Behavioral/Systems/Cognitive

Modification of Social Memory, Hypothalamic-Pituitary-

Adrenal Axis, and Brain Asymmetry by Neonatal
Novelty Exposure
Akaysha C. Tang,
1,2,3
Bethany C. Reeb,
1
Russell D. Romeo,
4
and Bruce S. McEwen
4
Departments of
1
Psychology,
2
Neurosciences, and
3
Computer Sciences, University of New Mexico, Albuquerque, New Mexico 87131, and
4
The Laboratory
of Neuroendocrinology, The Rockefeller University, New York, New York 10021
Although corticosterone (a stress hormone) is known to influence social behavior and memory processes, little has been explored
concerning its modulatory role in social recognition. In rats, social recognition memory for conspecifics typically lasts 2 hr when
evaluated using a habituation paradigm. Using neonatal novelty exposure, a brief and transient early life stimulation method known to
produce long-lasting changes in the hypothalamic-pituitary-adrenal axis, we found that social recognition memory was prolonged to at
least 24 hr during adulthood. This prolonged social memory was paralleled by a reduction in the basal blood concentration of cortico-
sterone. The same neonatal stimulation also resulted in a functional asymmetry expressed as a greater right-turn preference in a novel
environment. Rats that preferred to turn right showed better social recognition memory. These inter-related changes in basal blood
corticosterone concentration, turningasymmetry, andsocial recognitionmemorysuggest that stress hormones andbrainasymmetryare
likely candidates for modulating social memory. Furthermore, given that neonatal stimulation has been shown to improve learning and
memory performance primarily under aversive learning situations, the neonatal novelty exposure-induced enhancement in social rec-
ognition broadens the impact of early life stimulation to include the social domain.
Key words: social recognition memory; novelty; neonatal stimulation; HPA axis; lateralization; rats; asymmetry; CORT; corticosterone;
neonatal handling; memory enhancement
Introduction
Through recognition sniffing (Barnett, 1958), rats acquire in-
formation about conspecifics after mutual exposures. Typically,
the frequency of such investigative behaviors decreases after an
exposure and increases when a new conspecific is introduced.
This decrease, or habituation, of investigative behavior has been
usedas anindex of social recognition(Thor andHolloway, 1982).
The increase, or dishabituation, to the novel conspecific has been
used as a control to rule out the possibility of generalized social
fatigue (Thor and Holloway, 1982). This form of social memory
can be corrupted by an exposure to a newconspecific, a phenom-
enon referred to as retroactive interference. Rodents reared in
social isolation show habituation for 2 hr after the initial expo-
sure if there is no influence of exogenous neuroendocrine mod-
ulators (Popik and van Ree, 1998; Ferguson et al., 2002).
Although the olfactory system is essential for this form of
social memory (Alberts andGalef, 1973; Guanet al., 1993; Dluzen
et al., 2000), it has been suggested that the septum (Popik et al.,
1992), hippocampus (Kogan et al., 2000), entorhinal cortex or
subiculum (Bannerman et al., 2002), nucleus accumbens
(Ploeger et al., 1991), and amygdala (Maaswinkel et al., 1996;
Fergusonet al., 2001) all play a role insocial recognitionmemory.
Vasopressin (Dantzer et al., 1987; Bluthe and Dantzer, 1993),
oxytocin (Insel, 1992), norepinephrine (Griffin and Taylor,
1995), acetylcholine (Winslow and Camacho, 1995), and dopa-
mine (Dluzen and Kreutzberg, 1993) also modulate this form of
social recognition memory (for review, see Popik and van Ree,
1998; Ferguson et al., 2002). These neuroanatomical, pharmaco-
logical, and genetic studies suggest that multiple brain structures
and multiple neuromodulatory systems may interact to influence
social recognition memory.
Although it remains to be determined how different modula-
tory systems and brain structures influence social memory, the
hypothalamic-pituitary-adrenal (HPA) axis may play a central
role, in part through its reciprocal interactions with neuromodu-
lators such as vasopressin and oxytocin (for review, see DeVries,
2002) and in part by its reciprocal interactions with the hip-
pocampus and prefrontal cortex (Diorio et al., 1993; Caldji et al.,
2000). Whereas multiple invasive methods are available to target
the HPA axis, mild neonatal stimulation via neonatal handling
reliably and noninvasively alters the HPA axis (Levine, 1957,
1960; Denenberg, 1964; Meaney et al., 1988). Given that stress
clearly affects social behavior and early life experience affects an
individuals stress response, it is surprising that thus far social
recognition memory has neither been examined within the con-
text of the HPA axis nor evaluated in the context of early life
Received June 10, 2003; revised July 18, 2003; accepted July 21, 2003.
We thank Drs. Victor Denenberg, Jereme Kagan, and Robert Sapolsky for comments on previous versions of this
manuscript.
Correspondence should be addressed to Akaysha C. Tang, Department of Psychology, Logan Hall, The University
of New Mexico, Albuquerque, NM 87131. E-mail: [email protected].
Copyright 2003 Society for Neuroscience 0270-6474/03/238254-07$15.00/0
8254 The Journal of Neuroscience, September 10, 2003 23(23):8254 8260
experience. Using neonatal novelty exposure (Tang, 2001), an
early life stimulation procedure that has been shown to affect
HPAfunction (Zou et al., 2001), memory (Tang, 2001), and syn-
aptic plasticity (Tang and Zou, 2002), we examined whether
adult social recognition can be enhanced by neonatal novelty
exposure, and whether the changes in social recognition are re-
lated to those in the HPA axis.
Interestingly, social recognition of a conspecific in the chick is
dominated by the right hemisphere (Vallortigara, 1992), parallel
to the right hemisphere superiority in human face recognition
(Warrington and James, 1967). In the rat, neonatal stimulation
procedures that result in changes in the stress response system
also induce the development of a right hemisphere dominance
(Denenberg et al., 1978; Verstynen et al., 2001; Tang and Ver-
stynen, 2002; Tang, 2003). It is possible that in the rat, this early
experience-dependent asymmetry is associated with individual
differences in social recognition. Thus, in the present study, we
investigated three potentially inter-related constructs: social rec-
ognition, the function of the HPA axis, and brain asymmetry.
Materials and Methods
Experimental animals. Nine pregnant Long Evans hooded dams (Harlan
Sprague Dawley, Indianapolis, IN) arrived at the vivarium 11 d before
giving birth. Twenty-four male pups born of these dams were included in
this study. Pups were housed with the dams until weaning at postnatal
day 21. After weaning, dams and pups were housed individually in trans-
lucent plastic cages (51 25 22 cm) with a 12 hr (7:00 A.M. to 7:00
P.M.) light/dark cycle and food and water ad libitum.
Neonatal novelty exposure. The neonatal novelty exposure procedure
(Tang, 2001) was derived but differs from the well known handling
method (Levine, 1957; Denenberg, 1964) and has been shown previously
to have a wide range of long-lasting behavioral (Tang, 2001, 2003; Tang
and Verstynen, 2002), neurophysiological (Zou et al., 2001; Tang and
Zou, 2002), and neuroanatomical (Verstynen et al., 2001) effects during
adulthood. We exposed rat pups individually to a novel cage (Novel
group) for 3 min per day during the first 3 weeks of their life while their
littermates remained in the home cage with their siblings (Home group).
On postnatal day 1, approximately one-half of each litter was pseudoran-
domly assigned to Novel and the other half to Home conditions (split-
litter design), with weights approximately matched between Novel and
Home animals. The dam was first removed from the home cage. The
Novel and Home pups were then identified by examining toe markings.
Once identified, Novel rats were placed in a new cage lined with fresh
sawdust, the normal bedding used in the home cages, for their 3 min
exposure and subsequently returned to their home cage in which the
Home rats remained. During this transfer, each Novel pup was yoked to
a Home pup that received a matching amount of experimenter contact at
approximately the same time as the yoked Novel pup. The dam was
returned to the litter after both the Novel and Home pups joined in the
home cage. The amount of touching by the experimenter and the dura-
tion of maternal separation during this novelty exposure procedure were
matched between the Novel and Home rats, thus ensuring that any dif-
ference in social recognition between the two groups was attributable to
neither the separation from the dam nor the touching per se by the
experimenter. This procedure was performed at ambient temperature
(21C) with a humidity of 25%.
Social recognition memory test. After weaning, all animals were housed
individually until 7 months of age, at which time adult social recognition
memory was assessed. The adultjuvenile pairing used in a typical social
recognition memory test entails a component of social dominance of the
testing animal (adult) over the stimulus animal (juvenile). To study so-
cial recognition in the absence of dominance-related issues, we tested
NovelHome pairs of identical age in a fresh neutral testing cage with the
weights of the pair matched. Aggression, motivated by territorial instinct
in the home cage, was minimized by testing the pair in a neutral cage and
reducing the within-pair weight difference. In fact, few incidences of
aggressive behaviors were observed in this experiment. Weights were
measured 2 d before social memory test. No siblings were used in a pair.
To allow group identification, each animal in a pair was marked on both
sides of the body, either with red or green food coloring. The colors were
counter-balanced between the Novel and Home groups.
Novel and Home rats were exposed to each other in pairs on two
consecutive days infour 5 minsessions (Ss) [day 1 (D1), S1S3; day 2, S1]
(Fig. 1). Within day 1, intertrial intervals (ITIs) of 10 and 2 min were
selected to maximize the amount of habituation to allow improved dis-
crimination among individual animals. During the ITIs, animals were
returned to their home cages, which were placed on a table in the corner
of the testing room. On each day, the social exposure sessions were pre-
ceded by a 5 min habituation session (Hab) to allow the animal to adapt
to the neutral testing cage. During Hab, the two animals were separated
by a cardboard partition. It is understood that the partition did not
prevent the rats from perceiving olfactory cues from each other, but
because these animals were housed in the same room throughout their
life, they were all familiar witholfactory cues fromeachother. All animals
experienced the same partner during day 1 S1 and S2, and day 2 S1.
Short-termhabituation (STH) was measured by comparing day 1 S1 and
S2, and long-term habituation (LTH) was measured by comparing day 1
S1 and day 2 S1.
One potential confounding factor for memory is generalized social
fatigue. In this case, the animal is simply satiated with any social stimuli
and thus does not discriminate between a familiar and new conspecific.
To rule out this possibility, on day 1 S3, we exposed some animals to the
same conspecific (FAMILIAR) and others to a newconspecific (NEW). A
difference in the frequency of social investigative behaviors between the
NEW and FAMILIAR animals would serve to rule out social fatigue as a
confounding factor (Thor and Holloway, 1982). This day 1 S3 manipu-
lation also allowed us to test for a possible retroactive interference effect
of new conspecifics on the 24 hr long-term habituation. Because we
tested two pairs of animals simultaneously, this exposure to newconspe-
cifics was implemented by swapping two rats between the two pairs of
cages. There are three possibilities for this swapping: no swapping, swap-
ping the Novel rats, and swapping the Home rats. This procedure yielded
approximately one-third of rats seeing the same partner in the same cage,
one-third seeing a new partner in the same cage, and a final one-third
seeing a new partner in a new cage. Because the cage effect was not
significant, we pooled the last two conditions together under NEW.
Thus, approximately one-third of the rats experienced FAMILIAR con-
ditions, and two-thirds experienced NEW conditions.
All sessions were videotaped for off-line analysis. Both the experi-
menter andthe data coder were blindto the identity of the animals. Social
investigative behaviors were defined as being proximally oriented to a
conspecific (the tip of the nose within 1 cm) or in direct contact while
sniffing, following, nosing, grooming, and generally inspecting any body
surface (Thor and Holloway, 1982). The frequencies of these behaviors
were measured from 60 5-sec video segments for each of the 5 min
sessions. If the behavior was present any time during the 5 sec duration,
an occurrence of one was counted. As a result of pairing animals of
similar age and size, a large percentage of social investigation time was
spent on mutual investigation (45%). This mutual investigation only
adds a constant value to both the Novel and Home measures. To increase
the sensitivity of the measures to the novelty manipulation, we per-
formed analysis on only the unidirectional investigation. Short-term
memory was assessed by a STHscore and defined as (S1 S2)/S1 100%.
Figure 1. The habituation procedure for social recognition memory. A pair of rats was first
habituatedtothetestingcageduringacagehabituationsessiononeachof the2d. Immediately
after Hab, the two rats were exposed to each other in a total of four sessions: day 1 S1S3 and
day 2 S1 (D2S1). Duration of all sessions was 5 min.
Tang et al. Novelty, Social Memory, HPA, and Lateralization J. Neurosci., September 10, 2003 23(23):8254 8260 8255
Long-term memory was assessed by a 24 hr LTH score and defined as
(S1 D2S1)/S1 100%. The interference effect from exposure to a new
conspecific during S3 was assessed separately for Novel and Home rats by
comparing LTHscores between animals experiencing a familiar and new
animal during S3.
General and lateralized activity in a novel testing environment. During
the cage habituation session, rats explored the testing cage. We separately
measured three types of movement during the 5 min cage habituation
immediately before S1: rearing as a measure of general activity level, and
left turns (Ls) and right turns (Rs) as measures for testing right brain
dominance. The frequencies of each complete updown movement and
each 90 left or right turn were counted by viewing videotapes off-line.
Turn preferences were measured by a lateralization score (L-score) de-
fined as (R L)/(R L) 100%.
Basal corticosterone concentration. Basal blood corticosterone (CORT)
measures were taken at 16 months of age when these animals were killed.
All rats received identical treatment throughout their life (same behav-
ioral tasks and same housing environment). Animals were anesthetized
using halothane and immediately decapitated, and trunk blood samples
were collected. Blood samples were centrifuged, and plasma was re-
moved and stored at 20C until radioimmunoassay was performed.
Plasma corticosterone concentrations were measured in duplicate in a
single assay using the Coat-a-Count Corticosterone Kit (Diagnostic
Products, Los Angeles, CA). The lower limit of detectability of the assay
was 17.23 ng/ml, and the intra-assay coefficient of variation was 13.5%.
The experimenter was blind to the sample identity.
Statistical analysis. Because more than one animal from a litter was
used, we tested for a litter effect using ANOVA. Because a litter effect was
not significant on any of the measures, we performed the rest of the
analysis using animals as units. On the basis of previous studies, we
predicted specific patterns of results. Therefore, directional tests were
performed for both pair-wise comparisons and correlations. Because of
heterogeneity of variance in the raw data, Spearmans rank order corre-
lation, r
s
, was used. To determine whether the correlation was indepen-
dent from the individual differences created by neonatal novelty expo-
sure treatment, we computed partial correlations as well. One outlier in
LTH and one in blood corticosterone measure were detected and re-
moved. Observations were considered outliers and removed if they fell
1.5 interquartile range above the top quartile (Agresti and Finlay,
1997).
Results
Short-term and long-term habituation of social investigation
and retroactive interference
Adult social recognition memory was assessed at 7 months of age
using a habituation paradigm consisting of 5 min initial cage
habituation sessions and 5 min social exposure sessions (S
i
).
Novel and Home animals did not differ in their baseline social
investigation (S1) (Fig. 2a). Although both groups reduced their
social investigation after a 10 min ITI, the amount of reduction,
or short-term habituation (10 min delay), was significantly
greater for the Novel thanthe Home animals (t 2.549; p 0.01;
df 21) (Fig. 2b). Long-termrecognition memory (24 hr delay),
evaluated by re-exposing each animal on the second day (D2S1)
to the conspecific they experienced on day 1 S1, was significantly
greater for Novel than Home rats (t 2.259; p 0.025; df 21)
(Fig. 2c). Although Home rats showed no 24 hr LTH (replicating
findings from many previous studies), LTH in Novel rats was
significantly 0 (t 2.791; p 0.01; df 11) (Fig. 2c). Thus,
only Novel rats showed 24 hr habituation to a previously encoun-
tered conspecific.
Like other forms of memory, recognition of a conspecific is
subject to retroactive interference. When an additional exposure
to a novel conspecific was added after the earlier exposures (S1
and S2), the memory for the first conspecific can be reduced or
completely blocked (Thor and Holloway, 1982). Using this inter-
ference effect as an additional probe for this 24 hr social recogni-
tion memory, we separately examined animals that did and did
not experience a new conspecific during the third session on day
1 (S3) (NEW vs FAMILIAR). We found that LTH in the Novel
animals was significantly higher for the condition of FAMILIAR
than the condition of NEW (t 2.524; p 0.05; df 10; direc-
tional) (Fig. 2d, left). Such a difference was not found for the
Home animals ( p 0.20) (Fig. 2d, right). Only the Novel rats
were able to show differential responses to the first conspecifics
according to whether they have experienced a newconspecific 24
hr earlier.
If a generalized social fatigue was the cause for the 24 hr ha-
bituation, we would expect to see the same amount of 24 hr
habituation in both animals exposed to a familiar (Novel-
FAMILIAR) and new (Novel-NEW) rat during day 1 S3. Despite
the fact that both Novel-NEW and Novel-FAMILIAR had the
same amount of social interactions (three sessions), Novel-NEW
showed retroactive interference (i.e., a blocking of habituation by
the additional exposure to a new conspecific), and only the
Novel-FAMILIAR showed a 24 hr habituation (Fig. 2d). There-
fore, the observed long-term habituation was not attributable to
generalized social fatigue but a memory for a specific individual.
Turning asymmetry and its relationship to habituation
We measured activity in the novel testing cage during the initial 5
min cage habituation before social exposures. Novel animals
made significantly more right turns than Home animals (t
3.022; p 0.005; df 21) but did not differ from Home animals
in either rearing or left turns ( p 0.20) (Fig. 3a,c,e). Turning
bias, measured by an L-score, differed between Novel and Home
rats (t 1.860; p 0.05; df 21) (Fig. 3g), with the Novel rats
showing a significant right-turn bias (t 2.546; p 0.025; df
11) anda lack of suchbias inthe Home rats (t 0.507; p 0.20;
df 11). Thus, the difference between Novel and Home groups
was not reflected in their rearing or left-turn activity but captured
preferentially by right-turn activity and right-turn bias.
In chicks, a right hemisphere bias was shown to be associated
with better social recognition memory (Vallortigara, 1992). To
examine this relationship in rats, we correlated turn bias with
social memory. Figure 3b shows that the individuals with a
Figure 2. Neonatal novelty exposure enhances both short-term(10 min) and long-term(24
hr) social recognition memory. a, Novel and Home rats did not differ in baseline social investi-
gation (D1S1). b, Novel rats showed significantly greater reduction in social investigation than
Home rats after 10 min ITI (STH). c, Novel rats showed significantly greater reduction in social
investigation than Home rats after a 24 hr delay (LTH). d, Interference effect from a single
exposure to a newconspecific: LTH in the Novel but not Home rats was significantly reduced by
the exposure to a new conspecific. *p 0.05; **p 0.025; ***p 0.01.
8256 J. Neurosci., September 10, 2003 23(23):8254 8260 Tang et al. Novelty, Social Memory, HPA, and Lateralization
greater bias for right-turn activity, which was increased by neo-
natal novelty exposure, were better at subsequent social recogni-
tion (r
s
0.612, p 0.05; partial r 0.404, p 0.031; n 23). In
contrast, the rearing and left turns, which were not modified by
neonatal novelty exposure, did not have any predictive power for
social recognition memory ( p 0.20) (Fig. 3d,f ). Furthermore,
the right-turn bias (L-score) is positively correlated with short-
termrecognition memory (r
s
0.521, p 0.05; partial r 0.445,
p 0.019; n 23) (Fig. 3h). A similar but not statistically signif-
icant correlation between turn measures and long-term habitua-
tion was found.
Basal level of blood corticosterone concentration and
habituation of social investigation
We found that basal CORT concentration in the blood was sig-
nificantly lower in Novel than that of Home animals (t 2.71;
p 0.005; df 20) (Fig. 4a). Given that exposure to stress can
impair learning (McEwen and Sapolsky, 1995; Lupien and McE-
wen, 1997; de Kloet et al., 1999; McGaugh and Roozendaal,
2002), a difference in basal corticosterone concentration is likely
to affect social recognition memory. Therefore, we predicted that
individual differences in basal corticosterone concentration
might partially account for the observed individual differences in
social recognition memory. Specifically, the lower the basal
corticosterone concentration, the better the social recognition
memory. Consistent with this prediction, basal corticosterone
concentration showed significant negative correlations with
both short-term (r
s
0.510; p 0.025; n 22) and long-
term habituation (r
s
0.934; p 0.002; n 6) [because of
the blocking of 24 hr recognition memory among the rats that
experienced the NEW condition during day 1 S3, the correla-
tions were calculated only for the group of rats (FAMILIAR)
that displayed 24 hr recognition memory]. After partialing out
the Novel-Home differences, the inverse relationship was sim-
ilar in direction (Fig. 4b,c, compare open squares and filled
circles) but no longer significant at p 0.05 level (partial
correlations: STH, r 0.3659, p 0.051, n 22; LTH, r
0.75, p 0.072, n 6). Because of the marginal statistical
significance (STH, p 0.051; LTH, p 0.072), the interpre-
tation of the relationship between individual differences in
social recognition and basal corticosterone requires additional
replication.
Discussion
We found that the animals that experienced neonatal novelty
exposure, a brief and transient early life stimulation procedure,
showed at adulthood greater long-term and short-term habitua-
tion in social investigation than their matched controls. Only
Novel rats showed significant long-term habituation to previ-
ously encountered conspecifics. Furthermore, the long-term ha-
bituation in Novel rats differed between those that did and did
Figure 3. Brain asymmetric activation in a novel environment (testing cage) contributes to
individual differences in STH. Open squares, Novel rats; filled circles, Home rats. a, Novel rats
made significantly more right turns than Home rats. b, The right-turn frequency positively
correlates with STH. c, Novel and Home rats did not differ in their frequency of left turns. d, The
left-turn frequency did not predict STH. e, Novel and Home rats did not differ in their frequency
of rearing. f, Rearing did not predict STH. g, Novel rats display a significantly greater right-turn
bias (L-score) than Home rats. h, The right-turn bias positively correlates with STH. *p 0.05;
***p 0.01.
Figure 4. Basal blood corticosterone concentration and social recognition memory. Open
squares, Novel rats; filled circles, Home rats. a, Basal corticosterone concentration of Novel rats
was significantly lower thanthat of Home rats. b, Basal corticosterone concentrationnegatively
correlates with STH. c, Basal corticosterone concentration negatively correlates with LTH.
***p 0.01.
Tang et al. Novelty, Social Memory, HPA, and Lateralization J. Neurosci., September 10, 2003 23(23):8254 8260 8257
not experience new conspecifics after the initial short-term ha-
bituation. This habituation of social investigation was not attrib-
utable to a generalized social fatigue. Parallel to this enhancement
in social recognition, the basal level of blood corticosterone con-
centration was significantly reduced in Novel rats in comparison
to the Home rats. Furthermore, Novel rats showed a greater
right-turn bias in the novel testing environment than the Home
rats, and the individual differences in social recognition were
significantly associated with individual differences in turning
asymmetry.
Early life stimulation enhances social recognition memory
When reared in social isolation (individual housing), rats only
habituate to a previously encountered conspecific within 2 hr of
the initial exposure (Thor and Holloway, 1982). This transient
recognition memory was prolonged by exogenous neuroendo-
crine modulators (Dantzer et al., 1987; Insel, 1992; Bluthe and
Dantzer, 1993) and by social housing immediately before the
social memory test (Kogan et al., 2000). We were able to prolong
the duration of social memory to at least 24 hr via neonatal nov-
elty exposure, a treatment that was provided 6 months before the
social memory tests. This result showed that even transient early
life stimulationcanhave a profound impact onadult social mem-
ory, and that mild neonatal stimulation may offer a new way to
counteract the negative effects of social isolation on conspecific
recognition. The attempt to show enhanced learning and mem-
ory via neonatal stimulation has a long history. Yet, as pointed
out by critical reviews, consistent findings were primarily ob-
tained from aversive tasks (Daly, 1973; Fernandez-Teruel et al.,
2000). Therefore, the impact of such an early life stimulation
method was limited in its scope and lacked critical external valid-
ity to generalize to a majority of learning situations that are nona-
versive in nature. The present finding suggests that the impact of
early life stimulation can be expanded to include the social
domain.
The behavioral origin of the neonatal novelty exposure effects
The neonatal novelty exposure procedure (Tang, 2001) used here
differs from the well known neonatal handling method (Levine,
1957; Denenberg, 1964) in that it isolates the novelty component
from maternal separation and experimenter handling per se, two
factors that confound the novelty factor in the original handling
design. Using a split-litter design, we were able to match the
amount of maternal separation and experimenter handling re-
ceived by the Novel and Home animals. This method allowed us
to discover that novelty exposure alone was sufficient to trigger
subsequent behavioral and neurophysiological changes that ulti-
mately led to an enhanced social recognition memory. Maternal
separation and experimenter handling per se were not necessary
for this enhancement. As in all developmental studies, the initial
treatment is inherently separated in time from the subsequent
assessment at different ages. Therefore, neonatal novelty expo-
sure will undoubtedly have continuing complex dynamic inter-
actions with numerous environmental and biological factors,
such as dampup social interaction (Liu et al., 1997; Denenberg,
1999) and the aging process (Meaney et al., 1988). It is not known
from the present study whether the dams responded differently
toward the Novel and Home pups within a given litter. If prefer-
ential maternal treatment of the Novel pups does occur, the brief
novelty exposure remains the trigger of such maternal discrimi-
nation. The mild early stimulation of the stress response system,
afforded by the neonatal novelty exposure procedure, may initi-
ate the early programming of adult stress response to novelty
(Dallman, 2000), which in turn can affect social memory.
Modulation of social recognition by changes in the HPA axis
Although corticosterone is known to affect memory and synaptic
plasticity (for reviews, see McEwen and Sapolsky, 1995; Lupien
and McEwen, 1997; de Kloet et al., 1999), the role of the HPAaxis
in social recognition has not been explored previously. In this
study, we found that brief neonatal exposure to a new cage alone
can reduce adult basal blood concentration of corticosterone ap-
proximately one and one-half years later. This finding is consis-
tent with findings from neonatal handling (Levine, 1957, 1972;
Meaney et al., 1988; Meaney et al., 1996), in that both types of
early life stimulation were effective in altering HPAfunction. It is
also consistent with the increased sensitivity to corticosterone
modulation in the neonatal novelty-exposed rats (Zou et al.,
2001) and with the increased glucocorticoid receptor concentra-
tion in the handled rats (Meaney et al., 1988). These changes at
the levels of circulating corticosterone and glucocorticoid recep-
tor concentration suggest that early life stimulation may result in
a more effective feedback control of the HPA axis (Sapolsky,
1992).
Exposure to corticosterone can affect both synaptic plasticity
(de Kloet et al., 1999) and the sensitivity to corticosterone mod-
ulation in the hippocampus (Meaney et al., 1996), a structure
which has been suggested recently to play a role in social recog-
nition (Kogan et al., 2000; Bannerman et al., 2002; but see Ban-
nerman et al., 2001 for negative results). Indeed, neonatal novelty
exposure, which reduced adult basal corticosterone concentra-
tion, also increased hippocampal synaptic plasticity (Tang and
Zou, 2002). Furthermore, it is known that moderate levels of
adrenal steroids are associated with enhanced synaptic plasticity,
whereas levels that are either too high or too low are associated
with lesser plasticity (Diamond et al., 1992; Pavlides et al., 1994,
1995). Thus, a more effective feedback control of the HPA axis,
indicated by the relatively low level of basal corticosterone con-
centration, is most likely to help maintain a moderate level of
corticosterone during times of stress and thus facilitate synaptic
plasticity, which in turn may mediate the observed enhancement
in social recognition memory.
Modulation of social memory by multiple hormonal systems
In addition to corticosterone, the peptides vasopressin and oxy-
tocin are known to affect social recognition memory (Dantzer et
al., 1987; Insel, 1992; Ferguson et al., 2001). Because both vaso-
pressin and oxytocin affect the HPA axis (DeVries, 2002), the
effects of vasopressin and oxytocin treatment on social memory
may be mediated by changes in the HPA axis. First, vasopressin
can influence the final output of the HPA axis by stimulating the
secretion of adrenocorticotropic hormone (ACTH) (Gillies et al.,
1982) and by potentiating the ACTH-releasing activity of
corticotropin-releasing factor (CRF) (Whitnall, 1989). In con-
trast, oxytocin induces a suppression of CRF (Neumann et al.,
2000), ACTH (Gibbs, 1986), and corticosterone release (Windle
et al., 1997). Second, neonatal handling resulted in decreases in
both basal vasopressin and CRF in the median eminence (Viau et
al., 1993) as well as a decrease in circulating corticosterone con-
centration. Manipulations that increased oxytocinproduced very
similar effects on social behavior, as did those that decreased
corticosteroid concentrations (Williams et al., 1994; DeVries et
al., 1995; Carter, 1998; Cho et al., 1999). These complex interac-
tions between vasopressin, oxytocin, and the HPA axis suggest
8258 J. Neurosci., September 10, 2003 23(23):8254 8260 Tang et al. Novelty, Social Memory, HPA, and Lateralization
that social recognition can be modulated by concentration
changes in multiple hormonal and transmitter systems.
Brain asymmetry modulates social recognition
We found that neonatal novelty exposure led to an increase in
right-turn bias. Because a right turn is typically associated with a
stronger push by the contralateral, or left paw (Tang and Reeb,
2003), an increase in right-turn preference therefore suggests an
increase in right-brain dominance. This interpretation is consis-
tent with an increase in right-brain dominance found in rats that
experienced neonatal stimulation (Denenberg et al., 1978; Ver-
stynen et al., 2001; Tang and Verstynen, 2002; Tang, 2003). It has
been suggested that brain asymmetry may offer adaptive advan-
tages to anorganism(Gunturkun, 2000; Vallortigara and Bisazza,
2002). Neonatal handling resulted in both right-hemisphere
dominance (Denenberg et al., 1978) and improved spatial learn-
ing (Meaney et al., 1988; Aguilar et al., 2002; Fernandez-Teruel et
al., 2002). Similarly, neonatal novelty exposure led to right dom-
inance in anatomical (Verstynen et al., 2001) and neurophysio-
logical (Tang, 2003) measures and an enhanced spatial working
memory and retention of a stimulus-reward relationship (Tang,
2001). This parallel of improved learning and increased right
dominance was once again found in the present study (both a
right-turn asymmetry and social memory were increased by the
neonatal novelty exposure). Furthermore, individual differences
in short-term social recognition memory were associated with
individual differences in right-turn preference, similar to the
finding from chicks (Vallortigara, 1992). These associated
changes provide support for the hypothesis that cerebral asym-
metry may be an important source of influence on the learning
capacity of an animal.
Summary
The present study examined the effects of early life experience on
adult social recognition memory within a broader context of
HPA regulation and brain asymmetry. Methodologically, we in-
troduced two experimental procedures: a novel social recogni-
tionmemory paradigmthat uses the retroactive interference phe-
nomenon as an additional probe to measure long-term social
recognition memory and the neonatal novelty exposure proce-
dure that reduces the number of factors that confound each other
in the original neonatal-handling method. Theoretically, our
findings: (1) broadened the impact of mild neonatal stimulation
fromthe explicitly stressful learning situations into the domainof
social cognition, (2) demonstrated an enhancement in adult so-
cial recognition memory inducible by transient and remote early
life experience, and (3) revealed parallel changes in HPA regula-
tion measured as a reduction in basal stress hormone corticoste-
rone concentration and an increase in brain asymmetry indexed
by a right-turn preference. These results add to the five decades of
handling literature by demonstrating the importance of seem-
ingly trivial early life events in adult social cognition.
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