Protein malnutrition during gestation and early life decreases neuronal size in the medial prefrontal cortex of post-pubertal rats

Abstract Rationale Several findings indicate that early-life dysfunction of N-methyl-d-aspartate (NMDA) receptors might cause schizophrenia-like abnormalities in adulthood that might be induced by impairments in epigenetic regulation. Objectives In the present study, we investigated whether postnatal blockade of NMDA receptors (within the first 3 weeks of life) by the competitive antagonist CGP 37849 (CGP) might affect some epigenetic markers in the adult medial prefrontal cortex (mPFC). Methods Histone H3 phosphorylation at serine 10 (H3S10ph), histone H3 acetylation at lysine 9 or 14 (H3K9ac or H3K14ac, respectively), or expression of histone deacetylase (HDAC) 2, HDAC5, myocyte enhancer factor (MEF) 2D and activity-regulated cytoskeleton-associated protein (Arc) were analysed. Moreover, we also evaluated whether the deacetylase inhibitor sodium butyrate (SB; 1.2 mg/kg, ip) could prevent behavioural and neurochemical changes in the mPFC induced by CGP during memory retrieval in the trace fear conditioning paradigm. Results The results showed that CGP administration increased the number of H3S10ph nuclei but did not affect H3K9ac and H3K14ac or HDAC2 protein levels. However, CGP administration altered the HDAC5 mRNA and protein levels and increased the mRNA and protein levels of MEF2D. CGP also increased Arc mRNA, which was correlated with an increase in the amount of Arc DNA bound to MEF2D. SB given 2 h after training prevented impairment of the freezing response and disruption of epigenetic markers (H3S10ph, HDAC5, MEF2D) and Arc expression during memory retrieval induced by CGP administration. Conclusions The early-life blockade of NMDA receptors impairs some epigenetic regulatory processes in the mPFC that are involved in fear memory formation.

Download Full-text

Reduced resting-state functional connectivity of the basolateral amygdala to the medial prefrontal cortex in preweaning rats exposed to chronic early-life stress

Brain Structure and Function ◽

10.1007/s00429-018-1720-3 ◽

2018 ◽

Vol 223 (8) ◽

pp. 3711-3729 ◽

Cited By ~ 12

Author(s):

Angela Guadagno ◽

Min Su Kang ◽

Gabriel A. Devenyi ◽

Axel P. Mathieu ◽

Pedro Rosa-Neto ◽

...

Keyword(s):

Prefrontal Cortex ◽

Functional Connectivity ◽

Medial Prefrontal Cortex ◽

Resting State ◽

Life Stress ◽

Early Life ◽

Basolateral Amygdala ◽

Early Life Stress ◽

Resting State Functional Connectivity

Download Full-text

Elevated fear responses to threatening cues in rats with early life stress is associated with greater excitability and loss of gamma oscillations in ventral-medial prefrontal cortex

10.1101/2021.07.28.454150 ◽

2021 ◽

Author(s):

Florencia M Bercum ◽

Maria Jose Navarro Gomez ◽

Michael P Saddoris

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Conditioned Suppression ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Gamma Oscillations ◽

Brain Maturation ◽

Ventral Medial Prefrontal Cortex

Stress experienced early in development can have profound influences on developmental trajectories and ultimately behaviors in adulthood. Potent stressors during brain maturation can profoundly disrupt prefrontal cortical areas in particular, which can set the stage for prefrontal-dependent alterations in fear regulation and risk of drug abuse in adulthood. Despite these observations, few studies have investigated in vivo signaling in prefrontal signals in animals with a history of early life stress (ELS). Here, rats with ELS experience on PND3-5 were then tested on a conditioned suppression paradigm during adulthood. During conditioned suppression, electrophysiological recordings were made in the ventral medial prefrontal cortex (vmPFC) during presentations of a fear-associated cues that resolved both single-unit activity and local field potentials (LFPs). Relative to unstressed controls, ELS-experienced rats showed greater fear-related suppression of lever pressing. During presentations of the fear-associated cue (CS+), neurons in the vmPFC of ELS animals showed a significant increase in the probability of excitatory encoding relative to controls, and excitatory phasic responses in the ELS animals were reliably of higher magnitude than Controls. In contrast, vmPFC neurons in ELS subjects better discriminated between the shock-associated CS+ and the neutral ("safe") CS- cue than Controls. LFPs recorded in the same locations revealed that high gamma band (65-95 Hz) oscillations were strongly potentiated in Controls during presentation of the fear-associated CS+ cue, but this potentiation was abolished in ELS subjects. Notably, no other LFP spectra differed between ELS and Controls for either the CS+ or CS-. Collectively, these data suggest that ELS experience alters the neurobehavioral functions of PFC in adulthood that are critical for processing fear regulation. As such, these alterations may also provide insight into to increased susceptibility to other PFC-dependent processes such as risk-based choice, motivation, and regulation of drug use and relapse in ELS populations.

Download Full-text

ALTERATIONS IN THE MRNA EXPRESSION OF D2 DOPAMINE RECEPTOR SPLICE VARIANTS AS POSSIBLE MECHANISM OF PREFRONTAL DYSFUNCTION AFTER EARLY-LIFE IMMUNE CHALLENGE

Medical academic journal ◽

10.17816/maj191s1109-111 ◽

2019 ◽

Vol 19 (1S) ◽

pp. 109-111

Author(s):

A P Schwarz ◽

A N Trofimov ◽

A M Ischenko ◽

O E Zubareva ◽

V M Klimenko

Keyword(s):

Prefrontal Cortex ◽

Dopamine Receptor ◽

Medial Prefrontal Cortex ◽

Early Life ◽

Splice Variants ◽

Neuropsychiatric Symptoms ◽

Developmental Expression ◽

Immune Challenge ◽

D2 Dopamine Receptor ◽

Adult Rats

Various detrimental factors during early life may affect CNS development and increase risk of neuropsychiatric symptoms in later life. Disruption in brain dopaminergic system maturation is believed to be one of the mechanism of different neurodevelopmental disordrers. In this article we review behavioral peculiarities and changes of prefrontal D2 dopamine receptor splice variants (D2S and D2L) expression in rats after chronic experimental increase of proinflammatory cytokine interleukin(IL)-1β during 3rd week of life. Early life IL-1β treatment produce long lasting working memory deficit originating in juvenile adult animals. Elevation of IL-1β during 3rd week of life also affect developmental expression of D2 dopamine receptor mRNAs leading to increased D2S/D2L ratio in the medial prefrontal cortex of adolescent but not adult rats. Early life IL-1β treatment cancelled the learning-induced D2L mRNA downregulation during active avoidance conditioning in adult rats. Thus, dysregulation of expression of distinct D2 dopamine receptor splice variants within medial prefrontal cortex is supposed to be implicated in cognitive decline caused by early life immune challenge.

Download Full-text