Distinct neurobehavioral dysfunction based on the timing of developmental binge-like alcohol exposure

Abstract

Gestational exposure to alcohol can result in long-lasting behavioral deficiencies generally described as fetal alcohol spectrum disorder (FASD). FASD-modeled rodent studies of acute ethanol exposure typically select one developmental window to simulate a specific context equivalent of human embryogenesis, and study consequences of ethanol exposure within that particular developmental epoch. Exposure timing is likely a large determinant in the neurobehavioral consequence of early ethanol exposure, as each brain region is variably susceptible to ethanol cytotoxicity and has unique sensitive periods in their development. We made a parallel comparison of the long-term effects of single-day binge ethanol at either embryonic day 8 (E8) or postnatal day 7 (P7) in male and female mice, and here demonstrate the differential long-term impacts on neuroanatomy, behavior and in vivo electrophysiology of two systems with very different developmental trajectories. The significant long-term differences in odor-evoked activity, local circuit inhibition, and spontaneous coherence between brain regions in the olfacto-hippocampal pathway that were found as a result of developmental ethanol exposure, varied based on insult timing. Long-term effects on cell proliferation and interneuron cell density were also found to vary by insult timing as well as by region. Finally, spatial memory performance was affected in P7-exposed mice, but not E8-exposed mice. Our physiology and behavioral results are conceptually coherent with the neuroanatomical data attained from these same mice. Our results recognize both variable and shared effects of ethanol exposure timing on long-term circuit function and their supported behavior.

Selective reduction of cerebral cortex GABA neurons in a late gestation model of fetal alcohol spectrum disorder

“…Whereas rodent PV cells originate from neurogenesis in the medial ganglionic eminence, CR cells originate in the caudal ganglionic eminence (Miyoshi et al, 2010; Rymar & Sadikot, 2007). Our results extend previous findings that immunolabeled PV cells are reduced in animal models of late gestational ethanol toxicity, in frontal cortex (Coleman et al, 2012), cingulate cortex (Moore, Ruygrok, Walker, & Heaton, 1997), piriform cortex and hippocampus (Sadrian et al, 2014), the medial septal area (Mitchell, Paiva, & Heaton, 2000), and striatum (De Giorgio, Comparini, Intra, & Granato, 2012). Our findings seem to contradict a finding of increased CR and unchanged PV cell density in rat cortex, after ethanol treatment at days P2–P6 (Granato, 2006).…”

“…For example, treatment of monkeys in early gestation or throughout pregnancy caused decreased GABA cell density, but it was not proportionally greater than the decrease of total neuron density (Miller, 2006). In mouse piriform cortex, ethanol causes reduced PV cell density at both late and early gestational periods, but in the hippocampus it reduces PV cell density with late treatment, but increases it with early treatment (Sadrian et al, 2014). …”

“…More detailed examinations found evidence of altered dendritic length and spine density (Berman & Hannigan, 2000; Cui et al, 2010; Lawrence, Otero, & Kelly, 2012; Susick, Lowing, Provenzano, Hildebrandt, & Conti, 2014), and found evidence of disrupted organization of cortical sensory areas (Margret et al, 2006; Medina, Krahe, & Ramoa, 2005; Miller & Potempa, 1990). Additionally, in several cortical and subcortical brain regions there are findings of reduced GABAergic cell density, suggesting that inhibitory circuits in the cerebral cortex may be especially vulnerable to ethanol toxicity (Coleman et al, 2012; Sadrian, Lopez-Guzman, Wilson, & Saito, 2014; Sadrian et al, 2013). At present, it is unclear to what extent these changes are the direct result of cell loss induced by ethanol toxicity, or are secondary effects caused by compensatory brain plasticity that occurs in response to ethanol-induced damage.…”

“…We recently demonstrated that mouse piriform cortex has reduced PV-immunolabeled GABA cells, along with increased neuron excitability, reduced paired-pulse inhibition, and enhanced oscillatory coherence, caused by ethanol treatment at both early and late gestational stages (Sadrian et al, 2013, 2014). The findings suggest that deficits of GABAergic inhibition may cause a characteristic profile of electrophysiological deficits.…”

Developmental ethanol exposure-induced sleep fragmentation predicts adult cognitive impairment

“…Developmental ethanol exposure disrupts proliferation, differentiation, migration, and survival of neurons (Bonthius and West, 1990, West et al, 1990, Ikonomidou et al, 2000, Klintsova et al, 2007, Gil-Mohapel et al, 2010), and FASD is associated with cognitive, behavioral, memory and sensory impairments, as well as heightened susceptibility to seizures (West et al, 1990, Berman and Hannigan, 2000, Riley and McGee, 2005, Morasch and Hunt, 2009, Bell et al, 2010, Carr et al, 2010, Mattson et al, 2010). The specific set of symptoms are dependent on the age, duration and intensity of the ethanol exposure (Riley and McGee, 2005, Sadrian et al, 2014). Beyond the initial wave of ethanol induced damage such as cell death, there is a cascade of cellular, synaptic and network consequences induced by early ethanol exposure – some as a direct result of the ethanol insult, and some as a secondary response to cellular changes induced by that initial insult.…”