Differential rearing affects corpus callosum size and cognitive function of rhesus monkeys
- Department
of Psychiatry and Behavioral Sciences, Yerkes Regional Primate Research
Center, Emory University School of Medicine, Atlanta, GA 30322, USA
Abstract
This study investigated the effects of different rearing conditions on neural and cognitive development of male rhesus monkeys (Macaca mulatta). Infants raised individually in a nursery from 2 to 12 months of age (NURSERY, n=9) were compared to age-matched infants raised in a semi-naturalistic, social environment (CONTROL, n=11).
Various brain regions were measured by MRI. Although overall brain
volumes did not differ between NURSERY and CONTROL animals, corpus
callosum (CC) size, measured in mid-sagittal sections, was significantly
decreased in the NURSERY group. Group differences were most evident in
the posterior aspects of the corpus callosum and appeared to result from
changes in the number of cross-hemispheric projections rather than from
a decrease in cortical gray matter volume. The decrease in corpus
callosum size in the NURSERY animals persisted after 6 months of social
housing in a peer-group. Rearing group differences were not found in
other structures analyzed, including the hippocampus, cerebellum and
anterior commissure. In cognitive testing, NURSERY animals had more
difficulty acquiring the delayed non-matching to sample (DNMS) task, but
showed no deficits in subsequent memory performance when a 2 or 10 min
delay was imposed. The NURSERY infant monkeys were also impaired in
object, but not in spatial, reversal learning, although there were no
differences in a simple object discrimination task. The cognitive
deficits exhibited by the NURSERY animals were significantly correlated
with the alterations found in the CC. In summary, rearing environment
was associated with sustained differences in cross-hemispheric
projections, white matter volume and cognitive performance.
Keywords
- Rearing environment;
- Corpus callosum;
- Cerebral cortex;
- MRI;
- Cognition;
- Rhesus monkey
1. Introduction
Social
experience appears to be essential for normal primate behavioral
development. In rhesus monkeys, social deprivation early in development
is associated with profound and enduring increases in abnormal
self-directed (autistic-like) behaviors, alterations in normal social
behavior, deficits in exploration, communication, emotionality and
sexual and maternal behaviors
33 and
63.
The precise behavioral consequences depend on the extent, the duration,
and the age at which social deprivation occurs, but there is little
question that infants are more vulnerable than adults and that isolation
through the first year leads to irreversible changes in behavior
[33].
Although
there has been extensive research into the mechanisms by which social
deprivation alters behavioral development, there have been relatively
few studies of its neurobiological consequences. Indeed, we know very
little about how social experience contributes to normal neural
development and, as a consequence, normal cognitive function in
primates. Early studies in macaques reported decreases in dendritic
branching in cortical stellate cells
[62]and cerebellar Purkinje cells
[22],
but these changes likely result from rearing in conditions of low
environmental complexity rather than a specific loss of social
interaction. Other groups have described neurochemical changes
subsequent to early social deprivation, such as decreases in dopamine
innervation of the neocortex and striatum, but not in other structures,
such as the amygdala
[47].
These results, however, are confounded by aging effects which might
have contributed to group differences. More recent studies that have
compared juvenile monkeys (19–27 months) raised in isolation or social
housing have found no differences in dopaminergic or noradrenergic
innervation of the hypothalamus, or in corticotropin releasing hormone
content in the hypothalamic paraventricular nucleus
26 and
27.
To
our knowledge, there has been no previous investigation of how social
experience contributes to primate brain development using structural
brain imaging. Several studies in rodents have described changes in
neuronal morphology based on environmental enrichment
1,
15,
18,
31,
41 and
64and
clinical studies using MRI have described decreased hippocampal volume
in adult post-traumatic stress disorder patients with a history of
childhood abuse
10 and
61.
The current study used high resolution MRI to investigate differences
in neural development associated with differential rearing of rhesus
monkeys (
Macaca mulatta). In addition, subsets of these animals
were assessed for specific cognitive functions, such as visual
recognition memory, visual formation habit, and executive function by
means of the delayed non-matching to sample (DNMS), simple object
discrimination and object/spatial reversal learning tasks, respectively.
2. Material and methods
2.1. Animals
The
experimental animals were obtained from a population of macaque infants
originally reared for immunologic studies. These studies required
nursery-rearing of the infants from the 7th until the 48th week of age
(NURSERY, n=9). Nursery-reared monkeys were housed in
individual cages in rooms with automatically regulated temperature and
lighting conditions (light/dark, 0600 h/1800 h). These animals could, at
any time, see and hear other animals in the colony, and had physical
contact with caretakers but not with conspecifics. Each monkey had
access to a fleece board for contact comfort and toys for manipulation.
At the end of the 48th week, a subset of these animals was introduced
into a peer-group with animals of the same condition (NURSERY-PEER, n=5), while the rest continued to be individually housed (NURSERY-IND, n=4). The control group (CONTROL, n=12)
consisted of age-matched infants raised in a semi-naturalistic, social
environment under field conditions. A subset of CONTROL animals were
caged as a peer-group adjacent to the NURSERY peer-group (n=4)
beginning at 48 weeks of age. NURSERY animals received milk formula
until 4 months old; after that age, all animals were fed a diet of
Primate Purina Chow supplemented with fruit and vegetables; water was
available ad libitum. Cognitive testing was started at approximately age
12 months on both NURSERY and CONTROL peer-housed groups; the MRI study
was performed at age 18 months. All data in this report were derived
from males. All procedures were approved by the Emory University IACUC
(MRI/cognitive protocol #:059-96Y and rearing protocol #:081-95Y).
2.2. Procedures
2.2.1. Quantitative brain magnetic resonance imaging
2.2.1.1. MRI procedure
A
total of 11 CONTROL and 9 NURSERY rhesus macaques were studied. MRI
scans were obtained with a high-field strength (1.5 T) MR imaging unit
(Philips Medical Systems, the Netherlands) on animals deeply
anesthetized with sodium pentobarbital (15–30 mg/kg BW, i.v.) using an
extremity coil. T1-weighted images were acquired using a gradient echo
protocol with the following parameters: TR=19 msec, TE=8.5 ms, field of
view=180 mm, flip angle=35°, matrix=256×256, number of signals
averaged=8, slice thickness=1.2 mm, interslice overlap=0.6 mm.
T2-weighted images were also acquired using an inversion recovery
protocol with the following parameters: TR=3000 ms, TE=40 ms, TI=200 ms,
field of view=260 mm, flip angle=180°, matrix=256×512, number of
signals averaged=2, slice thickness=2.0 mm (non-overlapping). The
inversion recovery protocol optimizes gray-white contrast and allows
some structures to be delineated more clearly than with the gradient
echo scan.
2.2.1.2. Image analysis
Images
were transferred to a SUN computer workstation and analyzed by means of
an image-analysis software program (Easyvision, Philips Medical
Systems, The Netherlands). All scans were reformatted into sagittal,
coronal and axial orthogonal planes (the latter, defined by a line
connecting the anterior and posterior commissures). The T1-weighted
scans were used to measure whole brain and cerebellar volumes. In each
slice, the structure of interest was selected through a combination of
computerized thresholding based on pixel signal intensities and manual
editing. Easyvision estimates structure volume by summing its volume
across all slices in which it is present.
The
corpus callosum (CC) and anterior commissure (AC) were manually traced
from 3 midsagittal sections (0.5 mm thick), where the spinal cord,
cerebellum, fourth ventricle and colliculi could be seen in their
maximum extension. After the entire CC was traced, it was divided into 5
subdivisions, according to a modification of the method described by
Biegon et al.
[9].
Briefly, the cursor was positioned at the most anterior point of the
genu of the CC, and a ruler tool was swivelled toward the most posterior
point of the splenium of the CC. The position at which the intersection
of the posterior end of the splenium produced the longest distance was
used to provide the longest axis of the CC, which was measured and
divided into five parts: the anterior 20% (first fifth) defined as genu,
the middle 60% as midbody (MB, with three subdivisions: rostral (rMB),
medial (mMB) and caudal (cMB)), and the posterior 20% (last fifth)
defined as splenium
[19]. The area of each of the 5 subregions of the CC was measured and the total area calculated as the sum of its five segments (
Fig. 1).
Fig. 1. (A)
Midsagittal MR T2-weighted image through the corpus callosum of a
CONTROL rhesus monkey infant. (B) Schematic diagram of the five corpus
callosum subregions studied; from rostral to caudal: genu, rostral
midbody (rMB), medial midbody (mMB), caudal midbody (cMB) and splenium.
Prefrontal brain volume was estimated based on criteria used in human MRI studies
12,
24 and
25where
a coronal plane perpendicular to the AC-posterior commissure line was
used to determine the volume of brain in front of the most anterior
point of the genu of the CC. This region overlaps primarily with
prefrontal cortex in rhesus monkeys, excluding 50% of area 25
5 and
30.
Three coronal sections (0.5 mm thick) caudal to the CC splenium were
analyzed within the parietal lobe according to primate neuroanatomical
Refs.
[35].
Gray and white matter areas were manually traced through the right and
left prefrontal and parietal cortices and their volumes measured. In
addition, the ratio of gray/white matter was calculated. The boundaries
of the prefrontal and parietal cortices were determined from internal
landmarks. In a separate study, we have shown, with a postmortem
validation, that gray/white matter segmentation obtained from MRI
correlates over 0.97 with values obtained from measures on fresh brain
material [J.K. Rilling and T.R. Insel, unpublished observations].
The
left and right hippocampi were manually traced through their whole
rostrocaudal extension from coronal T2 images, and the successive areas
were integrated to arrive at a volume estimate. The inversion recovery
protocol provided a strong contrast between gray and white matter, so
that the hippocampal formation (including: (a) the Cornu Ammonis -CA1 to
CA4- or hippocampus proper (b) the dentate gyrus and (c) the subiculum)
could be traced following the neuroanatomical landmarks defined for the
primate
[56].
When
the size of the neural structure analyzed was significantly correlated
with total brain volume, the ratio of structure volume to total brain
volume was used as the independent variable for statistical analysis;
otherwise, the absolute structure volume was used (
Table 1).
Table 1.
Correlations of brain volume with body weight and size of different neural structures measured by MRI
| Brain volume | Corrected for total brain vol? |
|---|
| Body weight | r=0.38, n.s. |
|
| Cerebellum | r=−0.11, n.s. | no |
| Hippocampus | r=0.29, n.s. | no |
| Corpus callosum | r=0.68, p<0 .005=".005" td="td"> | yes |
| Anterior commissure | r=0.27, n.s. | no |
| Prefrontal cortex | r=0.6, p<0 .01=".01" td="td"> | yes |
| Parietal cortex | r=0.84, p<0 .0001=".0001" td="td"> | yes |
2.2.1.3. Measurements reliability
Intra
and inter-rater reliability of volume and area estimates were assessed
using intraclass correlation coefficients (ICCs). Inter-rater
reliability was verified by analysis of scans performed by a different
experimenter (ICC were: r=0.95 for brain vol.; r=0.84 for cerebellum vol.; r=0.95 for CC area; r=0.97 for gray and r=0.92 for white cortical matter areas; r=0.87
for hippocampal vol.); intra-rater reliability was assessed by
measuring a subsample of the brains a second time, at least two months
later (ICCs: r=0.99 for brain vol.; r=0.98 for cerebellum vol.; r=0.97 for CC area; r=0.91 for gray and r=0.86 for white cortical matter areas; r=0.93 for hippocampal vol.).
2.2.2. Cognitive study
At 12 months of age NURSERY (n=5) and CONTROL (n=3)
monkeys were randomly selected for cognitive studies. Animals were
given a standard battery of cognitive tests, which were administered in a
Wisconsin General Testing Apparatus (WGTA) inside a darkened,
sound-shielded room, with additional sound-masking provided by a
white-noise generator. During intertrial and retention intervals, an
opaque screen separated the macaque infant from the three-well tray, and
a one-way vision screen separated the animal from the experimenter. The
cognitive tests performed included the acquisition and performance
phases of the delayed non-matching to sample (DNMS), simple object
discrimination, as well as spatial and object-reversal learning.
2.2.2.1. Delayed non-matching to sample
The
DNMS is a recognition memory task that assesses the monkey's ability to
distinguish a novel from a familiar stimulus following a specific delay
interval
[49].
Before testing began, all subjects were trained to displace a plaque
covering the food reward; this pre-training phase was completed when the
animal displaced the plaque in 20 consecutive trials in a 20 trial
session. In the acquisition phase of the DNMS, a sample object is
presented over the central, baited food well of the three-well tray.
Once the monkey displaces the sample object to retrieve the food reward,
a screen is lowered between the animal and the testing tray. A 10-s
second delay is imposed during which time one of the lateral wells is
baited, as pre-determined by a pseudo-random sequence, and covered with a
novel object while the sample object is positioned over the other
lateral well. On this recognition trial, successful performance is
defined as displacement of the novel object to obtain the reward. After
an inter-trial interval of 20 seconds, a different pair of objects is
used. Twenty trials per day are given until the animal reaches a
learning criterion of 90 correct responses in 100 consecutive trials in a
given 5-day period. The outcome measures for the acquisition phase of
the DNMS were the number of trials and incorrect responses (errors) made
by the monkey in reaching criterion.
Once
the DNMS learning criterion was attained, a 2- or a 10-min delay was
introduced between the sample presentation and recognition trial. Ten
trials per day were given for 10 days for each delay. The delay imposed
is a challenge for the monkey's recognition memory and the outcome
measure consisted of correct answers made during those 100 trials.
2.2.2.2. Simple object discrimination
This
task tests the monkey's ability to discriminate between two objects,
one that is always baited and one that is never baited. Thirty trials,
with 20 s between trials, were given each day and a pseudo-random
sequence determined which of the lateral wells was baited during each
trial. A correct response involves the monkey displacing the baited
object. Completion of the task consisted of 27 correct responses in 30
consecutive trials within a single session. The outcome measures were
the number of errors made to reach criterion.
2.2.2.3. Spatial and object reversal learning
In the
spatial reversal
task, two identical gray plaques were placed over the left and right
wells of the tray. Initially, either the left or the right side was
designated as correct, and that side was always baited. The monkey
obtained the reward by displacing the plaque always on the appropriate
side. When the monkey attained a criterion of 90% correct responses in
30 consecutive trials, a series of three reversals began, with the
correct side changing in each reversal. After the spatial reversal task
was completed, an
object reversal task was started. Two
different objects were used to cover the lateral wells, with one of the
objects randomly chosen to be correct. After the monkey reached
criterion (90% correct responses in 30 trials), the opposite object was
baited through a series of three reversals. Both procedures have been
described in detail elsewhere
[43].
The outcome measures for both spatial and object reversals were the
number of trials and the number of errors to reach criterion after each
reversal.
2.2.3. Statistical analysis
The
central question in this experiment was whether groups of animals
reared under different conditions (CONTROL vs. NURSERY) would differ in
brain anatomy or cognitive measures. For simple group comparisons on
independent means, we used the two-tailed Student's t-test (or the non-parametric Mann–Whitney U-test
when there was non-homogeneity of variance). For analyses with multiple
related outcome measures (e.g., corrected areas of the different CC
subregions or reversals in the object and spatial reversal learning
tasks), we used a repeated measures ANOVA to evaluate differences
between NURSERY and CONTROL groups. We then used the Hotelling T2
multiple comparison test to explore the source of significant effects.
When differences were found between the CONTROL and NURSERY groups, a
subsequent analysis was conducted in order to verify if NURSERY-IND
animals were different from NURSERY-PEER. The aim of this latter
comparison was to detect if the introduction of NURSERY animals into a
peer group for 6 months improved the alterations caused by such a
rearing condition. In the case of the CC, we also performed a repeated
measures analysis of covariance to evaluate inter-group differences
between `absolute' areas of the different subregions, after adjustment
for brain volume. This alternative analytical procedure was used to
validate the results obtained from the repeated measures ANOVA, where
the `corrected' areas were compared.
Relationships
between the brain volume and the size of the different neural
structures studied by MRI, between the CC size and cognitive measures,
as well as among sizes of the different CC subregions, were assessed
with Pearson product–moment correlations. The relationships among the
different CC subregions were analyzed by first using regression models
to fit each region to brain volume, and then correlating the residuals
of each model. In this way, we made sure that the effect of the brain
volume was eliminated from each region comparison. For all analyses, a
confidence level of
p<0 .05=".05" analysis="analysis" by="by" cary="cary" considered="considered" data="data" institute="institute" means="means" nc="nc" of="of" p="p" performed="performed" sas="sas" significant.="significant." software="software" statistical="statistical" usa="usa" was="was">
3. Results
3.1. General observations
As expected from previous descriptions
33 and
63,
NURSERY animals exhibited a syndrome of abnormal behaviors, including
increased locomotor activity, as well as stereotypic, self-injurious,
self-oral, or clinging behaviors not shown by the CONTROL infants. They
also showed reduced social contact in comparison to CONTROL animals
[57].
One of the animals in the CONTROL group had to be released from the
study due to chronic illness following his transfer from the Field
Station social group to the caged peer-group, leaving 11 CONTROL infants
for MRI and 3 for cognitive studies.
3.2. Quantitative MRI
As shown in
Table 2, CONTROL and NURSERY animals were not different in body weight (
t18=-0.21, Student's
t-test), overall brain volume (
U=125, Mann–Whitney
U-test), cerebellar volume (
t18=0.09,
t-test), or hippocampal volume (
t18=-1.86,
t-test).
The corpus callosum (CC) was traced in mid-sagittal sections and
subdivided into 5 different regions (genu, rostral midbody -rMB-, medial
midbody -mMB-, caudal midbody -cMB- and splenium) as represented in
Fig. 1. Although the CC length was not different between groups (
t18=−0.5,
t-test;
Table 2), its mean area (corrected for brain volume) was significantly smaller in NURSERY than in CONTROL animals (
t18=4.73,
p<0 .001=".001" em="em">t
-test), as shown in
Fig. 2A. When the five different subregions of the CC were considered in the analysis (
Fig. 2B), the effect of both rearing condition and subregion were significant (
F2,17=13.63,
p<0 .001=".001" and="and" em="em">F
4,68=400.73,
p<0 .0005=".0005" anova="anova" as="as" em="em" interaction="interaction" measures="measures" rearing="rearing" repeated="repeated" respectively="respectively" subregion="subregion" the="the" was="was">F
8,68=2.91,
p<0 .01=".01" a="a" adjusting="adjusting" among="among" analysis="analysis" and="and" animals="animals" between="between" both="both" brain="brain" but="but" cc="cc" cmb="cmb" comparison="comparison" comparisons="comparisons" control="control" controls="controls" covariance="covariance" differed="differed" differences="differences" each="each" effect="effect" em="em" especially="especially" for="for" groups="groups" had="had" identical="identical" in="in" indeed="indeed" indicate="indicate" infants="infants" its="its" measures="measures" mmb="mmb" nurs-peer="nurs-peer" nursery-rearing="nursery-rearing" nursery="nursery" obtained="obtained" of="of" on="on" pairwise="pairwise" performed="performed" repeated="repeated" results="results" robust="robust" showed="showed" significantly="significantly" size="size" sizes="sizes" smaller="smaller" subregion="subregion" subregions.="subregions." subregions="subregions" that="that" the="the" these="these" to="to" volume.="volume." was="was" were="were" when="when">p<0 .05=".05" em="em" hotelling="hotelling">T
2 post-hoc test). The Hotelling
T2
test did not detect significant differences between the NURS-PEER and
NURS-IND subgroups for any of the CC subregions analyzed, indicating
that the reduced CC size persisted in the NURSERY-reared animals even
after 6 months of peer-group housing.
Table 2.
Age, body weight and measurements obtained in different
neural structures by magnetic resonance imaging in CONTROL and NURSERY
infant macaques
| CONTROL (n=11) | NURSERY (n=9) | p values |
|---|
| AGE (months) | 18.32±0.25 | 17.55±0.26 | t18=2.09, n.s. |
| BODY WEIGHT (kg) | 2.99±0.09 | 3.01±0.11 | t18=−0.21, n.s. |
| BRAIN vol (cc) | 78.10±1.98 | 82.99±2.38 | U=125, n.s. |
| CEREBELLAR vol (cc) | 7.33±0.19 | 7.31±0.21 | t18=0.09, n.s. |
| CC length (mm) | 29.98±0.48 | 30.38±0.68 | t18=−0.5, n.s. |
| AC area (mm2) | 3.97±0.17 | 4.23±0.11 | t18=−1.24, n.s. |
| HIPPOCAMPUS vol (cc) | 0.84±0.03 | 0.90±0.03** | t16=−1.86, n.s. |
| Corrected PREFRONTAL vol ×102 | 8.3±0.16 | 7.8±0.23 | t18=1.81, n.s. |
| Corrected PARIETAL vol ×102 | 2.48±0.04 | 2.53±0.04* | t17=−0.80, n.s. |
Results are presented as mean±S.E.M.Student's t-test
was used to examine the statistical significance of between-group
differences in the measurements obtained, except for brain vol, where a
Mann-Whitney U-test was conducted.*n=8; **n=7; n.s.: non-significant.
Fig. 2. (A) Total corpus callosum (CC) corrected area of CONTROL and NURSERY animals (*p<0 .001=".001" em="em">t
18=4.73; Student's
t-test).
(B) Corrected area of the different CC subregions. Both groups of
NURSERY infants (NURS-IND and NURS-PEER) showed significantly smaller CC
subregions in comparison to CONTROLS (repeated measures ANOVA:
F2,17=13.63,
p<0 .001=".001" by="by" em="em" group="group">F
4,68=400.73,
p<0 .0005=".0005" by="by" em="em" subregion="subregion">F
8,68=2.91,
p<0 .01=".01" and="and" by="by" cmb="cmb" effect="effect" em="em" especially="especially" group="group" in="in" interaction="interaction" mmb="mmb" robust="robust" subregion="subregion" the="the" this="this" was="was">p<0 .05=".05" em="em" hotelling="hotelling">T
2 post-hoc test; CONTROL vs. NURSERY). The Hotelling
T2
test did not detect significant differences between NURS-PEER and
NURS-IND animals for any of the CC subregions analyzed. Data were ln
transformed for statistical analysis. rMB: rostral midbody; mMB: medial
midbody; cMB: caudal midbody.
To
determine if differences in the CC size were orderly, we examined the
correlations between the areas of the different CC subregions, after
eliminating the effect of brain volume (
Table 3). In CONTROL macaque infants, positive correlations were detected between the sizes of the genu and rMB (Pearson's
r=0.76,
p<0 .01=".01" and="and" cmb="cmb" em="em" genu="genu">r
=0.66,
p<0 .05=".05" and="and" em="em" mmb="mmb" rmb="rmb">r=0.84,
p<0 .01=".01" and="and" cmb="cmb" em="em" rmb="rmb">r=0.86,
p<0 .001=".001" and="and" as="as" between="between" cmb="cmb" em="em" mmb="mmb" well="well">r=0.86,
p<0 .001=".001" animals="animals" associations="associations" between="between" cc="cc" correlations="correlations" disrupted="disrupted" em="em" found="found" genu-rmb:="genu-rmb:" in="in" most="most" no="no" nursery="nursery" of="of" significant="significant" since="since" strong="strong" subregions="subregions" these="these" those="those" were="were">r=0.22; genu-cMB:
r=0.19; rMB-cMB:
r=0.24; mMB-cMB:
r=0.18), except between rMB and mMB (
r=0.96,
p<0 .0005=".0005" p="p">
Table 3.
Correlations between the size of different corpus
callosum subregions after eliminating the effect of brain volume in both
CONTROL and NURSERY groups
| CONTROL (n=11) | NURSERY (n=9) |
|---|
| Genu-rMB | r=0.76, p<0 .01=".01" td="td"> | r=0.22, n.s. |
| Genu-cMB | r=0.66, p<0 .05=".05" td="td"> | r=0.19, n.s. |
| rMB-mMB | r=0.84, p<0 .01=".01" td="td"> | r=0.96, p<0 .0005=".0005" td="td"> |
| rMB-cMB | r=0.86, p<0 .001=".001" td="td"> | r=0.24, n.s. |
| mMB-cMB | r=0.86, p<0 .001=".001" td="td"> | r=0.18, n.s. |
Relationships
were assessed with Pearson product-moment correlations.In order to
eliminate the effect of brain volume from each region comparison, we
first used regression models to fit each region to brain volume, and
then the residuals of each model were correlated.n.s.: non-significant;
rMB: rostral midbody; mMB: medial midbody; cMB: caudal midbody.
The
anterior commissure (AC), another structure containing interhemispheric
fibers, was not different between the two rearing conditions (
t18=−1.24,
t-test;
Table 2).
The
prefrontal and parietal total volumes (corrected for brain volume) were
not significantly different between NURSERY and CONTROL infants (
Table 2). Following segmentation, we found no differences in gray matter volume, but white matter appeared lower in the NURSERY group (
Fig. 3). The differences were statistically significant for parietal cortex (
t17=2.33,
p<0 .05=".05" em="em">t
-test) and marginally significant for prefrontal cortex (
t18=2.07,
p=0.053;
t-test). The parietal gray/white matter ratio was significantly increased in NURSERY animals, when compared to CONTROLs (
t17=2.58,
p<0 .05=".05" em="em">t-test).
Fig. 3. Gray
and white matter corrected volumes from parietal and prefrontal lobes.
NURSERY infants showed a significant decrease in parietal white matter
and, consequently, an increase in the gray/white matter ratio (*p<0 .05=".05" em="em">t
17=2.33 and
t17=2.58, respectively; Student's
t-test)
in comparison to CONTROL animals. The prefrontal white matter was also
reduced in the NURSERY group, but the effect was not so strong (#
p=0.053,
t18=2.07;
t-test).
3.3. Cognitive deficits
NURSERY monkeys at 1 year of age exhibited several cognitive deficits. NURSERY monkeys required more trials (t6=3.0, p<0 .05=".05" em="em">t
-test) and made significantly more errors (
t6=4.15,
p<0 .01=".01" em="em">t-test) than CONTROLs in reaching criterion on the DNMS (
Fig. 4A).
Once the criterion was achieved, however, NURSERY animals performed as
well as CONTROLs during the 2- and 10-min delay condition of the DNMS
(2-min:
t6=−0.96 and 10-min:
t6=-0.1;
t-test) as shown in
Fig. 4B.
Acquisition of the DNMS in the NURSERY group was associated with the
size of the caudal subregions of the CC, as demonstrated by the negative
correlations between the trials and errors to reach criterion and the
cMB and splenium corrected areas (trials:
rsplenium=−0.83,
p=0.08; errors:
rcMB=−0.88,
p=0.05 and
rsplenium=−0.81,
p=0.09).
The performance of the 2- and 10-min delay phase of the DNMS, however,
was strongly associated with the size of the genu of the CC, as shown by
the significant positive correlation between the number of correct
answers and the genu's corrected area (2-min:
r=0.93,
p<0 .05=".05" 10-min:="10-min:" em="em">r=0.82,
p=0.09).
Fig. 4. (A) Delayed non-matching to sample (DNMS) acquisition was impaired in NURSERY infant macaques, which required more trials (*p<0 .05=".05" em="em">t
6=3.0; Student's
t-test) and made more errors (**
p<0 .01=".01" em="em">t
6=4.15;
t-test)
than the CONTROL group. The bottom part of the graph represents a
diagram of the corpus callosum showing the correlations between the size
of its subregions and the trials and errors to reach criterion in the
NURSERY group; during the acquisition of the DNMS, negative correlations
were detected between the trials and errors to reach criterion and the
cMB and splenium corrected areas (trials:
rsplenium=−0.83,
p=0.08; errors:
rcMB=−0.88,
p=0.05 and
rsplenium=−0.81,
p=0.09).
(B) Once animals reached criterion, a delay of 2 or 10 min was imposed
to challenge recognition memory ability. The performance of this delay
phase of the DNMS was not different in both groups of animals (2-min: t
6=−0.96, n.s.; 10-min:
t6=−0.1,
n.s.). Bottom part of the graph: in the NURSERY animals the performance
of the delay phase of the DNMS was strongly associated with the size of
the genu of the CC, as shown by the significant positive correlation
between the number of correct answers and the genu's corrected area
(2-min:
r=0.93,
p<0 .05=".05" 10-min:="10-min:" em="em">r=0.82,
p=0.09).
In
order to verify if the alterations found in the DNMS were due to
impaired learning or to deficits such as attention or motivation, the
animals were subjected to a simple object discrimination task. NURSERY
and CONTROL groups did not differ in the acquisition of this task, as
reflected in the number of errors to reach criterion (
t6=1.75,
t-test;
Fig. 5).
Interestingly, a significant negative correlation was detected between
the number of errors to reach criterion and the cMB corrected area (
r=−0.97,
p<0 .01=".01" group.="group." in="in" nursery="nursery" p="p" the="the">
Fig. 5. Simple
object discrimination task. No statistically significant differences
were found between NURSERY and CONTROL groups in the acquisition of this
task, as reflected in the number of errors to reach criterion (t6=1.75, n.s.; Student's t-test).
Bottom: a significant negative correlation was detected between the
number of errors to reach criterion and the cMB corrected area (r=−0.97, p<0 .01=".01" group.="group." in="in" nursery="nursery" span="span" the="the">
CONTROL
and NURSERY animals did not differ in the acquisition of either spatial
or object reversal learning. However, the NURSERY group had more
difficulties than the CONTROL, once the reversals were imposed (
Fig. 6).
For object reversal learning, the NURSERY group required more trials
and made more errors during the three reversals than the CONTROL group
(trials:
F1,4=37.34,
p<0 .005=".005" em="em" errors:="errors:">F
=90.38,
p<0 .001=".001" across="across" change="change" criterion="criterion" em="em" errors="errors" in="in" made="made" no="no" number="number" of="of" or="or" reach="reach" required="required" reversals="reversals" the="the" there="there" three="three" to="to" trials:="trials:" trials="trials" was="was">F
2,8=0.58, n.s.; errors:
F2,8=2.68, n.s.), nor was there a significant interaction of treatment group with reversal number (trials:
F2,8=1.08, n.s.; errors:
F2,8=0.99,
n.s.). The NURSERY animals' shifting ability in the object reversal
learning was strongly associated with the size of the CC midbody, as
demonstrated by the significant negative correlations with the number of
trials (rMB:
r=−0.91,
p<0 .05=".05" em="em" mmb:="mmb:">r=−0.89,
p<0 .05=".05" and="and" em="em" errors="errors" rmb:="rmb:">r=−0.94,
p<0 .05=".05" em="em" mmb:="mmb:">r=−0.93,
p<0 .05=".05" and="and" between="between" control="control" criterion.="criterion." detected="detected" differences="differences" em="em" for="for" groups="groups" however="however" in="in" learning="learning" no="no" number="number" nursery="nursery" of="of" reach="reach" reversal="reversal" spatial="spatial" the="the" to="to" trials="trials" were="were">F
1,5=1.01, n.s.) or errors (
F1,5=1.85,
n.s.). In this case, there was a change across the three reversals in
the number of trials required, or errors made to reach criterion (
F2,10=8.12,
p<0 .01=".01" and="and" em="em">F
2,10=8.26,
p<0 .01=".01" but="but" detected="detected" em="em" group="group" interaction="interaction" no="no" number="number" of="of" respectively="respectively" reversal="reversal" significant="significant" treatment="treatment" trials:="trials:" was="was" with="with">F
2,10=0.40, n.s.; errors:
F2,10=0.79,
n.s.). No significant correlations were found between spatial reversal
learning performance and the size of the CC, either in the CONTROL or in
the NURSERY group.
Fig. 6. Object
and spatial reversal learning. (A) NURSERY animals were impaired in
object reversal learning, since they required significantly more trials
(repeated measures ANOVA: F1,4=37.34, p<0 .005=".005" by="by" em="em" group="group">F
2,8=0.58, n.s. by number of reversals;
F2,8=1.08, n.s. by group×number of reversals interaction) and made more errors (
F1,4=90.38,
p<0 .001=".001" by="by" em="em" group="group">F
2,8=2.68, n.s. by number of reversals;
F2,8=0.99,
n.s. by group×number of reversals interaction) to reach criterion
during the three reversals than CONTROLs. Bottom: diagram showing the
correlations between the CC subregions' sizes and the trials and errors
to reach criterion during the first reversal. (B) No significant
differences were detected between CONTROL and NURSERY groups in spatial
reversal learning (Trials:
F1,5=1.01, n.s. by group;
F2,10=8.12,
p<0 .01=".01" by="by" em="em" number="number" of="of" reversals="reversals">F
2,10=0.40, n.s. by group×number of reversals interaction. Errors:
F1,5=1.85, n.s. by group;
F2,10=8.26,
p<0 .01=".01" by="by" em="em" number="number" of="of" reversals="reversals">F
2,10=0.79,
n.s. by group×number of reversals interaction). Bottom: No significant
correlations were found between spatial reversal learning performance
and the size of the CC subregions, either in the CONTROL or in the
NURSERY group.
4. Discussion
NURSERY
animals showed a decrease in CC midsagittal area (especially in its
caudal aspects) accompanied by a decrease in white (but not gray) matter
volume in parietal and prefrontal cortex. Nursery-rearing had no
detectable effects on brain, cerebellar, hippocampal or prefrontal
cortex volumes, or on the size of the AC. The alterations found in CC
size persisted despite introduction of the NURSERY animals into a
peer-group for 6 months. In relation to cognitive function, the NURSERY
macaques were impaired on the acquisition, but not on the performance of
a DNMS. The NURSERY animals also showed impairment in object, but not
in spatial, reversal learning, although they learned a simple object
discrimination task as readily as the CONTROL group. These cognitive
deficits were significantly correlated with the alterations found in the
CC. Taken together, these results suggest that nursery-rearing was
associated with decreased cross-hemispheric projections, loss of
parietal and prefrontal white matter and impaired acquisition of complex
cognitive tasks.
Nursery-rearing
is a complex experimental condition and the observed differences between
the NURSERY and CONTROL groups could therefore be a consequence of
several different aspects of the early environment. The behavioral
abnormalities that accompany isolation rearing have been variously
attributed to lack of mother and social contact
33 and
63, reduced somatosensory stimulation
33 and
55, or loss of controllability over the environment
[48], any of which could contribute to the group differences observed in the present study.
In
spite of these limitations, we can conclude that the midsagittal CC
area was reduced in the NURSERY group when compared to the CONTROL.
These differences were found after adjustment for brain volume and were
especially robust in mMB and cMB. There was no evident measurement bias
in identifying the mMB and cMB as CC axis length was not different in
the two groups. The alterations found were not improved by introduction
of the NURSERY animals into a peer-group for 6 months, consistent with
the possibility that the changes are irreversible.
The
CC of the rhesus monkey shows a topographic segregation of callosal
fibers from different cortical regions along its anterior–posterior axis
50 and
52.
The rostral half carries fibers from the prefrontal, premotor and motor
areas, as well as anterior insular and anterior cingulate fibers, while
the caudal half carries fibers originating in the parietal, temporal
and occipital lobes. The reduced size detected in caudal CC subregions
of NURSERY animals (especially robust in the mMB and cMB), may therefore
reflect specific alterations in cross-hemispheric fibers originating in
the primary and second somatosensory areas, posterior parietal
association cortex, caudal superior temporal, posterior insular and
posterior cingulate gyri, and primary auditory area
2,
11,
45,
50 and
60.
Unlike
the CC, which contains interhemispheric fibers from all lobes, the AC
contains fibers mainly from the caudal orbitofrontal and rostral
temporal cortices
16 and
37.
The absence of group differences in AC size suggests a region-specific
effect of the rearing conditions on the cross-hemispheric projections.
This is further supported by the fact that the strong associations
between some CC subregions evident in CONTROL animals were disrupted in
NURSERY animals, since no significant correlations were found between
them.
A reduction in
cross-hemispheric projections could result from a reduced number of
callosal neurons, or from a reduction in the number of callosal axons
(and/or in their myelination and growth) from the same number of
neurons. The decrease in white (but not gray) matter volume found in the
parietal and prefrontal cortices of NURSERY infants is consistent with
the second possibility. In the primate brain, the frontal, parietal, and
temporal association areas have dense and widespread callosal
projections and terminations
40 and
51and the maturation of those tracts proceeds slowly
[23],
making them more vulnerable to the differential rearing conditions than
other systems. Although the white matter loss may reflect a reduction
in the number, myelination, and/or size or packing density of the
callosal axons from the parietal and prefrontal cortices, it could
equally reflect alterations in intracortical connectivity, since
neocortical white matter consists of about ten-fold as many intra- as
inter-hemispheric fibers
[58].
Our
observations are consistent with results from clinical studies in which
the size of the middle and posterior subregions of the CC were reduced
in autistic individuals
21 and
54and white matter volume loss was detected in the parietal lobes
13 and
14.
These findings are particularly intriguing given the autistic-like
behaviors (gaze avoidance, self-directed behaviors, stereotypies) of our
NURSERY-reared monkeys, behaviors previously reported in monkeys reared
in social isolation
[33].
The reduced CC size found in the NURSERY animals is also consistent with Denenberg's
[17]hypothesis
that the callosal cross-sectional area would be larger in animals
stimulated throughout development. Indeed, there are reports showing
that early handling in rats (from PND1-21) provokes an increase in the
adult CC size
[8]and that rats reared in a complex environment show increased area in middle and posterior callosal thirds
[38].
Now, how might early experience alter the size of the corpus callosum?
First, it is unlikely that it affected the initial callosal projections,
since the adult patterns of mosaic composition of axons in the CC and
of callosal connections
42,
45,
51 and
59are present before birth in the rhesus monkey
[44]. The postnatal development of the CC depends on, at least, two complex processes: axonal pruning and myelination
23,
36 and
44.
As for pruning, it has been demonstrated that early sensorial
experience affects which callosal neurons (or axons) are stabilized and
which are eliminated during development
[36].
In the rhesus monkey, callosal axon elimination after birth occurs in a
rapid phase during the first 3 postnatal weeks, and in a second slow
phase from 2–6 months of age, when 70% of axons are eliminated
[44].
This occurs within groups of axons that are already in their correct
location within the CC, due to retraction or cell death. A higher rate
of elimination of callosal axons in the NURSERY animals during such a
critical period of development (3–6 months) could have produced a
reduction in the CC size, due to different factors in their early
environment, such as the limited exposure to social and sensorial
stimuli. The AC shows a different temporal pattern of pruning and
myelination with relatively little loss of callosal axons after the
third postnatal month
[46].
The normal size of the AC in the NURSERY group in the face of reduced
CC size may therefore reflect the later pruning and myelination of
callosal fibers or nursery-rearing effect on specific callosal
projections that are not present in the AC.
As
for the second process, at 3–6 months all cortical areas in the rhesus
monkey contain some myelin, but the myelination and axonal growth in
tracts and layers involved in intra- or inter-cortical processing in
association areas proceed slowly and are not complete until 2.5–3 years
of age
23 and
44.
Since our infant macaques had different rearing environments from 2–12
months of age, one might speculate that myelination of specific callosal
(but also of intra-hemispheric) projections could have also been
altered by some aspect of the NURSERY condition. The parallel reduction
in parietal and prefrontal white matter volume detected in the NURSERY
animals would support this interpretation. An altered impulse
transmission secondary to a reduction in myelinated fibers could have
affected the survival and functional maturation of cortical synapses
[39]and, in consequence, higher cortical function.
The
NURSERY macaques were impaired in acquisition of the DNMS, but
performed normally in this task following delays as long as 10 minutes.
This finding suggests an impairment in new learning, but not in
performance of a visual recognition memory task. The results are
analogous to alterations in acquisition, but not in the delay phase of
DNMS reported in autistic children [E. Courchesne, personal
communication] and in other situations such as aging
[34].
The fact that NURSERY animals learned a simple object discrimination
task as readily as controls suggests that differences in acquisition of
DNMS were not attributable to an inadequacy of perception, attention,
motivation, or stimulus-response association, since these same factors
are required for visual discrimination learning tasks.
NURSERY
monkeys were impaired in object, but not in spatial, reversal learning
suggesting a task-specific impairment in learning plasticity (increased
perseveration) which seems to be related to the type of information
being processed (visual vs. spatial), rather than to a general rigidity
of responding. Task-specific impairments in shifting response patterns
have been previously reported in other situations, such as aging
43 and
65.
However, there is an alternative explanation for these findings; since
the object reversal learning was always followed by the spatial
reversals, it is possible that with experience on the first task the
monkeys got better at the reversal learning on the spatial task.
Consistent
with our results, previous studies have shown that rhesus monkeys that
have undergone early social deprivation perform adequately on simple
discriminations
[29]but show impairments in certain complex tasks
6,
7,
28 and
29.
It should be noted that these results were obtained mostly from adult
animals separated from their mothers at birth and reared in total
isolation for 9–12 months. Although different from our nursery-rearing
paradigm, some of the cognitive deficits found are similar, such as the
cognitive inflexibility and specific information processing deficits,
both of which are also observed in autistic children
[53].
The
two tasks in which we observed deficits in the NURSERY monkeys
(acquisition of DNMS and object reversal learning) both involve a
component of object discrimination. Nevertheless, since no deficits were
found on the acquisition of the simple object discrimination or on the
performance of the DNMS, the processing of the information about the
visual characteristics of objects does not seem to be impaired. The two
tasks on which NURSERY monkeys were impaired require the acquisition of a
rule of performance (i.e., the acquisition of the non-matching
principle in DNMS) or the learning of a change in an established rule of
performance (as in the object reversal), both of which may be
considered executive function. However, the deficits found cannot be
attributed to difficulties in set- or rule-changing per se, since
NURSERY and CONTROL monkeys performed equally well in spatial reversal.
Thus, it appears that NURSERY animals show deficits on tasks involving
new learning or executive function if object discriminations are involved.
What
is the relationship of these cognitive deficits to the corpus callosum
and cortical white matter changes observed in the NURSERY monkeys?
Although we observed a significant correlation between the size of
medial and caudal aspects of the CC, and the acquisition of the DNMS as
well as the object reversal learning, these results need to be
interpreted cautiously. The correlations are based on a small animal
sample and there should be no presumption that the CC alterations found
in NURSERY animals are directly responsible for the cognitive deficits
exhibited. Indeed, previous reports have demonstrated that
commissurotomized monkeys perform as well as controls in a simple object
discrimination task
[20],
so it would be surprising if a decrease in CC area `caused' a selective
deficit in executive function. Two alternative explanations for the
correlations are: (a) that the change in CC area represents a more
general loss of connectivity associated with impairment in complex
cognitive processes or (b) that the NURSERY animals are developmentally
delayed with both connectional and cognitive lags relative to CONTROLS.
Infant macaques (less than 1 year of age) perform poorly in the DNMS
task, which seems to be due to a functional immaturity of the neocortex,
rather than to immaturity of the limbic structures at that stage of
development
3 and
32.
Therefore, the NURSERY animals' impairment in acquisition of DNMS could
be due to alterations in the normal neocortical development, while
those cognitive functions more dependent on hippocampal function, such
as the delayed phase of the DNMS, were not affected (which is consistent
with the absence of a decline in hippocampal volume). On the other
hand, while the adult DNMS mastery is not achieved in rhesus monkeys
until they are 2 years old, by 3 months of age they form visual
discrimination habits as quickly as adult monkeys
[4].
Therefore, nursery-rearing from 2–12 months may have altered more
drastically neural systems still in development during that stage (such
as those underlying acquisition of the DNMS) than those developed
earlier (such as the ones underlying visual discrimination habit
formation).
In summary, monkeys
raised in a nursery from 2–12 months of age showed decreased midsagittal
CC area when scanned at 18 months using MRI. The loss of
cross-hemispheric projections was associated with a decrease in cortical
white matter volume. NURSERY animals also had selective cognitive
deficits which correlated with the changes found in the CC area. Animals
that experienced 6 months of peer-grouping after the nursery rearing
did not show improvements in relation to the animals that remained
single-housed.
Acknowledgements
This
work was supported by the Yerkes Regional Primate Research Center base
grant No. RR-00165 awarded by the Comparative Medicine Program, National
Center for Research Resources of the National Institutes of Health.
Support was also provided by NIH grant PO1-AG0001. The authors thank Dr.
R. Nisenbaum for statistical advice, and gratefully acknowledge Dr.
T.R. Insel's help during this study and his critical review of the
manuscript.
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