Our current research program focuses on two separate but related goals. The first is to develop mitochondrial therapeutics that can offset the profound mitochondrial dysfunction that occurs in neurodegenerative diseases, including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). The second is to uncover the brain mechanisms that lead to forgetting.

Mitochondrial dysfunction is a major hallmark of most neurodegenerative disorders, including AD, ALS, Parkinson’s disease, Huntington’s disease, and the neuropsychiatric diseases of schizophrenia, bipolar disorder, autism, and others. Although the initial cause for each of these devastating diseases is unknown – other than the single-gene heritable forms such as early-onset AD – it is easy to understand that mitochondrial dysfunction would lead to poor performance of neurons and other brain cells and the phenotypes associated with each of these diseases. Mitochondria serve neurons and other brain cells in many ways, including providing the major source of chemical energy and buffering of intracellular calcium levels. Many of the other cellular pathologies that occur in these diseases, such as synapse loss and neuroinflammation, may be downstream effects of mitochondrial dysfunction. Thus, mitochondrial therapeutics hold great promise to offset the effects of these brain disorders. We have completed small molecule screens searching for compounds that have desirable effects on mitochondrial form and function and are now testing these for efficacy in animal models for AD and ALS and in neurons derived from diseased induced pluripotent cell lines.

Learning and memory researchers have uncovered many of the brain mechanisms over the last 50 years that lead to the acquisition of information (learning) and its long-term storage (consolidation). However, little is known about how the brain forgets information once learned. We are focusing on this important issue using the fruit fly, Drosophila. We have discovered a forgetting mechanism that leads to the permanent loss of information, which involves the chronic release of dopamine from a very small number of dopaminergic neurons onto the neurons that store information. This leads to a slow but continual loss of memory unless other brain mechanisms, e.g., consolidation, over-ride this forgetting mechanism. In addition, we discovered that another small set of dopamine neurons respond to distracting environmental stimuli and cause a temporary inability to retrieve memory. This is transient forgetting, a phenomenon we all can identify with. These basic science studies that reveal insights into the brain functions of learning, memory storage, and forgetting, will with time offer novel routes for the development of small molecule therapies for the brain disorders that afflict the human population.

0000-0002-5986-7608