Inhibition of Cortical Activity and Apoptosis Caused by Ethanol in Neonatal Rats In Vivo

Abstract

Alcohol consumption during pregnancy causes fetal alcohol spectrum disorder, which includes neuroapoptosis and neurobehavioral deficits. The neuroapoptotic effects of alcohol have been hypothesized to involve suppression of brain activity. However, in vitro studies suggest that ethanol acts as a potent stimulant of cortical activity. We explored the effects of alcohol (1-6 g/kg) on electrical activity in the rat somatosensory cortex in vivo at postnatal days P1-23 and compared them with its apoptotic actions. At P4-7, when the peak of alcohol-induced apoptosis was observed, alcohol strongly suppressed spontaneous gamma and spindle-bursts and almost completely silenced neurons in a dose-dependent manner. The dose-dependence of suppression of neuronal activity strongly correlated with the alcohol-induced neuroapoptosis. Alcohol also profoundly inhibited sensory-evoked bursts and suppressed motor activity, a physiological trigger of cortical activity bursts in newborns. The suppressive effects of ethanol on neuronal activity waned during the second and third postnatal weeks, when instead of silencing the cortex, alcohol evoked delta-wave electrographic activity. Thus, the effects of alcohol on brain activity are strongly age-dependent, and during the first postnatal week alcohol profoundly inhibits brain activity. Our findings suggest that the adverse effects of alcohol in the developing brain involve suppression of neuronal activity.

Active Sleep Promotes Functional Connectivity in Developing Sensorimotor Networks

“…Importantly, selective manipulation of neuronal activity affects the rate of apoptosis in sensory and motor cortices. In support of this finding, the amount of alcohol‐induced suppression of early oscillatory bursts correlates with the amount of apoptosis detected in somatosensory cortex . These findings demonstrate that alteration of oscillatory activity in early development is detrimental to typical cortical development and can mediate the adverse effects of early exposure to teratogens.…”

“…Early oscillatory activity in vivo has been most extensively – but not exclusively – described in the cortex and hippocampus . In these forebrain structures, fragmented oscillatory activity is thought to assist in the development of local neuronal networks, with effects on synapse formation, neuronal differentiation and migration, programmed cell death (apoptosis), and formation and refinement of topographic maps …”

“…Perhaps the most direct, causal evidence for a role of oscillations in brain development comes from studies assessing their involvement in apoptosis . Apoptosis is the physiological process through which neurons and other cells die.…”

The Development of Nociceptive Network Activity in the Somatosensory Cortex of Freely Moving Rat Pups

“…At the end of the first postnatal week, intermittent burst activity in the whisker barrel cortex, driven by thalamic inputs, is replaced by an adult-like active cortical state and the emergence of organized sensory-evoked responses (Khazipov et al 2004; Minlebaev et al 2011) and a precise somatosensory map (Mitrukhina et al 2015). These elegant studies, including the recently reported effects of alcohol and serotonin reuptake inhibitors (Lebedeva et al 2015; Akhmetshina et al 2016), are particularly important because they were performed in vivo , using head fixed rat pups following withdrawal of anesthesia.…”

Neurotrophins in the Brain

“…Exposure to alcohol during the gestational period in primates or the early postnatal period in rodents produces massive stimulation of apoptosis in the immature brain (Farber, Creeley, & Olney, 2010; Ikonomidou et al, 2000; Olney et al, 2002). The mechanism of apoptosis includes the alcohol-driven decrease in neuronal activity in the developing brain through a suppression of glutamatergic NMDA receptors and potentiation of GABAergic receptors (discussed in Section 5.1), resulting in suppressed spontaneous network activity and the silencing of neurons in a dose-dependent manner (Lebedeva et al, 2015). Since synaptic activity is essential for neuronal survival during the gestational/early postnatal period, such silencing can result in activity-dependent apoptosis.…”