Memory and cognition require not just individual neurons to function properly, but also neurons to work properly together. Neuronal networks comprise thousands of neurons that fire electrical signals in delicately organized fashion. Rhythmic waves, known as oscillations, are a key part of this synchronization and emerge when neurons fire in unison. Waves are measured by the frequency with which they repeat in a per>second and different wave frequencies are observed when the brain is pursuing different activities; gamma oscillations (30–150 Hz) are particularly associated with cognitive functions like memory, motor control, and attention. In Alzheimer’s disease, gamma oscillations are significantly reduced, which correlates with cognitive decline and memory loss. Promising results from laboratory and clinical studies suggest that boosting the power and synchrony of gamma rhythms could help reduce Alzheimer’s pathology and improve cognitive outcomes.
Interneurons are a subtype of neurons that coordinate communication among different parts of the nervous system. Parvalbumin (Pvalb) and somatostatin (Sst) cells are interneurons that act as timekeepers and keep neurons firing in sync to produce different wave patterns. Preliminary work from the Palop lab unveiled that these two types of interneurons partner to generate gamma oscillations. The role of Pvalb cells as the main drivers of these rhythms has been previously recognized, but the Palop team discovered that Sst cells work with Pvalb cells to determine the amplitude – or strength —of gamma waves. In AD, interneurons lose their ability to synchronize neuronal firing, and a recent study showed that loss of Pvalb and Sst cells, along with changes in the genes expressed by surviving Pvalb and Sst cells, align with Alzheimer’s disease progression. The resulting loss of gamma oscillations disrupts brain networks and is hypothesized to contribute to cognitive decline, but why and how Alzheimer’s pathology leads to this outcome is unknown.
Although the field has recognized the importance of neuronal wave patterns and the role of interneurons in AD for a long time, technical challenges in monitoring and controlling specific interneurons in living animals have limited their investigation. However, in collaboration with the Allen Institute for Brain Science’s Viral Genetic Tools group, the Palop lab developed a new viral strategy that allows them to genetically modify interneurons to express calcium sensors and light-sensitive opsins. Calcium sensors enable the team to track interneuron activity, while opsins let them use light to turn on or off specific interneurons. With these tools, experiments can be conducted in live, awake animals, allowing Palop’s team to observe in real-time how interneuron activity and the relationship between Pvalb and Sst cells are linked to cognitive and behavioral outcomes. The Palop team hypothesizes that amyloid and tau disrupt the interaction and function of Sst and Pvalb interneurons, triggering the brain network dysfunction and cognitive decline seen in Alzheimer’s disease.
To investigate their hypothesis, the Palop lab will treat mouse models engineered to develop beta amyloid or tau pathology with their groundbreaking viral vectors so that they can monitor and control Pvalb and Sst interneuron signaling. These tools will enable them to analyze how calcium signaling, gamma oscillations, behavior and learning change naturally depending on the presence of AD pathology and upon experimental manipulation. The team will then assess how Pvalb and Sst activity change in conjunction with the development and aggregation of beta amyloid and tau as they accumulate during the mice’s lifespan, and how the interneuron activity changes are reflected in the behavior of these animals. Behavioral changes in normal daily activities and learning can be subtle yet important so they will use an advanced monitoring and machine learning algorithm, Variational Animal Motion Embedding (VAME) to collect and analyze an enormous amount of behavioral data. Since gamma waves are also detected during sleep and sleep is vital to appropriate brain processing of AD pathology, they will also analyze calcium signaling and brain oscillations – both gamma and other wavelengths — during different sleep stages.
Finally, using data developed during the observational stages of their project from brain regions typically affected early in AD, the team will target specific interneurons and/or combinations of interneurons in the mice to determine whether stimulating them restores normal brain function, corrects gene activity disruptions, improves AD pathology outcomes, and/or improves cognition. This research holds promising therapeutic potential, as scientists are already actively developing viral vectors to deliver therapeutics to brain cells. Palop and his team’s work could help pinpoint specific interneuron targets and refine viral vector strategies, paving the way for future treatments in humans.
