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RESEARCH VALIDATES DECADES OF WORK, POINTS TO FUTURE AVENUES FOR UNDERSTANDING LEARNING
10 August 2006 - Carnegie Mellon Universtity

Through a clever experimental design, Carnegie Mellon University neuroscientists have validated decades of experiments to show how learning and memory may be encoded in a living animal. The research, published in the March issue of Neuron, identifies for the first time the specific neural connections that strengthen as an animal's brain responds to new experiences.

"We are very excited by this finding and the ability of researchers worldwide to build upon it," said the study's principal investigator Alison Barth, assistant professor of biological sciences at the university's Mellon College of Science.

According to Barth, the study is the first to verify "synaptic plasticity" in a living animal's brain that has not been artificially altered to affect neural transmission. Synaptic plasticity is the process in which molecular changes modify a single neuron's activity in a living animal.

"Verifying this principle of synaptic plasticity to how neurons function in vivo is critical to advancing our knowledge of the mechanisms that underlie learning and memory," Barth added.

Many neuroscientists believe that the cellular basis of learning and memory results from molecular-scale changes occurring at synapses, the communication junctions between neurons. Although great strides have been made in identifying how different patterns of neuronal activity can alter synapses in vitro and in revealing long-term or short-term synaptic plasticity, Barth said it has been unclear whether these findings hold true in a normal, unaltered brain.

Previous research has artificially stimulated neurons or genetically modified them so that they produce an abundance of AMPA receptors, molecules on the surface of some neurons that are implicated in learning and memory. But such experiments alter the native environment of the brain and may influence the normal activity at a single synapse, explains Barth.

"Evidence from in vitro studies and in vivo studies using viral over-expression systems supports the notion that production of certain AMPA receptors is increased and that they are transported to the synapse during learning. Neuroscientists have always thought implicitly that this phenomenon underlies learning and memory," said Barth. "Our study reveals for the first time in vivo the dynamic activity of these receptors within a single synapse and that these changes result in experience-dependent plasticity during a specific behavioral experience."

Barth's strategy to reveal plasticity in a single synapse involved a two-step approach. First, she used a novel tool she created, a transgenic mouse that couples the green fluorescent protein with the gene c-fos, which turns on when nerve cells are activated. Using this method, Barth was able to "light up" clusters of neurons in living brain tissue that were activated during a specific rearing condition, experiencing the world through one whisker. By locating such a cluster of glowing neurons, she could precisely identify the area of the brain involved in processing sensory input from that single whisker. Once these neurons were located, Barth examined how the inputs to these neurons had been modified by experience.

Barth and graduate student Roger Clem, the lead author on the study, found that this change in sensory experience causes a subtle, but very significant, change in AMPA receptor properties at a defined group of synapses in an area of the brain identified by fos-GFP labeling. Barth and Clem achieved this finding by using an electrophysiological technique called patch clamping to detect unique voltage "signatures" that characterize and differentiate in real-time AMPA receptors.

Why would detecting different AMPA receptors be important? Different subtypes of AMPA receptors are highly regulated within a cell. Each AMPA receptor is made from varying combinations of four subunits: GluR1, GluR2, GluR3 or GluR4. The different ratios of these subunits alter their voltage signatures.

The GluR1 subunit is delivered to synapses specifically when a neuron is activated, according to earlier studies by other researchers. Conversely, GluR2 production is constitutive, meaning it basically occurs at a steady state. So AMPA receptors comprised of GluR1 would implicate neural activation and should have a specific voltage signature, in fact, what Barth and Clem found.

Barth's work is especially provocative given that previous electrophysiological studies have not been able to distinguish the voltage signal of AMPA receptors comprised exclusively of GluR1 subunits. It provides the first evidence that the same mechanisms that have been observed in cultured nerve cells are actually used by the brain during normal behavior.

"In sum, our data indicate that enhanced sensory experience alters the properties and subunit composition of AMPA receptors," Barth said. "These patch-clamping studies are the first to effectively reveal that the up-regulation of GluR1-only receptors is related to learning."

http://www.cmu.edu

About: Carnegie Mellon Universtity
The Carnegie Institution of Washington (www.carnegieinstitution.org) has been a pioneering force in basic scientific research since 1902. It is a private, nonprofit organization with six research departments throughout the U.S. Carnegie scientists are leaders in plant biology, developmental biology, astronomy, materials science, global ecology, and Earth and planetary science.

Since its founding in 1900 by industrialist and philanthropist Andrew Carnegie, Carnegie Mellon University has been a pragmatic institution, adapting rapidly to change. In fewer than 100 years it has changed its name three times--each transition marking a milestone in the institution's 20th century evolution.

Whether it was Carnegie Technical Schools, as it was in its first 12 years, Carnegie Institute of Technology, its name from 1912 to 1967, or Carnegie Mellon University, three primary purposes formed its foundation. Throughout this century, Carnegie Mellon has focused on delivering distinctive and first-quality education, fostering research, creativity and discovery, and using the new knowledge created on campus to serve our larger society.

When Arthur A. Hamerschlag served as the school's first president, Carnegie Technical Schools' 12 professors and six administrators sought to educate the sons and daughters of Pittsburgh workers for employment in the region's growing industries.

These educators served the vision of Carnegie by organizing into four faculties: the School of Science and Technology, the School of Fine and Applied Arts, the School of Apprentices and Journeymen, and the Margaret Morrison Carnegie School for Women.

In its earliest years, the institution served primarily part-time and undergraduate students. The faculty, many of whom did not have doctor's degrees, focused on teaching and curriculum development.

But research efforts began as early as 1916 when the Division of Applied Psychology of the Carnegie Institute of Technology developed rating scales for job placement. This rating system was used to classify two million men for placement in the armed forces during World War I. Research bureaus were organized in coal mining, nuclear physics, applied chemistry and metallurgy.

And by granting the nation's first undergraduate degree in drama in 1917, the institution began a tradition of leadership in the arts that spanned the century.

Through research and the education of its students during the administration of President Thomas S. Baker in the 1920s and '30s, the institution began its strong tradition of transferring knowledge and skills to industry and government.

Building on this firm foundation, the administration of President Robert E. Doherty introduced a new approach to education that would be used as a model by similar institutions around the nation. The Carnegie Plan for Professional Education, initiated in 1939-40, required engineering and science students to take a quarter of their courses in a new Humanistic and Social Relations sequence. In addition, its curriculum focused on teaching students problem-solving techniques, a hallmark of the Carnegie Mellon educational experience today.

While the Doherty administration has been credited with this educational innovation, it also oversaw growth in the institution's research capability. Between 1936 and 1950, the number of graduate students grew from 36 to more than 260. The research budget ballooned from $156,000 to $1 million.

In the 1950s, the newly formed Graduate School of Industrial Administration, endowed by William Larimer Mellon, emerged as one of the three or four best business schools in the nation. (In 2004 the school was renamed the David A. Tepper School of Business after benefactor and alumnus David Tepper (MBA '82).) Today, the school is recognized as a pioneer in the field of management science and one of the top business schools in the world.

The Warner administration oversaw the institution's burgeoning research enterprise. This period of research growth was aided by the work of the institution's Computation Center, founded in 1956 to provide computing services to the campus. A major grant from benefactor Richard K. Mellon in 1965 aided the establishment of a Computer Science Department, a department which would be the genesis of Carnegie Mellon's worldwide reputation in computer science.

By the end of the Warner administration and the start of the administration of President H. Guyford Stever in 1966, Carnegie Tech had most elements of a university. Its merger in 1967 with the Mellon Institute created Carnegie Mellon University and brought a $60 million endowment, extensive research facilities and renowned research personnel to the institution.

Five years later, President Richard M. Cyert (1972-90) began a tenure that was characterized by unparalleled growth and development. The university's research budget soared from about $12 million annually in the early 1970s to more than $110 million in the late 1980s. The work of researchers in new fields such as robotics and software engineering helped the university build on its reputation for innovative ideas and pragmatic solutions to the problems of industry and society. Carnegie Mellon began to be recognized as a truly national research university able to attract students from across the nation and around the world.

The Cyert administration stressed strategic planning and comparative advantage, pursuing opportunities in areas in which Carnegie Mellon could outdistance its competitors.

An archetypal example of this approach was the introduction of the university's "Andrew" computing network in the mid-1980s. This pioneering network, which linked all computers and workstations on campus, set the standard for educational computing and firmly established the university as a leader in the uses of technology in education and research.

Education and teaching also benefited in this period with the establishment of a University Teaching Center to improve faculty teaching and the renovation of many of the university's classrooms.

Cognizant of the university's heritage, President Robert Mehrabian (1990-97) invited alumni from the era of the institution's first president, Arthur A. Hamerschlag, to attend his inauguration in 1990. President Mehrabian emphasized Carnegie Mellon's traditional strengths in education, research and service to society while focusing on initiatives for leadership in the 21st century.

With the appointment of the university's first Vice Provost for Education, President Mehrabian placed renewed emphasis early in his administration on the quality of undergraduate education. He also moved aggressively to complete the most ambitious campus building plan since the Warner era. The University Center, which opened in August 1996, and the Purnell Center for the Arts, to be completed by the fall of 1999, are keys to enhancing the quality of life on campus, another priority of the Mehrabian administration.

Confronted by shrinking governmental support of university research, President Mehrabian diversified the university's research agenda. He stressed the need to build strong relationships with the business world, matching industry's needs with the university's areas of research strength. He also put new emphasis on productivity, improvement of administrative services and strategic management of university resources.

President Mehrabian established strong, new partnerships with the greater Pittsburgh community. He led a community-wide economic development initiative, spurred collaboration with primary and secondary schools, and worked closely with local community groups.

On April 15, 1997, Jared L. Cohon, former dean of Yale University's School of Forestry and Environmental Studies, was elected by the university's Board of Trustees to succeed President Mehrabian, who resigned to spend more time with his family in California.

"Since I was chosen, since this wonderful event has occurred, it has made me reflect on why you are choosing me," President Cohon said in his first speech to the university community. "And I've said to people since this was announced that the more I think about it, the more I realize how well I think this institution and I fit together. We'll see if that's true. I think it is.

"When I was at Johns Hopkins we used to always hold up Carnegie Mellon as an example," Cohon said. "So, for many years I've ... been jealous of what has been accomplished here across departmental lines. I celebrate that. I think it is so valuable in every aspect of this university and it will position Carnegie Mellon to be even better...."

During Cohon's presidency, Carnegie Mellon has continued its trajectory of innovation and growth. Today, President Cohon is leading implementation of a comprehensive strategic plan that aims to leverage the university's existing strengths to benefit society in the areas of biotechnology and the life sciences, information and security technology, environmental science and practices, the fine arts and humanities.

The university is also committed to broadening and enhancing undergraduate education to allow students to explore various disciplines while maintaining a core focus in their primary area of study. Realizing that today's graduates must understand international issues, Carnegie Mellon is committed to providing a global education for its students and is striving to expand its international offerings and to increase its presence on a global scale. Increasing diversity, in all aspects, and fostering the economic development of southwestern Pennsylvania, are also top priorities.

Over the years Carnegie Mellon's leaders have reflected Andrew Carnegie's original dedication and commitment to this institution. In his 1900 letter to the mayor of Pittsburgh establishing Carnegie Technical Schools, Andrew Carnegie wrote, "My heart is in the work." These words have been echoed by students, faculty and administrators throughout this century and they live on the Carnegie Mellon campus today.


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