A novel 3D cardiac microtissue model for investigation of cardiovascular complications in rheumatoid arthritis.

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects not only the joints but also has significant cardiovascular (CV) manifestations. The mechanistic interplay between RA and cardiovascular complications is not yet well understood due to the lack of relevant in vitro models. In this study, we established RA cardiac microtisses (cMTs) from iPSC-derived cardiomyocytes (CMs), endothelial cells (ECs) and cardiac fibroblasts (CFs) to investigate whether this fully human 3D multicellular system could serve as a platform to elucidate the connection between RA and CV disorders.

A novel developmental critical period of orexinergic signaling in the primary visual thalamus.

The orexinergic system of the lateral hypothalamus plays crucial roles in arousal, feeding behavior, and reward modulation. Most research has focused on adult rodents, overlooking orexins' potential role in the nervous system development. This study, using electrophysiological and molecular tools, highlights importance of orexinergic signaling in the postnatal development of the rodent dorsolateral geniculate nucleus (DLG), a primary visual thalamic center.

Upregulation of utrophin improves the phenotype of Duchenne muscular dystrophy hiPSC-derived CMs.

Duchenne muscular dystrophy (DMD) is a genetic neuromuscular disease. Although it leads to muscle weakness, affected individuals predominantly die from cardiomyopathy, which remains uncurable. Accumulating evidence suggests that an overexpression of utrophin may counteract some of the pathophysiological outcomes of DMD.

Circadian Clock and Nutrition.

Rhythmicity is a fundamental characteristic of every living organism [...

Metabolic cues impact non-oscillatory intergeniculate leaflet and ventral lateral geniculate nucleus: standard versus high-fat diet comparative study.

The intergeniculate leaflet and ventral lateral geniculate nucleus (IGL/VLG) are subcortical structures involved in entrainment of the brain's circadian system to photic and non-photic (e.g. metabolic and arousal) cues.

High-Fat-Diet-Evoked Disruption of the Rat Dorsomedial Hypothalamic Clock Can Be Prevented by Restricted Nighttime Feeding.

Obesity is a growing health problem for modern society; therefore, it has become extremely important to study not only its negative implications but also its developmental mechanism. Its links to disrupted circadian rhythmicity are indisputable but are still not well studied on the cellular level. Circadian food intake and metabolism are controlled by a set of brain structures referred to as the food-entrainable oscillator, among which the dorsomedial hypothalamus (DMH) seems to be especially heavily affected by diet-induced obesity.

Electrophysiological complexity in the rat dorsomedial hypothalamus and its susceptibility to daily rhythms and high-fat diet.

The dorsomedial hypothalamus (DMH) in amongst the most important brain structures involved in the regulation of feeding behaviour and metabolism. In contrast to other hypothalamic centres, its main role is related to the circadian rhythmicity of food intake and energy homeostasis; both reported to be disrupted in obesity. In modern world, overweight and obesity reached global epidemic proportions.

Intrinsic circadian timekeeping properties of the thalamic lateral geniculate nucleus.

Circadian rhythmicity in mammals is sustained by the central brain clock-the suprachiasmatic nucleus of the hypothalamus (SCN), entrained to the ambient light-dark conditions through a dense retinal input. However, recent discoveries of autonomous clock gene expression cast doubt on the supremacy of the SCN and suggest circadian timekeeping mechanisms devolve to local brain clocks. Here, we use a combination of molecular, electrophysiological, and optogenetic tools to evaluate intrinsic clock properties of the main retinorecipient thalamic center-the lateral geniculate nucleus (LGN) in male rats and mice.

Daily coordination of orexinergic gating in the rat superior colliculus-Implications for intrinsic clock activities in the visual system.

The orexinergic system delivers excitation for multiple brain centers to facilitate behavioral arousal, with its malfunction resulting in narcolepsy, somnolence, and notably, visual hallucinations. Since the circadian clock underlies the daily arousal, a timed coordination is expected between the orexin system and its target subcortical visual system, including the superior colliculus (SC). Here, we use a combination of electrophysiological, immunohistochemical, and molecular approaches across 24 h, together with the neuronal tract-tracing methods to investigate the daily coordination between the orexin system and the rodent SC.

Rhythmic neuronal activities of the rat nucleus of the solitary tract are impaired by high-fat diet - implications for daily control of satiety.

Temporal partitioning of daily food intake is crucial for survival and involves the integration of internal circadian states and external influences such as the light-dark cycle and dietary composition. These intrinsic and extrinsic factors are interdependent with misalignment of circadian rhythms promoting body weight gain, while consumption of a calorie-dense diet elevates the risk of obesity and blunts circadian rhythms. Recently, we defined the circadian properties of the dorsal vagal complex of the brainstem, a structure implicated in the control of food intake and autonomic tone, but whether and how 24 h rhythms in this area are influenced by diet remains unresolved.

LC-MS/MS Analysis Elucidates a Daily Rhythm in Orexin A Concentration in the Rat Vitreous Body.

Orexins are two neuropeptides synthesised mainly in the brain lateral hypothalamic area. The orexinergic system provides arousal-dependent cues for a plethora of brain centres, playing a vital role in feeding behaviour, regulation of the sleep-wake cycle and circadian rhythms. Recently, orexins were found to be produced in the retina of an eye; however, their content in the vitreous body and possible daily pattern of expression have not yet been explored.

Orexin A excites the rat olivary pretectal nucleus via OX receptor in a daily manner.

Pronounced environmental changes between the day and night led to evolution of specialised mechanisms organising their daily physiology, named circadian clocks. Currently, it has become clear that the master clock in the suprachiasmatic nuclei of the hypothalamus is not an exclusive brain site to generate daily rhythms. Indeed, several brain areas, including the subcortical visual system have been recently shown to change their neuronal activity across the daily cycle.

Modulation of the Rat Intergeniculate Leaflet of the Thalamus Network by Norepinephrine.

Circadian rhythms are regulated by a set of brain structures, one of which is the Intergeniculate Leaflet of the Thalamus (IGL). The most recognised role of the IGL is the integration of a variety of stimuli affecting rhythmicity, such as lighting conditions, received by the eye, or light-independent (non-photic) cues, the information about which is delivered via the activation of the non-specific projections. One of them is the norepinephrinergic system originating in the brainstem Locus Coeruleus (LC).

Short Wavelengths Contribution to Light-induced Responses and Irradiance Coding in the Rat Dorsal Lateral Geniculate Nucleus - An In vivo Electrophysiological Approach.

The dorsal lateral geniculate nucleus (dLGN) is the main neuronal station en route to higher visual areas. It receives information about environmental light from retinal photoreceptors whose sensitivity peaks are distributed across a visible spectrum. Here, using electrophysiological multichannel recordings in vivo combined with different light stimulations, we investigated short wavelength contribution to the dLGN responses to light and irradiance coding.

Daily changes in neuronal activities of the dorsal motor nucleus of the vagus under standard and high-fat diet.

Recently, we found that the dorsal vagal complex displays autonomous circadian timekeeping properties  The dorsal motor nucleus of the vagus (DMV) is an executory part of this complex - a source of parasympathetic innervation of the gastrointestinal tract  Here, we reveal daily changes in the neuronal activities of the rat DMV, including firing rate, intrinsic excitability and synaptic input - all of these peaking in the late day  Additionally, we establish that short term high-fat diet disrupts these daily rhythms, boosting the variability in the firing rate, but blunting the DMV responsiveness to ingestive cues  These results help us better understand daily control over parasympathetic outflow and provide evidence on its dependence on the high-fat diet ABSTRACT: The suprachiasmatic nuclei (SCN) of the hypothalamus function as the brain's primary circadian clock, but circadian clock genes are also rhythmically expressed in several extra-SCN brain sites where they can exert local temporal control over physiology and behaviour. Recently, we found that the hindbrain dorsal vagal complex possesses strong daily timekeeping capabilities, with the area postrema and nucleus of the solitary tract exhibiting the most robust clock properties. The possibility that the executory part of this complex - the dorsal motor nucleus of the vagus (DMV) - also exhibits daily changes has not been extensively studied.

Role of Heme-Oxygenase-1 in Biology of Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells.

Heme oxygenase-1 (HO-1, encoded by ) is a cytoprotective enzyme degrading heme into CO, Fe, and biliverdin. HO-1 was demonstrated to affect cardiac differentiation of murine pluripotent stem cells (PSCs), regulate the metabolism of murine adult cardiomyocytes, and influence regeneration of infarcted myocardium in mice. However, the enzyme's effect on human cardiogenesis and human cardiomyocytes' electromechanical properties has not been described so far.

Phasic Neuronal Firing in the Rodent Nucleus of the Solitary Tract .

Phasic pattern of neuronal activity has been previously described in detail for magnocellular vasopressin neurons in the hypothalamic paraventricular and supraoptic nuclei. This characteristic bistable pattern consists of alternating periods of electrical silence and elevated neuronal firing, implicated in neuropeptide release. Here, with the use of multi-electrode array recordings , we aimed to study the firing pattern of neurons in the nucleus of the solitary tract (NTS) - the brainstem hub for homeostatic, cardio-vascular, and metabolic processes.

Neuronal Responses to Short Wavelength Light Deficiency in the Rat Subcortical Visual System.

The amount and spectral composition of light changes considerably during the day, with dawn and dusk being the most crucial moments when light is within the mesopic range and short wavelength enriched. It was recently shown that animals use both cues to adjust their internal circadian clock, thereby their behavior and physiology, with the solar cycle. The role of blue light in circadian processes and neuronal responses is well established, however, an unanswered question remains: how do changes in the spectral composition of light (short wavelengths blocking) influence neuronal activity? In this study we addressed this question by performing electrophysiological recordings in image (dorsal lateral geniculate nucleus; dLGN) and non-image (the olivary pretectal nucleus; OPN, the suprachiasmatic nucleus; SCN) visual structures to determine neuronal responses to spectrally varied light stimuli.

Circadian actions of orexins on the retinorecipient lateral geniculate complex in rat.

Key Points: Rhythmic processes in living organisms are controlled by biological clocks. The orexinergic system of the lateral hypothalamus carries circadian information to provide arousal for the brain during the active phase. Here, we show that orexins exert an excitatory action in three parts of the lateral geniculate nucleus (LGN), in particular upon directly retinorecipient neurons in the non-image forming visual structures.

Melanopsin: From a small molecule to brain functions.

Melanopsin, a G family coupled receptor, found within the ganglion cell layer in the retina, plays an important role in non-image-forming visual functions, including hormone secretion, entrainment of circadian rhythms, cognitive and affective processes. Diffuse projections of melanopsin-containing cells to many brain areas suggest that different responses may involve different neural projections, thus different melanopsin cells. Considering the complexity of the melanopsin system, its contribution to so many different biological functions is not surprising.

Orexin A as a modulator of dorsal lateral geniculate neuronal activity: a comprehensive electrophysiological study on adult rats.

Orexins (OXA, OXB) are hypothalamic peptides playing crucial roles in arousal, feeding, social and reward-related behaviours. A recent study on juvenile rats suggested their involvement in vision modulation due to their direct action on dorsal lateral geniculate (dLGN) neurons. The present study aimed to verify whether a similar action of OXA can be observed in adulthood.

Altered oscillation frequencies in the lateral geniculate complex in the rat model of absence epilepsy.

Absence epilepsy (AE) is a neurological disease that manifests in spike-wave discharges not present in healthy neuronal circuits. Mutations in ion channels directly underlying this rhythmic discharge may additionally affect rhythms in multiple brain centres which disturbances contribute to the epileptic phenotype. Malfunctioning of the light detection system (from retina to subcortical visual structures), heavily dependent on oscillatory activities, could partially explain severe problems with sleep and arousal observed in epileptic patients.

Modulation of Spontaneous and Light-Induced Activity in the Rat Dorsal Lateral Geniculate Nucleus by General Brain State Alterations under Urethane Anesthesia.

The thalamic dorsal lateral geniculate nucleus (dLGN) serves as a gating station for the transfer of light information en route to the primary visual cortex (V1). Although the modulatory input arising from the V1 and several brainstem nuclei to the dLGN is well characterised in higher mammals, little is known about its influence on dLGN activity in rodents. Using simultaneous recordings of electrocorticogram (ECoG) and single unit neuronal activity under urethane anesthesia in Long Evans rats, we managed to show that cyclic changes in the general brain state strongly affect spontaneous activity and light encoding properties of dLGN neurons.

Orexin A depolarises rat intergeniculate leaflet neurons through non-selective cation channels.

Orexins/hypocretins are hypothalamic neuropeptides that have a variety of functions, including maintenance of arousal, control over the sleep/wake cycle, reward and feeding. Accumulating evidence links orexins to the time-keeping system with a documented action in the master clock-the suprachiasmatic nucleus. The intergeniculate leaflet (IGL) is a thalamic structure with the well-known function of collecting photic and non-photic cues to adjust the rhythm of the suprachiasmatic nucleus to changing environmental conditions.

Gamma and infra-slow oscillations shape neuronal firing in the rat subcortical visual system.

Key Points: Neuronal oscillations observed in sensory systems are physiological carriers of information about stimulus features. Rhythm in the infra-slow range, originating from the retina, was previously found in the firing of subcortical visual system nuclei involved in both image and non-image forming functions. The present study shows that the firing of neurons in the lateral geniculate nucleus is also governed by gamma oscillation (∼35 Hz) time-locked to high phase of infra-slow rhythm that codes the intensity of transient light stimulation.