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.


1. Harvard Health Publishing. What causes depression? — Harvard Health [Internet]. Harvard Health. [cited 2018 Oct 30]. Available from:

2. Sapolsky RM. Depression, antidepressants, and the shrinking hippocampus. Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12320.

3. Paul Hamilton J, Siemer M, Gotlib IH. Amygdala volume in Major Depressive Disorder: A meta-analysis of magnetic resonance imaging studies. Mol Psychiatry. 2008 Nov;13(11):993.

4. Levy MJF, Boulle F, Steinbusch HW, van den Hove DLA, Kenis G, Lanfumey L. Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression. Psychopharmacology . 2018;235(8):2195.

5. How Untreated Depression Changes the Brain Over Time [Internet]. Psychology Today. [cited 2018 Oct 30]. Available from:

6. Mu Y E al. Signaling in adult neurogenesis. — PubMed — NCBI [Internet]. [cited 2018 Dec 8]. Available from:

7. Galea LA E al. Sex, hormones and neurogenesis in the hippocampus: hormonal modulation of neurogenesis and potential functional implications. — PubMed — NCBI [Internet]. [cited 2018 Dec 9]. Available from:

8. Shohayeb B, Diab M, Ahmed M, Ng DCH. Factors that influence adult neurogenesis as potential therapy. Transl Neurodegener. 2018 Feb 21;7(1):4.

9. Mogi M E al. Brain-derived growth factor and nerve growth factor concentrations are decreased in the substantia nigra in Parkinson’s disease. — PubMed — NCBI [Internet]. [cited 2018 Dec 8]. Available from:

10. Molloy N, Read D, Gorman A. Nerve Growth Factor in Cancer Cell Death and Survival. Cancers . 2011 Feb 1;3(1):510–30.

11. Diniz BS E al. Reduced serum nerve growth factor in patients with late-life depression. — PubMed — NCBI [Internet]. [cited 2018 Dec 19]. Available from:

12. View All Posts by. Nerve Growth Factor Stack — 3 Simple Ingredients to Boost Performance [Internet]. Nootropedia. 2017 [cited 2019 Jan 23]. Available from:

13. Molendijk ML E al. Serum BDNF concentrations as peripheral manifestations of depression: evidence from a systematic review and meta-analyses on 179 associations (N=94… — PubMed — NCBI [Internet]. [cited 2018 Dec 15]. Available from:

14. Pandey GN E al. Brain-derived neurotrophic factor and tyrosine kinase B receptor signalling in post-mortem brain of teenage suicide victims. — PubMed — NCBI [Internet]. [cited 2018 Dec 15]. Available from:

15. Björkholm C, Monteggia LM. BDNF — a key transducer of antidepressant effects. — PubMed — NCBI [Internet]. [cited 2018 Dec 17]. Available from:

16. Zhang JC E al. Brain-derived Neurotrophic Factor (BDNF)-TrkB Signaling in Inflammation-related Depression and Potential Therapeutic Targets. — PubMed — NCBI [Internet]. [cited 2018 Dec 17]. Available from:

17. Erickson KI E al. The aging hippocampus: interactions between exercise, depression, and BDNF. — PubMed — NCBI [Internet]. [cited 2018 Dec 17]. Available from:

18. Diniz BS E al. Circulating Glial-derived neurotrophic factor is reduced in late-life depression. — PubMed — NCBI [Internet]. [cited 2018 Dec 17]. Available from:

19. Zhang X E al. Effect of treatment on serum glial cell line-derived neurotrophic factor in depressed patients. — PubMed — NCBI [Internet]. [cited 2018 Dec 17]. Available from:

20. Carvalho AF E al. Peripheral vascular endothelial growth factor as a novel depression biomarker: A meta-analysis. — PubMed — NCBI [Internet]. [cited 2018 Dec 17]. Available from:

21. Nowacka MM, Obuchowicz E. Vascular endothelial growth factor (VEGF) and its role in the central nervous system: a new element in the neurotrophic hypothesis of antidepressan… — PubMed — NCBI [Internet]. [cited 2018 Dec 17]. Available from:

22. Sharma AN, da Costa e Silva BFB, Soares JC, Carvalho AF, Quevedo J. Role of trophic factors GDNF, IGF-1 and VEGF in major depressive disorder: A comprehensive review of human studies. J Affect Disord. 2016 Jun;197:9.

23. Szczęsny E E al. Possible contribution of IGF-1 to depressive disorder. — PubMed — NCBI [Internet]. [cited 2018 Dec 15]. Available from:

24. Chigogora S E al. Insulin-like growth factor 1 and risk of depression in older people: the English Longitudinal Study of Ageing. — PubMed — NCBI [Internet]. [cited 2018 Dec 17]. Available from:

25. Lir-Wan Fan YP. Dysregulation of neurogenesis by neuroinflammation: key differences in neurodevelopmental and neurological disorders. Neural Regeneration Res. 2017 Mar;12(3):366.

26. ScienceDirect [Internet]. [cited 2018 Dec 19]. Available from:

27. Tang MM E al. Hippocampal neurogenesis dysfunction linked to depressive-like behaviors in a neuroinflammation induced model of depression. — PubMed — NCBI [Internet]. [cited 2018 Dec 19]. Available from:

28. Lu M E al. Iptakalim confers an antidepressant effect in a chronic mild stress model of depression through regulating neuro-inflammation and neurogenesis. — PubMed — NCBI [Internet]. [cited 2018 Dec 21]. Available from:

29. Genestine M, Lin L, Durens M, Yan Y, Jiang Y, Prem S, et al. Engrailed-2 (En2) deletion produces multiple neurodevelopmental defects in monoamine systems, forebrain structures and neurogenesis and behavior. Hum Mol Genet. 2015 Oct 15;24(20):5805.

30. Neurosci. Serotonin, depression, neurogenesis, and the beauty of science [Internet]. Neuroscientifically Challenged. [cited 2018 Dec 24]. Available from:

31. Petroff OA. GABA and glutamate in the human brain. — PubMed — NCBI [Internet]. [cited 2018 Dec 24]. Available from:

32. Vicini S. The role of GABA and glutamate on adult neurogenesis [Internet]. 2008 [cited 2018 Dec 24]. Available from:

33. Luscher B, Shen Q, Sahir N. The GABAergic Deficit Hypothesis of Major Depressive Disorder. Mol Psychiatry. 2011 Apr;16(4):383.

34. Rubio-Casillas A, Fernández-Guasti A. The dose makes the poison: from glutamate-mediated neurogenesis to neuronal atrophy and depression. — PubMed — NCBI [Internet]. [cited 2018 Dec 28]. Available from:

35. Banaudha K, Marini AM. AMPA prevents glutamate-induced neurotoxicity and apoptosis in cultured cerebellar granule cell neurons. Neurotox Res. 2000 Mar 1;2(1):51–61.

36. SAGE Journals: Your gateway to world-class journal research [Internet]. SAGE Journals. [cited 2019 Jan 2]. Available from:

37. Kippin TE, Kapur S, van der Kooy D. Dopamine Specifically Inhibits Forebrain Neural Stem Cell Proliferation, Suggesting a Novel Effect of Antipsychotic Drugs. J Neurosci. 2005 Jun 15;25(24):5815–23.

38. Höglinger GU, Rizk P, Muriel MP, Duyckaerts C, Oertel WH, Caille I, et al. Dopamine depletion impairs precursor cell proliferation in Parkinson disease. Nat Neurosci. 2004 Jun 13;7(7):726.

39. Duman RS E al. Regulation of adult neurogenesis by antidepressant treatment. — PubMed — NCBI [Internet]. [cited 2018 Dec 24]. Available from:

40. Wang JW E al. Chronic fluoxetine stimulates maturation and synaptic plasticity of adult-born hippocampal granule cells. — PubMed — NCBI [Internet]. [cited 2019 Jun 8]. Available from:

41. 5-Bromo-2′-deoxyuridine B5002 [Internet]. Sigma-Aldrich. [cited 2019 Jan 9]. Available from:

42. Coradazzi M, Gulino R, Fieramosca F, Falzacappa LV, Riggi M, Leanza G. Selective noradrenaline depletion impairs working memory and hippocampal neurogenesis. Neurobiology of Aging. 2016 Dec;48:93–102.

43. Bruel-Jungerman E E al. Cholinergic influences on cortical development and adult neurogenesis. — PubMed — NCBI [Internet]. [cited 2019 Jan 10]. Available from:

44. Mohapel P E al. Forebrain acetylcholine regulates adult hippocampal neurogenesis and learning. — PubMed — NCBI [Internet]. [cited 2019 Jan 10]. Available from:

45. He X E al. Structures, biological activities, and industrial applications of the polysaccharides from Hericium erinaceus (Lion’s Mane) mushroom: A review. — PubMed — NCBI [Internet]. [cited 2019 Jan 23]. Available from:

46. Friedman M. Chemistry, Nutrition, and Health-Promoting Properties of Hericium erinaceus (Lion’s Mane) Mushroom Fruiting Bodies and Mycelia and Their Bioactive … — PubMed — NCBI [Internet]. [cited 2019 Jan 23]. Available from:

47. Tsai-Teng T E al. Erinacine A-enriched Hericium erinaceus mycelium ameliorates Alzheimer’s disease-related pathologies in APPswe/PS1dE9 transgenic mice. — PubMed — NCBI [Internet]. [cited 2019 Jan 23]. Available from:

48. Bishop A E al. Pyrroloquinoline quinone: a novel vitamin? — PubMed — NCBI [Internet]. [cited 2019 Jan 23]. Available from:

49. Liu S E al. Enhanced rat sciatic nerve regeneration through silicon tubes filled with pyrroloquinoline quinone. — PubMed — NCBI [Internet]. [cited 2019 Jan 23]. Available from:

50. Ostrovskaya RU E al. Noopept stimulates the expression of NGF and BDNF in rat hippocampus. — PubMed — NCBI [Internet]. [cited 2019 Feb 2]. Available from:

51. Antipova TA E al. Dipeptide Piracetam Analogue Noopept Improves Viability of Hippocampal HT-22 Neurons in the Glutamate Toxicity Model. — PubMed — NCBI [Internet]. [cited 2019 Feb 2]. Available from:

52. Vakhitova YV, Sadovnikov SV, Borisevich SS, Ostrovskaya RU, Gudasheva TA, Seredenin SB. Molecular Mechanism Underlying the Action of Substituted Pro-Gly Dipeptide Noopept. Acta Naturae. 2016;8(1):82.

53. Dinoff A E al. The effect of acute exercise on blood concentrations of brain-derived neurotrophic factor in healthy adults: a meta-analysis. — PubMed — NCBI [Internet]. [cited 2019 Feb 2]. Available from:

54. Venezia AC E al. A single bout of exercise increases hippocampal Bdnf: influence of chronic exercise and noradrenaline. — PubMed — NCBI [Internet]. [cited 2019 Feb 2]. Available from:

55. De-Paula VJ E al. Long-term lithium treatment increases intracellular and extracellular brain-derived neurotrophic factor (BDNF) in cortical and hippocampal neurons … — PubMed — NCBI [Internet]. [cited 2019 Feb 2]. Available from:

56. Ricken R E al. Brain-derived neurotrophic factor serum concentrations in acute depressive patients increase during lithium augmentation of antidepressants. — PubMed — NCBI [Internet]. [cited 2019 Feb 2]. Available from:

57. Leyhe T E al. Increase of BDNF serum concentration in lithium treated patients with early Alzheimer’s disease. — PubMed — NCBI [Internet]. [cited 2019 Feb 2]. Available from:

58. Fanaei H E al. Effect of curcumin on serum brain-derived neurotrophic factor levels in women with premenstrual syndrome: A randomized, double-blind, placebo-contr… — PubMed — NCBI [Internet]. [cited 2019 Feb 2]. Available from:

59. Hurley LL E al. Antidepressant-like effects of curcumin in WKY rat model of depression is associated with an increase in hippocampal BDNF. — PubMed — NCBI [Internet]. [cited 2019 Feb 2]. Available from:

60. Yu JJ E al. Chronic Supplementation of Curcumin Enhances the Efficacy of Antidepressants in Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Cont… — PubMed — NCBI [Internet]. [cited 2019 Feb 2]. Available from:

61. Dolotov OV E al. Semax, an analogue of adrenocorticotropin (4–10), binds specifically and increases levels of brain-derived neurotrophic factor protein in rat basal… — PubMed — NCBI [Internet]. [cited 2019 Feb 10]. Available from:

62. Tsai SJ. Semax, an analogue of adrenocorticotropin (4–10), is a potential agent for the treatment of attention-deficit hyperactivity disorder and Rett syndr… — PubMed — NCBI [Internet]. [cited 2019 Feb 10]. Available from:

63. Tajiri N E al. NSI-189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats. — PubMed — NCBI [Internet]. [cited 2019 Mar 17]. Available from:

64. Mizuta, I., Ohta, M., Ohta, K., Nishimura, M., Mizuta, E., Hayashi, K. and Kuno, S. (2000). Selegiline and Desmethylselegiline Stimulate NGF, BDNF, and GDNF Synthesis in Cultured Mouse Astrocytes. Biochemical and Biophysical Research Communications, [online] 279(3), pp.751–755. Available at: [Accessed 8 Mar. 2019].

65. Naoi M E al. Revelation in the neuroprotective functions of rasagiline and selegiline: the induction of distinct genes by different mechanisms. — PubMed — NCBI [Internet]. [cited 2019 Feb 10]. Available from:

66. de Tassigny XD, Pascual A, López-Barneo J. GDNF-based therapies, GDNF-producing interneurons, and trophic support of the dopaminergic nigrostriatal pathway. Implications for Parkinson’s disease. Front Neuroanat [Internet]. 2015 [cited 2019 Feb 10];9. Available from:

67. Jennifer S. Buell BD-H. Vitamin D and Neurocognitive Dysfunction: Preventing “D”ecline? Mol Aspects Med. 2008 Dec;29(6):415.

68. Sanchez B E al. 1,25-Dihydroxyvitamin D3 administration to 6-hydroxydopamine-lesioned rats increases glial cell line-derived neurotrophic factor and partially rest… — PubMed — NCBI [Internet]. [cited 2019 Feb 10]. Available from:

69. Xu SL E al. Flavonoids induce the synthesis and secretion of neurotrophic factors in cultured rat astrocytes: a signaling response mediated by estrogen receptor. — PubMed — NCBI [Internet]. [cited 2019 Mar 17]. Available from:

70. Caltagirone C, Cisari C, Schievano C, Di Paola R, Cordaro M, Bruschetta G, et al. Co-ultramicronized Palmitoylethanolamide/Luteolin in the Treatment of Cerebral Ischemia: from Rodent to Man. Transl Stroke Res. 2016 Feb 1;7(1):54–69.

71. Chen WJ E al. Protective effects of resveratrol on mitochondrial function in the hippocampus improves inflammation-induced depressive-like behavior. — PubMed — NCBI [Internet]. [cited 2019 Mar 17]. Available from:

72. Moore A E al. Resveratrol and Depression in Animal Models: A Systematic Review of the Biological Mechanisms. — PubMed — NCBI [Internet]. [cited 2019 Mar 17]. Available from:

73. Ge L E al. Resveratrol abrogates lipopolysaccharide-induced depressive-like behavior, neuroinflammatory response, and CREB/BDNF signaling in mice. — PubMed — NCBI [Internet]. [cited 2019 Mar 17]. Available from:

74. Skaper SD E al. N-Palmitoylethanolamine and Neuroinflammation: a Novel Therapeutic Strategy of Resolution. — PubMed — NCBI [Internet]. [cited 2019 Mar 17]. Available from:

75. Skaper SD E al. Glia and mast cells as targets for palmitoylethanolamide, an anti-inflammatory and neuroprotective lipid mediator. — PubMed — NCBI [Internet]. [cited 2019 Mar 17]. Available from:

76. Scuderi C E al. Palmitoylethanolamide exerts neuroprotective effects in mixed neuroglial cultures and organotypic hippocampal slices via peroxisome proliferator-ac… — PubMed — NCBI [Internet]. [cited 2019 Mar 17]. Available from:

77. Mandolini GM E al. Pharmacological properties of cannabidiol in the treatment of psychiatric disorders: a critical overview. — PubMed — NCBI [Internet]. [cited 2019 Mar 17]. Available from:

78. Marchalant Y E al. Cannabinoids attenuate the effects of aging upon neuroinflammation and neurogenesis. — PubMed — NCBI [Internet]. [cited 2019 Mar 17]. Available from:

79. Campos AC, Ortega Z, Palazuelos J, Fogaça MV, Aguiar DC, Díaz-Alonso J, et al. The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system. Int J Neuropsychopharmacol. 2013 Jul 1;16(6):1407–19.

80. Huang L E al. Neuroprotective Effect of Curcumin Against Cerebral Ischemia-Reperfusion Via Mediating Autophagy and Inflammation. — PubMed — NCBI [Internet]. [cited 2019 Mar 17]. Available from:

81. Cai J E al. Curcumin mitigates cerebral vasospasm and early brain injury following subarachnoid hemorrhage via inhibiting cerebral inflammation. — PubMed — NCBI [Internet]. [cited 2019 Mar 17]. Available from:

82. Candelario M E al. Direct evidence for GABAergic activity of Withania somnifera on mammalian ionotropic GABAA and GABAρ receptors. — PubMed — NCBI [Internet]. [cited 2019 Mar 20]. Available from:

83. Singh N E al. An overview on ashwagandha: a Rasayana (rejuvenator) of Ayurveda. — PubMed — NCBI [Internet]. [cited 2019 Mar 20]. Available from:

84. Savage K E al. GABA-modulating phytomedicines for anxiety: A systematic review of preclinical and clinical evidence. — PubMed — NCBI [Internet]. [cited 2019 Mar 20]. Available from:

85. Rosalie Awad Asim Muhammad Tony Durst Vance L. Trudeau John T. Arnason. Bioassay‐guided fractionation of lemon balm (Melissa officinalis L.) using an in vitro measure of GABA transaminase activity [Internet]. Wiley Online Library. 2009 [cited 2019 Mar 20]. Available from:

86. Schmaal L, Veltman DJ, Nederveen A, van den Brink W, Goudriaan AE. N-Acetylcysteine Normalizes Glutamate Levels in Cocaine-Dependent Patients: A Randomized Crossover Magnetic Resonance Spectroscopy Study. Neuropsychopharmacology. 2012 Aug;37(9):2143.

87. Das P E al. Metabolite profiles in the anterior cingulate cortex of depressed patients differentiate those taking N-acetyl-cysteine versus placebo. — PubMed — NCBI [Internet]. [cited 2019 Mar 20]. Available from:

88. Chaki S, Fukumoto K. Potential of Glutamate-Based Drug Discovery for Next Generation Antidepressants. — PubMed — NCBI [Internet]. [cited 2019 Mar 20]. Available from:

89. Strzelecki D E al. Supplementation of antipsychotic treatment with sarcosine — GlyT1 inhibitor — causes changes of glutamatergic (1)NMR spectroscopy parameters in the… — PubMed — NCBI [Internet]. [cited 2019 Mar 20]. Available from:

90. Xue X-C, Wu Y-J, Gao M-T, Li W-G, Zhao N, Wang Z-L, et al. Protective effects of pentadecapeptide BPC 157 on gastric ulcer in rats. World J Gastroenterol. 2004 Apr 1;10(7):1032.

91. Sikiric P E al. Gastric mucosal lesions induced by complete dopamine system failure in rats. The effects of dopamine agents, ranitidine, atropine, omeprazole and p… — PubMed — NCBI [Internet]. [cited 2019 Mar 20]. Available from:

92. Sharma A, Gerbarg P, Bottiglieri T, Massoumi L, Carpenter LL, Lavretsky H, et al. S-Adenosylmethionine (SAMe) for Neuropsychiatric Disorders: A Clinician-Oriented Review of Research. J Clin Psychiatry. 2017 Jun;78(6):e656.

93. Miller AL. The methylation, neurotransmitter, and antioxidant connections between folate and depression. — PubMed — NCBI [Internet]. [cited 2019 Mar 21]. Available from:

94. The effects of Rhodiola rosea extract on 5-HT level, cell proliferation and quantity of neurons at cerebral hippocampus of depressive rats. Phytomedicine. 2009 Sep 1;16(9):830–8.

95. Rajan KE E al. Molecular and Functional Characterization of Bacopa monniera: A Retrospective Review. — PubMed — NCBI [Internet]. [cited 2019 Jun 7]. Available from:

96. Chatterjee M E al. Antipsychotic activity of standardized Bacopa extract against ketamine-induced experimental psychosis in mice: Evidence for the involvement of dopa… — PubMed — NCBI [Internet]. [cited 2019 Jun 7]. Available from:

97. van Diermen D, Marston A, Bravo J, Reist M, Carrupt P-A, Hostettmann K. Monoamine oxidase inhibition by Rhodiola rosea L. roots. Journal of Ethnopharmacology [Internet]. 2009 Mar [cited 2019 Jul 13];122(2):397–401. Available from:

98. Effect of choline-containing phospholipids on brain cholinergic transporters in the rat. J Neurol Sci. 2011 Mar 15;302(1–2):49–57.

99. Traini E E al. Choline alphoscerate (alpha-glyceryl-phosphoryl-choline) an old choline- containing phospholipid with a still interesting profile as cognition enha… — PubMed — NCBI [Internet]. [cited 2019 Jun 7]. Available from:

100. Taglialatela G E al. Acetyl-L-carnitine treatment increases nerve growth factor levels and choline acetyltransferase activity in the central nervous system of aged rats. — PubMed — NCBI [Internet]. [cited 2019 Jun 7]. Available from:

101. Carta A E al. Acetyl-L-carnitine and Alzheimer’s disease: pharmacological considerations beyond the cholinergic sphere. — PubMed — NCBI [Internet]. [cited 2019 Jun 7]. Available from:

Link to depression and brain changes — Part 1

This post is a bit of a long one, so I’m breaking into two sections for readability. Firstly, I’ll discuss how depression affects the brain and how long-term depression I believe it can make it harder to get out of depressive cycles. I mention this not to be a downer and pessimistic; instead, for me knowing this has made it possible to go easier on myself and become somewhat less frustrated through slow/lack of progress. Change takes time along with effort. Secondly, we’ll go into what influences these changes and how we can attempt to take advantage of these mechanisms to benefit us.

“Nothing in the world is worth having or doing unless it means effort, pain and difficulty… I have never in my life envied a human being who led an easy life. I have envied a great many people who led difficult lives and led them well.” 
― Theodore Roosevelt

Although the research is in its initial days (although the connection between hippocampal volume and depression has been reported for over 20 years), there’s a growing amount of data pointing to structural changes in the brain due to depression and other mood disorders. “One fMRI study published in The Journal of Neuroscience studied 24 women who had a history of depression. On average, the hippocampus was 9% to 13% [some studies indicate up to a 20% loss] smaller in depressed women compared with those who were not depressed. The more bouts of depression a woman had, the smaller the hippocampus.”(1). The hippocampus is an area of the brain responsible for processing long-term memory and recollection. It’s a part of the brain which registers fear from a given situation, the memory of which may affect how you relate and respond to that situation again. How does this occur? Possibly due to long-term stress. Firstly, stress can cause retraction of dendritic processes (a branching extension from the neurone cell body that receives information from other neurones. See figure below.)

in hippocampal neurons. A second adverse effect of stress is the inhibition of neurogenesis in the adult hippocampus. Finally, in some studies, sustained stress can cause loss of preexisting hippocampal neurons (i.e., neurotoxicity)(2)

The amygdala seems to be a bit more tricky when it comes to correlating volume loss and depression. The amygdala, crucial to perception and where emotional memories are retained, is often more active in depressive illness and post-traumatic stress disorder (PTSD). Repeated stressors may enlarge the amygdala. An overactive amygdala, coupled with atypical activity in other brain regions, leads to disturbed patterns of physical activity and sleep. It can also induce abnormal secretion of hormones and other chemicals that affect many systems of the body. A 2008 meta-analysis of magnetic imaging resonance studies wrote:

“Stress-induced glucocorticoid excitotoxicity, which has been postulated to underlie hippocampal atrophy in psychiatric illness, stands as a potential moderator of amygdala volume loss in depression. This is a possible hypothesis given that the amygdala, like the hippocampus, is dense with glucocorticoid receptors. However, if cumulative effects of glucocorticoid exposure are responsible for the volumetric reduction of the amygdala during depression, then we would also predict a negative correlation between amygdala volume and recurrence or level of chronicity of depression, which has been shown in studies of hippocampal volume and depression.”(3)

What was interesting in this particular analysis was that they found unmedicated depressed people showed a reduction in amygdala volume, however, medicated people showed an increase in size. 


Drevets et al. using positron emission tomography (PET) imaging reported an increase in amygdala activation and metabolism in depressed patients. The fact that more significant amygdala activity was often observed after negative stimuli would explain the increased ability for depressed people to encode and remember negative rather than positive information, therefore contributing to the negative bias often seen in depressed patients. So the relationship between amygdala size and depression doesn’t seem to be fully elucidated yet. 

The prefrontal cortex (PFC), an essential structure in emotional regulation, decision-making and memory, may also shrink with depression. The prefrontal cortex is connected with several brain structures, for processing sensory input and mediating executive motor functions. The ventromedial PFC, located in the frontal lobe and the orbitofrontal cortex, located above the eyes, is involved in the cognitive processing of emotional stimuli originating from the limbic system (e.g., amygdala, ventral striatum, hippocampus, and hypothalamus) and is chiefly engaged in memory consolidation and retrieval. As such, the PFC plays a significant role in regulating appropriate emotional responses, including mood, fear or anxiety. Furthermore, the PFC has been associated with decision-making, personality expression and social behaviour. Neuroimaging studies showed a reduction in the size of multiple areas of the PFC in subjects diagnosed with depression. In line with these studies, post-mortem brain analysis of depressed patients affirmed reduced neural cell size and neural and glial cell densities as well as synapse number in both the dorsolateral and subgenual PFC (4).

Psychology Today summed up these new findings saying; 

“[The] evidence is increasingly pointing to the possibility that in addition to being a biological disorder with immediate implications, over time depression may also alter the brain in ways requiring different forms of treatment…”(5).

So what do we do with all this information and how does it help us with treatment?

Adult Neurogenesis


Adult neurogenesis was first proposed in the 1960s; however, it wasn’t until the 1990s that the theory became widely accepted and that neurogenesis could play a substantial role in brain function. Although the functional significance of adult neurogenesis in humans — due to the difficulty in studying observing it, remains to be established, increasing evidence has implicated compromised neurogenesis as a possible contributor in the development of mental illnesses; one of which being major depressive disorder (MDD). Neurogenesis has been shown to occur in the hippocampi of adult humans, and more recently it has been accepted to occur in the amygdala, both of which we’ve established could become altered due to long-term depression.

The neurogenic niche, which is characterised by a comparatively high vascular density and, in many cases, interaction with the cerebrospinal fluid is a specialised microenvironment that has a significant role in maintaining and regulating neural stem cells (NSC) proliferation. Neural stem cells in the adult brain continuously supply new neurons to the hippocampal dentate gyrus(6). The dentate gyrus (DG) are thought to contribute to the formation of new episodic memories, the impromptu exploration of new environments, and other functions. Many intrinsic factors, such as hormones, trophic factors, glia (non-neuronal cells), and vasculature (the vascular system of a part of the body), contribute to the neurogenic niche.

Hormones and neurogenesis

Hormones are signalling factors of the neuroendocrine system with essential functions in regulating human physiology and behaviour. The hippocampus shows a high degree of plasticity when exposed to gonadal hormones and stress hormones. The hippocampus regulates the hypothalamic-pituitary-adrenal (HPA) axis through a negative feedback mechanism via mineralocorticoid (MR) and glucocorticoid (GR) receptors, both of which are expressed highly in the DG. Interestingly, newly-generated neurons in the DG may be particularly crucial in the HPA negative-feedback mechanism. Depressed patients show abnormal HPA function such as abnormal day secretion of cortisol, which results in an abnormal circadian rhythm, and the hypersecretion of cortisol. There may also be a significant difference in how hormones act in females and males. For example, peak levels of ovarian hormones during cycle is correlated with increased levels of proliferation; conversely, it has been noted in some animals less testosterone is associated with a reduction of new neurons. Given the dysregulation of HPA negative-feedback in depression, normalising the HPA axis is one of the leading targets of recent psychiatric interventions.

“The removal of testicular hormones through castration increases HPA activity in males, whereas testosterone replacement reverses this effect, acting to reduce corticosteroid levels. Conversely, ovariectomy results in decreased HPA activity, whereas oestradiol replacement reverses this effect through the enhancement of corticosteroid output in females…These findings suggest a causal relationship between gonadal hormones and HPA output, albeit in different directions in males and females. Given the apparent roles of testosterone and oestradiol in reducing and enhancing glucocorticoid release, respectively, both hormones have been implicated in depression and antidepressant treatment.”(7).

“To contrast estrogen, the depletion of androgens by castration in adult male rats didn’t impact proliferation in the hippocampus but reduced the survival rate of new neurons…However, androgen-receptors are absent from the dentate gyrus, which suggests that testosterone effects on new neuron survival may have indirect mechanisms.”(8)

“The chronic administration of corticosterone…reduced cell proliferation and the density of immature neurons in the adult hippocampus in both male and female rats. Furthermore, the depletion of glucocorticoids, through the removal of the adrenal gland, resulted in an increase in adult hippocampal neurogenesis and removed stress-induced suppression of cell proliferation in the hippocampus.”(8)

Neurotrophic growth factors

Endogenous neurotrophic growth factors, which include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glia-derived nerve factor (GDNF), vascular endothelial growth factor (VEGF) and insulin-like growth factor-one (IGF-1), have integral roles in stimulating neural stem cells proliferation, differentiation and central nervous system development. While it’s been established neurotrophic factors maintain the survival and function of cholinergic and dopaminergic neurons(9), there are emerging roles for neurotrophic factors, such as BDNF and NGF, in maintaining neurogenesis in the adult brain.


Nerve Growth Factor, NGF

Rita Levi-Montalcini discovered Nerve Growth Factor in the 1940s and pioneered the field of growth factor research. She identified NGF as a substance secreted from mouse sarcoma (cancerous, malignant tumours of the connective tissues) tissue that stimulated neuronal survival and neurite outgrowth from chicken ganglia (nerve clusters). This provided some of the first evidence of paracrine signalling, whereby cells in one tissue secreted a protein which readily diffused to another tissue to elicit cellular changes in the target tissue. NGF has been shown to promote the survival and differentiation of neurons, an outgrowth of neurites. NGF appears to play a role in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis-mediated stress response. The non-neural activity of NGF has also gained significant attention in recent years, and NGF has been shown to have roles in the development of the male and female reproductive systems, the endocrine, cardiovascular and immune systems(10).

“NGF levels were significantly reduced in depressed patients (p = 0.002) as compared with healthy elderly controls. Elderly control subjects [n=77] with previous depressive episode also showed a significant reduction in NGF levels as compared with controls (p <0.01); NGF levels were similar between patients with a current depressive episode and previous depressive episode (p = 0.2).”(11)

“Our study [n=40] showed a significant reduction in hippocampal NGF and [Tropomyosin receptor kinase A] TrkA and [messenger RNA] mRNA expression among the individuals who died by suicide compared to normal controls agree with the observations of Dwivedi et al.18 The results of the present study indicate significant insufficient brain neurotrophin environments in suicide victims, strengthening the role of neurotrophins in the pathophysiology of suicide.” 

However, additional nerve growth factor isn’t always a good thing, unfortunately. Because NGF increases the growth of neurons, it can contribute to more pain, exacerbating arthritis, psoriasis, and chronic injuries.

In some reports, NGF can increase the spread and life of some tumour cells as well. Unfortunately, NGF has a hard time picking which cells to maintain and protect versus the ones that it should not. In the case of some tumours, nerve growth factor helps increase the health of malignant cells.

Generally, NGF has a protective effect though, at times, it should be approached with caution(12).

Brain-derived neurotrophic factor, BDNF

BDNF is a neurotrophin involved in the production, differentiation, and survival of neurons and has also been shown to represent a vital factor in the regulation of neurogenesis and synaptic plasticity. It exerts its neurotrophic effects by stimulating the tropomyosin-related kinase receptor B (TrkB). An in-depth meta-analysis by Molendijk et al. showed that, despite study heterogeneity, serum BDNF levels are overall lowered in patients with depression(13). Also, a reduction in BDNF and TrkB expression in the hippocampus and prefrontal cortex has been reported in post-mortem brain examinations of teenagers who committed suicide [n=29](14).

“Studies showed that a single bilateral infusion of BDNF into the ventricles or directly into the hippocampus is sufficient to induce a relatively rapid and sustained antidepressant-like effect.”(15)

“Signaling via brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB) plays a key role in the pathophysiology of depression and in the therapeutic mechanisms of antidepressants.”(16)

“There is strong evidence that decreased BDNF is associated with age-related hippocampal dysfunction, memory impairment, and increased risk for depression.”(17)


Glial cell line-derived neurotrophic factor, GDNF

HAMD = Hamilton depression rating scale also referred to as HDRS. Source:

GDNF was first discovered in a glial cell line but is expressed in many parts of the brain. It is a member of the transforming growth factor β (TGF-β) superfamily and is essential for neuronal survival, especially for dopaminergic and serotonergic neurons. Thus far, the exact involvement of GDNF in the biology of depression is not entirely understood, but its neuroprotective ability might make it an attractive future target for antidepressant treatment.

“Patients [n=34] with major depression showed a significant reduction in GDNF levels as compared to healthy elderly controls (p < 0.001). Also, GDNF level was negatively correlated with HDRS-21 [Hamilton Depression Rating Scale] scores (r = -0.343, p = 0.003).”(18)

“Serum GDNF was significantly lower in MDD patients [n=76] before treatment than in control subjects. From baseline to remission after 8 weeks of treatment, the increase in serum GDNF was statistically significant. The present study suggests that lowered serum GDNF might be involved in the pathophysiology of MDD, and antidepressant treatment increases the GDNF in MDD.”(19)

Vascular endothelial growth factor, VEGF

VEGF concentrations in suicide attempters vs healthy controls (n=63), measured with an MSD immunoassay. Horizontal lines indicate mean concentrations and standard error of mean (SEM). Here VEGF levels are significantly decreased compared to the controls. Source:

VEGF is primarily known for its induction of angiogenesis (the process through which new blood vessels form from pre-existing vessels) and modulation of vascular permeability during embryogenesis and growth, as well as pathological events such as in tumorigenesis. “Chronic stress in rats decreased the expression of VEGF and its receptor in the hippocampus (Heine et al. 2005). Further, VEGF is required for the proliferation of neural stem-like cells in the hippocampus following [electroconvulsive treatment] ECT.”(4). Along with this VEGF is involved in increased learning, neuroprotective in cases of hypoxia, and it also has been shown to increase expression of other neurotrophic growth factors. However, current research seems to be mixed with many studies showing increased expression of VEGF in depressed patients. The hypothesis then contrasts this that some anti-depressants may elicit their clinical benefits via an increase in VEGF.

“Fourteen studies met our eligibility criteria [n=1633]. VEGF was significantly elevated in individuals with MDD when compared to healthy controls. Funnel plot inspection and the Egger’s test did not provide evidence of publication bias. A significant degree of heterogeneity was observed (Q=38.355, df=13, P<0.001; I(2)=66.1%), which was explored through meta-regression and subgroup analyses. Overall methodological quality, a sample for the assay (plasma versus serum), as well as the matching of MDD and control samples for age and gender, emerged as significant sources of heterogeneity…Taken together, existing data indicate that VEGF shows promise as a biomarker for MDD, and supports that this mediator may be involved in neuroplasticity mechanisms underlying the pathophysiology of MDD.”(20)

“Antidepressant drugs were shown to induce hippocampal expression of VEGF. Also, the experiments in animals models of depression have demonstrated that VEGFR2 signalling is indispensable for the cellular and behavioural response to antidepressant drugs.”(21)

“VEGF levels were increased in the plasma or serum of depressed patients versus controls in eight studies…On the other hand, two studies demonstrated decreased plasma or serum VEGF levels in depressed patients compared to healthy individuals. No significant difference in VEGF levels between cases and controls were reported in three studies”(22)

Insulin-like growth factor, IGF-1

IGF-1 and its receptor IGF-1R are produced in the liver but are found in many tissues, including the brain and influences growth and differentiation processes. IGF-1 has been proposed as a potential therapeutic target for neurodegenerative diseases such as MDD (23). Various effects have been attributed to IGF-1 in terms of its role in neural signalling, neurotrophic mechanisms, and neuroprotection in pro-neuroinflammatory conditions. Intranasal administration has been proposed to provide a shorter path for IGF-1 to enter the brain, avoiding unwanted effects of IGF-1 in peripheral tissues. As with VEGF, the association between IGF and depression appears to be a complex one, where more or less, isn’t always better.

“The results from both the cross-sectional and longitudinal analyses revealed a ‘U’-shaped [n=6017 mean age 65] pattern of association, such that lower and higher levels of IGF-1 were associated with a slightly elevated risk of depression, whereas the lowest risk was seen around the median levels.”(24)

“Most data are very consistent and show that IGF-1 treatment exerts antidepressant like-activity by normalization of behavioural disturbances in various animal models of depression…Furthermore, the antidepressant-like effects of IGF-1 were often associated with an increase in cell proliferation in the hippocampus.”(23)

Neuroinflammation and adult neurogenesis


Neuroinflammation is comprised of biochemical and cellular responses of the nervous system to infection, neurodegenerative diseases and injury. These responses are directed at alleviating the triggering factors by involving the central nervous system (CNS) immunity to defend against potential harm. Responses are complex and include the activation of glia, release of inflammatory mediators; such as cytokines (small proteins) including chemokines, and generation of reactive oxygen and nitrogen species. The innate immune response of the CNS can be both protective and toxic; abnormal microglial activation, mitochondrial dysfunction, and protein aggregation can trigger an acute inflammatory response that, if unresolved, becomes chronic and damaging (25,26). Interestingly, the impact of pro-inflammatory cytokines on neurogenesis is not confined to proliferation, cell death, and neuronal differentiation, but may also be double-edged by impacting the integration of newly generated neurons in the adult brain. At present, the effect of neuroinflammation on neurogenesis remains controversial; however, based on studies in neurodegenerative disorders, it appears that in general, chronic neuroinflammation negatively regulates neurogenesis(25).

“These findings provide the first evidence that hippocampal neurogenesis dysfunction is correlated with neuroinflammation-induced depression, which suggests that hippocampal neurogenesis might be one of the biological mechanisms underlying depression induced by neuroinflammation.”(27)

“Iptakalim (Ipt), an ATP-sensitive potassium (K-ATP) channel opener that can cross the blood-brain barrier freely, has been demonstrated to inhibit neuroinflammation and enhance adult hippocampal neurogenesis….treatment with Ipt (10 mg/kg/day, i.p [intraperitoneal injection]) for 4 weeks restored the decrease of sucrose preference and shortened the immobile time in forced swimming tests and tail suspension tests in mice. Further, we found that Ipt reversed the induced reduction of the adult hippocampal neurogenesis and improved cerebral insulin signalling in the CMS mice. Furthermore, Ipt negatively regulated nod-like receptor protein 3 (NLRP3) expression and, in turn, inhibited microglia-mediated neuroinflammation by suppressing the activation of the NLRP3-inflammasome/caspase-1/interleukin 1β axis in the hippocampus of CMS mice.”(28)

“…mounting evidence suggests that neuroinflammation affects both embryonic and adult neurogenesis, contributing to the pathogenesis of numerous neurodevelopmental, neuropsychiatric, and neurological disorders.”(25)

This concludes part one, and part two will deal with neurotransmitters, turning all this into actionable information and the full list of references.


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.

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