The Neurobiology of Thought: The Groundbreaking Discoveries of Patricia Goldman-Rakic 1937-2003

Abstract

Patricia S. Goldman-Rakic (1937–2003) transformed the study of the prefrontal cortex (PFC) and the neural basis of mental representation, the basic building block of abstract thought. Her pioneering research first identified the dorsolateral PFC (dlPFC) region essential for spatial working memory, and the extensive circuits of spatial cognition. She discovered the cellular basis of working memory, illuminating the dlPFC microcircuitry underlying spatially tuned, persistent firing, whereby precise information can be held “in mind”: persistent firing arises from recurrent excitation within glutamatergic pyramidal cell circuits in deep layer III, while tuning arises from GABAergic lateral inhibition. She was the first to discover that dopamine is essential for dlPFC function, particularly through D1 receptor actions. She applied a host of technical approaches, providing a new paradigm for scientific inquiry. Goldman-Rakic's work has allowed the perplexing complexities of mental illness to begun to be understood at the cellular level, including atrophy of the dlPFC microcircuits subserving mental representation. She correctly predicted that impairments in dlPFC working memory activity would contribute to thought disorder, a cardinal symptom of schizophrenia. Ten years following her death, we look back to see how she inspired an entire field, fundamentally changing our view of cognition and cognitive disorders.

Dopamine’s Actions in Primate Prefrontal Cortex: Challenges for Treating Cognitive Disorders

“…2). Goldman-Rakic (1995) first studied this mechanism in regard to visuospatial working memory and the Prefrontal Dopamine and Cognitive Disorders dlPFC region that receives visuospatial inputs from the parietal association cortex but found that the same organization extended to other processing domains (O Scalaidhe et al, 1997), with spatial information localized more dorsally and feature information more ventrally (Romanski et al, 1999;Arnsten, 2013). She found that clusters of pyramidal cells receive highly processed information from the sensory association cortex and then were able to maintain the representation of the stimulus in the absence of sensory stimulation through their recurrent excitation within pyramidal cell networks (Goldman-Rakic, 1995).…”

Reduced Labeling of Parvalbumin Neurons and Perineuronal Nets in the Dorsolateral Prefrontal Cortex of Subjects with Schizophrenia

“…Working memory requires the synchronized activity of specific microcircuits in layer 3 of the dorsolateral prefrontal cortex (DLFPC) (Arnsten, 2013), consisting of reciprocal connections between excitatory pyramidal cells (PCs) and a subset of GABAergic interneurons that express the calciumbinding protein parvalbumin (PV) (Curley and Lewis, 2012). Consistent with working memory impairments in schizophrenia, multiple post-mortem studies have demonstrated morphological and/or molecular alterations in DLPFC layer 3 PCs and PV neurons in schizophrenia subjects.…”

Prefrontal cortex and the dysconnectivity hypothesis of schizophrenia

“…The major findings in schizophrenia include: spine loss and dendritic atrophy of PFC neurons; smaller PFC grey matter volume; profound dysfunction of the PFC (including defi cits in working memory); and changes in gene expression (for review, see [15] ). Among these, the changes in microcircuits of the PFC in schizophrenia suggest the possibility of altered connectivity between the PFC and other regions [15] .…”