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as bistable systems. An early example of such bistable
behavior can be found in the activation of protein kinase C
(PKC) and mitogen-associated protein kinases (MAPK) 1
and 2, induced by stimulation of a receptor tyrosine kinase,
such as the epidermal growth factor receptor (EGFR) [1] .
The signaling pathways that are activated are represented in
Figure 16.5 A, left panel. Stimulation of EGFR triggers two
interconnected pathways: the PLC g -PKC pathway and the
Ras-Raf-MAPK pathway ( Figure 16.5 A). These two path-
ways interact at two different levels: PKC activates Ras
regulators [78] and possibly Raf [79,80] , which in turn
activates MAPK. MAPK can activate through phosphory-
lation the cytosolic phospholipase A-2 (cPLA2) [81,82]
with production of arachidonic acid (AA). AA acts together
with diacylglycerol (DAG) to activate PKC. This constitutes
a positive feedback loop, and it is possible to computa-
tionally study the necessary conditions to achieve a sus-
tained activation of the system in response to a brief
stimulus. When the system is activated above a certain level
(indicated in Figure 16.5 A right panel by point T), both PKC
and MAPK can reach a steady-state level of activation
(point A); conversely, if the initial amount of stimulation is
below a certain threshold (below point T), the systemwill go
back to a basal level of activation (point B) after the ligand is
removed. Therefore, the system exhibits bistable behavior.
Biological systems that behave in such a bistable fashion
have the intrinsic property to store information, so that only
external stimuli able to induce activation of PKC or MAPK
above the intersection point Twill move the system to switch
fromone state to another. Signals of sufficient amplitude and
duration enable the network to switch from the 'low activity'
state to the 'high activity' state, so under certain conditions
the output signal can be sustained evenwhen the input signal
is removed [1,83] . The versatility and tissue level function of
the PKC-MAPK-cPLA2 feedback loop has been demon-
strated by Tanaka and Augustine [84] , who showed that this
positive feedback loop was necessary for cerebellar long-
term depression, a form of synaptic plasticity. The PKC-
MAPK-cPLA2 feedback loop functioned as a switch to
couple brief Ca 2 รพ input signals to protein synthesis that is
required for long-term depression (LTD).
A recent example of how positive feedback loops
function as memory storage devices to affect organismal
behavior [85] focused on the potential role of synaptic
plasticity during hunger. Yang and co-authors found that
food deprivation results in persistent upregulation of excit-
atory synaptic inputs to AGRP neurons (Agouti-related
protein, AgRP), which consequently display increased firing
rates. AGRP neurons are a population of neurons localized
in the hypothalamic arcuate nucleus that regulates feeding.
These neurons are interconnected with a separate and
functionally opposed population termed POMC neurons (so
called because they express pro-opiomelanocortin), which
indeed inhibit feeding [86] . The study showed the existence
of a dynamic neural circuit with a reversible memory
storage device that regulates food intake in response to
energy deficit, thereby ensuring physiological homeostasis.
The key control point is represented by excitatory synapses
onto AGRP neurons activated by the hormone ghrelin.
Ghrelin, released after food deprivation, binds to ghrelin
receptors (Ghsr) located presynaptically, increasing gluta-
mate release and so activating AGRP neurons through
ionotropic glutamate receptors. 5 0 Adenosine mono-
phosphate-activated protein kinase (AMPK) is involved in
the circuit and participates in a positive feedback loop that
results in a switch-like behavior: indeed, the AMPK-medi-
ated feedback upregulates activity at the presynaptic
terminals for at least 5 hours. This results in a memory
storage mechanism of the hormone ghrelin that would
persistently promote synaptic activity onto AGRP neurons
to stimulate feeding behavior (illustration of the model in
Figure 16.5 B, top panel). Simultaneously, those persistently
activated synapses do require a separate inhibitory signal to
switch off the upregulating inputs once the energy balance is
restored. The hormone leptin, which is associated with long-
term regulation of energy homeostasis [87] , is well suited
for this role. Yang et al. found that leptin is sufficient to
reverse the elevated presynaptic activity onto AGRP
neurons through an opioid receptor-dependent pathway.
Indeed, leptin promotes POMC neuron activation [88] and
the release of
b -endorphin which represses elevated
synaptic activity.
It is worth noting that this system presents similarities
to a set/reset (SR) flip-flop memory storage circuit, which
consists of two interconnected NOR logic gates (represented
in Figure 16.5 B, lower panel): the 'set' signal is the hormone
ghrelin (S) and the 'reset' signal is leptin (R), and respec-
tively they sense deficit or surfeit. This SR circuit is able to
maintain high activity in response to S (even after S is turned
off) until R becomes true. This bistablemechanismperfectly
responds to set a range for energy balance (and not a set
point) that is determined by respective thresholds for acti-
vation of S and R ( Figure 16.5 B, lower panel).
The physiological relevance of this circuit can be
readily understood: the presence of a system that can set
energy balance allows the organism to exhibit different
behaviors when the energy component is not critical and
does not represent a limiting factor. This switch controls the
regulatory release of the two 'feeding control hormones',
leptin and ghrelin, from the peripheral endocrine system in
response to either deficit or surfeit energy levels, without
necessarily reflecting the general energy state balance
coming from the entire organism. Indeed, food deprivation
usually leads to a rapid increase in ghrelin levels that are
maintained only for 1
2 hours after refeeding; however,
the time window of such hormonal activity, albeit transient
in time, is enough to produce elevated firing rate at the level
of AGRP neurons whose activation persists up to 24 hours
e
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