Psycbological Reports, 1975, 36, 703-712. @ Psychological Reports 1975

MAZE LEARNING: A GENETIC INVESTIGATION I N THE MOUSE1 MERRILL F. ELIAS Department of Psychology and AlGUniverrity Geronrology Center, Syracuse University, Syracuse, New York

ALBERT0 OLIVER10 hboratorie d i Pricobiologia e Prdco. farmacologia, Consiglio Nmionale delle Ricerche, Via Reno 1 Roms, Italy BASIL E. ELEFTHERIOU The Jrrckson Laboraro$ Bar Harbor, Mains

AND

C. CASTELLANO Laboratorie di Psicobiologia e Psicofannacologia, Consiglio Naziomle dslle Ricerche, Via Reno 1 Rome, Italy

Summary.-Recombinant inbred strains, their progenitor strains, and their reciprocal K hybrids were tested for maze learning in the Lashley 111 maze and in the Y-water maze. The resulting pattern of strain distribution suggested that the genetic model provided by the RI strains is based on at least two, and possibly many more, loci. There was no evidence of maternal effects or heterosis. Although the BALB/cBy strain represented an extremely high scoring strain for the Lashley maze and a low scoring strain for the Y-maze, presence of albino recombinant inbred strains intermediate to extreme strains and nonsignificantly different from pigmented recombinant inbred strains suggested that the albino gene was not responsible for the observed performance differences.

Numerous studies of strain differences in maze learning - have established clearly the fact that genotypic differences are associated with differences in maze learning ability (e.g., Bovet, Bovet-Nitti, & Oliverio, 1969; Elias, 1970; Meier, 1964; Wahlsten, 1972 ) . However, strain comparisons provide only the rather limited information that genotypic differences produce phenotypic differences in the trait or traits under consideration. More recent investigations have been concerned with the heritability of maze learning and with the mode of inheritance. These studies made use of the diallel cross method, sib correlations and parent offspring correlations between F3 progeny and their F3 parents. Heritability for maze learning, utilizing the sire d a m component has been estimated at h2 = .38 (Oliverio, Castellano, & Messeri, 1972) and the mode of inheritance has been observed to be dominant and, in some instances, overdominant, depending on the specific parental and hybrid crosses utilized (Oliverio, Castellano, & Messeri, 1972; Winston, 1964). Significant positive phenotypic correlation berween maze learning and shock avoidance learning for an F3 generation of mice, a positive genetic correla-

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'Supported in part by a Grant from European Training Program on Brain and Behavior: in part by N I H Grants HD 05860 and H D 08220, from the National Institute of Child Health and Human Developmcnt. T h e Jackson Laboratory is fully accredited by the American Association for Accreditation of Laboratory Animal Care.

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tion observed with the method of cross covariance of F3 mice and their Fp parents (Oliverio, Castellano, & Messeri, 1972), and a phenotypic correlation between maze and avoidance learning for two single gene mutants (Oliverio & Messeri, 1973), suggests pleiotropic effects for the same gene or genes affecting maze learning or alternatively suggests that both behavioral mechanisms are affected by a common underlying physiological mechanism. Coat color mutants and the neurological mutants have been utilized as a way of evaluating the contribution of single genes to additive and dominance genetic variance associated with maze learning ability. In a study by Oliverio and Messeri (1973), coat color mutants and neurological mutants segregating on a C57BL background were tested for mate learning. Albino c' and underwhite mice ( a w ) made fewer errors than the normal C57BL/6J mice. Thus, it appears that single genes may contribute substantially to additive and dominance genetic variance. However, a question has been raised (Wilcock, 1969) as to the extent that trivial pleiotropic effects involving peripheral mechanisms, e.g., albinism or severe neurological deficit, may explain the increase or decrease in maze-learning ability for single gene mutants relative to controls (Elias & Eleftheriou, 1972). Thus, alternative methods for establishing linkage are of considerable value. An alternative method of exploring the possibility of single gene effects and for locating the gene(s) responsible for a behavioral phenotype on a chromosome segment has been made possible by the development of the recombinant inbred strains (Bailey, 1971). The RI strains are derived from the cross of two unrelated inbred progenitor strains. The strains derived from this cross are maintained independently from the F2 generation under a regimen of strict inbreeding. This procedure progressively fixes the chance recombination of genes as inbreeding proceeds and as full homoqgosity is approached. The resulting battery of strains can be considered as a replicable recombinant population. The utility of these strains for analyzing gene systems involved in endocrine, behavioral and immunologic responses has been described in previous papers ( Eleftheriou & Bailey, 1972; Bailey, 197 1; Oliverio, Elef theriou, & Bailey, 1973). In the present experiment the RI strains were used to ( 1 ) determine whether discrimination learning in the Lashley 111 maze or a Y-maze requiring a visual (light-dark) discrimination is associated with a single gene and ( 2 ) establish linkage by comparing the strain distribution pattern for maze learning with those already determined for the H loci in the congenic lines. In view of the correlation between avoidance learning and maze learning and the demonstration of single-gene effect on avoidance learning (Eleftheriou & Bailey, 1973; Oliverio & Sprott, 1974; Royce, Yeudall, & Poley, 1971), it seemed reasonable to hypothesize a single-gene model for maze learning i n the RI strains.

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Fig. 1 shows the derivation of the RI strains. The RI strains were derived from the cross of two unrelated but highly inbred progenitor suains, BALB/cBy ( C ) and C57BL/6By (B6). Starting with the F2 generation, the RI strains were maintained under a strict regimen of inbreeding for over 40 generations. This procedure progressively fixes the chance recombination of genes as inbreeding continues and as full homozygosity is approached: The battery of strains resulting from this procedure may be considered a replicable recombinant population.

FIG. 1. A schematic diagram of the derivation of the RI strains by D. W. Bailey (1972)

In addition to the RI strains, a battery of congenic lines was developed from the same initial crossing of B6 and C by means of a regimen of skin graft testing and backcrossing B6 for at least 12 generations. This procedure, explained more fully in a previous report (Klein, 1973), resulted in congenic B6 lines which differed from B6 only by an introduced chromosomal segment carrying a C strain allele at a distinctive histocompatibility ( H ) locus. Each of these congenic lines has been tested against the RI strains by means of skin grafts to find which of the N strains carry the C sttain allele and which carry the B6 allele at the H locus distinguishing that particular Line. Thus, for each locus there is a characteristic RI strain discribution pattern. Scrain distribution patterns may be used to identify a congenic line for testing and comparison with

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the progenitor strains in an effort to establish linkage. It should be noted that use of the congenic lines in conjunction with the RI strains is necessary to establish linkage. Mice of the progenitor strains C and B6, their reciprocal hybrids, B6CFl and CB6F1, and the 7 RI strains were used in two experiments. Method: Experiment I Apparatus.-A 4 unit, 8-cul, grey Lashley 111 maze was used. Each alley was 45- cm long with choice point openings 59 mm from the end of each cul. A white line was painted on the floor 10 rnrn on either side of each choice point. Testing procedure.-Subjects were 55 to 80 days old for each RI strain, progenitor strain, and hybrid cross. There were 20 male mice in each of these groups. The animals were pretrained in a 226 rnm runway at 3 trials/day for 5 days, with Purina chow mash used for reward. They had access to food for 20 sec. Sufficient food was provided after each day's trial to maintain body weight at 75% of ad lib. weight. After the pretraining, mice were given three rewarded trials/day for 5 days in the maze. An error was recorded each time the head of a mouse crossed the white line in front of a cul. Testing was conducted with an overhead light source of 3.8 ft-c. Method: Experiment 2 Apparatas.-The apparatus consisted of two automated Y-water mazes with symmetrical arms (Sansone, Oliverio, Renzi, & Bovet, 1969). The walls were of black Plexiglas. At the end of each alley there was a swinging platform which could be raised automatically above the water level. A 3-w lamp screened by an opalescent screen was located 1 cm above each platform and indicated the correct choice on each trial. Temperature of the water ranged between 18 and 20°C The mouse was placed on a platform by hand to start the trials. The platform was submerged and the platform for the correct arm was raised. At fixed intervals the platform on which the animal stood, after locating the correct arm, was automatically submerged; a platform was raised in the correct alley for the next trial, and the light went on as a signal that the alley with the platform raised was correct. The correct alley for each trial was determined by a random table of numbers. Testing procedure.-There were 20 mice in each of the 11 groups. Mice were males ranging in age from 55 to 80 days. A day before training all mice were subjected to five pretraining trials (intertrial interval 1 min.) in a straight alley 70 cm long. At the end of the pretraining session the animals were subjected to five sessions, each session consisting of three trials spaced by 1 min. The sequence of the trials was randomly programmed and the responses were recorded by means of infrared photocells located in the middle of each alley. Testing was conducted with normal room illumination (3.8 ft-c). Statirticul Analyrir All data were analyzed statistically by an 11 (Strain) X 5 (Sessions)

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analysis of variance, the Student-Newman-Keuls multiple-range test, and the Duncan multiple-range test. The number of errors in Sessions 1 to 5 and the difference between errors on Sessions 1 and 5 constituted the scores of each mouse in the Lashley 111. The trials without errors on Days 1 to 5, and the increase in trials without errors between Sessions 1 and 5 constituted the performance measure for the Y-water maze.

RESULTS Experiment I : Lashley I11 Maze Learning Relative improvement in the performance of all strains during the five-day period is represented in Fig. 2. The 11 (Strains) X 5 (Sessions) analysis of variance (Winer, 1962, p. 303) indicated significant differences among strains

FIG. 2. Errors for each separate session for the 11 RI strains tested on the Lashley 111 mate

(F = 4.29, rlf = 10/209, p < .01) 4/836, p < .01). A significant Strain 40/836, p < .01) was also obtained. trasts following analyses of variance.

and among sessions (F = 5.30, df = X Sessions interaction (F = 1.74, df = Table 1 summarizes the statistical conWhen Session 1 is considered, the sta-

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PERFORMANCE (ERRORS) IN THE LASHLEY 111 MAZE FOR 1 1 STRAINS OF MICE TESTED INDICATING PWFORMANCE ON DAY1, DAY5, AND DIFFERENCE BETWEEN DAY 1 AND DAY5

Session 1

Difference ($4~)

Session 5

CXBH 9.10 CXBK 22.70 30.05 CXBD 21.45 CXBD 8.60 CXBK 28.25 CBGF, 20.85 CXBI 7.25 CXBH 27.85 CXBH 19.15 C57 BL/GBy CB6K 26.00 6.65 WLBE 18.00 CXBI 25.40 CXBJ 6.65 BALB/cBy 6.30 BGCFI 17.55 22.80 CXBJ CXBI 17.50 C57BL/GBy 21.55 CXBG 6.05 CXBJ 16.65 CXBG 21.35 CXBK 6.05 C57BL/6By 14.90 B6CK 21.25 CB6Fl 5.15 CXBG 14.75 CXBE 20.95 B6CR 3.70 BALB/cBy 12.30 CXBE 2.95 BALB/cBy 18.60 *Cell mean ranked high to low with vertical lines indicating nonsignificant ( P > .OS) differences (Student-Newman-Keuls). Based on Tukev's W estimate any mean on Day 1 differing by'8.78, on Day 5 differing by 5.02, and fir difference between Day 1 and 5 differing by 9.45, is significantly different from any other mean in that respective .05). column ( p

CXBD

Maze learning: a genetic investigation in the mouse.

Psycbological Reports, 1975, 36, 703-712. @ Psychological Reports 1975 MAZE LEARNING: A GENETIC INVESTIGATION I N THE MOUSE1 MERRILL F. ELIAS Departm...
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