Frontiers in Integrative Neuroscience www.frontiersin.org November 2009 | Volume 3 | Article 30 | 1
ORIGINAL RESEARCH ARTICLE
published: 10 November 2009
doi: 10.3389/neuro.07 .030.2009
In this study we examine the role of temporal aspects of prena-
tal infl uences, genotype, and postnatal dopamine (DA) function
on sensory processing patterns observed in macaque monkeys.
Previous work from several studies in our laboratory found that
prenatal alcohol exposure, prenatal stress, and postnatal lead expo-
sure induced deviations from typical sensory processing patterns in
monkeys (Moore et al., 2008; Schneider et al., 2008). Along related
lines, we found that prenatal alcohol-exposed monkeys carrying
the serotonin transporter gene polymorphic region (rh5-HTTLPR)
short (s) allele were more irritable and more stress responsive than
prenatal alcohol-exposed monkeys homozygous for the long allele
or controls regardless of genotype (Kraemer et al., 2008).
We tested the hypothesis that the timing of moderate dose prenatal
alcohol exposure would alter sensory responsivity in rhesus monkey
offspring as a function of the rh5-HTTLPR length polymorphism.
The short 5-HTTLPR results in reduced transcription of the 5-HTT
gene which may translate into altered uptake of synaptic serotonin
(Lesch et al., 1996). In rhesus macaques (Macaca mulatta), a 21 base
pair (bp) insertion/depletion polymorphism (rh5-HTTLPR) that is
present in the orthologous region and which is functionally simi-
lar to the human 5-HTTLPR variant has been shown to infl uence
transcriptional effi ciency (Bennett et al., 2002). Monkeys carrying a
Sensory processing disorder, a regulatory disorder characterized
by atypical under- and/or over-responsivity to non-noxious sen-
sory stimulation (Ayres and Robbins, 1979), is a common but
poorly understood disorder. Sensory processing disorders appear
to occur in several different syndromes including children who
spent time in Eastern European orphanages (Lin et al., 2005), as
well as boys with ADHD (Parush et al., 2007). Baranek et al. (2006)
reported that compared with typically developing children, 60% of
children with autism had increased sensory symptoms including
hyper- and hypo-responsiveness. While there are no comprehen-
sive prevalence studies on sensory processing problems in chil-
dren with FASD, Jirikowic et al. (2008) reported that “children with
FASD were three times more likely to be classifi ed in a clinically
signifi cant category on the Short Sensory Profi le than peers with
FASD is probably one of many environmental factors that can
induce sensory problems. We previously reported that postnatal
lead exposure induced sensory processing disorder in rhesus mon-
keys (Moore et al., 2008). Also, relevant to this study, Goldsmith
et al. (2006) found that tactile and auditory defensiveness showed
moderate genetic infl uences.
Timing of moderate level prenatal alcohol exposure
infl uences gene expression of sensory processing behavior
in rhesus monkeys
Mary L. Schneider1,2,3*, Colleen F. Moore2, Julie A. Larson1,3, Christina S. Barr4, Onofre T. DeJesus5 and
Andrew D. Roberts6
1 Department of Kinesiology, University of Wisconsin-Madison, Madison, WI, USA
2 Department of Psychology, University of Wisconsin-Madison, Madison, WI, USA
3 Harlow Center for Biological Psychology, University of Wisconsin-Madison, Madison, WI, USA
4 National Institute on Alcohol Abuse and Alcoholism National Institutes of Health, Bethesda, MD, USA
5 Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, USA
6 Department of Physics, Minnesota State University, Mankato, MN, USA
Sensory processing disorder, characterized by over- or under-responsivity to non-noxious
environmental stimuli, is a common but poorly understood disorder. We examined the role of
prenatal alcohol exposure, serotonin transporter gene polymorphic region variation (rh5-HTTLPR),
and striatal dopamine (DA) function on behavioral measures of sensory responsivity to repeated
non-noxious sensory stimuli in macaque monkeys. Results indicated that early gestation alcohol
exposure induced behavioral under-responsivity to environmental stimuli in monkeys carrying the
short (s) rh5-HTTLPR allele compared to both early-exposed monkeys homozygous for the long (l)
allele and monkeys from middle-to-late exposed pregnancies and controls, regardless of genotype.
Moreover, prenatal timing of alcohol exposure altered the relationship between sensory scores and
DA D2R availability. In early-exposed monkeys, a positive relationship was shown between sensory
scores and DA D2R availability, with low or blunted DA function associated with under-responsive
sensory function. The opposite pattern was found for the middle-to-late gestation alcohol-exposed
group. These fi ndings raise questions about how the timing of prenatal perturbation and genotype
contributes to effects on neural processing and possibly alters neural connections.
Keywords: environment by gene interaction, sensory processing disorder, sensory processing scale for monkeys,
genotype, dopaminergic D2R binding, serotonin transporter gene polymorphism, timing of moderate prenatal alcohol
exposure, early gestation alcohol exposure
John J. Foxe, Nathan S. Kline Institute
for Psychiatric Research, USA; City
College of the City University of
New York, USA
J. N. Reynolds, Queen’s University,
Pierfi lippo De Sanctis, Nathan S. Kline
Institute for Psychiatric Research, USA
Mary L. Schneider, Department of
Kinesiology, Occupational Therapy
Program, University of Wisconsin-
Madison, 2175 Medical Science
Center, 1300 University Ave. Madison,
WI 53706, USA.
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Schneider et al. Alcohol effects: gene × environment
copy of the rh5-HTTLPR short allele differed in levels of serotonin
metabolites in cerebral spinal fl uid, neonatal visual orienting to
stimuli, and ACTH levels during social separation when compared
to monkeys with the l/l genotype. However, these effects were only
observed in monkeys exposed to early stress in the form of peer rear-
ing (Bennett et al., 2002; Champoux et al., 2002; Barr et al., 2004).
We assessed behavioral responses to repeated tactile stimuli in
macaque monkeys from mothers that were randomly assigned to
consume alcohol during early gestation (0–E50), middle-to-late
gestation (E50–E135), continuous exposure (0–E135) or controls.
Rh5-HTTLPR genotype (l/l vs. l/s and s/s) were determined. We
also measured striatal DA D2R function in positron emission tom-
ography (PET) scans using [18F]-fallypride ([18F]FAL) developed
by Mukherjee et al. (1997). [18F]FAL is currently the PET tracer of
choice for DA D2 receptor studies because of its optimal imaging
properties (Kessler et al., 2009).
We assessed dopaminergic function for several reasons. First,
prenatal alcohol exposure has been shown to disrupt the DA sys-
tem, including DA uptake, receptor binding sites, and size of cell
bodies and dendritic growth in DA neurons in rats (Druse et al.,
1990; Shetty et al., 1993; Shen et al., 1999). Moreover, frontal-stri-
atal circuitry involved in inhibitory control, executive function and
regulatory function, relevant to this study, is dependent on DA
and disrupted by fetal alcohol exposure (Kodituwakku et al., 1995;
Mattson et al., 1999). We assessed DA D2R availability because the
process for assessing this receptor expression is well established
from decades of research into neurodegenerative disease such
as Parkinson’s. The tracer used to assess DA D2R availability was
[18F]fallypride (FAL), a fl uorine-18-labeled raclopride analogue
developed by Mukherjee et al. (1997). FAL has a high affi nity for
DA D2receptors and high brain uptake, almost three times higher
compared with [11C]raclopride.
Our results show that timing of prenatal alcohol exposure inter-
acts with genotype to infl uence the phenotypical sensory behavior.
More specifi cally, monkeys from early gestation alcohol-exposed
groups carrying the short rh5-HTTLPR allele showed lower sensory
responsivity scores compared to both alcohol-exposed monkeys
homozygous for the long allele and mid-to-late alcohol-exposed
monkeys and controls regardless of genotype. Moreover, the rela-
tionship between D2R availability and sensory responsivity was
altered by gestational timing of alcohol such that reduced D2R avail-
ability was associated with under-responsivity in early alcohol-
exposed groups and the opposite pattern was found for mid-to-late
MATERIALS AND METHODS
MATERNAL ALCOHOL TREATMENTS
Healthy adult female rhesus monkeys within the breeding colony
that voluntarily and reliably consumed 0.6 g/kg of a 6% vol-
ume/volume (v/v) alcohol solution sweetened with NutraSweet
(300 mg/100 ml) (Equal Sweetener, Merisant US, Inc., Chicago,
IL, USA) were used in this study. Prior to breeding, blood samples
were obtained 60 min after consumption of 0.6 g/kg alcohol, which
produced average blood alcohol concentrations of 20–50 mg/dL.
This dosage is comparable to an average-size woman consum-
ing two drinks daily. Females willing to consume alcohol prior
to breeding were randomly assigned to the control group or one
of three experimental groups (see below) with timing of prenatal
alcohol exposure as the independent variable. The alcohol-consum-
ing mothers voluntarily consumed the alcohol solution daily at
1600 hours. Water was available ad libitum, including during the
period when the alcohol solution was available. The animals had no
chow left by the time of day that the alcohol was introduced. The
control mothers consumed a sucrose solution that was designed to
be approximately equivolemic and equicaloric (8 g/100 ml water) to
the alcohol solution. All females were housed under identical condi-
tions, undisturbed except for necessary routine animal husbandry.
These studies were conducted in accordance with the Institutional
Animal Care and Use Committee.
The offspring subjects in this study were 35 male and female rhesus
monkeys (Maccaca mulatta), that are members of an ongoing lon-
gitudinal study that investigates the effects of moderate level fetal
alcohol exposure, during early or mid-late gestation, on brain and
neurobehavioral function (see Table 1).
The alcohol exposure periods (Early: days 0 through 50 and
Mid-to-Late: 50 through 135) were selected to approximate the
embryological and fetal periods in human development, respec-
tively. The embryological periods are extremely similar in rhesus
macaques and humans, with major organogenesis essentially com-
plete by approximately day 45 in the rhesus macaque and day 56 in
the human (Newell-Morris and Fahrenbruch, 1985). The species
differ with regard to the fetal period in that the duration in humans
is almost twice that of the macaque. By day 135, the macaque has
reached a percentage of brain growth similar to that of a human
newborn (Newell-Morris and Fahrenbruch, 1985).
All infant monkeys were housed with their mothers in indi-
vidual cages during the fi rst 6 months of life. They were separated
briefl y from their mothers during the fi rst month of life and tested
weekly for neonatal neurobehavioral function. At 6 months of age,
they were separated permanently from their mothers for wean-
ing. They were then reared in mixed-sex peer groups consisting
of 5–6 monkeys from similar prenatal conditions until they were
32 months old. At the time of the neuroimaging studies and sen-
sory testing they were approximately 5 years old, and their hous-
ing condition was pair-housing with same-sex peers from similar
treatment groups. At that time they were maintained on a diet of
Purina Monkey Chow supplemented three times weekly with fresh
fruit. All housing conditions were light (8 dark and 16 light) and
temperature (21 ± 0.5°C) controlled.
SENSORY PROCESSING SCALE FOR MONKEYS (SPS-M)
The SPS-M was developed by adapting procedures from laboratory
observational measures of sensory processing for children (Baranek
and Berkson, 1994; Miller et al., 1999). Correlations between
Table 1 | Sample size and genotype distribution as a function of prenatal
Genotype Control Mid-Late Early Continuous
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Schneider et al. Alcohol effects: gene × environment
parental reports and the laboratory observational measures of
sensory over-responsivity (including tactile defensiveness) have
been modest (correlations of .20 to .40) (Baranek and Berkson,
1994). The SPS-M was used in two previous studies with macaque
monkeys, one on the effects of moderate level fetal alcohol expo-
sure, alone or in conjunction with prenatal stress (Schneider et al.,
2008) and one on the effects of postnatal lead exposure (Moore
et al., 2008). Sensory processing testing in this study followed the
same procedures as previous studies. Testing was conducted in a
53 cm × 44 cm testing cage with vertical bars spaced 5.5 cm apart.
The cage was situated in a dimly lit and sound-shielded room
(62 dB) with a masking white noise of 65–70 dB. A human experi-
menter, who stood beside the cage and administered the tactile
items through the bars of the cage, tested each monkey individually.
A second experimenter videotaped the session for later scoring.
Both experimenters were blind to the experimental conditions of
the animals and unfamiliar to the animals.
The fi rst tactile stimulus consisted of a 12.5 cm feather, which
delivered light tactile stimulation. The second stimulus, a 7 cm
cotton ball, delivered a soft but slightly fi rmer tactile stimula-
tion. Finally, the third stimulus, a 15 cm stiff craft brush deliv-
ered a scratchy but innocuous tactile stimulation. All stimuli were
attached to a 91 cm dowel so the experimenter could maintain
a safe distance from the monkey’s cage. Six trials of each stimu-
lus were administered in an invariant order, as listed above, as a
swipe to the cheek and neck area. Prior to the fi rst presentation
of each stimulus, the stimulus was placed in full view and touch-
ing range of the monkey and remained there for approximately
3 s. Stimuli were then applied repeatedly to the same side of the
animal for approximately 2 s per trial, with an inter-trial interval
of approximately 2 s, and a pause between each of the textures of
approximately 4 s. The testing session lasted for approximately
10 min. Raters, blind to the treatment conditions of the animals,
scored the videotapes. Each of 18 trials was scored for degree of
withdrawal and negative reaction to the tactile stimulus using a
0 to 3 rating scale in 0.25 increments with the integers labeled as
follows: 0 = no withdrawal; 1 = slight withdrawal, such as turning
head away from the stimulation; 2 = moderate withdrawal, such
as turning full body away from stimulation; 3 = extreme with-
drawal, such as moving body away from stimulation. Inter-rater
reliability as percentage agreement within ±0.25 on the rating scale
POSITRON EMISSION TOMOGRAPHY (PET) PROCEDURE
All PET studies were performed as described previously (Roberts
et al., 2004; Schneider et al., 2005). Monkeys were fasted overnight
and anesthetized with ketamine (15 mg/kg) and transported to the
PET facility on campus. Anesthesia during PET scans was main-
tained with 1.25–2.0% isofl urane. Each anesthetized animal was
positioned in the ECAT 933 PET scanner with horizontal imag-
ing slices parallel to the orbital-meatus (OM) plane. The tracer
used to assess DA D2 receptors was [18F]-Fallypride ([18F]FAL),
an F-18-labeled raclopride analog developed by Mukherjee et al.
(1997). [18F]FAL was prepared using a procedure adopted from
Mukherjee et al. (1995). Five mCi in 1–5 ml normal saline of
[18F]FAL were administered as an intravenous bolus and a dynamic
sequence of images over 90 min, including a total of 13 frames with
duration increasing from 2 to 10 min was collected. At the end of
scanning, the animals were extubated, allowed to awaken, and then
returned to the animal care facility. The UW Animal Care and Use
Committee approved the protocol that was used in these studies
in compliance with NIH regulations on the use of non-human
primates in research.
PET images were reconstructed from the raw data using the
Ordered Subset Estimation Method (Hudson and Larkin, 1994).
Standard regions of interest (ROI) were placed on the occipital
cortex (an area known to contain little signifi cant DA-ergic innerva-
tion) in order to produce reference region time-activity curves for
use as input functions in graphical analysis. Other ROIs were placed
to cover both left and right caudate and putamen (jointly referred to
as the striatum) in the basal ganglia. For the reversible tracer, FAL,
time-activity data for the ROIs were analyzed with the graphical
method of Logan et al. (1996). The outcome measure obtained from
the Logan plot is the distribution volume ratio (DVR), the ratio of
the FAL distribution volume in the target region (striatum) to that
in the reference region (occipital cortex). DVR is related to D2R
availability by the following relationship: DVR = [(Bmax/Kd) + 1],
where Bmax is the mass-specifi c concentration of available recep-
tors, not occupied by endogenous DA, and Kd is the receptor-ligand
dissociation rate constant.
DNA EXTRACTION AND GENOTYPING
Blood samples for genotyping were collected when the animals
were approximately 6-to 9-years old. DNA was isolated from
whole blood using standard extraction methods. Using a pro-
tocol modifi ed from that of Lesch et al. (1997), rh5-HTTLPR
was amplifi ed from 25 ng of genomic DNA with oligonucle-
otide primers (stpr5, 5′-GGCGTTGCCGCTCTGAATGC; intl,
5′-CAGGGGAGATCCTGGGAGGG) in 15 µl reactions using
Platinum Taq and the PCRX Enhancer System kit, according to
the manufacturer’s protocol (Invitrogen, Carlsbad, CA, USA).
Amplifi cations were performed on a Perkin-Elmer (Fremont, CA,
USA) thermocycler (9700) (with one cycle at 96°C/5 min followed
by 30 cycles of 94°C/15 s, 60°C/15 s, 72°C/30 s, and a fi nal 3-min
extension at 72°C. Amplicons were separated by electrophoresis
on 10% polyacrylamide gels, and the short (s, 398bp) and long
(l, 419bp) alleles of the rh5-HTTLPR were identifi ed by direct
visualization following ethidium-bromide staining.
The rated response on each trial was the dependent variable in
an early alcohol exposure (early, not early) × late alcohol expo-
sure (late, not late) × genotype (short carrier, not short) × sex
(F, M) × texture (feather, cotton, brush) × trials (6) analysis of
variance (ANOVA) with repeated measures on the last two fac-
tors. Interactions of genotype × sex were deleted from the model.
There were no signifi cant trials or texture effects or interactions.
Therefore, we analyzed the overall mean rated reaction averaged
across both trials and textures in a 2 (early) × 2 (late) × 2 (geno-
type) × 2 (sex) ANOVA. Interactions of genotype × sex were deleted
from the model due to small n. Post hoc tests were conducted using
the Tukey-Kramer method (Keppel and Wickens, 2004). Pearson
product-moment correlations were calculated between SPS-M
scores and our measure of DA function.
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Schneider et al. Alcohol effects: gene × environment
OVERALL RESPONSE TO REPEATED TACTILE STIMULATION
Figure 1 shows that Early alcohol exposure reduced the response
to tactile stimuli in monkeys carrying the short rh5-HTTLPR allele
by comparison with l/l monkeys and monkeys not exposed to
alcohol during early gestation carrying the short allele. The 2 (Early
alcohol exposure) × 2 (Late alcohol exposure) × Genotype (Long,
Short) × Sex ANOVA with Sensory Responsivity as the dependent
variable revealed a signifi cant Early alcohol × genotype interaction,
F(1,23) = 6.88, p = 0.015. Carriers of the rh5-HTTLPR short allele
that were exposed to alcohol during Early gestation (Early (0–E50)
and Continuously (0–E135) exposed monkeys) showed the lowest
levels of responsiveness to tactile stimuli. Monkeys with the rh5-
HTTLPR l/l allele did not differ from controls in responsiveness
as a function of Early alcohol exposure. A main effect of Early
alcohol exposure approached signifi cance, F(1, 23) = 2.87, p = 0.10.
Sensory responsivity was slightly lower in Early-exposed monkeys
than in monkeys not exposed to alcohol during early gestation
(Early exposure M = 1.77, No Early alcohol exposure M = 2.35
SE’s = 0.30 and 0.27, respectively).
CORRELATION OF SENSORY SCORES WITH PET MEASURES
OF DA-ergic FUNCTION
Figure 2 displays the correlations of sensory scores with PET meas-
ures separately by treatment groups. Over all animals, there was
no relationship between sensory scores and DA D2R availability,
r = 0.08, ns. However, a test for difference of the regression slopes
across groups was signifi cant, p < 0.05. Sensory score correlated
FIGURE 1 | Interactions between timing of prenatal alcohol exposure and
rh5-HTTLPR genotype on sensory responsivity behavioral score. A
genotype × early alcohol exposure interaction shows behavioral under-
responsivity to tactile stimuli in monkeys carrying the short (s) rh5-HTTLPR
allele compared to middle-to-late exposed and controls regardless of genotype.
FIGURE 2 | (A–D) Correlations of DA-ergic parameters measured with PET and
mean sensory scores in (A) control, (B) early gestation, (C) middle-to-late
gestation, and (D) continuous prenatal alcohol-exposed monkeys. This fi gure
illustrates a signifi cant difference in correlations across groups (p < 0.05):
r = 0.87 p < 0.01 for (B) early gestation prenatal alcohol-exposed monkeys
compared to r = −0.728, p < 0.10 for (C) middle-to-late gestation exposed
monkeys. Closed circles represent monkeys carrying the short (s) allele and
open circles are monkeys with the l/l allele.
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Schneider et al. Alcohol effects: gene × environment
positively with PET measures of striatal DA D2R availability for
the Early alcohol-exposed monkeys (r = 0.87, p < 0.01) whereas
sensory scores tended to correlate negatively with striatal DA D2R
availability for the Mid-late alcohol-exposed monkeys (r = −0.728,
p < 0.10). There were no signifi cant correlations between sensory
scores and PET FAL binding for the controls (r = −0.38) or for the
Continuous-exposed (r = 0.077) groups.
We measured behavioral responses to non-noxious tactile stimula-
tion, rh5-HTTLPR genotype, and striatal DA D2R availability in
macaque monkeys to address the question of whether patterns of
sensory responsivity are associated with timing of prenatal alcohol
exposure, rh5-HTTLPR genotype, and striatal DA D2R availability.
There were two principal fi ndings of the present study. First, our
results demonstrated that the timing of prenatal alcohol exposure
affected the behavioral responsivity of monkeys to sensory stimuli
and that the response depended upon both genotype and timing
of alcohol exposure. Our second fi nding was that the timing of
prenatal alcohol exposure also infl uenced the relationship between
sensory processing behavior and striatal DA D2R availability. Here
we consider the potential mechanisms which underlie these results
as well as their functional implications.
GENE × × ENVIRONMENT EFFECT
Our fi rst fi nding is that the monkeys exposed to alcohol during early
gestation (early-exposed, 0–E50, and continuous-exposed, 0–E135)
and carrying the short rh5-HTTLPR allele showed reduced sensory
responsivity to tactile stimuli compared to other groups. This fi nd-
ing confi rms and extends our previous fi ndings that moderate level
prenatal alcohol exposure interacts with the short allele of the pro-
moter region of the serotonin transporter gene to alter behavioral
outcomes in rhesus monkeys (Kraemer et al., 2008). Thus, the effect
of genotype on response to sensory stimuli depends upon whether
they were exposed to alcohol during early gestation.
The most likely mechanism is interference with neurodevelop-
mental processes occurring during early gestation. Further, our
fi ndings suggest that the monkeys carrying the short rh5-HTTLPR
allele may be more vulnerable to early gestation disruption of neu-
rodevelopmental processes. Three broad phases of brain devel-
opment have been described in rhesus macaques. These phases
are: neurogenesis, neuronal migration, and synaptogenesis (Rakic,
1988). According to Rakic, in both humans and monkeys, cortical
neurons are generated near the surface of the cerebral ventricle
during early gestation (0–E40). Following their last division, post-
mitotic cells generated within the proliferation zone migrate along
radial glial fascicles and enter the developing cortical plate and form
ontogenetic columns (E40–E70.100) (Rakic, 1995). By day E112,
the developing cortex has its full complement of neurons. At day
E112, the phase of rapid synaptogenesis begins. This phase has been
shown to occur synchronously in the somatosensory, motor, and
associative areas (Zecevic and Rakic, 1991) and continues to the
third month postnatally (Bourgeois and Rakic, 1993).
Our present fi ndings advance our understanding of the timing
of prenatal alcohol exposure on sensory responsivity by demon-
strating that, in monkeys carrying the rh5-HTTLPR (s) allele,
exposure to a teratogen during neurogenesis (0–E40) differs from
exposure during other times. Studies have found that exposure to
teratogens during the period of neurogenesis in early gestation
can induce gross irreversible malformations of the brain. Some
have found that fetal alcohol exposure during early pregnancy, or
neurogenesis, is equally or most damaging to fetal CNS develop-
ment and function, than exposure during other periods, including
craniofacial anomalies, midline brain abnormalities, and reduced
cerebellar Purkinje cell number in humans, sheep, and rodents
(Sulik et al., 1981; Graham et al., 1988; Ramadoss et al., 2007).
This does not mean that later prenatal perturbations are inconse-
quential. Alcohol exposure during the latter part of pregnancy has
been shown to be more strongly associated with developmental
problems in some human studies (Richardson et al., 1989; Coles
et al., 1991; Cornelius et al., 1999; Day et al., 1999). Moreover,
in rodents, exposure to alcohol during the postnatal period of
high synaptogenesis (second and third trimester equivalent in
humans) produced neuronal loss, altered neuronal circuitry, and
altered gliosis and apoptotic neurodegeneration in the develop-
ing forebrain (Borges and Lewis, 1983; West et al., 1984; Guerri,
1987; Bonthius and West, 1991; Goodlett et al., 1993, 1998; Melcer
et al., 1994).
Studies have shown that the mid-gestational period of neuro-
nal migration is also highly sensitive to various insults, including
toxins, viruses, and genetic mutations (Rakic, 1988). Abnormal
neuronal migration is considered to cause both gross and subtle
synaptic circuit abnormalities (Barth, 1987; Rakic, 1988; Caviness
et al., 1989), including developmental dyslexia (Galaburuda et al.,
1989) and schizophrenia (Kotrla et al., 1997). Correct cell migration
is important for communication between early- and later-forming
neurons at critical developmental stages prior to making synaptic
connections (Rakic, 1985). Correct neural migration is important
for the appropriate neuron position, which subsequently impacts
brain morphology and function.
It is interesting to note that the effects of prenatal alcohol expo-
sure on sensory processing function in subjects in the continuous
group (0–E135) carrying the short allele are equivalent to those with
the early exposure group (0–E50) short allele carriers, in contrast to
those from the middle-to-late exposed group (E50–E135) carrying
the (s) allele. This suggests that, for monkeys carrying the short
allele, if the nervous system was exposed to alcohol during early
gestation, then middle-to-late exposure (in the continuous group)
induces different effects on sensory processing function relative to
middle-to-late exposure alone. In other words, this study shows that
the effects of prenatal alcohol exposure during middle-to-late gesta-
tion are dependent upon events that occur during early gestation
in the continuous-exposed group. Early exposure appears to have
altered the nervous system such that it responds to middle-to-late
exposure in a different way. Others have reported similar fi ndings.
For example, in rats, alcohol exposure during E14 and E15 lowered
the number of cells in the ventral lateral nucleus of the thalamus,
whereas alcohol exposure E11–E20 did not, suggesting that the
timing of the initiation and duration of exposure is critical (Livy
et al., 2001).
The fi nding that the timing of alcohol exposure interacted with
genotype to alter sensory responsivity is a novel and a potentially
important fi nding. The most likely mechanism underlying this
interaction is that rh5-HTTLPR genotype can infl uence the early
Frontiers in Integrative Neuroscience www.frontiersin.org November 2009 | Volume 3 | Article 30 | 6
Schneider et al. Alcohol effects: gene × environment
patterning of the brain and impact how alcohol exposure induces
brain changes at that time. Studies in mice have shown that car-
rying the short version can affect neurite growth, migration, and
synaptogenesis. (Lesch et al., 1997; Murphy et al., 2004) and in
humans, the 5-HTTLPR s allele has been linked to anxiety-related
personality traits in some studies (Lesch et al., 1996; Hamer et al.,
1999). It has also been demonstrated that 5-HTTLPR can interact
with various environmental stressors to increase risk for psycho-
pathology (Caspi et al., 2003). In monkeys reared without mothers
(a model of early adversity, which produces long-lasting effects on
brain structure and behavioral/endocrine stress responding), the
s allele predicts CSF levels of the serotonin metabolite 5-HIAA,
neonatal behavior, and stress responsivity (Bennett et al., 2002;
Champoux et al., 2002; Barr et al., 2004). It, therefore, is likely that
HTTLPR genotype might interact with other types of stressors that
impact brain development.
Variation in genotypes can play a role in 5-HT neurotrans-
mission by impacting the uptake of 5-HT into the presynaptic
neuron (Glatz et al., 2003). 5-HT is an important modulator of
early CNS development, including cell proliferation, migration and
differentiation (Lauder, 1990, 1993). 5-HT acts as a master con-
trol neurotransmitter, regulating several other neurotransmitters.
Because early gestation is a critical developmental period during
which time neurons are being generated, genetic variation that
impacts 5-HT system function during early embryonic/fetal devel-
opment might render an organism more or less sensitive to prenatal
alcohol exposure. Genetic effects on sensitivities to teratogenic con-
ditions (including alcohol exposure) might be a predictive response
for adaptation to environmental conditions present at the time of
birth, presumably also with environment risks, promoting better
opportunities for survival. That is, prenatal and postnatal environ-
mental risks may be correlated. In this case, genes might serve as
a protective function in relation to environmental insults. At the
same time, this variability might render some offspring vulner-
able or less well suited to adapt to, or even survive in a hazardous
environment. Interpreted within the context of an evolutionary
concept of natural selection, variation in an organism’s response
to the environment is important and serves as the basic ingredient
for natural selection (Ridley, 2003). It is important for an organ-
ism to adapt to its environment and such adaptation during the
prenatal period makes sense, given this is the formative period of
development. Thus, one can assume that one genetic variant versus
another might render the organism more or less sensitive to certain
environmental conditions occurring at the particular formative
time of development. This process could ultimately provide an
organism with a better fi t with the environment and thus promote
It is interesting that there were no main effects of genetic vari-
ant of the promoter region of the serotonin transporter gene on
sensory processing function in this study. This is consistent with
the notion that susceptibility genes for multifactorial psychological
disorders have very negligible effects by themselves, but can increase
risk when interacting with other gene variants and environmental
factors (Kendler, 2005). The idea is that susceptibility genes repre-
sent particular allelic variations of common genes or normal allelic
variation. Thus the genes may affect physiological pathways that
could render psychological disorders more or less inevitable, but
the genes do not cause the disorder directly (Rutter et al., 2006).
Rather they contribute to genetically infl uenced sensitivities to
specifi c environments.
RELATIONSHIP BETWEEN PET DA MEASURES AND BEHAVIORAL
MEASURES OF SENSORY RESPONSIVITY
We also found that the timing of gestational exposure to alcohol
affected the relationship between behavioral measures of sensory
responsivity and PET measures of DA-ergic function. For the
early alcohol-exposed monkeys, there was a positive relationship
between sensory responsivity and striatal DA D2R availability.
In other words, for early-exposed monkeys low levels of striatal
DA D2R availability, which is suggestive of blunted DA function
(Volkow et al., 2002), were related to sensory under- responsivity.
The opposite pattern was found for middle-to-late exposed
monkeys, in that low D2R availability was associated with high
It is interesting that our previous work showed that timing of
alcohol exposure disrupted striatal DA system function in different
ways (Schneider et al., 2005). Overall, striatal DA D2R density was
decreased in Early-exposed monkeys (Early only and Continuous
exposed) compared to monkeys not exposed to alcohol during early
gestation (Controls and Middle-to- late exposed) (Schneider et al.,
2005). This fi nding underscores the notion that exposure during
early gestation (0–E50), approximating the period of neurogen-
esis (0–E40) differs substantially from exposure during middle-to-
late gestation (E50–E135), approximating the period of neuronal
migration (E40–E70/100) and early synaptogensis (E112–third
month postnatally (Rakic, 1988). Either an increase or decrease in
DA function can have repercussions on normal functioning. It has
been shown that there is a critical range of DA activity for optimal
functioning (Arnsten, 1997).
DA is an important neurotransmitter, modulating activity in
many brain regions, promoting both excitatory and inhibitory
signals. The striatal region has a high density of D2R which are
considered to have a gating function in basal ganglia thalamocor-
tical circuits thought to underlie inhibitory control (Casey, 2001).
DA is considered to underlie the behavioral responses to impor-
tant or salient events, whether aversive or appetitive (Berridge
and Robinson, 1998; Redgrave et al., 1999). If DA D2R density is
low or activity blunted, it is thought that attention, motor func-
tion, or executive function could be disrupted. For example, DA
D2R defi cient mice need more trials to alter responses during
reversal testing than wild-type mice, suggesting DA D2R simula-
tion in striatum may brake or reduce excitatory corticostriatal
signaling so that goal-directed behavior can be guided by sign-
aling the organism about contingency changes (Carlsson et al.,
2001). If DA D2R is too high, sensitivity to novel stimuli is con-
sidered to be heightened. It has also been suggested that reduced
striatal D2R density could reduce sensitivity to hedonic positive
stimuli, increasing the compulsive drive to consume alcohol or
drugs (Volkow et al., 2002). Disruptions in DA-ergic transmission
contribute to neuropsychiatric disorders, including schizophrenia
and drug addiction (Bergman et al., 1998; Berke and Hyman,
2000). The nature of DA-mediated effects depends on DA recep-
tor subtype as well as other factors. Unmedicated patients with
schizophrenia have been found to have higher striatal D2R density
Frontiers in Integrative Neuroscience www.frontiersin.org November 2009 | Volume 3 | Article 30 | 7
Schneider et al. Alcohol effects: gene × environment
compared to normal controls (Laruelle, 1998). It could be hypoth-
esized that the timing of the alcohol exposure could alter the
relationship between DA-ergic function and sensory sensitivity
to environmental stimuli by altering one or more of the processes
of neurogenesis, cell proliferation, migration or synaptogenesis
leading to possible mis-wiring of neural processes and consequent
disrupted behavioral effects.
It was surprising to fi nd that the continuously exposed group,
consisting of both early and mid-late exposure and hence involv-
ing a longer duration of exposure, showed a different relationship
between D2R availability and SPS-M scores than that of the early or
mid-late exposed groups. However, fi ndings such as these are not
unprecedented in the literature. The way in which prenatal alco-
hol exposure impedes normal brain development remains unclear.
Alcohol has wide effects on the brain, neurotransmitter systems,
and behavior – possibly affecting a number of developmental proc-
esses concurrently. These effects differ by timing of exposure, region
and cell type. Interestingly, and relevant to our fi ndings, some areas
of the brain may be differentially affected by longer durations than
shorter exposures to alcohol (Sulik et al., 1981; Livy et al., 2001).
For example, Livy et al. (2001) found that in rats, alcohol exposure
during E14 and E15 resulted in lower numbers of cells in the ventral
lateral nucleus of the thalamus but that alcohol exposure during
E11 to E20 did not produce this effect. They speculated that the
timing of alcohol exposure initiation could be an important infl u-
ence on the effects of alcohol exposure. It has also been suggested
that the longer period of treatment might afford the opportunity to
habituate to the treatment and possibly to develop tolerance (Smith
et al., 1989). While it is unclear how this occurs at this time, there
is some evidence to support the notion that, in some cases, shorter
durations of exposure may induce adverse effects not observed with
longer periods of exposure.
Also relevant to our fi ndings, Clarren et al. (1990) found that,
in monkeys, a high alcohol exposure condition induced a nega-
tive correlation between offspring striatal DA and maternal blood
alcohol concentration whereas in a moderate alcohol condition,
the relationship between maternal blood alcohol concentration
and offspring straital DA was positive. More research is clearly
needed to understand how the intensity, duration, and timing of
alcohol exposure induces brain and related behavioral changes and
in affected offspring.
An important idea related to these fi ndings concerns the notions
of equifi nality and multifi nality, or that there are multiple path-
ways to adaptive and maladaptive outcomes and diverse outcomes
from individual risk factors (Cicchetti and Rogosch, 1996). For
example, in this study, while exposure to early gestation alcohol
yielded a positive relationship between DA-ergic function and sen-
sory responsivity, exposure during middle-to-late resulted in the
opposite pattern, suggesting that there are multiple outcomes for
individuals, despite similar exposure to environmental risk factors,
such as prenatal alcohol exposure. Thus one would expect a range
of patterns of responsivity to sensory stimuli in children with fetal
alcohol spectrum disorder (FASD), depending upon a variety of
variables including the timing of exposure and genotype. Indeed,
children with FASD were rated by parents as defi cient in visual-
spatial, auditory, and tactile processing (Morse and Cermak, 1994).
One would also expect that sensory processing disorder would be
associated with behavioral abnormalities in children especially
related to inhibitory control. Indeed studies have shown that chil-
dren with fetal alcohol spectrum disorder who demonstrate sensory
processing defi cits demonstrate externalizing problems, diffi culties
in attention, socialization, and rule breaking as well as thought
problems (Franklin et al., 2008; Jirikowic et al., 2008).
Another interesting implication is that early gestation alcohol
exposure, a time at which pregnancy might not yet be detected, is
a vulnerable time, especially for those individuals carrying genetic
vulnerability factors. Since both under-and over-responsivity to
sensory stimuli are associated with behavioral problems, the possi-
bility of different etiology and mechanisms must be taken seriously.
Perhaps prenatal alcohol exposure induces a range of alterations
in the generation, proliferation and migration of cells which could
then promote deviations in behavior, depending upon multiple
factors, including timing of exposure to environmental perturba-
tions and genotype.
There are several limitations of this study. One is that the can-
didate gene was limited to one functional 5-HTT marker (vs. hap-
lotype). Moreover, candidate loci that affect functioning of other
neurotransmitter systems are undoubtedly important and relevant
to contributing to behavioral disorders in fetal alcohol-exposed
individuals. Another limitation is that we only assessed one neu-
rotransmitter subtype in this study, D2R, and we were limited to
the striatum brain region. We are currently expanding our studies
to assess D1-type receptors and DA transporters in multiple brain
regions in these monkeys. Also, while experiments with non-human
primates permit control of the dose and timing of prenatal alcohol
exposure and control of potential co-variants, behavioral measures
that are relevant to humans and candidate genes and PET measures
of brain function similar to humans, caution is needed in general-
izing from monkeys to humans. Thus, it is critical to replicate these
fi ndings in human studies. Another limitation is that mothers were
pre-selected for consuming a moderate dose of alcohol. Whether
this involves genetic taste preference or susceptibility to alcohol-
induced effects is unknown. Finally, if these results replicate in
humans, treatment studies are critically needed to determine if
reduced sensory sensitivity can be reversed in infants and children
with genetic vulnerabilities and exposure to alcohol during early
gestation using sensory-based occupational therapy methodology
(Baranek, 2002; Miller et al., 2007; Schaaf and Nightlinger, 2007). If
such individuals can be identifi ed early in life, intervention studies
are possible early in life at the peak of brain plasticity. These studies
have the potential to signifi cantly reduce the pain and suffering
associated with the devastating effects of fetal alcohol spectrum
In summary, there is clear evidence from rat studies that prenatal
alcohol exposure effects are related to the region of the brain or
cell type undergoing rapid development at that time (Goodlett and
Johnson, 1999). Our fi ndings provide evidence in primates that
genetic factors might increase or decrease an organism’s sensitivity
to fetal alcohol effects during a particular gestation period.
This study was supported by AA10079 and AA12277 from the
National Institute of Alcoholism and Alcohol Abuse and Wallace
Research Foundation Grant to Mary L. Schneider.
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Conflict of Interest Statement: The
authors declare that the research was
conducted in the absence of any com-
mercial or financial relationships that
could be construed as a potential confl ict
Received: 10 April 2009; paper pend-
ing published: 11 August 2009; accepted:
23 October 2009; published online: 10
Citation: Schneider ML, Moore CF, Larson
JA, Barr CS, DeJesus OT and Roberts AD
(2009) Timing of moderate level prenatal
alcohol exposure infl uences gene expression
of sensory processing behavior in rhesus
monkeys. Front. Integr. Neurosci. 3:30. doi:
Copyright © 2009 Schneider, Moore,
Larson, Barr, DeJesus and Roberts. This is
an open-access article subject to an exclu-
sive license agreement between the authors
and the Frontiers Research Foundation,
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