392 research outputs found
Formation and function of neural circuitry in the olfactory bulb of mice with reduced afferent spontaneous activity
No full textFormation and function of neural circuitry in the olfactory bulb of mice with reduced afferent spontaneous activity
No full textNei sistemi sensoriali, i neuroni periferici proiettano i loro assoni in specifici loci del cervello.
La segregazione spaziale delle afferenze sensoriali provvede a creare mappe topografiche che definiscono la qualità e la localizzazione di complessi stimoli sensoriali.
L’attività elettrica gioca un ruolo chiave nella formazione di specifici contatti sinaptici tra i neuroni, sebbene resti ancora da definire il tipo di attività richiesta. In particolare il ruolo dell’attività elettrica spontanea nell’organizzazione topografica del sistema olfattivo, non è noto.
Per rispondere a questa domanda abbiamo studiato il ruolo dell’attività elettrica spontanea nella formazione e nella funzione dei circuiti neurali nel bulbo olfattivo.
Per raggiungere questo obiettivo abbiamo utilizzato una linea di topi geneticamente modificati, nei quali l’attività afferente spontanea è ridotta a causa della sovra-espressione di un canale potassio inward rectifier (Kir2.1), in tutti i neuroni olfattivi sensoriali (i topi Kir2.1).
Abbiamo analizzato la formazione della mappa sensoriale, in particolare se la convergenza dei neuroni sensoriali esprimenti il medesimo recettore olfattivo avveniva correttamente nei topi Kir2.1
La convergenza dei neuroni sensoriali in specifici loci del bulbo olfattivo, che porta alla formazione di glomeruli omogenei, cioé glomeruli formati esclusivamente da assoni esprimenti lo stesso recettore olfattivo, è una caratteristica critica della mappa sensoriale. Infatti i glomeruli definiscono le unità funzionali o colonne odorose del sistema.
Abbiamo trovato che in assenza di attività spontanea,
gli assoni dei neuroni sensoriali non convergono a formare un unico glomerulo ma proiettano in molti siti dando luogo a ulteriori glomeruli. Questi addizionali glomeruli sono caratterizzati da una organizzazione eterogenea, risultano cioè formati da assoni di neuroni sensoriali esprimenti recettori olfattivi diversi.
Per capire se l’attività afferente spontanea potesse avere un ruolo anche sulle cellule postsinaptiche del bulbo olfattivo, abbiamo analizzato le cellule mitrali, i principali neuroni di output, e le cellule dei granuli, i principali neuroni inibitori, del bulbo olfattivo.
Analizzando lo sviluppo morfologico del dendrite apicale delle cellule mitrali non abbiamo trovato alcuna differenza significativa nei topi Kir2.1 rispetto ai controlli. Per quanto concerne le cellule dei granuli, studiando la neurogenesi e la migrazione delle cellule dei granuli di nuova generazione, non abbiamo riscontrato differenze significative nei topi Kir2.1 rispetto ai controlli. Tuttavia l’analisi morfologica dell’arborizzazione dendritica delle cellule dei granuli ha messo in evidenza una ridotta densità di filopodi/spine nei topi Kir2.1 rispetto ai controlli.
Per analizzare le conseguenze funzionali di queste alterazioni anatomiche abbiamo eseguito specifici test comportamentali. I dati che abbiamo ottenuto indicano chiaramente che i topi Kir2.1 non erano in grado di discriminare tra due odori che attivano glomeruli che hanno distribuzione spaziale molto simile, quali gli enantiomeri. Tuttavia i topi Kir2.1 mantenevano la capacità di distinguere odori che attivano glomeruli posti in aree molto diverse del bulbo, quali l’acido 2-metilbutirrico e l’acido ciclobutancarbossilico (2Mb e CB).
Dato l’elevato grado di plasticità del sistema olfattivo, ci siamo chiesti se la manipolazione dell’attività elettrica in età adulta poteva influenzare la mappa sensoriale.
Sfruttando la possibilità di indurre l’espressione del gene Kir2.1 in momenti diversi della vita dell’animale, abbiamo fatto esprimere il gene Kir2.1 solo in animali adulti per 4 settimane. Abbiamo trovato che l’espressione del gene Kir2.1 in animali adulti alterava l’organizzazione della mappa sensoriale, cioé la specifica convergenza degli assoni dei neuroni sensoriali nel bulbo olfattivo. I dati ottenuti indicano che l’assenza di attività spontanea nell’età adulta causa una “regressione“ nell’organizzazione dei glomeruli. Abbiamo infatti trovato un elevato numero di glomeruli eterogenei che coesistevano coi principali glomeruli omogenei.
I nostri dati suggeriscono che l’attività elettrica spontanea è richiesta per lo sviluppo e il mantenimento della mappa sensoriale. Inoltre abbiamo trovato che le alterazioni morfologiche della circuiteria neuronale nel bulbo olfattivo contribuiscono ad alterare il comportamento olfattivo.In the sensory systems, peripheral neurons project axons in specific loci of the brain. The spatial segregation of the sensory afferents provides topographic maps that define the quality and the location of complex sensory stimuli. Electrical activity plays a critical role in the formation of specific synaptic contacts among neurons, although the type of activity required remains a matter of significant debate. In particular the role of spontaneous activity in the formation of the topographic organization of the olfactory system remains unknown. To address this question we investigated the role of spontaneous electrical activity in circuit formation and function in the olfactory bulb. To accomplish this goal, we took advantage of a line of mice engineered to have very little afferent spontaneous activity due to the over expression of the inward rectifying potassium channel Kir2.1 in the olfactory sensory neurons (Kir2.1 mice). We analyzed the formation of the sensory map, in particular whether the convergence of olfactory sensory neurons expressing the same odorant receptor took place properly in mice with reduced afferent spontaneous activity. The conflation of sensory axons to form homogeneous glomeruli, i.e. glomeruli formed exclusively by axons expressing the same olfactory receptor, in specific loci of the olfactory bulb is a critical feature of the sensory map that in turn defines functional units, i.e. odor columns. We found that in absence of spontaneous activity, the convergence of sensory neurons to form homogenous glomeruli took place but it was coarser than in controls. In particular we observed axons mistargeting that resulted in multiple heterogeneous glomeruli that persist also in adulthood. To ascertain the role of spontaneous activity on the post synaptic elements of the olfactory bulb, we analyzed the mitral cells, the principal output neurons, and the granule cells, the major component of the inhibitor interneurons of the olfactory bulb. We found no difference in the developmental refinement of the apical dendrite of mitral cells in Kir2.1 and in control mice. The neurogenesis and the migration of granule cells was unaltered. However the filopodia-spine density on the dendritic tree of the granule cells was significantly reduced in Kir2.1 mice. To analyze the functional outcome of these anatomical alterations, we performed behaviour experiments. We demonstrated that Kir2.1 mice were unable to discriminate between two odors, such as couple of enantiomers, that elicit very similar spatial patterns of activated glomeruli, while retained the ability to differentiate between odorants, such as 2-methylbutyric acid and cyclobutanecarboxylic acid (2Mb and CB) that activate patterns of glomeruli spatially very distinct. Due to the high degree of plasticity of the olfactory system, we asked whether manipulation of electrical activity in adulthood could affect the already refined neural circuitry in the olfactory bulb. Taking advantage of the inducible nature of the Kir2.1 construct, we allowed the expression of the Kir2.1 channels only in adulthood, for 4 weeks. We found that the expression of the Kir2.1 channel in adults disrupted the organization of the sensory map, namely the convergence of olfactory sensory neuron axons. The absence of spontaneous afferent activity in adults induced a regression in the glomeruli organization. We found supernumerary heterogeneous glomeruli that coexist with the main homogeneous glomeruli. In the sensory systems, peripheral neurons project axons in specific loci of the brain. The spatial segregation of the sensory afferents provides topographic maps that define the quality and the location of complex sensory stimuli. Electrical activity plays a critical role in the formation of specific synaptic contacts among neurons, although the type of activity required remains a matter of significant debate. In particular the role of spontaneous activity in the formation of the topographic organization of the olfactory system remains unknown. To address this question we investigated the role of spontaneous electrical activity in circuit formation and function in the olfactory bulb. To accomplish this goal, we took advantage of a line of mice engineered to have very little afferent spontaneous activity due to the over expression of the inward rectifying potassium channel Kir2.1 in the olfactory sensory neurons (Kir2.1 mice). We analyzed the formation of the sensory map, in particular whether the convergence of olfactory sensory neurons expressing the same odorant receptor took place properly in mice with reduced afferent spontaneous activity. The conflation of sensory axons to form homogeneous glomeruli, i.e. glomeruli formed exclusively by axons expressing the same olfactory receptor, in specific loci of the olfactory bulb is a critical feature of the sensory map that in turn defines functional units, i.e. odor columns. We found that in absence of spontaneous activity, the convergence of sensory neurons to form homogenous glomeruli took place but it was coarser than in controls. In particular we observed axons mistargeting that resulted in multiple heterogeneous glomeruli that persist also in adulthood. To ascertain the role of spontaneous activity on the post synaptic elements of the olfactory bulb, we analyzed the mitral cells, the principal output neurons, and the granule cells, the major component of the inhibitor interneurons of the olfactory bulb. We found no difference in the developmental refinement of the apical dendrite of mitral cells in Kir2.1 and in control mice. The neurogenesis and the migration of granule cells was unaltered. However the filopodia-spine density on the dendritic tree of the granule cells was significantly reduced in Kir2.1 mice. To analyze the functional outcome of these anatomical alterations, we performed behaviour experiments. We demonstrated that Kir2.1 mice were unable to discriminate between two odors, such as couple of enantiomers, that elicit very similar spatial patterns of activated glomeruli, while retained the ability to differentiate between odorants, such as 2-methylbutyric acid and cyclobutanecarboxylic acid (2Mb and CB) that activate patterns of glomeruli spatially very distinct. Due to the high degree of plasticity of the olfactory system, we asked whether manipulation of electrical activity in adulthood could affect the already refined neural circuitry in the olfactory bulb. Taking advantage of the inducible nature of the Kir2.1 construct, we allowed the expression of the Kir2.1 channels only in adulthood, for 4 weeks. We found that the expression of the Kir2.1 channel in adults disrupted the organization of the sensory map, namely the convergence of olfactory sensory neuron axons. The absence of spontaneous afferent activity in adults induced a regression in the glomeruli organization. We found supernumerary heterogeneous glomeruli that coexist with the main homogeneous glomeruli. All together our data suggest that spontaneous activity is required for the developmental refinement and maintenance of the sensory map. Furthermore we found that the unrefined connectivity of the neural circuitry of the olfactory bulb could affect olfactory discrimination behaviour
Role of the odorant receptor in neuronal connectivity in the olfactory bulb
No full textOlfaction is a highly sophisticated sensory modality able to detect and discriminate thousands of different odours, even at very low concentration. How such a challenging task is achieved remains to be fully understood. A unique feature of the olfactory system is the dual role of the odorant receptor: it does detect odours in the olfactory epithelium but it also contributes to neuronal circuit formation in the olfactory bulb. The odorant receptors are indeed expressed on the cilia that protrude in the nasal cavity, where they bind odorants, and at the axon termini, where they could act as axon guidance molecules. In this review we discuss findings that show how the odorant receptor contributes in regulating neuronal connectivity
THE ROLE OF SPONTANEOUS ACTIVITY IN SCULPITNG CIRCUIT FORMATION AND FUNCTION IN THE OLFACTORY BULB
No full textMitochondrial Ca2+ Signaling and Bioenergetics in Alzheimer’s Disease
No full textAlzheimer’s disease (AD) is a hereditary and sporadic neurodegenerative illness defined by the gradual and cumulative loss of neurons in specific brain areas. The processes that cause AD are still under investigation and there are no available therapies to halt it. Current progress puts at the forefront the “calcium (Ca2+) hypothesis” as a key AD pathogenic pathway, impacting neuronal, astrocyte and microglial function. In this review, we focused on mitochondrial Ca2+ alterations in AD, their causes and bioenergetic consequences in neuronal and glial cells, summarizing the possible mechanisms linking detrimental mitochondrial Ca2+ signals to neuronal death in different experimental AD models
ROLE OF OLIGOPHRENIN 1 IN CIRCUIT FORMATION IN THE OLFACTORY BULB OF A MOUSE MODEL OF x-LINKED INTELLECTUAL DISABILITY
No full textAccelerated Aging Characterizes the Early Stage of Alzheimer’s Disease
No full textFor Alzheimer’s disease (AD), aging is the main risk factor, but whether cognitive impairments due to aging resemble early AD deficits is not yet defined. When working with mouse models of AD, the situation is just as complicated, because only a few studies track the progression of the disease at different ages, and most ignore how the aging process affects control mice. In this work, we addressed this problem by comparing the aging process of PS2APP (AD) and wild-type (WT) mice at the level of spontaneous brain electrical activity under anesthesia. Using local field potential recordings, obtained with a linear probe that traverses the posterior parietal cortex and the entire hippocampus, we analyzed how multiple electrical parameters are modified by aging in AD and WT mice. With this approach, we highlighted AD specific features that appear in young AD mice prior to plaque deposition or that are delayed at 12 and 16 months of age. Furthermore, we identified aging characteristics present in WT mice but also occurring prematurely in young AD mice. In short, we found that reduction in the relative power of slow oscillations (SO) and Low/High power imbalance are linked to an AD phenotype at its onset. The loss of SO connectivity and cortico-hippocampal coupling between SO and higher frequencies as well as the increase in UP-state and burst durations are found in young AD and old WT mice. We show evidence that the aging process is accelerated by the mutant PS2 itself and discuss such changes in relation to amyloidosis and gliosis
„Ausatmungen“. Das Schofar und die Klänge der kommenden Zeit in der Lyrik von Nelly Sachs
No full textThis article deals with some intermedial aspects of Nelly Sachs' poetical work. The focus is on Nelly Sachs' literary confrontation with music; in particular the article will examine the role played by instruments, in particular the shofar, in the poetry of German-Jewish author. In doing so, a new scientific territory will be broached, since the significance of this old instrument - central to the Jewish religious rites to Sachs' oevre hase been regularly overlooked. The aim of the article is to shaw that the Shofar in Nelly Sachs' poems points to a dematerialization, to the dissolution of boundaries and, above all, to the time to come, to the hereafter in its metaphysical meaning of an after death time. Methodologically, a philological-hermeneutic as well as an intertextual approach is used. In addition, Nelly Sachs' poetry is analyzed under an interdisciplinary lens, taking into account not only the literary, but its musical and religious aspects, as well
Lighting Up Ca2+ Dynamics in Animal Models
No full textCalcium (Ca2+) signaling coordinates are crucial processes in brain physiology. Particularly, fundamental aspects of neuronal function such as synaptic transmission and neuronal plasticity are regulated by Ca2+, and neuronal survival itself relies on Ca2+-dependent cascades. Indeed, impaired Ca2+ homeostasis has been reported in aging as well as in the onset and progression of neurodegeneration. Understanding the physiology of brain function and the key processes leading to its derangement is a core challenge for neuroscience. In this context, Ca2+ imaging represents a powerful tool, effectively fostered by the continuous amelioration of Ca2+ sensors in parallel with the improvement of imaging instrumentation. In this review, we explore the potentiality of the most used animal models employed for Ca2+ imaging, highlighting their application in brain research to explore the pathogenesis of neurodegenerative diseases
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