Students and faculty gathered in Gerstenzang to hear a speech by renowned scientist H. Craig Heller, the Lorry I. Lokey/Business Wire Professor and a Professor of Biology at Stanford University on Sept. 18. Professor Michael Rosbash (BIO/NBIO) mediated the presentation.
Heller’s research is focused on the neurobiology of sleep, circadian rhythms and learning disabilities. He decided to focus his research on discovering therapies that may improve the cognition of individuals with Down syndrome. In this talk, he shared his findings of how the reduction of Gamma-Aminobutyric acid (GABA) activity restores the learning and memory abilities in mice with Down syndrome. GABA is a major inhibition system in the brain that is heavily involved in sleep and circadian rhythms.
According to Heller, Down syndrome is a “complex, clinically heterogeneous disorder that affects speech, language, declarative short-term and long-term memory,” affecting one in 700-1000 births in the United States every year. Of the three types of Down syndrome, the most prevalent type is Trisomy 21, where an individual is born with three copies of the 21st chromosome. People with Down syndrome also have an increased risk for early onset Alzheimer’s disease.
Heller began the talk by introducing the “Ts65Dn Mouse Model of DS” (TS), a model commonly used to study Down syndrome and Alzheimer’s disease. In this model, mice are genetically engineered to have three copies of 100 genes; the modifications mirrors the symptoms of Down syndrome in humans, as well as severe learning disabilities. Professor Fabian Fernandez, an Assistant Professor of Psychology and Neurology at the University of Arizona who worked under Heller as a graduate student, hypothesized that the over-inhibition of the central nervous system inhibits the transfer of short-term memories to long-term memories, causes learning disabilities.
The Novel Object Recognition (NOR) test, one of the main tests to study learning and memory in mice, utilized the TS mice to study the changes in GABA within the brains of the mice. The overall purpose of the study demonstrated that mice are able to recognize patterns of change within their surroundings.
Another common experiment that is utilized is seminal experiments that help to find the effects of chronic treatment with GABA antagonists on different forms of learning and memory. Three different drugs were used the the light sleeping phase to see the effects. The drugs were given over a period of over 17 days and given through chocolate milk.
A week after the treatment was given, all the mice were tested. Even though the medications did have a positive effect on their internal systems, researchers still do not why, or how, this occurred.
The overall conclusion of the study demonstrated that the short-term chronic treatment of the GABAA receptor antagonists at low doses improved the learning and memory of the mice, both in the short-term and long-term. But the mechanisms that code for these are based on the circadian phase.
Heller then states that GABA receptor antagonists can enhance learning and memory in DS models, but in actuality, these mechanisms depend on the circadian phases and sleep patterns of the mice. Studies show that the circadian rhythms can be eliminated, but sleep cannot be compromised.
Heller and his team used Siberian hamsters to study our biological need for circadian rhythms. Siberian hamsters are ideal for studying circadian rhythms because they follow Aschoff’s rule.
Aschoff’s rule states that if the intensity of light an organism is exposed to increases, the active period of diurnal animals shortens and that of nocturnal animals becomes longer than 24 hours.
Heller gave an example of how this rule applies to hamsters, saying that “if you put these animals on a plane and took them from Boston to San Francisco, they get jet lagged and you see this gradual re-entrainment to this light-dark cycle.”
Based on this rule, hamsters under prolonged light exposure, such as having an extra five hours of daylight, will have a disrupted phase response, and their circadian rhythms are permanently damaged—hamsters are able to be active regardless of the time of the day. Clock genes continue to be expressed after the damage is done, but the hamster is arhythmic for life.
Heller shifts to talking about short-term and long-term memory, beginning this section by explaining memory patterns in the brain. During memory creation, information that needs to be processed goes through the hippocampus and cortex, even though the cortex is unresponsive. However, while individuals are asleep, the hippocampus helps to strengthen the firing sequences in the primary cortex.
Memory storage is extremely vulnerable to changes during the transfer between temporary to long-term storage, which are housed in different areas of the brain. This means that memories are consolidated when individuals are sleeping, which can both be reactivated and modified during sleep.
