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The pioneering experimental studies on sleep deprivation
No full textThe experimental studies on sleep deprivation were initiated by the Russian physician and scientist, Mafie de Manaceine, who studied sleep-deprived puppies kept in constant activity. She reported in 1894 that the complete absence of sleep was fatal in a few days, pointing out that the most severe lesions occurred in the brain. In 1898, the Italian physiologists Lamberto Daddi and Giulio Tarozzi also kept dogs awake by walking them; the animals died after 9-17 days, and their survival was unrelated to food consumption. In the histological study performed by Daddi, degenerative alterations, mainly represented by chromatolytic changes, were observed in neurons of the spinal ganglia, Purkinje cells of the cerebellum, and neurons of the frontal cortex. Daddi ascribed these changes to a state of autointoxication of the brain during insomnia. In 1898, the psychiatrist Cesare Agostini, interested in the psychic phenomena caused by prolonged insomnia in humans, sleep deprived dogs by keeping them in a metallic cag e in order to avoid fatigue. The dogs survived about 2 weeks, and degenerative changes were observed in their brains. In these experimental paradigms, the effect of sleep loss was confounded by motor exhaustion and/or intense sensory stimulation. In spite of the absence of adequate controls, the pioneering studies performed at the end of the 19th century represented the first experimental attempts to relate sleep with neural centers and suggested that sleep is a vital function and that the brain may be affected by insomnia
Sleeping with the clock: pacemaker neurons enter the scene
No full textTheoretical contributions provided by Giuseppe Moruzzi in 1972 and Giovanni Berlucchi in 1970 are here revisited, highlighting an itinerary of knowledge on the relationships between sleep-wake alternation and biological clocks, and on the role of pacemaker neurons. With a modern insight, Moruzzi dealt with the role of homeostatic mechanisms and of "timing devices" in sleep and wake, and he referred to a theory formulated by Berlucchi. This theory, which has remained hidden in a book chapter, stemmed from a careful critical evaluation of previous experimental approaches and theories. With a remarkable intuition, Berlucchi proposed that the sleep-wake cycle is an endogenous biological rhythm, as other body rhythmic functions with which it interacts, and that this cycle is generated, as other rhythms, by a functional group of pacemaker neurons, endowed with endogenous rhythmic properties. Berlucchi viewed pacemaker neurons as hierarchically organized cells, entrained by the environment, controlled by intercellular, synaptic and nonsynaptic communication. All these hypotheses have been subsequently confirmed by discoveries that are here summarized. These issues are still at the forefront of research; many questions, however, are still open
Trypanosoma brucei and the nervous system
No full textAfrican sleeping sickness, characterized by a peculiar pain syndrome and prominent neuropsychiatric symptoms, is caused by the parasite Trypanosoma brucei (T.b.). In experimental T.b. infections, a molecule released from the trypanosomes has been isolated that binds to the CD8 molecule of T cells, whereby T cells are activated to secrete interferon gamma. This cytokine binds to the parasites and triggers them to proliferate, establishing a peculiar bidirectional activating signal system. The hypothesis is presented that the molecules involved in these bidirectional signals might also interact with neurons, thus causing brain dysfunctions. Studies on the molecular interactions between parasites and the nervous system in sleeping sickness might reveal basic mechanisms underlying other neuropsychiatric diseases
Chapter 15: Immediate early gene expression in sleep and wakefulness
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The expression of immediate early genes in the brain during sleep and wake
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Infezione cerebrale nella tripanosomiasi africana sperimentale: meccanismi patogenetici e biomarcatori
No full textIntroduzione. La tripanosomiasi africana umana, denominata anche “malattia del sonno”, è una malattia tropicale “negletta”, tuttora endemica in focolai in zone rurali e remote dell’Africa sub-Sahariana, causata dal parassita extracellulare Trypanosoma brucei (T.b.) trasmesso da punture di mosche del genere Glossina1-3. Nell’ultima decade sono state diagnosticate alcune decine di casi anche in zone non endemiche (in immigrati, espatriati o, raramente, turisti), ponendo un difficile problema diagnostico3. La malattia evolve, nell’uomo e nei modelli sperimentali in roditori, da una prima fase sistemica (emolinfatica) ad una seconda fase meningoencefalitica, con invasione parassitaria del parenchima encefalico e disturbi neuropsichiatrici ingravescenti, che includono caratteristiche alterazioni del sonno e del ciclo sonno/veglia1-4. I meccanismi patogenetici dell’evoluzione della malattia sono solo parzialmente noti1,4. L’infezione è fatale se non trattata. Sono cruciali a fini terapeutici non solo la diagnosi, ma anche la stadiazione della malattia, poiché il secondo stadio viene attualmente curato con farmaci di elevata tossicità che oltrepassano la barriera emato-encefalica. Il criterio di stadiazione tuttora utilizzato, basato sul numero di globuli bianchi nel liquor, non è sufficientemente sensibile. I nostri studi più recenti, basati su modelli animali, si sono prefissi un duplice obiettivo di ricerca di A) efficaci biomarcatori dell’infezione cerebrale, B) chiarimento di meccanismi patogenetici neuroimmunitari.
Metodi e Risultati. A) Riguardo al primo scopo, abbiamo valutato la correlazione tra le alterazioni del ciclo sonno/veglia (monitorate tramite elettroencefalogramma, EEG, in ratti infetti impiantati con sonde telemetriche) e le concentrazioni di interferone (IFN)-gamma e di chemochine IFN-gamma dipendenti (CXCL-9, CXCL-10, CXCL-11) nel siero e nel liquor (mediante saggi ELISA) e nell’encefalo (mediante qPCR). Le analisi dell’EEG di ratti infetti mostrano, durante la fase meningoencefalitica, una frammentazione del sonno e alterazioni della struttura del sonno (e, in particolare, della sequenza di sonno REM e non-REM, così come del sonno e della veglia). Lo studio dell’espressione genica ha mostrato un progressivo e significativo incremento nell’encefalo di IFN-gamma e chemochine IFN-gamma dipendenti e, in particolare, di CXCL-10, nella fase avanzata della malattia (4.8 volte rispetto al controllo), concomitante sia con un significativo incremento di parassiti nell’encefalo, che con un picco di concentrazione della CXCL-10 nel liquor. Di particolare interesse risulta la comparsa, nel siero, di un picco di CXCL-10 all’esordio della fase meningoencefalitica.
B) Per lo studio della risposta immunitaria dell’encefalo (che, come è noto, presenta caratteristiche ben diverse dall’immunità periferica) abbiamo recentemente indagato il ruolo delle cellule dendritiche (dendritic cells, DCs) cerebrali nella tripanosomiasi sperimentale. Le DCs modulano la risposta immunitaria mediante presentazione dell’antigene alle cellule T. In condizioni fisiologiche la presenza delle DCs all’interno del cranio è limitata alle regioni meningeee ed alle sedi perivascolari del parenchima cerebrale, suggerendo un ruolo di immunosorveglianza5. Con studi in vivo mediante microscopia multifotonica in topi infetti, abbiamo dimostrato che, nella fase sistemica della malattia, le DCs stabiliscono contatti con il parassita all’interno dei vasi cerebrali. Successivamente, all’esordio della fase meningoencefalitica, le DCs invadono il parenchima cerebrale, esibendo movimenti rapidi ed ampi che indicano un’attività “di esplorazione” del tessuto. Con il progredire della malattia, le DCs mostrano una significativa diminuzione dei parametri di motilità, tendendo ad aggregarsi in clusters statici che inglobano il parassita. Al contempo, cellule T citotossiche CD8+ ,extravasate nel parenchima, entrano in contatto con il parassita.
Conclusioni. A) I dati puntano a CXCL-10, unitamente al monitoraggio del sonno e della veglia (facilmente realizzabile nell’uomo mediante actigrafia), come possibili biomarcatori di infezione cerebrale nella tripanosomiasi africana. B) I risultati puntano anche ad un ruolo cruciale delle DCs nel presentare antigeni del tripanosoma alle cellule T, e quindi nei meccanismi patogenetici dell’infezione cerebrale, suggerendo la possibilità di controllare le funzioni delle DCs per dirigerle, a scopi terapeutici, verso un’attivazione protettiva.
Supportato dal Wellcome Trust (WT089992MA).
BIBLIOGRAFIA
1. Bentivoglio, M., Mariotti, R., Bertini, G. (2011) Neuroinflammation and brain infections: historical context and current perspectives. Brain Res Rev 66:152-173.
2. Bisoffi, Z., Buonfrate, D., Angheben, A. (2014) Travel, migration and neglected tropical diseases. In: Neglected tropical diseases and conditions of the nervous system (Bentivoglio M, Cavalheiro EA, Kristensson K, Patel N. Eds). Springer, New York, pp. 21-43.
3. Buguet, A., Mpanzou, G., Bentivoglio, M. (2014) Human African trypanosomiasis: a highly neglected neurological disease. In: Neglected tropical diseases and conditions of the nervous system (Bentivoglio M, Cavalheiro EA, Kristensson K, Patel N. Eds). Springer, New York, pp. 165-181.
4. Kristensson K, Nygard M, Bertini G, Bentivoglio M (2010) African trypanosome infections of the nervous system: parasite entry and effects on sleep and synaptic functions. Prog Neurobiol 91:152-171
5. Laperchia C., Allegra Mascaro A. L., Sacconi L., Andrioli A., Grassi-Zucconi G., Bentivoglio M., Buffelli M., Pavone F.S.(2013) Two-photon microscopy imaging of thy1GFP-M transgenic mice: a novel animal model to investigate brain dendritic cell subsets in vivo. PLoS ONE, 8,2, e56144 doi:10.1371/journal.pone.005614
Limbic thalamus and state-dependent behavior: the paraventricular nucleus of the thalamic midline as a node in circadian timing and sleep/wake-regulatory networks.
No full textThe paraventricular thalamic nucleus (PVT), the main component of the dorsal thalamic midline, receives multiple inputs from the brain stem and hypothalamus, and targets the medial prefrontal cortex, nucleus accumbens and amygdala. PVT has been implicated in several functions, especially adaptation to chronic stress, addiction behaviors and reward, mood, emotion. We here focus on the wiring and neuronal properties linking PVT with circadian timing and sleep/wake regulation, and their behavioral implications. PVT is interconnected with the master circadian pacemaker, the hypothalamic suprachiasmatic nucleus, receives direct and indirect photic input, is densely innervated by orexinergic neurons which play a key role in arousal and state transitions. Endowed with prominent wake-related Fos expression which is suppressed by sleep, and with intrinsic neuronal properties showing a diurnal oscillation unique in the thalamus, PVT could represent a station of interaction of thalamic and hypothalamic sleep/wake-regulatory mechanisms. PVT could thus play a strategic task by funneling into limbic and limbic-related targets circadian timing and state-dependent behavior information, tailoring it for cognitive performance and motivated behaviors
Mesenchymal cells from human amniotic fluid survive and migrate after transplantation into adult rat brain
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