Regenerating the brain : lessons from the Red Spotted Newt

Unlike mammals, adult salamanders can regenerate their brain after injury in a process fuelled by 
neurogenesis. The aim of this thesis is to identify the cells that give rise to new neurons after injury and 
examine the mechanisms controlling the initiation and termination of brain regeneration in the newt. 
The reasons why newts can regenerate their brain while mammals cannot are unknown, and it has been 
argued that the presence of constantly proliferating cells is a prerequisite for regeneration to occur.




In Paper I of this thesis we mapped the distribution of proliferating cells in the adult newt brain 
and identified the areas of the brain where neurons are added under normal conditions. We observed 
that similarly to mammals, neurons are continuously added to the newt forebrain, while no 
neurogenesis was detected in the midbrain. After injury to the newt midbrain, radial glia-like cells 
(RGLs) start to proliferate and progeny of these cells differentiate into neurons. These results show that 
regeneration is not dependent on constitutive neurogenesis.




In Paper II we wanted to test if the neurotransmitter dopamine is involved in controlling 
regeneration of dopaminergic (DA) neurons. We found that synthetically increasing the concentration 
of dopamine in the regenerating newt brain by administration of the dopamine precursor L-dopa, 
inhibits regeneration by blocking the proliferation of the progenitor cells. We also found that 
antagonizing dopamine signalling in the uninjured brain is sufficient to evoke proliferation of the 
otherwise quiescent RGLs and we found that progeny of these cells give rise to increased numbers of 
neurons in the midbrain.




The newt is not the only vertebrate animal able to regenerate its brain; both fish and reptile species 
can repair injured brain. Interestingly, fish and reptiles are also able to survive hypoxia and are exposed 
to these conditions in their natural habitat. In Paper III of my thesis we wanted to examine if the 
ability to regenerate brain tissue is linked to an animal’s ability to survive varying levels of oxygen. We 
observed that the red spotted newt is able to survive hypoxia, but this treatment leads to increased cell 
death in the brain. Reoxygenation of the brain leads to an elevated production of reactive oxygen 
species, which is concomitant with an increase in proliferation of the ventricular progenitor cells, 
suggesting that a regenerative process has been initiated. Inhibiting production of reactive oxygen 
species during reoxygenation results in reduced progenitor cell proliferation.    




The major findings of this thesis are summarized as follows: the red spotted newt is able to 
regenerate areas of the brain that are normally devoid of proliferating cells. In this process, ventricular 
RGLs act as progenitor cells in the adult newt brain and give rise to new neurons after injury. We have 
also shown that the neurotransmitter dopamine inhibits the proliferation of DA progenitor cells in a 
feedback-like manner and thus identified a mechanism for how the brain senses the degree of neuronal 
loss. These results pinpoint several features of naturally occurring brain regeneration and could aid the 
development of techniques to evoke brain regeneration in humans. Finally we have found that the newt, 
similarly to other animals capable of brain regeneration, is able to survive hypoxia. Hypoxia leads to 
increased cell death in the brain, but molecules that are activated by reoxygenation induce regenerative 
mechanisms such as increased proliferation of neural progenitor cells. These discoveries suggest that 
the trait of brain regeneration has evolved together with the capacity to survive variation in oxygen 
levels