Publications

JTD Keywords: clinical-trials, collagen i, discovery, mcf-7 cells, phenotype, progression, spheroids, translation, tumor microenvironment, Extracellular-matrix

The ability to control neural activity is essential for research not only in basic neuroscience, as spatiotemporal control of activity is a fundamental experimental tool, but also in clinical neurology for therapeutic brain interventions. Transcranial-magnetic, ultrasound, and alternating/direct current (AC/DC) stimulation are some available means of spatiotemporal controlled neuromodulation. There is also light-mediated control, such as optogenetics, which has revolutionized neuroscience research, yet its clinical translation is hampered by the need for gene manipulation. As a drug-based light-mediated control, the effect of a photoswitchable muscarinic agonist (Phthalimide-Azo-Iper (PAI)) on a brain network is evaluated in this study. First, the conditions to manipulate M2 muscarinic receptors with light in the experimental setup are determined. Next, physiological synchronous emergent cortical activity consisting of slow oscillations-as in slow wave sleep-is transformed into a higher frequency pattern in the cerebral cortex, both in vitro and in vivo, as a consequence of PAI activation with light. These results open the way to study cholinergic neuromodulation and to control spatiotemporal patterns of activity in different brain states, their transitions, and their links to cognition and behavior. The approach can be applied to different organisms and does not require genetic manipulation, which would make it translational to humans.

JTD Keywords: brain states, light-mediated control, muscarinic acetylcholine receptors, neuromodulation, Activation, Alternating/direct currents, Basal forebrain, Brain, Brain states, Clinical research, Clinical translation, Controlled drug delivery, Cortex, Forebrain cholinergic system, Genetic manipulations, Higher frequencies, Hz oscillation, Light‐, Light-mediated control, Mediated control, Muscarinic acetylcholine receptors, Muscarinic agonists, Muscarinic receptor, Neurology, Neuromodulation, Neurons, Noradrenergic modulation, Parvalbumin-positive interneurons, Photopharmacology, Receptor-binding, Slow, Spatiotemporal control, Spatiotemporal patterns

PURPOSE OF REVIEW: Obstructive sleep apnea (OSA) is a prevalent disorder with clinically well known mid-term and long-term consequences. It is difficult, however, to investigate the mechanisms causing morbidity in OSA from human studies, owing to confounding factors in patients. Animal research is useful to analyze the various injurious stimuli--intermittent hypoxia/hypercapnia, mechanical stress and sleep disruption--that potentially cause OSA morbidity. This review is focused on the most recent advances in our understanding of the consequences of OSA, achieved as a result of animal models. RECENT FINDINGS: Animal research has improved our knowledge of various aspects of the cardiovascular consequences of OSA: myocardial damage, left ventricular dysfunction, vasoconstriction, hypertension and atherosclerosis. The systemic and metabolic consequences of OSA--inflammation, insulin resistance, alterations in lipid metabolism and hepatic morbidity--have also been investigated with animal models. Our understanding of the mechanisms involved in the neurocognitive consequences of OSA--neuronal and brain alterations and cognitive dysfunctions--has also been improved through animal research. Moreover, animal models have recently been used to investigate the mechanisms of upper airway inflammation and dysfunction. SUMMARY: The simple experimental models used to investigate OSA morbidity are useful for investigating isolated mechanisms. However, more complex and realistic models incorporating the various injurious challenges characterizing OSA are required to more precisely translate the results of animal research to patients and to design potentially preventive and therapeutic strategies.

JTD Keywords: Animal model, Morbidity, Sleep apnea, Translational research