Key Factors That Regulate Neurogenesis

Published 2016-11-14 06:00:00 neurogenesis

Historical Backdrop of Neurogenesis

Neurogenesis has been a hot topic in neuroscience and psychiatry for decades now.

The classical view of the brain is that it is static; you have all the neurons you'll ever have after adolescence and the brain has a limited capacity to regenerate. This view was rejected with the discovery that new neurons are born in the adult brain.

What's The Function of Neurogenesis?

After the recognition that the adult mammalian brain is not static researchers started wondering about the functional significance of neurogenesis. Researchers also sought to characterize the regulation of neurogenesis and how it affects cognition, mood, and behavior.

Neurogenesis and Depression

Non-depressed individuals seem to be more plastic and resilient to stress. They may become temporarily unhappy due to adverse life events but this unhappiness never becomes chronic. Depression is essentially the chronification of stress and anhedonia. Chronic stress leads to synpatic "wear and tear" that sets the stage for depression.

I'm interested in the factors that confer vulnerability to depression. This naturally led me to research lifestyle choices, supplements, habits of thought and other factors that might increase neurogenesis and improve mental health. One interesting idea is using nootropics to combat depression.

Neurogenesis clearly plays a role in depression, schizophrenia, and other neuropsychiatric disorders. But there are many unanswered questions. Does impaired neurogenesis predispose one to depression or does depressed mood itself suppress neurogenesis?

Neurogenesis is required for the behavioral effects of antidepressants. In a famous study researchers irradiated the hippocampus of animals to suppress neurogenesis.

They found that when neurogenesis was halted by radiation antidepressants failed to have an effect. This result supported the suspicion that antidepressants might not improve mood simply by boosting neurotransmitters. The brain is not a hydraulic system, after all. Perhaps antidepressants "work" by enhancing neurogenesis.

Neurogenesis and Exercise

The most reliable way to increase neurogenesis is by vigorous exercise. The exercise-neurogenesis connection is well-studied, though the mechanism remains unclear.

The Regulation of Neurogenesis

If we could more directly dial up neurogenesis by manipulating some pathways, maybe we'd have better treatments for CNS disorders. So what pathways regulate neurogenesis?

Neurogenesis is regulated by:

  • adrenal corticosteroids
  • sex hormones (like estrogen)
  • neurosteroids
  • neurotransmitters
  • trophic factors
  • morphogenetic factors

Adrenal Corticosteroids

Corticosteroids were among the first molecules noted to influence adult neurogenesis1.

Corticosteroids are released into the bloodstream following the activation of the hypothalamic-pituitary-adrenal (HPA) axis, primarily by stress. Corticosteroids help "prime" your body to cope with threatening situations.

Corticosterone regulates its secretion through negative feedback, by associating with two receptors (the mineralocorticoid and glucocorticoid receptors) in the dentate gyrus.

Corticosteroids Suppress Neurogenesis

One way to test the effect of a molecule is to remove the anatomical structure that produces it. Adrenalecomy is the removal of the adrenals.

Quenching corticosterone secretion by adrenalectomy improves glial and neuronal survival in the dentate gyrus23. But mitotic activity in the subventricular zone remains unchanged, indicating a site-specific inhibitory influence of corticosteroids.

Along with the dentate gyrus and the olfactory bulb, the subventricular zone (SVZ) is one of three areas where neurogenesis occurs in the adult brain.

In one study, proliferation of new neurons increased within 24 hours after adrenalectomy and remained constant over 6 days. The newly created cells lived for at least 4 weeks in the absence of corticosterone, signaling that their survival is corticosterone independent4.

Adrenalectomy also suppresses cell death, but the populations of cells undergoing mitosis or apoptosis are different. Immature cells divide at the interface of the hilus, whereas more mature neurons, found at the interface of the molecular layer, expire5. These alterations are prevented by corticosterone replacement64.

Treatment with a glucocorticoid receptor agonist, RU-28362, prevents both adrenalectomy-induced cell death and birth. The stimulation of both MR and glucocorticoid receptor mediates the effects of corticosterone on cell proliferation and shields mature cells from cell death.

BrdU is used in the detection of proliferating cells in living tissues.

This inhibitory activity of corticosterone on neurogenesis has additionally been found in other experimental situations:

  • acute corticosterone administration 1 h before just one [H3]dT injection 17; implantation of a 200-mg corticosterone pellet followed by BrdU8
  • chronic corticosterone treatment9
  • stress
  • inter-individual differences in the activity of the HPA axis10

The mechanisms by which corticosterone hampers cell proliferation remain unknown.

Reducing stress will is important to maintaining a healthy rate of neurogenesis.

Glucocorticoids Block The Cell Cycle At Various Checkpoints

Glucocorticoids block the G1 phase of the cell cycle by repressing cyclin D1, cyclin D2, Cdk4 and Cdk6, and induction of the CDKIs p21Cip1 and p27Kip1111213.

These hypotheses have been developed:

  • Corticosterone could act on nearby neurons expressing corticosteroid receptors that restrain the cell cycle by releasing growth factors14.
  • Corticosterone could affect neurogenesis via glutamate release in the dentate gyrus15.
  • Corticosterone may also inhibit cell proliferation by downregulating the generation of insulin-like growth factor I (IGF-I)1617.
Fun fact: the adult human brain creates nearly 1000 new neurons every day.

Sex Hormones: Estrogen and Testosterone

The influence of female hormones continues to be investigated in the hippocampus. It's long been recognized that sex hormones have a neuroprotective effect. That is, they protect the brain from insult and injury.

Estrogen replacement therapy seems to reduce the risk of cognitive impairments in older adults18. But findings have not been unequivocal19:

On a positive note, a large epidemiological study found that estrogen given early in menopause reduced Alzheimer’s risk, and results from a small cohort indicated that early treatment with the hormone may have slowed amyloid accumulation. However, another study found that early treatment with the hormone shrank the brain. After many years of study and a batch of new data, the jury is still out on whether hormone replacement therapy is good or bad for the brain…

Estrogen Promotes Proliferation of Neuronal Progenitors

Since estrogen seems to promote neurogenesis, we might expect female animals to exhibit more proliferation. Although cell proliferation in the granule cell layer (but not the hilus) is higher in female than in male rats, the newly created cells do not survive. This explains the dearth of gender differences in the amount of BrdU-IR cells 2 weeks after tagging20.

Granule cells in the dentate gyrus receive the hippocampal formation's major excitatory input from the cortex.

Sex-dependent proliferation depends on the stimulating effect of estrogens. The amount of BrdU-labeled cells is highest when circulating levels of estrogens are maximum21.

Administration of 17-estradiol reverses the ovariectomy-induced decrease in neurogenesis22,23. Estradiol however does not change neuronal specialization/differentiation24.

7β-estradiol is a steroid and estrogen sex hormone.

Yet, discrepant results are reported following long-term administration of estradiol in animal models 25,26,27. Seemingly contradictory results might be described by a complex regulatory mechanism.

Estradiol initially enriches (within 4 h) and subsequently curbs (within 48 h) cell proliferation in the dentate gyrus of ovariectomized female rats or meadow voles2829.

The increase in cell proliferation is mediated by serotonin30, whereas the decrease is prevented by adrenalectomy31. This implies corticosterone involvement.

Although corticosterone-induced regulation of cell birth certainly includes NMDA receptors, estradiol's effects on cell proliferation are not mediated by these receptors32.

Estrogen may act directly on estrogen receptors subtype (ER) present on hippocampal precursors33 or through IGF-I receptors.

Neurosteroids

Neurosteroids are synthesized de novo in many brain regions34. They are synthesized in the hippocampus by glial cells and influence hippocampal-mediated functions35.

DHEA and Pregnenolone

Dehydroepiandrosterone (DHEA) and pregnenolone sulfate (Preg-S) are neurosteroids that act as allosteric antagonists of GABA-A receptors. Conversely, allopregnanolone (AlloP) is a positive modulator of these receptors.

An allosteric antagonist is a substance which indirectly decreases the activity of an enzyme or receptor.

Treatment of male rats with DHEA stimulates hippocampal cell proliferation measured 24 hours after BrdU injections given on the last 4 days of the steroid treatment36.

After an additional 16 days of treatment, the newly created cells live and express the neuronal marker NeuN.

NeuN is a neuronal nuclear antigen used to identify neurons. For this reason it's used as a biomarker in neurogenesis studies.

Interestingly, DHEA treatment also has the ability to reverse the suppressive effect of corticosterone on neurogenesis. This suggests that DHEA is an anti-stress neurohormone.

Infusion of PregS increases cell proliferation in the dentate gyrus of young adult rats within 24 hours. However, treatment with AlloP decreases it37. The newly created cells survive for at least one month and differentiate largely into neurons.

These activities of PregS are mediated by GABA-A receptors present on hippocampal precursors. Conversely, treatment with muscimol, a GABA-A agonist, blocks Preg S-induced cell proliferation.

GABA is the major inhibitory neurotransmitter in the brain.

Glutamate

What's the evidence that glutamate regulates neurogenesis?

Destruction of the perforant pathway, the primary glutamatergic afference to the dentate gyrus, increases cell proliferation.

This suggests that under these experimental conditions glutamate inhibits neurogenesis38.

As expected, blockade of NMDA glutamate receptors by the antagonist (MK801) increases cell genesis within several hours in rodents, tree shrews, gerbils, and ovariectomized adult female meadow voles.

Treatment with the competitive NMDA receptor antagonist CGP 37849 increases both cell proliferation and granule neurons density39.

But an inhibitory influence of glutamate receptor blockade on neurogenesis was reported in stroke-damaged brains.

Since glutamate seems to suppresses neurogenesis, you'd expect that blocking glutamate receptors would promote neurogenesis. This expectation was not born out in stroke-damaged brains.

The newly created cells induced by the inactivation of NMDA receptors differentiate into neurons, expressing DCX, TOAD-64, NSE, or NeuN markers40414243.

Also, the MK-801-induced neurons are functional as they respond to NMDA stimulation, measured by the phosphorylation of extracellular signal-regulated kinase (ERK), 29 days after their birth date44.

This indicates that newly created neurons obtain components for the intracellular signal transduction cascade linking NMDA receptors to phosphorylation of ERK45.

The mechanisms where precursor proliferation is inhibited by glutamate in vivo through NMDA receptors remain unknown46.

Because glutamate additionally acts on AMPA receptors, discovered in neural progenitors47, the influence of potentiators of AMPA receptors like LY451646 continues to be appraised on a hippocampal mitotic action. Acute administration of LY451646 does not determine the number of newly created cells observed 24 h after BrdU beat.

But the median dose increases the number of cells per bunch (64%) and the variety of bunches (45%)48. Moreover, chronic treatment (21 days) with LY451646 enhances the number of proliferating cells, of cells per bunch, and of bunches in a dose-dependent manner49.

This suggests glutamate exerts a complex influence on hippocampal cell proliferation. Glutamate increases it through activation of AMPA receptors and inhibits it through activation of NMDA receptors.

Finally, the recent discovery that GABA and glutamate are co-transmitted at the mossy fibers synapses adds additional complexity to the individual function of each neurotransmitter in neurogenesis50.

Serotonin

In the 70's it was proposed that early forming serotonin (5-HT) neurons act as humoral signals regulating neuronal growth and neurogenesis5152.

Since then, several strategies have revealed that serotonin upregulates cell proliferation in the adult dentate gyrus and subventricular zone. Inhibition of 5-HT synthesis (by long-term injections of PCPA for 6 days) and selective lesions of 5-HT neurons of the raphe decrease the amount of BrdU- and PSA-NCAM-IR cells in the dentate gyrus and the subventricular zone.

This upregulation of hippocampal cell proliferation depends upon serotonin as it is reversed by intrahippocampal grafts of embryonic 5HT neurons53.

Partial lesions of 5-HT raphe neurons lead to a spontaneous reinnervation of 5-HT fibers. At this interval, the drop of mitotic activity (and PSA-NCAM expression) is reversed (62).

These activities of serotonin are mediated by 5-HT1A receptors in the dentate gyrus and the subventricular zone54 while 5-HT2A and 5-HT2C receptors are selectively involved in the regulation of cell proliferation in the dentate gyrus and subventricular zone, respectively54.

Trophic Factors

Many trophic factors have been shown to have mitogenic activities in the adult brain neurogenic areas. Thus the proliferative effects of basic fibroblast growth factor (bFGF or FGF 2) have been clearly presented for the subventricular zone.

Chronic administration of bFGF intra-cerebroventricular or intranasally raises the number of mitotic nuclei in the subventricular zone within 24 hours.

This leads to an elevated number of newly born neurons that reach the olfactory bulb where they express NeuN.

In comparison, in the dentate gyrus, too little effect55 or a small but nonsignificant increase in cell arrival was reported56. Consistently, in mice lacking bFGF, basal hippocampal neurogenesis is "normal," suggesting that other factors may keep low amounts of precursor proliferation under resting conditions57.

Nevertheless, overexpression of bFGF by gene transfer in wild-type and bFGF-deficient mice upregulates dentate gyrus cell proliferation, which signifies that a solid and persistent bFGF expression is a necessary condition for raising cell arrival in this construction58.

Epidermal growth factor and heparin-binding epidermal growth factor provoke cell arrival in the subventricular zone (1 and 7 days after growth factor infusion, respectively) surely via epidermal growth factor receptors596061.

However, these two factors likely have distinct activities, since HB-EGF raises the variety of BrdU-IR cells expressing DCX or NeuroD in the subventricular zone together with the amount of newly generated cells reaching the olfactory bulb 6263. On the other hand, epidermal growth factor reduces the number of newly born neurons reaching the olfactory bulb64.

In the dentate gyrus, HB-EGF6566 but not epidermal growth factor 67 raises cell proliferation by interacting most likely with epidermal growth factor receptors expressed by the breaking up cells68. The adult-created cells express the neuronal marker NeuroD69.

Transforming growth factor (TGF)- is required for subventricular zone precursor proliferation. Truly, icv administration of TGF- induces a dramatic increase in precursor proliferation70, whereas TGF- null mice reveal a decline in proliferating cells in the subventricular zone, and in the total number of newly created cells within their target, the olfactory bulb71. No data on the influence of TGF- on hippocampal precursors are yet available.

IGF-I

IGF-I is a growth-promoting peptide hormone that's produced in the CNS by neurons and glial cells72 and exhibits neurotrophic properties in adulthood73. Its influence on neurogenesis continues to be examined in hypophysectomized rats presenting low amounts of circulating IGF I74.

Consequently, peripheral administration of IGF-I induces an increase of cell proliferation in the dentate granule cell layer and the hilus after 6 days. Long-term treatment raises both BrdU-labeled cell number and their differentiation into neurons as measured by the percentage of BrdU-IR cells expressing calbindin.

By comparison, an IGF I-caused increase in cell proliferation in non-hypophysectomized rats isn't associated with an enhancement of their differentiation potential toward a neuronal fate75.

In vitro experiments76 strongly suggest that IGF-I regulates cell proliferation in vivo by acting directly on IGF-I receptors expressed by newly created cells77, but a recent study, in addition, has revealed that estrogen receptors are essential for the induction of in vivo hippocampal cell proliferation by IGF I78.

BDNF

Brain-derived neurotrophic factor (BDNF) is a member of a family of associated neurotrophic proteins. One of BDNF’s function is to prevent neurons from dying during growth.

BDNF helps maintain neuroplasticity and buffers the brain against stress. It may play a pivotal role in depression.

The newly created cells expressed TuJ1 or MAP2. Survival7980 and/or differentiation8182 of the neuronal precursors and their progeny instead of proliferation appear to be determined by BDNF.

Heterozygous BDNF knockout mice exhibit reduced proliferation and survival of BrdU-labeled cells83 in the dentate gyrus, proposing a role for BDNF as a positive regulator of both proliferation and survival. However, repeated, but not single, management of a compound that stimulates endogenous BDNF, riluzole, raises cell arrival (3-fold) but not cell survival.

Most of the newly generated cells (90%) differentiate into granule neurons (expressing NeuN)84. This effect is blocked by administration of BDNF-specific antibodies, indicating that the increase in BDNF is essential for the boosting effect of riluzole on precursor proliferation. These data show that BDNF plays a crucial role in the regulation of neurogenesis85.

Vascular endothelial growth factor (VEGF) is a hypoxia-induced angiogenic protein that displays neurotrophic and neuroprotective properties.

Given that neurogenesis occurs in close proximity to blood vessels and that bunches of breaking up cells comprise endothelial precursors, the vascular epidermal growth factor may constitute the connection between neurogenesis and angiogenesis. Then, the newly created cells exhibit DCX and NeuN mark.

Morphogenic Factors

Sonic Hedgehog

Sonic hedgehog (Shh), an important morphogen in development, is a signaling glycoprotein that acts through Patched 1-Smoothened (Ptc1-Smo) receptor complex. Sonic hedgehog determines: - ventral nerve phenotypes - induction of oligodendrocyte precursors - the proliferation of special neuron progenitor populations - modulation of growth cone movements

Lai86 investigated the function of Shh in the mature brain. Lai showed that it increased proliferation of hippocampal progenitors in a dose- and time-dependent fashion. Administration of Shh increased cell proliferation in vivo.

Finally, the existence of the Shh receptor Patched in the dentate gyrus and Ammon's horn in the hippocampus, and the high levels of expression of Shh in constructions that project towards the dentate gyrus support the assumption that Shh could be a positive regulator of cell proliferation87.

BMPs

Another group of early neurological morphogens, the bone morphogenic proteins (BMPs), belongs to the TGF- superfamily.

Several BMPs, including BMP4, are involved in repression of the oligodendroglial lineage and generation of the astroglial lineage during development 88.

In the adult subventricular zone, BMPs inhibit neurogenesis and orchestrate astroglial differentiation. As expected, their antagonist Noggin promotes neurogenesis89.

BMP2, BMP4, and BMP7 activate a promoter of the gene for the HLH variable Id1. This promoter inhibits the function of neurogenic transcription factors including Mash1 and neurogenin. The switch from neuronal to astrocyte destiny realized by BMPs requires HLH proteins90.

Neurogenesin-1 (Ng1)

The above findings were extended to the hippocampus. A new secretary variable, neurogenesin-1 (Ng1) was discovered to determine neuronal fate in the mature hippocampus through antagonism of BMPs. 91.

Glial Cells

Glial cells have emerged as regulators of adult neurogenesis92. Astrocytes could modulate neurogenesis by secreting local signals93.

Some proliferating cells in the dentate gyrus express a receptor for S100. This finding supports a role for glial cells in the regulation of adult neurogenesis94.

S100 is a little acidic calcium binding neurotrophic protein released by astrocytes.

Apoptosis

An equilibrium between neurogenesis and cell death ensures homeostasis in the adult brain.

This hypothesis, predicated on the observation the neurogenic constructions do not grow in size, suggests that cell death provides a stimulus for increased neurogenesis, a hypothesis supported by several lines of argument:

  1. During growth, there is a balance between the birth and death of granule cells95.
  2. Lesioning stimulates neuronal precursor proliferation in the granule cell layer and/or the subventricular zone96979899100;
  3. Proliferation in the subventricular zone is upregulated under inflammatory conditions101.
  4. Adrenalectomy, seizures, and ischemia enrich both cell death and cell birth.
  5. The apoptotic degeneration of corticothalamic neurons (by means of targeted photolysis) causes neural precursors to differentiate into mature neurons in areas of the cortex undergoing targeted neuronal death102. The induction of neurogenesis in these areas of the mature neocortex that don't normally experience any neurogenesis103 may result in the removal of a normal inhibitory effect or the loss of a secreted stimulatory factor produced by the dying cells.

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