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Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale.

Arnsten AF, Jin LE - Yale J Biol Med (2012)

Bottom Line: It regulates behavior, thought, and emotion using working memory.A century of discoveries at Yale Medical School has revealed the neurobiology of PFC cognitive functions, as well as the molecular needs of these circuits.Recent research has found that the noradrenergic α2A agonist guanfacine can improve PFC function by strengthening PFC network connections via inhibition of cAMP-potassium channel signaling in postsynaptic spines.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, Yale School of Medicine, New Haven, CT 06510, USA. amy.arnsten@yale.edu

ABSTRACT
The prefrontal cortex (PFC) is among the most evolved brain regions, contributing to our highest order cognitive abilities. It regulates behavior, thought, and emotion using working memory. Many cognitive disorders involve impairments of the PFC. A century of discoveries at Yale Medical School has revealed the neurobiology of PFC cognitive functions, as well as the molecular needs of these circuits. This work has led to the identification of therapeutic targets to treat cognitive disorders. Recent research has found that the noradrenergic α2A agonist guanfacine can improve PFC function by strengthening PFC network connections via inhibition of cAMP-potassium channel signaling in postsynaptic spines. Guanfacine is now being used to treat a variety of PFC cognitive disorders, including Tourette's Syndrome and Attention Deficit Hyperactivity Disorder (ADHD). This article reviews the history of Yale discoveries on the neurobiology of PFC working memory function and the identification of guanfacine for treating cognitive disorders.

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The discovery of the key role of the dlPFC in working memory byJacobsen in 1936 [16]. A. Carlyle Jacobsen, in about 1940, wholater became the first President of SUNY Upstate Medical Center. Photocourtesy of the F.W. Kent Collection of Photographs, University of IowaArchives, University of Iowa Libraries. B. An artisticrendering based on a figure from Jacobsen’s paper showing the bilateraldlPFC lesion that gravely impaired spatial working memory. Unilateral PFClesions or lesions of the same size elsewhere in the cortex had much lesseffect on performance. C. Reconstruction of a portion of atable from Jacobsen’s paper showing the marked impairment on the delayedresponse spatial working memory task and preserved performance on the visualdiscrimination problems that did not require working memory to solve.
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Figure 2: The discovery of the key role of the dlPFC in working memory byJacobsen in 1936 [16]. A. Carlyle Jacobsen, in about 1940, wholater became the first President of SUNY Upstate Medical Center. Photocourtesy of the F.W. Kent Collection of Photographs, University of IowaArchives, University of Iowa Libraries. B. An artisticrendering based on a figure from Jacobsen’s paper showing the bilateraldlPFC lesion that gravely impaired spatial working memory. Unilateral PFClesions or lesions of the same size elsewhere in the cortex had much lesseffect on performance. C. Reconstruction of a portion of atable from Jacobsen’s paper showing the marked impairment on the delayedresponse spatial working memory task and preserved performance on the visualdiscrimination problems that did not require working memory to solve.

Mentions: The first groundbreaking studies of the PFC’s role in cognition began in the 1930s atYale School of Medicine. John Fulton arrived at Yale in 1930 to serve as Chair ofthe new Department of Physiology. He had been trained as a neurosurgeon by HarveyCushing at Harvard and was able to perform complex surgeries that opened new avenuesof research. Together with Carlyle Jacobsen (Figure2A), they examined the effects of specific brain lesions on behavior inprimates. Although they are widely known for their work relevant to lobotomies,i.e., that very large PFC lesions made aggressive animals calmer, their mostimportant breakthrough is rarely cited: the discovery that the dorsolateral regionof the PFC is essential for abstract thought [16]. Jacobsen published this finding in 1936 (citingthe key role of Fulton’s neurosurgical skills). He had designed a definitive studycomparing the effects of specific cortical lesions on a series of cognitive tasksduring which the information needed to solve the problem was either available in theenvironment or had to be held in working memory. He found that monkeys withbilateral lesions to the dorsolateral PFC (dlPFC), but not other cortical lesions,were markedly impaired on problems requiring working memory and that this impairmentwas permanent (Figure 2B-C). He wrote, “Theanimal without the frontal association area learns and retains sensory-motor habitsand visual discriminations but it is unable to remember for even a few seconds underwhich of two cups a piece of food is concealed . . . It is as if ‘out ofsight, out of mind’ were literally applicable” [16].


Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale.

Arnsten AF, Jin LE - Yale J Biol Med (2012)

The discovery of the key role of the dlPFC in working memory byJacobsen in 1936 [16]. A. Carlyle Jacobsen, in about 1940, wholater became the first President of SUNY Upstate Medical Center. Photocourtesy of the F.W. Kent Collection of Photographs, University of IowaArchives, University of Iowa Libraries. B. An artisticrendering based on a figure from Jacobsen’s paper showing the bilateraldlPFC lesion that gravely impaired spatial working memory. Unilateral PFClesions or lesions of the same size elsewhere in the cortex had much lesseffect on performance. C. Reconstruction of a portion of atable from Jacobsen’s paper showing the marked impairment on the delayedresponse spatial working memory task and preserved performance on the visualdiscrimination problems that did not require working memory to solve.
© Copyright Policy - open access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3313539&req=5

Figure 2: The discovery of the key role of the dlPFC in working memory byJacobsen in 1936 [16]. A. Carlyle Jacobsen, in about 1940, wholater became the first President of SUNY Upstate Medical Center. Photocourtesy of the F.W. Kent Collection of Photographs, University of IowaArchives, University of Iowa Libraries. B. An artisticrendering based on a figure from Jacobsen’s paper showing the bilateraldlPFC lesion that gravely impaired spatial working memory. Unilateral PFClesions or lesions of the same size elsewhere in the cortex had much lesseffect on performance. C. Reconstruction of a portion of atable from Jacobsen’s paper showing the marked impairment on the delayedresponse spatial working memory task and preserved performance on the visualdiscrimination problems that did not require working memory to solve.
Mentions: The first groundbreaking studies of the PFC’s role in cognition began in the 1930s atYale School of Medicine. John Fulton arrived at Yale in 1930 to serve as Chair ofthe new Department of Physiology. He had been trained as a neurosurgeon by HarveyCushing at Harvard and was able to perform complex surgeries that opened new avenuesof research. Together with Carlyle Jacobsen (Figure2A), they examined the effects of specific brain lesions on behavior inprimates. Although they are widely known for their work relevant to lobotomies,i.e., that very large PFC lesions made aggressive animals calmer, their mostimportant breakthrough is rarely cited: the discovery that the dorsolateral regionof the PFC is essential for abstract thought [16]. Jacobsen published this finding in 1936 (citingthe key role of Fulton’s neurosurgical skills). He had designed a definitive studycomparing the effects of specific cortical lesions on a series of cognitive tasksduring which the information needed to solve the problem was either available in theenvironment or had to be held in working memory. He found that monkeys withbilateral lesions to the dorsolateral PFC (dlPFC), but not other cortical lesions,were markedly impaired on problems requiring working memory and that this impairmentwas permanent (Figure 2B-C). He wrote, “Theanimal without the frontal association area learns and retains sensory-motor habitsand visual discriminations but it is unable to remember for even a few seconds underwhich of two cups a piece of food is concealed . . . It is as if ‘out ofsight, out of mind’ were literally applicable” [16].

Bottom Line: It regulates behavior, thought, and emotion using working memory.A century of discoveries at Yale Medical School has revealed the neurobiology of PFC cognitive functions, as well as the molecular needs of these circuits.Recent research has found that the noradrenergic α2A agonist guanfacine can improve PFC function by strengthening PFC network connections via inhibition of cAMP-potassium channel signaling in postsynaptic spines.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, Yale School of Medicine, New Haven, CT 06510, USA. amy.arnsten@yale.edu

ABSTRACT
The prefrontal cortex (PFC) is among the most evolved brain regions, contributing to our highest order cognitive abilities. It regulates behavior, thought, and emotion using working memory. Many cognitive disorders involve impairments of the PFC. A century of discoveries at Yale Medical School has revealed the neurobiology of PFC cognitive functions, as well as the molecular needs of these circuits. This work has led to the identification of therapeutic targets to treat cognitive disorders. Recent research has found that the noradrenergic α2A agonist guanfacine can improve PFC function by strengthening PFC network connections via inhibition of cAMP-potassium channel signaling in postsynaptic spines. Guanfacine is now being used to treat a variety of PFC cognitive disorders, including Tourette's Syndrome and Attention Deficit Hyperactivity Disorder (ADHD). This article reviews the history of Yale discoveries on the neurobiology of PFC working memory function and the identification of guanfacine for treating cognitive disorders.

Show MeSH
Related in: MedlinePlus