Probably one of the most exciting scientific findings of the last 50 years is the discovery that discrete brain regions generate new neurons throughout life, a concept known as adult neurogenesis. Despite the neurogenesis importance acquired nowadays, this emergent concept remained obscure until neurogenesis was found to occur in the brain of adult humans (Eriksson et al., 1998). In fact, until the 1990s the neuroscience field was under the dogma established in the late 19th to early 20th centuries by the most famous Spanish scientist and considered the father of the modern neuroscience, Santiago Ramon y Cajal (1852-1934). Unfortunately, despite his successful work (author of the ‘neuron theory’), Cajal’s observations made think that the nervous system was a non-variable system. Joseph Altman was the responsible of this new concept, publishing a series of works in the nineteen sixties showing evidence for adult neurogenesis in adult rats and cats (for review see Gross, C.G., 2000). Last year, the neuroscientific community celebrated the 50 anniversary of adult neurogenesis discovery.
Adult neurogenesis involves cell proliferation, survival, migration, and cell differentiation. This process occurs due to the cells that have this proliferative feature, named as Neural Stem Cells (NSCs). Neurogenesis, or the new neurons generation, was traditionally understood to be mainly an embryogenetic phenomenon, but research in the field has shown the existence of neural cells generation in several areas of the adult brain. These areas include the Dentate Gyrus (DG) in the hippocampus, subventricular zone (SVZ) around the lateral ventricles, olfactory bulb (OB), and other brain places where it was recently described such as the cortex, amygdala or hypothalamus, among other. However, in these last regions, neurogenesis function remains unclear (Gould, 2007; Ortega-Martinez, S. 2015) (Figure 1):
It was the use of a tritiated Thymidine analogue, Bromodeoxyuridine (BrdU), used as a proliferation marker, which allows the scientists to discover this exciting finding. BrdU can easily be labeled with immunohistochemical methods and investigated with a bright filter and fluorescence microscopy. In addition, specific antibodies against neuronal or glial markers were developed, providing easy methods to distinguish neurons from glia. Between the most relevant markers in the study of neurogenesis, it is possible to highlight the widely use of Sox2+/GFAP+ to label precursor or Neural Stem Cells (NSCs) (Type 1 cells), MCM2 for the analysis of amplifying progenitors (Type 2 cells), DCX to label neuroblasts/ immature neurons (Type 3 cells), and NeuN or Prox1 to distinguish mature neurons, among other. With the help of these methods, adult neurogenesis has been demonstrated to exist until senescence in numerous mammalian species including humans (Eriksson, 1998). Finally, the neuronal behavior of these new cells and their integration into the network was confirmed by experiments testing long-term potentiation (LTP), synapse formation and expression of immediate early genes after stimulation of the hippocampal network (Kempermann et al, 2003; Song et al, 2002; H.Van Praag et al, 1999).
The study of adult neurogenesis has been made at different levels. Indeed, in vivo models have been used aimed the neurogenesis removal such as for example X-ray (Saxe MD et al, 2006) or using transgenic models (as used by Jin K et al, 2010). In addition, this process has been analyzed through NSC in vitro culture. Nowadays, specific techniques to label these nascent neurons have emerged. In this regard, neurogenesis field has improved, a lot of thanks to the use of retrovirus (Zhao et al, 2006), which specifically infect cells in division allowing the visualization of these nascent cells along the route to neurogenesis (figure 2):
The essential neurogenesis area of research is the dentate gyrus of the hippocampus, named as Adult Hippocampal Neurogenesis (AHN). Since the general recognition and acceptance of AHN in the scientific community, many studies have been conducted to investigate how neurogenesis is regulated. Nowadays it is known that AHN is a process highly regulated by multiple factors such as hormones, growth factors, neurotransmitters, etc. (see Ortega-Martinez, 2015). AHN is extensively studied due to its important brain functions. In this sense, AHN has been widely described as occurring at the level of the subgranular zone (SGZ) and has been shown to contribute to learning and memory (Cameron et al, 2015; Fanselow et al, 2010), mainly in the dorsal hippocampus. AHN involves not only new neuron formation but also the integration of these new-born neurons into functional networks, making the process as a functional one. From this perspective, AHN facilitates memory consolidation via formation of networks (Deng et al., 2010; Weisz and Argibay, 2012; Ortega-Martinez, S. 2015). Furthermore, AHN provides plasticity required in memory processes and allows for ‘‘pattern separation mechanisms’’ which is crucial for memory consolidation (Bruel- Jungerman et al., 2007; Sahay et al., 2011; Bekinschtein et al., 2011; Yassa and Reagh, 2013; Ortega-Martinez, S. 2015).
In contrast, the ventral hippocampus has been related to emotional functions (Fanselow et al, 2010), involved in processes such as stress, depression, and anxiety. A great number of studies have demonstrated the relationship between hippocampal neurogenesis, stress, and depressive disorders (McEwen et al, 2001; Sapolsky, 2003). Consequently, AHN has been postulated as a key factor in these processes (Jun et al, 2012; Petrik et al, 2012) (Figure 3):
Thus, ‘The neurogenesis hypothesis of depression’ was coined, by which the recuperation of depressive symptoms are associated with an increase in AHN (Eisch et al, 2012). Later work has confirmed the association between hippocampal plasticity and stress (McEwen et al, 2001; Hirschfeld, R.M, 2000; Mahar et al, 2014). Even though the role of AHN in stress and anxiety is to some extent accepted, the molecular mechanisms involved in the regulation of these processes remain poorly understood.
In addition, there is extensive evidence for altered neurogenesis in neurodegenerative diseases such as Alzheimer’s disease (Mu et al, 2011). The memory loss of Alzheimer disease patients is related to a disturbed neurogenesis in the hippocampus, and hippocampal neurogenesis would constitute a potential target for therapy. The compensation for neuron loss in the hippocampus by controlled stimulation of endogenous neurogenesis might restore some of the lost hippocampal function (Mu et al, 2011).
Summary: adult hippocampal neurogenesis is extensively considered essential in memory and emotional processes. Numbers of papers related to neurogenesis and learning have exponentially increased since AHN discovery, 50 years ago (see Ortega-Martinez, S., 2015). Even recently, adult neurogenesis process has been described to occur in more brain areas, the link between memory and related neurogenesis primarily occurs in the DG of the hippocampus and OB. By the other hand, the adult hippocampus has been widely studied for its implications in numerous neurodegenerative and neuropsychiatric disorders, such as depression, anxiety, or Alzheimer´s disorder, among others. All these brain disorders also share, between other physiological features, its decreased AHN. In fact, and because hippocampus-dependent memory processes are altered in such diseases, understanding the underlying molecular mechanisms is important for restoring normal brain function. Indeed, some recent drug discovery efforts have focused on increasing AHN (Ortega-Martinez, S., 2015). To reach this functional ‘in vivo’ increase in hippocampal neurogenesis within the human brain, constitutes nowadays, an essential key target in neuroscience, for the future advance and development of new treatments for brain disorders, with all the societal and economic implications associated.
Bekinschtein, P. ,Oomen, C.A., Saksida, L.M.,andBussey, T.J (2011). Effects of environmental enrichment and voluntary exercise on neurogenesis, learning and memory and pattern separation: BDNF as a critical variable? Semin. Cell Dev. Biol. 22: 536–542.doi:10.1016/j.semcdb.2011.07.002
Brezun, J.M.; Daszuta, A. Depletion in serotonin decreases neurogenesis in the dentate gyrus and the subventricular zone of adult rats. Neuroscience 89, 999-1002 (1999).
Bruel-Jungerman, E.,Rampon,C.,and Laroche,S.(2007). Adult hippocampal neurogenesis, synaptic plasticity and memory: facts and hypotheses. Rev. Neurosci. 18: 93–114.
C. Zhao, E. M. Teng, R. G. Summers, Jr., G. L. Ming, and F. H. Gage, 'Distinct Morphological Stages of Dentate Granule Neuron Maturation in the Adult Mouse Hippocampus', J Neurosci, 26 (2006), 3-11.
Cameron, H.A.; Glover, L.R. Adult neurogenesis: beyond learning and memory. Annual review of psychology 66, 53-81 (2015).
Deng, W., Aimone, J.B., and Gage, F.H (2010). New Neurons and New Memories: How Does Adult Hippocampal Neurogenesis Affect Learning and Memory?. Nat Rev Neurosci, 11: 339-50.
Duman, R.S.; Aghajanian, G.K. Synaptic dysfunction in depression: potential therapeutic targets. Science 338, 68-72 (2012).
Eisch, A.J.; Petrik, D. Depression and hippocampal neurogenesis: a road to remission? Science 338, 72-75 (2012).
Eriksson, P.S., Perfilieva, E., Bjork-Eriksson, T., Alborn, A.M., Nordborg, C., Peterson, D.A., and Gage, F.H (1998). Neurogenesis in the Adult Human Hippocampus. Nat Med, 4: 1313-7.
Fanselow, M.S.; Dong, H.W. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65, 7-19 (2010).
Gould, E. (2007). How Widespread Is Adult Neurogenesis in Mammals?. Nat Rev Neurosci, 8: 481-8.
Gould, E., Cameron, H.A., Daniels, D.C., Woolley, C.S.; McEwen, B.S. Adrenal hormones suppress cell division in the adult rat dentate gyrus. The Journal of neuroscience : the official journal of the Society for Neuroscience 12, 3642-3650 (1992).
Gross, C.G. (2000). Neurogenesis in the Adult Brain: Death of a Dogma. Nat Rev Neurosci, 1: 67-73.
Hirschfeld, R.M. Antidepressants in long-term therapy: a review of tricyclic antidepressants and selective serotonin reuptake inhibitors. Acta psychiatrica Scandinavica. Supplementum 403, 35-38 (2000).
Jun, H., Mohammed Qasim Hussaini, S., Rigby, M.J. & Jang, M.H. Functional role of adult hippocampal neurogenesis as a therapeutic strategy for mental disorders. Neural plasticity 2012, 854285 (2012).
K. Jin, X. Wang, L. Xie, X. O. Mao, and D. A. Greenberg, 'Transgenic Ablation of Doublecortin-Expressing Cells Suppresses Adult Neurogenesis and Worsens Stroke Outcome in Mice', Proc Natl Acad Sci U S A, 107 (2010), 7993-8.
Kempermann G., Jessberger S, (2003). Adult-Born Hippocampal Neurons Mature into Activity-Dependent Responsiveness. The European journal of neuroscience, 18: 2707-12.
Kempermann, G., Gast, D., Kronenberg, G., Yamaguchi, M., and Gage, F.H. (2003). Early Determination and Long-Term Persistence of Adult-Generated New Neurons in the Hippocampus of Mice. Development, 130: 391-9.
M. D. Saxe, F. Battaglia, J. W. Wang, G. Malleret, D. J. David, J. E. Monckton, A. D. Garcia, M. V. Sofroniew, E. R. Kandel, L. Santarelli, R. Hen, and M. R. Drew, 'Ablation of Hippocampal Neurogenesis Impairs Contextual Fear Conditioning and Synaptic Plasticity in the Dentate Gyrus', Proc Natl Acad Sci U S A, 103 (2006), 17501-6.
Mahar, I., Bambico, F.R., Mechawar, N.; Nobrega, J.N. Stress, serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effects. Neuroscience and biobehavioral reviews 38, 173-192 (2014).
Malberg, J.E., Eisch, A.J., Nestler, E.J. & Duman, R.S. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. The Journal of neuroscience : the official journal of the Society for Neuroscience 20, 9104-9110 (2000).
McEwen, B.S. & Magarinos, A.M. Stress and hippocampal plasticity: implications for the pathophysiology of affective disorders. Human psychopharmacology 16, S7-S19 (2001).
Mu, Y. ; Gage, F.H. Adult hippocampal neurogenesis and its role in Alzheimer's disease. Molecular neurodegeneration 6, 85 (2011).
Ortega-Martinez, S. (2015). A new perspective on the role of the CREB family of transcription factors in memory consolidation via adult hippocampal neurogenesis. Front. Mol. Neurosci. 8(46). DOI: 10.3389/fnmol.2015.00046
Ortega-Martinez, S. (2015). Influences of prenatal and postnatal stress on adult hippocampal neurogenesis: The double neurogenic niche hypothesis. Behav. Brain Res. 281: 309–317.
Petrik, D., Lagace, D.C. & Eisch, A.J. The neurogenesis hypothesis of affective and anxiety disorders: are we mistaking the scaffolding for the building? Neuropharmacology 62, 21-34 (2012).
Sahay, A., Wilson, D.A., and Hen, R (2011). Pattern Separation: A Common Function for New Neurons in Hippocampus and Olfactory Bulb. Neuron, 70: 582-8.
Sahay,A.,Scobie,K.N.,Hill,A.S.,O’Carroll,C.M.,Kheirbek,M.A.,Burghardt,N.S.,etal.(2011). Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 472: 466–470
Sapolsky, R. Taming stress. Scientific American 289, 86-95 (2003).
Song, H., Stevens, C.F., and Gage, F.H (2002). Astroglia Induce Neurogenesis from Adult Neural Stem Cells. Nature, 417: 39-44.
Van Praag, H., Kempermann, G., and Gage, F.H (1999). Running Increases Cell Proliferation and Neurogenesis in the Adult Mouse Dentate Gyrus. Nat Neurosci, 2: 266-70.
Weisz, V.I., and Argibay, P.F.(2012). Neurogenesis interferes with the retrieval of remote memories: forgetting in neurocomputational terms. Cognition 125(1): 13-25.
Yassa, M.A., and Reagh, Z.M (2013). Competitive trace theory: a role for the hippocampus in contextual linterference during retrieval. Front. Behav. Neurosci. 7:107.
Written by Sylvia Ortega-Martínez for The All Results Journals. The author acknowledges Marie Curie fellowship and Åbo Akademi University for supporting Dr. Sylvia Ortega-Martinez. Dr. Sylvia Ortega-Martínez received a postdoctoral fellowship from the FP7 Marie Curie ITN r’BIRTH.