Forgetting

information to its successor will accumulate significant retention errors over the course of a lifetime. After all, a long-lived protein in a neuron has a half-life of about 24 hours. It will be broken down and resynthesized from scratch about 50 times over the course of a single year.

Although it is a stretch to go from molecules to cognitive psychology, it is entertaining to think of "sins" for which protein turnover may be the underlying culprit. The easiest example is transience. Transience is simply the diminution of a particular memory over time. Your memory for recent events is more robust and detailed for recent events than for those from farther in your past. Memory has a half-life because the molecules that store it have a half-life. In the case of those memories stored using a mnemogenic, self-perpetuating reaction, the memory half-life is basically determined by the error rate of the underlying mnemogenic reaction as it replicates itself.

Misattribution is a memory sin wherein an association is erroneous—for example you think you remember that Kim told you something when actually it was Eric. At the time Eric told you the story and shortly thereafter you obviously knew the source— over time the molecules subserving that particular association have been erroneously resynthesized in a configuration that has wired the memory up with Kim.

A final "sin," persistence, is the mirror image of transience. Persistence is basically remembering things you would prefer to forget, or would be better off forgetting. Persistence stands as testament to the robustness of the mnemogenic reaction—once it has been set in motion the molecular positive feedback cycle may difficult to break. This may be particularly true for highly emotional experiences—as we discussed in Chapter 6, many modulatory influences can enter into play in the initial establishment of highly emotional memories. A mnemogenic reaction that is established at a level high above the threshold needed for its maintenance will be particularly unsusceptible to subsequent erasure through active or passive processes.

system. As we discussed in Chapter 1, one of the great unifying theories to emerge out of neuroscience research in the last century was that synaptic plasticity subserves learning and memory. In the next section we will identify several examples of biochemical mechanisms operating in mammalian hip-pocampal long-term synaptic potentiation that fall into one of the three categories outlined before as general descriptors of the classes of chemical reactions involved in memory formation.

B. Long Half-Life Reactions

For an example of a long half-life biochemical reaction involved in LTP, we will focus on PKC. This is because, as described in Chapter 7, several of the mechanisms for persistent PKC activation that have been identified based on in vitro studies of the enzyme are now known to contribute to the persistent activation of PKC in LTP. For example, PKC was originally identified as an enzyme activated by calcium-dependent proteolysis, and proteolytic activation of classical PKC isoforms in TEA-induced NMDA receptor-independent LTP has been observed. In addition, as described in Chapter 7, Todd Sacktor has shown up-regulation, most likely mediated by increased synthesis, of an autonomously active truncated form of PKC-zeta in LTP. Oxidative activation of PKC renders the enzyme autonomously active, and this mechanism is likely to contribute to the persistent activation of PKC in the maintenance phase of LTP. Thus, all these mechanisms: proteolysis, increased synthesis, and oxidation, act on PKC to render it persistently activated in LTP. These reactions are examples of long half-life chemical reactions where decay depends on the breakdown of the persistently activated protein.

In this context, another interesting finding is that there is increased autophos-phorylation of PKC in LTP. PKC C-terminal autophosphorylation, such as is observed in LTP, preserves the enzyme against down-regulation and is correlated with PKC binding to actin microfilaments. Thus, the probable role of PKC autophospho-rylation in LTP is to preserve the persistently activated enzyme from proteolytic down-regulation and to maintain its localization to the appropriate synaptic region of the neuron. Thus, the generation of a long-lasting signal in LTP (i.e., persistent PKC activation) depends on two mechanisms: generation of autonomous PKC and protection from down-regulation. These two mechanisms act in concert to provide a persistent signal in the cell.

It is worth noting that PKC autophos-phorylation is intramolecular and, therefore, cannot be self-perpetuating. This means that the persistence of the autonomous activity will be limited by the half-life of the persistently activated PKC. Thus, while PKC activation in LTP is a persistent and long half-life reaction, it is not an example of an effect rendered immune to molecular turnover.

C. Ultralong-Term Memory: Mnemogenic Chemical Reactions

A variety of chemical reactions identified in mammalian cells qualify as mnemogenic. The first examples of reactions that qualify as mnemogenic were independently proposed by Francis Crick and John Lisman (15, 16 and see later discussion). Crick and Lisman focused on reactions that were enzymatic in nature, involving covalent modifications of inactive precursors (X) by activated forms of the enzyme (X*). This sort of reaction has been formalized and investigated experimentally in the context of the generation of autonomously active CaMKII by intersubunit autophos-phorylation.

CaMKII is synthesized in the inactive state and is normally regulated by calcium and calmodulin. As we discussed in detail in Chapter 7, while CaMKII can be transiently activated by calcium/calmodulin, CaMKII can also be triggered to undergo autophosphorylation by this same stimulus. After this occurs, the phosphorylated form of CaMKII is autonomously active, even in the absence of the calcium/calmodulin trigger (17). The critical feature of CaMKII is that the activated (X*) form can phos-phorylate the inactive (X) form of CaMKII in an intermolecular "mnemogenic" reaction. Thus, CaMKII theoretically remains autonomously active despite protein turnover.

Because this type of mnemogenic reaction has received considerable attention, I refer the reader to a recent treatment of this topic for additional details (18). I would be remiss if I did not point out, however, that to date there has been no direct experimental demonstration of CaMKII being rendered permanently active in a cell. It is likely that the necessary subunit turnover does not occur intracellularly. Regardless of the mechanistic basis for reversal of the activation, examples of autonomously active CaMKII that have been reported thus far in the literature have been observed to last only 1 to 2 hours. Thus, in real life, autonomous CaMKII probably falls into the category of a long half-life reaction, as opposed to generation of a self-perpetuating species. Nevertheless, the theoretical capacity of CaMKII to undergo self-perpetuating activation independent of subunit turnover makes this a good theoretical example of a mnemogenic chemical reaction.

Enzymatic mnemogenic reactions need not be based on phosphorylation reactions. For example, any reaction wherein a zymogen is cleaved into its final active product by that product is a mnemogenic reaction (19). In essence the active conformation of the enzyme serves to store the necessary information for converting the inactive precursor to the active product. Finally, as noted previously in discussing PKC autophosphorylation in LTP, only intermolecular (or intersubunit) reactions can be mnemogenic. Intramolecular reactions are unable to undergo self-perpetuation due to their self-delimiting nature.

There are a variety of other examples of mnemogenic reactions that can be found outside the realm of neuronal plasticity. Although the involvement of these other reactions in memory per se is unlikely, it nevertheless is instructive to consider them as examples of the diverse possibilities for types of mnemogenic reactions in neurons. Also, consideration of these other examples helps to illustrate that the mnemogenic chemical reaction solves a more general biological problem of maintaining long-lasting change. The mnemogenic reaction must be utilized in any example of lasting change persisting despite molecular turnover (e.g., in development, immunological memory, and certain pathological states).

Conformational mnemogenic reactions Prion proteins undergo a mnemogenic reaction that is not based on covalent modifications but rather on the self-promoted catalysis of a persisting conformational change (20). Prion proteins are hypothesized to exist in two conformations—the cellular form that is present normally in cells and a "scrapie" form that is an infectious particle and the cause of various neurodegenerative disorders. One molecule of the scrapie form catalyzes the conversion of a molecule of the cellular form into a second molecule of the scrapie form; a reaction of the type described by equation 1. Once converted to the scrapie conformation, the molecule is essentially irreversibly changed, and by promoting the generation of copies of itself, the scrapie conformation preserves itself against elimination by proteolytic cellular protein turnover.

Synthetic mnemogenic reactions Instead of eliciting an alteration in a pre-existing molecule of itself, a chemical species can participate in a mnemogenic reaction by promoting its own synthesis. Examples of this type of mnemogenic reaction are increasingly being found in the area of cellular differentiation, where transcription factors are being discovered to regulate their own synthesis as committed steps toward a final cellular phenotype. For example, the transcription factor myoD, a master control protein that elicits the conversion of a precursor cell into a differentiated myocyte, binds to an upstream regulatory sequence controlling its expression of its own gene (21). By this mnemogenic reaction, after a threshold level of myoD is reached in the cell, the cell is irreversibly committed to a lifetime of myoD protein expression and maintenance of the muscle phenotype. Interestingly, an extension of this concept is DNA itself, which catalyzes (indirectly) its own replication.

Autocrine mnemogenic reactions The example of the BMP-1/TGFp loop in Aplysia long-term facilitation, which was described previously, is but one specific example of a general form of mnemogenic reaction. As described by Shvartzman et al. (22), many types of cells can participate in autocrine loops of this sort. Autocrine loop simply refers to the cell's making and secreting a ligand that binds to a receptor on the surface of that same cell—a receptor that when activated, promotes synthesis of its activating ligand. This positive feedback loop can be set to either turn a transient signal into a persisting change or to establish a permanent change. To date, autocrine loops of this sort have been thought of mostly in the context of carcinogenesis, where a transient exposure to an extracellular signal can result in the permanent transformation of a cell.

Exploring EFT

Exploring EFT

EFT stands for Emotional Freedom Technique. It works to free the user of both physical and emotional pain and relieve chronic conditions by healing the physical responses our bodies make after we've been hurt or experienced pain. While some people do not carry the effects of these experiences, others have bodies that hold onto these memories, which affect the way the body works. Because it is a free and fast technique, even if you are not one hundred percent committed to whether it works or not, it is still worth giving it a shot and seeing if there is any improvement.

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