“Once again, a flurry of new research is suggesting neurogenesis may be more common than previously thought.”
Comb jellyfish can fully regrow their rudimentary “brains” (R, R), but in most mammals (including humans) neurogenesis largely ceases in adulthood. It has been observed in a few places, including the olfactory bulb and hippocampus (R). This is no coincidence, both are ancient parts of the brain we share with fish and reptiles.
The party line in neuroscience has been observational, first we believed no part of the human brain could regenerate. And we’ve added exceptions as our technology has improved.
Who’s to say we don’t find more exceptions?
Nothing in neuroscience is absolute because the brain is still a black box.
So that’s a piece of occipital cortex smaller than a spec of dust and it revealed cell types we had never seen before. Nor do we know how memories are stored. The working theory is long-term potentiation (LTP): neurons that fire together wire together. But that’s more a description than an explanation. We don’t know what induces LTP and when we temporarily block certain kinases to prevent neuronal connection (reconsolidation) it often reverts back (R).
So if your brain is more than your connectome (set of neuronal connections) what is it? We don’t know. There’s a lot of ongoing research. The scientists behind the video above just received a grant from DARPA to map an entire brain. I believe they mentioned Skynet as the end goal (I could be wrong).
And once again a flurry of new research is suggesting neurogenesis may be more common than previously thought. But what is neurogenesis exactly, and why does it matter?
(n.): the birth and development of new neurons.
Neurogenesis can include increased neuronal proliferation, differentiation, increased survival rate of new neurons and the rate of maturation and integration of new neurons.
This process is most active during prenatal development and has a lot to do with neuroplasticity, an umbrella term for the brain’s way of reorganizing itself and forming new neural connections.
Children’s high neuroplasticity is why they have such an easy time learning languages, and why it’s a hot field of research. DARPA is currently studying how it can leverage tDCS induced neuroplasticity to accelerate spy training. But the method of action behind tDCS is not well understood, nor is it particularly safe.
But who wouldn’t want to be able to learn new languages and skills in a few months?
Brief Brain History
Pioneering neuroanatomists like Raymon y Cajal believed the central nervous system, like the peripheral nervous system was static.
“In adult centres the nerve paths are something fixed, ended, immutable. Everything may die, nothing may be regenerated.”- Raymon y Cajal (doctrine of late 19th to early 20th century)
This was taken for granted late into the 20th century, and researchers like Altman were met with skepticism when they published evidence of neuronal proliferation (1962) (R).
(The first evidence of hippocampal neuron generation in an adult mammalian brain) (R)
Still, the lack of definitive markers regulated neurogenesis to speculation in the eyes of most neuroscientists.
The Two Regions of Proven Continual Neurogenesis
In healthy adult human brains continual neurogenesis is found in the following two regions:
- The subgranular zone (SGZ) in the dentate gyrus (DG) of the hippocampus (HP).
- The subventricular zone (SVZ) of the lateral ventricles (LV). This is where new neurons are generated. They then travel through the rostral migratory stream (RMS) to the olfactory bulb (OB) to become interneurons (R) (R2).
*So we’ve observed neural proliferation in the hippocampus and neural differentiation in the olfactory bulb.
Adult rodent brain highlighting these two main ‘areas’ that show active adult neurogenesis:
The hippocampus plays an important role in the nervous system (R) and is a control center for emotion, memory, and spatial navigation.
Humans have 2 hippocampi, one on either side of the brain.
The hippocampus also plays a big role in episodic (R) and relational memory (R). You know when you recognize a face but can’t quite place where you’ve seen it? That’s due to poor memory consolidation, which is a primary role of the hippocampus.
The Olfactory Bulb
Interestingly, olfactory impairment could be an important marker for presymptomatic alzheimer’s disease (R). Which suggests Alzheimer’s and other neurodegenerative diseases are at least in part due to impaired neurogenesis.
Evidence of Neurogenesis in Other Brain Regions?
Recent research suggests neuronal proliferation and differentiation occur in other parts of the brain too. Cells similar to those collected from the hippocampus and SVZ have been found in the cerebral cortex, septum, striatum, spinal cord, hypothalamus and white matter (R), suggesting the occurrence of at least the first stages of neurogenesis.
Evidence for new neurons in areas other than the two regions is controversial. This is due in part because of the difficulties that come with analyzing the neuronal cells that divide slowly or infrequently. There are questions of what constitutes proof that a cell is newly born and if it is, in fact, a neuron.
But we’re certain of the act of neurogenesis in the dentate gyrus of the hippocampus, and SVZ, and it’s important to note that the most common techniques used to demonstrate new neurons in these regions have been the same techniques/tests used in these other regions with success.
These tests and analysis methods for quantifying brain growth include:
- (BrdU) – Quantifying fluorescent microscopy images of cell proliferation marker Bromodeoxyuridine (BrdU) used to detect rapid reproduction of cells
- Identifying groups of 2 – 3 cells with small nuclei that are close or overlapping. This happens to cells that have recently divided or are undergoing cell division (R).
- 3H-dT – (a process of tritiated thymidine) -this was previously more common than BrdU.
BrdU labeling is the current way of indicating cell proliferation and new cell generation in the SVZ.
Though it is a pretty effective test, one of the issues is that BrdU can cause both false positive and false negative results (R). This means it requires more careful interpretation and proper controls.
However both methods BrdU and 3H-dT have been used to discover neurogenesis in the thalamus (although the study that used 3H-dT methods was in 1977, and the scientists’ goal at the time was to determine prenatal neurogenesis).
Injury Causes Widespread Neurogenesis
For those struggling with brain injury, there is hope. Induction of adult neurogenesis has been observed in normally non-neurogenic regions of the brain in response to injury and death of neurons (R).
Upon injury in the non-neurogenic regions, there have been reports of local precursor cells generating new neurons, migrating from the neurogenic to the non-neurogenic region.
Neurons that are continuously being generated in the subventricular zone are able to migrate to the injured striatum and differentiate into mature neurons. Here they may be able to repair neurological deficits (R).
Another study showed that mice, in response to cortical lesions, were able to produce new neurons in the ventricular areas. The new neurons then migrated and populated to the cortical areas (R).
The migration and differentiation of neurons to nonneurogenic regions suggests the brain might have much more potent regenerative capabilities than previously imagined.
If this is true it shows promise for individuals suffering any kind of brain damage or injury. And it’s reasonable to suspect this process can be augmented by supplements, drugs, and lifestyle.
Is Neurogenesis Always Functional?
If we want to repair brain damage or heighten our capacity to learn our goal is to produce new neurons that are also functional and improve quality of life. While there’s nothing definitive in mammals yet, we have seen this process in songbirds: when neurogenesis occurred in their song nuclei, it peaked when they acquired new songs (R).
These new neurons were not stagnant, they were operable, useful neurons (R).
Unfortunately, just because neurons have formed doesn’t always mean they’re performing properly…
This could explain the hallucinatory experiences some with epilepsy encounter. Writer Fyodor Dostoevsky described this feeling through one of his characters in novel ‘The Idiot,’ through character Myshkin:
“…there was a moment or two in his epileptic condition almost before the fit itself…when suddenly…his brain seemed to catch fire at brief moments…His sensation of being alive and his awareness increased tenfold at these moments which flashed by like lightning. His mind and heart were flooded by a dazzling light…culminating in a great calm, full of understanding…” (R)
Targeting and controlling epileptic neurogenesis might diminish these euphoric states, but at the same time could lessen seizures and restore cognitive function after epileptic episodes.
Neurotrophins Promote Neurogenesis
Neurotrophins are a subtype of growth factor proteins that help to promote the survival of neurons.(R)
Growth factor proteins are what signal particular cells to survive, differentiate, or grow.
- nerve growth factor (NGF)-see post for more
- brain derived neurotrophic factor (BDNF)-see post for more
- glial cell line-derived trophic factor (GDNF)
BDNF usually increases neurogenesis and improves cognition. But recent research has shattered that view (R). BDNF, when overexpressed in the forebrain, can actually cause learning and memory impairments. Maybe this explains cognitive impairment in the case of epilepsy.
This and other research points to the disappearance of brain plasticity in adulthood being a feature, not a defect. To be sure, there’s a balance to strike.
How to Shrink Your Brain
Brief stress can promote hippocampal neurogenesis by increasing cell proliferation R, but what is more common in modern society is chronic stress. Chronic stress leads to atrophy of the hippocampus and loss of neurons (R).
Exposure to neurotoxins in the form of mold, biotoxins, certain chemicals, and some infections can cause atrophy in the caudate nucleus, as seen in NeuroQuant (an MRI software program).
Mice became anxious and forgetful after inhaling mold spores, which correlated with a decrease of new brain cells in the hippocampus as compared to the control mice (R).
This seems to reverse with treatment like cholestyramine, and the therapies below, but some neurotoxins can promote degenerative disease and halt neurogenesis entirely.
How to Grow Your Brain
Here’s a breakdown of some of the best methods to promote functional neurogenesis.
Lifestyles that Promote Neurogenesis
1. Exercise and Enriched Environment
Enriched environment consists of many components including expanded learning opportunities, increased social interaction, more physical activity, and larger housing. All of these things increase neurogenesis (R).
Regularly running nearly doubled the number of surviving newborn neuronal cells in amounts similar to other enriched conditions (R).
There’s also evidence to suggest different methods of action. Enriched environment increases the survival rate of new cells, while voluntary exercise increases the level of proliferation of progenitor cells (R).
So long runs outside (sustained exercise in an enriched environment) while making more friends (social enrichment) and not taking yourself too seriously (decreased chronic stress) are all lifestyle changes that promote neurogenesis.
The ways which sleep disruption inhibits neurogenesis is not fully understood, but they seem to be very important.
Disruptions of sleep over 24 hours significantly inhibit cell proliferation and in some cases neurogenesis (R).
But in the case you’re dealing with other brain problems especially, this isn’t a great idea.
4. ‘Chronic’ Sex
But chronic sexual experience no longer increased these stress hormones (yay!), while continuing to promote adult neurogenesis, enhanced cell proliferation, and the number of dendritic spines in the dentate gyrus of adult male rats. It also reduced anxiety (R, R).
Diet and Foods that Promote Neurogenesis
Rather than comprehensively list foods that increase neurogenesis (all of which are included on the neurotrophin posts), the following is a list of recipes.
5. DHA (Docosahexaenoic acid)
DHA is an important omega 3 fatty acid found throughout the body. It makes up to 97% of the omega-3 fats in the brain and up to 93% of the Omega-3 fats in the retina. It’s extremely important for brain and eye health and can help repair cognitive decline (R).
It’s found in fish oil, salmon, and other seafood.
We have a bunch of recipes for salmon in the lectin avoidance cookbook.
Ketones represent an alternative fuel for both the normal and the injured brain (R).
Ketones can provide up to 70% of the brain’s energy needs (R).
Ketones (BHB) increase BDNF, and this is one way in which exercise increases BDNF – through BHB (R).
In one study of 152 people with Alzheimer’s disease, those who received an MCT supplement for 90 days had much higher ketone levels and a significant improvement in brain function compared to a control group (R).
When people were treated with MCTs, higher ketone levels were associated with greater improvement in paragraph recall relative to placebo across all subjects (R).
Interestingly, on cognitive testing, MCT treatment facilitated performance for APOEε4-negative but not APOE ε4-positive subjects (R).
The inflammatory protein (NF-kB) increased in animals in brain injury, but a decrease was noticed in these animals upon ketone (BHB) treatment (however, ketones actually increased brain barrier permeability in healthy animals) (R).
Ketones (BHB) demonstrated protective effects on cerebral hypoxia in animals (R).
Ketones (BHB) is more energy efficient than glucose and can stimulate new mitochondria (R).
Also, ketones enhance the conversion of glutamate to GABA (R, R) and increases blood flow to the brain (R). Studies have demonstrated a 39% increase in cerebral blood flow following an infusion of ketones (sodium BHB).
While some studies have shown positive effects of a ketone-rich diet, studies have found that astrocytes may be impaired when ketones (BHB) is substituted for glucose (R).
7. Curcumin-Increases BDNF and acts as an antidepressant
See the post on curcumin.
8. Avoid sugar
Sugar can decrease neurogenesis due to its deleterious effect on glucose metabolism, raw fruits and vegetables have the ability to modulate this effect.(R) So it would be prudent to eat sugar only in the company of flavonoid and polyphenol rich foods. This means no-pulp juice is as bad an idea as kool-aid.
Blueberries and flavonoid-rich foods promote BDNF.(R)
9. Intermittent Fasting and Caloric Restriction
Fasting helps protect the brain from oxidative stress and injury.
Calorie restriction increases expression of several nerve growth factors including BDNF and GDNF in the hippocampus and basal ganglia.(R) It also improved memory function in rats.
Drugs that Promote Neurogenesis
Nootropics are substances that improve cognitive and mental ability. There are several but I will highlight only a few.
A family of nootropics known as “racetams” are known to promote neurogenesis. Piracetem had positive therapeutic effects on impairments to memory, attention and coordination in patients with brain injury of closed craniocerebral trauma (R).
Noopept is structurally similar to racetams and is a promising nootropic for promoting neurogenesis and increasing the expression of GNF and BDNF in the hippocampus (R).
Another popular nootropic known to promote BDNF is Selank (R).
Perhaps the most promising neurogenic compound is NSI-189 (R). It has been shown to increase hippocampal volume by 20% and reduce depressive and cognitive symptoms across all measures (R). It is currently under phase 2 clinical trial for treatment of age related decline in cognitive ability and depression (R).
SSRIs and many different classes of antidepressants are known to upregulate neurogenesis in the hippocampus (R).
However, this study demonstrated that neurogenesis is actually required for the effects of antidepressants (R). Chicken or egg?
If you suffer from traumatic brain injury, stroke, or dementia, the neurotrophic drug Cerebrolysin looks promising.
This peptide mimics the action of neurotrophic factors, and has been demonstrated to enhance neurogenesis in the dentate gyrus (hippocampus) in neurogenerative disease. Cerebrolysin is neuroprotective and promotes the repair and regeneration processes (R).
Taken within 24-48 hours after a stroke Cerebrolysin enhances neurogenesis in the ischemic brain and improves functional outcome (R).
Folklore describes the discovery of Ibogaine:
Deep in the African forest, there was a porcupine happily munching on the root of an Iboga plant before a shaman found it and slew it for dinner. He brought it back to his wife to prepare and then left to continue the hunt. The shaman didn’t make it home in time for dinner, and so the wife began to eat. Soon after she experienced 2 full days of visions. After the horror faded she arrived with such mystical clarity that bewildered all people of the land. The shaman returned to the chewed root the porcupine left behind and gathered its magical bark.
There started the Iboga Bwiti tradition, at least this is what fable tells us (R).
Ibogaine is a naturally occurring psychoactive substance found in plants in the Apocynaceae family. It has a long term effect on GDNF (one of the neurotrophins) and has been used for spiritual exploration (R).
It’s also been proven to reduce drug cravings in humans and drug and alcohol intake in rodents, and in some countries, it is used to treat drug addiction (R).
However, it’s not currently approved for medical use in the US. The dangers and difficulties of taking it in high dose are real and shouldn’t be taken lightly. If done in a clinic and with proper medical screening, risks are lessened but they’re still very much present (R). Derivatives of ibogaine without psychedelic properties are under development (R).
It shows promise as a neurogenerative treatment (R).
I’m intrigued by ibogaine, especially with its derivatives’ potential.
Psilocybin is a naturally occurring psychedelic compound produced by hundreds of different species of mushrooms (R).
It’s been found to increase hippocampal neurogenesis in mice and increased the speed of their unlearning of negative fear behavior responses (R).
Studies with high doses of psilocybin can induce long term positive change in personality, feelings of life satisfaction and well being.
*Just another word of caution, in rare cases HPPD (hallucinogen persisting perception disorder) has been correlated with the use of psychedelics like psilocybin and LSD.(R) HPPD is also correlated with neurotoxins from mold and other biotoxins. Several cases have been attributed to psychiatric medication. Is any of this causal? Maybe (R).
Rg3, a ginsenoside compound found in Panax ginseng, is able to decrease excitotoxic and oxidative stress in the brain while also promoting neurogenesis. The effects are improved memory and lessened brain fog caused by autoimmune conditions.
Dr. Andrew Heyman compounds nicotinamide riboside and Rg3 in one solution for his Lyme and brain disorder patients to start the process of repairing the central nervous system.
He’s also been using an Rg3 nose spray on the Corvette race car drivers of Le Mans (an American version of 24 Hours of Le Mans) to help them maintain focus during races.
The Corvette drivers were taking Rg3 nose sprays when they won the Le Mans in 2011 (R).
It can be found in supplement form or made as a compounded nasal spray.
16. Nicotinamide Riboside (NR)
Nicotinamide Riboside (NR) is a form of vitamin B3 that raises NAD+ in the brain. You need NAD+ in order to repair brain disorders like Alzheimer’s and improve mitochondrial function. Joe’s written a lot about NAD+ in this post.
Dr. Andrew Heyman has had clinical success using it to treat neurotoxins from several diseases, including Lyme.
Other Therapies to Promote Neurogenesis
17. Transcranial Magnetic Stimulation
Transcranial Magnetic Stimulation (TMS) is a noninvasive way to stimulate parts of the brain with a magnetic field generator (R).
Chronic repetitive transcranial magnetic stimulation also increases hippocampal neurogenesis in rats (R).
18. Transcranial Direct Stimulation
19. Targeted Oxidative Stress
Oxidative stress has long been recognized for importance in longevity medicine and aging associated brain dysfunctions. Targeting oxidative stress provides a new way to regulate adult neurogenesis and manage different brain diseases (R).