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Office:
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ND4.502A |
214-645-6251/ 214-645-6240(FAX),
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Lab:
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ND4.504 |
214-645-6202
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Opportunities:
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Actively seeking interested Postdoctoral Fellows and Graduate Students
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My laboratory is focused on the molecular and cellular mechanisms of cognition with an emphasis on learning and memory. We are interested in how molecular and cellular alterations lead to behavioral changes that last for the better part of a lifetime in response to relatively brief environmental stimuli.
To elucidate the molecular basis of learning and memory, we use a truly multidisciplinary approach. One approach is to use both traditional and conditional knockout mice to alter specific molecules and then examine subsequent changes in learning and memory behavior as well as synaptic plasticity. A complimentary approach is to train animals in learning and memory tasks and measure subsequent biochemical changes in the relevant brain regions. Similarly, we induce lasting synaptic plasticity in hippocampal slices and measure subsequent biochemical changes. Using these approaches and others, we relate molecules, electrophysiology, and behavior with top-down and bottom-up approaches.
Proteomic Approaches to Learning and Memory
We are now in the process of identifying biochemical changes induced at synapses in the brain after learning. We are focusing specifically on synaptic proteins since lasting synaptic plasticity is likely to play a primary role in learning and memory.
To date, we have observed increased phosphorylation of the glutamate receptor subunit GluR1 in the hippocampus after learning in vivo. The pattern of GluR1 phosphorylation resembles that which is known to occur during long-term synaptic potentiation (LTP) in the hippocampus. We are currently focused on proving that these biochemical changes occur at synaptic rather than extra-synaptic receptors. These data provide convincing evidence that LTP-like biochemical changes occur in the hippocampus during learning.
Now that we can observe biochemical changes at synapses during learning in vivo, we hope to identify longer-lasting, synaptic molecular changes that are likely responsible for lasting, protein synthesis-dependent phases of memory. Toward this end, we are isolating postsynaptic densities (PSD’s) from animals either trained in learning and memory tasks or subjected to plasticity-inducing stimuli in vivo such as electroconvulsive shock and chemically induced seizure activity. Using unbiased proteomic approaches, we are identifying alterations in levels of synaptic proteins and subsequently correlating these changes with learning in vivo. Ultimately, we will use conditional knockout approaches to ascertain the relevance of the changes we observe for later phases of memory in vivo.
Neuroligins in Cognitive Function
The transsynaptic cell adhesion molecules known as neuroligins have been implicated in human X-linked mental retardation with and without autistic features. We have recently begun to characterize neuroligin knockout mice as a potential animal model of X-linked mental retardation. Using neuroligin 1 and 2 double knockouts, we have identified profound deficits in learning and memory including social learning, emotional learning, and spatial learning. Neuroligins have been implicated in maintaining inhibitory to excitatory synapse ratio and may also play a role in synaptic plasticity. We now plan to thoroughly characterize the role of the various neuroligin alleles in learning and memory and other behaviors. We will also further examine synaptic plasticity and excitatory to inhibitory synaptic ratio in these mice with the help of collaborators. We believe these mice may represent animal models of X-linked mental retardation and provide insights into the future treatment of this disorder.
Presynaptic Proteins and Plasticity in Learning and Memory
Recent genetic studies of learning and memory have made significant progress in identifying postsynaptic mechanisms involved in learning and memory. Relatively little effort has been aimed at elucidating the role of presynaptic proteins and presynaptic plasticity in mammalian learning and memory.My laboratory has begun a systematic effort to understand the role of presynaptic proteins and presynaptic function in learning and memory. Our primary hypothesis is that presynaptic proteins, in particular the active zone protein RIM1a, play a critical role in synaptic plasticity and learning and memory.
Extensive preliminary data from my laboratory indicate that RIM1a is critical for normal learning and memory. RIM1a knockout (RIM1a-/-) mice have deficits in learning and memory. Additional preliminary data indicate that RIM1a is phosphorylated at its major protein kinase A (PKA) site in the hippocampus during learning and that this phosphorylation is specific to associative learning.
My laboratory will now further characterize the role of RIM1a and its regulation by PKA in both synaptic plasticity and learning and memory. Also, we will conditionally delete RIM1a from specific synapses and examine the effect on learning and memory. These studies will provide the most direct evidence to date that regulation of presynaptic release machinery is involved in learning and memory.
Glucocorticoid System Modulation of Fear Memory/PTSD
My laboratory has recently discovered that the body’s own natural stress hormone, cortisol, may be useful to treat acquired anxiety disorders such as post-traumatic stress disorder, phobias and other stress-induced neuropsychiatric illnesses. Specifically, we used an animal model to demonstrate that the injection of corticosterone, the animal equivalent of cortisol, after recalling a traumatic memory decreases the fearful nature of the memory in a lasting way. This treatment does not erase the initial traumatic memory, but rather augments a competing memory that decreases the fearful response to the initial memory (known as extinction memory). These findings suggest that the release of stress hormones during recall of a fearful memory may be a natural mechanism to decrease the negative emotional aspects of traumatic memory.
Conversely, patients with post-traumatic stress disorder (PTSD) have blunted stress hormone responses and thus, may not decrease fearful memories normally over time. It is thought that this abnormal persistence of traumatic memory is responsible for PTSD symptoms. This suggests that patients with post-traumatic stress disorder may be treated by pairing reactivation of their fearful memories during therapy with stress hormone treatment. Treatment with stress hormones is relatively non-specific and may have adverse side effects. Thus, we are now examining the precise molecular mechanisms of corticosterone’s effect in the brain on fearful memories to identify more specific targets for treatment of PTSD, phobia, and other stress-induced neuropsychiatric illness.
Summary and Clinical Relevance
Neurons in the central nervous system are complex machines designed to accept a rich diversity of inputs and alter their responses in meaningful and lasting ways. The molecular signal transduction events that translate certain input patterns into lasting alterations of neuronal function are beginning to be elucidated. How these molecular and cellular alterations conspire to alter behavior in a lasting fashion in response to external cues remains largely a mystery. Understanding this complex interplay between molecules, neuronal function, and behavior is the focus of my laboratory
Understanding the molecular basis of cognitive function is critical for a complete understanding of the pathophysiology and potential treatment of neuropsychiatric disorders involving human cognition. These include schizophrenia, Alzheimer’s disease, learning disability, mental retardation, post-traumatic stress disorder, and cognitive deficits associated with post-traumatic brain injury and major depression. In order to understand complex behavior, my laboratory is examining the molecular basis of cognition at multiple levels.
Recent Publications:
Powell, C.M., Schoch, S., Monteggia, L., Barrot, M., Matos, M., Sudhof, T.C., & Nestler, E.J. (2004) The Presynaptic Active Zone Protein RIM1a is Critical for Normal Learning and Memory, Neuron 42, 143-153.
Monteggia, L., Barrot, M., Powell, C.M., Berton, O., Nagy, A., Greene, R.W., & Nestler, E.J. (2004) Essential Role of BDNF in Adult Hippocampal Function. PNAS 101, 10827-10832.
Powell, C.M. (2006) Gene Targeting of Presynaptic Proteins in Synaptic Plasticity and Memory: Across the Great Divide. Neurobiology of Learning and Memory 85, 2-15.
Powell, C.M. & Miyakawa, T. (2006) Schizophrenia-relevant Behavioral Testing in Rodent Models: A Uniquely Human Disorder? Biological Psychiatry 59, 1198-1207.
Kim, J. & Powell, C.M. (2007) Learning-induced GluR1 phosphorylation in the hippocampus resembles that induced by LTP. (in revision)
Cai, W., Blundell, J., Han, J., Greene, R.W., Powell, C.M. (2006) Post-reactivation Glucotorticoids Impair Recall of Established Fear Memory. J. Neuroscience 26, 9560-9566.
Powell, C.M., Kaeser, P., Sudhof, T.C., & Nestler, E.J. (2007) RIM1a Knockout Mice Exhibit Multiple Abnormal Behaviors Related to Schizophrenia. (in preparation).
Kwon**, C., Luikart**, B.W., Powell**, C.M., Zhou, J., Matheny, S.A., Zhang, W., Li, Y. Baker, S.J., & Parada, L. (2006) Pten Regulates Neuronal Arborization and Social Interaction in Mice. Neuron 50, 377-388.
**Equal Contribution
