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Exposure to a mildly aversive early life experience leads to prefrontal cortex deficits in the rat

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Abstract

Aversive early life experiences in humans have been shown to result in deficits in the function of the prefrontal cortex (PFC). In an effort to elucidate possible neurobiological mechanisms involved, we investigated in rats, the effects of a mildly aversive early experience on PFC structure and function. The early experience involved exposure of rat pups during postnatal days (PND) 10–13 to a T-maze in which they search for their mother, but upon finding her are prohibited contact with her, thus being denied the expected reward (DER). We found that the DER experience resulted in adulthood in impaired PFC function, as assessed by two PFC-dependent behavioral tests [attention set-shifting task (ASST) and fear extinction]. In the ASST, DER animals showed deficits specifically in the intra-dimensional reversal shifts and a lower activation—as determined by c-Fos immunohistochemistry—of the medial orbital cortex (MO), a PFC subregion involved in this aspect of the task. Furthermore, the DER experience resulted in decreased glutamatergic neuron and dendritic spine density in the MO and infralimbic cortex (IL) in the adult brain. The decreased neuronal density was detected as early as PND12 and was accompanied by increased micro- and astroglia-density in the MO/IL.

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Abbreviations

ANOVA:

Analysis of variance

ASST:

Attention set-shifting task

CTR:

Control animals

DAB:

3,3′-Diaminobenzidine

DER:

Animals denied the expected reward

GAD67:

Glutamate decarboxylase, MW 67 kDa

GFAP:

Glial fibrillary acidic protein

Iba-1:

Ionized calcium-binding adapter molecule 1

IL:

Infralimbic cortex

MO:

Medial orbital cortex

NDS:

Normal donkey serum

NGS:

Normal goat serum

PBS:

Phosphate-buffered saline

PFC:

Prefrontal cortex

PND:

Postnatal day

PrL:

Prelimbic cortex

RER:

Animals receiving the expected reward

roCg1:

Rostral part of area 1 of cingulate cortex

roVLO:

Rostral part of ventral lateral orbital cortex

SEM:

Standard error of the mean

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Acknowledgments

The authors would like to thank Ms. Konstantina Nikolakaki for her technical assistance in the immunohistochemical and immunofluorescence experiments. This work has been supported by the John S. Latsis Public Benefit Foundation (#12020). The sole responsibility for the content lies with its authors.

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  1. Biology-Biochemistry Lab, School of Health Sciences, National and Kapodistrian University of Athens, Papadiamantopoulou 123, 11527, Athens, Greece

    Antonios Stamatakis, Vasileios Manatos, Theodora Kalpachidou & Fotini Stylianopoulou

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  1. Antonios Stamatakis
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  2. Vasileios Manatos
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  3. Theodora Kalpachidou
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  4. Fotini Stylianopoulou
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Correspondence to Antonios Stamatakis.

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Stamatakis, A., Manatos, V., Kalpachidou, T. et al. Exposure to a mildly aversive early life experience leads to prefrontal cortex deficits in the rat. Brain Struct Funct 221, 4141–4157 (2016). https://doi.org/10.1007/s00429-015-1154-0

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