I risultati presentati dimostrano che nel ratto l’allevamento in un ambiente arricchito fin dalla nascita determina un’accelerazione dello sviluppo del sistema visivo, in par-ticolare dell’acuit`a visiva.
Tuttavia, la scoperta pi`u eclatante di questo studio `e che il fattore di crescita insulino-simile IGF-I `e il mediatore degli effetti dell’arricchimento sullo sviluppo dell’acuit`a visiva.
L’arricchimento ambientale accelera lo sviluppo
del-l’acuit`
a visiva
Negli ultimi 50 anni si sono succeduti numerosi lavori, che hanno dimostrato che l’arricchimento ambientale ha molteplici effetti sul sistema nervoso maturo a livello funzionale, anatomico e molecolare (per una review, Rampon e Tsien,2000).
Mancavano, per`o, in letteratura lavori designati ad analizzare un effetto dell’arric-chimento ambientale fin dai primi giorni di vita sullo sviluppo del sistema nervoso. Tale mancanza `e stata recentemente colmata: Bartoletti et al.(2004) e Cancedda et al.(2004) hanno, infatti, dimostrato che un protocollo di arricchimento ambientale precoce ha una robusta influenza sullo sviluppo del sistema visivo.
Il lavoro di Bartoletti et al. (2004) ha chiarito che l’arricchimento ambientale previene gli effetti del dark-rearing sulla maturazione della corteccia visiva, promuovendone il normale sviluppo.
Il lavoro di Cancedda et al. (2004) ha dimostrato, invece, che l’esperienza in un ambiente arricchito, a partire dalla nascita, determina un’accelerazione dello svilup-po dell’acuit`a visiva nel topo, accompagnata a livello elettrofisiologico da un precoce
declino del WM-LTP e preceduta a livello biochimico da un innalzamento dei livelli proteici di BDNF e di GAD65 in corteccia visiva, nonch´e da un’espressione pi`u pre-coce dei geni mediati da CRE.
Noi abbiamo effettuato un’analisi dello sviluppo dell’acuit`a visiva in ratti arricchiti ed in ratti standard, utilizzando il metodo elettrofisiologico di registrazione dei poten-ziali visivi evocati. La tecnica elettrofisiologica, rispetto alla valutazione dell’acuit`a visiva con il metodo comportamentale (Prusky et al., 2000a), ha il vantaggio di dare la possibilit`a di testare le capacit`a visive anche di animali non a criterio per il test comportamentale (Porciatti et al., 1999).
Abbiamo riscontrato che l’arricchimento ambientale determina una consistente acce-lerazione dello sviluppo dell’acuit`a visiva: i ratti arricchiti raggiungono l’acuit`a visiva di un ratto adulto gi`a al giorno postnatale 25 (P25).
Si tratta di un’ulteriore dimostrazione che l’ottimizzazione delle condizioni ambientali fornita dal protocollo di arricchimento abbia un effetto non solo sul cervello adulto, ma anche sulla maturazione del sistema nervoso.
Tuttavia, quali siano i mediatori molecolari dell’arricchimento sullo sviluppo del-l’acuit`a visiva non `e noto.
E’ interessante notare che il lavoro di Bartoletti et al. (2004) ha dimostrato che l’ar-ricchimento ambientale promuove lo sviluppo del sistema visivo anche in condizioni di completa deprivazione di stimoli visivi.
Questo suggerisce che anche fattori, che non sono sotto il diretto controllo dell’espe-rienza visiva, possano contribuire allo sviluppo della corteccia visiva e che sia tramite tali fattori che l’arricchimento ambientale esercita i suoi effetti sul sistema visivo in sviluppo.
Un candidato particolarmente interessante `e IGF-I.
L’arricchimento ambientale influenza i livelli
prote-ici di IGF-I in corteccia visiva
E’ noto ormai da qualche anno che l’attivit`a fisica determina un aumento dei livelli ematici di IGF-I (Schwarz et al., 1996; Wallace et al., 1999).
del-l’uptake dell’IGF-I ematico nel tessuto cerebrale: infatti, in ratti sottoposti ad una sola ora di corsa sulla ruota si pu`o evidenziare una diffusa marcatura di differenti aree cerebrali (corteccia, ippocampo, striato, setto, talamo, ipotalamo, cervelletto e molti nuclei del tronco encefalico) con anticorpi contro IGF-I (Carro et al., 2000).
Dal momento che l’esercizio fisico `e una componente fondamentale della stimolazione fornita dall’arricchimento ambientale, `e ragionevole ritenere che anche l’arricchimento ambientale possa influenzare i livelli di IGF-I nel cervello.
Noi abbiamo, dunque, analizzato i livelli proteici di IGF-I nella corteccia visiva di animali arricchiti e non arricchiti a diverse et`a con un convenzionale protocollo di immunoistochimica. La nostra indagine si `e focalizzata su una finestra precoce della vita postnatale degli animali, da P15 a P25.
Si tratta del primo studio che si propone di esaminare la presenza e lo sviluppo dei livelli proteici di IGF-I in corteccia visiva. Studi precedenti avevano analizzato il pattern di espressione di IGF-I a livello del sistema visivo, ma solo nelle strutture periferiche e sottocorticali (Bondy, 1991).
I dati riportati dimostrano che, per quanto concerne lo sviluppo dei livelli corticali di IGF-I da P15 a P25, negli animali non arricchiti si pu`o osservare un lieve effetto dell’et`a, anche se non si riscontrano differenze significative nella valutazione compa-rativa delle diverse coppie di et`a.
E’ interessante notare che tra P15 e P25 non appare evidente la presenza di un picco dei livelli di IGF-I.
Tuttavia, `e stato osservato che IGF-I nei sistemi sensoriali viene espresso pi`u preco-cemente nelle strutture periferiche e solo successivamente nelle strutture pi`u centrali (Bondy, 1991): dal momento che nella retina le maggiori quantit`a di IGF-I si riscon-trano a cavallo tra la vita embrionale e la vita postnatale, sembra legittimo suggerire che in corteccia visiva si potrebbe ravvisare un transiente aumento dei livelli proteici di IGF-I dopo la nascita, ma prima dell’inizio del periodo critico. Tale ipotesi prende corpo se si pensa all’azione antiapoptotica di IGF-I durante lo sviluppo del sistema nervoso centrale, documentata da numerosi lavori (per una review, vedi D’Ercole et al., 1996; Varela-Nieto et al., 2003), dato che la fase di morte neuronale massiva in corteccia si osserva nei primi 10 giorni di vita postnatale (Hicks e D’Amato, 1968; Spreafico et al., 1995).
l’espres-sione di IGF-I in corteccia visiva ad et`a pi`u precoci di P15.
Negli animali arricchiti lo sviluppo dei livelli di IGF-I in corteccia visiva assume un profilo differente da quello che abbiamo descritto per gli animali non arricchiti: in-fatti, `e evidente la presenza di un picco di IGF-I a P18.
Abbiamo riscontrato una differenza statisticamente significativa tra i livelli di IGF-I nella corteccia di animali arricchiti e quelli degli animali non arricchiti a P18, mentre n´e a P15 n´e a P25 si pu`o rilevare una variabilit`a significativa tra le due condizioni di allevamento.
L’arricchimento ambientale modula, dunque, i livelli proteici di IGF-I nella corteccia visiva in un periodo cruciale della maturazione della stessa, ovvero all’inizio del pe-riodo critico (Berardi et al., 2000): tale osservazione avvalora l’ipotesi, secondo cui questo fattore di crescita possa essere coinvolto nei processi di plasticit`a neurale, che determinano l’accelerazione dello sviluppo dell’acuit`a visiva negli animali allevati in condizioni di arricchimento ambientale.
Resta da chiarire se l’arricchimento ambientale determina un incremento fattivo dell’e-spressione di IGF-I in corteccia visiva o se l’aumento dei livelli della proteina osservato sia dovuto ad un’intensificazione dell’uptake dell’ormone dal circolo ematico.
Inoltre, pensiamo sarebbe stimolante verificare se l’arricchimento ambientale influenzi il contenuto di IGF-I della corteccia visiva anche in stadi pi`u precoci dello sviluppo, considerata l’ipotesi secondo la quale, durante la crescita dei piccoli, due distinte fasi temporali sono importanti nel mediare gli effetti dell’ambiente arricchito sul sistema visivo (Cancedda et al., 2004).
IGF-I media gli effetti dell’arricchimento
ambien-tale sul sistema visivo
Abbiamo dimostrato che i livelli proteici di IGF- I sono incrementati dall’arricchi-mento ambientale in corteccia visiva.
Questo fattore, legandosi ai recettori presenti sulle cellule nervose, determina un sostanziale aumento della loro attivit`a elettrica, inducendo anche la produzione di fattori importanti per la plasticit`a neurale, ed in particolare per la plasticit`a corticale visiva, quali BDNF e NGF (Carro et al., 2000, Berardi et al., 2003). I recettori per
IGF- I sono presenti nella corteccia occipitale (Frolich et al., 1998) e quindi IGF- I potrebbe stimolare il processo di produzione di molecole che favoriscono la plasticit`a corticale.
Noi ci siamo proposti di verificare se IGF- I possa essere un mediatore degli effetti dell’arricchimento sullo sviluppo della corteccia visiva. Abbiamo, quindi, sommini-strato IGF-I per via intracorticale ad animali non arricchiti da P18 a P25.
La scelta dell’et`a a cui iniziare a somministrare IGF-I `e stata effettuata in relazione alla valutazione comparata dell’espressione di IGF- I durante lo sviluppo della cortec-cia visiva in animali allevati in condizioni standard e di arricchimento.
A P25 l’acuit`a visiva degli animali trattati in questo modo non differisce dal valore misurato negli animali allevati nelle gabbie di arricchimento. Quindi, `e sufficiente far aumentare la disponibilit`a di IGF-I per una settimana nella corteccia visiva per mimare il robusto effetto dell’arricchimento sullo sviluppo dell’acuit`a visiva.
Questo suggerisce che l’aumento di IGF-I riscontrato a P18 nella corteccia visiva di ratti arricchiti sia un fattore importante per gli effetti dell’arricchimento sullo svilup-po della corteccia visiva.
Tuttavia, `e possibile che l’incremento delle quantit`a di IGF-I in corteccia visiva, prodotto dal nostro protocollo sperimentale, sia superiore a quello osservabile negli animali arricchiti dalla nascita.
Per dare ulteriore corpo all’ipotesi che l’aumento di IGF-I sia componente cruciale dei meccanismi d’azione dell’arricchimento, abbiamo effettuato l’esperimento oppo-sto, disegnato per verificare se il blocco di IGF- I annulla l’accelerazione dello sviluppo del sistema visivo osservato negli animali arricchiti. Abbiamo, dunque, somministrato JB-1, antagonista di IGF-I per il legame al suo recettore (Pietrzkowski et al., 1992), per via intracorticale ad animali arricchiti da P18 a P25 ed abbiamo riscontrato che a P25 l’acuit`a visiva dei ratti arricchiti trattati con il bloccante non `e statisticamente differente da quella dei ratti allevati in condizioni standard.
I valori di acuit`a visiva misurati nei ratti impiantati con le minipompe contenenti JB-1 sono leggermente inferiori rispetto a quelli ottenuti negli animali standard, ma tale differenza non `e significativa.
Questo risultato dimostra che l’azione di IGF-I `e necessaria affinch´e l’arricchimento ambientale possa esercitare i suoi effetti sullo sviluppo della corteccia visiva. Quindi, nonostante l’arricchimento ambientale possa promuovere l’attivazione di altri fattori,
il fatto che sia sufficiente bloccare IGF-I per cancellare l’azione dell’arricchimento ambientale suggerisce che o tali fattori sono sotto il controllo di IGF-I o non sono sufficienti a promuovere lo sviluppo dell’acuit`a visiva.
Nel complesso, i nostri risultati mostrano, quindi, che IGF-I, essendo necessario e sufficiente per l’accelerazione dello sviluppo dell’acuit`a visiva, pu`o essere considerato un fattore cruciale per l’accelerazione dello sviluppo del sistema visivo, determinato dall’arricchimento ambientale, almeno per quanto riguarda lo sviluppo dell’acuit`a vi-siva.
Si tratta della prima dimostrazione del fatto che un fattore molecolare sia responsa-bile, almeno in parte, degli effetti dell’esperienza ambientale sul sistema nervoso. Come pu`o realizzare l’azione di IGF-I sullo sviluppo dell’acuit`a visiva?
L’espressione dei geni sotto il controllo del promotore CRE `e stata coinvolta in molti paradigmi di plasticit`a in vivo e in vitro nella corteccia visiva, cos`ı come in molte altre regioni cerebrali (Impey et al., 1996; Impey et al., 1998 a, b; Pham et al., 1999a; Barth et al., 2000; Watt e Storm, 2001; Athos et al., 2002; Barrot et al., 2002). Re-centemente `e stato suggerito che essa sia coinvolta nelle fasi precoci del sistema visivo (Pham et al., 2001): infatti questo studio indica che esiste una definita finestra tempo-rale durante lo sviluppo del talamo, in cui `e particolarmente intensa la trascrizione dei geni CRE, in coincidenza con il periodo di raffinamento delle connessioni talamiche. Il lavoro di Cancedda et al. (2004) ha successivamente dimostrato che `e possibile individuare una finestra di espressione dei geni CRE anche durante lo sviluppo della corteccia visiva intorno a P25. Inoltre, la stessa ricerca ha evidenziato che tale finestra `
e anticipata di circa cinque giorni negli animali arricchiti, quindi intorno a P20, e che l’induzione farmacologica del sistema cAMP/CREB mima gli effetti dello sviluppo dell’attivit`a visiva (Cancedda et al., 2004).
Dal momento che l’attivazione della via di cAMP/CREB `e una delle pi`u importanti cascate di trasduzione del segnale, innescate dal legame di IGF-I con il suo recettore (per una review vedi D’Ercole et al., 1996), tali risultati ci suggeriscono che l’azione di IGF-I sullo sviluppo dell’acuit`a visiva possa essere mediata da questo pathway molecolare.
Come abbiamo precedentemente discusso, l’arricchimento ambientale dalla nascita e-sercita i suoi effetti sullo sviluppo della corteccia visiva in due distinte fasi temporali: in un primo tempo l’arricchimento ambientale agisce indirettamente, determinando
un trasferimento di fattori importanti per lo sviluppo dalla madre al piccolo, attra-verso la barriera placentare o attraattra-verso il latte materno, o un incremento dei livelli di cure materne; successivamente, quando i piccoli iniziano ad esplorare attivamente l’ambiente, la complessa stimolazione sensori-motoria fornita dall’ambiente arricchito pu`o direttamente influenzare lo sviluppo del sistema visivo.
Noi abbiamo dimostrato che IGF-I media l’azione diretta dell’ambiente arricchito sullo sviluppo del sistema visivo. Tuttavia, sarebbe interessante esaminare se l’e-spressione di IGF-I sia influenzata anche pi`u precocemente dal nostro protocollo di arricchimento ambientale e se la sua azione in questa finestra temporale possa essere ugualmente essenziale per la maturazione corticale del sistema visivo.
Recentemente `e stato dimostrato che `e possibile rilevare nel latte materno degli ani-mali arricchiti un cospicuo contenuto di IGF-I, statisticamente maggiore di quello del latte materno degli animali non arricchiti (Sale et al., dati non pubblicati). Resta ancora da chiarire, per`o, se questo maggiore apporto trofico a favore dei piccoli arric-chiti abbia un effetto rilevante sullo sviluppo del sistema nervoso.
Infine, ci sembra opportuno sottolineare che i nostri risultati si riferiscono solo allo sviluppo precoce dell’acuit`a visiva indotto dall’arricchimento ambientale; `e stato di-mostrato, tuttavia, che l’ambiente arricchito promuove la maturazione di altri aspetti funzionali del sistema visivo, come lo sviluppo delle colonne di dominanza oculare (Bartoletti et al., 2004): sarebbe doveroso verificare se sia possibile identificare una relazione causale tra tali effetti dell’arricchimento ambientale e l’incremento di IGF-I in corteccia visiva, osservato nel nostro lavoro.
Anche in questo caso IGF-I sembrerebbe un buon candidato, dal momento che `e noto che IGF-I influenza l’espressione di NGF e BDNF (Carro et al., 2000; Thoenen and Sendtner, 2002) e che la sovraespressione di BDNF e la somministrazione di NGF in-fluenzano fortemente i fenomeni di plasticit`a della corteccia visiva (Huang et al.,1999; Lodovichi et al., 2000; Gianfranceschi et al., 2003).
Plasticit`
a corticale nell’adulto
Come abbiamo gi`a ricordato, lo sviluppo della corteccia visiva `e fortemente influen-zato dall’esperienza visiva durante specifici intervalli temporali della vita postnatale, detti periodi critici (Berardi et al., 2000). Durante tali periodi di intensa plasticit`a
l’esperienza sensoriale pu`o produrre modificazioni estese e permanenti dell’organiz-zazione corticale.
Alla fine del periodo critico, la plasticit`a corticale declina. Per alcune strutture, come per esempio la corteccia visiva, il declino della plasticit`a `e molto evidente, mentre in altre aree corticali, come la corteccia somatosensoriale, la corteccia acustica primaria e la corteccia motoria primaria, la plasticit`a `e ancora presente, bench`e si osservi una chiara riduzione della modificabilit`a delle mappe corticali.
La corteccia visiva dell’adulto risponde ancora all’esperienza sensoriale con modifica-zioni plastiche, come documentato dagli effetti dell’apprendimento percettivo (Schoups et al., 2001) e delle lesioni retiniche (Dreher et al., 2001). Tuttavia la misura in cui `e possibile osservare fenomeni di plasticit`a `e fortemente ridotta nell’adulto: la deprivazione monoculare o lo strabismo nell’adulto non hanno effetti e il recupero dell’ambliopia `e molto limitato una volta terminato il periodo critico.
Diversi lavori si sono proposti di identificare fattori che stabilizzano le connessioni sinaptiche e limitano la plasticit`a al periodo critico (Berardi et al., 2003), sui quali potere agire al fine di ripristinare la plasticit`a nell’adulto. Tuttavia gli approcci finora impiegati (Pizzorusso et al., 2002) non sembrano poter avere sbocchi clinici imme-diati.
Dato che IGF-I risulta mediatore della plasticit`a corticale durante lo sviluppo e che i fattori medianti la plasticit`a del periodo critico potrebbero essere cruciali per riaprire la plasticit`a nell’adulto, ci proponiamo di verificare in futuro se la somministrazione di IGF-I ripristina l’efficacia della deprivazione monoculare sulla corteccia visiva del-l’adulto.
IGF-I potrebbe rappresentare un buon candidato per la sperimentazione clinica, in quanto, attraversando la barriera ematoencefalica (Duffy et al., 1988; Reinhardt e Bondy, 1994; Armstrong et al., 2000; Carro et al., 2000; Pulford e Ishii, 2001), pu`o essere somministrato per via sistemica.
I nostri risultati indicano che esperire la complessa stimolazione sensoriale e motoria, fornita dall’ambiente arricchito, durante lo sviluppo postnatale precoce, non solo in-fluenza la maturazione funzionale del sistema visivo nel ratto, ma determina anche alterazioni quantitative del fattore neurotrorofico IGF-I.
Questo effetto pu`o rappresentare un meccanismo tramite il quale il protocollo di ar-ricchimento ambientale dalla nascita determina modificazioni a lungo termine della funzionalit`a e della plasticit`a corticale; infatti, l’azione di questo fattore sembra es-sere necessaria e sufficiente per gli effetti dell’arricchimento ambientale sullo sviluppo dell’acuit`a visiva.
Noi proponiamo che negli animali arricchiti, l’incremento dei livelli proteici di IGF-I in corteccia visiva, come attivatore diretto o indiretto dell’espressione dei geni sot-to il controllo del promosot-tore CRE, possa essere responsabile dell’accelerazione dello sviluppo dell’acuit`a visiva.
Alla luce di questi risultati, `e possibile ipotizzare che lo sviluppo precoce del sistema visivo abbia il suo primum movens in un aumento del passaggio di fattori trofici, come BDNF o IGF-I, dalla madre all’embrione o dalla madre al piccolo e in un’in-tensificazione delle cure materne ricevute dagli animali arricchiti. Successivamente, quando i piccoli iniziano a muoversi e ad esplorare l’ambiente, la ricchezza dell’ambi-ente stesso pu`o direttamente influenzare lo sviluppo della corteccia visiva, tramite la mediazione del fattore di crescita insulino-simile IGF-I.
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