How neurons recover
Everything You've Always Wanted To Know About Adult Neurogenesis, But Were Afraid to Ask
Alexander Taskeev, "Biomolecule"
The expression "nerve cells do not regenerate" is one of the leaders among the commonly used statements about the human brain. At the same time, its falsity has been proven for 20 years, and the number of articles considering this very restoration is still increasing almost exponentially. The zones where it passes, its functional significance, as well as a huge number of factors affecting it have already been established. And how much remains to be discovered...
It was not easy to shake the stereotype...Even at the beginning of the last century, the loss of neurons as a result of injury or aging was considered fatal – after all, even the best minds insisted on the impossibility of neuron neoplasm (or neurogenesis) in adult individuals of higher vertebrates.
For the first time, this was postulated by the brilliant S. Ramon-i-Cajal [1], who at that time simply could not have brain research tools capable of recording low-intensity postnatal processes. Ramon y Cajal's authority was enormous, and it was also known that the brain mass decreases with age. There was no reason to think about the presence of a small pool of stem cells, and the lack of knowledge about the plasticity of the brain did not allow solving the problem of integrating new neurons into the most complex system of old ones.
As a result, the belief in the impossibility of the formation of nerve cells in adulthood was so firm that it caused a number of dramatic stories in science. One of the first to talk about the existence of adult neurogenesis was Joseph Altman. Using a new method of autoradiography with labeled thymidine for that time (Fig. 1), he and his collaborators published in the 60s a number of works that confirmed the course of neurogenesis in the dentate fascia of the hippocampus, olfactory bulbs and cerebral cortex in adult rats, guinea pigs, as well as in the new cortex in cats [2].
Figure 1. The first signs of adult neurogenesis. Animals were injected with 3H-thymidine, a radioactive analogue of the usual thymidine nucleotide, which is also embedded in the DNA of a dividing cell, but which can then be recorded by autoradiography. Figure from [2].Altman also suggested that "adult-born" neurons are of key importance in the processes of learning and memory formation.
Despite the fact that the papers were published in leading scientific journals, the scientific community ignored their conclusions, which contradicted the established stereotype. As a result, Altman stopped working in this direction. In the early 80s, his statements were supplemented by ultrastructural evidence that cells that arise in the brain of adult rats are similar to neurons. In addition, the processes of division have already been recorded in the brains of adult primate macaques. These results were obtained by Michael Kaplan, a well-known biologist and physician, who later worked at Johns Hopkins University and the National Institute on Aging (USA). In response to his articles, some eminent scientists said that such results obtained on rats cannot be indicative, since rats do not stop growing during their lifetime, therefore, they cannot ever be considered "adults". And the detected divisions in the brain of macaques were considered insufficient to prove the existence of significant neurogenesis in them. Such reactions did not inspire Kaplan to continue researching this problem, and he took up rehabilitation medicine [3].
... and yet it succeeded!One of the turning points in the study of neurogenesis was a series of articles by Fernando Nottebohm, published in the 80s and 90s.
Now Nottebohm is the head of the Department of Ecology and ethology at Rockefeller University, and then he was engaged in the brain of birds, in particular, the vocal center of canaries. In the course of his work, it turned out that in the parts of their brain homologous to the primate cortex and hippocampus, in addition to death, a huge number of new cells are formed! At the same time, many new cells are neurons and form synapses, and the activity of this whole process correlates with the complexity of the environment surrounding the bird. Despite the fact that many of these results were attributed to some specifics of birds, they greatly shifted public opinion [3].
The study of neurogenesis continued with renewed vigor after the introduction of synthetic analogues of thymidine into scientific practice. Such analogues are much easier to detect later in tissues than the radioactive ones that Altman used. In addition, markers of different types of cells were discovered: neurons of varying degrees of maturity, glial cells, as well as any cells in the mitosis phase, that is, dividing. This made it possible to speak even more confidently about active neurogenesis in the dentate fascia of the hippocampus and in the walls of the ventricles of the brain with projections into the olfactory bulbs (Fig. 2) [4].
Figure 2. Areas of the brain in which neurogenesis occurs: the subventricular zone of the brain (SVZ) in the lateral walls of the first two ventricles and the subgranular zone of the dentate fascia of the hippocampus (SGZ). In rodents, the cells formed in SVZ then migrate along the rostral migration tract to the olfactory bulbs. Drawing from the website aboutcancer.com .Recent studies demonstrate neurogenesis in a number of other brain structures: in the caudate nucleus, frontal cortex, primary and secondary motor and somatosensory cortex (Fig. 3) [5, 6].
But the insufficiently high activity of the process still does not allow us to call these zones neurogenic, unlike the two above-mentioned.
Figure 3. Areas of the human brain in which neurogenesis occurs. In primates, cells formed in the subventricular region also migrate to the striatum, which is an anatomical structure of the brain responsible for muscle tone, the formation of conditioned reflexes, and also regulating some behavioral reactions. Drawing from the website experimenta.ifc.unam.mx .Neurogenesis in the ventricles of the brain is significantly enhanced during any olfactory experience, as well as during pregnancy in rodents, since the recognition of cubs in them is strongly associated with the sense of smell [7, 8].
The results of studies on neurogenesis in this zone in humans do not yet lead to definitive conclusions: some of them indicate its course in humans, while others question the migration of neurons into the olfactory bulbs. It has recently been shown that in primates, newly formed neurons from the subventricular zone can migrate to the striatum (or striatum), which is responsible for complex motor reactions and the formation of conditioned reflexes [9]. Damage to the striatum is associated with Tourette's syndrome, as well as more serious problems such as Parkinson's and Huntington's diseases. Therefore, in the future, we can count on the appearance of a number of works on neurogenesis related to this area.
Neurogenesis has proven to be an important tool in our body...Perhaps, for a person, the most important neurogenic zone can still be called the dentate fascia of the hippocampus.
The hippocampal formation is part of the limbic system and participates in the performance of such brain functions as the integration and distribution of sensory information in the brain, the response to novelty, the regulation of mood and activity of the body. Being part of the Papetz circle, the hippocampus retains information while awake and participates in its translation into the cerebral cortex during sleep, that is, from short-term memory to long-term memory. Neurogenesis is involved in the implementation of some of these functions, the performance of which becomes possible due to the specific characteristics of the resulting cells – in particular, young granular cells of the dentate fascia have a lower threshold of long-term potentiation than older ones [10]. It is believed that such plasticity plays a role in learning and memory processes [11].
The rate of formation of new hippocampal neurons for an adult rat is estimated at 9,000 cells per day, however, most newly formed cells die between the first and second weeks after their birth, which is why the number of new neurons finally integrated into the hippocampus per month is approximately 25,000, which is about 3.3% of their population [12]. The rate of neurogenesis in humans is estimated at 700 neurons daily, and about 1.75% of the entire hippocampus or 0.004% of the neurons of its dentate fascia are renewed per year [13]. There is no sexual specificity in these indicators, and with age the activity of the process decreases, while the "quality" of the precursors remains the same, since they are cultivated in vitro as well as at a young age. This suggests that the lengthening of the cell cycle of nerve cell precursors in vivo occurs with age [14].
The stages of neurogenesis in the dentate fascia are described in detail by cell morphology and a set of specific cellular markers (Fig. 4) [15].
Figure 4. Scheme of differentiation of neural stem cells of the dentate fascia with specific markers of different stages. Resting neural progenitors (quiescent neural progenitors, called radial glia in the early classification), after activation by cytokines, growth or other factors, begin to divide by asymmetric mitosis with the formation of a dividing neural progenitor in the basal part (amplifying neural progenitor, in the early classification – a non-radial precursor). It, in turn, having divided twice, leaves the cell cycle and becomes a postmitotic neuroblast (neuroblast 1, previously an intermediate progenitor). It is at this stage that most cells die. The remaining ones turn into neuroblasts of the second order (neuroblasts 2, previously neuroblasts) and then into immature neurons migrating to the granular layer, where their maturation is completed. The complete transformation of a neural stem cell into a functional neuron takes about a month. Figure from [15]. Click on the drawing to view it in a separate window in full size.Currently, there is a debate about the fate of QNP (quiescent neural progenitors, resting neural progenitors) after division.
According to the "optimistic" model, brain stem cells – by analogy with hematopoietic stem cells – are self-renewing: as a result of asymmetric division, they give a cell that then differentiates into a neuron, and then return to a resting state and can be reactivated. In contrast, according to the "pessimistic" model, the stem cells of the dentate fascia are not capable of self-reproduction, and their activation eventually leads to transformation into astrocytes. It is assumed that the stem cells themselves are used only once during adult life, leaving this pool after a series of rapid divisions, as a result of which progenitors are formed. This explains and connects the decrease in the rate of neurogenesis and the increase in the number of astrocytes during life (Fig. 5) [16].
Figure 5. "Optimistic" (left) and "pessimistic" (right) models of stem cell division. Figure from [16].At the same time, the second model does not exclude the possibility of finding in the dentate fascia or small populations of self-reproducing stem cells, or cells with elongated G2/M phases, or some specific cells that do not express nestin.
In the latter case, they simply could not be detected with the design of the experiment used.
...whose work can be influenced by many thingsThe level of neoplasm of nerve cells – in particular, in the dentate fascia – can change under the influence of many factors.
If we take into account the "pessimistic" model and the role of neurogenesis in the implementation of some functions of the hippocampus, as well as the pathogenesis of a number of neurodegenerative diseases, it becomes obvious the importance of identifying targets for these factors – whether they affect silent stem cells, consuming their pool, or contribute to the survival of their descendants, or increase the number of their divisions. All the effects on neurogenesis can ultimately be divided into positive and negative according to the result of their action. The former include both banal (content in an enriched environment, physical activity, taking antidepressants or melatonin, social interactions) and specific – like one-night insomnia or taking cannabinoids. The second is radiation, stress, chronic lack of sleep, abuse of opiates, alcohol and many other things that are generally negative for the brain.
Although, in general, the result of the impact of many of these factors can be predicted, the mechanism of their impact, as well as the impact of their combinations, require study – both for building the correct general prevention and for the treatment of specific diseases. Among the so-called positive factors, an enriched environment that includes physical exercises is especially effective. According to various data, being in such an environment for a small amount of time (from about a week to a month) steadily and significantly increases the level of neurogenesis, and the increase may even be fivefold – depending on age, health status and other parameters [17]. Despite the active study of the effects of the enriched environment on neurogenesis, at the present stage of research, the question remains open as to which of its components (physical or research activity) influence the process of formation of new neurons in the brain, as well as to which stages of neurogenesis these effects extend. The resolution of these issues is important for the search for new therapeutic and neuroprotective effects and for finding effective ways to regulate neurogenesis in the adult brain. That is why interest in this topic is only increasing, and the number of articles on it will grow for a long time.
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02.10.2015