2006, Brain and Beh Dev

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Dev Psychobiol. 2006 November ; 48(7): 583–602.
The International Society for Developmental Psychobiology

Annual Meeting Symposium: Impact of Early Life Experiences on
Brain and Behavioral Development
Regina Sullivan and Donald A. Wilson

Department of Zoology University of Oklahoma Norman, OK 73072
Joram Feldon, Benjamin K. Yee, and Urs Meyer
Laboratory of Behavioral Neurobiology ETH Zurich, Switzerland
Gal Richter-Levin, Avital Avi, and Tsoory Michael
Department of Psychology Faculty of Social Sciences and the Brain and Behavior Research Center,
University of Haifa, Hafia, Israel
Michael Gruss, Jörg Bock, Carina Helmeke, and Katharina Braun

Department of Zoology and Developmental, Neurobiology, Institute of Biology, Otto-von-Guericke
University Magdeburg, Magdeburg, Germany
Abstract
Decades of research in the area of developmental psychobiology have shown that early life experience
alters behavioral and brain development, which canalizes development to suit different environments.
Recent methodological advances have begun to identify the mechanisms by which early life
experiences cause these diverse adult outcomes. Here we present four different research programs
that demonstrate the intricacies of early environmental influences on behavioral and brain
development in both pathological and normal development. First, an animal model of schizophrenia
is presented that suggests prenatal immune stimulation influences the postpubertal emergence of
psychosis-related behavior in mice. Second, we describe a research program on infant rats that
demonstrates how early odor learning has unique characteristics due to the unique functioning of the
infant limbic system. Third, we present work on the rodent Octodon degus, which shows that early
paternal and/or maternal deprivation alters development of limbic system synaptic density that
corresponds to heightened emotionality. Fourth, ajuvenile model of stress is presented that suggests
this developmental period is important in determining adulthood emotional well being. The approach
of each research program is strikingly different, yet all succeed in delineating a specific aspect of
early development and its effects on infant and adult outcome that expands our understanding of the
developmental impact of infant experiences on emotional and limbic system development. Together,
these research programs suggest that the developing organism’s developmental trajectory is
influenced by environmental factors beginning in the fetus and extending through adolescence,
although the specific timing and nature of the environmental influence has unique impact on adult
mental health.
Correspondence to: R. Sullivan, E-mail: rsullivan@ou.edu

Contract grant sponsor: German Science Foundation (DFG); State of Saxony-Anhalt, VolkswagenStiftung, German-Israeli Foundation
(GIF); ETH Zurich, NCCR: Neural Plasticity and Repair; Swiss National Science Foundation; NIH-NICHD; OCAST; The Israel
Foundation Trustees; NARSAD Independent Investigator Award
Sullivan et al. Page 2
Keywords
development; learning; stress; juvenile; infant; schizophrenia; limbicsystem; amygdala; olfaction;
maternal deprivation
INTRODUCTION
Over half a century ago, developmental psychobiologists demonstrated the profound, enduring
effects of early life experience on behavioral development using a rodent model (Denenberg,
1963;Greenbough, 1975;Levine, 1962;Turkewitz, Gordon, & Birch, 1965). This work clearly
demonstrated the interplay between an organism’s genes and the environment, which produces
a bidirectional cascading interaction between genes and environment (Schneirla, 1966). This
work was quickly replicated in nonhuman primate models (Harlow & Harlow, 1965;
Levine ;Suomi, Harlow, & Domek, 1970) and applied to humans (Ainsworth, 1969;Bowlby,
1965). This research has profoundly influenced how we think about child development. It is
now clear that early life experiences canalize behavioral development and initiate a
developmental trajectory that predisposes one to physical and psychiatric health or illness. A
theoretical framework that guides much developmental work is the assumption that early life
events enable the infant to form characteristics that will be valuable for the environment it is
likely to encounter in adulthood. This process must occur within a behavioral system that is
designed specifically to enable the infant to cope with the unique environmental demands of
infancy. Thus, while the infant must modify its behavior to cope with the demands of infancy,
such as learning about its caregiver and finding the nipple for nursing, the brain is being
organized for an environment that the infant has not yet encountered. Thus far, behavioral
literature suggests that a stressful early life prepares infants for a stressful adult life. However,
early life experiences can also increase the probability of diseases that are not adaptive and do
not prepare the infant for adult life, such as the long-term disability caused by schizophrenia.
The overriding theoretical commonality of both pathological and adaptive outcomes is that
complex interactions between genes and the environment at specific times in development
result in specific outcomes. Remarkably, this is the same framework that guided developmental
research decades ago, although current methodological techniques have begun to identify
specific genetic and neural mechanisms that produce specific behavioral endpoints.
Particularly, the development of new and powerful techniques to monitor physiological,
cellular, and molecular events has begun to highlight mechanisms of early experiential effects.
These advances have permitted the integration of our existing behavioral understanding with
anatomical, physiological, cellular, and molecular processes that underlie behavioral
development. Understanding the mechanisms that “decide” and control developmental
trajectory is necessary for successful childrearing, as well as therapeutic intervention to

ameliorate or attenuate mistakes in gene expression or a harsh environment.
Unique problems are encountered by researchers when assessing infant development and adult
outcome. The infant brain is not an immature version of the adult brain; rather it is designed
to function within the unique ecological niche of infancy. For example, while the infant must
have a neurobehavioral repertoire to optimize finding a nipple with milk, the adult must have
a neurobehavioral repertoire optimizing foraging for food. While both systems have the similar
end result of procuring food, striking differences are found with respect to sensory information
integration with past experiences and learning, as well as the motor output.
Here, we present four different research programs that demonstrate the intricacies of early
environmental influences on behavioral and brain development in both pathological and normal
development. The approach of each research program is strikingly different, yet all succeed in

delineating a specific aspect of early development and its effects on infant and adult outcome
that expand our understanding of developmental impact of infant experiences on emotional
and limbic system development.
PRENATAL IMMUNOLOGICAL PRECIPITATION OF MAL-

NEURODEVELOPMENT: RELEVANCE FOR SCHIZOPHRENIA AND BEYOND
Research from the laboratory of Joram Feldon at the Swiss Federal Institute of Technology
Zurich assesse: environmental effects on development during the fetal period, eloquently
illustrating that early life in utero represents a period of unique vulnerability with potentially
longlasting effects on mental health. Disturbances directed at the maternal host can lead to
direct physiological changes in the fetal environment when the fetus is undergoing rapid
development, notably in the central nervous system. This is supported by epidemiological
studies showing that maternal bacterial and viral infections during pregnancy are linked to a
number of neuropsychiatric disorders with a presumed neurodevelopmental origin, including
schizophrenia (Brown et al., 2004a;Mednick, Machon, Huttunen, & Bonett, 1988;O’Callaghan
et al., 1994), autism (Miller et al., 2005;Rodier & Hyman, 1998) and mental retardation
(Rantakallio & von Wendt, 1985;Revello & Gerna, 2004). Although the precise mechanisms
underlying these epidemiological associations remain to be fully worked out, one favored
hypothesis suggests that the maternal immune response to the infectious process may be the
critical causative event, as the precise identity of the infectious agents do not seem to matter
(Brown et al., 2004a,b;Buka et al., 2001;O’Callaghan et al., 1994;Patterson, 2002;Pearce,

2001).
The Cytokine Hypothesis of the Maternal Infection Model of Schizophrenia

Recently, several research groups, including Feldon and colleagues at ETH Zurich, have
brought this epidemiologically motivated hypothesis into the realm of laboratory
experimentation by establishing an animal model of prenatal maternal infection in mice for the
evaluation of adult brain and behavioral pathology with an initial focus on schizophrenia
(Meyer, Feldon, Schedlowski, & Yee, 2005,2006a;Meyer et al., 2006b,Meyer, Schwendener,
Feldon, & Yee, 2006c;Ozawa et al., 2006;Shi, Fatemi, Sidwell, & Patterson, 2003;Zuckerman,
Rehavi, Nachman, & Weiner, 2003;Zuckerman & Weiner, 2003,2005). A single intravenous
injection of the inflammatory agent PolyI:C (polyriboinosinic-polyribocytidilic acid) to
pregnant dams was used to induce an acute immune response in the maternal host in activating
the release of a host of immunologically relevant cytokines.
Cytokines are low molecular-weight proteins, which function as the main chemical mediators
of the host’s immune response against various infectious agents (Borish and Steinke,
2003;Curfs, Meis, & Hoogkamp-Korstanje, 1997). Besides their crucial roles in the recruitment
and proliferation of T- and B-lymphocytes in the periphery, cytokines also modulate the
survival and differentiation of neurons (Ling, Potter, Lipton, & Carvey, 1998;Marx, Jarskog,
Lauder, Lieberman, & Gilmore, 2001;Potter, Ling, & Carvey, 1999) as well as the growth and
organizational complexity of dendrites (Gilmore, Jarskog, Vadlamudi, & Lauder, 2004).
Alterations in cytokine levels are expected to exert multiple effects on the developing central
nervous system. Amongst the diverse repertoire of cytokine responses associated with an
infection, elevation of proinflammatory cytokines in the maternal host, and subsequently in
the fetal environment, has been considered as the key trigger for malneurodevelopment in the
developing fetus (Brown et al., 2004b;Buka et al., 2001;Gilmore & Jarskog, 1997;Patterson,
2002;Pearce, 2001). The faulty development of the central nervous system initiated in utero
may remain relatively silent and only lead to the overt psychopathological traits in later life.
This is a hallmark of the ontogenesis of several psychiatric disorders, including schizophrenia,
of which early life events as well as genetic predisposition are of etiological relevance (Bracha,

Torrey, Bigelow, Lohr, & Linington, 1991;Bracha, Torrey, Gottesman, Bigelow, & Cunniff,
1992;Gilmore et al., 1996;Jakob & Beckman, 1986;Murray, Jones, & O’Callaghan, 1991).
Maternal Immune Challenge in Pregnancy Leads to Multiple Psychopathology

There is considerable experimental evidence in animals supporting a causal link between
prenatal immune challenge and the postpubertal emergence of multiple brain and behavioral
abnormalities. The multiplicity of psychopathology observed in the adult offspring readily
suggests that the perturbations caused by maternal immune challenge are widespread, and
fundamental to a range of normal psychological functions. Characterization at the behavioral
phenotypic levels thus demands the use of multiple behavioral paradigms, as important factors
such as the intensity and timing of the immune challenge (Meyer et al., 2005,2006a,b,c) may
not reveal their impacts unless a sufficient comprehensive portrayal of the adult
psychopathology is achieved (to be discussed later).
Amongst the multitude of behavioral, cognitive and psychopharmacological deficits revealed,

many could be related to the endophenotypes of schizophrenia and related disorders. Psychosis-
like abnormalities have been detected in adult offspring following prenatal exposure to
bacterial endotoxin (Borrell, Vela, Arévalo-Martin, Molina-Holgado, & Guaza, 2002;Fortier,
Joober, Luheshi, & Boksa, 2004;Golan, Lev, Hallak, Sorokin, & Huleihel, 2005), human
influenza virus (Shi et al., 2003), or the viral mimic PolyI:C (Meyer et al., 2005,
2006a,b,c;Ozawa et al., 2006;Zuckerman et al., 2003;Zuckerman & Weiner, 2003,2005). The
wide spectrum of behavioral and cognitive dysfunctions observed in offspring subjected to

prenatal immune activation included deficits in exploratory behavior and social interaction
(Meyer et al., 2005,2006b;Shi et al., 2003), deficiency in sensorimotor gating in the form of
reduced prepulse inhibition (Borrell et al., 2002;Meyer et al., 2005; Ozawa et al.; Shi et al.,
2003), impaired selective learning (Meyer et al., 2005,2006a,c;Zuckerman et al.,
2003;Zuckerman & Weiner, 2003,2005), perseverative behavior (Meyer et al., 2006b), as well
as working memory deficits in the watermaze (Meyer et al., 2005) and impaired cognitive
performance in novel object recognition tasks (Ozawa et al., 2006). Adult animals subjected
to prenatal immune activation also display an enhanced locomotor reaction to indirect
dopamine-receptor agonists such as D-amphetamine and methamphetamine (Meyer et al.,
2005;Ozawa et al., 2006;Zuckerman et al., 2003) and the noncompetitive NMDA-receptor
antagonist, dizocilpine (MK-801) (Meyer, Schwendener, Feldon, Yee, unpublished
observation;Zuckerman & Weiner, 2003).
The responsiveness of these various behavioral deficits to known antipsychotic drug (typical
and atypical neuroleptics) treatment has also been examined. Normalization of behavioral and
cognitive performance in prenatally immune challenged offspring has been demonstrated in
the paradigms of prepulse inhibition (Borrell et al., 2002;Shi et al., 2003), latent inhibition
(Zuckerman et al., 2003;Zuckerman & Weiner, 2003,2005), and novel object recognition task
(Ozawa et al., 2006). These findings have added to the predictive and construct validity of the
model.
Notably the maternal infection model captures the expectation of the neurodevelopmental
perspective of schizophrenia in that the underlying pathophysiological and neuropathological
mechanisms are progressive in nature. The affected subjects do not exhibit the full range of
functional impairments until after puberty (Meyer et al., 2006c;Ozawa et al., 2006;Zuckerman
et al., 2003;Zuckerman & Weiner, 2003) even though signs of neuroanatomical changes could
be identified before adulthood (Fatemi et al., 1999,2002;Meyer et al., 2006c). The model thus
offers the possibile identification of prodromal psychosis and the investigation of possible
prevention interventions (Remington & Shammi, 2004), highlighting the potential of cytokine-
oriented intervention as preventive treatment.

The Psychopathological Profile Depends on the Precise Time of Maternal Infection

The impact of maternal infection on neurodevelopment is expected to vary during the course
of fetal life. First, the physiological changes experienced by the mother during the course of
pregnancy can influence the precise pattern of immune responses (Entrican, 2002;Sargent,
1993). Second, it is expected that the vulnerability of the fetus to inflammation-mediated
malneurodevelopment critically depends on the precise stage of prenatal development. In
relation to schizophrenia, there is a debate over the suggestion that the second trimester of
human pregnancy confers the maximal risk for schizophrenia in the resultant offspring
(reviewed in Cannon & Clarke, 2005;Machón, Mednick, & Huttunen, 1995;McDonald &
Murray, 2000;McGrath, Castle, & Murray, 1995). Although there is support that maternal
infection subsequent to the second trimester is not involved ( Machón et al.; McGrath et al.,
1995), several studies have questioned if the second trimester is critical (e.g., Crow & Done,
1992;Mino, Oshima, Tsuda, & Okagami, 2000;Morgan et al., 1997;Selten & Slaets, 1994).
Indeed, serologic evidence of prenatal infuenza in the etiology of schizophrenia has indicated
that maternal infection particularly in the first trimester is associated with a higher incidence
of schizophrenia in the offspring (Brown et al., 2004a). Hence, maternal infections over a more
extended period, from early- to mid-pregnancy, can increase the risk of schizophrenia.
Experiments have been conducted in Feldon’s laboratory to address this issue by comparing
the phenotypic profiles of offspring having experienced maternal PolyI: C-induced immune
activation on gestation days (GD) 6, 9, 13, and 17 (Meyer et al., 2006a,b). In one study, they
demonstrated a loss of latent inhibition in adult mice following prenatal immune challenge on
GD 6 and GD 9; this effect was marginal in mice treated on GD 13, and was absent in mice
treated on GD 17. Hence, the vulnerability of latent inhibition impairment appears to decrease
as a function of gestation days. On the other hand, the expression of the US-preexposure effect
was abolished by the prenatal immunological manipulation regardless of the precise time of
maternal immune challenge (Meyer et al., 2006a). In another study, Meyer et al. (2006b) added
to their initial findings by demonstrating a functional double dissociation between prenatal
immunological stimulation on GD 9 and on GD17: the former suppressed spatial exploration,
while the latter led to response perseveration in discrimination reversal (Meyer et al., 2006b).
Maternal immune activation in early, mid, and late pregnancy can indeed lead to divergent
behavioral dysfunction. However, the characterization should not be considered as “all-or-
none”: a distinct pattern of psychopathology can be expected depending on the time of maternal
immune activation. A similar conclusion can be derived from analyses at the immunological
and anatomical levels (see Meyer et al., 2006b). However, the data are in support for the general
impression that comparison between immune activations at early/mid and at late pregnancy
yielded qualitatively more distinct patterns of pathology than the comparison between early
and mid-pregnancy treatment. The conclusion based on the PolyI:C maternal infection model
indicates that early/mid and late gestation periods in mice correspond to two windows with
differing vulnerability to adult behavioral dysfunction, brain neuropathology in early

adolescence, and of the acute cytokine responses in the fetal brain.
Feldon and colleagues also raised the interesting hypothesis that the behavioral contrast
between early/mid and late pregnancy immune activation may be related to differing symptom
clusters of schizophrenia. It is known that schizophrenia is associated with a myriad of
psychological and cognitive abnormalities. Symptoms tend to segregate into clusters (e.g., the
positive-negative symptoms dichotomy in schizophrenia), which appear to follow separate
developmental courses (Gross, 1997;Murray, O’Callaghan, Castle, & Lewis, 1992;Sporn et
al., 2004). They also respond differentially to distinct classes of pharmacotherapy (Kapur and
Remington, 2001;Maguire, 2002;Miller, 2004), and are suggested to be associated with
dysfunctions localized to discrete brain regions (Liddle et al., 1992). The possibility that these
symptom clusters or even subtypes of schizophrenia may correspond to distinct

neurodevelopmental disturbances has been suggested based on genetic and epidemiological

evidence (e.g., Cannon et al., 2003;Stöber, Franzek, Beckmann, & Schmidtke, 2002).
One hypothesis emerging from this large collection of data set postulates that the distinction
between early/mid and late pregnancy immune challenge may capture the positive-negative
dichotomy of schizophrenia. Experimental data available so far readily indicate that prenatal
immune challenge at early/mid pregnancy in mice leads to a variety of abnormalities associated
with positive symptoms of schizophrenia, including increased sensitivity to acute
dopaminergic stimulation (Meyer et al., 2005), loss of latent inhibition (Meyer et al., 2005,
2006a), and deficits in sensorimotor gating (Meyer et al., 2005; Meyer, Yee, Feldon,
unpublished observation), while prenatal immune activation on late gestation particularly leads
to the emergence of behavioral, cognitive, and pharmacological dysfunctions associated with
negative symptoms such as perseverative behavior (Meyer et al., 2006b), and increased
sensitivity to NMDA-receptor antagonism (Meyer, Feldon, Yee, unpublished observation; see
also Zuckerman & Weiner, 2005). Further examination and evaluation of the structural and
functional consequences of in utero immune challenge at different times of gestation may
provide important insight into the fundamental neuroimmunological mechanisms underlying
the segregation of positive and negative symptoms in schizophrenia from a
neurodevelopmental point of view.
Maternal–Infant Interaction in Early Postnatal (Preweaning) Life in the Infection Model of

Schizophrenia
Feldon and colleagues have also extended their studies to examine the possible contributions
of early postnatal mother–infant interaction following prenatal maternal infection. Until now,
the putative roles of postnatal maternal factors have received little attention in the causal
relationship between prenatal immune challenge and the post-pubertal emergence of
psychosis-related abnormalities.
It is known that immunological stimulation is strongly associated with the activation of the
stress response axes, including the hypothalamic-pituitary-adrenal (HPA) axis (Goebel et al.,
2002;Haddad, Saade, & Safieh-Garabedian, 2002;Webster & Sternberg, 2004), and maternal
physiological and/or psychological stress during pregnancy has been shown to alter postpartum
maternal behavior (Brayden, Altemeier, Tucker, Dietrich, & Vietze, 1992;Meek, Dittel,
Sheehan, Chan, & Kjolhaug, 2001;Patin et al., 2002). However, it has not yet been shown
whether gestational immunological stress is associated with alterations in postpartum maternal
factors that may result in an unfavorable rearing environment for neonatal development. Since
the rodent and primate brain undergoes significant development and maturation in early
postnatal life, disruption of the intricate mother–infant relationship as a result of gestational
immune challenge may confer additional risk for the early-life organism to develop psychosis-
related behavior in later life. Indeed, human adoption studies have demonstrated that adoptees
with a high-genetic risk for schizophrenia are significantly more sensitive to adverse rearing
patterns in adoptive families than are adoptees at low risk (Mäki et al., 2005;Tienari et al.,
2004;Wahlberg et al., 1997), who therefore are more prone to the emergence of psychosis in
later life. This is in full agreement with the hypothesis that the early external environmental
factors in combination with genetic predisposition determine the eventual expression of the
diseased phenotype (Cardno et al., 1999;Franzek & Beckmann, 1996;Petronis, 2004;Tsuang,
2000).
In the first attempt to dissect the prenatal and postnatal maternal contributions in the infection
model of schizophrenia and related disorders in mice, Feldon and colleagues used a
crossfostering design to directly compare the relative impact of mid-pregnancy inflammatory
events and postnatal maternal factors on the emergence of selective learning deficits in juvenile
and adult offspring (Meyer et al., 2006c). The authors found that prenatal immunological

stimulation led to the postpubertal emergence of selective learning deficits regardless of the
postnatal adoption procedure, that is, latent inhibition deficiency was equally observed in
prenatally immunechallenged offspring that were adopted by control or immune-stimulated
surrogate mothers. This readily suggested that the adoption of prenatally immune challenged
neonates by control surrogate rearing mothers did not confer any protective effects against the
subsequent emergence of selective learning deficits. Hence, inflammation-mediated disruption
of fetal brain development as such is sufficient to induce significant adult psychopathology
(Brown et al., 2004a,b;Gilmore & Jarskog 1997;Patterson, 2002;Pearce, 2001).
In addition, Meyer et al. (2006c) went on to show that control neonates born to nonchallenged
dams but raised by immune-challenged surrogate mothers displayed learning disabilities (in
the form of impaired aversive conditioning) upon reaching the juvenile and preadolescent stage
of development. This suggests that immunologically induced stress (e.g., activation of the HPA
axis and subsequent sickness behavior) experienced during pregnancy may affect maternal
postpartum factors in such a way that neonatal adoption by immune-challenged surrogate
mothers is sufficient to induce maturationindependent learning disabilities in the fostered
offspring. Since the association of the adoption by immunechallenged surrogate mothers and
the emergence of learning impairments may have important implications in the area of
developmental psychobiology, further effort is warranted to investigate more thoroughly the
neurodevelopmental and neurophysiological consequences of this crossfostering procedure.
One clear approach would be to obtain direct measures of postpartum maternal behavior and
physiology following immunological stress during pregnancy in order to identify the critical
pathological factors in postnatal mother–infant interaction.
According to the analysis of the relative contributions of pre- and postnatal factors by Feldon
and colleagues, inflammation-mediated events occurring during prenatal fetal brain
development may be critical in precipitating adult deficit in selective learning (perhaps more
closely related to positive symptomatology), while postnatal maternal factors may act in
precipitating general learning disabilities, reflecting a more global deterioration of brain
function (and perhaps more closely related to negative symptomatology).
Summary
An integrative summary of the data from the laboratories of Feldon and others is schematized
in Figure 1, which also includes specific working hypotheses addressed by on-going research.
The prenatal immune activation in rodents represents a novel and powerful class of
environmental-neurodevelopmental animal models to study the disease process of
schizophrenia and related disorders. It enjoys a high level of face, construct, and predictive
validity, with intrinsic epidemiological and immunological relevance known to the disease. Its
formulation is also unique in not being based on any specific neurological features of the
disease, and thus does not rely on any specific presumption of the disease’s neural substrate.
The fact that the critical experimental manipulation is conducted prenatally allows a
multifaceted, longitudinal monitoring of the disease process as it unfolds during the course of
neurodevelopment from childhood to adulthood, and the concomitant evaluation of the
influence of external environmental factors. It is a clear illustration of how early life experience
in the form of a single welldefined biologically relevant manipulation can, over development
of time, cumulate into specific psychopathology and pathophysiology in adulthood
experienced during pregnancy may affect maternal postpartum factors and thus interfere with
normal maternal–infant interactions in early postnatal life. This may modulate postnatal brain
maturation processes and additionally induce behavioral and cognitive dysfunctions in later
life.

RESEARCH CORTICAL AND LIMBIC SENSORY PROCESSING DURING

ONTOGENY
Recent work in Regina Sullivan’s lab suggests that an infant’s unique processing of sensory
information simultaneously shapes both the infant’s behavior to its present environment, and
also sends the limbic system on a trajectory to prepare it for adult life (Sullivan et al.,
2000;Morriceau & Sullivan 2006). A major focus of this work has been an exploration of the
experience-dependent emergence of amygdala (and more generalized limbic system) function
on behavior in mother–infant interactions. The limbic system integrates physiological,
emotional, and memorial components of an individual’s response to its sensory environment.
As in other brain systems, limbic system function, and thus this integration, is shaped by early
experience. A number of labs have examined the development of limbic system function
through, for example, description of the ontogeny of hippocampal synaptic plasticity, the
ontogeny of fear or stress responses, or the ontogeny of associative memory—all approaches
primarily representative of limbic system intrinsic activity and output.
A new collaborative effort between the laboratories of Donald Wilson and Regina Sullivan at
the University of Oklahoma, however, has focused on understanding ontogeny of limbic system
input, with a goal of understanding how limitations or unique characteristics of neonatal
sensory processing may shape limbic system function and development. In rodents, the single
largest sensory input to the limbic system is olfaction, with the olfactory cortex, amygdala, and
hippocampus only two to three synapses from the nose. The results to date suggest that while
sensory input can drive limbic system neurons early in development, the dramatic change in
temporal structure of these responses with age may influence processing by limbic circuits.
Odors are transduced by a large array of olfactory receptor neurons in the nose, each of which
appears to express a single member of the large (1,000 member) family of G-protein coupled
olfactory receptor genes (Buck, 1996). Most naturally occurring odors are complex mixtures
composed of many different molecules, each activating different olfactory receptors. Thus, we
have no individual receptor for “coffee” but rather synthesize the multiple molecular features
of that stimulus into a unitary percept, or odor object. This process has been hypothesized to
be similar to visual object or face recognition (Wilson & Stevenson, 2003). Processing of odor
feature information is refined by the local circuits of the olfactory bulb, while synthesis is
believed to occur primarily within the primary olfactory (piriform) cortex.
While there is a strong spatial dimension to odor feature encoding within the olfactory bulb
(Leon & Johnson, 2003), the temporal characteristic of neural firing and subthreshold activity
may also serve as an important factor in encoding odor identity. As in many sensory systems,
neural activity within the olfactory bulb and cortex is oscillatory, in part due to the cyclic nature
of respiration, but also due to local inhibitory-excitatory circuit interactions that create medium
(10–40 Hz) and high frequency (40–90 Hz) oscillations (Freeman, 2000). The role of these
oscillations in olfaction is not known, but evidence suggests they may (1) serve as a source of
synchrony to finely control timing of action potentials in disparate neurons (Laurent et al.,
2001), (2) serve as a mechanism to enhance synaptic plasticity within the olfactory system or
downstream of the olfactory system, and thus store memories of familiar odor input patterns
(Haberly, 2001), and/or (3) reflect higher order feedback to the olfactory system, signaling
important or learned stimuli (Kay, Lancaster, & Freeman, 1996).
Of importance to the developmental discussion here is the fact that expression of high-
frequency oscillations (gamma frequency oscillations) are heavily dependent on local
GABAergic interneurons, especially within the olfactory bulb. Despite the early emergence
and critical role of olfaction in the neonatal rodent, these interneurons—granule cells—do not
develop until relatively late postnatally (peak neurogenesis at around postnatal day 21; Brunjes

& Frazier, 1986). Given the hypothesized functions of circuit oscillations, we predicted that in
very young rat pups with very few granule cells, olfactory system temporal processing of odors
should be impaired, with concomitant impairment in odor discrimination/ perception. In fact,
rat pups during the first postnatal week had no detectable odor-evoked gamma frequency
oscillations in either their olfactory bulb or piriform cortex (Figure 2 Fletcher, Smith, Best, &
Wilson, 2005). However, odor discrimination of molecularly dissimilar (e.g., banana and
peppermint) or similar (ethyl butyrate and ethyl proprionate) was comparable between 1-week
and 3-week old pups (Fletcher et al., 2001,2005.). These results suggest that high-frequency
oscillations are not critical for odor discrimination per se. However, we are currently examining
how the emergence of mature temporal response patterns over early development influences
synaptic plasticity within the olfactory system and its direct targets (e.g., the amygdala).
A second process involved in olfactory perception is habituation—the ability to filter out

background and/or stable inputs while remaining response to new, dynamic stimuli. In
olfaction, habituation may also be important for figure-ground separation where a target odor
presented against a background is perceived as that target alone, and not a mixture of the two.
Work in our lab has demonstrated that odor habituation is largely a cortical phenomenon,
mediated by depression of cortical afferent synapses (Best & Wilson, 2004;Wilson, 1998).
Pharmacological blockade of this synaptic depression prevents adaptation of cortical odor
responses (Best & Wilson), and habituation of both odor-evoked reflexes (Best, Thompson,
Fletcher, & Wilson, 2005) and odor investigation (Yadon & Wilson, 2005).
Given that synaptic activity plays a critical role in shaping the development of local circuits in
the brain (e.g., Hubel & Wiesel, 1970), the ability to filter relatively unimportant information
may be just as critical during early development as it is in mature organisms. Our recent work
has demonstrated that habituation of an odor-evoked reflex is expressed normally by at least
the first postnatal week in rats (Fletcher & Wilson, 2001), as is the synaptic mechanisms of
cortical adaptation (Thompson, Best, & Wilson, 2005).
Together, these two series of studies suggest that understanding limbic system function during
development, and the effects of early experience on later limbic system function must take into
account the unique features of sensory input occurring at that time. Thus, while both a neonate
and an adolescent may share some similar olfactory processing abilities, the fine structure of
sensory input to the limbic system is not the same in these two organisms. How these differences
in sensory input limit or extend immediate and eventual limbic system function are currently
being explored.
EARLY EMOTIONAL MEMORIES ARE STORED IN THE BRAIN

Research from the laboratory of Katharina Braun at the University of Magdeburg, Germany,
suggests that deprivation from parental care can dramatically alter emotional development.
Whereas the basic wiring of the mammalian central nervous system is genetically
preprogrammed, its fine tuning throughout the phases of infancy and childhood is highly
dependent on experience. Experience that is encountered during time windows of elevated
synaptic plasticity “imprint” on this highly adaptive brain substrate and leave their “footprints,”
that is, “carve” templates into limbic synaptic wiring patterns, which will determine emotional
as well as cognitive “grammars” and strategies and thereby optimize or limit cognitive as well
as emotional capacity throughout life.
Although the impact of early environment on the development of behavior has been
acknowledged during the past decades and has been studied extensively by the different
research disciplines of psychology, neurobiology, psychiatry, and neurology, and although our
insight into the molecular and genetic principles of brain development has increased

exponentially in the past decade through the experimental work in the field of neurobiology,
these different sets of knowledge have not yet been conceptually linked. Only the understanding
of the interplay between early experience and the neuron’s molecular machinery will guide us
to understand that early childhood presents itself as an investment opportunity for our society,
and that it takes a well-functioning family and educational system to grow a brain.
The critical impact of the early socio-emotional environment on behavioral development is

well documented by observations from clinical studies, which showed that disturbances or
interruptions of the child–parent interaction lead to behavioral disturbances, including the so-
called hospitalism syndrome, and later can result in severe and permanent deficits in speech
behavior, personality development, intellectual and social capacity, and mental disturbances.
Brain developmental studies indicate that juvenile emotional experience interferes with the
establishment and maintenance of neuronal networks in the developing limbic system.
One important aim of brain development is to learn how to attend effectively to relevant
environmental information (to “essentializa”) and to simultaneously discard all unimportant
data—distinguishing the relevant from the superfluous. Moreover, the brain has to develop an
internal emotional judgment system which controls not only perceptions, but which is also
essential for higher cognitive tasks. The development of higher cognitive and emotional
functions is tightly linked also with respect to their functional representation in the same brain
regions, and thereby determine together the way in which the more mature or adult brain
handles cognitive tasks.
Brain development is driven by a highly complex interaction between genetic disposition and
experienceinduced adaptation of neuronal networks. Experimental research in animal models
reveals that the enrichment and complexity of the environment eventually determines the
complexity of the cellular signal transduction systems in the brain. Pre- and early postnatal
experience and learning events, such as the formation of an attachment to a caregive are
processed by neurons and their synaptic networks during developmental periods of highly
elevated plasticity, during which the neurons (and glia) run their genetic and molecular
machinery at high-activity levels. Thus, early experience and learning events interfere with a
much more dramatic influence on the establishment, refinement, and functional maturation of
neuronal and synaptic networks than learning and memory formation in the more mature, adult
brain.
Impact of Early Emotional Experience on Synaptic Reorganization of Limbic Brain Regions

The balance of the intricate and only poorly understood interaction between genetic and
epigenetic factors shifts during maturation of functional brain systems. Starting at birth, the
sensory, motor and in particular, the emotional experiences are gaining more influence over
the cellular genetic and molecular machinery and thereby refine and optimize the respective
brain systems, and shape the individual’s behavior for coping with the environment in later
life.
Although studies in animal models and in humans have revealed convincing evidence for the
critical impact of neonatal and juvenile emotional experiences, the systematic experimental
analysis has mainly focused on changes of endocrine function and behavior, whereas
comparably little is known about brain functional changes in response to emotional experience
during childhood and adolescence. The early studies of Scheibel, Lindsay, Tomiyasu, and
Scheibel (1975,1976), Rosenzweig and Greenough and colleagues (Rosenzweig & Bennett,
1996;Turner & Greenough, 1985) have shown that the degree of sensory and motor experience
is related to synaptic densities in the sensory and motor cortex areas. For instance, neurons in
the visual cortex of rats which have been raised in an impoverished environment show reduced
dendritic arborization and synaptic density, compared to control animals, which were raised

in an enriched environment. Similar results were obtained in the somatosensory and motor
cortex of monkeys, which during their first 6 months of life had been raised in environments
of different complexity: those animals who had been raised in an impoverished environment
displayed reduced synaptic density (Bryan & Riesen, 1989).
These studies remained restricted to the analysis of developing sensory and motor cortical areas
in relation to sensory and motor activation, and only recently, the impact of neonatal emotional
experience and learning on synaptic development in the limbic system has been discovered.
Experimental analysis in an animal model for filial imprinting (Lorenz, 1935;Hess, 1959), that
is, the very first neonatal emotional learning event in vertebrates including human and
nonhuman primates, which results in the formation of an emotional bond to the mother or
caregiver, has revealed dramatic changes of synaptic connectivity in prefrontal forebrain
regions in relation to this learning process. Domestic chicks, which were imprinted on an
artificial acoustic or visual stimulus representing the mother, showed increasedsynaptic
densities in an associative forebrain region (Horn, Bradley, & McCabe, 1985;Horn, Nicols, &
Brown, 2001) but decreaseddensities of excitatory spine synapses in two other higher
associative forebrain regions (Bock & Braun, 1998,1999a,b;Wallhausser & Scheich, 1987).
The reduction of spine synapses which was observed after acoustic filial imprinting critically
depends on the activation of glutamatergic NMDA receptors (Bock, Schnabel, & Braun,
1997;Bock & Braun, 1999a), and appears to reflect a synaptic network which responds with a
potentiated response upon recall of the learned, emotionally relevant stimulus. In fact, the
successfully imprinted animals respond to the presentation of the learned imprinting stimulus
with enhanced electrical (Bredenkotter & Braun, 1997;Brown & Horn, 1994) and metabolical
(Bock, Wolf, & Braun, 1996;Maier & Scheich, 1983; Wallhausser & Scheich) activity, which
is accompanied by increased release of glutamate (Gruss & Braun, 1996) when the animals
are exposed to the learned acoustic imprinting stimulus. Interestingly, this almost 45% decrease
of excitatory spine synapses in the prefrontal forebrain regions of chicks only occurs if the
animal is given the opportunity to associate the acoustic stimulus with a positive emotional
situation, that is, when it learns that this (initially irrelevant and emotionally neutral) stimulus
represents its mother. Passive acoustic stimulation during which the chick is not allowed to
display a behavioral approach response does not alter spine densities, indicating the critical
importance of the emotional component in this learning-related synaptic reorganization.
Regressive synaptic changes might be a typical characteristic for juvenile imprinting-like

learning as opposed to adult learning, where increased numbers of synapses have been observed
(Kleim et al., 1998;Moser, Trommald, & Andersen, 1994;O’Malley, O’Connell, Murphy, &
Regan, 2000). Similar reductions in dendritic spine density have been observed during and
after sexual (Bischof & Rollenhagen, 1999) and song imprinting (Nixdorf-Bergweiler,
Wallhausser-Franke, & DeVoogd, 1995) in song birds, and in mynah birds who were trained
to imitate human speech (Rausch & Scheich, 1982). The “trick” used by the juvenile brain to
achieve high-speed “turbo” learning appears to be a synaptic selection process, similar to what
has been described for the activity-dependent maturation of sensory cortical regions (Goodman
& Shatz, 1993;Singer, 1995) and the innervation of skeletal muscle fibers (Changeux &
Danchin, 1976). In the course of synaptic selection the initial synaptic composition at birth,
and the abundance of synaptic connections which is built up during late prenatal and early
postnatal periods is selectively pruned during the learning process, and thereby the network is
selectively tuned to the specific emotional experience, which the animal has encountered
during infancy. It is tempting to speculate that this experience-expectant synaptic
reorganization process results in emotional “templates,” which are continuously refined and
adapted in response to emotional experience until adolescence. Neuroanatomical investigations
of Huttenlocher (Huttenlocher, 1979;Huttenlocher & Dabholkar, 1997) and Rakic and
colleagues (Rakic, Bourgeois, & Goldman-Rakic, 1994) in human and nonhuman primates
have clearly shown that each cortical region has specific time windows of synaptic proliferation

and of synaptic pruning, which most likely reflects synaptic reorganization in the course of
experience-dependent or experience-expectant competitive synaptic selection. It appears likely
that this is also the case for limbic regions which are involved in emotional modulation such
as the anterior cingulate and orbitofrontal cortex, nucleus accumbens, and the amygdala. The
biological advantage and the outcome of this synaptic competition mechanism is the optimal
adaptation of functional brain systems to a given environment which thereby increases the
chance for survival and reproduction.
The disadvantage of experience-driven synaptic reorganization lies in the enhanced

vulnerability of brain systems during developmental time periods of pronounced neuronal
plasticity, during which adverse (or the complete lack of) environmental influences, equally
can “imprint” in the brain and most likely result in retarded, malfunctioning, and “defective”
synaptic wiring patterns. Early traumatic experience, such as repeated exposure to brief
separation from the mother or both parents, repeated (unpleasant and mildly painful) injections,
handling, chronic social isolation, or the loss of one parent have also been shown to induce
dramatic region-specific synaptic changes in the developing brain, in particular in limbic
regions.
Investigations in young Octodon degus demonstrated that repeated separation from the parents,
daily saline injections or handling, and deprivation from paternal care alters limbic neuronal
connections. Octodon degus, a semiprecocial lagomorph/rodent that is becoming increasingly
popular as a laboratory animal, displays the same principal brain anatomy as common
laboratory rodents. Compared to laboratory rats or mice this species displays closer similarities
to human and nonhuman primate behavior and development, such as the presence of cortisol
in the blood and the maturity of their sensory systems, which allows them to perceive and
respond to familiar and novel stimuli from their environment immediately after birth. Similar
to human babies (DeCasper & Fifer, 1980), the newborn degu pups learn to recognize and to
respond to their mothers’ vocalizations within the first days of life, and this vocal
communication appears to be an important component for the establishment and maintenance
of the emotional attachment to the parents. Whereas common laboratory rodents appear not to
exhibit a filial attachment of the kind shown, for example, by young primates, in the biparental
species Octodon degus the pups have been shown to develop a strong attachment to both
parents.
Functional imaging studies in 1-week-old degus during acute separation stress identified the
brain areas which are responsive to this type of acute stress. After a 45-min period of separation
from the family and the home cage the stressed animals showed a decreased metabolic activity
in most limbic cortical and subcortical regions, as well as in some sensory cortex areas (Braun
& Bock, 2003). It remains to be determined whether this acute downregulation of brain activity
becomes chronic if the juvenile animals repeatedly or chronically have to cope with separation
stress or social deprivation. This idea would be in line with the hypothesis of a dysmaturational
pathogenesis for hypofrontality, which has been detected in Romanian orphans using the PET
technique (Chugani et al., 2001), as well as in patients suffering from attention deficit
hyperactivity syndrome, schizophrenia, or criminal aggression (Brower & Price,
2001;Manoach, 2003;Raine, Buchsbaum, & LaCasse, 1997;Rubia et al., 1999).
On the cellular and synaptic level it appears likely that this reduction of brain activity during
stressful experience or as a result of deprivation reflects metabolic mechanisms which underlie
experience-dependent (in this case stressdependent) synaptic reorganization. In line with this
idea we found in 21- and 45-day-old degus, which were repeatedly exposed to daily parental
separation during the first three weeks of life significantly elevated (up to 143%) densities of
dendritic spines in the anterior cingulate cortex ( Helmeke, Ovtscharoff, Poeggel, & Braun,
2001a ;Helmeke, Poeggel, & Braun, 2001b;Poeggel et al., 2003a). The repeatedly stressed

animals also showed significantly elevated spine densities on the hippocampal CA1 pyramidal
neurons (up to 109% on the distal apical segments and up to 106% on the basal segment),
whereas significantly reduced spine densities were observed on the granule cell dendrites in
the dentate gyrus (down to 92%) and on the apical dendrites in the medial nucleus of the
amygdala (down to 95%) (Poeggel et al., 2003a). Studies in laboratory rats which experienced
maternal separation between postnatal days 14–16 confirmed the findings in degus, and in
addition revealed a possible link between the synaptic changes and endocrine function (Bock,
Gruss, Becker, & Braun, 2005). When rats are exposed to maternal separation during the stress
hyporesponsive period of the hypothalamic-pituitary-adrenal (HPA) axis no synaptic changes
were observed on layer II/III pyramidal neurons in the anterior cingulate cortex. Thus, the
magnitude and direction of such stress-induced synaptic changes appears not only to depend
on the brain region and cell type, but also on the time during which stress is induced. Rats
which experienced maternal separation between postnatal days 3–5 ended up with fewer
dendritic spines in the anterior cingulate cortex, as opposed to the animals which experienced
the same amount of maternal separation at days 14–16 (Bock et al.). Chronic social isolation
after weaning resulted in reduced numbers of perforated synapses and smaller synaptic contact
zones in the dorso-medial amygdala (Ichikawa, Mastuoka, & Mori, 1993) of rats, whereas an
increased density of dendritic spines was found in the preoptic region of deprived rats (Sanches-
Tosccano, Sanchez, & Garzon, 1991). Furthermore, rats which were exposed to stress in utero
during the last week of gestation (i.e., the pregnant dams were exposed to different types of
stress) showed changes in the density of dendritic spines in the anterior cingulate and
orbitofrontal cortex compared to control animals (Murmu et al., 2006).
On the neurochemical level, neonatal and juvenile exposure to stress and social deprivation
induces changes in the balance of neurotransmitters in the limbic system, in particular of
catecholaminergic systems (Holson, Ali, & Scallet, 1988), which play a major role in the
modulation of emotional responses. Avariety of studies have revealed that the activation of the
HPA-axis, as it occurs, for instance, during the separation from the mother or both parents
(Gruss, Westphal, Luley, & Braun, 2006;Lehmann & Feldon, 2000) and other juvenile and
adult stress paradigms (Kudielka & Kirschbaum, 2005), modulate monoaminergic systems in
adult animals (Fuchs & Flugge, 2002) and also during development. For instance, rats which
have been raised in social isolation display dramatically decreased dopamine metabolites
(Miura, Qiao, & Ohta, 2002). This is in line with anatomical findings in degus and gerbils
which were raised under socially deprived conditions and which as adolescents showed reduced
densities of dopaminergic fiber innervation in some subregions of the prefrontal cortex (Braun,
Lange, Metzger, & Poeggel, 2000;Winterfeld, Teuchert-Noodt, & Dawirs, 1998). In the
ventrolateral orbital prefrontal cortex and agranular insular cortex of deprived animals
significantly increased density of tyrosine hydroxylase-immunoreactive fibers were found (up
to 172% in the ventrolateral orbital prefrontal cortex and up to 143% in the agranular insular
cortex). The lateral orbital prefrontal cortex showed increased 5-hydroxytryptamine-positive

fiber densities (up to 118%) (Poeggel, Nowicki, & Braun, 2003b). The neonatally stressed and
later socially deprived animals also showed increased tyrosine hydroxylase (TH)-
immunoreactive fiber densities (representing dopaminergic and noradrenergic fibers,
respectively) in the core (up to 115%) and shell region (up to 113%) of the nucleus accumbens,
whereas decreased fiber densities (down to 84%) were observed in the hilus of the dentate
gyrus. In the stratum granulosum and subgranular layer the fiber densities increased up to 168%
and 127%, respectively. Serotonergic innervation in the deprived animals was increased (up
to 126%) in the core region of the nucleus accumbens, in the central nucleus of the amygdala
(up to 112%) and in the outer subregion of the dentate gyrus stratum moleculare (up to 149%),
whereas decreased fiber densities were detected in the dentate subgranular layer (down to 86%)
and in the stratum lacunosum of the hippocampal CA1 region (down to 86%) (Gos et al.,
2006). Monkeys which have been raised under conditions of maternal deprivation showed

significantly reduced density of dopaminergic innervation in the striatum and in the nucleus
accumbens (Martin, Spicer, Lewis, Gluck, & Cork, 1991).
On the behavioral level it remains to be characterized in which way the metabolic,

neurochemical, and anatomical changes within the limbic system affect cognitive and
emotional behavior of the stressed and/or deprived animals. So far, a consistent behavioral
observation in stressed or deprived rats and degus was an increased “hyper-” activity in the
open field (Braun, Kremz, Wetzel, Wagner, & Poeggel, 2003;Hall, 1998). In neonatally
stressed (by repeatedly separating the pups from their parents and siblings) degus we, in
addition, observed a significantly reduced responsiveness of 2-week-old pups towards maternal
vocalizations, reflected by their reduced approach behavior and the absence of distress calls
(Braun et al.).
Based on the pioneering work of Spitz (1945),Bowlby (1954,1959), Mary Ainsworth

(Ainsworth, Boston, Bowlby, & Rosenbluth, 1956;Ainsworth, 1962), and Skeels (1966) in
humans it has been suspected for quite sometime that early traumatic experience, such as the
loss or the separation from one or both parents, can be one of the major factors for developing
anxiety and depressive disorders in adulthood. Spitz and colleagues have shown that the loss
of the mother or parents leads to dramatic emotional disorders in the deprived infants
(hospitalism) (Emde, Polak, & Spitz, 1965; Spitz). Recent studies in the biparental species
Octodon degus showed that animals which had been raised without a father display
significantly reduced densities (−33%) of symmetric shaft synapses layer II of the anterior
cingulate cortex compared to biparentally raised controls (Ovtscharoff et al., 2006). The major
importance of emotional environment, that is, a stable emotional attachment to the parents or
caregivers, in addition to the intellectual input, is illustrated by the studies in Romanian orphans
(O’Connor & Rutter, 2000). Clinical studies revealed a significant coincidence between the
separation from or the loss of one or both parents and the chance of developing affective
disorders (Gilmer & McKinney, 2003;Heim & Nemeroff, 2001), and one of these studies
(Canetti et al., 2000) revealed that the separation from the parents due to divorce has a higher
impact than the death of one or both parents.
JUVENILE STRESS IMPAIRS ADULT AVOIDANCE LEARNING IN RATS

Research from the laboratory of Gal Richter-Levin at the University of Haifa has shown that
stress during adolescence can result in developmental abnormalities, clearly illustrating stress
exposure prior to puberty has dramatic effects on later life. Exposure to early life stress is
suggested as a significant contributing factor for the emergence of these psychopathologies.
Epidemiological studies indicate that early-life stress or childhood emotional trauma is
predominantly associated with higher prevalence of both mood and anxiety disorders,
particularly depression and PTSD (Agid et al., 1999;Arborelius, Owens, Plotsky, & Nemeroff,
1999;Briere & Elliott, 1994;Draijer & Langeland, 1999;Furukawa et al., 1999;Maughan &
McCarthy, 1997;Weiss, Longhurst, & Mazure, 1999). Yet, while some researchers claim that
younger children are more vulnerable to trauma due to their impressionability (Browne &
Finkelhor, 1986) and show greater symptomology as a result of abuse (Beitchman, Zucker,
Hood, daCosta, & Akman, 1992), others claim that young children’s naiveté protects them,
especially if children are unaware of the social stigma associated with the type of victimization
they have suffered (Browne & Finkelhor).
The significance of the age or developmental stage at the onset of the adversity was also
questioned. Heim and colleagues (Heim, Meinlschmidt, & Nemeroff, 2003;Heim, Plotsky, &
Nemeroff, 2004) argued that any form of stress—short-term, acute, or chronic may be classified
as early life stress as long as it occurs prior to sexual maturity onset—hence constitute a risk
factor for the later development of depression and other stress-related psychopathologies. Yet

others (Kiser, Heston, Millsap, & Pruitt, 1991) maintain that no systematic relationship exists
between the age of the emotional assault and the degree of disturbance.
Studies examining the impact of early life experience in rats usually focus on the first two
postnatal weeks (Levine, Huchton, Wiener, & Rosenfeld, 1991;Van Oers, de Kloet, & Levine,
1998). This period of postnatal development (i.e., 3–14 days postnatal) has been suggested to
correspond roughly to the 23rd week of gestation in humans (Fitzgerald & Anand, 1993).
We have recently started to study a later developmental period; the Juvenile stage (PND 26–
28) (Avital & Richter-Levin, 2005;Tsoory & Richter-Levin, 2005). The Juvenile period, a life
period not widely targeted before, is suggested to be of relevance to human childhood (Spear,
2000). At this age the pups become more independent and spend more time in social
interactions. Yet, they are still sexually immature (Martin & Berthoz, 2002).
We first examined the ability of adult animals to cope with stress as a function of whether or
not they had been exposed to juvenile stress. The exposure to the combination of juvenile and
adulthood stress increased anxiety levels as measured in the open field and startle response
tests, compared to animals that were exposed to stress only in adulthood (Avital & Richter-
Levin, 2005). To verify whether the impact of exposure to juvenile stress was due to the
developmental period within which it was applied, or if the effects were due to repeated
exposure to the stressor, we compared the juvenile + adulthood stress to a double exposure to
stress during adulthood. The exposure to juvenile stress was found to have a significantly
stronger impact than a double exposure to stress during adulthood (Avital & Richter-Levin).
The impact of the juvenile + adulthood exposure to stress was found to be long lasting.
Examined up to 3 weeks after the adulthood exposure to stress, rats still showed enhanced
anxious responses.
In fact, the exposure to stress in juveniles by itself had long-term effects well into adulthood.
Adult rats exposed to juvenile stress exhibited reduced exploratory behavior in a novel setting
(Tsoory & Richter-Levin, 2005). This was associated with marked alterations in neurosteroid
levels in the rat hypothalamus and entorhinal cortex. Juvenile stress increased DHEAS but not
DHEA concentrations both in the hypothalamus and the entorhinal cortex, indicating that an
exposure to juvenile stress has long-lasting effects on DHEAS levels (Avital, Ram, Maayan,
Weizman, & Richter-Levin, 2006).
To examine the impact of an exposure to juvenile stress on the ability to learn under stressful
conditions in adulthood, we further examined the ability of adult rats to acquire the two-way
shuttle avoidance task, depending on whether or not they were previously exposed to juvenile
stress. Juvenile rats exposed to juvenile stress exhibited poor avoidance learning in adulthood,
implying that their coping response to the stressful experience might have been compromised
by heightened anxiety (Tsoory & Richter-Levin, 2005).
Interestingly, two levels of impairment were evident in the juvenile stress-exposed rats, as
indicated by the frequency of no-response trials in the two-way avoidance task. The less severe
level of impairment was characterized by poor avoidance learning accompanied by a low
frequency of no-response trials; hence it was termed “maladaptive behavior.” The more severe
level of impairment was typified by poor avoidance learning and a high frequency of no-
response trials, and was termed “learned helplessness-like behavior.” Approximately two-
thirds of the juvenile stress rats were characterized by maladaptive behavior in response to the
stressful challenge of the avoidance task, while the remaining third was characterized by
learned helplessness-like behaviors.

Interestingly, traumatic events often trigger the emergence of a variety of stress-related

psychopathologies, including not only acute stress disorder (ASD) and posttraumatic stress
disorder (PTSD), but also depressive and anxiety symptoms (Moreau & Zisook, 2002). It is
tempting to suggest that the dissociation we observed between maladaptive and learned
helplessness-like behaviors is related to that possibility.
The dichotomy among the juvenile stressed rats between two levels of impairment was not
found when the young animals were exposed to similar stressors just 1 week later. Adolescent
stressed rats exhibited only the less severe level of impairment and were all characterized as
maladaptive (Tsoory & Richter-Levin, 2005). Together with finding that juvenile + adulthood
stress resulted in more severe impairments than repeated exposures in adulthood (Avital &
Richter-Levin, 2005), the results suggest that the juvenile period represents a particularly
sensitive developmental period.
DISCUSSION
While each research program reviewed here has taken a unique approach to studying the
influences of the environment on emotional development, all show the critical importance of
the timing and nature of the environmental conditions to produce the outcome. Indeed, these
strikingly different approaches have all contributed a basic research result that expands our
understanding of developmental impact of infant experiences on emotional and limbic system
development.
The importance of animal models in understanding adult human mental health relies, in part,
on homologies between the animal model and humans. Mechanisms underlying the
developmental animal models presented here and human adult outcome may not always be
identical. Indeed these models clearly illustrate that similar outcomes in adulthood can be
achieved through divergent developmental pathways. For example, the detrimental effects of
stress on adult emotion may appear similar, yet stress experienced in infancy and the juvenile
period may have different pathways to that outcome. Overall, these studies suggest that
applying specific mechanisms found in animal models to the myriad adult outcomes and
pathologies should be done with caution. Importantly, the research programs outlined here
suggest general principles of development that can be readily applied to human populations.
The strength of animal models in research is that they can answer questions concerning specific
mechanisms of developmental trajectories through an integrated approach that assesses
biological processes throughout development and adulthood. Clinicial studies on human
emotional differences and pathologies so often rely on extrapolating backward from the adult
disease state to identify developmental time points when genes and environment interact to
produce the trajectory to the disease state. Animal research helps us identify developmental
time points and types of environmental insults to guide the extrapolating into the clinical
populations’ history.
Acknowledgements
The authors thank NICHD for support of the symposium presented at the 2004 International Society for Developmental
Psychobiology Annual meeting in Aix-en-Provence, France. Support for research presented in the manuscript was
provided for by the German Science Foundation (DFG), the state of Saxony-Anhalt, the VolkswagenStiftung, German-
Israeli Foundation (GIF) to K.B.; ETH Zurich, the NCCR: Neural Plasticity and Repair, Swiss National Science
Foundation to J.F., U.M., B.K.Y.; NSF, NIH-NICHD, OCAST to R.M.S.; NIH-NIDCD, OCAST to D.A.W.; and The
Israel Foundation Trustees, NARSAD Independent Investigator award to G.R.L.

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FIGURE 1.
The diagram illustrates the hypothesized early prenatal and postnatal factors involved in the
precipitation of brain and behavioral pathology following prenatal immune challenge.
Exposure to viral and bacterial pathogens rapidly results in the production of pro-(●) and anti-
inflammatory (▲) cytokines in the maternal host. The specificity of the pathogen-induced
cytokine production is critically influenced by the genetic background (not shown) as well as
the gestational stage. Immunological stimulation is also strongly associated with the activation
of the stress response axes such as the hypothalamic-pituitary-adrenal (HPA) axis. Trans-
placental transfer of maternally produced cytokines and/or production of cytokines at the

maternal-fetal interface lead to an elevation of these molecules in the fetal environment,
including the fetal brain. The fetal system at late but not early/mid gestation contributes to this
process by endogenously synthesizing and secreting specific cytokines following maternal
immune activation. Once in the fetal brain, cytokines affect ongoing neurodevelopmental
processes depending on the fetal developmental stage and cytokine specificity. Disturbance of
normal fetal brain development by cytokine-associated inflammatory events results in altered
neonatal brain maturation and ultimately leads to the emergence of adult psychopathology.
The precise pattern of brain and behavioral pathology emerging in adulthood is also critically
determined by the time of prenatal immune challenge, that is, prenatal immune activation at
early/mid gestation precipitates behavioral dysfunctions associated with (but not limited to)
the positive symptoms of schizophrenia, whereas prenatal immune activation at late gestation
triggers behavioral pathology associated with the negative symptoms of the disease.
Immunologically induced stress (e.g., via activation of the HPA axis).

FIGURE 2.
Gray-scale images of odor-evoked local field potential (LFP) oscillatory activity in the
basolateral amygdala of immature and adult rats. Light gray and white regions represent high
power in an FFT analysis of LFP activity within specific frequency bands. In young rats, odor
stimulation evokes strong, low frequency activity with minimal high-frequency components.
In contrast, odors evoke strong high-frequency activity (low gamma/high beta) in adults. These
results are similar to those observed in olfactory bulb and piriform cortex (Fletcher et al.,
2005), and could have an important impact on local circuit processing of odors and their
associations (see text).

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Dev Psychobiol. 2006 November ; 48(7): 583–602.

The International Society for Developmental Psychobiology

Regina Sullivan and Donald A. Wilson

Michael Gruss, Jörg Bock, Carina Helmeke, and Katharina Braun

Correspondence to: R. Sullivan, E-mail: rsullivan@ou.edu

trajectory is necessary for successful childrearing, as well as therapeutic intervention to

Dev Psychobiol. Author manuscript; available in PMC 2007 August 27.

PRENATAL IMMUNOLOGICAL PRECIPITATION OF MAL-

(Brown et al., 2004a,b;Buka et al., 2001;O’Callaghan et al., 1994;Patterson, 2002;Pearce,

The Cytokine Hypothesis of the Maternal Infection Model of Schizophrenia

Dev Psychobiol. Author manuscript; available in PMC 2007 August 27.

Maternal Immune Challenge in Pregnancy Leads to Multiple Psychopathology

Amongst the multitude of behavioral, cognitive and psychopharmacological deficits revealed,

wide spectrum of behavioral and cognitive dysfunctions observed in offspring subjected to

Dev Psychobiol. Author manuscript; available in PMC 2007 August 27.

The Psychopathological Profile Depends on the Precise Time of Maternal Infection

differing vulnerability to adult behavioral dysfunction, brain neuropathology in early

Dev Psychobiol. Author manuscript; available in PMC 2007 August 27.

neurodevelopmental disturbances has been suggested based on genetic and epidemiological

Maternal–Infant Interaction in Early Postnatal (Preweaning) Life in the Infection Model of

Dev Psychobiol. Author manuscript; available in PMC 2007 August 27.

Dev Psychobiol. Author manuscript; available in PMC 2007 August 27.

RESEARCH CORTICAL AND LIMBIC SENSORY PROCESSING DURING

Dev Psychobiol. Author manuscript; available in PMC 2007 August 27.

A second process involved in olfactory perception is habituation—the ability to filter out

EARLY EMOTIONAL MEMORIES ARE STORED IN THE BRAIN

Dev Psychobiol. Author manuscript; available in PMC 2007 August 27.

The critical impact of the early socio-emotional environment on behavioral development is

handles cognitive tasks.

Impact of Early Emotional Experience on Synaptic Reorganization of Limbic Brain Regions

Dev Psychobiol. Author manuscript; available in PMC 2007 August 27.

displayed reduced synaptic density (Bryan & Riesen, 1989).

Regressive synaptic changes might be a typical characteristic for juvenile imprinting-like

Dev Psychobiol. Author manuscript; available in PMC 2007 August 27.

The disadvantage of experience-driven synaptic reorganization lies in the enhanced

Dev Psychobiol. Author manuscript; available in PMC 2007 August 27.

orbitofrontal cortex compared to control animals (Murmu et al., 2006).

cortex). The lateral orbital prefrontal cortex showed increased 5-hydroxytryptamine-positive

Dev Psychobiol. Author manuscript; available in PMC 2007 August 27.

On the behavioral level it remains to be characterized in which way the metabolic,

Based on the pioneering work of Spitz (1945),Bowlby (1954,1959), Mary Ainsworth

JUVENILE STRESS IMPAIRS ADULT AVOIDANCE LEARNING IN RATS

Dev Psychobiol. Author manuscript; available in PMC 2007 August 27.

Dev Psychobiol. Author manuscript; available in PMC 2007 August 27.

Interestingly, traumatic events often trigger the emergence of a variety of stress-related

Dev Psychobiol. Author manuscript; available in PMC 2007 August 27.

Dev Psychobiol. Author manuscript; available in PMC 2007 August 27.

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