top of page
  • Writer's pictureDale DeBakcsy

Making Working Memory Work: The Multidisciplinary Neuroscience of Patricia Goldman-Rakic

You’re a monkey, and somebody in a white lab coat has shown you a location where a delicious, ever-so-nummy, bit of banana has been placed, and then obscured your visual field. It is up to you, my good monkey, to hold the location of the food in your monkey mind as second by agonizing second drags on so that, when the obstruction is at last removed, you can identify which location has the banana and claim your reward. To pull this feat off, you are going to have to access the capacities of your “working memory” - the system that allows you to hold things in your mind for a few seconds, without necessarily storing them in your brain forever by placing them into “long-term memory.”


Working memory represents a tantalizing middle ground of semantic knowledge. There are things that we know because they are right in front of us, and things that we know because our hippocampi have made the effort to package them away in our permanent memory system, and then there are those things that we can’t see, and don’t remember forever, but DO remember for a short while, which begs the question, how does memory like that, which clearly must be using its own unique system, work?


Ask any neuroscientist who, more than anyone else, gave us the keys to unlocking working memory, and they will say, without hesitation, Patricia Goldman-Rakic (nee Shoer, 1937-2003), the multidisciplinary researcher whose many-angled investigations of the prefrontal cortex beginning in the 1970s peeled back its mysteries down to the molecular level, and gave us our sense not only of where the capacity for working memory is located in the brain, but how the neuronal structures that make up that location allow us to hold onto knowledge for short but crucial spans of time.


Her mother was a Russian immigrant and her father was the son of Latvian immigrants, and when she was born with her twin sister Ruth on April 22, 1937, in Salem, Massachusetts, her parents could hardly have realized the heights awaiting her. With Ruth she attended Peabody High School, and the pair moved on together to Vassar, where Ruth began her path towards a career as an esteemed virologist and vaccine researcher, and Patricia graduated cum laude in neurobiology in 1959. She went on to receive her PhD from UCLA in 1963, and eventually found her way to the lab of Haldor Rosvold at the National Institute of Mental Health in 1965, a posting that would determine the course of her career.



Rosvold was experimenting with discovering the purpose and functioning of the prefrontal cortex through the application of targeted lesions on the brains of monkeys (and now is as good a time as any to once again step back and appreciate how much sacrifice of non-human life has been made in the quest for better understanding our brains, and how fortunate we are to be living in an age now where better and better imaging techniques and computer models are beginning to lead the way out of the absolute charnel house of neurobiology’s past). Put somewhat brutally, this work involved damaging a portion of a monkey’s brain, and then testing what deficits in function resulted. Goldman-Rakic, as it turned out, was a positive maestro of surgical technique, able to tightly target regions of the prefrontal cortex for lesioning (sometimes even in utero), and thereby to localize with great accuracy what parts of the PFC are responsible for what functions.


Her work determined that a caudal portion of the principal sulcal cortex is the region most responsible for the spatial aspect of working memory, which was an important result, but Goldman wanted to know more, and with improvements in neural visualization that were occuring in the 1970s, and which she went to MIT to study in 1974, she was able to use amino acids that had been tagged with tritium to find columns of neurons in the PFC which she recognized at once as being similar to those found earlier in the primary visual cortex (V1), which meant that the methods that had been developed for studying V1 could be brought to bear on studying the PFC. In 1975 she was made Chief of Developmental Neurobiology, and began assembling a team of research all-stars (including Roger Brown and Tom Brozoski) with complementary but very different skill sets, her neurobiological Ocean’s 11, to focus in at the cellular level on how the PFC does what it does.


The result was a chain of some of neurobiology’s most cited papers, including “Columnar Distribution of Cortico-Cortical Fibers in the Frontal Association, Limbic, and Motor Cortex of the Developing Rhesus Monkey” (1977), “Cognitive Deficit Caused by Regional Depletion of Dopamine in Prefrontal Cortex of Rhesus Monkeys” (1979), and “Development of Cortical Circuitry and Cognitive Function” (1987). What Goldman-Rakic (who added the Rakic to her name upon her 1979 marriage to neuroscientist Pasko Rakic) and her colleagues discovered was that the PFC had different regions for attending to the spatial features of a scene, than for attending to the nature of the objects within it, with the spatial neurons interconnected in a way that allows continued short-term firing of the neurons associated with one region which then trigger inhibition of neurons associated with other regions. If, for example, I know that the bucket with my beloved banana is located at an angle of 40 degrees to the left of me, then during the Obscuring phase of my test, the neurons responsible for that region of my vision will keep firing on a loop, and sending out signals to other neurons responsible for monitoring other angles that inhibit them from firing, so that I can keep the one desired region active and accessible for when I need it during the Reveal phase. The architecture and interconnectedness of the PFC, then, gave rise to its ability to temporarily hold information in our minds, and then to let it disappear without a trace.



These results would have been more than enough to retire on, but of course Goldman-Rakic did not stop there, and pushed her investigations from the cellular level down to the molecular one, investigating the chemical components of PFC function, and in particular on the crucial role that dopamine receptors seemed to play for the carrying out of working memory tasks. These studies on the neurotransmitters of the PFC, then, led to important insights into the nature of schizophrenia, which had until the 1960s been most commonly treated through lobotomization, when it wasn’t shrugged away as the result of bad parenting. Goldman-Rakic saw that some of the symptoms associated with schizophrenia were similar to those she had witnessed in her lesioned rhesus monkeys, and when pursuing the matter saw that the schizophrenic patients had marked decreases in dopamine receptors in their PFC, meaning that the intricate ballet of neuronal firing required to support the working memory system which she had discovered was essentially knee-capped for these individuals, preventing them from effectively holding things in short term memory, with resulting deficits in ability to communicate and function. Even something like forming a meaningful sentence is made much more difficult without the aid of working memory, which allows us to hold the different parts of a proposed sentence in place while we are linearly communicating them, and as to the ability to remember a phone number, the name of a person you just met, or even getting an object from a room that you need, deficits in working memory can add up to a much more challenging life.


Uncovering the neurochemical nature of at least part of the symptoms of schizophrenia went far to promoting a wider sympathy for those living with the disease, and certainly promoted a more targeted investigation into it as a complicated biological, rather than unfortunate social, condition. By the early 2000s, she was pushing forward the boundaries of our understanding of schizophrenia, and of the interconnectedness of the PFC with other regions of the brain, while the scientific community honored her with a slew of awards including the Merit Award of the National Institute of Mental Health (1990), the Karl Lashley Award of the American Philosophical Society (1996), the Ralph Gerard Prize (2002), and the Gold Medal for Distinguished Scientific Contributions of the American Psychological Association (2002). At the peak of her abilities, with her multidisciplinary approach to team-building and problem solving allowing her to attack the problems that interested her on multiple simultaneous fronts, yielding groundbreaking strings of scientific papers, she ought to have had another two decades to act as a wise, rigorous, and guiding force in neuroscientific research, but fate intervened on July 29, 2003, when a car struck her while she was crossing the street in Hamden, Connecticut.



Patricia Goldman-Rakic died of her injuries two days later, on July 31, and the neuroscientific community rose as one in a chorus of shock at the loss of such a talented colleague and good friend, and respect for all that she had done in taming the wilderness of the prefrontal cortex. When it comes to the great mass brain of civilization, most of us are destined for its working memory - present for a few lingering moments after our passing and then allowed to slip quietly into oblivion - but Patricia Goldman-Rakic, for all that she accomplished, and all that she taught us, will never have that fate. The individual who showed us how working memory works has ironically slipped its grasp, and nestled her way firmly into the long-term memory of our species, there to reside for as long as the human race continues living, and remembering, and occasionally hiding bananas from monkeys.


FURTHER READING:


There were many obituaries and remembrances released upon the death of Goldman-Rakic in 2003, but I think the most complete and characteristic by far was that by Kavli Institute neuroscientist Amy Arnsten, who worked with Goldman-Rakic in the late 1990s, in the pages of Neuron. Goldman-Rakic wrote a number of papers summarizing some of her most important work in an accessible form, and if I had to recommend just two which are available free from pay-walls, I’d say “Cellular Basis of Working Memory” (1995) and “Working Memory Dysfunction in Schizophrenia” (1994) are two good starting points.


And if you want to read more tales of great women neuroscientists, keep an eye out for my History of Women in Psychology and Neuroscience, due out Spring 2024 from Pen and Sword Books!

Comments


bottom of page