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Physiol. Genomics 26: 145-151, 2006; doi:10.1152/physiolgenomics.00019.2006
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Received 9 February 2006; accepted in final form 27 April 2006.
Physiological Genomics 26:145-151 (2006)
1094-8341/06 $8.00 © 2006 American Physiological Society

Genome-wide scan for quantitative trait loci influencing spatial navigation and social recognition memory in Dahl rats

Nelson Ruiz-Opazo 1 and John Tonkiss 2

1 Section of Molecular Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
2 Center for Behavioral Development and Mental Retardation, Boston University School of Medicine, Boston, Massachusetts


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The genetic determinants of learning and memory have been difficult to unravel because of the complex inheritance of these forms of cognitive behavior encompassing multiple genetic and environmental factors. Indeed, genes that can account for strain and individual variations in learning and memory are largely unknown. Here we report a genome-wide scan for quantitative trait loci (QTLs) affecting spatial learning and memory and social recognition memory in an F2 population derived from Dahl rats. We detected five QTLs on chromosomes 1, 8, 11, 17, and 20 affecting spatial acquisition performance and five QTLs on chromosomes 2, 3, 9, and 20 influencing spatial accuracy (once information about the target location had been acquired). None of these QTLs overlap, indicating the existence of independent genetic determinants for these two distinct behavioral components of spatial navigation. Moreover, five QTLs affecting social recognition memory were detected, two on chromosome 9 and three on chromosome X. The chromosomal regions linked to social recognition memory performance in the rat are syntenic to regions that have been linked to autism in humans. Thus our results could have paradigmatic value in guiding the experimental investigation of similar pathways in genetic susceptibility to this disorder, which results in profound impairments in social behavior.

genetics; Morris water maze; acquisition; spatial accuracy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
ONE COGNITIVE TASK frequently utilized to evaluate learning and memory performance in rodents is the hippocampus-dependent Morris water maze (MWM) test of spatial navigation (2, 22). This task measures the subject's ability to navigate (via the flexible use of distal cues) while swimming to find a submerged escape platform located in a fixed position relative to those cues (2, 5, 22). Numerous studies have shown that hippocampal damage impairs spatial navigation across all species tested (7). Moreover, spatial navigation performance exhibits age-dependent decline in many species, including humans (6, 33, 35), monkeys (15, 24), rats (9, 18), and mice (1), and hippocampal dysfunction has been reported as one of the earlier hallmarks of Alzheimer disease (23). Thus identification of genes that influence spatial navigation in rats could help to establish a paradigm for investigation in humans.

On the other hand, social recognition refers to the ability to recognize a familiar conspecific, a cognitive function that is critical for the establishment of all mammalian relationships (8). "Social neuroscience" remains an emerging field (12), but recent studies show that lesions of the hippocampus do not impair social recognition memory in rats (29), indicating that social recognition memory is ostensibly a hippocampus-independent form of cognition. Given the prominent social dysfunction associated with abnormal social cognition, observed in such disorders as autism (34) and schizophrenia, the elucidation of genes that affect social recognition could provide novel insights into genetic mechanisms underlying these conditions (12).

We previously reported (25, 27) significant behavioral differences between two closely related inbred rat strains, the Dahl R and Dahl S strains, in both spatial navigation performance and social recognition memory. Here we extend this work and report a comparative genome scan performed on an F2 intercross of these strains (Dahl R x Dahl S) phenotyped for performance on these same behavioral tests to assess whether unique and/or shared genetic determinants affect these two distinct cognitive tasks.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Study cohort.
All animal experimentation was conducted in accordance with protocols approved by the Boston University Medical Center Institutional Animal Care and Use Committee. Dahl S/hsd and Dahl R/hsd rats were obtained from Harlan (Indianapolis, IN). A cohort was derived from brother-to-sister mating of F1 (R female x S male) hybrids to produce an F2 male segregating population (n = 200). In our laboratory, all rats were maintained on LabDiet 5001 rodent chow (Harlan Teklad, Madison, WI) containing 0.4% NaCl available ad libitum. Behavioral testing was performed on the F2 cohort at 10 wk of age. All 200 subjects were phenotyped for social recognition memory, and a subset of 178 were characterized in the MWM task.

Social recognition task.
Two hundred F2 subjects were characterized in this task for genetic analysis. All tests were conducted in dim red light during the dark phase of a 12:12-h light-dark cycle and after a 2-h acclimation period. All observations were recorded onto videotape with a video camera equipped with an infrared light source. Seven-week-old male Sprague-Dawley rats (Harlan) were used as social stimuli. Testing began when a juvenile was introduced in the subject's home cage for a 5-min initial exposure (sample phase). At the end of the trial, the juvenile was removed and returned to its cage. A second 5-min exposure (test phase) to the same juvenile was conducted after a 30-min interexposure interval time. Social-investigatory behavior was defined as described previously (26–28, 32) and included direct contact while sniffing, close following, nosing, pawing, grooming, or generally inspecting any body surface of the juvenile as well as the tip of the subject's nose being proximally oriented to within ~1 cm of the juvenile. Observational data were scored and analyzed with the Observer Base Package for Windows Version 3.0 (Noldus Information Technology, Wageningen, The Netherlands). Over the first minute, the time spent in social-investigatory behavior (as defined above) was analyzed from videotape.

MWM task.
The MWM task was performed as described previously (25) with a 1.5-m-diameter circular water maze (filled with water at 25°C ± 0.5) and a computer tracking system (Polytrack software program, San Diego Instruments, San Diego, CA). Distance was used to evaluate performance because swim speed was found to be significantly different between parental and F1 intercross populations (25). Twelve swim trials were given per day (for 2 consecutive days). Animals were placed into the maze (at 1 of 3 randomized start positions located adjacent to the wall) and were allowed to traverse the maze in search of the escape platform. On each trial, a maximum swim time of 60 s was imposed. Between trials, a 35-s interval was imposed with the rat on the platform. At the end of the twenty-fourth trial, the platform was removed (probe trial) and the rat was allowed to search for 1 min. A total of 178 F2 subjects were characterized in this MWM task for subsequent genetic analysis.

Intercross linkage analysis.
Genotyping was done with 122 markers, including EA4, a previously described SSCP marker for the Dear locus detecting the S44P/M74T (Dahl R) and S44/M74 (Dahl S) gene variants (13). Markers were distributed with an average density of 12.4 cM, with a maximum of 32.5 cM distance between markers. Quantitative trait locus (QTL) analysis for navigational performance was performed, using the cumulative distance traveled over 24 trials as an index of acquisition performance (ACQTD) and the average distance from the platform on the probe trial (see above) as an index of spatial accuracy (SpA). QTL analysis for social recognition memory (SR) was done, using the difference between the sample phase and the test phase in seconds as a quantitative trait (the larger the difference, the better the performance). Linkage map, marker regression, and interval mapping analyses were done with the Map Manager QTXb19 program (16), which generates a likelihood ratio statistic (LRS) as a measure of the significance of a possible QTL. Genetic distances were calculated with Kosambi mapping function (in cM). Critical significance values (LRS values) for interval mapping were determined by a permutation test (2,000 permutations at 10-cM interval) on our informative progeny with Kosambi mapping function. For suggestive linkage LRS = 8.7 [logarithm of the odds score (LOD) 1.9]; for significant linkage LRS = 14.7 (LOD 3.2); for highly significant linkage LRS = 20.7 (LOD 4.5). An LRS of 4.6 is equivalent to 1 LOD. Regression analysis using a free model fit as well as constrained additive, dominant, and recessive models were applied. Data are presented for the free model fit because this analysis fits separate regression coefficients for both additive and dominance components (QTX Map Manager, MMQTXb19). The confidence interval for a QTL location was estimated by a bootstrap resampling method in which a histogram single peak delineates the QTL and peak widths define the confidence interval for the QTL. Histograms that show more than one peak warn that the position for the QTL is not well defined or that there may be multiple linked QTLs (QTX Map Manager).

Interaction analysis.
Interaction analysis was done with the Map Manager QTXb19 program, applying a two-stage test paradigm for determination of interaction in which the pair of loci must pass two tests to be reported as having a significant interaction effect. First, the significance of the total effect of the two loci must be <0.00001, and second, the pairs of loci must exhibit a P value <0.01 for the interaction effect.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
F2 intercross linkage analysis for spatial navigation performance.
Our initial studies in Dahl rats showed that the MWM task is amenable to genetic analysis (25). More specifically, we detected two QTLs on chromosome X influencing spatial navigation performance in Dahl rats. One QTL (Nav-1) influenced acquisition performance without affecting spatial accuracy performance, and the second QTL (Nav-2) affected spatial accuracy performance without influencing acquisition performance (25). Here we extend our genetic analysis to include all autosomes in a genome-wide scan for QTLs influencing spatial learning and memory performance on a male F2 [R x S] intercross rat population phenotyped for navigational performance. Two distinct behavioral components associated with spatial navigational performance were investigated: ACQTD, defined as the cumulative distance traveled over 24 trials (the greater distance traveled, the poorer the performance), and SpA, defined as the average distance from platform on the probe trial (the greater the search distance from the platform location, the poorer the performance). As shown in Table 1, acquisition and spatial accuracy performance were significantly better in Dahl R than in Dahl S rats (ACQTD, P < 0.03; SpA, P < 0.0001). The F2 average values (Table 1) were found to be much closer to the Dahl R than the Dahl S parental values for these two behavioral components of spatial navigation, implying directional dominance of the Dahl R alleles. The distribution of these two traits in the F2 male hybrids (Fig. 1) suggests a polygenic model of inheritance.


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  		Table 1. Spatial learning and memory and social recognition memory performance in Dahl S, Dahl R, and F2 cohort

 

Figure 1
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  		Fig. 1. Distribution of acquisition (A), spatial accuracy (B), and social recognition memory performance (C) in Dahl S, Dahl R, and F2 male hybrids. ACQTD, index of acquisition performance.

 
To identify potential QTLs influencing spatial navigation in Dahl rats, we performed QTL analysis on an F2 [R x S] intercross male cohort (n = 178) phenotyped for spatial learning and memory performance. Distributions were analyzed for normality; data transformations were done, and data sets that passed Kolmogorov-Smirnov normality testing (SigmaStat) were used for linkage analysis. QTL analysis was performed with log[ACQTD] and log[SpA] as quantitative traits. With a free regression model, four QTLs influencing ACQTD were detected with suggestive to highly significant linkage (Fig. 2; \. Table 2): one QTL on chromosome 1, Nav-3 (LOD = 4.5); one QTL on chromosome 8, Nav-4 (LOD = 2.5); one QTL on chromosome 17, Nav-5 (LOD = 4.8); and one QTL on chromosome 20, Nav-6 (LOD = 3.1). The genome search for QTLs affecting SpA revealed five QTLs (Fig. 3; Table 2): two QTLs on chromosome 2, Nav-8 (LOD = 3.3) and Nav-9 (LOD = 3.6); one QTL on chromosome 3, Nav-10 (LOD = 2.0); one QTL on chromosome 9, Nav-11 (LOD = 2.5); and one QTL on chromosome 20, Nav-12 (LOD = 2.4).


Figure 2
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  		Fig. 2. Quantitative trait loci (QTLs) for acquisition performance in male F2 [R x S] intercross rats. Chromosomes with suggestive or significant QTLs were analyzed by interval mapping with a bootstrap resampling method to estimate a confidence interval: Nav-3 on chromosome 1 (A), Nav-4 on chromosome 8 (B), Nav-5 on chromosome 17 (C), and Nav-6 on chromosome 20 (D). Yellow histograms represent the bootstrap-based confidence intervals for the detected QTLs. Horizontal green lines mark logarithm of the odds score (LOD) values for significance of linkage, from top to bottom: highly significant LOD ≥ 4.5, significant LOD ≥ 3.2, and suggestive LOD ≥ 1.9. LOD (black curve), regression coefficient for additive effect (red curve), and regression coefficient for dominance effect (blue curve) are shown.

 

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  		Table 2. QTLs with significant and suggestive linkage for traits associated with spatial navigation and social recognition memory performance in male F2 [R x S] intercross rats

 

Figure 3
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  		Fig. 3. QTLs for spatial accuracy performance in male F2 [R x S] intercross rats. A: Nav-8 and Nav-9 on chromosome 2. B: Nav-10 on chromosome 3. C: Nav-11 on chromosome 9. D: Nav-12 on chromosome 20. Yellow histograms represent the bootstrap-based confidence intervals for the detected QTLs. Horizontal green lines mark LOD values for significance of linkage, from top to bottom: highly significant LOD ≥ 4.5, significant LOD ≥ 3.2, and suggestive LOD ≥ 1.9. LOD (black curve), regression coefficient for additive effect (red curve), and regression coefficient for dominance effect (blue curve) are shown.

 
The genome-wide scan revealed that the parental S allele improved cognitive performance in most detected QTLs, except for Nav-3, which tended to worsen cognitive performance (Table 2). In the previously reported chromosome X Nav-1 and Nav-2 QTLs affecting ACQTD and SpA, respectively, the parental S allele impaired cognitive performance for both QTLs in the same male F2 [R x S] intercross rat population (25).

Putative interactive loci were investigated by using a two-stage test. A positive interaction is deemed to be present when pairs of loci show a P value <0.00001 (LOD > 8.0) for the total effect and a P value <0.01 (LOD > 4.1) for the interaction effect (16). Our analysis detected one interacting pair for ACQTD that surpassed the threshold criteria, Nav-5, with a locus on chromosome 11 (Nav-7) marked by D11Mgh5 (Table 3). The combined effect of Nav-5 and Nav-7 (LOD = 9; Table 3) could explain as much as 22% of the total trait variance.


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  		Table 3. Interaction analysis for navigational performance

 
F2 intercross linkage analysis for social recognition memory performance.
Social recognition memory performance was significantly better in Dahl R than Dahl S rats (P < 0.02; Table 1). The F2 average value (Table 1) was closer to the Dahl R than the Dahl S parental value, suggesting directional dominance of the Dahl R alleles. The distribution of social recognition memory performance in the F2 male hybrids (Fig. 1) is consistent with a polygenic model of inheritance for this type of cognition.

To identify putative QTLs influencing social recognition memory in Dahl rats, we performed QTL analysis on an F2 [R x S] intercross male cohort phenotyped for social recognition memory performance. Two hundred F2 male hybrids were genotyped at 122 markers informative for Dahl S and Dahl R strains. Distribution of social recognition memory performance (sample phase-test phase) passed Kolmogorov-Smirnov normality testing (SigmaStat); thus it was used as a quantitative trait for linkage analysis. The total genome search revealed five QTLs affecting social recognition memory (SR): a cluster of three closely linked QTLs on chromosome X (Fig. 4A; Table 2), SR-1 (LOD = 3.2), SR-2 (LOD = 4.5), and SR-3 (LOD = 4.4), and two on chromosome 9 (Fig. 4B; Table 2), SR-4 (LOD = 1.9) and SR-5 (LOD = 2.2). The S allele was found to impair performance in the chromosome X-detected QTLs, whereas it tended to improve performance in the chromosome 9 QTLs. Interaction analysis did not elucidate additional loci for social recognition memory performance.


Figure 4
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  		Fig. 4. QTLs for social recognition memory in male F2 [R x S] intercross rats. A: SR-1, SR-2, and SR-3 on chromosome X. B: SR-4 and SR-5 on chromosome 9. Yellow histograms represent the bootstrap-based confidence intervals for the detected QTLs. Horizontal green lines mark LOD values for significance of linkage, from top to bottom: highly significant LOD ≥ 4.5, significant LOD ≥ 3.2, and suggestive LOD ≥ 1.9. LOD (black curve), regression coefficient for additive effect (red curve), and regression coefficient for dominance effect (blue curve) are shown.

 
Analysis of quantitative traits specific to genotype for the QTL peak marker showed significant differences between S allele and R allele effects that were consistent with the level of significance detected in the total genome search for spatial navigation and social recognition memory performance (Table 4).


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  		Table 4. Genotype-specific trait means of QTLs with significant linkage for ACQTD, SpA, and SR

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
This report presents the first genome-wide scan for QTLs affecting spatial navigation and social recognition memory performance in rats. The F2 [R x S] intercross linkage analysis mapped QTLs for distinct behavioral components associated with spatial learning and memory. For acquisition performance we detected five QTLs and for spatial accuracy performance a further five QTLs. None of the QTLs detected for ACQTD and SpA overlap, suggesting that distinct genetic variants affect these two quantitative traits despite the fact that these traits are highly interdependent for spatial navigation.

QTLs affecting spatial learning were recently reported in mice on chromosomes 1, 4, 5, and 12 (20, 30). However, these regions are not syntenic with the chromosomal regions detected in our F2 [R x S] intercross rat cohort, suggesting that different genetic variants account for the effect in the reported mouse intercrosses and Dahl rats. Moreover, the genome search for QTLs affecting spatial learning in the mouse detected only two QTLs, one on chromosome 4 and one on chromosome 12, that surpassed the 5% threshold (30). These QTLs were detected only after jointly using two measures taken on the probe trial of the MWM (the time spent in the target quadrant and the number of passes through the platform's location) as quantitative traits. The loci on chromosomes 4 and 12 accounted for 3.4% and 2.9% of the total trait variance of the joint phenotype, respectively (30). In contrast, we used a univariate analysis for acquisition of the MWM task and for spatial accuracy on the probe trial detecting QTLs that explained 5–13% of the total trait variance, showing that ACQTD and SpA are robust quantitative traits of spatial learning and memory performance in Dahl rats.

One of the factors known to be involved in learning and memory is the transcription factor cAMP response element binding protein (CREB) (3), and effects of signaling pathways involving adenylyl cyclase and cAMP on CREB-regulated transcription have been associated with long-term memory formation (3). The mechanisms underlying the ability of CREB to modulate memory function are not entirely understood, and several neuronal processes have been postulated to be involved, including induction of long-term potentiation or depression of synaptic strength (17), growth and formation of new synaptic connections (17, 19), and protein synthesis-dependent mechanisms (14). Thus CREB and associated factors are envisioned as key players in modulation of memory function. We note two candidate genes localized within the confidence intervals for Nav-5 on chromosome 17 and Nav-11 on chromosome 9 that could underlie the effects of these QTLs on spatial learning and memory (Table 2): Crem (an antagonist/modulator of CREB function) (21) for Nav-5 and Creb1 (associated with olfactory learning in Drosophila and mammals) (3) for Nav-11. Interestingly, Nav-1, Nav-4, and Nav-10 mapped to syntenic regions in humans linked to late-onset Alzheimer disease (LOAD; Table 5) (31), suggesting that elucidation of the variants underlying these QTLs could give insights into genes affecting LOAD susceptibility in humans.


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  		Table 5. Rat QTL regions syntenic to genomic regions linked to LOAD and autism

 
The search for QTLs influencing social recognition memory detected three loci on chromosome X and two loci on chromosome 9. SR-3 on chromosome X and SR-5 on chromosome 9 appear to overlap with Nav-1 and Nav-11, respectively, suggesting the existence of common genetic components affecting spatial navigation and social recognition memory performance. It is noteworthy that Creb1 on chromosome 9 (position 63.2 Mbp; Table 2) could be one of the common genetic determinants of both spatial navigation and social recognition memory performance and hence could explain the effects of Nav-11 and SR-5, respectively. Identification of corresponding genes underlying these QTLs will be necessary to evaluate this hypothesis.

Social recognition memory showed strong genetic linkage to chromosome X, a finding that is congruent with the possible involvement of chromosome X in autism (Ref. 4; Table 5). This hypothesis has been advanced based on the higher prevalence of autism observed in males compared with females (4) and other studies showing genetic linkage to X (10, 11). We note also that the chromosome 9 region influencing social recognition memory in our rat intercross is syntenic with 2q in humans, a region that has also been linked to autism (4).

In summary, we report a genome-wide scan for QTLs affecting spatial learning and memory and social recognition memory in an F2 male population derived from Dahl salt-resistant (Dahl R) and Dahl salt-sensitive (Dahl S) hypertensive inbred rat lines. A number of QTLs influencing these two cognitive tasks were identified; some of them overlapped, suggesting that some genes might influence two distinct cognitive tasks known to be subserved by different neural substrates. The complexity of these results is in accord with the multifaceted and intricate nature of cognitive behavior. Our results also highlight the Dahl rat as a useful model for elucidating genetic mechanisms underlying spatial navigation and social recognition memory performance. This information could have immediate paradigmatic value in guiding the experimental investigation of similar pathways pertinent to age-dependent cognitive decline, Alzheimer disease, and autism, the latter constituting a disorder involving profound impairments in social behavior.


   GRANTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by grants to N. Ruiz-Opazo from the National Institutes of Health.


   ACKNOWLEDGMENTS
 
We thank L. V. Lopez and P. Bagamasbad for excellent technical assistance.


   FOOTNOTES
 
Article published online before print. See web site for date of publication (http://physiolgenomics.physiology.org).

Address for reprint requests and other correspondence: N. Ruiz-Opazo, Whitaker Cardiovascular Inst., W609, Boston Univ. School of Medicine, 700 Albany St., Boston MA 02118 (e-mail: nruizo{at}bu.edu).


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Bach ME, Barad M, Son H, Zhuo M, Lu YF, Shih R, Mansuy I, Hawkins RD, and Kandel ER. Age-related defects in spatial memory are correlated with defects in the late phase of hippocampal long-term potentiation in vitro and are attenuated by drugs that enhance the cAMP signaling pathway. Proc Natl Acad Sci USA 96: 5280–5285, 1999.[Abstract/Free Full Text]
  2. Brandeis R, Brandys Y, and Yehuda S. The use of the Morris water maze in the study of memory and learning. Int J Neurosci 48: 29–69, 1989.[Web of Science][Medline]
  3. Carlezon WA, Duman RS, and Nestler EJ. The many faces of CREB. Trends Neurosci 28: 436–445, 2005.[CrossRef][Web of Science][Medline]
  4. Chudley AE. Genetic landmarks through philately—autism spectrum disorders: a genetic update. Clin Genet 65: 352–357, 2004.[CrossRef][Web of Science][Medline]
  5. D'Hooge R and De Deyn PP. Applications of the Morris maze in the study of learning and memory. Brain Res Rev 36: 60–90, 2001.[CrossRef][Medline]
  6. Duke LM and Kaszniak AW. Executive control functions in degenerative dementias: a comparative review. Neuropsychol Rev 10: 75–99, 2000.[CrossRef][Web of Science][Medline]
  7. Erickson CA and Barnes CA. The neurobiology of memory changes in normal aging. Exp Gerontol 38: 61–69, 2003.[CrossRef][Web of Science][Medline]
  8. Ferguson JN, Young LJ, and Insel TR. The neuroendocrine basis of social recognition. Front Neuroendocrinol 23: 200–224, 2002.[CrossRef][Web of Science][Medline]
  9. Gallagher M and Rapp PR. The use of animal models to study the effects of aging on cognition. Annu Rev Psychol 48: 339–370, 1997.[CrossRef][Web of Science][Medline]
  10. Gauthier J, Joober R, Dube MP, St-Onge J, Bonnel A, Gariepy D, Laurent S, Najafee R, Lacasse H, St-Charles L, Fombonne E, Mottron L, and Rouleau GA. Autism spectrum disorders associated with X chromosome markers in French-Canadian males. Mol Psychiatry 11: 206–213, 2006.[CrossRef][Web of Science][Medline]
  11. Hallmayer J, Hebert JM, Spiker D, Lotspeich L, McMahon WM, Petersen PB, Nicholas P, Pingree C, Lin AA, Cavalli-Sforza LL, Risch N, and Ciaranello RD. Autism and the X chromosome. Multipoint sib-pair analysis. Arch Gen Psychiatry 53: 985–989, 1996.[Abstract]
  12. Insel TR and Fernald RD. How the brain processes social information: searching for the social brain. Annu Rev Neurosci 27: 697–722, 2004.[CrossRef][Web of Science][Medline]
  13. Kaneko Y, Herrera VL, Didishvili T, and Ruiz-Opazo N. Sex-specific effects of dual ET-1/ANG II receptor (Dear) variants in Dahl salt-sensitive/resistant hypertension rat model. Physiol Genomics 20: 157–164, 2005.[Abstract/Free Full Text]
  14. Kida S, Josselyn SA, Peña de Ortiz S, Kogan JH, Chevere I, Masushige S, and Silva AJ. CREB required for the stability of new and reactivated fear memories. Nat Neurosci 5: 348–355, 2002.[CrossRef][Web of Science][Medline]
  15. Lai ZC, Moss MB, Killiany RJ, Rosene DL, and Herndon JG. Executive system dysfunction in the aged monkey: spatial and object reversal learning. Neurobiol Aging 16: 947–954, 1995.[CrossRef][Web of Science][Medline]
  16. Manly KF, Cudmore RH Jr, and Meer JM. Map Manager QTX, cross-platform software for genetic mapping. Mamm Genome 12: 930–932, 2001.[CrossRef][Web of Science][Medline]
  17. Marie H, Morishita W, Yu X, Calakos N, and Malenka R Generation of silent synapses by acute in vivo expression of CaMKIV and CREB. Neuron 45: 741–752, 2005.[CrossRef][Web of Science][Medline]
  18. Markowska AL, Stone WS, Ingram DK, Reynolds J, Gold PE, Conti LH, Pontecorvo MJ, Wenk GL, and Olton DS. Individual differences in aging: behavioral and neurobiological correlates. Neurobiol Aging 10: 31–43, 1989.[CrossRef][Web of Science][Medline]
  19. Martin KC, Casadio A, Zhu H, Yaping E, Rose JC, Chen M, Bailey CH, and Kandel ER. Synapse-specific, long-term facilitation of Aplysia sensory to motor synapses: a function for local protein synthesis in memory storage. Cell 91: 927–938, 1997.[CrossRef][Web of Science][Medline]
  20. Milhaud JM, Halley H, and Lassalle JM. Two QTLs located on chromosomes 1 and 5 modulate different aspects of the performance of mice of the B x D Ty RI strain series in the Morris navigation task. Behav Genet 32: 69–78, 2002.[CrossRef][Web of Science][Medline]
  21. Mioduszewska B, Jaworski J, and Kaczmarek L. Inducible cAMP early repressor (ICER) in the nervous system—a transcriptional regulator of neuronal plasticity and programmed cell death. J Neurochem 87: 1313–1320, 2003.[Web of Science][Medline]
  22. Morris RGM, Garrud P, Rawlins JNP, and O'Keefe J. Place navigation impaired in rats with hippocampal lesions. Nature 297: 681–683, 1982.[CrossRef][Medline]
  23. Panegyres PK. The contribution of the study of neurodegenerative disorders to the understanding of human memory. QJM 97: 555–567, 2004.[Abstract/Free Full Text]
  24. Rapp PR, Kansky MT, and Roberts JA. Impaired spatial information processing in aged monkeys with preserved recognition memory. Neuroreport 8: 1923–1928, 1997.[Web of Science][Medline]
  25. Ruiz-Opazo N and Tonkiss J. X-linked loci influence spatial navigation performance in Dahl rats. Physiol Genomics 16: 329–333, 2004.[Abstract/Free Full Text]
  26. Ruiz-Opazo N, Kosik KS, Lopez LV, Bagamasbad P, Ponce LRB, and Herrera VLM. Attenuated hippocampus-dependent learning and memory decline in transgenic TgAPPswe Fischer-344 rats. Mol Med 10: 36–44, 2004.[Web of Science][Medline]
  27. Ruiz-Opazo N, Lopez LV, and Tonkiss J. Modulation of learning and memory in Dahl rats by dietary salt restriction. Hypertension 43: 797–802, 2004.[Abstract/Free Full Text]
  28. Sawyer TF, Hengehold AK, and Perez WA. Chemosensory and hormonal mediation of social memory in male rats. Behav Neurosci 98: 908–913, 1984.[CrossRef][Web of Science][Medline]
  29. Squires AS, Peddle R, Milway SJ, and Harley CW. Cytotoxic lesions of the hippocampus do not impair social recognition memory in socially housed rats. Neurobiol Learn Mem 85: 95–101, 2006.[CrossRef][Web of Science][Medline]
  30. Steinberger D, Reynolds DS, Ferris P, Lincoln R, Datta S, Stanley J, Paterson A, Dawson GR, and Flint J. Genetic mapping of variation in spatial learning in the mouse. J Neurosci 23: 2426–2433, 2003.[Abstract/Free Full Text]
  31. Tanzi RE and Bertram L. Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective. Cell 120: 545–555, 2005.[CrossRef][Web of Science][Medline]
  32. Thor DH and Holloway WR. Social memory of the male laboratory rat. J Comp Physiol Psychol 96: 1000–1006, 1982.[CrossRef]
  33. Uttl B and Graf P. Episodic spatial memory in adulthood. Psychol Aging 8: 257–273, 1993.[CrossRef][Web of Science][Medline]
  34. Vorstman JAS, Staal WG, van Daalen E, van Engeland H, Hochstenbach PFR, and Franke L. Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism. Mol Psychiatry 11: 18–28, 2006.[CrossRef][Web of Science]
  35. Wilkniss SM, Jones MG, Korol DL, and Manning CA. Age-related differences in an ecologically based study of route learning. Psychol Aging 12: 372–375, 1997.[CrossRef][Web of Science][Medline]
  36. Zubenko GS, Stiffler JS, Hughes HB, Hurtt MR, and Kaplan BB. Initial results of a genome survey for novel Alzheimer's disease risk genes: association with a locus on the X chromosome. Am J Med Genet 81: 98–107, 1998.[CrossRef][Web of Science][Medline]




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