Antenatal maternal stress alters functional brain responses in adult offspring during conditioned fear

Abstract

Antenatal maternal stress has been shown in rodent models and in humans to result in altered behavioral and neuroendocrine responses, yet little is known about its effects on functional brain activation. Pregnant female rats received a daily foot-shock stress or sham-stress two days after testing plug-positive and continuing for the duration of their pregnancy. Adult male offspring (age 14 weeks) with and without prior maternal stress (MS) were exposed to an auditory fear conditioning (CF) paradigm. Cerebral blood flow (CBF) was assessed during recall of the tone cue in the nonsedated, nontethered animal using the ¹⁴C-iodoantipyrine method, in which the tracer was administered intravenously by remote activation of an implantable minipump. Regional CBF distribution was examined by autoradiography and analyzed by statistical parametric mapping in the three-dimensionally reconstructed brains. Presence of fear memory was confirmed by behavioral immobility (“freezing”). Corticosterone plasma levels during the CF paradigm were measured by ELISA in a separate group of rats. Antenatal MS exposure altered functional brain responses to the fear conditioned cue in adult offspring. Rats with prior MS exposure compared to those without demonstrated heightened fear responsivity, exaggerated and prolonged corticosterone release, increased functional cerebral activation of limbic/paralimbic regions (amygdala, ventral hippocampus, insula, ventral striatum, and nucleus accumbens), the locus coeruleus, and white matter, and deactivation of medial prefrontal cortical regions. Dysregulation of corticolimbic circuits may represent risk factors in the future development of anxiety disorders and associated alterations in emotional regulation.

Introduction

Maternal psychological stress during pregnancy has been implicated as a risk factor for the development of affective disorders and schizophrenia in exposed offspring, as well as for decrements in their cognitive and language abilities (Koenig et al., 2002, Kofman, 2002, Weinstock, 2008, Laplante et al., 2008). Antenatal maternal stress (MS) has been shown to elicit changes in brain structure (Kawamura et al., 2006, McClure et al., 2004, Murmu et al., 2006, Salm et al., 2004, Wiggins and Gottesfeld, 1986, Zhu et al., 2004), brain neurochemistry (Adrover et al., 2007, Son et al., 2007, Van den Hove et al., 2006, Barros et al., 2006), stress hormone release (Kapoor et al., 2006) and behavior (Bowman et al., 2004, Lemaire et al., 2000, Louvart et al., 2005, Sternberg and Ridgway, 2003, Takahashi et al., 1992). The effects early life stress has on adult brain functional activation are just beginning to be examined. Prior work examining the effects of MS on functional brain activation during an acute stress challenge has been limited to a few studies documenting alterations in c-fos expression in isolated brain areas (hypothalamus, locus coeruleus) (Del Cerro et al., 2010, Fujita et al., 2010, Humm et al., 1995, Viltart et al., 2006). Using a rodent model, our study is the first to examine functional brain activation using whole brain perfusion mapping during a stress challenge in adult rats with or without a prior history of MS.