Neurobehavioural complications of sleep deprivation: Shedding light on the emerging role of neuroactive steroids

Abstract

Sleep deprivation (SD) is associated with a broad spectrum of cognitive and behavioural complications, including emotional lability and enhanced stress reactivity, as well as deficits in executive functions, decision making and impulse control. These impairments, which have profound negative consequences on the health and productivity of many individuals, reflect alterations of the prefrontal cortex (PFC) and its connectivity with subcortical regions. However, the molecular underpinnings of these alterations remain elusive. Our group and others have begun examining how the neurobehavioural outcomes of SD may be influenced by neuroactive steroids, a family of molecules deeply implicated in sleep regulation and the stress response. These studies have revealed that, similar to other stressors, acute SD leads to increased synthesis of the neurosteroid allopregnanolone in the PFC. Whereas this up-regulation is likely aimed at counterbalancing the detrimental impact of oxidative stress induced by SD, the increase in prefrontal allopregnanolone levels contributes to deficits in sensorimotor gating and impulse control, signalling a functional impairment of PFC. This scenario suggests that the synthesis of neuroactive steroids during acute SD may be enacted as a neuroprotective response in the PFC; however, such compensation may in turn set off neurobehavioural complications by interfering with the corticolimbic connections responsible for executive functions and emotional regulation.

Keywords: allopregnanolone; neurosteroids; prefrontal cortex; sleep deprivation.

Figure 1.. Simplified schematization of neurosteroids biosynthesis by 5-alpha reductase pathway.

For a complete steroid synthesis pathway including other neurosteroids, see Frau and Bortolato 2018.

Figure 2.. Diagram of the hypothesized role of neurosteroids in the neurobehavioral complications induced by sleep deprivation.

Similar to other stressors, acute sleep deprivation leads to increased expression of 5-alpha reductase and synthesis of the neurosteroid allopregnanolone in the PFC. Whereas this upregulation is likely aimed at counterbalancing the detrimental impact of oxidative stress induced by sleep deprivation, such compensatory mechanism may in turn set off neurobehavioral complications by interfering with the corticolimbic connections responsible for executive functions and emotional regulation. Enzymes: CYP21A2: Steroid 21-hydroxylase; 3β-HSD; 3β-hydroxysteroid dehydrogenase; 3α-HSOR: 3α-hydroxysteroid oxidoreductase. Steroids: DOC, deoxycorticosterone; 5α-DHDOC, 5α-dihydro deoxycorticosterone; 3α,5α-THDOC, 3α,5α-tetrahydrodeoxycorticosterone, DHP, 5α-dihydroprogesterone. See text for further details.