From Memory To ResearchMaps

Our lab studies mechanisms of memory and memory disorders. We use a number of techniques and approaches that allow us to study memory from molecular mechanisms to the cells they affect, the circuits and neuroanatomy they modulate, all the way to behavioral studies in rodents and patients. For example, recently we have discovered the first mechanisms of memory allocation and memory linking, as well as potential treatments for cognitive deficits associated with Neurofibromatosis type I, Tuberous Sclerosis, Noonan syndrome and HIV. To help integrate all of this information we have devised ResearchMaps, an invaluable informatics tool for experiment integration and planning.

How Do We Structure Our Memories?
Although mechanisms involved in encoding, storing and retrieving memory have attracted a great deal of attention, the processes that allocate individual memories to specific neurons within a network have remained elusive. Similarly, although the processes that connect and link information across time are critical for survival, they have also remained unexplored. Recent findings from our laboratory, using methods, such as optogenetics and a new generation of head mounted fluorescent microscopes, unraveled the first insights into the mechanisms that modulate memory allocation in neuronetworks, and showed that they are critical to link memories across time.

How Does Memory Change With Aging?
Learning and memory changes with aging, but little is known about what causes these changes. Studies in our laboratory demonstrated that just as humans and other animals, mice show age-related deficits in a variety of learning tests designed to test young mice. Interestingly, cells in the brain become progressively less excitable with age, and previous studies suggested that this decrease in excitability could cause deficits in learning and memory. We have also recently discovered that there are pronounced changes in memory linking with aging. What is the reason for these changes? Are they a reflection of the final stage of development of the brain?

Re-Imagining The Future of Intellectual Disabilities
Specific intellectual disabilities are the most common neurological complication of children with Neurofibromatosis type I (NF1) and Noonan Syndrome (NS). The inherent complexity of these cognitive deficits, and the complications of pursuing their study in patients, motivated us to study them in mice. We have shown that these mice have very specific learning deficits that have striking similarities to the deficits in individuals with NF1 and NS. Our biological studies of mice with NF1 and NS have yielded not only the mechanism for the learning deficits in these two disorders, but also a treatment . Studies in patients have suggested that there are similar deficits in patients to the ones we identified in mice, and therefore, it is possible that the treatments we developed may be effective in patients.

Transforming How we Treat Brain Injury
Most studies of brain injury, such as stroke, have traditionally focused on preventing neurodegeneration and death of affected brain cells. Comparatively little has been done to maximize and optimize the plasticity processes involved in repair and recovery after brain injury. Our laboratory is involved in a new initiative directed at leveraging brain plasticity in efforts to enhance repair and recovery following brain injury. In particular, in collaboration with the Carmichael, Shohami and Dobkins laboratories, we are using manipulations that enhance learning and memory to accelerate and optimize recovery after brain injury.

What Extraordinary Cognition Teaches Us?
In our studies of the mechanistic underpinnings of extraordinary problem solving, we have studied different strains of mice with dramatic enhancements in learning and memory. Understanding enhancements in learning and memory will be key to understanding extraordinary problem solving. Insights into extraordinary learning and memory will lead us a step closer to a mechanistic understanding of the biological processes responsible for historically creative achievements. Insights into extraordinary cognition have also led us to treatments for cognitive deficits. For example, our efforts to identify memory enhancing mutations in mice led us to null mutations in CCR5, the receptor for HIV! In turn, this discovery led us to a brand new way to understand cognitive deficits associated with HIV and to a treatment for these cognitive deficits. Our work showed that stimulation of CCR5, a memory suppressor, by viral proteins may account for some of the cognitive deficits associated with HIV.

Hope For HIV Associated Cognitive Deficits!
Our Our laboratory is investigating the molecular, cellular and circuit mechanisms underlying HIV associated cognitive impairment. We discovered that key neuronal and cognitive deficits caused by HIV could be prevented by manipulations that decreased function of the CCR5 receptor, a known target for the virus. Overall, our results demonstrate that CCR5 plays an important role in neuroplasticity and memory, and indicate that over-activation of this receptor contributes to HIV-associated neurocognitive disorders.

Computational Tools For Integrating And Planning Experiments
Our laboratory developed a framework and as set of algorithms to create maps (simplified abstractions) of causal information in research findings that can be used to integrate information and guide research planning. Based on this framework and algorithms, we developed a free web application that helps biologists keep track and interact with causal information in research papers (www.researchmaps.org).