Genetic Analysis and the Targeting of HippocampalFunction

Wim E. Crusio1* and Aryeh Routtenberg2

1Brudnick Neuropsychiatric Research Institute,University of Massachusetts Medical School, Worcester,Massachusetts2Cresap Neuroscience Laboratory, Departments ofPsychology and Neurobiology and the Institute forNeuroscience, Northwestern University, Evanston,Illinois

Behavior genetics has been around for a long time. The early Drosoph-ila geneticists, such as A.H. Sturtevant in the early part of the 20thcentury, were interested in the inheritance of behavior (von Schilcher,1988), only a few years after the rediscovery of Mendel’s laws by Hugo deVries. Mammals, and rodents in particular, were studied almost from thebeginning, and learning and memory were among the earliest interests, asattested by Tryon’s classical selection experiment resulting in the still-existent Tryon Maze Bright and Tryon Maze Dull rats (Tryon, 1929). Inthe 1950s, the budding field of behavior genetics really took off, with thepublication of several landmark works, such as Hall’s chapter on behav-ior genetics and a first-course book (Fuller and Thompson, 1960). Un-fortunately, behavior genetics had to row against the tide of history. Atthe time, behaviorist theories were predominant in psychology and, inthe field of animal behavior, ethologists were more interested in between-species than within-species variation studied by behavior geneticists.Researchers at the time were often reduced to trying to convince col-leagues that, yes, genes can influence behavior.

The molecular-genetic revolution of the last decade caused thependulum to swing to the other extreme. Now, it seems that eachweek a gene “for” this or that characteristic is announced in thepopular press. From aggression to IQ, mood to criminality, every-thing nowadays seems to be under genetic “control.” Animals and hu-mans alike are being reduced to puppets on a string, with genes as thepuppeteers.

But now the two extreme views are moderating to a centrist position:genes influence behavior, but do so in additive and interactive ways with theenvironment in which an organism develops. Moreover, even in the moststrictly controlled environments, behavioral variation persists withinhighly inbred strains of animals, each one being as genetically similar tothe next as if they were clones. And nobody doubts that monozygotictwins, despite often being referred to as identical, are separate in-dividuals.

With the current publicity, it is often overlookedthat behavior genetic analyses, especially when com-bined with the powerful tools of molecular genetics,can offer valuable insights into the organization andregulation of behavior and its underlying brain sys-tems. The present special issue is devoted to the appli-cation of genetic methods to the analysis of brain-behavior relationships, with a special focus on thehippocampus. To this end, we have tried to providethe reader of Hippocampus with a selection of researcharticles spanning the methodological gamut offered bymodern genetics.

In a first approach, Fitch et al. use two well-character-ized inbred strains, C57BL/6J and DBA/2J, to validate amodified learning paradigm, fear conditioning, someforms of which are known to be hippocampus-depen-dent. Next, Graves et al. and Vyssotski et al. addresscontroversies in the analysis of knockout animals, inwhich a specific gene has been rendered nonfunctional bymeans of homologous recombination. Graves et al. ana-lyze CREB mutants on two different genetic back-grounds and report that the results depend critically onwhich background is used. This effect of genetic back-ground should not be confused with another potentialconfound, spurious effects caused by flanking alleles(Crusio, 1996; Gerlai, 1996). It raises the question ofwhich, if any, genetic background is most appropriateto analyze the effects of an induced mutation. Theproblem is analogous to similar discussions of the suit-ability of a particular environment in which to testone’s animals (van der Staay FJ and Steckler, 2002;Wurbel, 2002). Vyssotski et al. address the problemthat an induced mutant often does not appear to havea phenotype that deviates from that of wild-type ani-mals. Their solution is to study genetically modifiedanimals in natural conditions, which are presumablymore discriminative than laboratory conditions.

One obvious application of genetically defined ani-mals is to provide models of neurological disorders in

*Correspondence to: Wim E. Crusio, Brudnick Neuropsychiatric ResearchInstitute, University of Massachusetts Medical School, 303 Belmont St.,Worcester, MA 01604. E-mail: wim.crusio@umassmed.eduAccepted for publication 1 August 2001Published online 00 Month 2001

HIPPOCAMPUS 12:2–3 (2002)DOI 10.1002/hipo.10001

© 2002 WILEY-LISS, INC.

humans. Mineur et al. and Ivanco and Greenough present behav-ioral and neuroanatomical data on the Fmr1 knockout mouse, amodel for human fragile-X syndrome. Again, the importance ofgenetic background becomes evident: both groups report effects ofthe same induced mutation in opposite directions, Mineur et al.studying the mutation on a C57BL/6J background, and Ivancoand Greenough using an FVB background. Next, Stephan et al.present an analysis of APP-overexpressing mice; their resultshave some bearing on our understanding of one of the best-known disorders involving the limbic system, Alzheimer’sdisease.

The articles by Passino et al. and Smith and Wehner illustratethe fact that genetic strategies, using less flashy forward geneticmethods, can still render valuable insights into the neuronalmechanisms underlying behavior. Guzowski reviews findingson immediate early gene expression in the hippocampus, usingmethods that enable one to visualize at two points in time afterthe event has occurred IEG activity at the cellular level in thesame brain section. Routtenberg discusses the difficulties ingene targeting studies and proposes a potential avenue forsolution to deal with genetic background, or “species geneensemble.”

As the contributions to this special issue illustrate, it is unlikelythat the study of single-gene mutants will teach us everything thereis to know about complex phenotypes such as learning and mem-ory. On this the co-editors of this issue are in strong agreement.Knowledge about the proper function of certain receptors, neuro-transmitters, and enzymes will help elucidate the physiologicalprocesses underlying information storage at the cellular level. Wealso agree that application of high-throughput DNA microarrays

will not fundamentally change this picture. In this respect, we arecautious about the impact of genetics on behavioral neuroscience.In this new spirit one would do well to emphasize the fact thatgenotype-environment and genotype-treatment interactions pro-vide a valuable opportunity, rather than an inconvenient challenge,for the behavioral neuroscientist (van Abeelen, 1974, 1989). Thefuture is to those that succeed in integrating genetics into theirphenotypic research!

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Crusio WE. 1996. Gene-targeting studies: New methods, old problems.Trends Neurosci 19:186–187.

Fuller JL, Thompson WR. 1960. Behavior genetics. 1st ed. New York:John Wiley & Sons.

Gerlai R. 1996. Gene-targeting studies of mammalian behavior: is it themutation or the background genotype? Trends Neurosci 19:177–181.

Tryon RC. 1929. The genetics of learning ability in rats. Preliminaryreport. Univ Calif Publ Psychol 4:71–89.

van Abeelen JHF. 1974. Genotype and the cholinergic control of explor-atory behaviour in mice. In: van Abeelen JHF, editor. The genetics ofbehaviour. Amsterdam: North-Holland. p 347–374.

van Abeelen JHF. 1989. Genetic control of hippocampal cholinergic anddynorphinergic mechanisms regulating novelty-induced exploratorybehavior in house mice. Experientia 45:839–845.

van der Staay FJ, Steckler T. 2002. The fallacy of behavioural phenotypingwithout standardisation. Genes Brain Behav 1:9–13.

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