Phencyclidine Disrupts Neural Coordination and Cognitive Control by Dysregulating Translation.

Background: Phencyclidine (PCP) causes psychosis, is abused with increasing frequency, and was extensively used in antipsychotic drug discovery. PCP discoordinates hippocampal ensemble action potential discharge and impairs cognitive control in rats, but how this uncompetitive NMDA receptor (NMDAR) antagonist impairs cognition remains unknown. Methods: The effects of PCP were investigated on hippocampal CA1 ensemble action potential discharge in vivo in urethane-anesthetized rats and during awake behavior in mice, on synaptic responses in ex vivo mouse hippocampus slices, in mice on a hippocampus-dependent active place avoidance task that requires cognitive control, and on activating the molecular machinery of translation in acute hippocampus slices. Mechanistic causality was assessed by comparing the PCP effects with the effects of inhibitors of protein synthesis, group I metabotropic glutamate receptors (mGluR1/5), and subunit-selective NMDARs. Results: Consistent with ionotropic actions, PCP discoordinated CA1 ensemble action potential discharge. PCP caused hyperactivity and impaired active place avoidance, despite the rodents having learned the task before PCP administration. Consistent with metabotropic actions, PCP exaggerated protein synthesis-dependent DHPG-induced mGluR1/5-stimulated long-term synaptic depression. Pretreatment with anisomycin or the mGluR1/5 antagonist MPEP, both of which repress translation, prevented PCP-induced discoordination and the cognitive and sensorimotor impairments. PCP as well as the NR2A-containing NMDAR antagonist NVP-AAM077 unbalanced translation that engages the Akt, mTOR (mechanistic target of rapamycin), and 4EBP1 translation machinery and increased protein synthesis, whereas the NR2B-containing antagonist Ro25-6981 did not. Conclusions: PCP dysregulates translation, acting through NR2A-containing NMDAR subtypes, recruiting mGluR1/5 signaling pathways, and leading to neural discoordination that is central to the cognitive and sensorimotor impairments.

Sleep-wake dynamics pre- and post-exposure to chronic social stress.

An analytical approach combining the statistical distributions of the sleep-wake bouts and the Markov transition matrix is used to explain the under-examined association between the microarchitecture of the sleep-wake cycle and susceptibility to chronic social stress in C57BL/6J mice. We separated the sleep-wake transitions into distinct sleep-wake sequences, NREM↔Wake and NREM→REM→Wake, which are controlled by independent neural circuits. Our findings imply greater pull toward the wake leading to early termination and fragmentation of the sleep bouts in the light in both sleep-wake sequences pre- and post-stress. Moreover, the stability of NREM in the NREM↔Wake transition was lower, and the probability of transitioning to wake was higher in susceptible relative to resilient or stress-naïve mice pre- and post-stress. Our findings help elucidate the mechanistic interplay between sleep and mood by suggesting the potential neural underpinnings of sleep disturbances responsible the aberrant transitions of sleep-wake bouts exhibited by the stress-susceptible phenotype.

Blunted diurnal firing in lateral habenula projections to dorsal raphe nucleus and delayed photoentrainment in stress-susceptible mice.

Daily rhythms are disrupted in patients with mood disorders. The lateral habenula (LHb) and dorsal raphe nucleus (DRN) contribute to circadian timekeeping and regulate mood. Thus, pathophysiology in these nuclei may be responsible for aberrations in daily rhythms during mood disorders. Using the 15-day chronic social defeat stress (CSDS) paradigm and in vitro slice electrophysiology, we measured the effects of stress on diurnal rhythms in firing of LHb cells projecting to the DRN (cellsLHb→DRN) and unlabeled DRN cells. We also performed optogenetic experiments to investigate if increased firing in cellsLHb→DRN during exposure to a weak 7-day social defeat stress (SDS) paradigm induces stress-susceptibility. Last, we investigated whether exposure to CSDS affected the ability of mice to photoentrain to a new light-dark (LD) cycle. The cellsLHb→DRN and unlabeled DRN cells of stress-susceptible mice express greater blunted diurnal firing compared to stress-näive (control) and stress-resilient mice. Daytime optogenetic activation of cellsLHb→DRN during SDS induces stress-susceptibility which shows the direct correlation between increased activity in this circuit and putative mood disorders. Finally, we found that stress-susceptible mice are slower, while stress-resilient mice are faster, at photoentraining to a new LD cycle. Our findings suggest that exposure to strong stressors induces blunted daily rhythms in firing in cellsLHb→DRN, DRN cells and decreases the initial rate of photoentrainment in susceptible-mice. In contrast, resilient-mice may undergo homeostatic adaptations that maintain daily rhythms in firing in cellsLHb→DRN and also show rapid photoentrainment to a new LD cycle.

Prolonged Exposure to Social Stress Impairs Homeostatic Sleep Regulation.

Stress and sleep are tightly regulated as a result of the substantial overlap in neurotransmitter signaling and regulatory pathways between the neural centers that modulate mood and sleep-wake cycle. The chronicity of the stressor and variability in coping with it are major determinants of the psychiatric outcomes and subsequent effect on sleep. The regulation of sleep is mediated by the interaction of a homeostatic and a circadian process according to the two-process model. Chronic stress induces stress-related disorders which are associated with deficient sleep homeostasis. However, little is known about how chronic stress affects sleep homeostasis and whether the differences in adaptation to stress distinctively influence sleep. Therefore, we assessed sleep homeostasis in C57BL6/J mice following exposure to 15-d of chronic social defeat stress. We implemented wake:sleep ratio as a behavioral correlate of sleep pressure. Both stress-resilient and stress-susceptible mice displayed deficient sleep homeostasis in post-stress baseline sleep. This was due to poor temporal correlation between frontal slow wave activity (SWA) power and sleep pressure in the dark/active phase. Moreover, the buildup rate of sleep pressure in the dark was lower in susceptible mice in comparison to stress-naïve mice. Additionally, 4-h SD in the dark caused a deficient sleep recovery response in susceptible mice characterized by non-rapid eye movement (NREM) sleep loss. Our findings provide evidence of deficient homeostatic sleep process (S) in baseline sleep in stress-exposed mice, while impaired sleep recovery following a mild enforced wakefulness experienced during the dark was only detected in stress-susceptible mice. This alludes to the differential homeostatic adaptation to stress between susceptible and resilient mice and its effect on sleep regulation.

Abnormal Sleep Signals Vulnerability to Chronic Social Defeat Stress.

There is a tight association between mood and sleep as disrupted sleep is a core feature of many mood disorders. The paucity in available animal models for investigating the role of sleep in the etiopathogenesis of depression-like behaviors led us to investigate whether prior sleep disturbances can predict susceptibility to future stress. Hence, we assessed sleep before and after chronic social defeat (CSD) stress. The social behavior of the mice post stress was classified in two main phenotypes: mice susceptible to stress that displayed social avoidance and mice resilient to stress. Pre-CSD, mice susceptible to stress displayed increased fragmentation of Non-Rapid Eye Movement (NREM) sleep, due to increased switching between NREM and wake and shorter average duration of NREM bouts, relative to mice resilient to stress. Logistic regression analysis showed that the pre-CSD sleep features from both phenotypes were separable enough to allow prediction of susceptibility to stress with >80% accuracy. Post-CSD, susceptible mice maintained high NREM fragmentation while resilient mice exhibited high NREM fragmentation, only in the dark. Our findings emphasize the putative role of fragmented NREM sleep in signaling vulnerability to stress.

The role of dopamine in mood disorders and the associated changes in circadian rhythms and sleep-wake cycle.

Dopamine is primarily produced in the substantia nigra (SN) and the ventral tegmentum area (VTA) in the brain. It plays a well-established role in the motor control, reward, mood regulation and addiction behaviour. Dopamine release has been shown to be regulated by the circadian clock and hence, plays a regulatory role in the sleep-wake cycle. Clinically, dopaminergic agents have been widely used to modulate alertness. The following review offers a demonstration of the heterogeneous dopamine system in the brain and the various studies investigating the circadian rhythmicity of the dopamine system and its regulation of sleep-wake behaviour. Additionally, it suggests a potential link between the circadian clock and the sleep-wake cycle in mood regulation through the dopaminergic system.

Control of recollection by slow gamma dominating mid-frequency gamma in hippocampus CA1.

Behavior is used to assess memory and cognitive deficits in animals like Fmr1-null mice that model Fragile X Syndrome, but behavior is a proxy for unknown neural events that define cognitive variables like recollection. We identified an electrophysiological signature of recollection in mouse dorsal Cornu Ammonis 1 (CA1) hippocampus. During a shocked-place avoidance task, slow gamma (SG) (30-50 Hz) dominates mid-frequency gamma (MG) (70-90 Hz) oscillations 2-3 s before successful avoidance, but not failures. Wild-type (WT) but not Fmr1-null mice rapidly adapt to relocating the shock; concurrently, SG/MG maxima (SGdom) decrease in WT but not in cognitively inflexible Fmr1-null mice. During SGdom, putative pyramidal cell ensembles represent distant locations; during place avoidance, these are avoided places. During shock relocation, WT ensembles represent distant locations near the currently correct shock zone, but Fmr1-null ensembles represent the formerly correct zone. These findings indicate that recollection occurs when CA1 SG dominates MG and that accurate recollection of inappropriate memories explains Fmr1-null cognitive inflexibility.

Impaired cognitive discrimination and discoordination of coupled theta-gamma oscillations in Fmr1 knockout mice.

Fragile X syndrome (FXS) patients do not make the fragile X mental retardation protein (FMRP). The absence of FMRP causes dysregulated translation, abnormal synaptic plasticity and the most common form of inherited intellectual disability. But FMRP loss has minimal effects on memory itself, making it difficult to understand why the absence of FMRP impairs memory discrimination and increases risk of autistic symptoms in patients, such as exaggerated responses to environmental changes. While Fmr1 knockout (KO) and wild-type (WT) mice perform cognitive discrimination tasks, we find abnormal patterns of coupling between theta and gamma oscillations in perisomatic and dendritic hippocampal CA1 local field potentials of the KO. Perisomatic CA1 theta-gamma phase-amplitude coupling (PAC) decreases with familiarity in both the WT and KO, but activating an invisible shock zone, subsequently changing its location, or turning it off, changes the pattern of oscillatory events in the LFPs recorded along the somato-dendritic axis of CA1. The cognition-dependent changes of this pattern of neural activity are relatively constrained in WT mice compared to KO mice, which exhibit abnormally weak changes during the cognitive challenge caused by changing the location of the shock zone and exaggerated patterns of change when the shock zone is turned off. Such pathophysiology might explain how dysregulated translation leads to intellectual disability in FXS. These findings demonstrate major functional abnormalities after the loss of FMRP in the dynamics of neural oscillations and that these impairments would be difficult to detect by steady-state measurements with the subject at rest or in steady conditions.