Mechanisms of Sleep/Wake Regulation under Hypodopaminergic State: Insights from MitoPark Mouse Model of Parkinson's Disease.

Sleep/wake alterations are predominant in neurological and neuropsychiatric disorders involving dopamine dysfunction. Unfortunately, specific, mechanisms-based therapies for these debilitating sleep problems are currently lacking. The pathophysiological mechanisms of sleep/wake alterations within a hypodopaminergic MitoPark mouse model of Parkinson's disease (PD) are investigated. MitoPark mice replicate most PD-related sleep alterations, including sleep fragmentation, hypersomnia, and daytime sleepiness. Surprisingly, these alterations are not accounted for by a dysfunction in the circadian or homeostatic regulatory processes of sleep, nor by acute masking effects of light or darkness. Rather, the sleep phenotype is linked with the impairment of instrumental arousal and sleep modulation by behavioral valence. These alterations correlate with changes in high-theta (8-11.5 Hz) electroencephalogram power density during motivationally-charged wakefulness. These results demonstrate that sleep/wake alterations induced by dopamine dysfunction are mediated by impaired modulation of sleep by motivational valence and provide translational insights into sleep problems associated with disorders linked to dopamine dysfunction.

Motivational and Valence-Related Modulation of Sleep/Wake Behavior are Mediated by Midbrain Dopamine and Uncoupled from the Homeostatic and Circadian Processes.

Motivation and its hedonic valence are powerful modulators of sleep/wake behavior, yet its underlying mechanism is still poorly understood. Given the well-established role of midbrain dopamine (mDA) neurons in encoding motivation and emotional valence, here, neuronal mechanisms mediating sleep/wake regulation are systematically investigated by DA neurotransmission. It is discovered that mDA mediates the strong modulation of sleep/wake states by motivational valence. Surprisingly, this modulation can be uncoupled from the classically employed measures of circadian and homeostatic processes of sleep regulation. These results establish the experimental foundation for an additional new factor of sleep regulation. Furthermore, an electroencephalographic marker during wakefulness at the theta range is identified that can be used to reliably track valence-related modulation of sleep. Taken together, this study identifies mDA signaling as an important neural substrate mediating sleep modulation by motivational valence.

Induced Cognitive Impairments Reversed by Grafts of Neural Precursors: A Longitudinal Study in a Macaque Model of Parkinson's Disease.

Parkinson's disease (PD) evolves over an extended and variable period in humans; years prior to the onset of classical motor symptoms, sleep and biological rhythm disorders develop, significantly impacting the quality-of-life of patients. Circadian-rhythm disorders are accompanied by mild cognitive deficits that progressively worsen with disease progression and can constitute a severe burden for patients at later stages. The gold-standard 6-methyl-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) macaque model of PD recapitulates the progression of motor and nonmotor symptoms over contracted periods of time. Here, this multidisciplinary/multiparametric study follows, in five animals, the steady progression of motor and nonmotor symptoms and describes their reversal following grafts of neural precursors in diverse functional domains of the basal ganglia. Results show unprecedented recovery from cognitive symptoms in addition to a strong clinical motor recuperation. Both motor and cognitive recovery and partial circadian rhythm recovery correlate with the degree of graft integration, and in a subset of animals, with in vivo levels of striatal dopaminergic innervation and function. The present study provides empirical evidence that integration of neural precursors following transplantation efficiently restores function at multiple levels in parkinsonian nonhuman primates and, given interindividuality of disease progression and recovery, underlines the importance of longitudinal multidisciplinary assessments in view of clinical translation.

Heterogenous electrophysiological responses of functionally distinct striatal subregions to circadian and sleep-related homeostatic processes.

Basal ganglia (BG) are a set of subcortical nuclei that are involved in the control of a wide variety of motor, cognitive, and affective behaviors. Although many behavioral abnormalities associated with BG dysfunction overlap with the clinical picture precipitated by the lack of sleep, the impact of sleep alterations on neuronal activity in BG is unknown. Using wild-type C57BI mice, we investigated the circadian and sleep-related homeostatic modulation of neuronal activity in the three functional subdivisions of the striatum (i.e. sensorimotor, associative, and limbic striatum). We found no circadian modulation of activity in both ventral and dorsomedial striatum while the dorsolateral striatum displayed a significant circadian rhythm with increased firing rates during the subjective dark, active phase. By combining neuronal activity recordings with electroencephalogram (EEG) recordings, we found a strong modulation of neuronal activity by the nature of vigilance states with increased activity during wakefulness and rapid eye movement sleep relative to nonrapid eye movement sleep in all striatal subregions. Depriving animals of sleep for 6 h induced significant, but heterogenous alterations in the neuronal activity across striatal subregions. Notably, these alterations lasted for up to 48 h in the sensorimotor striatum and persisted even after the normalization of cortical EEG power densities. Our results show that vigilance and sleep states as well as their disturbances significantly affect neuronal activity within the striatum. We propose that these changes in neuronal activity underlie both the well-established links between sleep alterations and several disorders involving BG dysfunction as well as the maladaptive changes in behavior induced in healthy participants following sleep loss.

The circadian system in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy.

Circadian organization of physiology and behavior is an important biologic process that allows organisms to anticipate and prepare for predictable changes in the environment. Circadian disruptions are associated with a wide range of health issues. In patients with neurodegenerative diseases, alterations of circadian rhythms are among the most common and debilitating symptoms. Although a growing awareness of these symptoms has occurred during the last decade, their underlying neuropathophysiologic circuitry remains poorly understood and, consequently, no effective therapeutic strategies are available to alleviate these health issues. Recent studies have examined the neuropathologic status of the different neural components of the circuitry governing the generation of circadian rhythms in neurodegenerative diseases. In this review, we will dissect the potential contribution of dysfunctions in the different nodes of this circuitry to circadian alterations in patients with parkinsonism-linked neurodegenerative diseases (namely, Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy). A deeper understanding of these mechanisms will provide not only a better understanding of disease neuropathophysiology but also holds promise for the development of more effective and mechanisms-based therapies.

Circadian alterations in patients with neurodegenerative diseases: Neuropathological basis of underlying network mechanisms.

Circadian organization of physiology and behavior is an important biological process that allows organisms to anticipate and prepare for daily changes and demands. Disruptions in this system precipitates a wide range of health issues. In patients with neurodegenerative diseases, alterations of circadian rhythms are among the most common and debilitating symptoms. Although a growing awareness of these symptoms has occurred during the last decade, their underlying neuropathophysiological circuitry remains poorly understood and consequently no effective therapeutic strategies are available to alleviate these health issues. Recent studies have examined the neuropathological status of the different neural components of the circuitry governing the generation of circadian rhythms in neurodegenerative diseases. In this review, we will dissect the potential contribution of dysfunctions in the different nodes of this circuitry to circadian alterations in patients with neurodegenerative diseases. A deeper understanding of these mechanisms will provide not only a better understanding of disease neuro-pathophysiology, but also hold the promise for developing effective and mechanisms-based therapies.

Circadian and Sleep Dysfunctions in Neurodegenerative Disorders-An Update.

Disruptions of sleep and circadian rhythms are among the most debilitating symptoms in patients with neurodegenerative diseases. Their underlying pathophysiology is multilayered and multifactorial. Recent evidence suggests that sleep and circadian disturbances may influence the neurodegenerative processes as well as be their consequence. In this perspective, we provide an update of the current understanding of sleep and circadian dysregulation in Alzheimer's, Parkinson's, and Huntington's diseases.

Chronotherapies for Parkinson's disease.

Parkinson's disease (PD) is the second-most common progressive neurodegenerative disorder. Although the clinical diagnosis of PD is still based on its cardinal motor dysfunctions, several non-motor symptoms (NMS) have been established as integral part of the disease. Unlike motor disorders, development of therapies against NMS are still challenging and remain a critical unmet clinical need. During the last decade, several studies have characterised the molecular, physiological and behavioural alterations of the circadian system in PD patients. As a consequence, and given the ubiquitous nature of circadian rhythms in the entire organism, the biological clock has emerged as a potential therapeutic target to ease suffering from both motor and NMS in PD patients. Here we discuss the emerging field of using bright light, physical exercise and melatonin as chronotherapeutic tools to alleviate motor disorders, sleep/wake alterations, anxiety and depression in PD patients. We also highlight the potential of these readily available therapies to improve the general quality of life and wellbeing of PD patients. Finally, we provide specific data- and mechanisms-driven recommendations that might help improve the therapeutic benefit of light and physical exercise in PD patients.

Circadian and Homeostatic Modulation of Multi-Unit Activity in Midbrain Dopaminergic Structures.

Although the link between sleep disturbances and dopamine (DA)-related neurological and neuropsychiatric disorders is well established, the impact of sleep alterations on neuronal activity of midbrain DA-ergic structures is currently unknown. Here, using wildtype C57Bl mice, we investigated the circadian- and sleep-related modulation of electrical neuronal activity in midbrain ventral-tegmental-area (VTA) and substantia nigra (SN). We found no significant circadian modulation of activity in SN while VTA displayed a low amplitude but significant circadian modulation with increased firing rates during the active phase. Combining neural activity recordings with electroencephalogram (EEG) recordings revealed a strong vigilance state dependent modulation of neuronal activity with increased activity during wakefulness and rapid eye movement sleep relative to non-rapid eye movement sleep in both SN and VTA. Six-hours of sleep deprivation induced a significant depression of neuronal activity in both areas. Surprisingly, these alterations lasted for up to 48 hours and persisted even after the normalization of cortical EEG waves. Our results show that sleep and sleep disturbances significantly affect neuronal activity in midbrain DA structures. We propose that these changes in neuronal activity underlie the well-known relationship between sleep alterations and several disorders involving dysfunction of the DA circuitry such as addiction and depression.

Heterogeneity in the circadian and homeostatic modulation of multiunit activity in the lateral hypothalamus.

The lateral hypothalamus (LH) is a relatively large hypothalamic structure containing several neurochemically different, but spatially intermingled, neuronal populations. While the role of these neurons in the homeostatic regulation of diverse physiological and behavioral functions such as sleep/wake cycle has been studied extensively, the impact of sleep history on the electrophysiology of the LH and whether this effect is homogenous across LH is unknown. By combining multiunit activity (MUA) recordings in different regions of LH with electroencephalogram recordings in freely moving rats, we unravelled a heterogeneity of neural-activity patterns within different subregions of LH. This heterogeneity was evident in both the circadian and the vigilance state-dependent modulation of MUA. Interestingly, and consistent with this heterogeneity under baseline conditions, the magnitude of MUA suppression following 6 hr of sleep deprivation (SD) was also different within different locations of LH. Unlike the cortex and in contrast to the predictions of the synaptic homeostatic hypothesis, no correlation was found between the magnitude of activity increase during SD and the percentage of suppression of MUA during recovery sleep. These data provide in vivo evidence of a functional heterogeneity in the circadian and homeostatic modulation of neuronal activity in LH.

Light Therapy in Parkinson's Disease: Towards Mechanism-Based Protocols.

A growing body of work is investigating the safety and efficacy of light in Parkinson's disease (PD). Here we discuss the potential of this emerging therapy to improve both motor and non-motor symptoms of PD. We also highlight directions for future basic, translational, and clinical research that are critical for the development of mechanism-based protocols of light therapy in PD.

Long-term effects of sleep deprivation on neuronal activity in four hypothalamic areas.

Lack of adequate sleep has become increasingly common in our 24/7 society. Unfortunately diminished sleep has significant health consequences including metabolic and cardiovascular disease and mental disorders including depression. The pathways by which reduced sleep adversely affects physiology and behavior are unknown. We found that 6h of sleep deprivation in adult male rats induces changes in neuronal activity in the lateral hypothalamus, the paraventricular nucleus, the arcuate nucleus and the mammillary bodies. Surprisingly, these alterations last for up to 48h. The data show that sleep loss has prolonged effects on the activity of multiple hypothalamic areas. Our data indicate also that measuring electroencephalographic slow wave activity underestimates the amount of time that the hypothalamus requires to recover from episodes of sleep deprivation. We propose that these hypothalamic changes underlie the well-established relationship between sleep loss and several diseases such as metabolic disorders, stress and depression and that sufficient sleep is vital for autonomic functions controlled by the hypothalamus.

Alterations of the circadian system in Parkinson's disease patients.

Alterations of circadian rhythms are among the most debilitating non-motor symptoms in Parkinson's Disease (PD). Although a growing awareness towards these symptoms has occurred during the last decade, their underlying neuropathophysiology remains poorly understood and consequently no effective therapeutic strategies are available to alleviate these problems. Recent studies have investigated multiple circadian rhythms at different stages of PD. The advances made have allowed an accurate evaluation of the affected underlying pathways and mechanisms. Here I dissect, over disease progression, the relative causal contribution to health impairments in PD patients of dysfunctions in the different components of the neural network governing circadian rhythms. A deeper understanding of these mechanisms will provide not only a greater understanding of disease neuropathology, but also hold the promise for effective therapies. © 2016 International Parkinson and Movement Disorder Society.

Consequences of manganese intoxication on the circadian rest-activity rhythms in the rat.

Manganese (Mn) intoxication is associated with neurological dysfunctions collectively known as Parkinsonism or Manganism. Like in Parkinson's disease, Manganism is associated with motor disturbances, together with non-motor symptoms including cognitive and neuropsychiatric deficits. Although sleep dysfunctions are commonly reported among workers exposed to Mn, their underlying pathophysiology remains unknown. In this study, we investigated the rest-activity rhythms in rats treated daily with MnCl2 (10mg/kg, i.p) for 5weeks. Locomotor activity was assessed under a light-dark (LD) cycle, constant darkness (DD) and during adjustment to 6h shifts of the LD cycle. In LD conditions, Mn-treated rats exhibited a more fragmented and less stable rest-activity rhythm in addition to a reduction in the total 24-h amount of locomotor activity as well as in the activity confined to the active dark phase of the LD. Consequently, a significant decrease in the amplitude of the rest-activity rhythm was observed. These disturbances were displayed during and after Mn treatment. Furthermore, after the 6-h phase advance of the LD cycle, Mn-treated rats failed to re-adjust accurately their behavioral activity to the new shifted LD cycle. Upon release from LD into DD, Mn-treated rats expressed a normal and stable free-running period of their rest-activity rhythm (23.92±0.07h in Mn group vs. 24.01±0.04h in control rats). However, their rest-activity rhythm remained highly fragmented and less stable. Our results provide the first evidence that chronic Mn intoxication leads to impairment of rest-activity rhythms in addition to the motor and non-motor disturbances reported in Manganism.

Modeling sleep alterations in Parkinson's disease: How close are we to valid translational animal models?

Parkinson disease is one of the neurodegenerative diseases that benefited the most from the use of non-human models. Consequently, significant advances have been made in the symptomatic treatments of the motor aspects of the disease. Unfortunately, this translational success has been tempered by the recognition of the debilitating aspect of multiple non-motor symptoms of the illness. Alterations of the sleep/wakefulness behavior experienced as insomnia, excessive daytime sleepiness, sleep/wake cycle fragmentation and REM sleep behavior disorder are among the non-motor symptoms that predate motor alterations and inevitably worsen over disease progression. The absence of adequate humanized animal models with the perfect phenocopy of these sleep alterations contribute undoubtedly to the lack of efficient therapies for these non-motor complications. In the context of developing efficient translational therapies, we provide an overview of the strengths and limitations of the various currently available models to replicate sleep alterations of Parkinson's disease. Our investigation reveals that although these models replicate dopaminergic deficiency and related parkinsonism, they rarely display a combination of sleep fragmentation and excessive daytime sleepiness and never REM sleep behavior disorder. In this light, we critically discuss the construct, face and predictive validities of both rodent and non-human primate animals to model the main sleep abnormalities experienced by patients with PD. We conclude by highlighting the need of integrating a network-based perspective in our modeling approach of such complex syndrome in order to celebrate valid translational models.

Behavioral effects of D3 receptor inhibition and 5-HT4 receptor activation on animals undergoing chronic cannabinoid exposure during adolescence.

Chronic exposure to cannabinoids during adolescence results in long-lasting behavioral deficits that match some symptomatologic aspects of schizophrenia. The aim of this study was to investigate the reversibility of the emotional and the cognitive effects of chronic exposure to cannabinoids during adolescence, via subsequent modulation of the serotoninergic 5-HT4 and dopaminergic D3 receptors. RS67333 as a 5-HT4 agonist and U-99194A as a D3 antagonist were administered separately at 1 mg/kg and 20 mg/kg, and in combination at 0.5 mg/kg and 10 mg/kg to adult animals undergoing chronic treatment with the synthetic cannabinoid receptor agonist WIN55,212-2 (1 mg/kg) during adolescence. Animals were tested for anxiety-like behavior and episodic-like memory in the open field and novel object recognition tests respectively 30 minutes after the last drug administration. Chronic WIN55,212-2 treated animals exhibited a lasting disruption of episodic memory and increased anxiety levels. The effect on episodic-like memory were partially restored by acute administration of RS67333 and U-99194A and completely by administration of both drugs in combination at lower doses. However, only RS67333 (20 mg/kg) improved the anxiogenic-like effect of WIN55,212-2. These findings give further support that chronic exposure to cannabinoids during adolescence may be used as an animal model for schizophrenia, and highlight D3 and 5-HT4 receptors as potential targets for an enhanced treatment of the cognitive aspect of this disease.

Increased DAT binding in the early stage of the dopaminergic lesion: a longitudinal [11C]PE2I binding study in the MPTP-monkey.

The delayed appearance of motor symptoms in PD poses a crucial challenge for early detection of the disease. We measured the binding potential of the selective dopamine active transporter (DAT) radiotracer [(11)C]PE2I in MPTP-treated macaque monkeys, thus establishing a detailed profile of the nigrostriatal DA status following MPTP intoxication and its relation to induced motor and non-motor symptoms. Clinical score and cognitive performance were followed throughout the study. We measured longitudinally in vivo the non-displaceable binding potential to DAT in premotor, motor-recovered (i.e. both non-symptomatic) and symptomatic MPTP-treated monkeys. Results show an unexpected and pronounced dissociation between clinical scores and [(11)C]PE2I-BP(ND) during the premotor phase i.e. DAT binding in the striatum of premotor animals was increased around 20%. Importantly, this broad increase of DAT binding in the caudate, ventral striatum and anterior putamen was accompanied by i) deteriorated cognitive performance, showing a likely causal role of the observed hyperdopaminergic state (Cools, 2011; Cools and D'Esposito, 2011) and ii) an asymmetric decrease of DAT binding at a focal point of the posterior putamen, suggesting that increased DAT is one of the earliest, intrinsic compensatory mechanisms. Following spontaneous recovery from motor deficits, DAT binding was greatly reduced as recently shown in-vivo with other radiotracers (Blesa et al., 2010, 2012). Finally, high clinical scores were correlated to considerably low levels of DAT only after the induction of a stable parkinsonian state. We additionally show that the only striatal region which was significantly correlated to the degree of motor impairments is the ventral striatum. Further research on this period should allow better understanding of DA compensation at premature stages of PD and potentially identify new diagnosis and therapeutic index.