Abnormal Trajectories of Neurodevelopment and Behavior Following In Utero Insult in the Rat

doi:10.1016/j.biopsych.2011.06.007

Biological Psychiatry

Volume 70, Issue 9, 1 November 2011, Pages 842-851

https://doi.org/10.1016/j.biopsych.2011.06.007 Get rights and content

Background

Environmental or genetic disturbances of early brain development are suggested to underlie the pathophysiology of several adult-onset neuropsychiatric disorders. We traced the developmental trajectories of brain structural and behavioral abnormalities from adolescence to young adulthood in rats born to mothers exposed to the viral mimic polyriboinosinic-polyribocytidylic acid (poly-I:C) in pregnancy.

Methods

Pregnant rats were injected on gestational day 15 with poly-I:C (4 mg/kg) or saline. Volumes of lateral ventricles, hippocampus, striatum, and prefrontal cortex in male and female offspring were assessed longitudinally at postnatal days 35, 46, 56, 70, and 90 using in vivo magnetic resonance imaging. At parallel time windows, groups of offspring from the same litters underwent behavioral testing (latent inhibition and amphetamine-induced activity) and magnetic resonance imaging (cross-sectional assessment).

Results

The specific developmental trajectories of volumetric changes in both control and poly-I:C offspring were region-, age-, and sex-specific, but overall, poly-I:C offspring had smaller volumes of the hippocampus, striatum and prefrontal cortex, and larger ventricular volume. Structural pathology in different regions had different times of onset and was gradually accompanied by behavioral deficits, disrupted latent inhibition, and excessive amphetamine-induced activity. The onset of structural frontocortical and ventricular abnormalities and behavioral abnormalities was delayed in females. In both sexes, hippocampal and striatal volume reduction predated the appearance of behavioral abnormalities.

Conclusions

Prenatal insult interferes with postnatal brain maturation, which in turn may result in behavioral abnormalities.

Section snippets

Animals

Male and female Wistar rats were housed 2 to 4 per cage under reversed-cycle lighting with ad libitum food and water (except for latent inhibition [LI] experiments described later in the article).

Prenatal Poly-I:C Treatment

Prenatal treatment was performed as described previously (33, 44) (see also Supplement 1). On gestation day 15, pregnant dams were injected intravenously with poly-I:C (4 mg/kg/mL, Sigma, Rehovot, Israel) or saline under 3% isoflurane (Nicholas Piramal, Northumberland, United Kingdom) anesthesia. At

Longitudinal Course of Structural Brain Changes Following Prenatal Poly-I:C Exposure

In all four groups of offspring, HIP volume increased with age, but poly-I:C offspring of both sexes had smaller volume than saline offspring on all PNDs except PND 35 (Figure 2). ANOVA yielded main effects of prenatal treatment, sex, and age [F(1,29) = 29.08, F(1,29) = 22.84, and F(4,116) = 26.35, respectively; all ps < .0001], and prenatal treatment × age interaction [F(4,116) = 12.04, p < .0001). Post hoc analyses of the interaction confirmed significant differences in HIP volume between

Discussion

This study provides the first in vivo longitudinal characterization of volumetric and behavioral changes occurring as a consequence of in utero insult in rats of both sexes. Main findings include the following: 1) prenatal exposure to the viral mimic poly-I:C leads to abnormal postnatal trajectories of neurodevelopment, 2) there are conspicuous sex differences in both structural and behavioral trajectories, and 3) low striatal volume and HIP volume loss in adolescence predate the appearance of

References (81)

J. Savitz et al.
Bipolar and major depressive disorder: Neuroimaging the developmental-degenerative divide
Neurosci Biobehav Rev
(2009)
T. Tenyi et al.
Minor physical anomalies in affective disordersA review of the literature
J Affect Disord
(2009)
B.L. Thompson et al.
The clinical-basic interface in defining pathogenesis in disorders of neurodevelopmental origin
Neuron
(2010)
F. Fumagalli et al.
Stress during development: Impact on neuroplasticity and relevance to psychopathology
Prog Neurobiol
(2007)
M. Weinstock
The long-term behavioural consequences of prenatal stress
Neurosci Biobehav Rev
(2008)
C. Heim et al.
The role of childhood trauma in the neurobiology of mood and anxiety disorders: Preclinical and clinical studies
Biol Psychiatry
(2001)
M. Sanches et al.
Neurodevelopmental basis of bipolar disorder: A critical appraisal
Prog Neuropsychopharmacol Biol Psychiatry
(2008)
B.L. Thompson et al.
Now you see it, now you don't—Closing in on allostasis and developmental basis of psychiatric disorders
Neuron
(2010)
H. Jaaro-Peled et al.
Neurodevelopmental mechanisms of schizophrenia: Understanding disturbed postnatal brain maturation through neuregulin-1-ErbB4 and DISC1
Trends Neurosci
(2009)
R. Smieskova et al.
Neuroimaging predictors of transition to psychosis—A systematic review and meta-analysis
Neurosci Biobehav Rev
(2010)

U. Rao et al.

Hippocampal changes associated with early-life adversity and vulnerability to depression

Biol Psychiatry

(2010)

M. Berk et al.

Pathways underlying neuroprogression in bipolar disorder: Focus on inflammation, oxidative stress and neurotrophic factors

Neurosci Biobehav Rev

(2011)

E. Bora et al.

Voxelwise meta-analysis of gray matter abnormalities in bipolar disorder

Biol Psychiatry

(2010)

M. Niwa et al.

Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits

Neuron

(2010)

M. Baharnoori et al.

Prenatal immune challenge induces developmental changes in the morphology of pyramidal neurons of the prefrontal cortex and hippocampus in rats

Schizophr Res

(2009)

K. Cui et al.

Effects of prenatal immune activation on hippocampal neurogenesis in the rat

Schizophr Res

(2009)

S.H. Fatemi et al.

Maternal infection leads to abnormal gene regulation and brain atrophy in mouse offspring: Implications for genesis of neurodevelopmental disorders

Schizophr Res

(2008)

B. Abazyan et al.

Prenatal interaction of mutant DISC1 and immune activation produces adult psychopathology

Biol Psychiatry

(2010)

K. Ozawa et al.

Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: A neurodevelopmental animal model of schizophrenia

Biol Psychiatry

(2006)

U. Meyer et al.

Towards an immuno-precipitated neurodevelopmental animal model of schizophrenia

Neurosci Biobehav Rev

(2005)

U. Meyer et al.

Epidemiology-driven neurodevelopmental animal models of schizophrenia

Prog Neurobiol

(2010)

L. Zuckerman et al.

Maternal immune activation leads to behavioral and pharmacological changes in the adult offspring

J Psychiatr Res

(2005)

U. Meyer et al.

Neural basis of psychosis-related behaviour in the infection model of schizophrenia

Behav Brain Res

(2009)

Y. Piontkewitz et al.

Clozapine administration in adolescence prevents postpubertal emergence of brain structural pathology in an animal model of schizophrenia

Biol Psychiatry

(2009)

R.K. Lenroot et al.

Brain development in children and adolescents: Insights from anatomical magnetic resonance imaging

Neurosci Biobehav Rev

(2006)

L.P. Spear

The adolescent brain and age-related behavioral manifestations

Neurosci Biobehav Rev

(2000)

C.M. McCormick et al.

Adolescent development, hypothalamic-pituitary-adrenal function, and programming of adult learning and memory

Prog Neuropsychopharmacol Biol Psychiatry

(2010)

G. Grecksch et al.

Disruption of latent inhibition in rats with postnatal hippocampal lesions

Neuropsychopharmacology

(1999)

K.Y. Tseng et al.

The neonatal ventral hippocampal lesion as a heuristic neurodevelopmental model of schizophrenia

Behav Brain Res

(2009)

D.J. Lodge et al.

Developmental pathology, dopamine, stress and schizophrenia

Int J Dev Neurosci

(2011)

C.L. Sisk et al.

Pubertal hormones organize the adolescent brain and behavior

Front Neuroendocrinol

(2005)

S.J. Borgwardt et al.

Reductions in frontal, temporal and parietal volume associated with the onset of psychosis

Schizophr Res

(2008)

D.E. Job et al.

Grey matter changes over time in high risk subjects developing schizophrenia

Neuroimage

(2005)

A.M. McIntosh et al.

Longitudinal volume reductions in people at high genetic risk of schizophrenia as they develop psychosis

Biol Psychiatry

(2011)

D. Sun et al.

Progressive brain structural changes mapped as psychosis develops in “at risk” individuals

Schizophr Res

(2009)

V.A. Mittal et al.

Striatal volumes and dyskinetic movements in youth at high-risk for psychosis

Schizophr Res

(2010)

J.M. Stone et al.

Altered relationship between hippocampal glutamate levels and striatal dopamine function in subjects at ultra high risk of psychosis

Biol Psychiatry

(2010)

L.M. Ellman et al.

Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8

Schizophr Res

(2010)

S.H. Fatemi et al.

Prenatal viral infection of mice at E16 causes changes in gene expression in hippocampi of the offspring

Eur Neuropsychopharmacol

(2009)

P. Boksa

Effects of prenatal infection on brain development and behavior: A review of findings from animal models

Brain Behav Immun

(2010)

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Archival ReportAbnormal Trajectories of Neurodevelopment and Behavior Following In Utero Insult in the Rat

Background

Methods

Results

Conclusions

Section snippets

Animals

Prenatal Poly-I:C Treatment

Longitudinal Course of Structural Brain Changes Following Prenatal Poly-I:C Exposure

Discussion

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Archival Report
Abnormal Trajectories of Neurodevelopment and Behavior Following In Utero Insult in the Rat