Regulation of orexin neurons by the monoaminergic and cholinergic systems

Abstract

Orexins, also called hypocretins, are a recently described pair of neuropeptides orexin-A and -B. Orexins are implicated in energy homeostasis and arousal. Orexin-containing neurons are specifically located in the perifornical, dorsomedial, lateral, and posterior hypothalamus. Orexin neurons have been shown to regulate directly or indirectly the activity of aminergic nuclei. However, little is known about how the orexin neuronal activity is regulated in the brain. Despite the importance to study orexin neurons, it has been difficult to identify and directly examine their electrophysiological properties, because orexin neurons of the LHA are scarce, diffusely distributed, and lack distinct morphological features. To facilitate finding orexin neurons, we made transgenic mice in which orexin neurons specifically express enhanced green fluorescent protein (EGFP). Here we characterize the electrophysiological properties of orexin neurons using slice preparations from transgenic mice in which orexin neurons specifically express green fluorescent protein. Orexin neurons showed high frequency firing with little adaptation by injecting a positive current. The hyperpolarizationactivated current was observed in orexin neurons by a negative current injection. The neurotransmitters, which were implicated in sleep/wake regulation, affected the activity of orexin neurons; norepinephrine, dopamine, and serotonin hyperpolarized, while carbachol depolarized orexin neurons in either the presence or absence of tetrodotoxin. It has been reported that orexins directly or indirectly activate the nuclei that are the origin of the neurons containing these neurotransmitters. Our data suggest that orexin neurons have reciprocal neural circuits between these nuclei for an either positive or negative feedback loop and orchestrate the activity of these neurons to regulate the vigilance states.

Selective loss of GABA B receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture

“…We have previously studied the regulatory mechanisms of orexin neurons in vitro (7,8,19,(23)(24)(25). However, the physiological relevance of the regulatory mechanisms or inputs affecting the activity of orexin neurons remains unknown.…”

“…Orexin neurons also receive glutamatergic and GABAergic innervations from local interneurons (1,7). In vitro electrophysiological studies showed that both GABA A and GABA B agonists inhibit the activity of orexin neurons (7)(8)(9), but the physiological relevance of such regulation in vivo is unknown.…”

Neurobiological basis of state-dependent control of motor behaviors

“…The orexinergic system also excites dopaminergic (Korotkova et al, 2003), serotonergic (Liu et al, 2002;Takahashi et al, 2005), cholinergic (Burlet et al, 2002;Wu et al, 2004), glutamatergic (Li et al, 2002), peptidergic (Horvath et al, 1999) and GABAergic neurons (Korotkova et al, 2002;Wu et al, 2002). Orexin neurons, in turn, receive either excitatory or inhibitory effects from these neurons (Li and van den Pol, 2005;Yamanaka et al, 2003). The orexinergic system also contributes to regulation of somatomotor control, feeding and energy balance, and to the control of vigilance states (Nishino, 2003;Okumura et al, 2001;Sakurai, 2002;Siegel, 2004).…”

Regionally selective effects of GABA on hypothalamic GABAA receptor mRNA in vitro

“…In another series, one half-slice was superfused with 10 :M muscimol and 1 μm TTX, and the other with TTX only. TTX was used to suppress synaptic interactions among cells in the slice, with 1 μm being sufficient to block synaptic transmission in hypothalamic slices [18]. To determine mRNA levels under baseline conditions, separate half-slices were superfused with ACSF for 90 min at 34°C.…”

“…Transverse slices, 400 μm thick, were cut, and one was selected from the region just caudal to the decussation of the optic tract and divided along the midline. Each half-slice was initially placed in a separate perfusion chamber (0.4 ml) and superfused (1ml/min) for 1 h at room temperature with O 2 -saturated artificial cerebrospinal fluid (ACSF, see [17] for composition; the same medium was previously used to record from hypothalamic neurons [18]). …”