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David M. Lyons, PhD; Chou Yang, MA; Anne M. Sawyer-Glover, RT(R)(MR); Michael E. Moseley, PhD; Alan F. Schatzberg, MD

Arch Gen Psychiatry. 2001;58:1145-1151.

ABSTRACT
Background  Opportunities for research on the causes and consequences of stress-related hippocampal atrophy are limited in human psychiatric disorders. Therefore, this longitudinal study investigated early life stress and inherited variation in monkey hippocampal volumes.

Methods  Paternal half-siblings raised apart from one another by different mothers in the absence of fathers were randomized to 1 of 3 postnatal conditions that disrupted diverse aspects of early maternal care (n = 13 monkeys per condition). These conditions were previously shown to produce differences in social behavior, emotional reactivity, and neuroendocrine stress physiology. Hippocampal volumes were subsequently determined in adulthood by high-resolution magnetic resonance imaging.

Results  Adult hippocampal volumes did not differ with respect to the stressful postnatal conditions. Based on paternal half-sibling effects, the estimated proportion of genetic variance, ie, heritability, was 54% for hippocampal size. Paternal half-siblings with small adult hippocampal volumes responded to the removal of all mothers after weaning with initially larger relative increases in cortisol levels. Plasma cortisol levels 3 and 7 days later, and measures of cortisol-negative feedback in adulthood were not, however, correlated with hippocampal size.

Conclusions  In humans with mood and anxiety disorders, small hippocampal volumes have been taken as evidence that excessive stress levels of cortisol induce hippocampal volume loss. Results from this study of monkeys suggest that small hippocampi also reflect an inherited characteristic of the brain. Genetically informed clinical studies should assess whether inherited variation in hippocampal morphology contributes to excessive stress levels of cortisol through diminished neuroendocrine regulation.

INTRODUCTION

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SMALL HIPPOCAMPAL volumes are found in adult humans with recurrent major depression^{1, 2} and posttraumatic stress disorder.^{3, 4} Childhood stress increases the risk of developing these mood and anxiety disorders,⁵ and small hippocampal volumes are evident in adult survivors of childhood maltreatment.^{6, 7} Hippocampal morphology is altered by stress in carefully controlled studies of rodents,^{8, 9, 10, 11} and small hippocampal volumes in humans have been taken as evidence that stress-related disorders induce hippocampal volume loss.^{2, 11, 12} An alternative possibility that cannot be dismissed in the absence of prospective longitudinal research is that small hippocampal volumes are inherited and predispose toward the development of psychiatric disorders that are triggered or aggravated by stress.^{3, 11}

Aside from a limited number of reports on inherited variation in autonomic activity¹³ and cerebrospinal fluid monoamine levels,^{14, 15} primate research on stress neurobiology has focused on maternal deprivation.¹⁶ Rhesus macaque monkeys raised without mothers exhibit increased brain dopamine and norepinephrine sensitivity,^{17, 18} exaggerated hypothalamic-pituitary-adrenal (HPA) responses to stress,^{19, 20} altered regulation of autonomic activity,²¹ fragmented sleep patterns,²² depressionlike behavior,¹⁸ and excessive consumption of alcohol.²³ Ecologically informed research on maternal availability has likewise identified untoward effects on primate postnatal development. Bonnet macaque monkeys raised by their mothers in variable foraging-demand conditions are impaired in social and emotional development.^{24, 25} In early adulthood, these same monkeys exhibit elevated cerebrospinal fluid levels of monoamines, somatostatin, and corticotropin-releasing factor (CRF).^{26, 27}

Studies of stress and hippocampal plasticity in primates have produced conflicting results. Maternal deprivation in rhesus macaque monkeys increases dentate gyrus non–phosphorylated neurofilament protein levels, a neuronal marker of vulnerability in Alzheimer disease, Huntington disease, Parkinson disease, and amyotrophic lateral sclerosis.²⁸ Hippocampal cell damage in adult vervet monkeys is induced by sustained and fatal stress²⁹ or long-term treatment with cortisol implanted in adult hippocampus.³⁰ Yet elderly adult pigtailed macaque monkeys treated long-term with oral cortisol do not respond with diminished volumes or neuron numbers in any hippocampal cell field.³¹ Rhesus macaque monkeys raised in social isolation also fail to show altered hippocampal volumes as determined in vivo at 18 months of age by magnetic resonance imaging (MRI).³²

Here we test for early stress effects and inherited variation in hippocampal volumes in 39 squirrel monkeys. Paternal half-siblings raised apart from one another by different mothers in the absence of fathers were randomized to conditions that disrupted diverse aspects of early maternal care. In one condition on 5 occasions offspring were briefly separated from groups composed of 3 or 4 mother-infant pairs. Intermittent separations consistently elicit short-term elevations in cortisol levels with baseline cortisol levels restored soon after the subsequent social reunions.^{33, 34, 35} In 2 other postnatal rearing conditions, differences in maternal availability were produced by manipulating the effort required to find food. Body weights and amounts of food consumed in each foraging condition were not significantly different, but high-foraging demand mothers stopped carrying their infant earlier, and these infants displayed modest prolonged increases in cortisol levels throughout the high-demand condition.^{36, 37}

Following completion of each 12-week condition at 21 weeks of age, all mothers were removed from natal groups after weaning at 36 weeks. At this stage of development squirrel monkeys are no longer reliant on maternal care. Sexual maturity is achieved at 3 years, and the squirrel monkey life span is approximately 21 years.³⁸ As previously described elsewhere in greater detail,³⁹ social behavior, emotional responses, and increases in cortisol levels elicited by removing all mothers after weaning were examined at 36 weeks of age for the study cohort. In early adulthood at 5 years we tested for differences in cortisol-negative feedback regulation of the HPA-axis response to exogenous stimulation by CRF.⁴⁰ Then 5 weeks later hippocampal volumes were determined by high-resolution MRI.

MATERIALS AND METHODS

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MATERIALS

Forty infants sired by fathers that had no contact with their offspring were distributed randomly in groups each composed of 3 or 4 mother-infant pairs. All monkeys were of Guyanese origin (Saimiri sciureus) and were born and maintained at the Stanford University Primate Facility, Stanford, Calif. One monkey from the low-foraging demand condition (see "Experimental Design and Procedures" section) was excluded for reasons unrelated to the study. Twelve fathers and 30 mothers produced the 39 monkeys that constituted the study cohort. Twenty-one mothers each contributed 1 offspring, and 9 mothers produced with different fathers on separate occasions 2 offspring. Two fathers each sired a single offspring, 3 fathers each sired 2 offspring, 2 fathers each sired 3 offspring, 3 fathers each sired 4 offspring, 1 father sired 5 offspring, and 1 father sired 8 offspring. All procedures were conducted in accord with and as required by the Animal Welfare Act, and approved by Stanford University's Administrative Panel on Laboratory Animal Care.

EXPERIMENTAL DESIGN AND PROCEDURES

Four natal groups were randomly assigned to each of the following 3 rearing conditions when infants were 10 weeks old (age range, 8-13 weeks).

1. Low-foraging demands. Thirteen infants (7 males and 6 females) and their 13 mothers were maintained from 10 to 21 weeks post partum in low-foraging demand conditions. Each group received 600% by weight of their normal daily food intake buried in foraging boards.³⁷ All 80 holes in the foraging boards contained abundant amounts of food.
   
2. High-foraging demands. Thirteen infants (7 males and 6 females) and 13 mothers were maintained from 10 to 21 weeks post partum in high-foraging demand conditions where each group was provisioned with 120% of their daily food intake buried in the foraging boards. Many holes in the foraging boards contained little or no food, so more time and effort were required to find food.
   
3. Intermittent social separations. Thirteen infants (6 males and 7 females) and 13 mothers fed from standard food-hoppers were separated intermittently for 5 sessions each lasting 5 hours in duration. Every other week from 13 to 21 weeks post partum, each infant was removed one at a time, placed in a cage adjacent to unfamiliar monkeys, and temporarily deprived of all contact with members of the natal group.
   

RESULTS

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Analysis of adult hippocampal volumes revealed a brain side main effect (F_1,24 = 6.78, P = .02). Right hippocampal volumes were 4% larger than hippocampal volumes on the left side of the brain. Neither sex nor rearing condition differences were discerned, and none of the brain side interactions was significant, but the repeated measures ANOVA uncovered a paternity main effect (F_11,24 = 2.47, P = .03).

Certain fathers produced monkeys with large hippocampi, other fathers produced monkeys with smaller hippocampi, and similar hippocampal volumes were found among monkeys that shared a common father (Figure 2). Right and left hippocampal volumes were correlated with one another (Figure 3), and these measures were added together to create a total hippocampal volume score. The estimated proportion of genetic variance, ie, heritability, was 54% for total hippocampal volume size (F_11,27 = 2.58, P = .02). Heritabilities for the right (h² = 49%, F_11,27 = 2.34, P = .04) and left hippocampal volumes (h² = 52%, F_11,27 = 2.45, P = .03) were not significantly different. The distribution of total hippocampal volumes was Gaussian in the sample of 39 monkeys (Figure 4), suggesting contributions from multiple additive genetic effects on hippocampal size.

View larger version (19K): [in this window] [in a new window] Figure 2. Adult hippocampal volumes grouped according to each monkey's father (average n = 3.25 offspring per father). Error bars signify mean ± SD.

View larger version (14K): [in this window] [in a new window] Figure 3. Correlation between mean right and mean left hippocampal volumes grouped according to each monkey's father (average n = 3.25 offspring per father). Dashed lines signify 95% confidence intervals.

View larger version (40K): [in this window] [in a new window] Figure 4. Distribution of total hippocampal volumes in 39 monkeys.

Following completion of the rearing conditions at 21 weeks of age, all mothers were removed well after weaning at 36 weeks post partum. Plasma cortisol levels in their offspring 1 day later were 146% higher than the preseparation levels assessed with identical procedures (197 ± 9 µg/dL vs 485 ± 27 µg/dL). Significant differences in these relative elevations in cortisol levels were produced by the prior rearing conditions (F_2,24 = 18.11, P.001), but these rearing-related differences were not associated with significant differences in hippocampal size (Figure 5).

View larger version (41K): [in this window] [in a new window] Figure 5. Postnatal rearing effects on the relative increase in cortisol levels elicited by removing all mothers and subsequent adult hippocampal volumes (n = 13 monkeys per condition). Error bars signify mean ± SD.

Paternal half-siblings that responded with larger relative 1-day increases in cortisol levels had smaller adult hippocampal volumes after correcting for sex, rearing condition, and overall brain size (r = -0.58, df = 10, P = .048; Figure 6). Half-sibling group differences in hippocampal volumes were not correlated with differences in overall brain size, and the relation between cortisol and hippocampal volume was absent when the 1-day cortisol measures were analyzed as absolute cortisol concentrations. Average cortisol levels remained higher than baseline 3 and 7 days after the removal of all mothers, but these cortisol levels were not correlated with differences in adult hippocampal size. Half-sibling group differences in hippocampal volumes were also not correlated with subsequent measures of cortisol negative feedback in early adulthood.

View larger version (17K): [in this window] [in a new window] Figure 6. Correlation between mean increases in cortisol levels elicited by removing all mothers after weaning and mean total adult hippocampal volumes grouped according to each monkey's father (average n = 3.25 offspring per father). Dashed lines signify 95% confidence intervals.

COMMENT

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In previous studies the subset of monkeys that we separated intermittently prior to weaning differed in assessments of social behavior, emotional reactivity, and cortisol-induced suppression of CRF-stimulated secretion of adrenocorticotropic hormone.^{39, 40} Rearing-related differences in these monkeys were not found in adult hippocampal volumes. Rhesus monkeys raised in social isolation also fail to show altered hippocampal volumes as determined in vivo by MRI,³² despite striking changes in other brain systems and numerous aspects of behavior.^{17, 18, 19, 20, 21, 22, 23} Maltreated children with posttraumatic stress disorder do not differ from healthy children in hippocampal volumes,⁴⁵ but show elevated baseline urinary free cortisol and catecholamine concentrations.⁴⁶ Chronic alcohol abuse is known to produce hippocampal atrophy in humans⁴⁷ and rats,⁴⁸ but alcohol abuse was not common in the studies of children with posttraumatic stress disorder, and was absent altogether in monkeys. Early life stress without alcohol abuse may have minimal effects on hippocampal volumes determined in human and nonhuman primates by high-resolution MRI.

Paternal half-sibling group differences were apparent in monkey hippocampal volumes. Certain fathers produced offspring with large hippocampi, other fathers produced offspring with smaller hippocampi, and similar adult hippocampal volumes were found in monkeys that shared a common father. Since paternal half-siblings were raised apart from one another by different mothers in the absence of fathers, phenotypic similarities within half-sibling groups cannot be attributed to shared family environments. Based on a standard half-sibling analysis the estimated heritability was 54% for total hippocampal size. This estimate is not inflated by including in the sample 9 maternal half-sibling pairs.³⁹

High heritabilities for overall brain size have been reported in humans^{49, 50, 51} and rhesus macaque monkeys,⁵² but little is known about the genetics of variation in regional brain morphologies. Neuroimaging research has identified in human twins a genetic basis for differences in surface features of cerebral cortex,^{49, 53} corpus callosum size,^{51, 54} and volumetric measures of other subcortical structures.⁵⁰ Our findings support preliminary evidence in humans⁵⁵ indicating that individual differences in hippocampal volumes are in part determined by genes. The Gaussian distribution of hippocampal volumes in monkeys suggests a polygenic trait, and not the effects of genetic epistasis nor a single major gene. Inherited variation in volumes may reflect heritable differences in hippocampal cell numbers,^{56, 57} or differences in physiological factors related to in vivo tissue perfusion.

Paternal half-siblings with small adult hippocampal volumes responded to the removal of all mothers after weaning with larger relative 1-day elevations in cortisol levels. In humans with mood and anxiety disorders small hippocampal volumes have been taken as evidence that excessive stress levels of cortisol induce hippocampal volume loss.^{2, 11, 12} But in monkeys large rearing-related differences in cortisol levels elicited by removing all mothers after weaning did not produce differences in hippocampal size. An alternative explanation for the observed correlation is that small hippocampal volumes are inherited and predispose toward excessive stress levels of cortisol through diminished neuroendocrine regulation. The hypothesis that genes affect cortisol levels by acting on aspects of hippocampal morphology is consistent with evidence that the hippocampus plays a role in suppressing the HPA-axis stress response.^{58, 59} Various measures of cortisol negative feedback in monkeys were not, however, correlated with hippocampal size.

A limitation of our finding heritable differences in monkey hippocampal volumes is that heritabilities are specific to the population and circumstance in which they are assessed. Genetically diverse populations in homogeneous environments demonstrate larger heritabilities than do inbred populations in diverse environments.⁴⁴ Very few parents that produced the study cohort shared a common mother or father, but extended family pedigrees could not be determined from monkey breeding colony records. The generality of our findings should therefore be tested in studies of other populations.

The absence of postnatal rearing effects must likewise be considered with caution. Rodent research has convincingly demonstrated that stress or glucocorticoids alone induce altered regulation of hippocampal serotonin receptor expression,⁶⁰ apical dendritic atrophy of CA3 pyramidal cells,⁸ suppression of neurogenesis, and decreased survival of newborn granule cells.¹⁰ Our failure to uncover neuroimaging-based differences does not rule out the possibility that microstructural plasticity occurs in the primate hippocampus.^{28, 29, 30} There are, in fact, excellent reasons to expect subcellular plasticity in monkeys.

Following completion of the rearing conditions and well after weaning at 36 weeks of age, the monkeys we separated intermittently responded to the removal of all mothers with smaller increases in cortisol levels, fewer distress peep-calls, and more time spent near peers.³⁹ Monkeys from the low-foraging and high-foraging demand conditions did not differ on any of these measures. In early adulthood at 5 years of age, only the intermittently separated monkeys showed signs of enhanced negative feedback regulation of the HPA-axis response to stimulation by exogenous CRF.⁴⁰ These findings parallel studies indicating that in rats brief postnatal intermittent social stress diminishes emotionality and HPA-axis reactivity throughout adolescence and adulthood.^{61, 62} In rats blunted HPA-axis stress responses are mediated by enhanced negative feedback regulation resulting from increased glucocorticoid receptor expression in adult hippocampus.⁶² Experience-dependent augmentation of glucocorticoid receptor densities might likewise account for enhanced negative feedback described elsewhere for the intermittently separated monkeys.⁴⁰

A final aspect of this study that warrants comment concerns the lack of long-lasting foraging demand effects on squirrel monkey brain and behavior. Squirrel monkey mothers in the high-foraging demand condition consistently exhibit increased cortisol levels relative to mothers in the low-foraging demand condition where food is easy to find.³⁷ High-foraging demand condition mothers stop carrying infants earlier, but continue to demonstrate otherwise normal nursing patterns.³⁷ By selectively accelerating certain aspects of development, squirrel monkey mothers apparently spare their offspring from abnormal outcomes previously reported for bonnet macaque monkeys raised by mothers under variable-foraging demands.^{25, 26, 27} The high-foraging demand condition does not subsequently alter social or emotional aspects of behavior, HPA-axis stress physiology, or adult hippocampal volumes.

AUTHOR INFORMATION

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Accepted for publication June 26, 2001.

This work was supported in part by the Nancy Pritzker Network, New York, NY, and Public Health Service grant MH47573 from the National Institute of Mental Health, Bethesda, Md.

We thank Blake Mobley and Nadia Sachs for assistance with MRI processing, and Robert Sapolsky, PhD, and Bruce McEwen, PhD, for thoughtful comments on this research.

From the Departments of Psychiatry and Behavioral Science (Drs Lyons and Schatzberg and Mr Yang) and Radiology (Ms Sawyer-Glover and Dr Moseley), Stanford University Medical School, Stanford, Calif.

Corresponding author: David M. Lyons, PhD, Department of Psychiatry and Behavioral Science, 1201 Welch Rd, Medical School Laboratory Surge Bldg, Room P104–Mail Code 5485, Stanford University School of Medicine, Stanford, CA 94305-5485 (e-mail: dmlyons{at}stanford.edu).

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