Phosphodiesterase 10A inhibition attenuates sleep deprivation-induced deficits in long-term fear memory

Abstract

Sleep, particularly rapid eye movement (REM) sleep, is implicated in the consolidation of emotional memories. In the present study, we investigated the protective effects of a phosphodiesterase 10A (PDE10A) inhibitor MP-10 on deficits in long-term fear memory induced by REM sleep deprivation (REM-SD). REM-SD caused deficits in long-term fear memory, however, MP-10 administration ameliorated the deleterious effects of REM-SD on long term fear memory. Brain-derived neurotropic factor (BDNF) and phosphorylated cAMP response element-binding protein (pCREB) were altered in specific brain regions associated with learning and memory in REM-SD rats. Accordingly, REM-SD caused a significant decrease of pCREB in hippocampus and striatum and a significant decrease of BDNF in the hippocampus, striatum and amygdala, however, MP-10 reversed the effects of REM-SD in a dose-dependent manner. Our findings suggest that REM-SD disrupts the consolidation of long-term fear memory and that administration of MP-10 protects the REM-SD-induced deficits in fear memory, which may be due to the MP-10-induced expression of BDNF in the hippocampus, striatum and amygdala, and phosphorylation of CREB in the hippocampus and striatum.

Convergent Mechanisms Underlying Rapid Antidepressant Action

“…In addition, administration of ketamine, GluN2-NMDAR antagonists, mGluR 2/3 antagonists and electroconvulsive shock reverse chronic stress-induced reduction in BDNF levels in the PFC [95, 198] and hippocampus [198, 310–312] of rodents, suggesting that BDNF induction could be considered as a marker of rapid antidepressant efficacy. Short-term (6–48 h) sleep deprivation has been shown to both increase [303, 313] or decrease [314, 315] hippocampal BDNF levels in stress-naïve rats, and has been shown to restore decreased BDNF levels in the hippocampus following chronic stress [316]. Moreover, although scopolamine administration has been shown to exert its antidepressant actions via a mechanism requiring activity-dependent increased BDNF release [298], there are controversial results showing decreased BDNF levels following scopolamine administration [317–322].…”

Activation of brain‐derived neurotrophic factor signaling in the basal forebrain reverses acute sleep deprivation‐induced fear memory impairments

“…Interestingly, the enhanced BDNF expression could also activate basal forebrain cholinergic neurons (Nonomura & Hatanaka, 1992) and then resulted in an increase of BDNF mRNA expression in the hippocampus (Boatell et al, 1992). Moreover, rescue of impaired cAMP signaling after short‐term sleep deprivation could enhance BDNF expression in the hippocampus and mitigate sleep deprivation‐induced fear memory impairments (Vecsey et al, 2009) (Guo et al, 2016). Considering that the main subcortical input of hippocampus is from the medial septum of the basal forebrain cholinergic system (Solari & Hangya 2018) and the septo‐hippocampal pathway, the main projection of medial septal neurons (Everitt & Robbins, 1997), is also important for processing of aversive information during fear conditioning (Calandreau, Jaffard, & Desmedt, 2007; Stepanichev, Lazareva, Tukhbatova, Salozhin, & Gulyaeva, 2014), there might be a possibility that sleep deprivation‐induced increase in basal forebrain BDNF might activate basal forebrain cholinergic neurons which further increased hippocampal BDNF expression and fear memory consolidation.…”

Interactions between Sleep and Emotions in Humans and Animal Models

“…As a result, some animal model studies managed to describe a correlation between REM sleep deprivation and decreased emotional learning. Thus, it was proven that in a paradigm using electrical foot shock fear conditioning learning in rats, REM sleep deprivation or sleep fragmentation could lead to impaired extinction of conditioned fear as well as long-term fear memory deficits [30,31]. Consequent to the cause-effect bidirectional relationship previously discussed in humans, Wellman et al 2017 [32] showed that fear conditioning and fearful context re-exposure altered subsequent REM sleep in Wistar rats [32].…”

“…Furthermore, evidence showed that sleep impairment could also alter fear/emotional memory consolidation through the cyclic adenosine monophosphate (cAMP) and its related transcriptional pathway (CREB) which has been suggested to intensify during REM sleep [78]. In this way, in a study regarding the alleviation of sleep deprivation-induced deficits in long-term fear memory it was demonstrated that under REM sleep deprivation conditions, fear memory deficits observed in rats were accompanied by decreases in CREB proteins and increased catalysis of cAMP in the hippocampus and striatum [31], suggesting that REM sleep plays an important role in the consolidation of long-term fear memory through mechanisms localized in the hippocampus, striatum, and amygdala.…”

“…Selective REM sleep deprivation in rats caused a progressively increased homeostatic drive for REM sleep that correlated with increased brain-derived neurotrophic factor (BDNF) protein expression in the pedunculopontine tegmentum and nucleus subcoeruleus [83], important areas that regulate REM sleep [84]. Guo et al 2016 found that 6 h of REM sleep deprivation in rats did not affect BDNF in the prefrontal cortex, but induced a decrease in BDNF in the hippocampus, striatum, and amygdala, disrupting long-term fear memory [31]. Moreover, early age stress caused by cross-fostering in Wistar rat pups, which altered the REM sleep onset at adulthood and increased the duration during the light period, also lowered the BDNF expression in the basal forebrain, which may reflect cholinergic neurotransmission defects and suggest that this is a risk factor for developing later cognitive impairment [85].…”