98
et al. ( 2016 )). Nevertheless, it is still early days and no solid hypotheses can be
formed. Many factors such as BDNF and orexin-A have been identified (Chieffi
et al. 2017 ), but much more details have been generated regarding the role of oxy-
gen. Low O 2 tensions induce expression of hypoxia-inducible factors (HIFs) which
are heterodimers consisting of a constitutively expressed β-subunit and an oxygen-
regulated α-subunit and regulate oxygen homeostasis and direct molecular responses
to hypoxia (Semenza 2012 ). HIF1α promotes self-renewal (via Notch signalling)
and blocks apoptosis and differentiation (Panchision 2009 ). Indeed, deep within the
nervous tissue, and especially in the SGZ, normally hypoxic conditions seem to
enhance Wnt/β-catenin signalling that—as described above- is essential for NSC
self-renewal and lineage progress (Mazumdar et al. 2010 ). As soon as neuroblasts
migrate away from this hypoxic microenvironment they become vulnerable to oxi-
dative stress and apoptosis occurs. If HIF1α becomes stabilized, then apoptotic cell
death is significantly reduced (Chatzi et al. 2015 ). Finally, a mechanism coupling
levels of exogenous glucose to NSC activity was described. High glucose levels
lead to reduced Hes-1 expression, through reduced CREB activity, and subsequent
inactivation of NSCs; the same effect being achieved in CREB-deficient NSCs
(Fusco et al. 2016 ).
6.3.2.4 Neurotransmission, Neuropeptides-Neurohormones
Various neurotransmitters and neurohormones have been identified as significant
modulators of neurogenesis in the hippocampus. Glutamate, the major excitatory
neurotransmitter, can act on NSCs mostly via the metabotropic glutamate receptor
5 (mGluR5) that is highly expressed on them. When norbin, which is a positive
regulator of mGluR5, was knocked-out it led to impaired proliferation and matura-
tion of newborn neurons without affecting cell-fate specification (Wang et al. 2015 ).
Because norbin is expressed in granule cells, its effect seems to be non-cell autono-
mous for NSCs and is probably mediated by cell-cell contact. Importantly, norbin-
deficient mice exhibit depressive-like behaviour. Moreover, a newly identified target
of neural activity and especially of glutamatergic neurotransmission is the family of
BMP/RA-inducible neural-specific proteins (BRINP) (Motomiya et al. 2007 ).
BRINP-1 expression is increased in response to kainic acid stimulation of the hip-
pocampus and in BRINP-1 deficient mice neurogenesis is significantly deregulated
with the generation of more immature neurons and the emergence of symptoms
relevant to human mental disorders such as schizophrenia and attention-deficit/
hyperactivity disorder (Kobayashi et al. 2014 ). Another neurotransmitter that has
been directly linked to NSC activity is norepinephrine, acting through β3 adrener-
gic receptors that are specifically expressed in Hes5-expressing progenitors in the
SGZ. Notably, serotonin was found not to exert any effects of NSCs of the SGZ
(Jhaveri et al. 2010 ).
Additional indications for the role of peripheral cues, such as of neurohor-
mones, have been recently provided in cell culture assays. Ghrelin, which acts pri-
marily in the hypothalamus but it has been also observed in other regions such as the
E. Andreopoulou et al.