Goldman-Rakic, Patricia Shoer

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GOLDMAN-RAKIC, PATRICIA SHOER

(b. Salem, Massachusetts, 22 April 1937; d. New Haven, Connecticut, 31 July 2003),

neuroscience, prefrontal cortex, schizophrenia, brain anatomy and physiology.

Goldman-Rakic defied tradition and became one of the first female tenured neuroscientists, first at the National Institute of Mental Health and then later at Yale University. Known especially for her work on the anatomy and physiology of the prefrontal cortex, she was the first to see the prefrontal cortex as the locus of short-term memory. Goldman-Rakic described this memory system as the “blackboard of the mind.” The driving issue for her was to determine how the brain represents information in short-term memory and how this information is accessed. Her work also provided anatomical and physiological bridges between the neurotransmitter dopamine and psychiatric ailments connected to disrupted cognition, such as schizophrenia and Alzheimer's. She was one of the earliest to demonstrate connections between what the brain is doing and how things seem in the mind.

Childhood . Patricia Shoer Goldman-Rakic, known to family, friends, and colleagues as Pat, was born on 22 April 1937 in Salem, Massachusetts. Her father, Irving Shoer, was the son of Latvian immigrants; her mother, Jennie Pearl, was a Russian immigrant herself. Soon after Goldman-Rakic was born, her family moved to Peabody, Massachusetts, where she remained until she left to attend college. Goldman-Rakic grew up with her twin sister Ruth and younger sister Linda; all three graduated from Peabody High School, each winning the George Peabody Medal, and each eventually earned a doctorate in the sciences. During her youth, Goldman-Rakic never expected to become a scientist. As a teenager, she played piano for a dance studio in the afternoons and waited tables at a local restaurant in the evenings. She also studied violin and even mastered the art of calligraphy.

Goldman-Rakic earned a bachelor’s degree in experimental psychology at Vassar College, graduating summa cum laude in 1959. She then went to graduate school in psychology at the University of California, Los Angeles (UCLA), and completed her PhD in 1963 under the mentorship of developmental psychologist Wendell Jeffrey. Goldman-Rakic’s dissertation concerned the effects of stress on the cognitive development of rats. That research marks the beginning of her lifelong interest in the connections between brain development and behavior, with the rest of her career focused almost exclusively on the frontal lobes.

National Institute of Mental Health . Hired as a staff member at the National Institute of Mental Health (NIMH) in 1965, Goldman-Rakic started research on the frontal lobe under the tutorship of and in collaboration with Enger “Hal” Rosvold, who established the first laboratory at NIMH for the study of higher cortical function and complex behavior. There she investigated the

associative cortex of the frontal lobe, also known as pre-frontal cortex, in monkeys. She and Rosvold showed that lesions in certain areas of prefrontal cortex, such as the sulcus principalis, caused difficulties in short-term memory. In particular, monkeys with these deficits could not perform delayed-response tasks, a psychological research protocol used in the early twentieth century to study retention in primates and younger children. Goldman-Rakic saw that this task could also be used to examine the biological substrates of short-term memory.

Goldman-Rakic would show an animal a bit of food and then hide the food in one of two containers. Then, for a varying period, she would prevent the animal from seeing the containers. Once the animal could see the containers again, she would note whether it would look at the container that contained the hidden food. It turns out that rhesus monkeys have difficulties with this task if their prefrontal cortex is lesioned, even though they can perform the task normally if they are allowed to see the containers for the duration of the experiment. That is, lesioning the prefrontal cortex in rhesus monkeys appears to impair their short-term memory systems.

At the NIMH, she also studied the effects of early (pre- and postnatal) lesions of the prefrontal cortex on development and behavior. She was one of the first researchers to document and measure functional plasticity in the cortex. In particular, she showed that monkeys performed remarkably well when their prefrontal cortices are damaged early in life, but detrimental cognitive abnormalities appear when the lesion occurs in postadolescence.

It is noteworthy that Goldman-Rakic was not promoted to a tenure track position at the NIMH until 1975—eight years after she joined the program. Eventually, in the years before she left, she was named chief of the Section on Developmental Neurobiology. Her career was not without its challenges, not the least of which was being a woman in what was then a man’s career. Throughout her professional life, Goldman-Rakic worked tirelessly as a mentor to female graduate students and young faculty. It is not mere chance that at the time of her death, more than 50 percent of all new neuroscience PhDs worldwide were women.

Massachusetts Institute of Technology . In 1974 the Massachusetts Institute of Technology (MIT) hired Goldman-Rakic as a visiting scientist. There she worked closely with Walle Natua, an authority on central nervous system anatomy. Natua and Goldman-Rakic investigated the internal connections of the prefrontal cortex and its connections with the caudate nucleus. Together, they made an important discovery: the axons—the ends of neurons—were distributed in a regular pattern. In the prefrontal cortex in particular, the terminal arbors were arranged in a regular fashion. Cross-sections of cortex revealed that columns of axonal ends spanned the entire gray matter, interrupted by columns of space that presumably contained the terminals of other areas.

These discoveries strongly influenced her later research. Finding columns in prefrontal cortex told her that these areas were functionally specialized in some way, just as previously discovered columns in primary sensory cortex had indicated functional specialization. The Nobel Prize–winning studies of David Hubel and Torsten Wiesel established that the neurons in brain regions that processed sensory inputs were grouped vertically in columns and that these columns were differentiated in terms of their function. Scientists assumed that these columns were therefore a basic unit of information processing. Goldman-Rakic had isolated similar structural components in the frontal cortex.

Also in 1974, Goldman-Rakic met her future husband, Pasko Rakic, who then was on the faculty at Harvard. They began a personal and professional collaboration that would change the course of contemporary neuroscience. They married in 1979 and moved as a couple to Yale University, where he headed the newly created Section of Neurology; she joined the Section of Neuroanatomy. Together, they built those units into one of the premier departments of neurobiology in the world. By all accounts, theirs was a strong, happy, and successful marriage, one in which they each viewed the other as a friend, colleague, and supporter. They had no children.

Yale University . At Yale, Goldman-Rakic continued the anatomical and histochemical studies of prefrontal cortex that she started at NIMH, though she was now more focused on the cognitive and behavioral contexts of memory. She launched a series of experiments that traced cortico-cortical connections using just about every axon-tracing technique available, eventually characterizing the three-dimensional structure of individual prefrontal cortical cells and the thousands of connections each cell makes to other cells. As cognitive scientists and other brain researchers around her were proposing parallel processing as the model of cognition in the brain as a theoretical possibility, she continued her detailed study of the connections between areas of frontal cortex, with the goal of outlining the actual parallel processes there.

One of her most important discoveries was the alternating columns of the sulcus principalis, which confirmed her previous work with Nauta. Many believed that the alternating inputs into the prefrontal cortex indicated that this area integrated information; Goldman-Rakic, however, remained committed to the idea of cortical modularity, that the cortex was divided into discrete areas, each of which handled a different processing job. Her laboratory

produced a large body of evidence illustrating that the organizational structure of the neocortex was conserved across different areas, extending from the primary sensory systems to the frontal lobes. In all regions, parallel streams of information flowed next to one another.

At the same time, Goldman-Rakic, in collaboration with Pasko Rakic and Jean-Pierre Bourgeois and others, ran detailed studies of neurochemical development. They discovered that all areas of the cerebral cortex, including primary sensory, motor, and associative regions, develop at the same rate. That is, synapses grow and proliferate at the same speed in all cortical areas. This evidence for concurrent synaptogenesis belied earlier theories of brain development, which tied neural cell growth to myelination schedules.

Additionally, with Gallager, Kostovic, Levitt, Lidow, Mrzljak, and others, she demonstrated the presence of several neurotransmitters in the prefrontal cortex, including gamma-aminobutyric acid, acetylcholine, serotonin, and, most importantly, dopamine. She and her colleagues worked to discover what each of them was doing functionally in the prefrontal cortex, especially as their activities pertained to memory. In particular, she showed that dopamine and its receptors were crucially important to the development and maintenance of short-term memory, again by using the delayed response task paradigm. She also tied a decrease in dopaminergic activity to schizophrenia, Parkinson’s disease, Alzheimer’s dementia, and general aging.

The reasons Goldman-Rakic linked schizophrenia to the prefrontal cortex were threefold; each of these also shaped psychiatrists’ understanding of how the disease fundamentally operated. First, Goldman-Rakic saw schizophrenics as having difficulties with integrating reasoning and behavior across time, which, according to her, demonstrated failures in short-term memory. This interpretation of schizophrenic behavior was a relatively new one in psychiatry when Goldman-Rakic first advanced it. Second, many antipsychotic medications that help schizophrenics target dopamine interactions. Prior to Goldman-Rakic’s work, antipsychotic medications were often dispensed without any deep understanding of exactly what they were doing in the brain. Third, Goldman-Rakic learned that the prefrontal cortex of schizophrenics is structurally abnormal. This last fact she discovered through careful study of the prefrontal cortex of autopsies of patients diagnosed with schizophrenia. She later connected those data to brain imaging studies taken of live schizophrenia patients.

In addition to helping psychiatrists understand schizophrenia, Goldman-Rakic’s analysis of dopamine receptors in the prefrontal cortex have also pointed to new treatments for schizophrenia and Parkinson’s disease. She and her colleagues identified the hitherto unknown protein calcyon in the brain, which pharmaceutical developers are trying to target to improve the signaling in cells that are otherwise desensitized to dopamine. Near the time of her death, she was working on understanding how abusing amphetamines, even for short periods, in childhood or early adulthood can lead to long-lasting cognitive difficulties.

Goldman-Rakic’s Legacy . Goldman-Rakic is perhaps best known for her role in connecting the prefrontal cortex to short-term memory. Though she used multidisciplinary techniques in her research, this connection is best highlighted through her single-celled microelectrode recordings of neuronal firing patterns in the prefrontal cortex of monkeys performing a delayed-response task in the late 1980s. She and her colleagues showed that neurons fired more and more rapidly during the delay or memory portion of the task. While similar firing patterns had been documented before in the prefrontal cortex, what stood out about Goldman-Rakic’s cells was their finely tuned sensitivity to location. Thus, she was able to show that the memory in the prefrontal cortex could be mapped modularly and was arranged in columns. This contradicted the prevailing views of the times, which held that memory was a single process located in a single place in the brain.

At about the same time, Goldman-Rakic began to use the term working memory (as well as representational memory) to refer to the presumed function of these cells. Psychologists had used the term working memory for years to describe the short-term retention of information during cognitive problem solving. Goldman-Rakic used the delayed-response task as a way to operationalize the idea of working memory and suggested that the cells she had recorded were the neural underpinnings for this psychological concept. Later, using the data from additional microelectrode recordings, she argued that the prefrontal cortex contained segregated processing streams for memories of the different modalities of information (e.g., visual memory vs. spatial memory).

In addition to her work on memory, Goldman-Rakic also is well known for her work on the plasticity of the prefrontal cortex. She found that brains could change fairly easily early in development, compensating for injuries and sparing critical functions—processes that cannot occur later in life. This realization stimulated her to study the ontogenetic development of prefrontal cortex, using radioactive tracers to follow individual cellular activities. She uncovered many influences on brain development, including gender and age.

Over the course of her career, she published—either as sole author or as a coauthor—more than 250 articles, many of which are considered seminal in the early

twenty-first century. In 1991 she and Pasko Rakic founded the journal Cerebral Cortex. As the chief coeditors, they made that journal into the premier publication for basic cortical research.

Patricia Goldman-Rakic received numerous honors and awards. She was elected president of the Society for Neuroscience in 1989; she was elected to the National Academy of Sciences (U.S.) in 1990, the American Academy of Arts and Sciences in 1991, and the Institute of Medicine of the National Academy of Sciences in 1994. She received France’s Fyssen Prize in Neuroscience in 1990, the Merit Award of NIMH in 1990, the Lieber Award for the National Alliance for Research on Schizophrenia and Depression in 1991, the Karl Lashley Award of the American Philosophical Society in 1996, the Ralph Gerard Award of the Society for Neuroscience in 2002, and the Gold Medal for Distinguished Scientific Contributions from the American Psychological Association. She was awarded a doctor honoris causa from the University of Utrecht in 2000 and an honorary degree from St. Andrews College of the University of Edinburgh in 2003, just a few months before her death.

Goldman-Rakic died at the age of sixty-six on 31 July 2003 from injuries sustained when a car struck her as she was crossing a street in Hamden, Connecticut. At the time of her death, she held appointments at Yale as professor in the Departments of Neurobiology, Psychiatry, Neurology, and Psychology. She was struck down at the pinnacle of her career and died one of the most innovative and dedicated neuroscientists in the modern era of brain research.

BIBLIOGRAPHY

WORKS BY GOLDMAN-RAKIC

With Howard T. Crawford, Linton P. Stokes, Thelma W. Galkin, et al. “Sex-Dependent Behavioral Effects of Cerebral Cortical Lesions in the Developing Rhesus Monkey.” Science 186 (1974): 540–542.

“Neuronal Plasticity in Primate Telencephalon: Anomalous Projections Induced by Prenatal Removal of Frontal Cortex.” Science 202 (1978): 768–776.

With Thelma W. Galkin. “Prenatal Removal of Frontal Association Cortex in the Fetal Rhesus Monkey: Anatomical and Functional Consequences in Postnatal Life.” Brain Research 152 (1978): 451–485.

“Contralateral Projections to the Dorsal Thalamus from Frontal Association Cortex in the Rhesus Monkey.” Brain Research 166 (1979): 166–171.

With Lynn D. Selemon and Michael L. Schwartz. “Dual Pathways Connecting the Dorsolateral Prefrontal Cortex with the Hippocampal Formation in the Rhesus Monkey.” Neuroscience 12 (1984): 719–743.

“Circuitry of Primate Prefrontal Cortex and Regulation of Behavior by Representational Memory.” In Handbook of Physiology: The Nervous System: Higher Functions of the Brain, edited by Vernon B. Montcastle, Fred Plum, and Stephen R. Geiger, 373–417. Bethesda, MD: American Physiological Society, 1987.

“Topography of Cognition: Parallel Distributed Networks in Primate Association Cortex.” Annual Review of Neuroscience 11 (1988): 137–156.

With Shintaro Funahashi and Charles J. Bruce. “Mnemonic Coding of Visual Space in the Monkey’s Dorsolateral Prefrontal Cortex.” Journal of Neurophysiology 61 (1989): 331–349.

“Cortical Localization of Working Memory.” In Brain Organization and Memory: Cells, Systems, and Circuits, edited by James L. McGaugh, Norman M. Weinberger, and Gary Lynch, 285–298. New York: Oxford University Press, 1990.

With Michael S. Lidow and D. W. Gallager. “Overlap of Dopaminergic, Adrenergic, and Serotonergic Receptors and Complementarity of Their Subtypes in Primate Prefrontal Cortex.” Journal of Neuroscience 10 (1990): 2125–2138.

“Regional and Cellular Fractionation of Working Memory.” Proceedings of the National Academy of Sciences of the United States of America 93 (1996): 13473–13480.

With Amy F. Arnsten. “Noise Stress Impairs Prefrontal Cortical Cognitive Function in Monkeys: Evidence for Hyperdopaminergic Mechanism.” Archives of General Psychiatry 55 (1998): 362–628.

With Srinivas G. Rao and Graham V. Williams. “Isodirectional Tuning of Adjacent Interneurons and Pyramidal Cells during Working Memory: Evidence for Microcolumnar Organization in PFC.” Journal of Neurophysiology 81 (1999): 1903–1916.