The major thrust of our research is directed towards an understanding of how the brain forms and stores memories. We examine how neuronal activity controls the strength of communication between neurons, at sites called synapses. Such synaptic plasticity is thought to underlie the formation and storage of memories. Synapses are key sites affected by diseases of cognition. A large part of our basic research program is tailored towards gaining a detailed understanding of synaptic plasticity to help elucidate root causes of age-related dementias like Alzheimer's disease. Such an understanding will eventually help inform treatments that prevent or mitigate brain diseases.

Understanding Brain Disease

Our laboratory has expanded its focus to include brain-disease related studies, including dementia, schizophrenia, and depression. In a series of studies we've examined the effects of A-beta on synapses. Aβ peptide, a preteolytic product of APP, is thought to be central to the pathogenesis of Alzheimer's disease; however, the functional relationship of APP and A-beta to neuronal conductance is mostly unexplored territory. Our laboratory has recently shown that neuronal activity modulates the formation and secretion of Aβ peptides from neurons. In turn, Aβ depresses synaptic transmission. Synaptic depression from excessive Aβ could contribute to cognitive decline during early Alzheimer's disease. In addition, activity-dependent modulation of Aβ production may normally participate in a negative feedback that could keep neuronal hyperactivity in check. Disruption of this feedback system could contribute to disease progression in Alzheimer's disease. These studies shed new light on the role of Aβ in normal and diseased states, and may lead to new treatments of Alzheimer's disease.

In a project related to depressive disorders, we have found that a group of excitatory synapses in the lateral habenula are dramatically potentiated in rodent models of depression. The lateral habenula was shown to encode ‘disappointment’ signals in monkey studies. Thus, negative rewards are likely heightened while positive rewards are diminished. We seek to understand the nature of synaptic potentiation in this circuit and its relationship to mood disorders, and plan to utilize our arsenal of techniques to test if these hyperactive synapses are responsible for behavioral depression.

Neural Dynamics

A large portion of our research remains dedicated towards charactarizing fundamental neural phenomena. Several years ago we established AMPA receptor trafficking as a major component of synaptic potentiation in hippocampal slice LTP. By applying similar concepts and reagents we found that synaptic modification during fear conditioning was distributed among many neurons in the amygdala. Surprisingly, preventing plasticity in 10-20% of these neurons was sufficient to degrade significantly learning. These finding have implications regarding the nature of circuits that underlie memory. Taking this a step further, we are using computational methods to simulate neural dynamics in virtual 3D models of neurons and neural networks .