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Figure 1. Obesity-induced cellular and circuit level changes in the orexin system are associated with maladaptive behavioral responses. Chronic HFF
alters glutamatergic inputs to orexin/hypocretin neurons (Ox/Hcrt), thereby increasing overall inhibitory tone and inducing a state of hypoarousal. Altered
cellular activity of orexin neurons influences the activity of downstream neural networks in the lateral hypothalamus and hippocampus and decreases
reward-seeking and coping behaviors. Chemogenetic activation of orexin neurons reverses changes in network activity and corrects the behavioral conse-
quences of HFF (14). GluR, glutamate receptor; D1R, dopamine 1 receptor; hM3Dq, chemogenic receptor.
with a therapeutic for narcolepsy (modaf- orexin neurons, which then reverses with this relationship is bidirectional (21), and
inil) to enhance alertness, the mice also longer-term consumption (17). Together, connections between orexin neurons
overcame the obesity-induced stress defi- these studies demonstrate that multiple and the energy-sensing arcuate nucleus
cit. Collectively, these findings suggest pre- and postsynaptic mechanisms serve neurons likely contribute to such circuit
that hypoarousal mediated by the orexin to dynamically regulate glutamatergic function changes. These data raise the
system may cause the neural circuit and inputs to orexin neurons, which parallel possibility that multiple signals reflective
behavioral changes observed with HFF. short- and long-term changes in the met- of metabolic status may influence orexin
abolic state. system function. While it is interesting
Physiological significance and The orexin system adaptation to HFF to speculate, further work is required to
future studies likely serves to regulate arousal and the determine the precise factors driving the
Glutamatergic synaptic activity contrib- motivation for reward relative to meta- synaptic changes with HFF.
utes to the basal electrical excitability bolic status. However, the paper by Tan Additional remaining questions relate
of orexin neurons (15), and increasing and Hang et al. raises additional questions to the outputs driving the behavioral con-
evidence suggests that metabolic sta- about what is driving the effect. DIO asso- sequences. Although it is likely that orexin
tus is central in setting this tone. While ciates with multiple physiological chang- itself mediates the effects, orexin neurons
Tan and Hang et al. (14) demonstrate es, and orexin neurons are responsive to coexpress glutamate, and chemogenic acti-
that chronic HFF decreased signaling various signals reflective of energy status, vation of orexin neurons provides limited
at glutamatergic synapses onto orex- including circulating nutrients, endo- control over selective release of peptides or
in neurons, fasting has been shown to cannabinoids, and hormones (12, 18). A fast neurotransmitters (22). Furthermore,
have the opposite effect and rapidly large component of the diet-driven effect both orexin receptor (OxR) subtypes are
promotes excitatory neurotransmission appears to involve presynaptic mecha- expressed in regions of the brain implicat-
at orexin synapses (16). These synaptic nisms. Given that leptin administration can ed in arousal, motivation, and reward (12).
changes are likely crucial for orexin neu- prevent fasting-induced synaptic changes While the OxR1 may be more relevant for
rons’ ability to formulate the appropri- at orexin synapses (16), persistently elevat- reward and OxR2 for arousal (13), the con-
ate autonomic, endocrine, or behavioral ed leptin levels may also contribute to the tribution of each receptor to the observed
responses according to metabolic status; synaptic changes seen with HFF. effects is unknown. Moreover, the down-
they also raise questions about how the Notably, the central melanocor- stream target neurons mediating these
orexin system may change over time with tin system innervates orexin neurons, effects remain undetermined. Although
exposure to HFF. Conveniently, data including excitatory inputs from proop- orexin neurons directly project to the hip-
recently published demonstrates that iomelanocortin neurons (19). The mela- pocampus and reward systems, they also
HFF produces a time-dependent change nocortin system is crucial in detecting heavily innervate monoaminergic arous-
in orexin neuron synaptic plasticity (17). energy status and signals to other arous- al-promoting neurons (12). This includes
Short-term HFF (1 day to 1 week) is asso- al centers via perifornical lateral hypo- the histaminergic neurons of the tubero-
ciated with increased excitatory drive to thalamic neurons (20). Furthermore, mammillary nucleus, which are important
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