Regenerating brains….. NOT :(

Slide 01

This is cell CIO 4-5-1, one of my favorite cells of all time. I injected this cell with dye in the late 1980s and I still remember the joy that I felt when I found it under the microscope.

Two readers have asked whether the brain regenerates. The answer is “No.” Let’s start by defining regeneration. A salamander that loses a limb will regenerate that limb, meaning that out of the stump grows a new limb that looks and functions as did the previous limb. Octopi regenerate arms. In contrast to amphibians and octopi, many animals including mammals and birds, do not regenerate limbs or even digits. That is why we see 3-legged dogs, one-legged birds and people with missing phalanges with some frequency.

Unlike the limbs of amphibians, vertebrate brains do not regenerate. When part of the brain is removed either because of epilepsy or a brain tumor, people do not re-grow the excised part of the brain. A particularly dramatic illustration of this is the outcome of removing an entire cerebral hemisphere. Hemispherectomy is used (infrequently) to treat intractable epilepsy, most commonly in young children or babies that do not respond to pharmacological treatments. Importantly for our purposes here, the hemisphere does not grow back, meaning there is no anatomical regeneration of the cerebrum. On the other hand, some degree of functional recovery is common, particularly in the youngest patients.

You may be wondering if some degree of regeneration occurs on a microscopic scale. Unfortunately, here too, the answer is largely negative. Consider a tract, meaning a group of axons traveling through the central nervous system. If a tract is severed, the axons on either side of the cut do not re-connect. In contrast, the peripheral environment is far more hospitable to axonal repair. Peripheral axons can re-connect across a lesion. A great deal of research is aimed at identifying the factors that promote axon regrowth peripherally as well as those factors that oppose it centrally. One key piece is that trauma induces glial cells (the non-neuronal cells that outnumber neurons by 10 to 1) to make a scar. The glial scar serves as a barrier and axons have difficultly crossing it. Progress has been made to the extent that a “soup” of growth–promoting and anti-growth-limiting factors can stimulate at least some central re-growth under experimental conditions. This anatomical victory is somewhat Pyrrhic as functional recovery is typically not observed.

The situation is even worse for neurons than for axons. Neurons that die are not replaced. This no-replacement rule stems from the fact that neurons are post-mitotic; once born, neurons do not divide again. They are cells that cannot have progeny.

As I write this, I can hear a cacophony of objections, “what about stem cells?” arising from readers. Well, indeed there are special cells, called progenitor cells, that can give rise to new neurons. These progenitor cells are not themselves neurons. Instead progenitor cells are undifferentiated, holdovers from embryonic and post-natal development. They essentially have not “decided what they are going to be when they grow up”. They remain permanent cellular “children,” not having taken the plunge yet to become neurons or any other differentiated type of cell.

The adult brain has two sources of progenitor cells. Streams of progenitor cells are found in the olfactory bulbs and in the dentate gyrus of the hippocampus. The circumstances under which progenitor cells differentiate into neurons and the fate of neurons born in the adult brain are under active investigation. However, suffice it to say that wholesale production of new neurons is just not happening in the central nervous system.

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