Endocannabinoids (eCBs) are signaling molecules synthesized from membrane lipid components and are derivatives of arachidonic acid, forming the two major eCBs 2-arachidonoyl glycerol (2-AG), and arachidonoyl ethanol amide (also called anandamide, AEA). The high lipophilicity prevents storage in vesicles, and therefore, the intensity of eCB signaling is driven by the activities of the eCB synthesizing and degrading enzymes. eCBs can act in an autocrine and paracrine manner, and are ligands for different receptors, whereby the major receptors are the cannabinoid type 1 receptor (CB1) and type 2 receptor (CB2)
[163][157]. Yet, AEA can also activate TRPV1 (transient receptor potential cation channel subfamily V member 1), while 2-AG also stimulates the GABA
A receptor
[164,165][158][159]. The eCB signaling is involved in many physiological and pathophysiological processes both in the CNS and in peripheral organs
[164][158]. In the context of adult neurogenesis, the research has focused on CB1 and CB2. While these receptors and eCB synthesizing and degrading enzymatic machinery have been reported to be present in NPCs in the SVZ of the adult hippocampus
[25[25][160],
166], the intensity and exact mode of eCB signaling in NPC or onto NPC are difficult to be determined. As these eCB components are additionally expressed in cells surrounding the neurogenic niches in the SGZ, the functionality of eCB signaling regarding the regulation of adult neurogenesis is complex and may act in a paracrine and/or autocrine manner onto neural stem cells and NPCs.
It has been reported that, in general, eCB signaling, as well as phytocannabinoids regulate adult neurogenesis positively, mostly via CB1 and CB2
[166[160][161],
167], possibly through multiple mechanisms, including proliferation, antiapoptotic defense, antioxidant defense, immunoregulation, and autophagy/mitophagy
[166][160]. Most of the investigations have addressed these functions under physiological conditions, and only a few investigations addressed stimulated conditions, with positive (e.g., exercise) or negative (e.g., stress) annotation. As discussed above, a link between antidepressant intervention and adult neurogenesis has frequently been reported. In fact, in a mouse model of depressive-like behavior by using CUS, the inhibition of the 2-AG degrading enzyme monoacyl glycerol lipase (MAGL) by chronic application of JZL184 prevented the CUS-induced increase of feeding latency in the novelty-induced suppression of feeding, and immobility time in the forced swim test
[168][162]. The positive behavioral outcome went along with the prevention of CUS-induced impaired adult neurogenesis in the SGZ, and a form of LTP in the DG known to be neurogenesis-dependent. These effects were associated with the normalization of CUS-induced decrease of mTOR (mammalian target of rapamycin)
[169][163]. The mTOR signaling pathway was shown to be compromised in MDD subjects
[170][164], whereas mTOR activation acts in an antidepressant manner
[171][165]. Along with this, activation of mTOR signaling is known to play pivotal roles in adult neural stem cell regulation by particularly upregulating proliferation of the transient amplifying stem cell pool
[172][166], but also by impacting NPC differentiation (for review, see the work by the authors of
[173][167]). A recent other investigation addressed the influence of the microbiome on the eCB system and adult neurogenesis
[174][168]. In an elegant set of experiments using unpredictable chronic mild stress (UCMS) as a mouse model of depression, and fecal microbiota transfer from these mice to non-UCMS mice, the authors rescued the microbiota-transmitted depressive-like behavior by pharmacological inhibition of MAGL with JZL184, concomitantly with the restoration of adult neurogenesis. Furthermore, it was also shown that complementation of UCMS microbiota with
Lactobacillaceae alleviated depressive-like symptoms and restored neurogenesis levels in recipients of UCMS microbiota.
As outlined above, exercise is an efficient intervention for increasing adult neurogenesis. Pharmacological blockade of the CB1 alleviated the exercise-induced increase in proliferation in the SGZ
[175][169]. In another study, though, using CB1 deficient mice, such a CB1 dependency on neurogenesis was not observed upon a 6-week running period, but the CB1 deficient mice showed reduced motivation to run
[176][170]. The reasons for these divergent observations have not been clarified.
In summary, the current data on the involvement of the eCB system in stress coping and neurogenesis suggest that the enhancement of eCB signaling, in particular 2-AG, is beneficial for alleviating stress-induced depressive-like behavior, and concomitantly, to the stress-induced blunting of adult neurogenesis. The underlying mechanisms of the stimulatory effects on neurogenesis have still to be further investigated.
3.1.3. Brain-Derived Neurotrophic Factor (BDNF)
The neurotrophin BDNF regulates survival, proliferation, differentiation, and migration of neural stem and progenitor cells in vitro and in vivo during neural development of the embryo, as well as in adult neurogenesis
[177,178,179,180][171][172][173][174]. In mature neurons, BDNF is also well known for its function in synaptic plasticity and LTP formation, thereby controlling cognition, learning, and memory, but also mood
[43,181,182,183][43][175][176][177]. BDNF is secreted at the pre- and postsynaptic side either as proprotein or mature BDNF in an activity-dependent manner or by the constitutive pathway of exocytosis
[184,185,186][178][179][180]. BDNF exerts its functions through binding to its two receptors, the high affinity tropomyosin receptor kinase B (TrkB) and the low-affinity p75 pan neurotrophin receptor (p75NTR). Besides being expressed on the vast majority of neurons, the occurrence of both receptor types has been demonstrated in both adult neurogenic niches exhibiting dynamic expression during distinct stages of adult neurogenesis
[187,188][181][182]. BDNF signaling through the TrkB receptor acts mainly via the PI3K/Akt pathway to positively regulate cellular survival and structural plasticity, whereas the MAP kinase pathway in concert with PLCγ is the main player in regulating cellular proliferation and differentiation. Binding to p75NTR was demonstrated to have opposing functions, e.g., the reduction of dendritic arborization, apoptosis, and long-term depression, also reflecting the enhanced binding of pro-BDNF, for which opposing physiological roles have been demonstrated
[189,190,191,192][183][184][185][186].
Role of BDNF in MDD
It has been widely shown that serum BDNF availability correlates with mood changes and reflects the pathophysiological state in mood disorders, as well as with structural changes in specific brain regions, such as the hippocampus and cortical areas
[193,194,195,196,197][187][188][189][190][191]. Moreover, BDNF serum levels seem to reflect BDNF brain levels
[198][192]. Altogether this implicates BDNF as a potential biomarker for MDD, but also for other mood disorders
[199][193]. Indeed, recently, also DNA-methylation profiles of the BDNF promoter were suggested as MDD biomarker, because depressed and healthy individuals could be clearly classified into two groups by this epigenetic modification
[200][194]. The BDNF hypothesis of depression is justified because opposing actions of stress and antidepressant treatment are observed on existing BDNF levels in serum and limbic brain regions, such as the hippocampus
[182][176]. Stress significantly suppresses mRNA and protein BDNF levels in the hippocampus, particularly in the DG and CA3 hippocampal subfields, and thereby impairs downstream targets of signaling pathways implicated in neuroplasticity
[201,202][195][196]. Two important meta-analyses could directly prove decreased serum BDNF levels in depressed, suicidal patients, whereas BDNF was increased after antidepressant treatment in humans
[195,196][189][190]. The question of how BDNF exerts its antidepressant effect is still not fully understood, since the regulation by BDNF could appear at the level of neuronal excitability, as well as regarding the regulation of adult neurogenesis or both. Furthermore, brain atrophy caused by stress
[203][197] could be potentially counteracted by BDNF, serving as a survival factor for degenerating neurons. However, this last point is unlikely because some antidepressants reported an increase of BDNF that did not reverse stress-induced atrophy
[182,203][176][197].
3.2. Negative Modulation of Adult Neurogenesis by Stress
Long-term exposure to environmental, physical, and psychosocial stress is a recognized risk factor for MDD, also referred to as stress-related disorder
[132][126]. A plethora of stressors contributes to the development of MDD, including traumatic events, such as bereavement, repetitive job hassles, diagnosis of a disabling disease, physical or sexual abuse. The time-window of trauma exposure has a leading role in determining the body’s structural and functional changes in response to stress. In this respect, early life stress (ELS), such as childhood trauma (for example, abuse), lack of maternal care, poor nutritional intake, triggers significant changes in the brain with psychological consequences in adulthood
[226][198]. The hippocampus, which mostly develops postnatally in both humans and rodents
[227[199][200],
228], is highly sensitive to precocious stress. ELS in rodents was shown to impair adult neurogenesis, in correlation with impaired learning and memory functions (reviewed by the authors of
[226][198]) specifically in male rodents
[229[201][202],
230], reviewed by the authors of
[231][203].
From a neuroendocrine point of view, acute stress engages a fast and self-limiting body reaction that implicates the involvement of the stress hormones, cortisol, norepinephrine, and epinephrine, the immune system, and stress-sensitive brain areas, such as the hippocampus. The complex interaction among these factors underlying the so-called “fight or flight response” is a beneficial protective mechanism that prepares the body to react to stressors
[232][204]. A crucial role in the stress system is played by GCs and the HPA axis. Activation of the HPA axis starting from the release of corticotropin-releasing hormone (CRH) from the hypothalamus to stimulate the pituitary release of adrenocorticotropin hormone (ACTH) leads to the final synthesis and release of cortisol in humans and corticosterone in rodents from adrenal glands
[146][140]. GC levels, in turn, block the HPA axis, through negative feedback over the hypothalamus, and as mentioned above, the hippocampus. This area is particularly rich in GC receptor (GR), which, in contrast to the other GC responsive receptor, the mineralocorticoid receptor (MR), has been implicated in the negative feedback to stress
[233][205].