dr. Hengen’s team made impressive strides across their aims. Their recordings and subsequent analysis of the APP mice revealed a progressive impairment of the brain’s criticality, mirroring results they initially observed in a tau mouse model. Additionally, their studies indicate that as pathology and age progress, the separation from the criticality baseline becomes great enough that sleep no longer fully restores the brain’s networks to the set point. Dr. Hengen notes that sleep modification may hold greater potential in combatting cognitive decline than previously believed. The team also began to tease apart regional differences in network susceptibility, finding that failure of criticality maps to the brain regions where AD pathology arises and that are implicated in AD-associated cognitive dysfunction. The results regarding Aim 2 and the role of sleep deprivation in this disruption of criticality were striking and counterintuitive. Dr. Hengen found that chronic intermittent sleep deprivation might actually strengthen the brain’s homeostatic set point rather than weaken it as expected. Dr. Hengen compared this to intermittently lifting weights to induce muscle hypertrophy. Their data indicates that structured sleep deprivation resulted in deeper, more restorative sleep. In collaboration with Dr. Holtzman, Dr. Hengen observed a potent restoration of brain function when employing this structured sleep in both tau and amyloid animal models. Although this work must still be translated into human patients, this exciting result indicates sleep training and modification may be a viable therapeutic route in slowing Alzheimer’s disease.
