How To: Grow Your Own Brain Cells

In what the New York Times called the most profound brain-related finding of the 1990s [1], the understanding of the growth of new brain cells has flourished this millennium. Here I explore how new brain cell growth, or neurogenesis, can be influenced and whether such influence -- with exercise, sleep, diet, drugs, or stress -- has an impact, positive or negative.

There are two parts of the adult mammalian brain that host neurogenesis. The first is the hippocampus, a seahorse-shaped structure near the centre of the brain (highlighted in red) that's key to memory storage and spatial navigation. The second is in the olfactory system, i.e., the sensory system that enables smell. In this post, I focus on the hippocampus alone because its functions are more integral components of being human than olfaction.

A Short History of Neurogenesis

Initial evidence for new brain cell growth in the hippocampus of adult mammals can be traced to the publications of American biologist Joseph Altman in the 1960s [2,3,4]. These findings encountered weighty resistance, however, from the established writings of Nobel prize-winning Spanish neuroanatomist Santiago Ramon y Cajal (pictured), who in 1928 declared: "In the adult centres, the nerve paths are something fixed, and immutable: everything may die, nothing may be regenerated" [5].

Such skeptical sentiment was upheld by mainstream developmental neuroscientists [6] until unmistakeable affirmations of adult neurogenesis accumulated in the '90s [7,8], enabled by the advent of methodological advances in the study of living tissues and microscopy. These findings were bolstered by the discovery of a plausible mechanism for adult neurogenesis: neural stem cells in the adult brain [9,10,11], thereby eliminating the need for dubious neurogenesis theories involving cell division (i.e., mitosis) in mature neurons.

Despite its background shrouded in doubt, the existence of neurogenesis is strongly supported by modern studies [12].

A Crash Course in Hippocampal Neuroanatomy

The process underlying adult hippocampal neurogenesis is not simple or fully understood, but I'll elaborate on it a bit here before getting into practical applications. All the sweet brain cell-growing action happens in the subgranular zone (SGZ) of the hippocampus, a region named by the aforementioned Altman in 1975 [13]. The SGZ is tiny: It's only 25 micrometres wide [14] (about twice the width of a red blood cell), and located within the dentate gyrus (DG; visible in both images in this section).

I'll spare you the details of the creation of SGZ neurons [15,16,17], how they migrate to the SGZ [18] then grow [20-25], and how a select few fully mature [26] until they are indistinguishable from their older brain cell neighbours [27].

Regardless of mechanism specifics, adult neurogenesis occurs into very old age, although the rate decreases immensely with age [8,28,29]. Throughout the lifespan of a mouse or rat (and depending on the genetic strain [30]), there is about a 40% volume increase in the DG [31,32] because the new neurons created by the ongoing neurogenesis do not necessarily replace older, dying cells [4,33]. Despite all the new brain cell growth, the size of the DG is restricted by most young brain cells dying within just a few days [34], while a minority are saved from this tragic fate by being recruited into use [18,35]. Thus, many brain cells being created is a weak indicator of net neurogenesis [30,36] because neurogenesis is primarily regulated by low survival rates between immaturity and becoming a fully-functional adult [18]. The good news is that the lucky few that survive the first weeks of their young lives tend to remain alive for long periods of time -- at least a year in rodents [37,38,39].

The above was likely boring enough, so I won't delve further into hippocampal neuroanatomy, except to say that it's complex, with nerves stretching to it from the far corners of the brain. For example, the DG receives input from many neurotransmitter systems (e.g., dopamine, serotonin, noradrenaline) from the cortex on the outside of the brain that is essential for our most complex thoughts and behaviours [14,41]. The complexity of the hippocampus is not surprising given its incredible functionality -- examined next.

The Purpose of Growing New Brain Cells

The hippocampus is required for forming memories including knowledge of facts (semantic memory) and events (episodic memory) [42]. Although the memories are ultimately stored in the cortex at the outer edges of the brain [43], the centrally-located hippocampus is essential for memory of factual information because it associates incoming experiences with your internal map of the world's geography and history (your temperospatial coordinates) [44] and helps identify consistencies across multiple life experiences [45,46]. Whoa, trippy, man. For these associations to be possible after a single experience, the content is stored temporarily in the hippocampus [47] before being transferred onward to the cortex for long-term consolidation [48].

Interestingly, the growth of new brain cells in the hippocampus appears to help with acquiring these long-term memories of facts and events. This is corroborated by behavioural tests in adult mice that have found improved memory acquisition but not improved memory retention when rates of new brain cell growth in the hippocampus are high [36,49,50].

A popular theory of the relationship between hippocampal neurogenesis and memory acquisition is that when we encounter a new situation that requires the formation of many new memories, a higher proportion of young brain cells are recruited into meaningful functions, thereby increasing the probability that the cells survive and helping transfer memories to the cortex [51]. In addition to the behavioural evidence, this theory has been supported by computer-based simulations [52,53,54] and it may explain why older animals -- who are more familiar with their surroundings -- experience lower neurogenesis rates unless transferred to a new and interesting environment [8,28,29].

Factors Affecting the Growth of New Brain Cells

At long last, you've reached the fun part: Having covered the fundamentals of adult hippocampal neurogenesis, the remainder of this post focuses on how you can influence it. I'll cover exercise, sleep, diet, drugs, stress and cognitive stimulation. Each of these factors affects neurogenesis via complex multidimensional regulatory pathways involving often-redundant molecular cascades and an interdependent network of cause and effect relationships at systemic (e.g., physical exercise increasing cerebral blood flow), cell-to-cell [55], and intra-cellular [56] levels.

In addition to environmental factors, genetic differences have been demonstrated to cause hippocampal neurogenesis to vary greatly across rats [57] and mice [36,58,59]. Controlling for environmental influences, the number of new neurons in the hippocampus of one strain of mice was found to be a monumental 26 times great than another strain [36], implying your genetic makeup could broadly impact your neurogenesis too.

Cognitive Stimulation

Cognitive stimulation, such as that provided by opportunities to learn [38,60] and enriched living conditions (e.g., larger cages containing toys and more animals than standard environments) [19,61,62] increases hippocampal neurogenesis in mice. Depending on the genetics of the animal, this could be due to either increased cell growth but not increased cell survival [61] or vice versa [62]. As mentioned above, environmental enrichment strengthens neurogenesis even in mice that are quite old [29]. Although the absolute numbers of new cells are lower in older mice, the proportional increase is greater relative to younger mice. Additionally, long-term environmental enrichment diminishes the decreases in adult neurogenesis that accompanies aging [63]. Keep yourself engaged, regardless of your age!

Exercise

Physical activity (e.g., mice voluntarily running in a stationary wheel in their cage) increases neurogenesis by encouraging the proliferation of neural cells in the hippocampus [50,64,65]. Although this increase peaks after just three days of exercise and eventually returns to baseline levels, ongoing exercise nevertheless decreases the age-dependent decline in adult neurogenesis, probably by promoting the survival of the cells [65].

Particular molecules (e.g., insulin-like [66] and vascular endothelial growth factors [67]) have been found to be required for exercise to increase hippocampal neurogenesis in adults, suggesting their involvement in the pathways linking physical activity to new brain cell growth.

Sleep

Seventy-two hours of sleep deprivation decreases hippocampal neurogenesis in rats [68]. This effect is probably mediated by the increases in a type of steroid hormone (i.e., glucocorticoids) that accompany sleep deprivation: When these hormones were prevented from elevating by experimental intervention during extended wakefulness, the decrease in new brain cell growth was eliminated [68]. Thankfully, the effects of sleep deprivation on neurogenesis appear to be reversible: One week following the 72-hour deprivation period, rates of neurogenesis entered an apparently compensatory phase by exceeding normal levels, with rates returning to standard after two weeks [68].

Diet

Caloric restriction -- limiting consumption to two-thirds of the baseline level -- is well-known to dramatically increase lifespan [69]. Caloric restriction also increases the proliferation of cells in the hippocampus [55,70]. This neurogenic effect may occur by decreasing how quickly we age, thereby delaying the onset of aging-induced neurogenesis reduction.

Antidepressants

In rats, long-term but not short-term treatment with several different classes of antidepressants -- including selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, and tricyclics -- have been demonstrated to increase hippocampal cell growth [71]. In mice, the SSRI-type drug fluoxetine was found to increase both new brain cell growth and performance on a test of anxiety. The increase in anxiety test performance was not found if neurogenesis was disrupted by irradiating the hippocampus with X-rays [72], suggesting a role for hippocampal neurogenesis in alleviating anxiety.

The finding that antidepressants affect new brain cell growth has led some to hypothesise that these pharmacological agents do not directly alleviate depression by altering levels of neurotransmitters [73]. Rather, they contend that the neurotransmitter changes have a modulating impact upon the SGZ hippocampal substructure, thereby increasing neurogenesis that, in turn, alleviates depression. Because it takes about two weeks for antidepressants to bring about a significant change in the number of new brain cells that functionally integrate into the hippocampus, this hypothesis could explain why the drugs affect neurotransmitter levels almost instantly but do not bring about changes in mood for several weeks [74].

Recreational Drugs

In Western culture, the two most popular recreational drugs are alcohol and cigarettes [74]. Rat-based experiments of either one or four days of binge drinking have resulted in acute decreases in hippocampal cell proliferation, while the four-day version also acutely decreased new cell survival [75]. Both proliferation and survival decreases are perhaps due to general oxidative stress [76]. Interestingly, the effects of binge drinking were reversed to some extent by physical activity [77].

Of concern for cigarette smokers, and similar to the alcohol studies, it was found that with increasing doses of self-administered nicotine, rat neurogenesis decreased and cell death increased [78].

Stress

An abundance of stressful psychological factors have been demonstrated to decrease hippocampal neurogenesis in adult rats. These factors include social isolation [79], restraint [80], shock [81], and exposure to the odour of predatory foxes [82]. Glucocorticoids, the hormones mentioned in the paragraph on sleep above, are manufactured in the adrenal glands with levels elevated by stress, and play a major role in attenuating neurogenesis: Studies have shown that removal of the adrenal glands increases hippocampal neurogenesis, while the introduction of external glucocorticoids decreases it [83].

Increasing Hippocampal Neurogenesis at Home

If results from the above studies predict with reasonable accuracy how neurogenesis operates in humans, then the age-dependent decline in adult hippocampal neurogenesis should be reduced by cognitive stimulation (e.g., lifelong learning, engaging in changing environments), exercise, avoiding overeating, getting a good night's rest, minimising heavy drinking, not smoking, and generally steering clear of stress. Based on the evidence reviewed in this post, encouragement of new brain cell growth by these means could reduce anxiety and depression, and it could improve your ability to acquire memories about facts and events.

If the implications of these findings end up being completely off base, it nevertheless shouldn't hurt to follow the recommendations: Avoiding overconsumption and stress should benefit you one way or another!

References

1 Blakeslee, S. (2000, January 4) A decade of discovery yields a shock about the brain. New York Times

2 Altman, J. (1962) Are new neurons formed in the brains of adult mammals? Science 135, 1128-1129

3 Altman, J. (1963) Autoradiographic investigation of cell proliferation in the brains of rats and cats. The Anatomical Record 145, 573-591

4 Altman, J., and Das, G.D. (1965) Autoradiographic and histological evidence of postnatal neurogenesis in rats. Journal of Comparative Neurology 124, 319-335

5 Ramon y Cajal, S. (1928) Degeneration and regeneration of the nervous system. Oxford: Oxford University Press

6 Rakic, P. (1985) Limits of neurogenesis in primates. Science 227, 1054-1056

The remaining 77 references can be found on my website.