The use of genetics in the investigation of the structure and function of the nervous system

Already in its infancy, psychobiology became fascinated by the role of heredity in behaviour. Foci of interest ranged from the inheritance of blushing (Darwin 1872) to that of exceptional talent (Galton 1869).1 At first the approach was only observational ("method), and mostly anecdotal. But hardly half a century later, leading investigators were already engaged in the systematic selection of'bright' vs. 'dull' strains in the rodent-in-a-"maze "paradigm (Tolman 1924). This approach was usually 'top-down', from the population and the behaviour to the individual and its genetics; the study of specific mutants, and the analysis of the effect of the mutation on the physical structure of the nervous system was still a rarity (Yerkes 1907). The newly formed discipline of behavioural genetics combined methods from ethology, experimental psychology, and quantitative genetics (Falconer 1960; Hirsch 1963). Only little was known at that time about the physical nature and structure of the genetic material and about the mechanisms by which the genetic information is transformed into physiological processes.

The revolution that has converted neurogenetics into the success story it is today, took place only after the overall strategy has been changed to 'bottom-up', i.e. searching for the role of identified single genes in physiology and behaviour (Benzer 1967). Single-gene analysis of learning and memory started in the fruit fly, "Drosophila (Dudai et al. 1976; Dudai 1988; Tully 1996; Dubnau and Tully 1998). Over the years, learning mutants of Drosophila have contributed significantly to our current knowledge about the molecular mechanisms of "acquisition and "consolidation of simple memory ("CREB, "intracellular signal transduction cascade). Yet Drosophila, in spite of offering unique advantages to the geneticist, is not the dream machine of the neurophysiologist. With time it became indeed possible to identify the effect of specific mutations in identified brain regions and even single neurons that subserve learning (Corfas and Dudai 1990; Waddell et al. 2000; Zars et al. 2000; Dubnau et al. 2001), but central neurons in the fruit fly do not yet succumb to the electrode in the same way that central mammalian neurons do. Furthermore, being an invertebrate, Drosophila is incapable of providing clues to the operation of the mammalian brain at the circuit and "system "level. Neither does it disclose anything about issues such as emotional memory ("amygdala, "fear conditioning) or "declarative memory.

Enters the "mouse. In the past decade or so several spectacular developments have taken place in the field of mouse genetics, which now make it possible to add engineered genes to the mouse genome or remove other genes at will, and generate mouse lines that will express the mutation and propagate it in their progeny. Genes can be added or lesioned in other organisms as well, e.g. Drosophila or zebrafish, using a variety of methods. The point is, however, that the ability to engineer the mouse genome in an efficient, flexible, and reproducible manner has swept the mammalian brain for the first time to the forefront of neurogenetic analysis. Among mammals, the mouse is still unique in this respect; appropriate neurogenetic techniques are not yet available, for example, in the rat.

In the present context we need to become familiar with two specific terms only, 'transgenic' (TG) and 'knockout' (KO) mice. Without going into the methods in which TGs and KOs are actually generated (Jaenisch 1988; Joyner 1993; Wassarman and DePamphilis 1993; Nagy 1996; Torres and Kuhn 1997), suffice it to say that TG is the generic term for an organism with foreign pieces of DNA incorporated into its genome, and KO for an organism in which a gene is ablated in situ. TGs are used to test the effect on physiology and behaviour of extra genes, normal or mutated. KOs are used for the analysis of the loss of normal gene function. 'First generation KOs' affect the expression of the gene throughout the body, during "development and in adulthood. The absence of regional and temporal specificity makes it impossible to conclude that the effect of the KO on learning and memory is independent of developmental or general anatomical and physiological impairments. In 'second generation KOs', the KO is targeted to a specific region or cell type (Tsien et al. 1996a; Wilson and Tonegawa 1997). In 'third generation KOs', the expression of the mutation is also regulated in time in a reversible manner (Mayford et al. 1996; Shimizu et al. 2000). This permits exploration of the role of the gene in discrete "phases of learning and memory. At the time of writing, the onset or offset time of gene expression in third generation KOs is measured in hours, which is not terrific for the analysis of acquisition, consolidation, or "retrieval of memory, but this is likely to improve.2

The use of transgenic mice has already contributed markedly to our knowledge on the role of identified molecular processes in "plasticity, learning, and memory. To name just a few selected examples, KOs have been used to identify the role of types of a variety of "protein kinases, of subtypes "glutamatergic receptors, and of "CREB and other transcription factors in "long-term potentiation and in a variety of "classical and "instrumental learning situations. They have also proved useful in probing the relations between "long-term potentiation and learning, and the role of "hippocampus in learning and memory (Grant et al. 1992; Silva et al. 1992; Abeliovich et al. 1993;

Fig. 49 A suspected case of reverse genetics. The group that has isolated dunce, the first memory mutant in the fruit fly, *Drosophila, headed by Seymour Benzer, shortly after making their discovery at the California Institute of Technology (Dudai et al. 1976). This discovery started the now flourishing discipline of the molecular-genetic analysis of learning and memory.

Fig. 49 A suspected case of reverse genetics. The group that has isolated dunce, the first memory mutant in the fruit fly, *Drosophila, headed by Seymour Benzer, shortly after making their discovery at the California Institute of Technology (Dudai et al. 1976). This discovery started the now flourishing discipline of the molecular-genetic analysis of learning and memory.

Bourtchuladze et al. 1994; Mayford et al. 1996; Rotenberg et al. 1996; Tsien et al. 1996b; Wilson and Tonegawa 1997; Shimizu et al. 2000). Interestingly, the overexpression of the glutamatergic N-methyl-o-aspartate receptor in the forebrain of a transgenic mouse was shown to enhance the performance of some learning tasks (Tang et al. 1999), indicating that genetic engineering could potentially be used not only to investigate memory, but also to improve it. In addition to their use in research of neuronal plasticity and elementary learning mechanisms, transgenic mice are employed to "model the aetiology and mechanisms of Alzheimer's disease (Price et al. 2000; "dementia).

There is no doubt that state-of-the-art neurogenetics is extremely useful in elucidating the molecular and cellular machinery of developmental and behavioural plasticity. The sophistication of the current molecular neurogenetic methodologies is really impressive. However, from the point of view of learning research, similarly to other cutting-edge techniques such as "functional neuroimaging, it is only a tool, not the goal. To become really useful, it must be teamed with additional methodologies and levels of analysis, such as cellular and circuit physiology, neuroimaging, and, clearly, fine behavioural analysis.

Another point to remember is the distinction between neurogenetics as a research tool and neuro-genetics as a philosophy. There is a big gap between the demonstration that a gene product influences learning, memory, or any other cognitive faculty, and the conclusion that the gene product is deterministic for the behaviour in question (Rose 1995a). The more we learn about the role of development in moulding physiology and behaviour, the more we understand the complexity of the genome, the more we realize how complicated is the behaviour-/(genes) equation. The impressive success of the Human Genome project (International Human Genome Sequencing Consortium 2001; Venter et al. 2001), provides us with new powerful experimental tools, and with a marvellous potential for further understanding of the brain. But they also call for proper humbleness: we still have to travel a long way to unravel the real contribution of identified genes to learning, memory, and other aspects of cognition in humans (e.g. Flint 1999; Plomin 1999).

Selected associations: Development, Drosophila, Immediate early genes, Intracellular signal transduction cascade, Mouse

''Scientists were not, of course, the first to pay attention to the genetics of behaviour. They were preceded by countless animal breeders, pet lovers, circus owners, and other entrepreneurs, who were collecting and breeding useful mutations and strains for commercial purposes or just for fun.

2For comparison, the onset and offset time of conditional, temperature-sensitive mutations in Drosophila is only a few minutes (Kitamoto 2001).

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