Novel murine closed-loop auditory stimulation paradigm elicits macrostructural sleep benefits in neurodegeneration.

Boosting slow-wave activity (SWA) by modulating slow waves through closed-loop auditory stimulation (CLAS) might provide a powerful non-pharmacological tool to investigate the link between sleep and neurodegeneration. Here, we established mouse CLAS (mCLAS)-mediated SWA enhancement and explored its effects on sleep deficits in neurodegeneration, by targeting the up-phase of slow waves in mouse models of Alzheimer's disease (AD, Tg2576) and Parkinson's disease (PD, M83). We found that tracking a 2 Hz component of slow waves leads to highest precision of non-rapid eye movement (NREM) sleep detection in mice, and that its combination with a 30° up-phase target produces a significant 15-30% SWA increase from baseline in wild-type (WT) and transgenic (TG) mice versus a mock stimulation group.

Role of sleep in neurodegeneration: the consensus report of the 5th Think Tank World Sleep Forum.

Sleep abnormalities may represent an independent risk factor for neurodegeneration. An international expert group convened in 2021 to discuss the state-of-the-science in this domain. The present article summarizes the presentations and discussions concerning the importance of a strategy for studying sleep- and circadian-related interventions for early detection and prevention of neurodegenerative diseases.

Visualizing alpha-synuclein and iron deposition in M83 mouse model of Parkinson's disease .

Background: Abnormal alpha-synuclein and iron accumulation in the brain play an important role in Parkinson's disease (PD). Herein, we aim at visualizing alpha-synuclein inclusions and iron deposition in the brains of M83 (A53T) mouse models of PD .

Methods: Fluorescently labelled pyrimidoindole-derivative THK-565 was characterized by using recombinant fibrils and brains from 10-11 months old M83 mice, which subsequently underwent concurrent wide-field fluorescence and volumetric multispectral optoacoustic tomography (vMSOT) imaging.

Natural Age-Related Slow-Wave Sleep Alterations Onset Prematurely in the Tg2576 Mouse Model of Alzheimer's Disease.

Introduction: Sleep insufficiency or decreased quality have been associated with Alzheimer's disease (AD) already in its preclinical stages. Whether such traits are also present in rodent models of the disease has been poorly addressed, somewhat disabling the preclinical exploration of sleep-based therapeutic interventions for AD.

Methods: We investigated age-dependent sleep-wake phenotype of a widely used mouse model of AD, the Tg2576 line.

Down-phase auditory stimulation is not able to counteract pharmacologically or physiologically increased sleep depth in traumatic brain injury rats.

Modulation of slow-wave activity, either via pharmacological sleep induction by administering sodium oxybate or sleep restriction followed by a strong dissipation of sleep pressure, has been associated with preserved posttraumatic cognition and reduced diffuse axonal injury in traumatic brain injury rats. Although these classical strategies provided promising preclinical results, they lacked the specificity and/or translatability needed to move forward into clinical applications. Therefore, we recently developed and implemented a rodent auditory stimulation method that is a scalable, less invasive and clinically meaningful approach to modulate slow-wave activity by targeting a particular phase of slow waves.

Non-invasive imaging of tau-targeted probe uptake by whole brain multi-spectral optoacoustic tomography.

Purpose: Abnormal tau accumulation within the brain plays an important role in tauopathies such as Alzheimer's disease and frontotemporal dementia. High-resolution imaging of tau deposits at the whole-brain scale in animal disease models is highly desired.

Methods: We approached this challenge by non-invasively imaging the brains of P301L mice of 4-repeat tau with concurrent volumetric multi-spectral optoacoustic tomography (vMSOT) at ~ 115 μm spatial resolution using the tau-targeted pyridinyl-butadienyl-benzothiazole derivative PBB5 (i.

Altered sleep intensity upon DBS to hypothalamic sleep-wake centers in rats.

Deep brain stimulation (DBS) has been scarcely investigated in the field of sleep research. We hypothesize that DBS onto hypothalamic sleep- and wake-promoting centers will produce significant neuromodulatory effects and potentially become a therapeutic strategy for patients suffering severe, drug-refractory sleep-wake disturbances. We aimed to investigate whether continuous electrical high-frequency DBS, such as that often implemented in clinical practice, in the ventrolateral preoptic nucleus (VLPO) or the perifornical area of the posterior lateral hypothalamus (PeFLH), significantly modulates sleep-wake characteristics and behavior.

Slow-wave sleep affects synucleinopathy and regulates proteostatic processes in mouse models of Parkinson's disease.

Slow-wave sleep (SWS) modulation in rodent models of Alzheimer’s disease alters extracellular amyloid burden. In Parkinson’s disease (PD), SWS appears to be closely linked with disease symptoms and progression. PD is characterized by damaging intracellular α-synuclein (αSyn) deposition that propagates extracellularly, contributing to disease spread.

Closed-loop auditory stimulation method to modulate sleep slow waves and motor learning performance in rats.

Slow waves and cognitive output have been modulated in humans by phase-targeted auditory stimulation. However, to advance its technical development and further our understanding, implementation of the method in animal models is indispensable. Here, we report the successful employment of slow waves' phase-targeted closed-loop auditory stimulation (CLAS) in rats.

Improved functional and histochemical outcomes in l-DOPA plus tolcapone treated VMAT2-deficient mice.

Parkinson disease is typically treated with L-3,4-dihydroxyphenylalanine (or levodopa) co-prescribed with concentration stabilizers to prevent undesired motor fluctuations. However, the beneficial role of the chronic combined therapy on disease progression has not been thoroughly explored. We hypothesized that tolcapone, a catechol-O-methyl-transferase inhibitor, co-administered with levodopa may offer beneficial long-term disease-modifying effects through its dopamine stabilization actions.

Slow-wave sleep and motor progression in Parkinson disease.

Growing evidence from Alzheimer disease supports a potentially beneficial role of slow-wave sleep in neurodegeneration. However, the importance of slow-wave sleep in Parkinson disease is unknown. In 129 patients with Parkinson disease, we retrospectively tested whether sleep slow waves, objectively quantified with polysomnography, relate to longitudinal changes in Unified Parkinson's Disease Rating Scale motor scores.

Increased Sleep Need and Reduction of Tuberomammillary Histamine Neurons after Rodent Traumatic Brain Injury.

Although sleep-wake disturbances are prevalent and well described after traumatic brain injury, their pathophysiology remains unclear, most likely because human traumatic brain injury is a highly heterogeneous entity that makes the systematic study of sleep-wake disturbances in relation to trauma-induced histological changes a challenging task. Despite increasing interest, specific and effective treatment strategies for post-traumatic sleep-wake disturbances are still missing. With the present work, therefore, we aimed at studying acute and chronic sleep-wake disturbances by electrophysiological means, and at assessing their histological correlates after closed diffuse traumatic brain injury in rats with the ultimate goal of generating a model of post-traumatic sleep-wake disturbances and associated histopathological findings that accurately represents the human condition.

Preliminary Evidence of Apathetic-Like Behavior in Aged Vesicular Monoamine Transporter 2 Deficient Mice.

Apathy is considered to be a core feature of Parkinson's disease (PD) and has been associated with a variety of states and symptoms of the disease, such as increased severity of motor symptoms, impaired cognition, executive dysfunction and dementia. Apart from the high prevalence of apathy in PD, which is estimated to be about 40%, the underlying pathophysiology remains poorly understood and current treatment approaches are unspecific and proved to be only partially effective. In animal models, apathy has been sub-optimally modeled, mostly by means of pharmacological and stress-induced methods, whereby concomitant depressive-like symptoms could not be ruled out.

Damage to Arousal-Promoting Brainstem Neurons with Traumatic Brain Injury.

Study Objectives: Coma and chronic sleepiness are common after traumatic brain injury (TBI). Here, we explored whether injury to arousal-promoting brainstem neurons occurs in patients with fatal TBI.

Methods: Postmortem examination of 8 TBI patients and 10 controls.

Sleep Modulation Alleviates Axonal Damage and Cognitive Decline after Rodent Traumatic Brain Injury.

Unlabelled: Traumatic brain injury (TBI) is a major cause of death and disability worldwide. It produces diffuse axonal injury (DAI), which contributes to cognitive impairment, but effective disease-modifying treatment strategies are missing. We have recently developed a rat model of closed skull TBI that reproduces human TBI consequences, including DAI and clinical sequelae such as memory impairment.

Novel Rat Model of Weight Drop-Induced Closed Diffuse Traumatic Brain Injury Compatible with Electrophysiological Recordings of Vigilance States.

Traumatic brain injury (TBI) is a major cause of persistent disabilities such as sleep-wake disorders (SWD). Rodent studies of SWD after TBI are scarce, however, because of lack of appropriate TBI models reproducing acceleration-deceleration forces and compatible with electroencephalography/myography (EEG/EMG)-based recordings of vigilance states. We therefore adapted the Marmarou impact acceleration model to allow for compatibility with EEG-headset implantation.

Brain catecholamine depletion and motor impairment in a Th knock-in mouse with type B tyrosine hydroxylase deficiency.

Tyrosine hydroxylase catalyses the hydroxylation of L-tyrosine to l-DOPA, the rate-limiting step in the synthesis of catecholamines. Mutations in the TH gene encoding tyrosine hydroxylase are associated with the autosomal recessive disorder tyrosine hydroxylase deficiency, which manifests phenotypes varying from infantile parkinsonism and DOPA-responsive dystonia, also termed type A, to complex encephalopathy with perinatal onset, termed type B. We generated homozygous Th knock-in mice with the mutation Th-p.

Baclofen facilitates sleep, neuroplasticity, and recovery after stroke in rats.

Objective: Sleep disruption in the acute phase after stroke has detrimental effects on recovery in both humans and animals. Conversely, the effect of sleep promotion remains unclear. Baclofen (Bac) is a known non-rapid eye movement (NREM) sleep-promoting drug in both humans and animals.

Selective disruption of dopamine D2 receptors in pituitary lactotropes increases body weight and adiposity in female mice.

Prolactin, a pleiotropic hormone secreted by lactotropes, has reproductive and metabolic functions. Chronically elevated prolactin levels increase food intake, but in some hyperprolactinemic states such as in the global dopamine D2 receptor (D2R) knockout mouse, food intake is not increased. Here, we conduct a cell-specific genetic dissection study using conditional mutant mice that selectively lack D2Rs from pituitary lactotropes (lacDrd2KO) to evaluate the role of elevated prolactin levels without any confounding effect of central D2Rs on motor and reward mechanisms related to food intake.

Central dopamine D2 receptors regulate growth-hormone-dependent body growth and pheromone signaling to conspecific males.

Competition between adult males for limited resources such as food and receptive females is shaped by the male pattern of pituitary growth hormone (GH) secretion that determines body size and the production of urinary pheromones involved in male-to-male aggression. In the brain, dopamine (DA) provides incentive salience to stimuli that predict the availability of food and sexual partners. Although the importance of the GH axis and central DA neurotransmission in social dominance and fitness is clearly appreciated, the two systems have always been studied unconnectedly.