Mechanisms of information-processing and executive deficits caused by sleep deprivation

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PROJECT SUMMARY / ABSTRACT Sleep loss leads to cognitive disturbances and increases the risk of depression and other psychiatric disorders. These complications pose a staggering socioeconomic burden, yet their biological mechanisms remain poorly understood, limiting the development of effective therapeutic interventions. One of the best tools to elucidate the neurobiological effects of sleep loss is afforded by animal models; however, most of the available behavioral tasks for rodents are inadequate to capture the same manifestations observed in sleep-deprived humans. To overcome this barrier, we developed several information-processing paradigms with high translational validity. These tasks revealed that, in rats, the information-processing deficits caused by acute sleep deprivation (aSD - a manipulation reproducing short-term sleep loss) were due to the activation of GABAA receptors in the prefrontal cortex (PFC). Building on this result, we found that aSD leads to the accumulation of chloride ions inside the pyramidal neurons of the PFC. This alteration reverses the function of GABAA receptors from inhibitory (hyperpolarizing) to excitatory (depolarizing). Furthermore, we found that aSD stimulates the synthesis of allopregnanolone, a neurosteroid that activates these GABAA receptors in the PFC. In contrast with these data, we found that chronic sleep restriction (cSR, a manipulation mimicking prolonged sleep curtailment) reduces allopregnanolone levels in the PFC, and these changes are accompanied by the emergence of depression-related responses. These preliminary data prompt us to hypothesize that sleep loss causes behavioral deficits through converging alterations of chloride homeostasis and neurosteroid synthesis, which in turn lead to GABAA receptor abnormalities in the PFC. The three Aims of our proposal will test this hypothesis by studying the contribution of these mechanisms to the neurobehavioral complications caused by aSD and cSR. These studies will help elucidate the neurobiological mechanisms of the information-processing deficits and depressive symptoms associated with sleep loss. Furthermore, our results may inform the development of new, effective interventions for these complications.