A Memoir on Memory

Memories Are Made of This By Rusiko Bourtchouladze New York: Columbia University Press (2002). 208 pp. $25.00It's a heady time for memory research. A quick search of Medline will find about 5000 articles on “memory AND brain” and that's just since the year 2000. Among these are 1000 reviews of the subject.This burst of industry reflects a recent and creative confluence of several research traditions, perspectives, and methodologies. For 50 years, clinical psychologists had been observing patterns of forgetfulness in humans who had suffered brain lesions. Behavioral psychologists had been studying rats to see how they learn to run mazes. Biologists with a bent toward “simple systems” had been isolating mutant strains of fruit flies that they named for vegetables (in recognition of diminished mental capacities). Other biologists had been working out first the behavior, and next the neural circuitry, and then the neuronal physiology responsible for forms of simple conditioning in sea slugs. And neurophysiologists had been poking electrodes into brain tissue to find evidence for the elusive engram—the trace that a learned experience must leave on the dynamic function of some neurons, somewhere, in the brain.All these strands began to melt together in the 1980s, under the solvent of molecular genetics. Genes that had been first identified in defective fruit flies (incapable of remembering which way to turn in the face of a paralyzing shock) turned out to have close relatives expressed in parts of the rodent brain—parts homologous to regions of the human brain that, when lesioned, led to specific memory loss. These genes defined a biochemical pathway leading from neurotransmitter receptor activation, through cyclic AMP and calcium second messengers, to the modulation of gene expression in the neuronal nucleus. Molecular genetic manipulations of this pathway would disrupt memory formation in tractable models like the sea slug.The melting pot heated up another notch in the early 1990s, when the brand-new technique of making targeted gene knockouts in mice afforded the opportunity to test the necessity of this pathway for memory formation in an animal with a brain perhaps not so different from our own. The initial results (positive) were bracing and dramatic. A completely new approach to memory research was suddenly at hand, an approach that combined the molecular precision of reverse genetics with the anatomical relevance and behavioral richness of a small mammal. (A mere 10 years later, there are now 250 articles on memory transgenics in Medline).In 1992, onto the scene walked an eager postdoc from Russia, Rusiko Bourtchouladze. Trained in the “classical” methods of neurosurgery and behavioral analysis, she had barely stepped off the plane before she was interviewing with Alcino Silva, Tim Tully, and other gurus of memory genetics at Cold Spring Harbor. In a surprisingly short time, Rusiko Bourtchouladze first-authored one of the classics of the new literature, a paper showing that mice need a healthy creb gene to form at least some types of memory (Cell 79, 59–68, 1994). She went on to work with another of the founding fathers of the field, Eric Kandel, and then moved into the orbit of entrepreneurial memory science as a “director of model systems” at Helicon Therapeutics.In this book, Dr. Bourtchouladze has produced a charming little introduction to the history of research on mechanisms of memory, written from her unique vantage point and with periodic light reference to her own interesting personal history. The book is chock-full of quotations from many sources, reinforcing a sense of perspective and balance. Her title (Memories Are Made of This) is actually a bit of a non sequitur: reading the book, one will quickly grasp that we don't know “what” any particular memory is “made of,” or precisely “where” it lives. We have an idea that memories are resident somehow in the functional activities of interconnected neurons—in the dynamics of their mutual inhibition and excitation (e.g., see Martin et al., Annu. Rev. Neurosci. 23, 649–711, 2000). But as to what is special about any particular memory, what makes it different from any other memory, and hence “specific” and useful—this we don't know yet. Nonetheless, the avalanche of research has produced real insight into the neurophysiological processes that underlie memory formation and retrieval. We know more and more about how a memory gets made, even if we still don't know what it is.In the preface, the author begins by saying, “this book has been written for anyone who is curious about how memories are made.” Thus, the emphasis is on readability and accessibility (the only prerequisite being a sense of curiosity), yet I found the book potentially useful even for the practicing memory researcher or college-level instructor. The author has done a nice job of annotation; she has culled and documented high points from all the different traditions noted above. Indeed, in her first chapter, she travels all the way back to ancient Egypt and the invention of writing to contemplate the roots of “memory” as an explicit, externalized concept. By the end of this chapter, she has reached Ebbinghaus and the Introspectionists of the 19th century, who began the formal scientific characterization of human memory.In the second chapter, the author traces the emergence of the concept of multiple memory systems, compelled by the striking evidence of clinical patients with highly selective forms of amnesia. The third chapter moves more specifically to the hippocampus and the forms of memory that depend especially on it. Parts of this chapter reminded me of the writings of Oliver Sacks (and an appropriate annotation is included). Other parts of this chapter I found a bit confusing, however, as the author attempts to work out the distinctions between “recall” and “recognition,” or “availability” and “accessibility” of a memory. Yet a simple observation directly conveys another important insight about the structure of human memory: “it takes us longer to learn that a person's name is Mr. Cook than to learn that a person is a cook” (p. 67).No contemporary account of memory that describes the hippocampus (or the most popular assays of mouse memory) can afford to ignore the amygdala, and the fourth chapter is devoted to this brain structure and its role in the processing of emotional memory. A major theme here is summed up in a quote from Marcus Raichle, cited by the author: “Memory is like a piece of music—it has lots of different parts that come together to create the whole” (p. 86). My favorite line in the whole book comes in this observation by the author herself, toward the end of this chapter: “It seems to me as a general principle that every time we remember something we have previously experienced, we are merely having a new present experience” (p. 104). This captures the diabolical challenge of pinning memory down as a static “thing” and goes to the heart of the current active debate on mechanisms of memory reconsolidation (a topic not explicitly developed in this book). A very brief fifth chapter then follows on the essential topic of forgetting.With two chapters remaining, the author turns to the cell biological (chapter 6) and reverse genetic (chapter 7) perspectives. A fair amount of energy is expended in Chapter 6 on the now-discredited idea that specific memories reside in specific molecules (e.g., planarian RNAs or scotophobin), and the reader is quickly pulled through Hebb, Aplysia, and LTP. Chapter 7 is identified by the author as her “own,” and it includes a set of five rules for interpreting the behavior of transgenic mice, under the heading, “A Few Thoughts from a Mouse Veteran.” Although these two chapters are ostensibly the closest to the author's most recent work, I found them less engaging and effective than the previous chapters emphasizing the “systems” perspectives. Here, the front line of research is moving especially quickly and already some of the experiments reported are being reevaluated (e.g., Pittenger et al., Neuron 34, 447–462, 2002). The interested reader will do well to seek out a good recent short review (e.g., Matynia et al., Neuron 32, 557–559, 2001) from among the hundreds that are accumulating in Medline each year.Having surveyed memory research in its history and breadth, what future does the author project? Here she pleads restraint and refrains from extensive forecasting, although she is clearly enthusiastic about the potential for developing “smart” memory enhancing drugs. Before that becomes a reality, though, we clearly need to know more about how relatively universal cellular mechanisms are selectively recruited or activated in specific parts of the nervous system, and at specific times, to drive specific memory formation. The fact that such an objective can even be framed now is a testimony to the profound intellectual progress reviewed in this book.