In Search of Memory: The Emergence of a New Science of Mind (60 page)

Other information in this chapter was drawn from the following:

Agnihotri, N. T., R. D. Hawkins, E. R. Kandel, and C. G. Kentros. “The long-term stability of new hippocampal place fields requires new protein synthesis.”
Proc. Natl. Acad. Sci. USA
101 (2004): 3656–61.

Bushnell, M. C., M. E. Goldberg, and D. L. Robinson. “Behavioral enhancement of visual responses in monkey cerebral cortex. 1: Modulation in posterior parietal cortex related to selective visual attention.”
J. Neurophysiol
. 46, no. 4 (1981): 755–72.

Kentros, C. G., N. T. Agnihotri, S. Streater, R. D. Hawkins, and E. R. Kandel. “Increased attention to spatial context increases both place field stability and spatial memory.”
Neuron
42 (2004): 283–95.

McHugh, T. J., K. I. Blum, J. Z. Tsien, S. Tonegawa, and M. A. Wilson. “Impaired hippocampal representation of space in CA1-specific NMDAR1 knockout mice.”
Cell
87 (1996): 1339–49.

O’Keefe, J., and J. Dostrovsky. “The hippocampus as a spatial map: Preliminary evidence from unit activity in the freely-moving rat.”
Brain Res
. 34, no. 1 (1971): 171–75.

Rotenberg, A., M. Mayford, R. D. Hawkins, E. R. Kandel, and R. U. Muller. “Mice expressing activated CaMKII lack low frequency LTP and do not form stable place cells in the CA1 region of the hippocampus.”
Cell
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Theis, M., K. Si, and E. R. Kandel. “Two previously undescribed members of the mouse CPEB family of genes and their inducible expression in the principal cell layers of the hippocampus.”
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Zeki, S. M. A
Vision of the Brain.
Oxford: Oxford University Press, 1993.

24: A Little Red Pill

For a discussion of Pasteur’s contribution to science and industry, see R. J. Dubos,
Louis Pasteur
(Boston: Little, Brown, 1950); and M. Perutz, “Deconstructing Pasteur,” in
I Wish I’d Made You Angry Earlier: Essays on Science, Scientists and Humanity
(Plainview, N.Y.: Cold Spring Harbor Laboratory Press, 1998), pp. 119–30.

For a discussion of Dale’s interaction with academic and industrial life, see H. H. Dale,
Adventures in Physiology
(London: Pergamon, 1953).

For a discussion of the early history of biotechnology, see S. Hall,
Invisible Frontiers: The Race to Synthesize a Human Gene
(New York: Atlantic Monthly Press, 1987); and J. D. Watson and A. Berry,
DNA: The Secret of Life
(New York: Alfred A. Knopf., 1987). Hall (p. 94) is the source for “sin” and “purist heaven.”

Kenney, M.
Biotechnology. The University-Industrial Complex.
New Haven: Yale University Press, 1986.

For a discussion of neuroethics, see M. J. Farah, J. Illes, R. Cook-Deegan, H. Gardner, E. R. Kandel, P. King, E. Parens, B. Sahakian, and P. R. Wolpe. “Science and society: Neurocognitive enhancement: What can we do and what should we do?”
Nat. Rev. Neurosci
. 5 (2004): 421–25; S. Hyman, “Introduction: The brain’s special status,”
Cerebrum 6
, no. 4 (2004): 9–12, quotation from p. 9. S. J. Marcus, ed.
Neuroethics: Mapping the Field
(New York: Dana Press, 2004).

Other information in this chapter was drawn from the following:

Bach, M. E., M. Barad, H. Son, M. Zhuo, Y.-F. Lu, R. Shih, I. Mansuy, R. D. Hawkins, and E. R. Kandel. “Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation
in vitro
and are attenuated by drugs that enhance the cAMP signaling pathway.”
Proc. Natl. Acad. Sci. USA
96 (1999): 5280–85.

Barad, M., R. Bourtchouladze, D. Winder, H. Golan, and E. R. Kandel. “Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory.”
Proc. Natl. Acad. Sci. USA
95 (1998): 15020–25.

25: Mice, Men, and Mental Illness

Another major impetus behind the rise of molecular neurology was the early emergence of patient advocacy groups. Groups of patients and their families and friends have formed around particular diseases since at least the 1930s, when the Infantile Paralysis Foundation initiated the March of Dimes, spurred by President Franklin D. Roosevelt, who had contracted poliomyelitis in 1921. The foundation supported both the basic and the clinical research that led to the development of the polio vaccines, which ultimately eradicated the disease. This was a remarkable process and it was based on the ability of the foundation to raise substantial sums of money and to select scientific advisors who supported imaginative, rigorous research.

In the 1960s a similar approach was taken toward genetic diseases of the nervous system. As the historian Alice Wexler, herself a member of a patient advocate group, has written: “The decade of the 1960s, with its blossoming of social activism, also helped foster a political atmosphere favorable to mobilizing families directly affected by the illness. Civil rights activism, the feminist health movement, and the patient rights movement of the sixties and seventies all created an environment that encouraged families [of patients with genetic diseases of the nervous system]…to act on their behalf” (A. Wexler,
Mapping Fate: A Memoir of Family, Risk, and Genetic Research
[New York: Times Books/Random House, 1995], p. xv).

In 1967 songwriter and poet Woody Guthrie died of Huntington’s disease. This terrible illness mobilized his former wife, the dancer Marjorie Guthrie, to organize families of people with the disease into a group called the Committee to Combat Huntington’s, which later evolved into the Huntington’s Disease Society of America. This advocacy group lobbied Congress to speed up the development of effective therapies and to obtain greater support for efforts to alleviate the consequences of the disease by educating family members and training health professionals.

The same year that Woody Guthrie died, Leonore Wexler was diagnosed with Huntington’s disease, as her two siblings had been before her. Leonore’s husband, Milton Wexler, a gifted and farsighted psychoanalyst with a successful practice in Los Angeles, realized that having one parent with Huntington’s disease gave his daughters, Alice, the historian, and Nancy, a psychologist who later became a friend and colleague of mine at Columbia, a 50–50 chance of inheriting the disease. Worried about his daughters and pained by his ex-wife’s illness, Wexler formed the Hereditary Disease Foundation. This foundation had a different orientation from Guthrie’s and produced a paradigm shift not only in patient advocacy, but also in how to carry out effective research on a genetic disorder.

Wexler decided not to focus on treatment of the disease because too little was known about it to make such an effort productive. Rather, he turned to basic science and raised money for research targeted at finding and characterizing the mutant gene that causes the disease. Wexler did not simply provide scientists with resources, however. He set up and led working groups of the best scientists to debate alternative strategies and to delineate the ones most likely to succeed. He then recruited and supported scientists with those strategic skills, and he met with them frequently to review progress and plan the next steps.

This strategy, initiated by Milton and carried forward for the next thirty years by Nancy, proved amazingly successful. People with Huntington’s disease were identified, their families’ medical histories established, and tissue banks organized. The scientific community was kept informed of these efforts, so each step the foundation took—from locating the gene (by Nancy Wexler and Jim Gusella) to cloning it and to developing animal models of the disease—was cause for general celebration for the whole scientific community.

This is described in A. Wexler,
Mapping Fate: A Memoir of Family, Risk, and Genetic Research
(New York: Times Books/Random house, 1995).

Indeed, the success of the Hereditary Disease Foundation did not go unnoticed by the relatives of the mentally ill. A number of patient-interest groups related to mental illness have now been formed, of which the most influential has been the National Association for Research in Schizophrenia and Depression (NARSAD). Founded in 1986 by Connie and Steve Lieber and Herbert Pardes, former director of the National Institute of Mental Health, NARSAD provided major direction and support for research in mental illness. Now several other foundations based on patient interest groups also are having an important impact in mental health research including the National Alliance for Mental Illness, the Fragile-X Foundation, and Cure Autism Now.

For a general review of the biology of emotional states, see C. Darwin,
The Expression of Emotion in Man and Animals
(New York: Appleton, 1873); W. B. Cannon, “The James-Lange theory of emotions: A critical examination and an alternative theory,”
Am. J. Psychol
. 39 (1927): 106–24; W. B. Cannon,
The Wisdom of the Body
(New York: W. W. Norton, 1932); A. R. Damasio,
The Feeling of What Happens: Body and Emotion in the Making of Consciousness
(New York: Harcourt Brace, 1999); M. Davis, “The role of the amygdala in fear and anxiety,”
Annu. Rev. Neurosci
. 15 (1992): 353–75; J. E. LeDoux,
The Emotional Brain
(New York: Simon & Schuster, 1996); J. Panskseep,
Affective Neuroscience: The Foundations of Human and Animal Emotions
(New York: Oxford University Press, 1998); W James, “What is an emotion?”
Mind 9
no. 34 (1884): 188–205; and C. G. Lange,
Om Sindsbe Vaegelser et Psycho
(Copenhagen: Kromar, 1885). James republished Lange’s theory in his
Principles of Psychology
, now available in a definitive three-volume set,
The Works of William James
, ed. F. Burkhardt and F. Bowers (1890; reprint, Cambridge, Mass.: Harvard University Press, 1981).

Other information for this chapter was drawn from the following:

Cowan, W. M., and E. R. Kandel. “Prospects for neurology and psychiatry,”
JAMA
285 (2001): 594–600. Huang, Y.-Y., K. C. Martin, and E. R. Kandel. “Both protein kinase A and mitogen-activated protein kinase are required in the amygdala for the macromolecular synthesis-dependent late phase of long-term potentiation.”
J. Neurosci
. 20 (2000): 6317–25.

Kandel, E. R. “Disorders of mood: Depression, mania and anxiety disorders,” in
Principles of Neural Science
, 4th ed., E. R. Kandel, J. H. Schwartz, and T. M. Jessell, eds. New York: McGraw Hill, 2000, pp. 1209–26.

Rogan, M. T., M. G. Weisskopf, Y.-Y. Huang, E. R. Kandel, and J. E. LeDoux. “Long-term potentiation in the amygdala: Implications for memory.” Chapter 2 in
Neuronal Mechanisms of Memory Formation: Concepts of Long-Term Potentiation and Beyond
, edited by C. Hölscher, 58–76. Cambridge: Cambridge University Press, 2001.

Rogan, M. T., K. S. Leon, D. L. Perez, and E. R. Kandel. “Distinct neural signatures for safety and danger in the amygdala and striatum of the mouse.”
Neuron
46 (2005): 309–20.

Shumyatsky, G. P., E. Tsvetkov, G. Malleret, S. Vronskaya, M. Hatton, L. Hampton, J. F. Battey, C. Dulac, E. R. Kandel, and V. Y. Bolshakov. “Identification of a signaling network in lateral nucleus of amygdala important for inhibiting memory specifically related to learned fear.”
Cell
111 (2002): 905–18.

Snyder, S. H.
Drugs and the Brain
. New York: Scientific American Books, 1986.

Tsvetkov, E., W. A. Carlezon, Jr., F. M. Benes, E. R. Kandel, and V. Y. Bolshakov. “Fear conditioning occludes LTP-induced presynaptic enhancement of synaptic transmission in the cortical pathway to the lateral amygdala.”
Neuron
34 (2002): 289–300.

26: A New Way to Treat Mental Illness

Information for this chapter was drawn from the following:

Abi-Dargham, A., D. R. Hwang, Y. Huang, Y. Zea-Ponce, D. Martinez, I. Lombardo, A. Broft, T. Hashimoto, M. Slifstein, O. Mawlawi, R. VanHeertum, and M. Laruelle. “Quantitative analysis of striatal and extrastriatal D2 receptors in humans with [18 F]fallypride: Validation and reproducibility.” In preparation.

Ansorge, M. S., M. Zhou, A. Lira, R. Hen, and J. A. Gingrich. “Early-life blockade of the 5–HT transporter alters emotional behavior in adult mice.”
Science
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Baddeley, A. D.
Working Memory.
Oxford: Clarendon Press, 1986.

Carlsson, M. L., A. Carlsson, and M. Nilsson. “Schizophrenia: From dopamine to glutamate and back.”
Curr. Med. Chem.
11, no. 3 (2004): 267–77.

Fuster, J. M. “The prefrontal cortex—an update: Time is of the essence.”
Neuron
30, no. 2 (2001): 319–33.