Developmental alcohol exposure is exhausting: Sleep and the enduring consequences of alcohol exposure during development

Abstract

Prenatal alcohol exposure is the leading nongenetic cause of human intellectual impairment. The long-term impacts of prenatal alcohol exposure on health and well-being are diverse, including neuropathology leading to behavioral, cognitive, and emotional impairments. Additionally negative effects also occur on the physiological level, such as the endocrine, cardiovascular, and immune systems. Among these diverse impacts is sleep disruption. In this review, we describe how prenatal alcohol exposure affects sleep, and potential mechanisms of those effects. Furthermore, we outline the evidence that sleep disruption across the lifespan may be a mediator of some cognitive and behavioral impacts of developmental alcohol exposure, and thus may represent a promising target for treatment.

Keywords: Fetal alcohol spectrum disorder; Insomnia, sleep-dependent memory consolidation; NREM sleep; Sleep homeostasis.

Figure 1

A) Prenatal alcohol exposure has impacts throughout the body and brain in both humans and animal models. B) In the brain, both glutamatergic (Glu) neurons and GABAergic neurons, including those expressing parvalbumin (PV) and somatostatin (SST) are impacted. Glial cells are also modified both anatomically and functionally. In addition, both growth factors such as Brain Derived Neurotrophic Factor (BDNF) and neuromodulators such as acetylcholine (ACh) and orexin are modified, all of which may impact sleep-wake states. While other cells and systems may be impacted, those listed here are most relevant for sleep/wake cycling. C) Finally, these biological changes contribute to a wide range of behavioral, cognitive and emotional symptoms, including sleep disturbances. Created with BioRender.com

Figure 2

A) Sleep and wake states, in both humans and animal models, can be divided into waking, NREM sleep and REM sleep states based on EEG and EMG activity. Waking is characterized by high frequency cortical oscillations and high levels of EMG activity. NREM activity is characterized by high levels of slow-wave and delta band oscillations and reduced EMG activity. REM sleep is characterized by high frequency cortical activity similar to that in waking and very low EMG activity. Recordings displayed are from rat. B) Circuit schematic of networks controlling in sleep and waking. Primary contributors promoting waking are the excitatory projections from the pedunculopontine tegmental nucleus (PPT) and the parabrachial nucleus (PB) to basal forebrain (BF) which broadly projects throughout neocortex. Lateral hypothalamic (LH) neurons contribute to inhibition of sleep promoting regions. Dopamine release by the periaqueductal grey (PAG) area promotes waking, while histamine from the tuberomammillary nucleus (TMN), serotonin from the raphe nucleus (RN) and norepinephrine from the locus coeruleus (LC) have more modulatory roles in promoting cortical arousal. Sleep promoting regions include the preoptic area (POA), specifically the ventrolateral preoptic (VLPO) and median preoptic (MnPO) areas which send GABAergic projections to nodes of the waking system. C) An example of the role of inhibitory interneurons in in sleep features such as slow-waves and delta oscillations. During NREM sleep, subcortical inputs, such as from the claustrum, activate GABAergic interneurons to induce down-states in cortical pyramidal cells, with somatostatin neurons especially critical in this process (Funk et al., 2017; Niethard et al., 2018). D) Summary of the ontogeny of vigilance states in rodents and humans. In both rodents and humans, following an early period of sleep not easily classified as REM or NREM, the percentage of time in REM is relatively high and then reduces as the balance of REM/NREM shifts toward greater NREM. Overall, the amount of time in waking increases with development. Created with BioRender.com based on (Wintler et al., 2020).

Figure 3

A) Summary of the diverse impacts of prenatal alcohol exposure on sleep. Most of these effects have been observed in both humans and animal models. B). Of the diverse impacts of prenatal alcohol exposure on the brain, these specific factors are likely to be the main contributors to sleep disruption. See text for specific examples and details. Created with BioRender.com