Knifefish brain | Laboratory of Neurobiology

Research using standard mammalian model systems of senescence has suggested that a progressive decline in brain structure and function is the inevitable outcome of aging. This process starts shortly after puberty and leads, among others, to stem cell attrition and dramatic decline in adult neurogenesis. However, this notion is challenged by the recent discovery by our laboratory that knifefish lack these hallmarks of gradual brain senescence, thus making this organism a suitable model of negligible (healthy) brain aging.

In our investigations, we have examined possible age-related changes associated with adult neurogenesis in the brain of brown ghost knifefish (Apteronotus leptorhynchus), a teleost fish distinguished by its enormous neurogenic potential. Contrary to the well-established alterations in the mammalian brain during aging, in the brain of this teleostean species we could not find evidence for any significant age-related decline in the absolute levels of stem/progenitor cell proliferation, neuronal and glial differentiation, or long-term survival of newly generated cells. Moreover, there is no indication that the amount of glial fibrillary acidic protein or the number of apoptotic cells in the brain is altered significantly over the course of adult life.

We hypothesize that this first demonstration of negligible cellular senescence in the vertebrate brain is related to the continued growth of this species and to the lack of reproductive senescence during adulthood. The establishment of the adult brain of this species as a novel model of negligible senescence provides new opportunities for the advancement of our understanding of the biology of aging and the fundamental mechanisms that underlie senescence in the brain.

Age-related changes in cell proliferation and stem cell activity. Mitotic cells were labeled through administration of a single pulse of BrdU, followed by a survival time of 2 hours. To identify proliferating stem cells, double immunostaining against BrdU and Sox2 was performed. A-A”: Overview of the distribution of mitotic cells and/or stem cells in the molecular layer of the valvula cerebelli pars medialis, a proliferation zone displaying high mitotic activity in the brain of A. leptorhynchus. The majority of the BrdU-positive cells also express Sox2 (arrows), indicating that they are active stem cells. Note the abundance of cells undergoing mitosis and/or expressing Sox2 in this section, which was taken from the brain of one of the oldest fish used in the present study. Scale bar = 40 μm. B: High-magnification confocal image illustrating actively proliferating (arrows) and quiescent (arrowheads) Sox2-positive stem cells. Scale bar = 5 μm. C-C’: Total and relative numbers of BrdU-labeled cells in the whole brain, as a function of total length of the fish. D-D’: Total and relative numbers of BrdU/Sox2 double-labeled cells in the whole brain, as a function of total length. Closed lines indicate linear regression fits. Dashed lines represent the 90% confidence bounds of these fits. The red dotted lines indicate 2.5-fold decreases over the examined range. (From Traniello et al., 2014.)

Publications:

Traniello, I.M.*, Sîrbulescu, R.F.*, Ilieş, I.*, Zupanc, G.K.H.: Age-related changes in stem cell dynamics, neurogenesis, apoptosis, and gliosis in the adult brain: A novel teleost fish model of negligible senescence. Developmental Neurobiology 74, 514-530 (2014), doi:10.1002/dneu.22145 (* equal contributions)

Ilieş, I.*, Traniello, I.M.*, Sîrbulescu, R.F.*, Zupanc, G.K.H.: Determination of relative age using growth increments of scales as a minimally invasive method in the tropical freshwater Apteronotus leptorhynchus. Journal of Fish Biology 84, 1312-1325 (2014), doi:10.1111/jfb.12354 (* equal contributions)

Ilieş, I.*, Sîrbulescu, R.F.*, Zupanc, G.K.H.: Indeterminate body growth and lack of gonadal decline in the brown ghost knifefish (Apteronotus leptorhynchus), an organism exhibiting negligible brain senescence. Canadian Journal of Zoology 92, 947-953 (2014), doi:10.1139/cjz-2014-0109 (* equal contributions)

Knifefish as a novel vertebrate model system of negligible brain senescence

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