Help Make Cognitive Associations Happen Faster
The Genetic Leap to Greater Memory 
By Will Block

he momentous waves of a brave new world are crashing the future down around us - whether we like it or not. In August, the news arrived that a great leap had taken place: the manipulation of a single gene had created a smarter mouse! How much smarter? A lot smarter, and not just in one category, but across the board of intelligence (see Figure 1). "This points to the possibility that enhancement of learning and memory or even IQ is feasible through genetic means, through genetic engineering," says Dr. Joe Z. Tsien, the Princeton University molecular biologist who led the research effort to alter one minor gene so as to build, not a better mousetrap, but a better mouse.1

 

Figure 1. Curious mouse. One measure of a mouse's intelligence is the time spent in exploring novel objects placed into its environment. The more curious the mouse, the smarter the mouse. The transgenic mice created by Dr. Tsien in this experiment were significantly more curious than ordinary mice.

To be sure, humans - some humans - will be next. And Dr. Tsien is not just talking about helping patients with memory loss, or restoring the fading memory of the elderly - his techniques are intended to make healthy individuals smarter. Those who are first will genetically cross over to a new frontier of self-improvement that will make the "me generation" of the 1970s look like a bunch of befuddled altruists.

EINSTEIN, ANYONE?
Without the reassurances of clear answers, the ethical issues posed by the mouse-leap breakthrough may be frightening to some. Again listening to Dr. Tsien, "We're in an era when breakthroughs in biology and intelligence are outpacing the culture's capacity to deal with the ethics." But there are no clear answers, so already the fearful weep for our collective "loss of innocence." Others see a new apple of knowledge into which they are bravely eager to bite . . . for the prospects of delight, the "gain of wisdom."

Those who live in the clutches of fear hunger for the days when the frontier was just a physical place. Yet for others, the frontier of the mind is exhilarating; they welcome the chance to make something more of themselves, to burst into their dreams. Who knows? Perhaps to live the life of a Mozart or an Einstein. The question is defined with the logic of a computer. Do we enhance our lives with the rapidly unfolding discoveries of the human genome . . . or . . . do we resist that knowledge because it is too complex? One thing is sure. No one can stop the gene locomotive. You can get out of the way, or hop aboard. The choice is yours.

ENHANCING THE BRAIN AND ITS FUNCTIONS
The paper announcing the transgenic breakthrough of Dr. Tsien and colleagues opens with an homage to a theory of the father of psychobiology, Donald O. Hebb, a Canadian scientist who paved the way for the hypothesis that led to the discovery of how to make a smart mouse.2 Hebb's rule (1949) states that learning and memory are based on changes that occur at the neuronal synapses, the passageways that separate the neurons in the brain; they are in fact the "inner spaces" of the brain.3

Under special circumstances of simultaneous activity, when brain signals arrive at the same place at the same time, synaptic strength increases. In these synchronized moments, the brain is like a subway, with trains of information rushing in for the momentary intensity of a brief station stop, where crowds of data hustle off while other data bustle on. In the brain, pregnant data rub shoulders with other data, expectant with ideas. Things happen. Lightning flashes. In significant learning processes, when neurons are simultaneously active and when the signals they generate arrive at the same synaptic "station" at the same time, big learning and memory advantages occur.

The significance of Hebb's rule is that the brain and its functions are enhanced when two (or more) messages arrive in the synapse together and are detected. This detection is a function of the NMDA (N-methyl-D-aspartate) receptor, which, upon binding with the excitatory neurotransmitter glutamate, controls the formation of learning and memory in most hippocampal pathways (the hippocampus is the part of the brain where much of this activity occurs). NMDA forms a channel that does not open unless two conditions are satisfied simultaneously:

  1. Glutamate binds to the NMDA receptor.
  2. The membrane in which the receptor is embedded is strongly stimulated.

LOSING INSTANT INTEGRATION POWERS
As we age, however, there are protein components of NMDA that become less sensitive to the job of detecting simultaneous signals. This means that the two (or more) signals must arrive at exactly the same time, rather than merely at about the same time. Otherwise, the synaptic strength increase does not occur, and big memory and learning do not take place. Invoking the subway metaphor, less sensitivity means that the two "trains" must arrive at the "station" at the same time, or lose the opportunity to exchange and amplify information. Tragically, this loss of sensitivity starts to occur between our childhood and young-adult stages, resulting in fewer and fewer memory strengthenings. As Wordsworth put it, "The things which I have seen I now can see no more." We lose the power of instant integration we experienced as children.

SUPERIOR LEARNING AND MEMORY ABILITY
The breakthrough of Tsien and collegues was their realization that the NMDA receptor's most critical element, the protein subunit NR2B, could be enhanced by creating a mouse that overexpressed (was especially effective at) the production of this protein. When the transgenic mice produced NR2B in abundance, synaptic potentiation was increased, and the exhibition of  superior ability in learning and memory in various behavioral tasks followed (see Figure 2).

 

Figure 2. More NR2B=Better Memory. At a synaptic junction in the brain's hippocampus, a variety of neurotransmitters can carry nerve impulses to the NMDA receptor. A prevalence of the protein subunit NR2B in the NMDA receptors expands the window of time in which two or more signals can be detected "simultaneously" and thus contribute to learning and memory.

This accomplishment offers proof that NR2B is critical in opening the gates at the threshold for indelible memory formation. It also represents a unifying mechanism for understanding associative learning and memory. For the first time, it is clear that the genetic enhancement of mental and cognitive attributes such as intelligence and memory in mammals is feasible.

LONG-TERM POTENTIATION AND MEMORY
When a strong memory connection occurs in our central nervous system, scientists refer to the process as long-term potentiation (LTP). Originally discovered in 1973, the underlying mechanism of LTP has been extensively studied, both in terms of its action and, more recently, in terms of its behavioral significance.4 LTP is not invoked unless the messages are of a specific variety, one that obeys a version of Hebb's rule. First, there must be sufficient release of the amino acid glutamate and an increase in glutamate binding. In addition, the synapse must alter in response to receipt of the messages, and the NMDA receptor must be "plastic" (it must be responsive).

THE RISKS OF GENE SUPPLEMENTS
There are scores of gene therapy trials now going on in the world, seriously aimed at, for example, cystic fibrosis and peripheral vascular disease. Because the vehicle for gene switching is typically a disarmed adenovirus reprogrammed to change specific genes, it is easy to deliver these "good viruses" via the gastrointestinal tract, from which they easily pass into the blood. In other words, gene supplements are coming.

"To jump from this very elegant molecular work in a mouse model to humans is a very, very big jump," said Dr. Robert Malenka, a psychiatrist and behavioral sciences specialist at Stanford University School of Medicine.  "Nevertheless, it is a jump we can make and will make eventually. When we jump to humans, it will probably be a lot more complicated." Increasing NR2B (the same gene exists in humans) might also increase the risk of a stroke, owing to the commonality of the neurological switches in the brain the relate to both learning and stroke.

WHAT ABOUT MEMORY NOW?
When the transgenic findings were first published in Nature, indicating that a common mechanism lies at the root of all learning, and identifying the protein NR2B as a key to brain function, pharmaceutical companies were fast to respond: "Maybe we could create a drug that mimics NR2B." Alternatively, for those of us not on the well-worn patentability path - "If it's patentable and thus protectable, it's worth doing; otherwise why bother?" - it might be possible to do something right now, short of a gene supplement, by finding a way to increase NR2B production, the decline of which occurs with age. Some drug companies have already been investigating the manipulation of NR2B levels to treat strokes.

NUTRIENTS THAT SPEED ASSOCIATIONS
Curiously, one of the ways the transgenic mice represented their higher intelligence was through their preference for a novel, enriched environment. Some of us are already opting for such environments and enhancing ourselves with cognitive supplements that help us to prefer and choose an enriched environment too.

But the essence of the NMDA-receptor empowerment was an increase in speed and endurance of the neural signal, facilitating easier learning and better memory. Are there any nutrients, herbs, hormones, or other dietary supplements that can have a similar or even the same impact as the doubly expressed gene on the protein that increases intelligence?

VINPOCETINE AND LTP
Vinpocetine has been found to help restore long-term potentiation (LTP) when given after its disruption; LTP is the memory quality that is associated with prolonged and profound learning and memory.5 Researchers generated a lesion in the area of rats' brains found to be responsible for LTP. What resulted was a significant decrease in LTP's signals, indicating that memory formation had been halted. But after the rats received vinpocetine for six days, LTP was induced and found to be completely restorable. In this study too, vinpocetine was tested against Hydergine®, a legendary cognitive enhancer, and found to be equally effective. Hydergine increases the release of brain-derived neurotrophic factor (BDNF) in the hippocampus, activating both glutamatergic synaptic transmission and, in turn, NR2B-containing NMDA receptors.6 Its dramatic enhancement of conceptual ability may be an example of Hebb's rule. Could vinpocetine do the same?

PREGNENOLONE PROTECTS NMDA RECEPTORS
The NMDA receptor is believed to play a major role in learning and in excitotoxic neuronal damage associated with stroke and epilepsy. As we have already indicated, there is some concern that the stimulation of this receptor is a two-way street and can have negative as well as positive effects. Therefore it is important to note that pregnenolone in low doses has been found to protect mice against NMDA-induced seizures and mortality.7 It is a neurosteroid made in the central and peripheral nervous systems, largely from cholesterol. Pregnenolone can act as a modulator of neurotransmitter receptors, such as NMDA, and has been found to be a powerful memory enhancer.8

CHOLINE: THE GRAND POTENTIATOR
In many ways, choline is the most important cognitive-enhancing agent you can take. This is because it is needed for the production of acetylcholine (ACh), one of the principal brain neurotransmitters. Without adequate levels of ACh, no messages would be adequately amplified for delivery throughout the central nervous system. At the same time, choline appears to be necessary for optimal growth. During pregnancy and lactation, the availability of choline for normal development of the brain is critical. Variations in choline intake by mothers influence memory performance in their offspring.9

Acetylcholine, produced from choline and pantothenic acid, is critical for LTP.10 Only through ACh is the brain able to change the synaptic strength in response to stimuli that leave a memory trace. Without adequate ACh, it can be speculated, children would likely never gain the plasticity of instant integration that is normally characteristic of new life. Could inadequate supplies affect adults in a similar way?

Citicoline (also know as CDP-choline) has been found to have neuroprotective properties and can help moderate NMDA excitation. While participating in the moderating process, its memory-enhancing effect is synergized.11 With few side effects of any consequence, citicoline appears to provide memory benefits independent of any clear indication of the aging process.12 In a study with dogs, citicoline was found to exert facilitory effects on learning, memory, and retrieval processes.

DMAE: STEADY AND PROLONGED LEVEL OF ATTENTIVENESS
Dimethylaminoethanol (DMAE), a cholinergic agonist (promoter) that crosses the blood/brain barrier more quickly than choline supplements, is associated with neurological calmness in kids, because of its use for this purpose by Dr. Carl Pfeiffer, a pioneer in the field of nutrition.13 What is often missing from that equation, however, is the role that it plays as a gentle cholinergic agonist, capable of promoting a steady and prolonged level of attentiveness.14 In principle, it is this type of mental state that is associated with mental focus, memory, and mood enhancement. It has been argued that cell-membrane degradation can be slowed by DMAE's involvement in cell-membrane repair, particularly in the central nervous system.

DMAE can also dispose of lipofuscin, a type of cellular debris resulting from the energy activity of the cell.15 Lipofuscin deposits are "age spots" in the brain that impede neurological activity and reduce mental capacity. Mice with bad learning and memory genes develop lipofuscin deposits in the hippocampus (where LTP is widespread) in proportion to their decelerating memory.16 As well, DMAE can reduce cell-membrane degradation and boost cognitive function.

THE ROLE OF PHOSPHATIDYLSERINE
As we age, NMDA receptors are constantly antagonized, to the point of reducing their memory-enhancing qualities. Phosphatidylserine counteracts this damaging abuse to the binding properties of NMDA, in part by altering the lipid composition of synaptic membranes.17 This alteration may be an important mechanism for regulating the properties of other receptors that could also be involved in producing long-lasting changes in synaptic memory enhancement. Earlier work had shown that phosphatidylserine increases hippocampal synaptic efficacy through its impact on NMDA receptors and their associated channels.18

In a study investigating the effect of aging on the properties of NMDA receptors in mice, phosphatidylserine was given at about 10 mg daily for three weeks. This dose greatly enhanced the efficacy of the NMDA receptors, by improving the affinity of the participating amino acids L-glutamate and glycine, and by elevating NMDA receptor density by approximately 25%.19 These findings are consistent with the assumptions that deficits of the NMDA receptor are one of the mechanisms of age-related cognitive impairment and that the beneficial effects of phosphatidylserine treatment on cognitive deficits of aged individuals might be partially due to its effects on age-related NMDA receptor deficits.

FOR AS LONG AS IT TAKES
All seven of the nutrients, phytonutrients, and hormones discussed above are served up in nutritional supplements: vinpocetine, pregnenolone, choline, pantothenic acid, citicoline, DMAE, and phosphatidylserine. They are present in meaningful levels that have been shown in scientific studies to be of benefit for age-related memory impairment. While none of these ingredients would seem as poignant as gene-switched receptor proteins, most provide many of the same attributes identified in the transgenic mice: enhanced spatial memory, improved recall, novelty preference, active relearning, and context specificity. Studies have shown cognitive synergy when substances such as these are taken together. As long as we remain the kinds of biochemical machines that we are, we will require high levels of benefit-producing dietary supplements, so even when gene therapy becomes a reality for "healthy" individuals, nutritional products will help keep us cognitively youthful.

EVOLUTION DRIVEN BY INTELLIGENCE
Getting back to Dr. Tsien: he is skeptical of the "natural wisdom" argument that is hurled cavalierly at pioneers. Nature does many things that are not in the individual's best interest, such as letting people's bodies run down and die, he notes. Moreover, he believes that improving people's intelligence, whether by drugs, nutritional supplements, or genetic alteration, could have profound effects throughout society.

"Civilization is based on our extraordinary human intelligence," Dr. Tsien said. "That is why our society evolves and civilization evolves, and if there is a way to enhance intelligence, then it may not be surprising to see a change in the evolution of society."

References

  1. Miller HI. Better genes for better living. The Wall Street Journal Interactive Edition September 8 1999.
  2. Tang YP, Shimizu E, Dube GR, Rampon C, Kerchner GA, Zhuo M, Liu G, Tsien JZ. Genetic enhancement of learning and memory in mice. Nature 1999 Sep 2;401(6748):63-9.
  3. Hebb DO. The Organization of Behaviour. A Neuropsychological Theory. John Wiley, New York, 1949.
  4. Teyler TJ. Long-term potentiation and memory. Int J Neurol 1987-88;21-22:163-71.
  5. Molnar P, Gaal L, Horvath C. The impairment of long-term potentiation in rats with medial septal lesion and its restoration by cognition enhancers. Neurobiology (Bp) 1994;2(3):255-66.
  6. Pearson D, Shaw S. Enriched environment may reduce apoptosis in the brain. Life Extension News 1999 June;2(4): http://www.life-enhancement.com/907mwebsite/907lifeexnews.htm
  7. Budziszewska B, Siwanowicz J, Leskiewicz M, Jaworska-Feil L, Lason W. Protective effects of neurosteroids against NMDA-induced seizures and lethality in mice. Eur Neuropsychopharmacol 1998 Feb;8(1):7-12.
  8. Baulieu EE. Neurosteroids: of the nervous system, by the nervous system, for the nervous system. Recent Prog Horm Res 1997;52:1-32.
  9. Zeisel SH. Choline: essential for brain development and function. Adv Pediatr 1997;44:263-95.
  10. Jerusalinsky D, Kornisiuk E, Izquierdo I. Cholinergic neurotransmission and synaptic plasticity concerning memory processing. Neurochem Res 1997 Apr;22(4):507-15.
  11. Onal MZ, Li F, Tatlisumak T, Locke KW, Sandage BW Jr, Fisher M. Synergistic effects of citicoline and MK-801 in temporary experimental focal ischemia in rats. Stroke 1997 May;28(5):1060-5.
  12. Bruhwyler J, Liegeois JF, Geczy J. Facilitatory effects of chronically administered citicoline on learning and memory processes in the dog. Prog Neuropsychopharmacol Biol Psychiatry 1998 Jan;22(1):115-28.
  13. Pfeiffer CC, Goldstein L, Munoz C, Murphree HB, Jenney EH. Quantitative comparisons of the electroencephalographic stimulant effects of deanol, choline, and amphetamine. Clin Pharmacol Ther 1963 Jul-Aug;4:461-6.
  14. Murphree HB Jr, Pfeiffer CC, Backerman IA. The stimulant effect of 2-dimethylaminoethanol (deanol) in human volunteer subjects. Clin Pharmacol Ther 1960 May-June;1:303-10.
  15. Stenback F, Weisburger JH, Williams GM. Effect of lifetime administration of dimethylaminoethanol on longevity, aging changes, and  cryptogenic neoplasms in C3H mice. Mech Ageing Dev 1988 Feb;42(2):129-38.
  16. Flood JF, Morley PM, Morley JE. Age-related changes in learning, memory, and lipofuscin as a function of the percentage of SAMP8 genes. Physiol Behav 1995 Oct;58(4):819-22.
  17. Suzuki T, Ogita K, Yoneda Y. Potentiation by polyamines of an interaction of noncompetitive antagonists at the n-methyl-d-aspartate receptor ionophore complex with phosphatidylserine. Neurochem Int 1993 Nov;23(5):427-40.
  18. Borghese CM, Gomez RA, Ramirez OA. Phosphatidylserine increases hippocampal synaptic efficacy. Brain Res Bull 1993;31(6):697-700.
  19. Cohen SA, Muller WE. Age-related alterations of NMDA-receptor properties in the mouse forebrain: partial restoration by chronic phosphatidylserine treatment. Brain Res 1992 Jul 3;584(1-2):174-80.

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