Fino a quasi tutto il secolo scorso era convinzione radicata nella comunità scientifica che il cervello umano, come quello degli altri mammiferi, si stabilizasse subito dopo la nascita e non potesse avere alcuna possibilità di nuova crescita neuronale e di rimodellamento della propria architettura per tutto il resto dei suoi giorni. Nel 1962 uscì un lavoro su Science di Joseph Altman, un biologo americano, che per la prima volta nella storia della scienza riportava dei dati (ottenuti utilizzando timidina radioattiva per marcare la produzione di nuove cellule nervose), a sostegno della tesi che il cervello dei mammiferi potesse produrre nuovi neuroni.
Questi dati furono criticati e duramente attaccati, in quanto rappresentavano un salto di paradigma rispetto al dogma della indivisibilità dei neuroni e della fissità strutturale del Sistema Nervoso Centrale. Pertanto i lavori di Altman furono ben presto messi da parte e dimenticati per più di 20 anni. Nella seconda metà degli anni ’80, ad opera di Fernando Nottebhom, altro geniale biologo ricercatore americano, uscirono altri lavori che supportavano la neurogenesi nei cervelli dei canarini, e sottolineavano come questa produzione di nuovi neuroni fosse fondamentale per il canto, avvenisse costantemente nell’età adulta e fosse più evidente negli uccelli in libertà piuttosto che in quelli in cattività. Negli anni successivi si andarono progressivamente sommando le evidenze della ricerca sulla possibilità per il cervello di produrre nuovi neuroni. In particolare i dati, ottenuti soprattutto da studi effettuati su topi e scimmie di laboratorio, deponevano per la presenza di neurogenesi anche in età adulta in particolare nella regione dell’ippocampo (Shors, 2008). La questione sulla possibilità di neurogenesi nel cervello umano è stata a lungo dibattuta: il problema era spiegare come potevano inserirsi nuovi neuroni in circuiti sofisticati e ad alta specializzazione senza modificarne l’architettura. Un dato, che sembrerebbe definitivo, a conferma di questa tesi è stato pubblicato nel 2013 da un gruppo di ricercatori del Karolinska Institute di Stoccolma, guidati da Jonas Frisèn. L’idea di questi ricercatori é stata quella di sfruttare il Carbonio14 (presente nell’atmosfera in maniera significativa dai tempi degli esperimenti nucleari su suolo durante la Guerra Fredda, 1955-63) e utilizzarlo come marcatore biologico dell’età dei neuroni: il carbonio infatti entra nella catena alimentare e si fissa nel DNA dei nuovi neuroni, che a questo punto possono essere datati come se fossero un ‘reperto archeologico’. In base a queste misurazioni Frisèn e collaboratori hanno dimostrato che ogni giorno in un umano adulto si formano mediamente circa 700 nuovi neuroni nella regione ippocampale, con un ricambio annuale di circa l’1,75% dei neuroni dell’area, e tale produzione di neurogenesi declina solo lievemente con gli anni. Questo vuol dire che nel corso di una vita di un uomo circa 1/3 dei suoi neuroni ippocampali vengono rinnovati (K.L. Spalding et al, 2013)
Inoltre c’è da considerare che la evidenza di nuovi neuroni era anche difficile da dimostrare in laboratorio, in quanto la neurogenesi (e anche la sopravvivenza dei neuroni neoformati) é molto legata alle condizioni ambientali. E in animali di laboratorio, in condizioni di deprivazione esperenziale, la neurogenesi non avviene (come aveva intuito Nottebhom), o comunque i nuovi neuroni muoiono rapidamente. Interessanti da questo punto di vista sono i dati che depongono per un’aumentata neurogenesi (soprattutto a livello ippocampale) in condizioni di maggiore complessità ambientale (Tashiro et al, 2007), in condizioni di maggiore attività fisica (Stranahan et al, 2006), in situazioni di richieste di apprendimento (Hernandez-Rabaza et al, 2009) (é universalmente riconosciuto in letteratura il ruolo dell’ippocampo nelle funzioni di apprendimento e memoria). Così come è stato dimostrato in animali di laboratorio che situazioni traumatiche perinatali, o nelle prime fasi di vita, determinano una persistente riduzione nella neurogenesi e ridotte capacità di apprendimento in adulto (Lemaire et al, 2000).
Come possiamo definire la neurogenesi?
Quelli presentati in questo post sono una serie di articoli (abstract) sul fenomeno della neurogenesi nei mammiferi e in umano. Gli articoli per intero si possono trovare sul sito http://www.ncbi.nlm.nih.gov/pubmed , quelli indicati come FREE sono scaricabili gratuitamente
Brain Res Bull. 2002 Apr;57(6):737-49.
Neuronal replacement in adult brain. Nottebohm F.
The RockefellerUniversity, New York, NY12545, USA. nottebo@rockvax.rockefeller.edu
The discovery of spontaneous neuronal replacement in the adult vertebrate brain has changed the way in which we think about the biology of memory. This is because neuronal replacement is likely to have an impact on what a brain remembers and what it learns. Neuronal replacement has also changed the way in which we go about exploring new strategies for brain repair. Our new outlook on both these matters is all the more remarkable because of the pervasiveness of the earlier dogma, which for warm-blooded vertebrates relegated neurogenesis to embryonic development and, for a few neuronal classes, early postnatal life. The discovery of constant neuronal replacement in the adult brain was remarkable, too, in that it was not required by what we thought to be the logic of nervous system function. Moreover, no previous facts prepared us for it. Much of the modern theory of learning embraced the view of modifiable synapses as the key players in learning and as the repositories of memory. But if this were so, what would be the point of neuronal replacement in healthy brain tissue? In what follows, I will briefly review the work of Joseph Altman, because he was the first one to challenge the notion that new neurons were not produced in adulthood. I will then review what we know about neuronal replacement in the song system of birds, which my laboratory has studied for many years. In closing, I will offer a general theory of long-term memory that, if true, might explain why adult nervous systems constantly replace some of their neurons.
Lab Anim (NY). 2004 May;33(5):23-5.
A conversation with Fernando Nottebohm, PhD. Interviewed by Michael Eisenstein. Nottebohm F.
During the last 30 years, a number of revolutionary discoveries in the field of neuroscience have come from what was, at first, an unexpected direction: songbird research. Investigations into seasonal and sex-specific differences in birdsong development have led to important revelations about the impact of sex hormones on brain development and the hormonally controlled plasticity of brain structure, as well as the particularly surprising discovery that neurogenesis continues to occur in the adult brain (see Harding, p. 28). The work of Fernando Nottebohm is widely recognized as having played a key role in bringing these findings to light and thus forcing a general re-examination of established principles of neuroscience. Fernando Nottebohm is Dorothea L. Leonhardt Distinguished Professor at The Rockefeller University, and Director of The Rockefeller Field Research Center for Ethology and Ecology, a 1,200-acre facility located in Millbrook, NY, that provides researchers the opportunity to study behavior and brain function under natural conditions. Nottebohm’s pioneering work on the neural control of birdsong has led to major discoveries with large impacts in the fields of animal behavior and neuroscience, and has made him one of the founders of neuroethology, the study of how the nervous system controls animal behavior. Nottebohm is a Member of the National Academy of Sciences, USA, and a Fellow of the American Association for the Advancement of Science and of the AmericanAcademy of Arts and Sciences. We had a chance to sit down with him to discuss his distinguished career working with laboratory birds
Cell. 2013 Jun 6;153(6):1219-27. (FREE in PubMed)
Dynamics of hippocampal neurogenesis in adult humans. Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, Boström E, Westerlund I, Vial C, Buchholz BA, Possnert G, Mash DC, Druid H, Frisén J.
Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.
Adult-born hippocampal neurons are important for cognitive plasticity in rodents. There is evidence for hippocampal neurogenesis in adult humans, although whether its extent is sufficient to have functional significance has been questioned. We have assessed the generation of hippocampal cells in humans by measuring the concentration of nuclear-bomb-test-derived ¹⁴C in genomic DNA, and we present an integrated model of the cell turnover dynamics. We found that a large subpopulation of hippocampal neurons constituting one-third of the neurons is subject to exchange. In adult humans, 700 new neurons are added in each hippocampus per day, corresponding to an annual turnover of 1.75% of the neurons within the renewing fraction, with a modest decline during aging. We conclude that neurons are generated throughout adulthood and that the rates are comparable in middle-aged humans and mice, suggesting that adult hippocampal neurogenesis may contribute to human brain function
Behav Brain Res. 2012 Feb 14;227(2):380-3.
Adult neurogenesis: optimizing hippocampal function to suit the environment. Glasper ER, Schoenfeld TJ, Gould E.
Department of Psychology and Neuroscience Institute, PrincetonUniversity, Princeton, NJ08544, USA. eglasper@princeton.edu
Numerous studies have attempted to determine the function of adult neurogenesis in the hippocampus using methods to deplete new neurons and examine changes in behaviors associated with this brain region. This approach has produced a set of findings that, although not entirely consistent, suggest new neurons are associated with improved learning and reduced anxiety. This paper attempts to synthesize some of these findings into a model that proposes adaptive significance to experience-dependent alterations in new neuron formation. We suggest that the modulation of adult neurogenesis, as well as of the microcircuitry associated with new neurons, by experience prepares the hippocampus to meet the specific demands of an environment that is predictably similar to one that existed previously. Reduced neurogenesis that occurs with persistent exposure to a high threat environment produces a hippocampus that is more likely to respond with behavior that maximizes the chance of survival. Conversely, enhanced neurogenesis that occurs with continual exposure to a rewarding environment leads to behavior that optimizes the chances of successful reproduction. The persistence of this form of plasticity throughout adulthood may provide the neural substrate for adaptive responding to both stable and dynamic environmental conditions
Exp Neurol. 2012 Jan;233(1):12-21 (FREE in PubMed)
Stress, stress hormones, and adult neurogenesis. Schoenfeld TJ, Gould E.
Department of Psychology, Neuroscience Institute, PrincetonUniversity, Princeton
The dentate gyrus of the hippocampus continues to produce new neurons throughout adulthood. Adult neurogenesis has been linked to hippocampal function, including learning and memory, anxiety regulation and feedback of the stress response. It is thus not surprising that stress, which affects hippocampal function, also alters the production and survival of new neurons. Glucocorticoids, along with other neurochemicals, have been implicated in stress-induced impairment of adult neurogenesis. Paradoxically, increases in corticosterone levels are sometimes associated with enhanced adult neurogenesis in the dentate gyrus. In these circumstances, the factors that buffer against the suppressive influence of elevated glucocorticoids remain unknown; their discovery may provide clues to reversing pathological processes arising from chronic exposure to aversive stress.
dott. Pasquale Parise
Psichiatria e Psicoterapeuta
Riferimenti bibliografici:
Altman J.Are new neurons formed in the brains of adult mammals? Science, 1962, 135
Boldrini M, Underwood MD, Hen R, Rosoklija GB, Dwork AJ, et al. Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology 2009;34:2376–89
Hernández-Rabaza V, Llorens-Martín M, Velázquez-Sánchez C, Ferragud A, Arcusa A, et al.Inhibition of adult hippocampal neurogenesis disrupts contextual learning but spares spatial working memory, long-term conditional rule retention and spatial reversal. Neuroscience 2009;159:59–68.
Hodes GE, Yang L, VanKooy J, Santollo J, Shors TJ. Prozac during puberty: distinctive effects on neurogenesis as a function of age and sex. Neuroscience2009;163:609–17.
Lemaire V, Koehl M, LeMoal M, Abrous DN. Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus. Proc. Natl. Acad. Sci. USA 2000;97:11032–37.
Nottebohm F. From bird song to neurogenesis Scientific American 1989 Feb
Shors TJ. From stem cells to grandmother cells: how neurogenesis relates to learning and memory. Cell Stem Cell 2008;3:253–58.
K. L. Spalding, O. Bergmann, K. Alkass, S. Bernard, M. Salehpour, H. B. Huttner, et al. Dynamics of Hippocampal Neurogenesis in Adult Humans Cell, vol. 153, 1219-1227, 6 June 2013
Stranahan A, Kahlil D, Gould E. Social isolation delays the positive effects of running on adult neurogenesis. Nat. Neurosci 2006; 9:526–33.
Tashiro A, Makino H, Gage FH. Experience-specific functional modification of the dentate gyrus through adult neurogenesis: a critical period during an immature stage. J. Neurosci 2007;27:3252–59.
