What is Neurogenesis? Definition, Mechanisms, and its Role in Brain Plasticity

Introduction to Adult Neurogenesis

Neuroplasticity refers to the nervous system's adaptive capabilities to change itself over a lifetime. The brain can create new, or strengthen existing connections between nerve cells (neurons) and groups of nerve cells (neural circuits). This process of enhancing communication is called synaptic plasticity. The brain can also, at least in some areas, produce progenitor cells that result in neurogenesis—the process of giving birth to new neurons—to change itself. 

Until relatively recently, neuroscientists believed that adult neurogenesis did not occur. It was assumed that the birth of neurons was restricted to the time period during embryonic development and our very early childhood years (i.e., developmental neurogenesis) and that, after this period of rapid growth, the nervous system was incapable of regeneration. This belief stemmed from the fact that, unlike most cells in our body, mature neurons do not undergo cell division. Cell division is a process through which one cell (the parent cell) divides into two or more new cells (the daughter cells).

This dogma was challenged starting a couple of decades ago when evidence of neurogenesis in the adult human brain was first reported [1]. Since then, a growing body of research has indicated that new neurons are born throughout life in specific neurogenic areas of the brain (e.g., dentate gyrus [DG], subventricular zone [SVZ]), not from the division of mature cells, but from the differentiation of neural stem cells (NSC).

Fernando Nottebohm’s studies during the 1980's [2], where he discovered that adult songbirds grow new neurons as they prepared to learn songs, helped shift the neuroscience paradigm about the adult brain’s capability for neurogenesis.

What Are Neural Stem Cells?

Stem cells are undifferentiated biological cells that can generate different types of specialized cells through a process designated as differentiation. Some stem cells can become any type of differentiated cell in our body (these are called totipotent stem cells) or nearly any type of cell (pluripotent stem cells). Other categories of stem cells already have some degree of specialization. These can only become specific, closely related cell types (multipotent stem cells), such as the different types of cells in a tissue. There are also stem cells that are already committed to being one specific type of cell (unipotent stem cells), but that have the capacity to self-renew through cell division. This capacity to self-renew is another distinctive characteristic of stem cells. This property allows stem cells to maintain a pool of parent cells that can originate new cells in our body [3,4].

Neural stem cells (NSCs) are the self-renewing, multipotent stem cells of the nervous system. NSCs can generate both new neurons and glial cells (the non-neuronal brain cells that provide support and protection for neurons, also known as neuroglia or simply glia).

A cell's ability to differentiate into other types of cells is called its potency. The more cell types it can differentiate into, the greater a cell’s potency. Potency exists on a continuum, from most to least differentiation potential, of Totipotency → Pluripotency → Multipotency → Oligopotency → Unipotency.

Where Does Neurogenesis Occur in the Brain?

NSCs reside in specific regions of the brain known as “neurogenic niches.” These regions have molecular and cellular characteristics that create a microenvironment that allows neuronal development to occur [5]. In adult mammals, there are two canonical neurogenic regions where NSCs reside: (1) the subventricular zone (SVZ) lining the lateral ventricles (the ventricles are fluid-filled cavities in the brain), and (2) the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus [3,6].

Neurogenesis outside these two regions is generally considered to be very restricted (i.e., relatively inactive) in the adult mammalian brain. However, non-canonical sites of neurogenesis have been reported in different species (with regions vary between species), including the neocortex, striatum, amygdala, hypothalamus, substantia nigra, cerebellum and brain stem [7].

Most research on adult neurogenesis has focused on the DG area of the hippocampus.  Hippocampal adult neurogenesis has been observed in all mammalian species studied to date. In the adult human brain, neurogenesis appears to occur in the hippocampus, a brain area that is particularly important for cognitive functions such as learning and memory, and for emotions, mood, anxiety, and stress response [1,8,9].

Another area where evidence of adult neurogenesis has been found in humans is the striatum [10,11]. The striatum is mostly known for its role in motor coordination, but it also has important roles in the regulation of reward, aversion, motivation, and pleasure. The striatum is also recognized as a key structure in higher cognitive functions, particularly in “cognitive flexibility,” the ability to adapt behavioral goals in response to changing contextual demands [12].

Neural stem cells give birth, if needed, to new cells that replace dead or dying ones in the dentate gyrus, where adult neurogenesis might support processes involved in storing and retrieving memories.

How Are New Neurons Born?

NSCs transition between quiescent (dormant) and active states by exiting and entering the cell division cycle, respectively. NSCs can remain quiescent for prolonged periods of time. Once activated, NSCs can self-renew (undergo cell division to yield other NSCs) and/or generate neural progenitor cells that can differentiate into neurons (neurogenesis) or glial cells (gliogenesis) [13]. NSCs thereby maintain a persistent pool of putative adult-born neurons.

For new neurons to be fully generated, cells have to go through the multiple stages of adult neurogenesis: activation of NSCs, proliferation of progenitor cells, differentiation and fate specification (the irreversible commitment to becoming a specific type of cell), migration, maturation, and integration into the existing neuronal circuitry [14].

While maturing, newborn neurons start acquiring their typical morphology by extending and branching their axons and dendrites, the projections that allow them to reach other neurons (collectively known as neurites); this process is called neuritogenesis [15]. They then establish contact by forming new synapses (the neuronal communication structures) with other neurons, in a process known as synaptogenesis [16]. This allows them to transmit information to other neurons and become fully integrated in functional neuronal circuits.

In experiments, NSCs have migrated long distances to injured brain areas. Once there, the NSCs differentiate into mature neurons [17]. This suggests that adult neurogenesis is one way the brain tries to heal itself.

Mechanisms of Brain Plasticity: Neurogenesis, Neuritogenesis and Synaptogenesis

The brain has an outstanding capacity to adjust in response to cognitive, emotional, and environmental challenges. Neuronal plasticity is a term that refers to this capacity of our nervous system for continuous change and adaptation.

The plastic nature of the brain is one of its most distinctive characteristics. Brain plasticity allows for a constant enhancement of neuronal functions, a continuous optimization of performance, and an incessant fine-tuning to our environment. The generation of new neurons through neurogenesis, as well as the establishment of new connections between neurons through neuritogenesis and synaptogenesis, are at the core of our brain’s plasticity.

During their maturation and functional integration, newborn neurons in the adult brain are able to sense information and fine-tune their synapses to the ongoing activity. Maturing neurons have outstanding synaptic plasticity, manifested as changes in the number, structure, and strength of synapses. This plasticity gives them a higher degree of adaptability and makes them particularly sensitive to cognitive demands, environmental stimuli, and behavioral or sensory experiences. Even stimuli and experiences that would have little effect on the synaptic processes of mature neurons can potentiate synaptic plasticity in young neurons [14,18].

Neuroplastic change occurs because of our environment and behavior. Our thoughts and emotions might also cause the brain to change itself.

Neurogenesis and Cognition

Neurogenesis is an intrinsic process of hippocampal function that acts as an adaptive mechanism and as a substrate for experience-dependent changes. The generation of new neurons allows the hippocampus to more effectively respond to cognitive demands that may benefit from the integration of new neurons into existing neural circuits.

By allowing the constant modification and refinement of neuronal circuits, neurogenesis and synaptogenesis contribute to the brain’s structural and functional plasticity throughout life, optimizing its performance and our cognitive responses to environmental demands. Neurogenesis allows the brain to adapt to new environmental needs and contexts by creating the building blocks for cognitive enhancement, acquisition of new skills, improvement of movement coordination, and improvement of emotional control [19].

Adult hippocampal neurogenesis, in theory, provides a continuous source of new neurons to support cognitive processes, especially when combined with other existing neuroplastic capacities. Use of cognitive functions and personal experiences results in learning and the formation of new memories. This activity-dependent synaptic remodeling allows the brain to shape connectivity based on current experience and, consequently, make neuronal networks more effective in new cognitive contexts [14].

Studies suggest that the brain will recruit its neuroplastic capacities much more quickly when we learn a new task (in contrast to continued training in a task we have already learned) [20]. 

Neurogenesis Is Impacted By Our Environment and Behaviors

Neurogenesis is very sensitive to external and endogenous factors [19]. Our environment and daily behaviors will greatly influence our cognitive abilities. A stimulating environment, entailing higher levels of mental and physical activity, social interaction, and sensory and motor stimulation can enhance the rate of neurogenesis, potentiating the different stages of hippocampal neurogenesis, from NSC proliferation, differentiation, and survival, to synaptic plasticity. As an example of behavior, good nutrition can affect the rate of neurogenesis [21-23]. Sufficient sleep might also be needed for adult hippocampal neurogenesis [24].

Therefore, we can actively promote neurogenesis by adjusting our habits and lifestyle. But actively supporting neurogenesis can go beyond physical activity and cognitive stimulation—supplements and nootropics may also be tools to hack neurogenesis.

Exercise promotes adult neurogenesis, leading to better spatial memory and improvements in processes that allow us to better choose and control the behaviors needed to accomplish goals. 

Nootropic Support of Neurogenesis, Neuritogenesis, and Synaptogenesis

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are two neurotrophins—signaling compounds that act as neuronal growth factors. They influence processes that promote the development, maintenance, survival and function of the nervous system. Because of their key roles in these processes, they are preferential targets for nutritional support.

BDNF is of particular relevance in the context of neurogenesis. BDNF has been associated with the proliferation of neuronal precursors and the differentiation, maturation, and integration of newborn neurons in the hippocampus. BDNF has also been positively linked to dendritic branching, length, and complexity, and to synaptogenesis and synaptic maturation [25-28]. NGF has been associated with the proliferation, growth, maintenance, and survival of neurons, particularly peripheral nerve growth and myelin production [29].

There are several ingredients in QUALIA MIND that may support the production of neurotrophins.* The production and action of BDNF may be supported by Ginkgo biloba [30], Taurine [31], L-Theanine [32], and the combination of Vitamin B12 and Docosahexaenoic Acid (DHA) [33].* The synthesis and activity of NGF may be supported by Huperzine A [34], PQQ [35], and Phosphatidylserine [36].* As a consequence of this support of neurotrophin production, these ingredients may contribute to supporting specific steps in the process of neuronal differentiation and growth.* 

In addition to their support of neurotrophic factors, Ginkgo biloba may support progenitor cell proliferation and differentiation and neuronal survival [30,37].* Huperzine A may support proliferation of hippocampal neural stem cells [34].* Vitamin D may support the synthesis of neurotrophic factors and neurotrophin receptors, and thereby support NSC proliferation and differentiation, neuronal maturation and growth, neuronal survival, and synaptogenesis [38-40].*

There are other ingredients that may also participate in pro-neurogenic, pro-neuritogenic or pro-synaptogenic processes, even though it is still unclear if they are able to support neurotrophin production. For example, Rhodiola rosea has been reported to support neurogenesis and neuronal regeneration [41,42].* Uridine Monophosphate supports neurite outgrowth and the proliferation of dendritic spines [43,44].* Bacopa monnieri also appears to support neurite branching and proliferation [45].*

Several B vitamins appear to be involved in neurogenesis and might be particularly important under circumstances characterized by higher stress or injury. Vitamin B1 (Thiamin) might help prevent stress-induced inhibition of hippocampal neurogenesis [46].* Vitamin B3 (Niacinamide)—a substrate to produce NAD⁺—might play a significant role in regenerative neurogenesis after injury or trauma [47].* Vitamin B6 (Pyridoxine 5-Phosphate) appears to be involved in promoting neurogenesis in the dentate gyrus [48].*

Choline precursors capable of crossing the blood-brain barrier support neurogenesis in animal experiments. Citicoline supports neurogenesis in the dentate gyrus and subventricular zone, and may also be important for regenerative neurogenesis after injury or trauma [49].* Alpha Glycerylphosphorylcholine (Alpha-GPC) appears to promote neurogenesis and have neuroprotective effects [50].*

Acetyl-L-Carnitine might enhance NSC proliferation and adult hippocampal neurogenesis by regulating proneural genes and cell survival-related signals [51].* 

Why support neurogenesis?

Neurogenesis is an important mechanism of cognitive adaptation. Supplements and nootropics may allow us to support the molecular and cellular mechanisms that contribute to the maintenance of the biochemical processes that drive neurogenesis.* Importantly, supplements and nootropics may contribute to the brain’s intrinsic ability to upregulate neurogenesis in response to cognitively demanding contexts and or circumstances that produce a greater need for regenerative support.*

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