Connect
To Top

Neurogenesis in the Adult Brain and its Implications in Neural Circuit Plasticity

Few issues in modern neuroscience have provoked as much controversy or confusion as the ability of the adult nervous system to generate new neurons. Nevertheless, it is now established that throughout adulthood, new neurons are continuously born in two germinal regions of the mammalian adult brain: the subgranular zone (SGZ) of the hippocampal dentate gyrus and the subventricular zone (SVZ).

Astrocytes in the SVZ have been identified as the neural stem cell population able to produce neural progenitor cells that proliferate and differentiate into functional interneurons in the adult olfactory bulb (OB). The functional integration of newborn neurons into OB’s existing circuitry occurs through an activity dependent process, implying the presence of intricate modulatory processes during circuit formation and maintenance.


Astrocytes and the Subventricular Zone


   

The SVZ is located on the walls of the lateral ventricle and is home to a large number of new neurons destined to become interneurons in the OB1. The SVZ is organized into four layers and consists of four cell populations: migrating neuroblasts, immature precursors, astrocytes and ependymal cells.

During neural development, astrocytes are generated from radial glia, and have different types, which can be found between layers II and III of the SVZ2. Experiments on the adult rodent brain, have led to the classification of a subset astrocytes lining the border between the striatum and the lateral ventricles, as the primary progenitors of new neurons in the adult brain2.

This finding was counter to expectations, since astrocytes were considered to be differentiated cells belonging to the glial lineage. However, after anti-mitotic treatment of neuroblasts and immature precursors in the corresponding region, these cell types could be regenerated by type B astrocytes; additionally, the presence of proliferative markers in astrocytes (GFAP+) and the ability to retrovirally label them, showed that these cells have olfactory neuron daughters in mice2, reinforcing the stem cell like features of astrocytes.

 

1

Figure 1| Stages in development of new OB interneurons from neural stem cells (astrocytes) in the subventricular zone (SVZ)4.

 

To produce a differentiated population of neurons, astrocytes, must first give rise to an intermediate class of cells, generating a progeny of neuroblasts precursors (transit amplifying cells)2, which preserve their capacity to divide asymmetrically, albeit at a much faster rate than those of stem cells, where they ultimately give rise to neuroblasts2

Intrinsic and extrinsic factors act bidirectionally to control the rate of stem cell proliferation. In intrinsic regulation, factors such as retinoblastoma, necdin and E2F family of transcription factors, which are key elements in cell cycle mechanism, influence cell proliferation5. For example, E2F1 (transcription factor) deficient adult mice, show dampened levels of cell proliferation and neuron generation in their neurogenic areas5.

Ephrins and their Eph receptors are also implicated in controlling cell proliferation. Interaction between astrocyte’s ephrins-B ligand and tyrosine kinase EphB1-3 receptor is thought to increase neuroblasts proliferation while ceasing the rate at which they migrates6.

Other important developmental signalling pathways, such as Shh7, and Wnts8 are also held responsible for raising the levels of neurogenic proliferation in the SVZ and SGZ in the adult brain respectively.

Extrinsic factors such as environmental variations necessitate the modulation of neuronal developmental. Hippocampal activity is believed to directly affect proliferation5. For example, glutamate action through NMDA and GABA’s action through GABAA ceases proliferation, but glutamates action through AMPA receptor promotes proliferation9. In addition neurotransmitters, growth factors and hormones like 5-HT, thyroid hormone and FGF are involved in control of cell proliferation in SVZ5.


Fate Determination


 

Intrinsic and extrinsic factors act bidirectionally to control the rate of stem cell proliferation. In intrinsic regulation, factors such as retinoblastoma, necdin and E2F family of transcription factors, which are key elements in cell cycle mechanism, influence cell proliferation5. For example, E2F1 (transcription factor) deficient adult mice, show dampened levels of cell proliferation and neuron generation in their neurogenic areas5.

Ephrins and their Eph receptors are also implicated in controlling cell proliferation. Interaction between astrocyte’s ephrins-B ligand and tyrosine kinase EphB1-3 receptor is thought to increase neuroblasts proliferation while ceasing the rate at which they migrates6.

Other important developmental signalling pathways, such as Shh7, and Wnts8 are also held responsible for raising the levels of neurogenic proliferation in the SVZ and SGZ in the adult brain respectively.

Extrinsic factors such as environmental variations necessitate the modulation of neuronal developmental. Hippocampal activity is believed to directly affect proliferation5. For example, glutamate action through NMDA and GABA’s action through GABAA ceases proliferation, but glutamates action through AMPA receptor promotes proliferation9. In addition neurotransmitters, growth factors and hormones like 5-HT, thyroid hormone and FGF are involved in control of cell proliferation in SVZ5.


Migration of Neuroblasts to the Olfactory Bulb


After generation and initial differentiation in the SVZ, neuroblasts migrate towards the OB in distinctly oriented pathways and patterns. Each day, in excess of 30,000 neuroblasts travel along the rostral migratory stream (RMS) as neuronal chains, sliding along each other10. This migratory process is very precise, without any neuroblast deviating from the path; suggesting the presence of positional cues inside the RMS or in its vicinity.

Regulation of neuroblasts in the RMS is achieved through a combination of repulsive and attractive cues10. The fact that after ablation of the OB, neuroblasts continue their typical path into the RMS, suggests that long-distance signals from the OB may not be necessary for a directed migration; instead, short-distance and intrinsic cues may provide the required gradient for oriented migration in the RMS3.

Neuroblasts travelling through the RMS are mitotically active. Within the RMS radial glia give rise to specialised astrocytes, which form glial tubes that surround the migrating neuroblasts. These glial tubes may act to orient neuroblasts migration. Additionally, it is believed that various astrocytes within the RMS, also have stem cell like properties, able to generate glial cells and neurons that can functionally integrate in to the OB circuits11.

Neuroblasts travel from their birthplace towards their target by two types of migration: tangential and radial migration. During Tangential migration, Glial cells encourage movement by releasing migration-inducing activity (MIA) proteins10. When MIA protein encounters Slit, a guidance molecule, Slit becomes a repulsive cue, directing cells away from the SVZ. Cell adhesion molecules such as polysialiated10 neuronal cell adhesion molecule (PSA-NCAM) maintain neuroblast migration. Tangential migration terminates by neuroblast entry into the OB through actions of ARX transcription factors.

Ultimately, during radial migration in the ventricular zones, reciprocal interactions occur between migrating neurons and radial glial cells. Reelin protein signals to initiate the detachment of migrating neurons and Tenascin-R is responsible to carry out this detachment process, putting an end to radial migration10.


Maturation, Integration and Survival of Olfactory Bulb Interneurons


 

Once neuroblasts detach from chains, they occupy their corresponding layers in the OB where they start to differentiate into two GABAergic interneuroal subtypes: periglomerular cells (PGC) and granule cells (GC). Approximately 95% of all interneurons in the OB are granule cells5.

 

2

Figure 2| The morphology of a granular cell9

 

During maturation neuroblasts express different types of receptors at different stages. Early in maturation, newborn GC undergoes a rapid phase of dendritic growth, increasing the total number of inhibitory synapses in the OB. GCs have proximal, distal and basal synapses (figure 2), this morphology is determined by sequential development of receptors; which is thought to be important in their bulbar integration9; initially tangentially migrating neuroblasts express extrasynaptic GABAA receptors and then AMPA receptors, followed by later expression of NMDA receptors in radially migrating neuroblasts12.

Input synapses (Glutamatergic) develop first to control global excitation before developing input/output dendro-dendritic contacts at distal synapses that induce recurrent inhibition of the circuit. GCs first develop their synapses followed by their sodium channels, whereas PG cells acts in an opposite manner9.

Regardless of a total increase in the number of inhibitory synapses in the Granular cell layer, the density of GABAergic contacts during maturation does not change. Additionally, patch clamp assessments of GABAergic events on GC’s basal synapses (which contain recurrent input and output synapses) shows that during early maturation there is no change in inhibitory postsynaptic currents (IPSCs)13 suggesting an early establishment of inhibitory contacts and fast maturation of inputs in these new cells.

Conversely, the maturation of PGC’s glutamatergic inputs occurs in a different fashion. Within the first week of PGC’s arrival in the OB, their proximal glutamatergic synapses begin to significantly increase in density13, this is accompanied by pre and postsynaptic modification, such as changes in the shape of post synaptic density (PSD) or AMPA/NMDA receptor ratios, displaying the progressive maturation of these neurons.

In order to become an active part of the OB circuitry, newborn neurons must be able to release neurotransmitters as well as receiving synaptic inputs12. Integration of adult generated GCs occurs very fast, yet even after their integrations some of their functional characteristics (i.e. rate of glutamate release), continues to change, displaying prolonged maturation even after their integration.

Despite the large number of new neurons born into the OB, yet only a fraction of these cells survive. Initially, the number of newborn neurons in the OB increases as they arrive from the RMS, but after a 2-4 week period their numbers start to decline, this period is when neuron’s survival/death decisions take effect. This period is a critical one that can be regulated by activity9.

Newborn neuron survival is modulated in respond to behavioural stimuli, including physical activity, exposure to complexity and learning, leading to an increased chance of survival, whereas sensory deprivation has the opposite effect. More recently postprandial behaviours such as sleeping have emerged to affect cell survival. Using Caspase-3 labelling, it was observed that the survival rate of GCs is significantly reduced in rodent’s OB after a meal14.

Experiments involving Olfactory enrichment and learning show an increased rate of cell survival, whereas olfactory deprivation is associated with a decreased rate of survival15. Olfactory experience is linked to neuronal activity and manipulation of neuronal activity is perceived to affect cell survival. Experiments involving manipulation of GCs intrinsic activities showed that a reduction in excitability using a variant potassium channel, which imposes a more negative resting membrane potential, decreased the survival rate of newborn cells16. Increasing cell excitability had an opposite effect.

Glutamate activity through NMDA receptor has been previously documented to cease proliferation, however NMDA deficient neurons do not survive16, and it is believed that glutamate’s action through this channel promotes cell survival by increasing excitability, suggesting that the survival of these new neurons is competitively regulated by their own NMDARs during the critical period.

Survival of newborn neurons in the OB is also under influence by tropic factors such as brain-derived neurotrophic factor (BDNF). It is believed that the activity dependent BDNF-TrkB signalling initiates a BDNF Autocrine loop, which prevents neuronal death, while promoting neurogenesis and synapse formation17.


Plasticity in Circuit Formation


The ability of neural circuits in processing sensory information depends on their functional architecture and specific patterns of synaptic connectivity. Conventionally, circuits develop their architectural blueprint early in development; yet, specific patterns of synaptic connectivity continue to mature and refine further into postnatal life. Brain circuits should adapt their function throughout the life of an organism, conceivably due to changes in environmental factors and exposures to new complexities, which all require adaptive behaviours that should be reflected in neurons and circuits, suggesting the presence of functional plasticity in such circuits.

The continuous re-innervation of the OB and replacement of its interneurons makes it a good model to examine circuit formation and maintenance. The idea that neuronal circuits can change to hone their functions in response to different behavioural stimuli (as shown in activity-dependent experiments on rodent’s), suggests that these circuits can be highly flexible; but this flexibility may compromise neuronal stability, which may seem more critical for such an intricate system.

The idea of addition and removal of new cells from functional circuits may seem a risk to circuit stability5. However, in the OB, certain features during the integration of GCs minimize the disruption to circuit function, such as the sequential development of synapses in new neurons. The establishment of GABA-mediated synaptic inputs before glutamatergic inputs allows new neurons to integrate “silently” into the existing circuitry, and wait to be activated once mature.

The continuous change in morphology of interneurons’ dendrites, even after maturation, hints at synaptic plasticity, both during development and later in postnatal life. Young neurons are biophysically and anatomically different from more mature neurons and have unique patterns of synaptic plasticity18. This synaptic plasticity is important in modulating synaptic strength. During circuit formation, synaptic scaling controls the increase or decrease in sensitivity to synaptic inputs18 across the entire neuron without disrupting the relative strength of individual synapses.

Nevertheless, the death of most of the newly generated neurons suggests that there may be a premium placed on stability in the mammalian brain, thus limiting opportunities for new neurons to join existing circuits. On the other hand this limitation may be explained by activity-dependent regulation, in which circuits make sure to correspond to changing environments when they need to, ensuring fine-tuning of neuronal circuits


Conclusion


 In summary, SVZ astrocytes are the primary precursors for new neuron in the adult mammalian brain; new neurons go through extended maturational processes and eventually functionally integrate as interneurons into the existing OB circuitry. The integration, maturation and survival of GCs and PGCs is linked to neuronal activity, whereby cell-intrinsic excitability is perceived to enhance their functional integration. From the development of the nervous system and for the entire life span of an individual, neurons are continuously undergoing synaptic plasticity and remodelling as they extend and withdraw their processes, forming new and severing old targets. This plasticity may be necessary in circuit’s regulation in response to changing environments or stimuli that necessitate a change in neuronal activity; showing that the idea of developmentally finite capacity for plasticity in adult’s neuronal circuits set down by Ramon y Cajal was in error.

 

References

  1. Quiñones-Hinojosa, A. et al. Cellular composition and cytoarchitecture of the adult human subventricular zone: A niche of neural stem cells. J. Comp. Neurol. 494, 415–434 (2005).
  2. Doetsch, F., Caillé, I., Lim, D.A., García-Verdugo, J.M. & Alvarez-Buylla, A. Subventricular Zone Astrocytes Are Neural Stem Cells in the Adult Mammalian Brain. Cell 97, 703–716 (1999).
  3. Kirschenbaum, B., Doetsch, F., Lois, C. & Alvarez-Buylla, A. Adult subventricular zone neuronal precursors continue to proliferate and migrate in the absence of the olfactory bulb . J. Neurosci. 19, 2171–2180 (1999).
  4. Ming, G. Adult Neurogenesis in Mammalian Central Nervous System – Annual Review of Neuroscience, 28(1):223. Annu Rev Neurosci (2005).
  5. Lledo, P.-M., Alonso, M. & Grubb, M.S. Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci 7, 179–193 (2006).
  6. Conover, J. et al. Disruption of Eph/ephrin signaling affects migration and proliferation in the adult subventricular zone. Nat Neurosci 3, 1091–1097 (2000).
  7. Lai, K., Kaspar, B. & Gage, F. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nature (2003).
  8. Lie, D.-C. et al. Wnt signalling regulates adult hippocampal neurogenesis. Nature 437, 1370–1375 (2005).
  9. Kelsch, W., Lin, C. & Mosley, C. A Critical Period for Activity-Dependent Synaptic Development during Olfactory Bulb Adult Neurogenesis. J. Neurosci. (2009).
  10. Ghashghaei, H.T., Lai, C. & Anton, E.S. Neuronal migration in the adult brain: are we there yet? Nat Rev Neurosci 8, 141–151 (2007).
  11. Alonso, M. et al. Turning Astrocytes from the Rostral Migratory Stream into Neurons: A Role for the Olfactory Sensory Organ. Journal of Neuroscience 28, 11089–11102 (2008).
  12. Carleton, A., Petreanu, L. & Lansford, R. Becoming a neuron in the adult olfactory bulb. Nature (2003).
  13. Panzanelli, P. et al. Early synapse formation in developing interneurons of the adult olfactory bulb. Journal of Neuroscience 29, 15039–15052 (2009).
  14. Yokoyama, T.K. et al. Elimination of adult-born neurons in the olfactory bulb is promoted during the postprandial period. Neuron 71, 883–897 (2011).
  15. Nissant, A. & Pallotto, M. Integration and maturation of newborn neurons in the adult olfactory bulb – from synapses to function. European Journal of Neuroscience 33, 1069–1077 (2011).
  16. Lin, C.-W. et al. Genetically increased cell-intrinsic excitability enhances neuronal integration into adult brain circuits. Neuron 65, 32–39 (2010).
  17. Acheson, A. et al. A BDNF autocrine loop in adult sensory neurons prevents cell death. Nature 374, 450–453 (1995).
  18. Meltzer, L. & Yabaluri, R. ScienceDirect – Trends in Neurosciences : A role for circuit homeostasis in adult neurogenesis. Trends in neurosciences (2005).

 

Leave a Reply

Your email address will not be published.

More in Neuroscience