Plasticity in developing and adult neocortex.
Research in the lab centers around one overriding question: how does experience selectively activate and change neuronal properties? Although we are beginning to understand the neural basis for discrete behaviors in invertebrates, this question is exponentially more complex and challenging in vertebrates. In the mammalian cortex, complex behaviors and learning are mediated through the activity of hundreds of thousands -- if not millions -- of the trillions of neurons. Finding the right brain area, and indeed, the right neurons, is a critical step in enabling to identify the cellular and molecular basis for behavioral plasticity. We are addressing this question using a novel strain of transgenic mice that express GFP under the control of the c-fos promoter (fosGFP transgenic mice), coupling fluorescent gene expression to neural activity. This technique has allowed us to focus on changes occurring in the neurons that have initiated gene expression in response to in vivo experience. Once we know where in the brain to look, it becomes possible to ask highly sophisticated questions that bring together systems-level neuroscience, cellular electrophysiology, and molecular biology.
1. Identifying the plasticity transcriptome. It has long been recognized that learning requires the transcription of new genes, and there is abundant experimental evidence supporting a role for two transcription factors, CREB and zif268/egr-1, in initiating activity-dependent transcription. After identifying CREB and zif268 gene targets, we are now interested in how these targets are regulated by neuronal activity in seizure disorders and learning.
2. How do seizures alter programs of gene expression and alter neuronal excitability in cortical networks? Understanding how brain activity is abnormal after seizures can lead to the development of new anticonvulsant therapies. We have identified one new ion channel target that is functionally enhanced after seizures and can show that channel antagonists can block further seizures.
3. How does in vivo experience change synaptic and cellular responses? The somatosensory cortex of rodents contains a precise anatomical representation of the body surface, and it has long been know that over- or understimulation of some areas result in altered neuronal response properties. Using a single-whisker activation protocol in the fosGFP transgenic mice, we can show that some synapses are specifically altered by in vivo experience, and we are beginning to understand how previous synaptic modifications set the stage for future changes to occur, a process known as metaplasticity.
Clem, R.L. and Barth, A.L. Ongoing in vivo experience triggers synaptic metaplasticity in the neocortex. Science 319: 101-104, 2008.
Barth, A.L. Visualizing circuits and systems using transgenic reporters of neural activity. Curr Opin Neurobiol 17(5): 567-71, 2007.
Glazewski, S., Benedetti, B.L. and Barth, A.L. Ipsilateral sensory deprivation enhances cortical plasticity. J Neurosci 27(14): 3910-20, 2007.
Pfenning, A.R., Schwartz, R. and Barth, A.L. A comparative genomics approach to identifying the plasticity transcriptome. BMC Neurosci 8: 20, 2007.
Clem, R.L. and Barth, A.L. Pathway-specific trafficking of native AMPARs by in vivo experience. Neuron 49(5): 663-70, 2006.
Barth, A.L., Gerkin, R.C. and Dean, K.L. Alteration of neuronal firing properties in a fosGFP transgenic mouse. J Neurosci 24: 6466-6475, 2004.