Strains Rodents Pharmacology Learning Memory

NEURAL PLASTICITY VOLUME 11, NO. 3-4, 2004

Strains of Rodents and the Pharmacology of Learning and Memory

Martine Ammassari-Teule 1,2 and Claudio Castellano

CNR Institute ofNeuroscience, Laboratory ofPsychobiology and Psychopharmacology,Rome, ltaly; 21RCCS S. Lucia Foundation, Rome, ltaly

SUMMARY

Mendelian genetic tools have extensivelybeen used to improve the description of thepharmacological mechanisms involved inlearning and memory. The first part of thisshort review describes experiments involvingthe bidirectional selection of rats or mice forextreme behavioral characteristics or forsensitivity to pharmacological treatments.The second part focuses specifically on in-breeding. In conclusion, the advantages andthe limits of a Mendelian pharmacogeneticapproach of learning and memory arediscussed.

INTRODUCTION

The idea that genes can affect behavior andthat variability in behavior among species,populations, or individuals has some genetic basisis now widely accepted. Evolutionary biologistshave been primarily imerested in this issue toassess whether variation in behavior within aspecies had any genetic basis and, if so, howgenetic variation was maintained acrossgenerations. The interest of neuroscientists forbehavior genetics developed later, that is, when it

Reprint requests to: M. Ammassari-Teule CNR Institute ofNeuroscience, Laboratory of Psychobiology and Psychophar-macology, IRCCS S. Lucia Foundation, 306 Via Ardeatina,00179-Rome Italy. E-mail address: [email protected]

became apparent that genetically associatedvariations in behavior were providing a powerfultool for revealing correlated variations in brainarchitecture, neurochemistry, and neural plasticity.This approach was fundamentally based upon theprinciple that phenotypic characters in a populationcannot be classified into discrete categories but aredistributed quantitatively over a Gaussian (bell-shape) curve. This phenomenon means that in anatural populationmeven if such characters arecontinually varyingmmost individuals are groupedaround the central value of the Gaussian curve andtend to present similar phenotypes. Artificialselection techniques, however, allow the generationof well-differentiated subpopulations showingrobustmsometimes extremedifferences inbehavioral traits with rather ’intra-population’homogeneity. This subdivision, in turn, makes itpossible to describe the neural characteristics ofeach subgroup and, therefore, to identify accuratelythe neural substrate of specific behaviors. Inrodents, bidirectional selection and inbreedingrepresent the most widely used tools. The aim ofthe present paper is to underline the importance ofsuch tools in the analysis of the pharmacologicalaspects of learning and memory. The first partfocuses on bidirectional selectionnthat is, on rator mouse lines selected for opposite behavioralcharacteristics or for sensitivity to pharmaco-logical treatments. The second part concernsexperiments specifically carried out in inbredstrains of mice showing distinct geneticallyassociated learning and memory abilities, althoughno behavioral criterion is involved in the selection

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206 M. AMMASSARI-TEULE AND C. CASTELLANO

process. In conclusion, the advantages and thelimits of a genetic dissection based uponMendelian principles in the field of pharmacologyofmemory are discussed.

BIDIRECTIONAL SELECTION

Behavioral traits

Bidirectional selection for behavioral traitsconsists of submitting large samples of rodents to a

given situation and scoring their behavior. Malesand females reaching the higher scores aresystematically mated, as are males and femalesreaching the lower scores. Following severalgenerations, this selection, strictly based upon aperformance criterion, provides two well-differentiated subpopulations, allowing a searchfor the neural markers of each behavioral profile.For example, rats selected by Tryon (1940), Heron(1941), or Thompson (1954) for their poor versusgood maze-learning abilities, or by Bignami(1965), as well as by Brush (1979), for their highversus low active avoidance scores were the resultof a bidirectional selection strictly based upon a

learning performance criterion. Nevertheless, asevery learning task involves sensorial, emotional,and motivational peculiarities, it became rapidlyclear that a number of other behavioral traits werealso segregated in high and low learners. Forexample, Brush (1979), who selected the Syracuse(SHA/bru and SLA/bru) lines of hooded rats fordifferences in active two-way shuttle box avoidancelearning, recently claimed (2003a, b) that the low-avoidance phenotype (SLA) was bettercharacterized in terms of a high level of anxiety,whereas the reverse was true for the highavoidance phenotype (SHA). The author concludedthat having selected rats for a difference inavoidance learning, factors in the affective domaininfluencing more performance than learning per sewere the primary selected traits.

This aspect illustrates, in fact, the mostcriticized aspect of this selection method, namely,that possible confounders cannot be excludedwhen conclusions regarding the neural bases oflearning and memory are drawn from experimentsinvolving bidirectional selection based upon aperformance criterion. An indirect demonstrationof this aspect was provided by rats not bred fordifferences in learning performance, like theMaudsley reactive and non-reactive lines, selectedfor their different level of emotionality (defecation)in an open field (Broadhurst, 1960), or the NaplesHigh-Excitable and Naples Low-Excitable ratlines, selectively bred since 1976 by Sadile andcolleagues (see Lipp et al., 1987) on the basis ofdifferent behavior arousal in a novel situation. Allthese lines show line-dependent specific learningabilities. Nevertheless, these strains have beensuccessfully used to emphasize an aspect ofparticular relevance for pharmacological studies,i.e., that responsiveness to one drug strongly variesas a function ofthe genetic background.

This phenomenon, early suggested byBroadhurst (1964) was reported for the first timein Roman high-avoider (RHA) and Roman low-avoider (RLA) rats selected by Bignami (1965) forextreme active avoidance scores. Injecting suchrats with amphetamine and other psychotropicagents, before the training sessions, Bignami andcolleagues found a selective enhancing effect ofdrugs on RLA performance.

Indeed this observation was followed by anumber of experiments showing that many drugsexert line-specific effects on memorization.Among those, two findings require particularattention. First, differences in the opiate bindingand behavioral effects of morphine were foundbetween RLA and RHA injected with morphine(Lazega et al., 1986), already suggesting (1) a

genetic-dependent responsiveness to opiates and(2) the possibility of searching for mechanismscommon to memory and drug addiction. Second,the observation that rats differing in active avoidance

PHARMACOLOGY OF LEARNING AND MEMORY IN RODENT STRAINS 207

scores also showed distinct performance-relatedtraits allowed a more precise identification of drugtargets. For example, Satinder (1980) observedthat scopolamine disrupted responsiveness tovisual but not to auditory stimuli in the RLA line,whereas d-amphetamine, otherwise affectingactivity and reaction time, did not affect thisparameter. Satinder suggested that responsivenessto visual stimuli is influenced by bidirectionalgenetic selection via the segregation of line-specific cholinergic mechanisms.

The observation that heritable factors controlthe responsiveness to drugs clearly led to analysesof the consequence of bidirectional selection at theneurochemical level. Using the same rats, Giorgi etal. (1994) reported line-specific differences relatingto the GABAergic and dopaminergic systems. Inparticular, the authors showed that the stimulatoryeffect ofGAIA on 36C1 uptake was less pronouncedin the cerebral cortex of RLA as compared withRHA, whereas no line-related change was detectedin [3H]GABA and [3H]flunitrazepam binding. Fordopamine, the density of D1 dopamine receptorswas found to be lower in the nucleus accumbens ofRLA as compared with RHA, whereas no line-dependent change was observed for D1 dopaminereceptors located in the striatum, the amygdala,and the prefrontal cortex. Thus, site-specificbiochemical markers of inter-individual variabilityin emotional learning were identified.

The possibility of observing neurochemicaldifferences in lines of rats selected for behavioraltraits has rapidly been considered a valuable toolfor describing the role of various neurotransmittersin cognition. For example, investigations on theneurochemical characteristics of inbred MaudsleyReactive (MR) and Non-Reactive (MNR) rat strainsshowed that MR rats had lower concentrations ofnorepinephrine in the hypo-thalamus than MNRArats. By contrast, MR rats had a higherconcentration of telencephalic norepinephrine thanMNRA rats (Liang & Blizard, 1978). Possiblyindicative of a higher rate of norepinephrine

metabolism, the percentage of 3H-labeled non-catechol metabolites relative to the total countswas higher in the brainstem of MNRA rats whenmeasured 90 minutes after the intraventricularinjection of 3H-norepinephrine (Slater et al., 1977).Interestingly, both lines showed an elevation of 3,4dihydroxiphenylacetic acid levels in the locuscoeruleus following a single session of acuteimmobilization stress compared with non stressedcontrols, but this elevation was stronger in thereactive line (Buda et al., 1994). Such well-characterized differences between noradrenergicand cholinergic systems and their relation to thebehavioral profile led Sara et al. (1994) to considerthe M.audsley rat strains as a ’probe’ to investigatenoradrenergic-cholinergic interaction in learningand memory. The authors reported that, incomparison with the Reactive line, the Nonreactive line was characterized by a greater [25I]clonidine binding to alpha 2 receptors in the locuscoeruleus, a higher behavioral sensitivity toclonidine, and a greater availability of muscarinicreceptors correlating with superior spatial workingmemory performance.

Similarly, the Naples High-Excitable and Low-Excitable rat lines, bred for their different levels ofactivity reflecting behavioral arousal in a novelsituation, show interesting behavioral and neuralproperties for investigating the role of themesocortical dopaminergic system in cognitiveand motor behavior In particular, the two linesdiffer in spatial learning, active avoidance, andconditioned taste aversion, with the High-Excitable line showing a performance very similarto that of rats injected with a dopaminergic agonist(Viggiano et al., 2002). In agreement with thebehavioral data, regional examination ofdopaminergic metabolism in these animalsrevealed a hyperdopaminergic innervation in theprefrontal cortex of the High-Excitable line, with adown regulation of dopamine D receptors makingthis line particularly suitable to the study ofhyperactivity and attentional disorders (Carey et


al., 1998), as well as drug abuse (Viggiano et al.,2003).

Differential sensitivity to pharmacologicaltreatment

Indeed, pharmacologists interested in thefunctional role of a specific neurotransmittersystem can directly use the responsiveness to apharmacological agent for selecting lines showingextreme phenotypes. For example, Gallaher et al(1987) selected mice according to the effect ofdiazepam known for its anxyolitic, myorelaxing,and anticonvulsive properties in the rotarod test,which measures both muscular strength and motorcoordination. Binding experiments, successivelyconducted on these subpopulations, showed line-dependent differences in the number of benzo-diazepine receptors that correlate with rotarodperformance and seizure thresholds induced byconvulsant agents. Interestingly, when lines ofmice were also selected for their differentsensitivity to diazepam but using a physiological(sleep time) instead of a behavioral (rotarodperformance) criterion (Yoong & Wong, 1988),the line with the lower reaction (and lower numberof benzodiazepine receptors) also showed superiorrotarod performance but, contrary to that observedin the Gallaher’s experiments, no protectionagainst pentylenetrazol-induced seizure. This setof findings underline that changing one element ina complex criterion of selection (drug responsive-ness x behavioral vs physiological trait) can lead tothe segregation ofvery selective phenotypes.

This aspect is well illustrated by Chapouthieret al. (1998), who selected lines for their differentsensitivity to the benzodiazepine receptor inverseagonist methyl-13-earboline-3-earboxylate (13-CCM),known for its convulsant, anxiogenic, and learningenhancing effects. In these experiments, thecriterion of selection was the latency to convulsefollowing 13-CMM administration. The two lineswere easily separated: one line convulsing with

short latencies and one line resistant to 13-CMMadministration. Binding analysis of benzodiazepinereceptors in these two subpopulations indicated adecreased Bmax in the resistant line compared withthe convulsing line. Interestingly, although selectedfor their responsiveness to a drug, these mice alsoshowed a variety of line-specific, anxiety-relatedbehavioral traits. In particular, the resistant linewas found to display poor intermale aggression(Guillot et al., 1999), low anxiety levels (Suaudeauet al., 2000), and reduced sensitivity to otherconvulsive (GABA-A) agents (Rinaldi et al.,2000). The point to be examined now is whether aselection process based upon responsiveness to13-CCM, that is, a drug having learning-enhancingproperties, also segregates for distinct learningabilities. Preliminary data indicate that segregationdoes occur, with the sensitive line showing thehigher performance in spatial discrimination tasks(Venault et al., 2003)

INBREEDING

Inbreeding, also aimed at the production ofdistinct lines or strains, consists of mating closelyrelated individuals (sisters and brothers) for manygenerations. In the mouse, for example, about 20generations are necessary to produce an inbredline, the members of which are homozygous, i.e.,have the same genotype. Worth remembering isthat inbred mice were initially generated for physio-pathologists, who early identified the advantage ofhaving a homogeneous population of individualsshowing a clear symptomatology. Therefore, thecriteria of selection used by C.C. Little (1916) toproduce inbred strains in the early 20tc enturywere, for example, "immunohistocompatibilityresponse" or "predisposition to develop neoplasia",to determine if cancer was inherited. Incidentally,Bagg (1920) tested various inbred strains of micein several multiple-choice mazes and found thatthe learning performance strongly varied between


strains whereas it was remarkably homogeneouswithin each strain. Later, Vicari (1929), whoexamined the time spent by DBA/2J and BALBc/Jinbred mice, as well as by "Japanese Waltzer" and"Myencephalic Blebs" mutant mice to run a three-unit maze, also observed that maze-running timeswere strain-dependent.

These observations led to an abundant body ofliterature dealing with inter-strain comparisons.Clearly, one advantage of inbreeding over bi-directional selection is that no learning-task-relatedcriterion is involved in the selection process sothat possible confounders relating to the effectiveperformance-related criterion of selection areexcluded. Another interesting aspect of inbreedingis that the individuals of a given strain are likehomozygous twins, i.e., have identical genotypes.It turns out that an entire population exhibits thephenotype of a single randomly bred individual sothat interstrain comparisons are overall a tool foranalyzing interindividual phenotypic variabilitywithin natural populations. As many strains havebeen now accurately characterized (see Ingram &Corfman, 1982, for an overview ofneurobiologicaldifferences in mouse strains), any neuroscientistinterested in analyzing a particular behavioral orneural phenotype can select a priori either onestrain expressing the behavioral or neural trait ofinterest, or several strains to be compared for their

difference relating to this trait.

Strain differences in learning and memoryperformance: examples from C57BL/6 vs DBA/2

comparisons

The initial observation of spontaneousdifferences in performance among inbred mice

subjected to one learning task generated an

impressive amount of experiments aimed at

comparing strains in a variety of tasks tapingdifferent forms of memorization. The resultsshowed no general learning superiority in any

strain but did show frequem strain x task specificlevels of performance. For example, C57BL/6

(C57) mice were found to perform worse thanDBA/2 (DBA) mice in tasks having a strongprocedural component, such as the Lashley maze

(Oliverio et al., 1972) the active avoidance task(Bovet et al., 1969; Oliverio et al., 1972) orvarious situations of operant conditioning (Renzi& Sansone, 1971). The C57 mice performed betterin tasks requiring spatial (Ammassari et al., 1985;Crusio et al., 1980; Upchurch & Wehner,1989;Passino et al., 2002) or contextual (Castellano &Puglisi-Allegra, 1983; Weinberger et al., 1992;Restivo et al., 2002; Ammassari-Teule et al., 2000)information processing. A specific deficit in tracefear conditioning was reported in DBA mice

(Holmes et al, 2002) otherwise showing superiorperformance in various protocols of conditionedtaste aversion in comparison with C57 mice

(Ingram 1982; Dudek & Fuller, 1982; Risinger &Cunningham, 1995) Conversely, both strainsshowed similar learning visual discriminationlearning abilities (Castellano, 1977), as well associal transmission of social food preference(Holmes et al., 2002).

It is worth noting that such geneticallyassociated differences in performance are not

completely rigid because they can be either

emphasized or attenuated through manipulatingexperimental factors. For example, when C57 andDBA mice are trained to press a lever to avoid an

electric foot shock predicted by an auditory or a

visual stimulus, DBA mice show superior avoidance

performance when the duration of the predictivesignal is short. Conversely, when the duration ofthe predicting signal is increased, interstrain

differences in performance were no longer evident

(Renzi & Sansone, 1971).Indeed, in view of the well-differentiated

spatial learning abilities of C57 and DBA mice, an

extensive description of the neural characteristicsof the hippocampus was carried out in both strains


to gain further insight on the relation betweenhippocampal functionality and spatial informationprocessing. In agreement with the behavioralfindings, C57 mice were found to show moremossy fiber terminals in the hippocampal regio

inferior (Barber et al., 1974; Crusio et al., 1987;Schwegler et al., 1988), a higher hippocampalprotein kinase C activity (Wehner et al., 1990),and a longer duration ofthe late phase of long term

potentiation (Matsumaya et al., 1997; Nguyen etal., 2000; Jones et al., 2001) than DBA mice.

Fewer linear correlations emerged, however,when the cholinergic function, which plays acentral role in spatial learning, was examined. Thatis, although interstrain differences regardingvarious aspects of cholinergic metabolism wereclearly established, stating which strain waspresenting the ’cholinergic properties’ susceptibleto mediate superior spatial learning and memorywas impossible. For example, C57 mice showed ahigher concentration and turnover of acetylcholinein the total brain, in the fronto-parietal cortex, andin the caudate nucleus than DBA mice (Durkin etal., 1973; Racagni et al., 1977). The synthesis ofacetylcholine, estimated by measuring the activityof the enzyme choline acetyltransferase, was,however, more important in DBA than in C57mice (Ebel et al., 1973; Mandel et al, 1974).Conversely, the degradation of acetylcholine,estimated by measuring the enzyme acetyl-cholinesterase, was found to be more intense inC57 than in DBA (Pryor et al., 1966), even if ahigher content of acetylcholinesterase in thestriatum of DBA was also found (Iacopino et al.,1985). Examination of the density of muscarinicreceptors by autoradiographic methods, using[3H]quinuclidinyl benzilate (QNB) and [3H]piren-zepine as ligands revealed lower [3H]QNB bindingin the frontal cortex, in the hippocampus, and inthe striatum of C57 as compared with DBA,whereas [3H]pirenzepine binding in the temporalcortex was found to be higher in C57 (Marks et al.,

1981; Schwab et al., 1990) than in DBA. Theseobservations underline the difficulty of establishingfully consistent causal relations when variouslevels of analysis are taken into account.Nevertheless, the well-differentiated reactivity ofinbred strains to pharmacological agents hasproved to be useful for unveiling how variousmodalities of interaction between neurotransmitterssystems exert a specific control on behavior.

Inbred mice: variable responsiveness to drugs inlearning and memory tasks

Experiments widely based on the post-trainingadministration of drugs in the passive avoidancetask have shown that inbred mice show a variableresponsiveness to drugs, with differences in theintensity as well as in the direction of the effects.A few examples still relating to C57 and DBAstrain comparisons illustrate this phenomenon. Forinstance, the cholinergic muscarinic agonist oxo-tremorine improves passive avoidance retention inboth strains, with a stronger effect in DBA,whereas the serotonergic agonist 5-MeODMTimpairs retention to the same extent in eachgenotype. The simultaneous administration of5MeODMT and oxotremorine, however,specifically blocks the improving effect of thecholinergic agonist on memory consolidation onlyin the DBA strain (Pavone et al., 1993).

In the same fashion, also the interplay betweencholinergic and dopaminergic mechanisms inmediating memory consolidation differs accordingto genotype. That is, the D2 dopaminergic agonistquinpirole and the D2 antagonist (-) sulpiride werereported to impair retention in C57 and to produceinverted effects in DBA. Nevertheless, the strain-related facilitating or impairing effects ofquinpirole and sulpiride are blocked by thesimultaneous administration of oxotremorine(Gasbarri et al. 1997; Castellano et al., 1999). Bothseries of experiments demonstrated, therefore, that


in each genotype, the serotonergic as well as thedopaminergic modulation of memory processes aremediated via muscarinic receptors. Consistent withthese observations is the finding that the effect ofdopamine agonists on hippocampal acetylcholinerelease in vivo is also strain-dependent (Imperato etal., 1996). Indeed, genotype-specific effects ofsingle drugs mediated by complex interactionsbetween distinct neurotransmitters systems were alsoreported for cholinergic muscarinic (Ammassari-Teule & Caprioli, 1985; Marks et al., 1981) or fornicotinic agents (Gilliam & Schlesinger, 1985;Marks et al., 1986), glutamate NMDA-competitiveand NMDA-noncompetitive antagonists (Ungerer etal., 1993, Cestari et al, 1999; Ciamei et al., 2000),opioids agonists (Castellano, 1980; Puglisi-Allegraet al., 1994; Castellano & Pavone, 1987; Castellanoet al., 1996; Ciamei et al., 2000), GABA(Castellano et al., 1993), endogenous cannabinoids(Castellano et al., 1999), and adenosine (Castellano,1977a), as well as antipsychotic and antidepressantagents broadly interacting with the catecholamines(Castellano, 1977b).

Interesting properties of cognitive enhancershave also been unveiled by comparing their effect indifferent inbred strains of mice. For example, thenootropic drug oxiracetam was found to producestronger enhancing effects on avoidance acquisitionin the good-performer strain (BALB/cJ) than in thepoor-performer strain (C57), whereas the nootropicdrug piracetam facilitated acquisition only in thegood-performer strain BALB/cJ. These observationsled to the conclusion that nootropics have amarginal influence on individuals spontaneouslyshowing low levels of performance (Sansone et al.,1985). Importantly, the combination of oxiracetamand methamphetamine boosted the active avoidanceperformance of poor-performer strain C57 mice upto the level of the good-performer strain BALBc/J

(Sansone & Oliverio, 1989), with the enhancingeffect of the drug combination being superior to theeffect of oxiracetam or methamphetamine alone.

CONCLUSIONS

Although non-exhaustive, this short reviewallows certain conclusions to be drawn about theinterest and the limits of a genetic dissection basedupon Mendelian principles in the field of thepharmacology ofmemory.

Certainly, what both bidirectional andinbreeding experiments show is that segregatinglines or strains for one complex behavioral traitimplies the selection of a variety of superimposedtraits. Independently of the precise geneticmechanism underlying the multiple-segregationphenomenon (linkage, polygenic systems), there isno doubt that a stable set of associated traitsprovided a unique opportunity to identify causalrelations between phenomena at different levels ofintegration.

Another advantage deriving from the selectionof extreme phenotypes is the possibility ofestimating the amplitude of normal inter-individualvariations for a particular trait. In fact, asbidirectional selection and inbreeding techniquesare applied on normal populations, the point to beremembered is that ’low’ learners are still ’normal’learners, and that the sometimes opposite effects ofone drug on strain-specific levels of performanceare within the normal range of this drug’s effects.Nevertheless, that the neurochemical characteristicsof low learners can be considered as ’pre-pathological’ and can serve to identify earlymarkers of cognitive dysfunction is also true. Forexample, the properties of the noradrenergicsystem of non-reactive Maudsley rats (Slater et al.,1977; Buda et al., 1994), of the dopaminergicsystem of High Excitable Naples rats (Carey et al.,1998), or of the glutamatergic system of DBAmice (Ungerer et al., 1993), although in a normalrange, are highly predictive of learning andmemory dysfunction.

Finally, beyond the mere observation of strain-specific differences in performance, quantitative


genetics methods have also used inbreeding toidentify single gene or polygenic systemscontrolling specific behavioral or biological traits.These methods are largely based upon crossingtechniques aimed at segregating various genecombinations. Among those are the classicalMendelian analysis (cross of two parental strainsgiving a F1 generation, subsequent cross of F1individuals to obtain a F2 generation, andbackcross of F2 individuals with the parentalstrains), the diallelic crossing (set of possiblecombinations between six or eight homozygousstrains), the production of congenic lines (cross oftwo parental strains and subsequent backcross ofF1 individuals with one parental strain) or ofrecombinant lines (cross of two homozygousparental strains giving a F1 generation maintainedunder a strict inbreeding regimen). This approach,however, has shown that single gene-dependentbehaviors are rare (Oliverio et al., 1973).Conversely, many single genes were found toinfluence multiple behavioral and physiologicaltraits, which were in turn controlled by multiplegenes acting at various levels: enzymatic activity,hormones, neurochemistry, neurophysiology, neuro-morphology, neural differentiation. For instance,phenylketonuric patients have a metabolic defectcontrolled by a single mutated autosomal recessivegene that influences a variety of genes, therebypromoting a complete biochemical and mentalsyndrome.

Additionally, the calculation of heritability--abiometric method considering the ratio betweenthe observed and the expected variance of abehavioral traithas been widely used bybehavioral geneticists, although it sometimesprovided unreliable results. For example, in a crossbetween the alcohol-preferring C57 and thealcohol-avoiding A strain, the F1 and F2 means ofheritability were found to be intermediate betweenthe parents, and backcrosses to the parental strainswere also in the expected directions. The varianceof the F3 generation, however, was smaller than

that of the F1, making the computation ofheritability maninglss (Rodgers & McClarn,1962)

Thus, although bidirectional and inbreedingstill provide excellent tools for dissecting theneurochemical bases of memory through thesegregation of well-differentiated phenotypes, theinterest for the quan6tative genetics approach isprogressively decreasing in favor of moleculargenetics. There is no doubt that gene sequencingand microarray techniques can provide a moredirect picture on what is really happening at thechromosomal level. Nevertheless, the lessonslearned from Mendelian genetics should beretained by molecular geneticists. Among those are

controlling gene dominance, recession,heterosis, and recombination when varioustransgenic mice are crossed to produce doubleor triple transgenic individuals, andkeeping in mind that if inbred strains showsingle-individual phenotypes, transgenic orknockout mice derived from such strains willprovide marginally-relevant information forthe majority ofrandom bred individuals.

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