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2012; Tena-Sempere & Huhtaniemi, 2003 ). The function of this neurohor-
monal system primarily relies on the dynamic interaction of three major
groups of signals, generated at the three major levels of the axis: (a) the hypo-
thalamus, where a relatively scarce population of neurons episodically release
the decapeptide gonadotropin-releasing hormone (GnRH) into the portal
circulation; (b) the anterior pituitary, that secretes gonadotropins,
luteinizing hormone (LH), and follicle-stimulating hormone (FSH); and
(c) the gonads, which are responsible not only for the generation of gametes
but also for the release of sex steroids and peptides ( Tena-Sempere &
Huhtaniemi, 2003 ). These major components of the HPG axis are con-
nected via feedforward and feedback loops (see Fig. 11.1 ). In this system,
GnRH neurons hold a major hierarchical role and operate as the final output
pathway for different regulatory signals, including central neuropeptides and
neurotransmitters, as well as peripheral hormones ( Fink, 2000 ).
A hallmark of puberty onset is the increase of the neurosecretory activity
of GnRH neurons ( Ojeda et al., 2006; Ojeda & Skinner, 2006 ). Episodic
secretion of GnRH, which is mandatory for proper stimulation of gonado-
tropin release and, hence, of gonadal function, is the result of the interplay
between the intrinsic oscillatory nature of GnRH neurons and a wide array
of excitatory and inhibitory afferents that integrate at the so-called GnRH
pulse generator ( Ojeda & Skinner, 2006 ). On the later, it has been docu-
mented that pubertal changes in pulsatile GnRH secretion are caused by
the concerted modifications in transsynaptic and glial inputs to the GnRH
neuronal network ( Ojeda et al., 2006; Ojeda & Skinner, 2006 ). Within this
complex circuitry, neuronal afferents to GnRH neurons likely operate as
ultimately responsible for the triggering of puberty. While the nature of such
a network of neuronal transmitters has been partially elucidated in recent
years, our understanding of the whole set of regulatory signals that project
onto GnRH neurons, as well as of their effects and major mechanisms of
action, remains incomplete. Similarly, the molecular mechanisms whereby
these signals are integrated at the level of GnRH neurons to define specific
patterns of pulsatile secretion of the decapeptide are still poorly understood.
Of note, system biology approaches have recently allowed the identification
of sets of genes/proteins that become activated at the time of puberty. This
has led to the hypothesis that, rather than the consequence of the action of a
single trigger, puberty is the end point of the concerted and hierarchical acti-
vation/inactivation of excitatory and inhibitory networks ( Ojeda, Dubay,
et al., 2010; Ojeda et al., 2006; Ojeda, Lomniczi, Sandau, & Matagne,
2010; Ojeda & Skinner, 2006 ). The timed regulation of those networks
seemingly requires
the operation of precise and multifaceted control
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