Nongenomic transmission across generations of maternal behavior and stress responses in the rat

Science

Volumn 286, Issue 5442, 1999, Pages 1155-1158

  Francis, Darlene ^a   Diorio, Josie ^a   Liu, Dong ^a   Meaney, Michael J ^a  

^a MCGILL UNIVERSITY   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ANIMAL EXPERIMENT; ARTICLE; BEHAVIOR GENETICS; ENVIRONMENTAL FACTOR; FEMALE; GENE EXPRESSION; MATERNAL BEHAVIOR; NONHUMAN; PRIORITY JOURNAL; RAT; STRESS;

AMYGDALA; ANIMALS; BRAIN; CORTICOTROPIN-RELEASING HORMONE; FEMALE; GENE EXPRESSION; HANDLING (PSYCHOLOGY); HIPPOCAMPUS; MALE; MATERNAL BEHAVIOR; PARAVENTRICULAR HYPOTHALAMIC NUCLEUS; RATS; RECEPTORS, GABA-A; RECEPTORS, GLUCOCORTICOID; STRESS;

ANIMALIA;

EID: 0033527727     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.286.5442.1155     Document Type: Article

References (54)

1. R. Plomin, J. C. De Fries, G. E. McClearn, M. Rutter, Behavioral Genetics (Freeman, New York, ed. 3, 1997).
2. J. Bowlby, Maternal Care and Mental Health (World Health Organization, Geneva, 1951); H. F. Harlow, Am. Psychol. 13, 673 (1958); S. J. Suomi, Br. Med. Bull. 53, 170 (1997); M. Rutter, Am. Psychol. 52, 603 (1997); S. Levine and E. B. Thoman, in Postnatal Development of Phenotype, S. Kazda and V. H. Denenberg, Eds. (Academia, Prague, 1970).
3. J. Bowlby, Maternal Care and Mental Health (World Health Organization, Geneva, 1951); H. F. Harlow, Am. Psychol. 13, 673 (1958); S. J. Suomi, Br. Med. Bull. 53, 170 (1997); M. Rutter, Am. Psychol. 52, 603 (1997); S. Levine and E. B. Thoman, in Postnatal Development of Phenotype, S. Kazda and V. H. Denenberg, Eds. (Academia, Prague, 1970).
4. J. Bowlby, Maternal Care and Mental Health (World Health Organization, Geneva, 1951); H. F. Harlow, Am. Psychol. 13, 673 (1958); S. J. Suomi, Br. Med. Bull. 53, 170 (1997); M. Rutter, Am. Psychol. 52, 603 (1997); S. Levine and E. B. Thoman, in Postnatal Development of Phenotype, S. Kazda and V. H. Denenberg, Eds. (Academia, Prague, 1970).
5. J. Bowlby, Maternal Care and Mental Health (World Health Organization, Geneva, 1951); H. F. Harlow, Am. Psychol. 13, 673 (1958); S. J. Suomi, Br. Med. Bull. 53, 170 (1997); M. Rutter, Am. Psychol. 52, 603 (1997); S. Levine and E. B. Thoman, in Postnatal Development of Phenotype, S. Kazda and V. H. Denenberg, Eds. (Academia, Prague, 1970).
6. J. Bowlby, Maternal Care and Mental Health (World Health Organization, Geneva, 1951); H. F. Harlow, Am. Psychol. 13, 673 (1958); S. J. Suomi, Br. Med. Bull. 53, 170 (1997); M. Rutter, Am. Psychol. 52, 603 (1997); S. Levine and E. B. Thoman, in Postnatal Development of Phenotype, S. Kazda and V. H. Denenberg, Eds. (Academia, Prague, 1970).
7. D. Liu et al., Science 277, 1659 (1997).
8. C. Caldji et al., Proc. Natl. Acad. Sci. U.S.A. 95, 5335 (1998).
9. J. R. Alberts and C. P. Cramer, in Handbook of Behavioral Neurobiology, vol. 9, E. M. Blass, Ed. (Plenum, New York, 1989); J. S. Rosenblatt, Acta Paediatr. Suppl. 397, 3 (1994); J. M. Stern, Dev. Psychobiol. 31, 19 (1997).
10. J. R. Alberts and C. P. Cramer, in Handbook of Behavioral Neurobiology, vol. 9, E. M. Blass, Ed. (Plenum, New York, 1989); J. S. Rosenblatt, Acta Paediatr. Suppl. 397, 3 (1994); J. M. Stern, Dev. Psychobiol. 31, 19 (1997).
11. J. R. Alberts and C. P. Cramer, in Handbook of Behavioral Neurobiology, vol. 9, E. M. Blass, Ed. (Plenum, New York, 1989); J. S. Rosenblatt, Acta Paediatr. Suppl. 397, 3 (1994); J. M. Stern, Dev. Psychobiol. 31, 19 (1997).
12. The animals were derived from Long-Evans hooded rats obtained from Charles River Canada (St. Constant, Québec), mated with males drawn randomly from our colony breeding stock, and maintained under previously described conditions (3, 4). In cases where the offspring of high or low LG-ABN mothers were used in studies, no more than two animals per group were drawn from any single mother. All procedures were performed according to guidelines developed by the Canadian Council on Animal Care and the protocol was approved by the McGill University Animal Care Committee. Mothers and their litters were housed in 46 cm by 18 cm by 30 cm Plexiglas cages and maternal behavior was scored [M. M. Myers, S. A. Brunelli, H. N. Shair, J. M. Squire, M. A. Hofer, Dev. Psychobiol. 22, 55 (1989) and (3, 4)] for six 100-min observation periods daily for the first 10 days postpartum by individuals unaware of the origin of the animals. The following behaviors were scored: mother off pups; mother licking/grooming any pup; and mother nursing pups in either an arched-back posture, a "blanket" posture (in which the mother lies over the pups), or a passive posture (in which the mother is lying either on her back or side). The data were analyzed as the percentage of total observations (frequency per total observations × 100) in which animals engaged in the target behavior (3, 4). In order to define populations, we observed the maternal behavior in a cohort of 32 mothers and devised the group mean and standard deviation for each behavior over the first 10 days of life. High LG-ABN mothers were defined as females whose frequency scores for both licking/grooming and archedback nursing were greater than 1 SD above the mean. Low LG-ABN mothers were defined as females whose frequency scores for both licking/grooming and archedback nursing were more than 1 SD below the mean. As in our previous reports (3, 4), the frequency of licking/ grooming and arched-back nursing were highly correlated (r > +0.90). The adult female offspring of high and low LG-ABN dams were then mated and observed for maternal behavior with the use of the same procedures described above over the first 10 days postpartum. As previously reported (3, 4), there were no differences in the percentage of total observations in which the offspring of high or low LG-ABN mothers were observed to be in contact with their pups (53 ± 5 versus 51 ± 4%; NS). Variations in licking/grooming or arched-back nursing were not related to differences in time spent with pups.
13. R. McCarty and J. H. Lee, Physiol. Behav. 59, 71 (1996). Female offspring of high or low LG-ABN dams were mated and allowed to give birth. Within 12 hours of birth, dams were removed from the home cage and two animals per litter were cross-fostered. The cross-fostered pups, along with two native pups, were labeled with a permanent marker (Codman pens, Johnson & Johnson) until day 10 of life and were identified by individual differences in the pattern of pelage pigmentation thereafter. All litters were culled to 12 pups. Subsequent studies showed that marking the pups had no effect on maternal licking/grooming; marked pups are licked/groomed no more or less frequently than unmarked pups (10). The dam was returned once the foster pups were introduced into the new litter. The entire procedure took less than 15 min. The data were analyzed using a two-way analysis of variance (ANOVA) (mother X cross-fostering condition).
14. S. Maccari et al., J. Neurosci. 15, 110 (1995).
15. Fearfulness under conditions of novelty was studied by means of an open-field test of exploration as previously described (4). Animals were placed one at a time, in a novel, circular open field 1.6 m in diameter for 5 min. The critical measure of exploration was the time (s) spent in the inner area of the novel arena (that is, entire body of the animal being > 10 cm away from any wall (> 10 cm) enclosing the open field.
16. D. Francis and M. J. Meaney, unpublished data.
17. The handling procedure involved removing the mother and then pups from their cage, placing the pups together in a small container, and returning the animals and their mothers to their cage 15 min later. The manipulation was performed daily for the first 14 days of life, and the animals were tested as fully mature adults. Nonhandled animals were left completely undisturbed until day 12 of life, at which time normal cage maintenance was initiated. Mothers of handled pups consistently showed an increased frequency of maternal licking/grooming [M. H. S. Lee and D. I. Williams, Anim. Behav. 22, 679 (1974); S. A. Barnett and J. Burn, Nature 213, 150 (1967); S. Levine, in Society, Stress and Disease, L. Levi, Ed. (Oxford Univ. Press, London, 1975); W. P. Smotherman and R. W. Bell, in Maternal Influences and Early Behavior, R. W. Bell and W. P. Smotherman, Eds. (Spectrum, New York, 1980); M. B. Hennessy, J. Vogt, S. Levine, Physiol. Psychol. 10, 153 (1982); (3).
18. The handling procedure involved removing the mother and then pups from their cage, placing the pups together in a small container, and returning the animals and their mothers to their cage 15 min later. The manipulation was performed daily for the first 14 days of life, and the animals were tested as fully mature adults. Nonhandled animals were left completely undisturbed until day 12 of life, at which time normal cage maintenance was initiated. Mothers of handled pups consistently showed an increased frequency of maternal licking/grooming [M. H. S. Lee and D. I. Williams, Anim. Behav. 22, 679 (1974); S. A. Barnett and J. Burn, Nature 213, 150 (1967); S. Levine, in Society, Stress and Disease, L. Levi, Ed. (Oxford Univ. Press, London, 1975); W. P. Smotherman and R. W. Bell, in Maternal Influences and Early Behavior, R. W. Bell and W. P. Smotherman, Eds. (Spectrum, New York, 1980); M. B. Hennessy, J. Vogt, S. Levine, Physiol. Psychol. 10, 153 (1982); (3).
19. The handling procedure involved removing the mother and then pups from their cage, placing the pups together in a small container, and returning the animals and their mothers to their cage 15 min later. The manipulation was performed daily for the first 14 days of life, and the animals were tested as fully mature adults. Nonhandled animals were left completely undisturbed until day 12 of life, at which time normal cage maintenance was initiated. Mothers of handled pups consistently showed an increased frequency of maternal licking/grooming [M. H. S. Lee and D. I. Williams, Anim. Behav. 22, 679 (1974); S. A. Barnett and J. Burn, Nature 213, 150 (1967); S. Levine, in Society, Stress and Disease, L. Levi, Ed. (Oxford Univ. Press, London, 1975); W. P. Smotherman and R. W. Bell, in Maternal Influences and Early Behavior, R. W. Bell and W. P. Smotherman, Eds. (Spectrum, New York, 1980); M. B. Hennessy, J. Vogt, S. Levine, Physiol. Psychol. 10, 153 (1982); (3).
20. The handling procedure involved removing the mother and then pups from their cage, placing the pups together in a small container, and returning the animals and their mothers to their cage 15 min later. The manipulation was performed daily for the first 14 days of life, and the animals were tested as fully mature adults. Nonhandled animals were left completely undisturbed until day 12 of life, at which time normal cage maintenance was initiated. Mothers of handled pups consistently showed an increased frequency of maternal licking/grooming [M. H. S. Lee and D. I. Williams, Anim. Behav. 22, 679 (1974); S. A. Barnett and J. Burn, Nature 213, 150 (1967); S. Levine, in Society, Stress and Disease, L. Levi, Ed. (Oxford Univ. Press, London, 1975); W. P. Smotherman and R. W. Bell, in Maternal Influences and Early Behavior, R. W. Bell and W. P. Smotherman, Eds. (Spectrum, New York, 1980); M. B. Hennessy, J. Vogt, S. Levine, Physiol. Psychol. 10, 153 (1982); (3).
21. The handling procedure involved removing the mother and then pups from their cage, placing the pups together in a small container, and returning the animals and their mothers to their cage 15 min later. The manipulation was performed daily for the first 14 days of life, and the animals were tested as fully mature adults. Nonhandled animals were left completely undisturbed until day 12 of life, at which time normal cage maintenance was initiated. Mothers of handled pups consistently showed an increased frequency of maternal licking/grooming [M. H. S. Lee and D. I. Williams, Anim. Behav. 22, 679 (1974); S. A. Barnett and J. Burn, Nature 213, 150 (1967); S. Levine, in Society, Stress and Disease, L. Levi, Ed. (Oxford Univ. Press, London, 1975); W. P. Smotherman and R. W. Bell, in Maternal Influences and Early Behavior, R. W. Bell and W. P. Smotherman, Eds. (Spectrum, New York, 1980); M. B. Hennessy, J. Vogt, S. Levine, Physiol. Psychol. 10, 153 (1982); (3).
22. S. Levine, Science 135, 795 (1962); _, G. C. Haltmeyer, G. G. Karas, V. H. Denenberg, Physiol. Behav. 2, 55 (1967); J. L. Hess, V. H. Denenberg, M. X. Zarrow, W. D. Pfeifer, Physiol. Behav. 4, 109 (1969); M. X. Zarrow, P. S. Campbell, V. H. Denenberg, Proc. Soc. Exp. Biol. Med. 356, 141 (1973); M. J. Meaney, D. H. Aitken, Ch. Van Berkel, S. Bhatnagar, R. M. Sapolsky, Science 239, 766 (1988); M. J. Meaney, D. H. Aitken, S. Sharma, V. Viau, A. Sarrieau, Neuroendocrinology 5, 597 (1989); M. Vallée et al., J. Neurosci. 17, 2626 (1993); S. Bhatnagar, N. Shanks, M. J. Meaney, J. Neuroendocrinol. 7, 107 (1995).
23. S. Levine, Science 135, 795 (1962); _, G. C. Haltmeyer, G. G. Karas, V. H. Denenberg, Physiol. Behav. 2, 55 (1967); J. L. Hess, V. H. Denenberg, M. X. Zarrow, W. D. Pfeifer, Physiol. Behav. 4, 109 (1969); M. X. Zarrow, P. S. Campbell, V. H. Denenberg, Proc. Soc. Exp. Biol. Med. 356, 141 (1973); M. J. Meaney, D. H. Aitken, Ch. Van Berkel, S. Bhatnagar, R. M. Sapolsky, Science 239, 766 (1988); M. J. Meaney, D. H. Aitken, S. Sharma, V. Viau, A. Sarrieau, Neuroendocrinology 5, 597 (1989); M. Vallée et al., J. Neurosci. 17, 2626 (1993); S. Bhatnagar, N. Shanks, M. J. Meaney, J. Neuroendocrinol. 7, 107 (1995).
24. S. Levine, Science 135, 795 (1962); _, G. C. Haltmeyer, G. G. Karas, V. H. Denenberg, Physiol. Behav. 2, 55 (1967); J. L. Hess, V. H. Denenberg, M. X. Zarrow, W. D. Pfeifer, Physiol. Behav. 4, 109 (1969); M. X. Zarrow, P. S. Campbell, V. H. Denenberg, Proc. Soc. Exp. Biol. Med. 356, 141 (1973); M. J. Meaney, D. H. Aitken, Ch. Van Berkel, S. Bhatnagar, R. M. Sapolsky, Science 239, 766 (1988); M. J. Meaney, D. H. Aitken, S. Sharma, V. Viau, A. Sarrieau, Neuroendocrinology 5, 597 (1989); M. Vallée et al., J. Neurosci. 17, 2626 (1993); S. Bhatnagar, N. Shanks, M. J. Meaney, J. Neuroendocrinol. 7, 107 (1995).
25. S. Levine, Science 135, 795 (1962); _, G. C. Haltmeyer, G. G. Karas, V. H. Denenberg, Physiol. Behav. 2, 55 (1967); J. L. Hess, V. H. Denenberg, M. X. Zarrow, W. D. Pfeifer, Physiol. Behav. 4, 109 (1969); M. X. Zarrow, P. S. Campbell, V. H. Denenberg, Proc. Soc. Exp. Biol. Med. 356, 141 (1973); M. J. Meaney, D. H. Aitken, Ch. Van Berkel, S. Bhatnagar, R. M. Sapolsky, Science 239, 766 (1988); M. J. Meaney, D. H. Aitken, S. Sharma, V. Viau, A. Sarrieau, Neuroendocrinology 5, 597 (1989); M. Vallée et al., J. Neurosci. 17, 2626 (1993); S. Bhatnagar, N. Shanks, M. J. Meaney, J. Neuroendocrinol. 7, 107 (1995).
26. S. Levine, Science 135, 795 (1962); _, G. C. Haltmeyer, G. G. Karas, V. H. Denenberg, Physiol. Behav. 2, 55 (1967); J. L. Hess, V. H. Denenberg, M. X. Zarrow, W. D. Pfeifer, Physiol. Behav. 4, 109 (1969); M. X. Zarrow, P. S. Campbell, V. H. Denenberg, Proc. Soc. Exp. Biol. Med. 356, 141 (1973); M. J. Meaney, D. H. Aitken, Ch. Van Berkel, S. Bhatnagar, R. M. Sapolsky, Science 239, 766 (1988); M. J. Meaney, D. H. Aitken, S. Sharma, V. Viau, A. Sarrieau, Neuroendocrinology 5, 597 (1989); M. Vallée et al., J. Neurosci. 17, 2626 (1993); S. Bhatnagar, N. Shanks, M. J. Meaney, J. Neuroendocrinol. 7, 107 (1995).
27. S. Levine, Science 135, 795 (1962); _, G. C. Haltmeyer, G. G. Karas, V. H. Denenberg, Physiol. Behav. 2, 55 (1967); J. L. Hess, V. H. Denenberg, M. X. Zarrow, W. D. Pfeifer, Physiol. Behav. 4, 109 (1969); M. X. Zarrow, P. S. Campbell, V. H. Denenberg, Proc. Soc. Exp. Biol. Med. 356, 141 (1973); M. J. Meaney, D. H. Aitken, Ch. Van Berkel, S. Bhatnagar, R. M. Sapolsky, Science 239, 766 (1988); M. J. Meaney, D. H. Aitken, S. Sharma, V. Viau, A. Sarrieau, Neuroendocrinology 5, 597 (1989); M. Vallée et al., J. Neurosci. 17, 2626 (1993); S. Bhatnagar, N. Shanks, M. J. Meaney, J. Neuroendocrinol. 7, 107 (1995).
28. S. Levine, Science 135, 795 (1962); _, G. C. Haltmeyer, G. G. Karas, V. H. Denenberg, Physiol. Behav. 2, 55 (1967); J. L. Hess, V. H. Denenberg, M. X. Zarrow, W. D. Pfeifer, Physiol. Behav. 4, 109 (1969); M. X. Zarrow, P. S. Campbell, V. H. Denenberg, Proc. Soc. Exp. Biol. Med. 356, 141 (1973); M. J. Meaney, D. H. Aitken, Ch. Van Berkel, S. Bhatnagar, R. M. Sapolsky, Science 239, 766 (1988); M. J. Meaney, D. H. Aitken, S. Sharma, V. Viau, A. Sarrieau, Neuroendocrinology 5, 597 (1989); M. Vallée et al., J. Neurosci. 17, 2626 (1993); S. Bhatnagar, N. Shanks, M. J. Meaney, J. Neuroendocrinol. 7, 107 (1995).
29. S. Levine, Science 135, 795 (1962); _, G. C. Haltmeyer, G. G. Karas, V. H. Denenberg, Physiol. Behav. 2, 55 (1967); J. L. Hess, V. H. Denenberg, M. X. Zarrow, W. D. Pfeifer, Physiol. Behav. 4, 109 (1969); M. X. Zarrow, P. S. Campbell, V. H. Denenberg, Proc. Soc. Exp. Biol. Med. 356, 141 (1973); M. J. Meaney, D. H. Aitken, Ch. Van Berkel, S. Bhatnagar, R. M. Sapolsky, Science 239, 766 (1988); M. J. Meaney, D. H. Aitken, S. Sharma, V. Viau, A. Sarrieau, Neuroendocrinology 5, 597 (1989); M. Vallée et al., J. Neurosci. 17, 2626 (1993); S. Bhatnagar, N. Shanks, M. J. Meaney, J. Neuroendocrinol. 7, 107 (1995).
30. A. J. Dunn and C. W. Berridge, Brain Res. Rev. 15, 71 (1990); M. J. Owens and C. B. Nemeroff, Pharmacol. Rev. 43, 425 (1991); P. M. Plotsky, J. Neuroendocrinol. 3, 1 (1991); M. F. Dallman et al., J. Neuroendocrinol. 4, 517 (1993); G. F. Koob, S. C. Heinrichs, F. Menzaghi, E. M. Pich, K. T. Britton, Semin. Neurosci. 6, 221 (1994); S. L. Lightman and M. S. Harbuz, Ciba Found. Symp. 172, 173 (1994); J. Schulkin, B. S. McEwen, P. W. Gold, Neurosci. Biobehav. Rev. 18, 1 (1994); J. P. Herman and W. E. Cullinan, Trends. Neurosci. 20, 78 (1997); J. A. Gray, The Psychology of Fear and Stress, (Cambridge Univ. Press, Cambridge, 1987); A. L. Malizia et al., Eds., GABAA Receptors and Anxiety: From Neurobiology to Treatment (Raven, New York, 1995); P. Roy-Byrne, D. K. Wingerson, A. Radant, D. J. Greenblatt, D. S. Cowley, Am. J. Psychiatry 153, 1444 (1996).
31. A. J. Dunn and C. W. Berridge, Brain Res. Rev. 15, 71 (1990); M. J. Owens and C. B. Nemeroff, Pharmacol. Rev. 43, 425 (1991); P. M. Plotsky, J. Neuroendocrinol. 3, 1 (1991); M. F. Dallman et al., J. Neuroendocrinol. 4, 517 (1993); G. F. Koob, S. C. Heinrichs, F. Menzaghi, E. M. Pich, K. T. Britton, Semin. Neurosci. 6, 221 (1994); S. L. Lightman and M. S. Harbuz, Ciba Found. Symp. 172, 173 (1994); J. Schulkin, B. S. McEwen, P. W. Gold, Neurosci. Biobehav. Rev. 18, 1 (1994); J. P. Herman and W. E. Cullinan, Trends. Neurosci. 20, 78 (1997); J. A. Gray, The Psychology of Fear and Stress, (Cambridge Univ. Press, Cambridge, 1987); A. L. Malizia et al., Eds., GABAA Receptors and Anxiety: From Neurobiology to Treatment (Raven, New York, 1995); P. Roy-Byrne, D. K. Wingerson, A. Radant, D. J. Greenblatt, D. S. Cowley, Am. J. Psychiatry 153, 1444 (1996).
32. A. J. Dunn and C. W. Berridge, Brain Res. Rev. 15, 71 (1990); M. J. Owens and C. B. Nemeroff, Pharmacol. Rev. 43, 425 (1991); P. M. Plotsky, J. Neuroendocrinol. 3, 1 (1991); M. F. Dallman et al., J. Neuroendocrinol. 4, 517 (1993); G. F. Koob, S. C. Heinrichs, F. Menzaghi, E. M. Pich, K. T. Britton, Semin. Neurosci. 6, 221 (1994); S. L. Lightman and M. S. Harbuz, Ciba Found. Symp. 172, 173 (1994); J. Schulkin, B. S. McEwen, P. W. Gold, Neurosci. Biobehav. Rev. 18, 1 (1994); J. P. Herman and W. E. Cullinan, Trends. Neurosci. 20, 78 (1997); J. A. Gray, The Psychology of Fear and Stress, (Cambridge Univ. Press, Cambridge, 1987); A. L. Malizia et al., Eds., GABAA Receptors and Anxiety: From Neurobiology to Treatment (Raven, New York, 1995); P. Roy-Byrne, D. K. Wingerson, A. Radant, D. J. Greenblatt, D. S. Cowley, Am. J. Psychiatry 153, 1444 (1996).
33. A. J. Dunn and C. W. Berridge, Brain Res. Rev. 15, 71 (1990); M. J. Owens and C. B. Nemeroff, Pharmacol. Rev. 43, 425 (1991); P. M. Plotsky, J. Neuroendocrinol. 3, 1 (1991); M. F. Dallman et al., J. Neuroendocrinol. 4, 517 (1993); G. F. Koob, S. C. Heinrichs, F. Menzaghi, E. M. Pich, K. T. Britton, Semin. Neurosci. 6, 221 (1994); S. L. Lightman and M. S. Harbuz, Ciba Found. Symp. 172, 173 (1994); J. Schulkin, B. S. McEwen, P. W. Gold, Neurosci. Biobehav. Rev. 18, 1 (1994); J. P. Herman and W. E. Cullinan, Trends. Neurosci. 20, 78 (1997); J. A. Gray, The Psychology of Fear and Stress, (Cambridge Univ. Press, Cambridge, 1987); A. L. Malizia et al., Eds., GABAA Receptors and Anxiety: From Neurobiology to Treatment (Raven, New York, 1995); P. Roy-Byrne, D. K. Wingerson, A. Radant, D. J. Greenblatt, D. S. Cowley, Am. J. Psychiatry 153, 1444 (1996).
34. A. J. Dunn and C. W. Berridge, Brain Res. Rev. 15, 71 (1990); M. J. Owens and C. B. Nemeroff, Pharmacol. Rev. 43, 425 (1991); P. M. Plotsky, J. Neuroendocrinol. 3, 1 (1991); M. F. Dallman et al., J. Neuroendocrinol. 4, 517 (1993); G. F. Koob, S. C. Heinrichs, F. Menzaghi, E. M. Pich, K. T. Britton, Semin. Neurosci. 6, 221 (1994); S. L. Lightman and M. S. Harbuz, Ciba Found. Symp. 172, 173 (1994); J. Schulkin, B. S. McEwen, P. W. Gold, Neurosci. Biobehav. Rev. 18, 1 (1994); J. P. Herman and W. E. Cullinan, Trends. Neurosci. 20, 78 (1997); J. A. Gray, The Psychology of Fear and Stress, (Cambridge Univ. Press, Cambridge, 1987); A. L. Malizia et al., Eds., GABAA Receptors and Anxiety: From Neurobiology to Treatment (Raven, New York, 1995); P. Roy-Byrne, D. K. Wingerson, A. Radant, D. J. Greenblatt, D. S. Cowley, Am. J. Psychiatry 153, 1444 (1996).
35. A. J. Dunn and C. W. Berridge, Brain Res. Rev. 15, 71 (1990); M. J. Owens and C. B. Nemeroff, Pharmacol. Rev. 43, 425 (1991); P. M. Plotsky, J. Neuroendocrinol. 3, 1 (1991); M. F. Dallman et al., J. Neuroendocrinol. 4, 517 (1993); G. F. Koob, S. C. Heinrichs, F. Menzaghi, E. M. Pich, K. T. Britton, Semin. Neurosci. 6, 221 (1994); S. L. Lightman and M. S. Harbuz, Ciba Found. Symp. 172, 173 (1994); J. Schulkin, B. S. McEwen, P. W. Gold, Neurosci. Biobehav. Rev. 18, 1 (1994); J. P. Herman and W. E. Cullinan, Trends. Neurosci. 20, 78 (1997); J. A. Gray, The Psychology of Fear and Stress, (Cambridge Univ. Press, Cambridge, 1987); A. L. Malizia et al., Eds., GABAA Receptors and Anxiety: From Neurobiology to Treatment (Raven, New York, 1995); P. Roy-Byrne, D. K. Wingerson, A. Radant, D. J. Greenblatt, D. S. Cowley, Am. J. Psychiatry 153, 1444 (1996).
36. A. J. Dunn and C. W. Berridge, Brain Res. Rev. 15, 71 (1990); M. J. Owens and C. B. Nemeroff, Pharmacol. Rev. 43, 425 (1991); P. M. Plotsky, J. Neuroendocrinol. 3, 1 (1991); M. F. Dallman et al., J. Neuroendocrinol. 4, 517 (1993); G. F. Koob, S. C. Heinrichs, F. Menzaghi, E. M. Pich, K. T. Britton, Semin. Neurosci. 6, 221 (1994); S. L. Lightman and M. S. Harbuz, Ciba Found. Symp. 172, 173 (1994); J. Schulkin, B. S. McEwen, P. W. Gold, Neurosci. Biobehav. Rev. 18, 1 (1994); J. P. Herman and W. E. Cullinan, Trends. Neurosci. 20, 78 (1997); J. A. Gray, The Psychology of Fear and Stress, (Cambridge Univ. Press, Cambridge, 1987); A. L. Malizia et al., Eds., GABAA Receptors and Anxiety: From Neurobiology to Treatment (Raven, New York, 1995); P. Roy-Byrne, D. K. Wingerson, A. Radant, D. J. Greenblatt, D. S. Cowley, Am. J. Psychiatry 153, 1444 (1996).
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42. 3H standards of (19). Autoradiographic data were analyzed with a two-way ANOVA (group X region).
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54. Supported by grants from the Medical Research Council of Canada (MRCC) and the National Institute of Mental Health to M.J.M., as well as an MRCC graduate fellowship (D.L.) and an MRCC Senior Scientist award (M.J.M.). The authors thank B. S. McEwen and M. Hofer for comments on an earlier draft of this paper.