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Modification of the Cerebral Cortex by Experience
Summary: Mark Bear is interested in how synapses in the cerebral cortex are modified by experience and store information. His current work is focused on the activity-dependent regulation of glutamate receptors and the contribution of these mechanisms to naturally occurring synaptic modifications in the visual cortex and hippocampus, and on the neurobiology of fragile X, the most common inherited form of human mental retardation.
Sensory experiences leave their mark on the brain by altering the effectiveness of synapses between neurons. Based on how active they are during an experience, some synapses on a neuron grow stronger and others grow weaker. The pattern of synaptic strength changes represents a memory of the experience. I seek to understand how synapses in the cerebral cortex are modified by experience.
Key insight into this process has been gained over the past 45 years by recording the activity of cortical neurons in vivo. These studies show that a cardinal feature of cortical neurons is stimulus-selective receptive fields. For example, neurons in primary visual cortex show selectivity to particular stimulus attributes, such as which eye is stimulated, or the orientation of a contrast border; neurons in the CA1 region of hippocampus show selectivity for positions in space; and so on. Selectivity in many cortical areas can be modified by experience—in fact, experience-dependent shifts in selectivity are the most common correlate of memory formation. Lasting shifts in selectivity are believed to reflect synaptic changes that, distributed over a population of cells, are the neural basis of memory storage. Thus, we frame the question as follows: How do cortical synapses adjust their effectiveness to modify neuronal selectivity and store information?
Our work has concentrated on two experimental model systems: the primary visual cortex, and the CA1 region of the hippocampus. The advantages of the primary visual cortex are that (1) during a critical period of postnatal development, simple manipulations of visual experience can produce striking changes in neuronal selectivity, (2) the site of synaptic modification is in the cortex, not at more peripheral stations in the ascending visual pathway, and (3) the synaptic modifications in visual cortex have clear consequences on the visual capabilities of the animal. Thus, the visual cortex is an excellent preparation to make the connection between the mechanisms of synaptic plasticity and behavior. A disadvantage of the visual cortex is that the circuitry is very complex, which presents obstacles for studies of the elementary mechanisms of synaptic plasticity. The CA1 region of hippocampus has a much simpler organization, and it has proved to be an advantageous preparation for studying the mechanisms of excitatory synaptic transmission and plasticity. A disadvantage of CA1 is that it is many synapses away from the sensory periphery, making assessment of the functional significance of synaptic plasticity in this region difficult. Our approach exploits the special strengths of each preparation. While these are very different types of cerebral cortex, we have found that insights gained in one preparation have been extremely valuable for understanding the other.
Work over the past several years has uncovered a possible synaptic basis for receptive field plasticity in hippocampus and visual cortex. It has now been established that strong activation of postsynaptic N-methyl-D-aspartate receptors (NMDARs) can trigger long-term potentiation (LTP) of excitatory synapses, that weak activation of NMDARs can trigger long-term depression (LTD), and that the LTD-LTP crossover point adjusts according to the history of integrated postsynaptic activity, a phenomenon called metaplasticity. Theoretical studies have shown that synaptic plasticity with these properties can account for aspects of experience-dependent shifts in neuronal stimulus selectivity. Work in my lab is now focused on several related questions. What is the molecular basis for LTD in hippocampus and visual cortex? What is the molecular basis for metaplasticity in the visual cortex? Do the mechanisms of LTP and LTD contribute to receptive field plasticity in visual cortex and hippocampus, as suggested by theoretical analysis? We are also beginning to apply our knowledge of synaptic plasticity to understand developmental disorders such as fragile X mental retardation and autism.
The increasingly detailed understanding of synaptic plasticity mechanisms will continue to suggest specific hypotheses that can be tested using genetically altered mice. Therefore, we have worked to establish a mouse model of ocular dominance (OD) plasticity in visual cortex that enables us to monitor the rate and type of synaptic modification elicited by monocular deprivation (MD) or other manipulations of experience. These efforts have already led to interesting and unexpected findings. Nathaniel Sawtell and Mikhail Frenkel found that comparable OD shifts can occur by depression of deprived-eye responses, enhancement of open-eye responses, or both, and the relative contributions of these vary with age and MD duration.
One mechanism for deprivation-induced synaptic depression appears to be NMDAR-dependent LTD, which Arnold Heynen and Bongjune Yoon recently showed is induced by MD. A molecular basis for LTD is internalization of postsynaptic glutamate receptors, and this can be blocked by introducing peptides into neurons that prevent endocytosis. In collaboration with Rachael Neve at Harvard, we are using herpes simplex virus to introduce these peptides into cortical neurons in vivo to assess the impact of blocking this type of LTD on the response to MD. Robert Crozier has also characterized a second type of LTD in visual cortex that requires signaling by presynaptic endocannabinoid CB1 receptors. Cheng-Hang Liu is therefore using highly selective CB1 antagonists to assess the contribution of this novel form of LTD to OD plasticity in mice.
Deprived-eye depression is down-regulated during development, and we aim to find out how this occurs. Because the synaptic depression is driven by the poorly correlated activity, or “noise,‿ from the deprived retina, Monica Linden is studying how this type of activity changes during development. We have hypothesized that down-regulation is a consequence of the late development of cortical inhibition, which filters the noise that drives LTD. We intend to test this hypothesis by transgenically silencing selected populations of GABAergic interneurons.
We discovered that deprivation can also be permissive for expression of experience-induced synaptic potentiation, even in adults. We are attempting to determine the mechanisms of the permissive metaplasticity and the experience-dependent potentiation. We previously found that several days of visual deprivation decreases the NR2A/B ratio of synaptic NMDARs and slows excitatory postsynaptic currents (EPSCs), and that reducing expression of NR2A mimics and occludes this change. Wendy Chen has established a culture model to investigate how activity regulates NR2A/B, and experiments are planned to manipulate expression levels in vivo to understand the consequences of this regulation on OD plasticity.
Another surprising manifestation of plasticity in adult visual cortex was recently discovered by Marshall Shuler. He found that when adult rats learn the association of a simple stimulus with a reward, the responses of a substantial fraction of neurons evolve from those that relate solely to the physical attributes of the visual stimulus to those that accurately predict the timing of reward. In addition to revealing a remarkable type of response plasticity in adult primary visual cortex, the data demonstrate that reward timing activity—a “higher‿ brain function—can occur very early in sensory processing paths (only two synapses from the retina). We are investigating the mechanism.
We are also tackling the question of whether LTP is actually induced by learning in the hippocampus, which has long been assumed but never demonstrated. By using biochemical markers that are selective for LTP, Jonathan Whitlock has obtained evidence that one-trial, inhibitory avoidance learning induces LTP. He is attempting to confirm this finding with electrophysiological methods.
In addition to our studies on synaptic plasticity in hippocampus and visual cortex, we are testing the metabotropic glutamate receptor (mGluR) hypothesis of fragile X mental retardation. We are studying synaptic and dendritic development in vivo and in vitro in Fmr1 knockout and wild-type mice to establish a phenotype that can be manipulated genetically or pharmacologically. One promising line of research comes from the study of OD plasticity in the mutant mice by Gül Dölen. We are excited to find that the knowledge gained by our studies of visual cortical plasticity might be usefully applied to develop novel therapies for developmental disorders.
Grants from the National Institutes of Health, the National Institute of Child Health and Human Development, and FRAXA Research Foundation provided support for the projects described above.
Last updated: May 6, 2008
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