Santiago Ramon y Cajal spent his life - he was born in 1852 - looking down a microscope at thin slices of the brain. You don’t see much unless you stain the slices in a way that shows up the nerve cells (neurons) and other cells of the brain.  Cajal used a method developed by Camillo Golgi, a contemporary Italian neuroscientist. The two were to become implacable enemies.  Cajal is revered as a great neuroscientist because, by careful observation, brilliant intuition and exquisite drawings (Cajal was a talented artist), he developed ideas about the brain, its structure, development and function that last to this day. Among his many discoveries was the realization that neurons didn’t connect directly to each other, but were separated by a space, which we now call a synapse. Golgi disagreed (he was wrong); but they were awarded a Nobel prize together. Cajal also thought that any replacement of neurons by new ones in the adult brain was impossible: “In adult centers the nerve paths are something fixed, ended, immutable. Everything may die, nothing may be regenerated.”  It’s what I was taught as a medical student in the 1960s.

Astonishingly, it's not entirely true (Cajal wasn’t often wrong). There are two or three areas in the adult brain where new neurons are formed, and one of them is the hippocampus. The hippocampus is essential for certain forms of memory.  Episodic memory is the kind that allows you to recall, in some detail, what you did on your last birthday - a kind of internal video. It also allows you to find your way to familiar places because you learn the route. If the hippocampus is damaged, so too are these functions.  There are reports that London taxi drivers, who spend about two years learning routes around London (‘the knowledge’) have larger than usual hippocampi, and that these get bigger as they learn more routes. But the hippocampus is also very prone to damage. For example, a brief period of oxygen lack, which might not affect most of the brain, may seriously damage the hippocampus. There are toxic substances that destroy nerve cells: the hippocampus is unusually sensitive to them. It’s a common source of epilepsy, one result of brain damage.

The hippocampus goes on making new neurons throughout life. This was first discovered in rats, and - as you might imagine - was not believed at the time. Now it’s been established to occur in many other species, including humans (though they make rather fewer than rats do).  Making new neurons, if they are to be effective, is not simple. There has to be a population of stem-like cells  - they are called ‘progenitors’ because, unlike true stem cells, they only seem able to make neurons or similar cells. That’s only the start: the new neurons have to make long processes (axons) that allow them to communicate with other neurons, and these axons have to find their way to the correct destination, otherwise the circuits of the brain become scrambled. This happens correctly during the development of the brain, but it has mostly stopped by adulthood. The adult hippocampus continues this – the new neurons find their destination.  This is quite amazing.

The obvious questions are: why does this occur in the hippocampus, and what does it mean for its function?  You might think the answer to the first is obvious: if the hippocampus is so vulnerable to damage, then it needs a way to repair itself.  A nice idea….but the uncomfortable fact is that it is particular neurons in the hippocampus that are so susceptible, and it’s not these are replaced, but others who are not so sensitive. One way of exploring the function of the new neurons is to stop them being formed experimentally. This turns out to be quite difficult without causing other damage, and thus complicating interpretation. There’s a lot of disagreement about these experiments, and the real answer to the second question is: we don’t yet know for certain, though there have been numerous suggestions.

What we do know is that the rate of formation of these new neurons can be altered. Stress an animal, or give it high doses of the stress-related hormone corticosterone (cortisol in humans) and the hippocampus practically stops making new neurons. On the other hand, exercise or giving drugs that are used to treat depression (SSRIs like Prozac) greatly increases it. This has led to the suggestion that this is why these drugs can be useful in depression, and that maybe the new neurons of the hippocampus are involved either in depression or recovery from it; but these ideas are far from established. So not only does the hippocampus make new nerve cells, this mechanism is sensitive to outside events, particularly stress. Life-style, it seems, is reflected in what goes on in the hippocampus

The really exciting aspect is that there is a part of the brain that, contrary to what Cajal and everyone else thought, can regenerate. What’s special about the hippocampus?  If we could find out, we might have a way to encourage other parts of the brain that normally do not repair themselves to start making new nerve cells after damage – for example, a stroke. The hippocampus has given us hope, maybe a key to the lock, and has also changed our ideas about the brain, which we now know is much more plastic than we once thought.

Camillo Golgi never accepted that he was wrong about the connections between nerve cells, and the two ignored each other at the Nobel ceremony. History proclaims Cajal the victor, but Golgi is not forgotten. There are a number of cellular structures named after him. Ironically, one of them (the Golgi apparatus) makes the small vesicles that are released into the gaps between nerve cells that Golgi thought did not exist.

We can now imagine a time when repairing brain damage may be possible. A time when, after a stroke that damages the part of the brain that controls, say, movement, we could transplant some progenitor cells into the damaged area, together with the compounds that restored their ability to develop into functional neurons and find their way to their correct destination.  Then, maybe after a few months, the damaged pathways would be - even partially - repaired, and paralysis would resolve. If it happens in the adult hippocampus, it could be made to happen elsewhere in the brain. It's a long way off, probably (predictions are always uncertain) but one day Cajal may, thankfully, prove to have been a little too pessimistic.  In no way would this diminish his reputation as one of the greatest neuroscientists.

Letting our imagination fly further, maybe there will be a time when we can correct malfunctioning circuits in the brain by judicious activation of new neurons and their connections.  One thinks particularly of disorders like schizophrenia.  The underlying cause of this condition is not known, but it does seem to involve abnormal brain activity from an early age.  If this is due to the growth of incorrect connections, then rectifying these with new neurons and their connections might alleviate the persistent and life-long forms of this serious illness. So the discovery of newly-formed neurons in the hippocampus, unknown for so long, may bring - in time - a revolution in the way we treat some of our most devastating and common illnesses. New treatments are badly needed. Those little stem-like cells in the hippocampus, for so long undiscovered, have given us new hope in this very difficult and important area.

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