Summary A General Chemical Model For Memory

Learning and memory have always intrigued those interested in the functioning of the brain. The mammalian CNS has an amazing capacity to store and recall diverse types of information, and learned responses shape to a great degree an animal's behavior. How are memories formed and stored? Contemporary understanding of this issue highlights the importance of changes in synaptic strength (synaptic plasticity) as the means whereby the nervous system forms and stores memory. But by what means are changes in synaptic strength achieved? The fundamental answer to this question is not a mystery: changes in synaptic strength must of necessity be mediated by chemical changes (i.e., changes in the fundamental properties of the enzymes and other proteins comprising the synapse).

What sorts of chemical changes underlie memory formation and storage? Memory has as its defining characteristic persistence: an environmental stimulus causes a change that greatly outlasts the duration of the triggering signal. Therefore, at the chemical level, memory must have as its hallmark changes in protein function that are able to persist beyond initial, triggering events. Understanding biochemical reactions that manifest this property will greatly increase our understanding of the mechanisms that must underlie memory. Though many papers have dealt with biochemical mechanisms potentially contributing to memory, few have focused on this essential, defining characteristic of the mechanism at the heart of memory.

In this chapter, my goal has been to identify and characterize the types and time courses of persisting biochemical reactions underlying learning and memory and, where possible, to highlight specific, well-documented examples from the literature. The types of biochemical reactions underlying information storage fall into three general classes:

Category 1 includes short-term changes that are mediated by the presence of extracellular or intracellular messenger molecules and that are subject to fairly rapid removal resulting from the specific breakdown or clearance mechanisms. The prototype example is the acute action of a neurotransmitter on cellular biophysical or synaptic properties. In this phase, the memory trace resides in the continued presence of the stimulus. The duration of the memory is dependent upon ongoing production of the signal (e.g., the continued release of neurotransmitter into the synaptic cleft).

Category 2 includes the intermediate-and long-term changes that are mediated by a transient signal producing a persisting chemical memory trace. The generation of the persisting species may be produced by direct covalent modification of a pre-existing molecule, the triggering of an enzymatic modification of a pre-existing molecule, increased synthesis of an active enzyme, or altered gene expression resulting in enzyme activation or synthesis. In general, the duration of the chemical trace is determined by the half-life of the activated protein. The half-life of the protein may be controlled by passive metabolic processes or alternatively may be regulated by specific control mechanisms. In some cases, the half-lives of the relevant species may be very long and capable of supporting a memory for hours, days, or even weeks. These memories cannot be stored indefinitely, however, because they remain susceptible in time to degradation of the trace molecule.

Category 3 includes lifelong changes that are mediated by mnemogenic chemical reactions. The mnemogenic reaction could be triggered by the transient signal of Category 1, the persisting signal of Category 2, or by a distinct and parallel mechanism. The mnemogenic reaction, being self-perpetuating, does not have a half-life in the normal sense, but it potentially can be reversed by a specific triggered mechanism. The activated mnemogenic species maintains the memory trace and results in the expression of memory by impinging on some biophysical, metabolic, or structural neuronal component.

While certainly lacking in specifics, the preceding general model serves as an organizing structure for thinking about various phases of memory from the perspective of their being subserved by specific subtypes of chemical reactions.

Returning to the conundrum raised in the beginning of this chapter: How are robust lifelong memories stored as a biochemical reaction when their constituent molecules are subject to molecular turnover? If memories are stored in a synapse (or any other cellular compartment), how does a sustaining chemical species necessary for the memory render itself immune to degradation or spontaneous decay? This problem is particularly profound when considering examples of lifelong memory that can be induced by a single, transient environmental stimulus. The generic answer to this question has historically been that long-term changes are mediated by "anatomical" or "structural" changes, somehow implying that these changes are somehow protected from degradation.

However, the same question of protein turnover applies to anatomical or structural changes. A structural feature does not "develop" and stay that way. It must be preserved (by being restored) on a minute-to-minute basis.

The erroneous assumption of structural stability has even been perpetuated in Hebb's Postulate:

and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells so that A's efficiency as one of the cells firing B is increased.

Hebb's flaw was to make a distinction between a growth process and a metabolic change. A growth process is a metabolic change. A "structure" is built of rapidly turning-over molecular components. Thinking of a "structural" change or "anatomical" change as being somehow uniquely stable is an erroneous assumption. Preservation of memories is an active, ongoing process at the chemical level. A molecule of finite lifetime that is involved in memory storage must somehow pass along its acquired characteristics to a successor molecule before it is degraded and the information is lost. The future of memory research is to identify the mechanisms for the preservation of acquired molecular characteristics.


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