Our research is concerned with two aspects of memory storage: (1) the physiological and biochemical processes responsible for rapidly producing stable changes in synapses, and (2) the anatomy and physiology of circuitries responsible for encoding certain types of memory.

We have found that brief episodes of high-frequency electrical stimulation of axons in the hippocampus alter the structure and number of synaptic connections; subsequent work in different laboratories has shown that this effect is correlated with an increase in synaptic strength that lasts indefinitely. Physiological experiments strongly suggest that the stable potentiation is triggered by an influx of calcium occurring during the brief stimulation period, and this led us to search for a calcium-sensitive process that could produce localized anatomical reorganization. A candidate for this role has been identified. Brain cells contain an enzyme that, in the presence of calcium, causes the breakdown of structural proteins responsible for maintaining the shape and biochemical organization of synapses. We have hypothesized that intense synaptic activity stimulates this enzyme by increasing intracellular calcium and that the resultant breakdown and reorganization of synaptic structure produces more potent connections between neurons. One of the more intriguing aspects of this enzyme is that under some circumstances it appears to produce degeneration in nerves and muscles. This raises the possibility that excessive stimulation of the mechanism postulated to produce brain plasticity is also responsible for some instances of brain pathology, particularly those linked to aging. Several studies to explore this idea are underway.

Two recent sets of findings increase the likelihood that at least some aspects of the mechanism described above are involved in memory. First was the discovery that a naturally occurring brain rhythm is exceedingly potent in eliciting the stable synaptic potentiation effect. Beyond providing evidence that potentiation could occur during certain behaviors, the results suggest that particular patterns of brain activity are used not only to process information but to encode it as well. Second, pharmacological agents that block the potentiation effect or the calcium-sensitive enzyme selectively block certain types of memory storage in rats.

The discovery of a physiological/chemical process that is at least a plausible candidate for the memory mechanism prompted us to begin analyzing memory in terms of brain circuitries. Cognitive psychologists and neurologists have established that humans possess multiple memory systems and have uncovered some important clues about the brain regions involved in these.

Our studies sought to use rat brain networks that include these same areas and to find behavioral tasks that sample memory systems which correspond to those described for humans. These constraints led our search to the little-studied olfactory system in the rat brain. Thus far we have found that the relevant circuitries in rat brains bear a surprising resemblance to networks designed by theorists in the computer sciences to accomplish human-like recognition and associative memory. It will be most interesting to compare computer simulations of the biological and theoretical networks. Moreover, amnesia syndromes characteristic of humans with certain types of brain damage can be reproduced by discrete damage in the rat’s olfactory networks. Techniques have now been developed to follow physiological events in the rat circuitries as the animals learn specific odor cues. Combining these methods with what has been learned from neurobiological experiments should lead to a far more complete picture of how, where, and when memories are stored.

In addtion, the laboratory has also focused on the molecular and cellular mechanisms of aging-related neurodegeneration. Several lines of evidence indicate that changes in endosomal-lysosomal functioning contribute significantly to brain aging and Alzheimer¹s disease (AD). In accord with this, our previous work showed that experimentally induced lysosomal dysfunction triggers the development of characteristic features of the aged human brain in cultured slices of rodent brain. Included among these are i) increases in the lysosomal hydrolase cathepsin D, ii) formation of hyperphosphorylated fragments of the microtubule crosslinking protein tau, iii) depletion of synaptic proteins, iv) development of meganeurites, and v) generation of neurofibrillary tangle-like structures. The primary objective of our first project is to study how lysosomal dysfunction is involved in generating AD like pathology.

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