Variation at the Corticotropin-releasing Hormone Gene (CRH) Locus and Individual Differences in Stress Physiology and Behavior in Captive Rhesus Macaques (Macaca Mulatta).

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ProQuest, 2007 - 335 pages
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This thesis was based on the premise that the manner in which an individual perceives and reacts to stress is persistent and heritable, affecting its interactions, and fitness, throughout its life. I hypothesized that variation in the corticotropin-releasing hormone gene (CRH) and its regulatory regions---a locus integral to an organism's stress responses---partially accounts for differences in temperament and behavior. The hypothesis was tested by: sequencing the CRH locus and roughly 3.5 kb of 5' flanking region in 20 rhesus monkeys (Macaca mulatta); identifying polymorphisms likely to be linked to differences in gene expression; and determining whether CRH genotype is associated with stress-related response or behavior in this species. Nucleotide variation was found at 40 sites, some of which also showed parallel variation in other primates---an indication that this polymorphism may have been maintained by balancing selection. One of two SNPs in the 5' regulatory region (CRH -530 C/G SNP) showed association between genotype ("normal," CC, or heterozygote, CG) and physiological response to the stress of experimental maternal separation. Furthermore, in young adult males, CRH concentration in CSF was higher in CG than in CC individuals. Among males, CG infants were more anxious and less gregarious and explorative than CC, but, unexpectedly, showed lower basal and stress-reactive levels of plasma cortisol. Their higher ACTH:cortisol ratios, however, suggested reduced adrenal sensitivity to pituitary ACTH, developed perhaps as an adaptation to chronic HPA overactivity. CG females, in contrast, did not differ from CC counterparts in these traits, but showed elevated acute cortisol response.
  

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Contents

DEDICATION
1
SEQUENCE AND VARIATION IN THE M MULATTA
42
1 Cycle sequencing protocols
48
1
52
2 Percent sequence identity of rhesus CRH to human
57
5 Most common haplotypes for CRH 18site haplotype block
63
INTRA AND INTERSPECIES CRH VARIATION
81
1A Papio DNA samples used in study
89
1 CSF CRH difference between young adult 530 CC and CG rhesus
156
37
163
4A Sex x genotype x phase interactive effect on plasma cortisol
165
2 Eigenvalues and factor loadings on infant behavior
169
7A Genotype effects on factor scores
174
4 Summary of findings
177
DISCUSSION
210
1 CRH genotypephenotype associations and potential
233

3
94
3 Rhesus CRH gene regions polymorphic within other taxa
100
5
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7
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21
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13B CRH promoter regulation in the hypothalamus with essential
125
ALLELEBASED ASSOCIATION WITH INDIVIDUAL
133
1 Operational definitions of infant behaviors used in factor analysis
145
33
149
APPENDICES
245
42
252
49
259
50
265
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268
52
272
111
276
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