General Neuroscience

Adult Neurogenesis: Then and Now

Stephen Bello


Abstract

Whether or not new neurons are born in the adult mammalian brain has been the topic of much debate in the early years of neuroscience. After the discovery that neurogenesis does indeed occur in the mammalian brain, it was hard for many to believe it was so. However, various studies with indisputable results supporting adult neurogenesis have been reported over the years. Much of adult neurogenesis occurs in the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus with different mechanisms of occurrence. Environmental factors and stress have been shown to influence adult neurogenesis. Neurogenesis in the adult brain occurs at a very low rate after maturity and the cells generated have limited inherent long-term restorative ability. Various drugs have been shown to enhance as well as inhibit adult neurogenesis. In order to determine the existence of adult neurogenesis, various markers have been developed to reveal this process in species. Alterations in adult neurogenesis have also been shown to be implicated in various diseases.

 

History

    There was a lot of controversy among early neuroscientists as to whether the adult mammalian brain undergoes neurogenesis, that is, whether new neurons are born in the adult mammalian brain. In fact, one of the leading early researchers in neuroscience, Ramon y Cajal, once stated that no new neurons are born in the mammalian brain. This statement was later accepted as a dogma in the early neuroscience community. Joseph Altman and Gopal Das published a research work in the 1960’s that challenged this belief by reporting evidence of adult neurogenesis in rodents. Even though their work was published in one of the leading journals of that time, they could not change the long-held scientific dogma that no new neurons are born in the adult brain due to the finding’s contradiction to Cajal’s interpretation of this matter. To further investigate whether new neurons are born in the adult mammalian brain and to validate or dispute the findings of Joseph Altman and Gopal Das, two other researchers in the 1970’s, Fernando Nottebohm [1] and Michael Kaplan [2], studied the brain of birds and rodents respectively.  Nottenbohm’s studies with birds showed the existence of adult neurogenesis in their brains. Kaplan further proved the existence of adult neurogenesis in rodents. These research findings, especially Kaplan’s, received a lot of criticism. Although the neuroscience community could accept the existence of adult neurogenesis in birds, they found it rather difficult to accept the existence of adult neurogenesis in rodents. Most research investigations supported the existence of adult neurogenesis, but one in particular casted doubts on the existence of this phenomenon.. In 1985, Pasko Rakic published a paper titled “Limits of Neurogenesis in Primates” and convinced many researchers that adult neurogenesis is restricted to evolutionarily lower order animals (rodents and birds), and that it is irrelevant for primates such as ourselves. The neuroscientific community went in the direction of Pasko Rakic until the 1990’s, when researchers such as Elizabeth Gould,  Fred Gage, and Peter Eriksson published a series of papers that initiated an explosion of research on the existence, function, and implications of adult mammalian neurogenesis.

    The loss of neurons in the adult human brain had long been thought to be irreversible and the inability to replace dead or disease neurons had been thought to be an important cause of neurological disease and impairment.  

 

Where does it occur?

     The generation of neurons is generally confined to a discrete developmental period. The hippocampus is one of only a few brain regions where production of neurons occurs throughout the lifetime of animals, including humans [3]. Two forebrain structures actively demonstrate adult neurogenesis, namely the subventricular zone of the lateral ventricles (SVZ) and the subgranular zone (SGZ) of the dentate gyrus. These structures actively demonstrate adult neurogenesis in several species and have been shown to generate new neurons well into the postnatal and adult period [4]. Granule neurons are generated throughout life from a population of continuously dividing progenitor cells residing in the subgranular zone of the dentate gyrus in the rodent brain. ‘Newborn’ neurons generated from these progenitor cells migrate into the granule cell layer, differentiate, extend axons and express neuronal marker proteins. The study of [5] has also shown that neurogenesis also occurs in the adult prefrontal cortex.

 

Mechanism of occurrence

     The proliferating radial glia-like cells in the adult SVZ give rise to transient amplifying cells, which in turn generate neuroblasts. In the Rostral Migratory Stream (RMS), neuroblasts form a chain and migrate towards the olfactory bulb through a tube formed by astrocytes [6]. Once these neuroblasts reach the core of the olfactory bulb, immature neurons detach from the RMS and then migrate radially towards glomeruli where they differentiate into different subtypes of interneurons [7]. The majority of the differentiated neuroblasts become GABAergic granule neurons, which lack axons and form dendro-dendritic synapses with mitral and tufted cells. A minority become GABAergic periglomerular neurons, a small percentage of which are also dopaminergic. It has been suggested that a very small percentage of new neurons develop into glutamatergic juxtaglomerular neurons [8].

 

 

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Adult neurogenesis in the subventricular zone of the lateral ventricle and olfactory bulb

 

     Summary of five developmental stages during adult SVZ neurogenesis: (1) activation of radial glia-like cells in the subventricular zone in the lateral ventricle (LV); (2) proliferation of transient amplifying cells; (3) generation of neuroblasts; (4) chain migration of neuroblasts within the rostral migratory stream (RMS) and radial migration of immature neurons in the olfactory bulb (OB); (5) Synaptic integration and maturation of granule cells (GC) and periglomerular neurons (PG) in the olfactory bulb. Also shown are expression of stage-specific markers, sequential process of synaptic integration, and critical periods regulating survival and plasticity of newborn neurons. GFAP: glial fibrillary acidic protein; DCX: doublecortin; NeuN: neuronal nuclei; LTP: long-term potentiation. Source: [9]

    On the other hand, in the adult SGZ, proliferating radial and non-radial precursors give rise to intermediate progenitors, which in turn generate neuroblasts (Figure 3). As the immature neurons migrate into the inner granule cell layer and differentiate into dentate granule cells in the hippocampus, newborn neurons begin to extend dendrites towards the molecular layer and project axons through the hilus toward the CA3. New neurons follow a stereotypic process for synaptic integration into the existing circuitry.

 

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Adult neurogenesis in the dentate gyrus of the hippocampus

Summary of five developmental stages during adult hippocampal neurogenesis: (1) activation of quiescent radial glia-like cell in the subgranular zone (SGZ); (2) proliferation of non radial precursor and intermediate progenitors; (3) generation of neuroblasts; (4) integration of immature neurons; (5) maturation of adult-born dentate granule cells. Also shown are expression of stage-specific markers, sequential process of synaptic integration, and critical periods regulating survival and plasticity. ML: molecular layer; GCL: granule cell layer; SGZ: subgranular zone; GFAP: glial fibrillary acidic protein; BLBP: brain lipid-binding protein; DCX: doublecortin; NeuN: neuronal nuclei; LTP: long-term potentiation. Source: [9]

 

Regulation 

     The regulation of neurogenesis can be targeted at several steps of the overall process. The morphological and genetic stages that characterize adult neurogenesis are taken advantage of in its regulation. Adult neurogenesis could be regulated by the local circuit factors [10], local signaling, and extrinsic factors such as learning, aging, and diet.

 

Factors influencing adult neurogenesis

     The neurogenesis of the hippocampus can be influenced by various environmental factors and stimuli. Stressful experiences, including both physical and psychosocial stress, suppress the formation of hippocampal granule cells in a number of mammalian species. The down regulation of granule cell genesis induced by stress, as well as atrophy and death of CA3 pyramidal neurons, also contributes to the reduction in hippocampal volume [11]. A decrease in the proliferation of cells has also been reported in response to both acute and chronic stress paradigms.

 

Rate of Occurrence

     Neurogenesis in the adult brain occurs at a very low rate after maturity. Many of the newly generated neurons do not survive for long. Therefore, the new neurons born in the adult brain may support plasticity on an acute time scale because they have an increased excitability. However, these cells have limited inherent long-term restorative ability. The ultimate survival of these newly generated neurons increases with some interventions such as learning and enriching the environment [12].  Dormant stem cells may also exist throughout the brain. These cells could potentially be stimulated to mature in pathological situations or after pharmacological interventions.

 

Drugs enhancing adult neurogenesis

      Antidepressants such as Tricyclic antidepressants and Selective serotonin reuptake inhibitors; Mood stabilizer such as Lithium and Valproic acid; Cognitive enhancers such as Galantamine and Memantine; Anesthetics such as Ketamine [13]; Steroids such as Estradiol and Dehydroepiandrosterone; and others include Rolipram, Statins and Sildenafil (Viagra).

 

Drugs inhibiting adult neurogenesis

     Chronic morphine or heroin use inhibits hippocampal neurogenesis. Also, alcohol induces inhibition of dentate gyrus neurogenesis.  

 

Markers of adult neurogenesis

Exogenous markers of adult neurogenesis

Endogenous Markers of adult neurogenesis

 

Diseases associated with adult neurogenesis

      Alterations in adult neurogenesis appear to be a common hallmark in different neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). This is remarkable because the distinct pathological proteins responsible for the different diseases induce the loss of different neural populations. Impaired adult neurogenesis has been shown in numerous animal models of neurodegenerative diseases; however, only few postmortem studies have been performed [14].


References


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  2. Keilhoff, G., Bernstein, H.G., Becker, A., Grecksch, G. and Wolf, G. (2004). Increased neurogenesis in a rat ketamine model of schizophrenia. Biol Psychiatry, 56:317.

  3. Kempermann, G., Cheslerm, E.J., Lu, L., Williams, R.W. and Gage, F.H. (2006). Natural variation and genetic covariance in adult hippocampal neurogenesis. Proc Natl Acad Sci U S A, 103(3):780-5.

  4. Duman, R.S., Malberg, J. and Thome, J. (1999) Neural plasticity to stress and antidepressant treatment. Biol. Psychiatry, 46, 1181–1191.

  5. Dranovsky, A., Picchini, A.M., Moadel, T., Sisti, A.C., Yamada, A., Kimura, S., Leonardo, E.D. and Hen, R. (2011). Neuron Experience dictates stem cell fate in the adult hippocampus. 9; 70(5):908-23.

  6. Ming, G. and Song, H. (2011). Adult Neurogenesis in the Mammalian Brain: Significant Answers and Significant Questions. Neuron 70(4):687–702. doi.org/10.1016/j.neuron.2011.05.001

  7. Brill, M.S., Ninkovic, J., Winpenny, E., Hodge, R.D., Ozen, I., Yang, R., Lepier, A., Gascón, S., Erdelyi, F., Szabo, G., Parras, C., Guillemot, F., Frotscher, M., Berninger, B., Hevner, R.F., Raineteau, O. and Götz, M. (2009). Adult generation of glutamatergic olfactory bulb interneurons. Nat Neurosci. 12(12):1524-33.

  8. Lledo, P.M, Alonso, M. and Grubb, M.S. (2006). Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci. 7(3):179-93.

  9. Lois, C., García-Verdugo, J.M. and Alvarez-Buylla, A. (1996). Chain migration of neuronal precursors. Science 271(5251):978-81.

  10. Gould, E., Beylin, A., Tanapat, P., Reeves, A. and Shors, T.J. (1999). Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci. 2(3):260-5.

  11. Olude, M.A., Olopade, J.O. and Ihunwo, A.O. (2014). Adult neurogenesis in the African giant rat (Cricetomys gambianus, waterhouse). Metab Brain Dis 29:857–866. doi:10.1007/s11011-014-9512-9.

  12. Eriksson, P., Perfileva, E., Bjork-Eriksson, T., Alborn, A., Nordborg, C., Peterson, D. and Gage F. (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:1313–1317.

  13. Kaplan, M.S. (2001). Environment complexity stimulates visual cortex neurogenesis: death of a dogma and a research career. Trends in Neurosciences 24:617-20.

  14. Nottebohm, F. (1989). From bird song to neurogenesis. Scientific American 260: 74-9.

Stephen Bello

Stephen Bello


Stephen Bello obtained his Bachelor of Science degree in Biochemistry in Nigeria after which he proceeded to begin his Doctor of Philosophy (PhD) degree in the Department of Biomedical Science, City University of Hong Kong where he is currently majoring in Neuroscience, researching on Temporal Lobe Epilepsy. Aside being a keen lover of brain research, he also takes pleasure in teaching and mentoring the younger generation of scientists. When he is not in the laboratory, he is either hiking, meeting with friends or writing poetry.