Link to depression and brain changes — Part 2

Neurotransmitters in adult neurogenesis

Several neurotransmitter systems may regulate adult CNS neurogenesis. Monoamine neurotransmitters are known to influence multiple aspects of neural development, including precursor proliferation, cell survival, axonal growth and synapse formation (29). The neurotransmitter systems covered here encompass the ‘traditional’ neurotransmitters, gamma-aminobutyric acid (GABA) and glutamate, and neuromodulatory transmitters or neuromodulators such as dopamine, serotonin, and acetylcholine that are secreted by a small group of neurons and can affect neuronal activity through large brain areas. It is often suggested that the delayed therapeutic response for antidepressants could be due to their effects on neurogenesis. Such as, although SSRIs increase serotonin levels hours after drug administration if their administration leads to beneficial impacts, it usually takes 2–4 weeks of daily administration for those effects to appear. One would assume that if serotonin levels were causally linked to depression, then soon after serotonin levels increased, the mood would begin to improve much more rapidly. (30)

neurotransmitters and neurogenesis

GABA & Glutamate

Glutamate is the primary excitatory and GABA the main inhibitory neurotransmitter in the mammalian cortex. Changes in glutamate and GABA metabolism may play essential roles in the control of cortical excitability (31). Growing evidence suggests that the neurotransmitters GABA and glutamate have a significant role in setting the timing for survival, proliferation, migration, synapse formation and integration of newly formed neurons in established synaptic networks (32).

“Even modest chronic deficits in GABAergic transmission in GABAAR γ2+/− mice impair the survival of adult-born hippocampal neurons, an effect that may explain hippocampal volume reductions were seen in chronically depressed patients”(33)

“Experimental evidence has demonstrated that glutamate is an essential factor for neurogenesis, whereas another line of research postulates that excessive glutamatergic neurotransmission is associated with the pathogenesis of depression….Low glutamate levels activate adaptive stress responses that include proteins that protect neurons against more severe stress. Conversely, abnormally high levels of glutamate, resulting from increased release and/or decreased removal, cause neuronal atrophy and depression. The dysregulation of the glutamatergic transmission in depression could be undermined by several factors including a decreased inhibition (γ-aminobutyric acid or serotonin) or an increased excitation (primarily within the glutamatergic system).”(34)

“…an excitotoxic concentration of glutamate, which killed between 60–80% of granule cell neurons on day 8 in vitro, mediated its toxic effect via a time-dependent apoptotic pathway.”(35)


Dopamine controls multiple physiological functions in the brain and periphery by acting on its receptors D1, D2, D3, D4, and D5. Dopamine receptors are G protein-coupled receptors (also called seven-transmembrane receptors) involved in the regulation of motor activity and several neurological disorders such as Parkinson’s disease (PD), schizophrenia, bipolar disorder, Alzheimer’s disease, and attention-deficit/hyperactivity disorder (ADHD). Reduced dopamine content in the nigrostriatal pathway is associated with the development of PD, along with the degeneration of dopaminergic neurons in the substantia nigra region.

“Dopamine receptors are widely expressed in the hippocampal dentate gyrus and SVZ [subventricular zone] region and are actively involved in the modulation of neurogenesis in basal forebrain structures, thereby supporting the hypothesis that dopamine plays a role in neurogenesis and brain plasticity.”(36)

“On top of its role in motor control, mood and as a neurotransmitter, dopamine also plays a vital role in neuronal proliferation and differentiation in the adult CNS. The dopaminergic projections directly innervate the SVZ and hippocampus, thus directly influencing the microenvironment of these niches to regulate neural stem cells dynamics…suggested that chronic treatment with the D2-like antagonist, haloperidol, in adult rats led to an increase in the number of primary neurospheres obtained from the SVZ.”(37)

“Consistently, the numbers of proliferating cells in the subependymal zone and neural precursor cells in the subgranular zone and olfactory bulb are reduced in postmortem brains of individuals with Parkinson disease. These observations suggest that the generation of neural precursor cells is impaired in Parkinson disease as a consequence of dopaminergic denervation [loss of nerve supply].”(38)

Serotonin & Norepinephrine 

Serotonin or 5-hydroxytryptamine (5-HT) has a popular image as a contributor to feelings of well-being and happiness, though its actual biological function is complex and multifaceted, modulating cognition, reward, learning, memory, and numerous physiological processes such as gut function. In the human body, the majority of serotonin is made, stored, and released by cells in the gut lining. These cells make serotonin from the amino acid L-tryptophan. Norepinephrine (NE) also called Noradrenaline (NA), or Noradrenaline, is a neurotransmitter that functions in the human brain and body as both a hormone and neurotransmitter. In the brain, norepinephrine increases alertness and arousal, promotes vigilance, enhances the formation and retrieval of memory, and focuses attention. In the other parts of the body, norepinephrine increases heart rate and blood pressure, triggers the release of glucose from energy stores, increases blood flow to skeletal muscle, reduces blood flow to the gastrointestinal system, inhibits urination and slows the gut flow.

serotonin and norepinephrine

“Lesion of the 5-HT system is reported to decrease neurogenesis (Brezun and Daszula 2000), and preliminary studies demonstrate that administration of fenfluramine, which causes the release of 5-HT, increases adult neurogenesis in the hippocampus (Jacobs et al. 1998). In contrast, administration of a 5-HT1A antagonist, WAY 100,635, blocks fenfluramine-induction of neurogenesis, as well as the basal rate of neurogenesis in the absence of fenfluramine (Jacobs et al. 1998). These studies suggest that regulation of the 5-HT system and 5-HT1A receptors could contribute to the induction of adult neurogenesis by antidepressants, at least the effect of a 5-HT selective reuptake inhibitor.” (39)

“These results show that the effects of fluoxetine on LTP [long-term potentiation ] and behaviour both require neurogenesis and follow a similar delayed time course. The effects of chronic fluoxetine on the maturation and functional properties of young neurons may, therefore, be necessary for its anxiolytic/antidepressant activity and contribute to its delayed onset of therapeutic efficacy.”(40)

“Likewise, the lack of lesion effects upon progenitor survival or differentiation reported by Kulkarni et al. (2002), three weeks after BrdU [5-Bromo-2′-deoxyuridine (5-BrdU) is a thymidine analogue which is incorporated into DNA. 5-BrdU is routinely and extensively used to measure DNA synthesis and to label dividing cells. Consequently, 5-BrdU is used to study cell signalling and other processes that induce cell proliferation. Labelling was consistent with that detected here over a similar period. Thus, a noradrenergic control is likely to be exerted upon cellular and molecular factors that either directly or indirectly influence SGZ [subgranular zone ] progenitor proliferation, but not upon those influencing progenitor survival or differentiation.”(41)

“The dentate gyrus granule cell layer, whose neurons are generated following monoamine innervation, exhibited a 16.2% decrease in absolute neuron number. Thus in the absence of En2, developmental deficits in forebrain growth occur that correlate with reductions in norepinephrine levels and innervation.”(29)


Acetylcholine, Ach, is an ester of choline and acetic acid and is the most widely spread neurotransmitter. It is also the most plentiful neurotransmitter, which may be found in both the peripheral and central nervous systems. It was discovered by Henry Hallett Dale in the year 1914, and its existence was later confirmed by Otto Loewi. Acetylcholine works in various brain regions, for instance, basal ganglia, cortex, and hypothalamus and is required for memory and cognition, as well as motor control. The action of acetylcholine released at a synapse is ended through the breakdown of ACh by the enzyme acetylcholinesterase. (42)

“The cholinergic system also seems likely to regulate hippocampal neurogenesis in the adult brain, positively promoting proliferation, differentiation, integration and potentially survival of newborn neurons.”(43)

“We find that changes of forebrain ACh level primarily influenced the proliferation and/or the short-term survival as opposed to the long-term survival or differentiation of the new neurons. We further demonstrate that these newly born cells express the muscarinic receptor subtypes M1 and M4. Our data provide evidence that forebrain ACh promotes neurogenesis, and suggests that the impaired cholinergic function in AD may in part contribute to deficits in learning and memory through reductions in the formation of new hippocampal neurons.”(44)

Putting it all together

Now that we’ve established some of the factors involved in neurogenesis, it’s time to examine how we can leverage these inputs to optimise for neurogenesis and mitigate some of the assumed damage that is incurred due to long term stress and depression. To keep this post at readable length (already much longer than I expected) I won’t go into great depth on each item, but I’ll add plenty of references in that you can follow up yourself.

Optimising hormones for neurogenesis

The best way to begin optimising your hormones will be getting a full hormone blood panel performed. Dr Mark Gordon from who specialises in treating traumatic brain injury via hormone modulation recommends getting these tested first;

Once you’ve had these tests done, you can start working with your primary care doctor (or an endocrinologist) to begin to address any irregularities. Some options could be; Testosterone replacement therapy (TRT)/Hormone replacement therapy (HRT), Clomiphene monotherapy, human chorionic gonadotropin (HCG), supplementing with; pregnenolone, DHEA, IGF-1, natural desiccated thyroid etc. It’s essential you work with a doctor due to the many feedback loops involved.

Optimising neurotrophic growth factors for neurogenesis

* Lion’s Mane Hericium erinaceus (45), (46), (47)
* PQQ Pyrroloquinoline quinone (48), (49)
* Noopept (50), (51), (52)
* Exercise (53), (54)
* Lithium (55), (56), (57)
* Curcumin (58), (59), (60)
* Semax** (61), (62)
* NSI-189** (63)
* NSI-189** (63)
* Selegiline* (64), (65), (66)
* Vitamin D (67), (68)
* Luteolin (69), (70 confounded by use of PEA as well and possible conflicts of interest)

(* = Prescription)
(**= Usually classed as a research chemical, as such long-term safety profile is undetermined)

Reducing neural inflammation
* Resveratrol (71), (72), (73)
* PEA N-Palmitoylethanolamine (74), (75), (76)
* CBD (77), (78), (79)
* Curcumin (80), (81)

Optimising neurotransmitter neurogenesis

Increasing neurotransmitters is the most common method for treating depression. It’s outside the scope of this article to go into detail on the variety of drugs that are used in this capacity. As such, I’ve limited this to a few over the counter methods, which are usually well tolerated and widely used as nootropics. If you want to do further research into prescription methods of modulation, I personally like these resources:

* Ashwagandha (82), (83)
* Lemon Balm (84), (85)
* NAC N-acetyl cysteine (86), (87)
* Sarcosine (88), (89)
* BPC157** (90), (91)
* SAM-e (92), (93)
* Rhodiola Rosea (94)
* Bacopa (95), (96)
* Rhodiola Rosea (97)
* Alpha GPC (98), (99)
* ALCAR (100), (101)

Concluding remarks

To conclude this quite lengthy post, it appears that depression, particularly long bouts, can induce brain changes that may increase susceptibility to future mood disturbances. It may also be a case of the chicken and the egg where reduced growth factors produce a depressed state. I’d like to end on a note of caution though that the study of human neurogenesis is still in its infancy, let alone conclusively linking it to depression or influencing it. However, it’s an exciting new avenue of research, and many (if not all) of the methods mentioned also have corresponding research showing improvements in depressing in other studies whether that effect is achieved via neurogenesis or not.


I’m not a doctor etc. no medical body or the like has evaluated this information. Information is shared for educational purposes only and acquired through studying for myself. You should consult your primary care doctor before acting on any content, especially if you are taking medication, or have a medical condition/s.

Please let me know in the comments if you have any idea’s or suggestions on this post. Also, if you’ve found this post useful please consider sharing it and/or subscribing. I also have a twitter page where I share studies or posts I’ve found interesting on mental health issues.


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3 thoughts on “Link to depression and brain changes — Part 2

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