Sunday, August 18, 2013

Remembering the Work of Dr. Patricia Goldman-Rakic

A touching and comprehensive review article in Cerebral Cortex commemorates the life and work of Dr. Patricia Goldman-Rakic on the ten year anniversary of her death (Arnsten, 2013). The author of over 600 publications, Goldman-Rakic worked at NIMH from 1965-1979 and was a professor at Yale from 1979-2003. She served as President of the Society for Neuroscience in 1989-90 and was elected to the National Academy of Sciences in 1990. The review was written by one of her former post-docs, Dr. Amy F.T. Arnsten, herself a professor at Yale.

Keeping a Life "in mind"

Dr. Goldman-Rakic is best known for her research on working memory and the prefrontal cortex (PFC). Working memory is a transient form of memory that actively maintains and manipulates information for brief periods of time (Goldman-Rakic, 1995):
Working memory in its most elementary form, the ability to keep events "in mind" for short periods of time, has been studied in nonhuman primates by delayed-response paradigms. Whereas in humans, facts and events accessed from long-term memory stores can be instigated by verbal instructions, in experiments with animals, the information to be processed has to be provided by the experimenter.

Building on the work of Fuster and colleagues, her studies demonstrated that neurons in the dorsolateral portion of the PFC fire more rapidly when a spatial location cue is removed from the visual field and must be remembered over a brief delay. The sample neuron in the figure below codes for targets located at 270 degrees and not for targets at other locations. Note that the neurons's response is specifically enhanced over the delay period (D).

Fig 1 (modified from Goldman-Rakic, 1995). Neuron during the Many Trials over Which a Monkey Performed an Oculomotor Delayed-Response Working Memory Task. The neuron's response for all trials at the preferred target location is shown as a histogram of the average response per unit time for that location. The activity is also shown in relation to task events (C, cue; D, delay; R, response) on a trial-by-trial basis.

These neurons are located in the dorsal bank of the principal sulcus in monkey dorsolateral PFC, equivalent to Brodmann area 46 in humans. Goldman-Rakic and colleagues conducted extensive neuroanatomical tracing studies in the 1980's to map out the connections of this region and the posterior parietal cortex, major hubs in the brain's larger scheme of visuospatial processing.

Fig. 2 (Arnsten, 2013). The cortical circuitry for spatial cognition, based on the work of Goldman-Rakic and Selemon. Note that both the dlPFC (area 46) and parietal cortex have many shared connections to subcortical structures that are not shown in this illustration, as well as “nonshared” connections that are not included in this diagram {from L. Selemon}.

Goldman-Rakic's work was enormously influential, as shown in the figure below.

Fig. 1 (Arnsten, 2013). Timeline of the discoveries of the PFC role in working memory (WM) and the key contributions of Goldman-Rakic. The graph shows the number of papers cited on PubMed using the search term “prefrontal cortex” for each decade ending in the year noted. Key publications by Goldman-Rakic and other early pioneers are indicated.

Other major areas of research reviewed by Arnsten (2013) include the Key Role of Dopamine and Neuromodulation (e.g., D1 vs. D2 Receptor Actions, the D1 Receptor “inverted-U” Dose–Response), the Neurobiological Foundations of Schizophrenia (e.g., Insults to dlPFC Microcircuitry), and the dlPFC Microcircuits that Generate Mental Representations. The tribute article is open access and can be read freely by all.

A Life of the Mind, Shaped by Working Memory
The significance of working memory for higher cortical function is not necessarily self-evident. Perhaps even the quality of its transient nature misleads us into thinking it is somehow less important than the more permanent archival nature of long-term memory. However, the brain’s working memory function, i.e., the ability to bring to mind events in the absence of direct stimulation, may be its inherently most flexible mechanism and its evolutionarily most significant achievement. Thus, working memory confers the ability to guide behavior by representations of the outside world rather than by immediate stimulation, and thus to base behavior on ideas and thoughts.

- Pat Goldman-Rakic (1991)


Arnsten AF (2013). The Neurobiology of Thought: The Groundbreaking Discoveries of Patricia Goldman-Rakic 1937-2003. Cerebral Cortex PMID: 23926115

Goldman-Rakic PS (1995). Cellular basis of working memory. Neuron, 14 (3), 477-85 PMID: 7695894