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Newborn Neurons for a Healthy Brain

Do you remember the last time you did something for the first time?

Maybe it was the first time you took a solo travel trip, tried to start learning a new language or yes, even THAT first time (wink wink). 

It was probably awkward and at least mildly uncomfortable. But before you knew it, something clicked and you grasped the basics (yes, even THOSE basics!). 
Most of us realize that we experience the world through our senses (touch, sight, smell, sound, taste).

Over the last several decades, research has shown that even if we are struggling through a new task, situation, or a quagmire of any sort, these sense experiences are coded into fresh memories and intentionally (or unintentionally) drive your brain to produce and integrate new neurons into its circuits.

But we didn't always think this possible. 

Back in the day, scientists thought neurons were irreplaceable cells, unable to divide or proliferate. However, we now know that new neurons are made throughout life, from scratch, by  neurogenesis [1,2]. This process provides protection and plasticity to the brain’s network architecture, helping us to understand the world better and keep learning. 

Are you ready to get out of your comfort zone?

Let's dive into what, the where, and the how of neurogenesis + 4 easy ways to boost it too. 

What is Neurogenesis?

After just 6 weeks of conception in our mother’s womb, a rudimentary, almost primitive, spinal cord and brain begin forming in the embryo. Neurons and other supporting cells in the brain emerge from neural stem cells at specific times and regions, shaping the newly developed nervous system. These “progenitor cells” can differentiate and become specialized, giving rise to neurons, glial cells, astrocytes, etc.

Through neurogenesis, new neurons are formed, growing axons, populating specific body regions, and sculpting the required circuitry in the central and peripheral nervous system via interaction with other neurons.

Until the 90s, neuroscientists believed this process was only possible in these initial embryological stages, meaning the nervous system could not regenerate. However, the scientific community has now accepted and proven that neurogenesis is an essential regular process for maintaining a healthy brain (1,2).

Neurogenesis is crucial in embryo development and continues throughout our lives, promoting learning, memory, and regulating mood. Keeping a pool of healthy brain cells across our lifespan can also help avoid the loss of cerebral mass and cognitive function decline as we age.

Where does Neurogenesis Occur? 

Even though cell renewal is lower in the central nervous system (CNS) compared to other regions, there are two main brain regions where neurons can be createdde novo. As remnants of the primitive embryo stages, these regions maintain neural stem/progenitor cells in a unique microenvironment.

Neurogenesis in the adult human brain mainly occurs in these two niches:

  • The subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus, involved in regulating learning and memory.

  • The subventricular zone (SVZ), producing neurons that integrate into the olfactory bulb responsible for our sense of smell.

However, breaking paradigms yet again, there have been several reports in recent years showing proliferative capacity in other CNS locations, suggesting that neurogenesis could be more common than previously believed (3,4).

Several subcortical areas, such as the hypothalamus, amygdala, habenula, and cerebellum, among others, have been described as neurogenic sites producing newborn neurons with different specializations related to their location.

For example, new neurons in the hypothalamus may specialize in energy balance and other homeostatic mechanisms or regulate circadian cycles (our internal biological clock) in the habenula region. Newly generated cells in the cerebellum may even play a role in motor skills learning or adaptation in response to environmental cues.

In addition, adult neurogenesis in the hippocampal DG might have been acquired through evolution pressure (5): the need to move and deal with the growing complexity of tasks and challenging stimuli. On top of that, smelling is crucial for survival and integration processes (6), and neurogenesis in the olfactory bulb may provide vital assistance when adapting to new surroundings.

It's possible that neurogenesis might have been the key component for adaptation, helping humans to be the ruling species on planet Earth.

How Does Neurogenesis Occur?

Several internal and external factors can regulate neurogenesis. Growth factors, signaling pathways, neurotransmitters, and specific genes expressed at the neurogenic sites can trigger the process. The microenvironment of these niches can help maintain and proliferate the neural progenitor cells and their maturation to fully functional neurons.

Lysine Acetyltransferase 6B (KAT6B) and Btg1 genes are highly expressed in the SVZ and have been confirmed to play essential roles in adult neurogenesis. The same results were also found for serotonin, a neurotransmitter known to modulate mood. Also, neurotrophic growth factors such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glia-derived nerve factor (GDNF), and insulin-like growth factor 1 (IGF-1) regulate the survival, growth plasticity, and synthesis of neurons.

Along with hormones, glia, and vasculature, these molecules stimulate the development and protect the CNS.

Teaching an old dog new tricks

Most neurons in the brain are excitatory: when they fire, they activate other neurons and propagate the electrical signal throughout the brain. On the other hand, there are inhibitory neurons, a tiny influential group that regulate the activity of their excitatory counterparts. Inhibition controls and allows firing synchronization. This gives rise to rhythmic activity oscillations or what we know as brain waves.

There are significant differences in how newborn and old neurons behave. Old neurons are largely inhibited and stuck in their ways. Sound familiar? Much like teenagers, young neurons are much more active; while maturing, they are hyperexcitable. Uninhibited, they can boost fast action potentials contributing to plasticity. Also, sound familiar?! 

Teenage neurons seem to be involved in stimuli processing and can incorporate and differentiate new information more rapidly by using already formed networks (gained experiences). Interestingly, researchers think that learning something new does not always happen at the expense of old memories, but it does rely on the authentic creation of new synapses by the integration of new neurons into the circuits (7, 8). For this reason, although the CNS is created during embryo development, the “mature” network architecture in the brain is not stabilized until later in life. 

You are already getting those neuron numbers up if you made it this far! Nice work! Learning new skills and taking up new intellectual challenges are some proven ways to stimulate neurogenesis.

So, if you are planning on keeping your mind razor-sharp, pay attention to these interventions to keep your neurogenesis flowing!

4 Easy Neurogenesis Tips

1. Keep that arse in gear! 

There are endless benefits to exercising and it is well known that physical activity improves cognition.  

Aerobic exercise increases neurogenesis in the hippocampus as well as its volume (9, 10).  On a molecular level, BDNF levels are elevated after long-term exercise in children, adolescents, younger adults, older adults, and even Alzheimer’s patients. Low hippocampal BDNF levels correlate with age-related difficulties in learning and memory. Exercising improves cognition, memory, mood, prevents dementia, and protects the brain from advancing neurodegenerative diseases. If you are into high-intensity workouts, even better! They enhance BDNF production and stimulate hippocampal neurogenesis (11). 

Also, several studies have shown that after 12 days of voluntary running, mice lacking the Btg1 gene could recover neurogenesis in the SVZ (12,13). There is animal evidence of the proliferation of progenitor cells in the DG and enhanced survival or hastened maturation of preexisting neurons after only 2 days of running (14). So, keep those muscles active!

2.  Explore psychedelics

Psilocybin and ayahuasca are natural psychedelics that stimulate neuroplasticity with astounding long-lasting effects (months or years) (15). They have shown potential to treat depression, anxiety, and addiction, especially when combined with psychotherapy. The compounds behind these herbs and mushrooms can provide rapid effects, so they are now being intensively investigated as “pyscoplastogens” (16).

Although results about BDNF levels are still inconsistent, brain imaging studies have evidenced changes in neural connectivity in healthy volunteers (15) after treatment with psilocybin and ayahuasca. Most studies indicate structural changes like dendritic growth in the brain’s frontal lobe, which controls movement, language, and higher level/more complex activities. This may happen because they are linked to specific serotonin receptors (5HT2A), which are highly represented in dendrites in this area. Also, psychedelics are associated with the upregulation of genes related to neuroplasticity (17).

Non-psychedelic side note:  Lion's mane (AKA hedgehog), an edible mushroom, has been largely used in East Asia as medicine. Interestingly, it’s mainly applied for low qi (life energy force) cases in Chinese traditional medicine related to muscle weakness and fatigue. Hericenones and erinacines, two compounds found in this mushroom, induce NGF synthesis, neural outgrowth (18) and may promote a speedy recovery from brain and spinal cord injuries (19).

3. Practice mindfulness meditation

Did you have a meditation or mindfulness practice? Staying present through breathing or other methods can be challenging, but it is immensely beneficial to our body and mind. Some of the many benefits include regulating your emotions,, enhancing your focus, and reducing stress.

Although not yet fully understood, meditation introduces changes in behavior, brain structure, and function (20). It increases the grey-matter volume and density in several brain regions, including the hippocampus (21). Studies using magnetic resonance imaging (MRI) revealed increased hippocampus activation and brain blood flow just after 4 days of meditation training.

Scientists from Rutgers University have combined aerobic exercise and meditation based on the idea that physical training can increase the proliferation of new neurons in the human hippocampus, whereas mental training can increase their survival (22). The Mental and Physical (MAP) training program creates a synergy from both activities in the brain. Although neurogenesis was not directly proven, they suggest there might be a link in the observed results.  

If you stack your exercise with meditation, you may be onto something, it seems! 

4.  Enrich your gut microbes

Microbes communicate via the “microbiota-gut-brain axis” using various signalstransmitted to the brain: neuronal (via a particular vagus nerve in our intestine), endocrine (via specific hormones), metabolite-driven, and immune pathways (by crosstalk with immune cells). Indeed, our body has more microbial cells than human cells, so it's not surprising that have a massive impact on our daily lives!

Pre-clinical animal studies have shown that microbiota can regulate neurogenesis in the hippocampus (23). Evidence in germ-free (sterile) mice and experiments involving antibiotics or fecal transplants have confirmed this link. Research shows that number of neural progenitor cells and microglia decrease when microbes are absent.

Quick definition: Microglia cells are the immune cells in the CNS and provide an essential balance of newborn and dead neuron. They also provide an enriched, low inflammatory environment for better neuron proliferation.

Further research is still needed, but there is mounting evidence that a healthier microbiota will improve your mental state, fitness, and induce neurogenesis when it's needed. And in the reverse, unhealthy microbes may have an active role in the progression of diseases and cognitive decline with age (23).

So when you can, avoid antibiotics, sugar, and processed foods as much as possible; use pre- and probiotics (supplemented yogurts, whole grains, flavonoids, etc.); and eat a diverse range of foods for a healthy brain and gut (24).

Healthy Lifestyle, Healthy Brain

Our brain is constantly rewiring and creating new neurons and new neural connections. But remember, neurogenesis is heavily influenced by our lifestyle decisions so  REMEMBER: Challenge yourself, stay active and be open to new experiences to keep that brain healthy.

References

[1] Li Y, Guo W. Neural Stem Cell Niche and Adult Neurogenesis. The Neuroscientist. 2021;27(3):235-245. doi:10.1177/1073858420939034

[2] Take comfort in human neurogenesis. Nat Med. 1998;4, 1207.https://doi.org/10.1038/3166

[3] Feliciano DM, Bordey A, Bonfanti L. Noncanonical Sites of Adult Neurogenesis in the Mammalian Brain. Cold Spring Harb Perspect Biol. 2015;7(10):a018846. doi: 10.1101/cshperspect.a018846.

[4] Leal-Galicia P, Chávez-Hernández ME, Mata F, et al. Adult Neurogenesis: A Story Ranging from Controversial New Neurogenic Areas and Human Adult Neurogenesis to Molecular Regulation.International Journal of Molecular Sciences. 2021; 22(21):11489.https://doi.org/10.3390/ijms222111489

[5] Kempermann, G. New neurons for 'survival of the fittest'. Nat Rev Neurosci. 2012;13:727–736.https://doi.org/10.1038/nrn3319

[6] Bonzano S, Bovetti S, Gendusa C, et al. Adult Born Olfactory Bulb Dopaminergic Interneurons: Molecular Determinants and Experience-Dependent Plasticity. Front Neurosci. 2016;10:189. doi: 10.3389/fnins.2016.00189.

[7] Barron HC. Neural inhibition for continual learning and memory. Curr Opin Neurobiol. 2021;67:85-94. doi: 10.1016/j.conb.2020.09.007

[8] Nakashiba T, Cushman JD, Pelkey KA, et al. Young dentate granule cells mediate pattern separation, whereas old granule cells facilitate pattern completion. Cell. 2012;149(1):188-201. doi: 10.1016/j.cell.2012.01.046.

[9] Yau SY, Gil-Mohapel J, Christie BR,et al. Physical exercise-induced adult neurogenesis: a good strategy to prevent cognitive decline in neurodegenerative diseases? Biomed Res Int. 2014;2014:403120. doi: 10.1155/2014/403120.

[10] Pastor D, Ballester-Ferrer JA, Carbonell-Hernández L,et al. Physical Exercise and Cognitive Function. Int J Environ Res Public Health. 2022;19(15):9564. doi: 10.3390/ijerph19159564.

[11] Brown J, Cooper-Kuhn CM, Kempermann G, et al. Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis. Eur J Neurosci. 2003;17(10):2042-6. doi: 10.1046/j.1460-9568.2003.02647.x.

[12] Mastrorilli V, Scopa C, Saraulli D, et al. Physical exercise rescues defective neural stem cells and neurogenesis in the adult subventricular zone of Btg1 knockout mice. Brain Struct Funct. 2017;222(6):2855-2876. doi: 10.1007/s00429-017-1376-4.

[13] Stefano Farioli-Vecchioli, Andrea Mattera, et al. Running Rescues Defective Adult Neurogenesis by Shortening the Length of the Cell Cycle of Neural Stem and Progenitor Cells. Stem Cells. 2014;32(7):1968–1982.https://doi.org/10.1002/stem.1679

[14] Schoenfeld TJ, Swanson C. A Runner's High for New Neurons? Potential Role for Endorphins in Exercise Effects on Adult Neurogenesis. Biomolecules. 2021;11(8):1077. doi: 10.3390/biom11081077.

[15] Calder, A.E., Hasler, G. Towards an understanding of psychedelic-induced  neuroplasticity. Neuropsychopharmacol. 2023;48: 104–112.https://doi.org/10.1038/s41386-022-01389-z

[16] Olson DE. Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics. J Exp Neurosci. 2018;12:1179069518800508. doi: 10.1177/1179069518800508

[17] Jefsen OH, Elfving B, Wegener G, et al. Transcriptional regulation in the rat prefrontal cortex and hippocampus after a single administration of psilocybin. J Psychopharmacol. 2020;35:269881120959614.

[18] Lai PL, Naidu M, Sabaratnam V, Wong KH, David RP, Kuppusamy UR, Abdullah N, Malek SN. Neurotrophic properties of the Lion's mane medicinal mushroom, Hericium erinaceus (Higher Basidiomycetes) from Malaysia. Int J Med Mushrooms. 2013;15(6):539-54. doi: 10.1615/intjmedmushr.v15.i6.30

[19] Samberkar S, Gandhi S, Naidu M, et al. Lion's Mane, Hericium erinaceus and Tiger Milk, Lignosus rhinocerotis (Higher Basidiomycetes) Medicinal Mushrooms Stimulate Neurite Outgrowth in Dissociated Cells of Brain, Spinal Cord, and Retina: An In Vitro Study. Int J Med Mushrooms. 2015;17(11):1047-54. doi: 10.1615/intjmedmushrooms.v17.i11.40

[20] Tang YY, Hölzel BK, Posner MI. The neuroscience of mindfulness meditation. Nat Rev Neurosci. 2015;16(4):213-25. doi: 10.1038/nrn3916

[21] Luders E, Toga AW, Lepore N, et al. The underlying anatomical correlates of long-term meditation: larger hippocampal and frontal volumes of gray matter. Neuroimage. 2009;45(3):672-8. doi: 10.1016/j.neuroimage.2008.12.061.

[22] Millon EM, Shors TJ. Taking neurogenesis out of the lab and into the world with MAP Train My Brain™. Behav Brain Res. 2019;376:112154. doi: 10.1016/j.bbr.2019.112154

[23] Guzzetta KE, Cryan JF, O'Leary OF. Microbiota-Gut-Brain Axis Regulation of Adult Hippocampal Neurogenesis. Brain Plast. 2022;8(1):97-119. doi: 10.3233/BPL-220141

[24] David LA, Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505(7484):559-63. doi: 10.1038/nature12820

[25] Mintzer J, Donovan KA, Kindy AZ, et al. Lifestyle Choices and Brain Health. Front Med (Lausanne). 2019;6:204. doi: 10.3389/fmed.2019.00204. 

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