CNR - Institute of Neuroscience CNR
Institute of Neuroscience
 

Project

Neurogenesis in the adult brain

Contrarily to the widely held belief that the number of neurons in the CNS is fixed shortly after birth and that it decreases progressively during life, accumulating evidence indicates that new neurons are generated in the adult brain of all mammalian species including rodents, primates and humans. Although the function of newly generated neurons is still debated, and even if most of them die, some of them are integrated into functional pre-existing circuits. Therefore understanding the factors and molecular mechanisms controlling adult neurogenesis may lead to eventually design experiments aimed to substitute lost neurons during aging or following trauma or as a consequence of neurodegenerative diseases.

Two main sites of neurogenesis exist in the adult brain: the sub-ventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate girus of the hippocampus. In such sites stem cells self-renew, divide to give rise to a large population of rapidly dividing progenitor cells which differentiate into immature neurons, migrate a long or short distance and integrate into functional circuits. It has become clear that stem cell interactions with the special microenvironment of the niche are critical for regulating cell proliferation and cell fate determination. For these reasons we focused our attention on the Rel-NF-κB family of transcription factors which integrate directly extracellular stimuli in rapid transcriptional responses.

We previously demonstrated the presence of distinct NF-κB family members in specific cell populations of the SVZ of the adult brain, suggesting their involvement in postnatal neurogenesis. Now, we extended our previous observations by evaluating the proliferation and maturation of newly generated progenitors in the adult hippocampus of mice carrying a homozygous deletion of the NF-κB1 gene (p50-/-) compared to wild type mice.

By using short time pulses of BrdU and the proliferation marker Ki 67, we demonstrated that proliferation of hippocampal stem/progenitor cells is not altered in p50-/- mice.

 

However when the survival of newly generated cells was evaluated 21 days after a single injection of BrdU, the total number of BrdU+ cells was drastically reduced in p50-/- mice compared to wild type mice, showing that late survival of newly generated cells is compromised in p50-/- mice (Figure 1).

To determine the events related to neuronal maturation that might be disrupted in the absence of p50, we used the microtubule associated protein doublecortin (DCX) as a first indicator of neuronal determination and the calcium binding protein calretinin (CR) as a marker of early postmitotic stages of granule cell development.

No difference could be observed in the number of DCX+ cells in the mutant compared to wild type mice. On the contrary, a significant (40%) reduction in the number of CR+ cells was observed in p50-/- mice with respect to wild type mice.

Altogether these results demonstrate a highly selective defect in adult neurogenesis in the absence of the p50 protein, possibly occurring at the transition between the maturation stages marked by the expression of DCX and CR, the time schedule when young neurons are recruited into functional circuits and network integration occurs.

The functional significance of adult neurogenesis is still highly debated.

To test for the physiological consequences of the alterations in hippocampal neurogenesis, we analyzed mutant and wild type animals for their cognitive performance in hippocampal-dependent learning and memory tasks. Mutant mice have normal learning capacity and their long term memory is intact. On the other hand, they exhibit selective deficits in short term spatial memory. This does not necessarily imply a cause-effect relationship between defective neurogenesis and short term spatial memory defect but the correlation between these phenomena is intriguing and deserves further investigation.
Our work illustrates a specific role for NF-κB p50 in regulating genes involved in the selection of newly generated neurons. Further work is needed to elucidate the complexity of adult neurogenesis regulation and to shed light on the process of neuronal integration into functional circuits.

Publications

  • Denis-Donini S, Dellarole A, Crociara P, Francese MT, Bortolotto V, Quadrato G, Canonico PL, Orsetti M, Ghi P, Memo M, Bonini SA, Ferrari-Toninelli G, Grilli M (2008) Impaired adult neurogenesis associated with short-term memory defects in NF-kappaB p50-deficient mice. J. Neurosci. 28:3911-9.
  • Denis-Donini S, Caprini A, Frassoni C, Grilli M (2005) Members of the NF-kappaB family expressed in zones of active neurogenesis in the postnatal and adult mouse brain. Brain Res. Dev. Brain Res. 154:81-9.

Collaborations

  • M. Grilli, DISCAFF, Università degli Studi del Piemonte orientale.
  • C. Frassoni, Fondazione Istituto Neurologico "C. Besta", Milan, Italy.

 

PI photo

Suzanne Denis-Donini

Contact information

email  E-mail

email  +39 02 5031 4783

Participating staff
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