99hippocampus, exerts a mitogenic effect in cultured hippocampal NSCs. This is due
to the enhanced progression from G1 to S phase mediated by the enhanced nuclear
expression of E2F1 and the balanced activity on positive and negative cell cycle
regulators (Chung and Park 2016 ). Finally, melatonin, which is secreted by the
pineal gland and has a remarkably pleiotropic nature is able to enhance the prolif-
eration of adult hippocampal NSC in vitro. Melatonin exerted its action via the
melatonin receptor, a G-protein coupled-receptor, and resulted in phosphorylation
of Raf, MEK, and ERK1/2 (Tocharus et al. 2014 ).
6.3.3 Hypothalamus
Although the main and better described neurogenic niches in the adult mammalian
brain are located in the SEZ of the lateral ventricle and the SGZ of the hippocampal
dentate gyrus, there is increasing evidence for adult neurogenesis also in the hypo-
thalamus (Batailler et al. 2016 ; Kokoeva et al. 2007 ), a brain region that is known
for its key role in the neuroendocrine regulations including reproduction, metabo-
lism or food intake. Recent lineage-tracing studies have convincingly demonstrated
the existence of neurogenic cells, capable of generating mainly neurons, within the
pool of tanycytes, the non-ciliated ependymoglial cells lining the ventral part of the
third ventricle (3V) (Haan et al. 2013 ; Lee et al. 2012 ; Robins et al. 2013 ). In light
of the function of the hypothalamus, cytogenesis within this niche is expected to be
regulated by extrinsic cues, linking it with metabolic and other behavioural condi-
tions (Lee et al. 2012 ; Migaud et al. 2015 ; Perera et al. 2011 ). Until now, though,
only limited progress has been made towards elucidating this regulation. Tanycytes
are expressing FGF10; hence, suggesting a role of this growth factor in the hypotha-
lamic niche (Haan et al. 2013 ). Other growth factors that when administered intra-
cerebroventricularly have been shown to induce neurogenesis in the hypothalamus
are BDNF (Pencea et al. 2001 ) and CNTF (Belsham et al. 2009 ). Finally, in sheep
that are a seasonal species, neurogenesis in the hypothalamus shows response to
seasonal stimuli (Batailler et al. 2016 ).
6.4 The NSC Microenvironment in the Aged
and the Pathological Brain
6.4.1 Ageing, Degeneration and the Cancer Stem Cell
Hypothesis
The NSC microenvironment changes significantly during ageing; however, very
little is known about the details of these changes and on how they might affect
NSCs. Within the ageing SEZ niche, the ECM structures called fractones seem to
6 Being a Neural Stem Cell: A Matter of Character But Defined...