Orexinergic projections to the cat midbrain mediate alternation of emotional behavioural states from locomotion to cataplexy

Abstract

Orexinergic neurones in the perifornical lateral hypothalamus project to structures of the midbrain, including the substantia nigra and the mesopontine tegmentum. These areas contain the mesencephalic locomotor region (MLR), and the pedunculopontine and laterodorsal tegmental nuclei (PPN/LDT), which regulate atonia during rapid eye movement (REM) sleep. Deficiencies of the orexinergic system result in narcolepsy, suggesting that these projections are concerned with switching between locomotor movements and muscular atonia. The present study characterizes the role of these orexinergic projections to the midbrain. In decerebrate cats, injecting orexin-A (60 µM to 1.0 mM, 0.20-0.25 µl) into the MLR reduced the intensity of the electrical stimulation required to induce locomotion on a treadmill (4 cats) or even elicit locomotor movements without electrical stimulation (2 cats). On the other hand, when orexin was injected into either the PPN (8 cats) or the substantia nigra pars reticulata (SNr, 4 cats), an increased stimulus intensity at the PPN was required to induce muscle atonia. The effects of orexin on the PPN and the SNr were reversed by subsequently injecting bicuculline (5 mM, 0.20-0.25 µl), a GABA A receptor antagonist, into the PPN. These findings indicate that excitatory orexinergic drive could maintain a higher level of locomotor activity by increasing the excitability of neurones in the MLR, while enhancing GABAergic effects on presumably cholinergic PPN neurones, to suppress muscle atonia. We conclude that orexinergic projections from the hypothalamus to the midbrain play an important role in regulating motor behaviour and controlling postural muscle tone and locomotor movements when awake and during sleep. Furthermore, as the excitability is attenuated in the absence of orexin, signals to the midbrain may induce locomotor behaviour when the orexinergic system functions normally but elicit atonia or narcolepsy when the orexinergic function is disturbed.

Electrophysiological characterization of neurons in the dorsolateral pontine rapid-eye-movement sleep induction zone of the rat: Intrinsic membrane properties and responses to carbachol and orexins

“…Presumably, the direct orexin excitation of these neurons is overwhelmed in vivo by orexin excitation of GABAergic neurons projecting to and inhibiting these same SubC neurons (e.g. those in the midbrain locomotor region (Takakusaki et al, 2005). Interestingly, apparently contradictory effects of orexin are also observed in the raphe nucleus, where orexins directly excite wake-on, REM-off serotonin neurons but at the same time increase inhibitory input to these neurons (Brown et al, 2001;Liu et al, 2002).…”

Possible Contribution of the Basal Ganglia Brainstem System to the Pathogenesis of Parkinson’s Disease

“…The orexin-containing neurons located in the prefornical lateral hypothalamic area are considered to control appetite, energy balance, and vigilance states via projections to various areas in the nervous system (Peyron et al, 1998;Sakurai, 2002;Siegel, 2004). The orexinergic projections to the MLR facilitated the activity of the locomotor system (Takakusaki et al, 2005), indicating that the hypothalamic orexinergic system contributes to appetitive behaviors.…”

“…Therefore it is interesting to elucidate how orexinergic projections to the midbrain are involved in alteration of sleep-awake states. Then we examined effects of injections of orexin-A into the MLR, PPN and the SNr upon motor behaviors in decerebrate cats (Takakusaki et al, 2005). Microinjections of orexin into the MLR facilitated locomotion, while those into either the PPN or the SNr suppressed PPNinduced muscular atonia.…”

“…Basal ganglia outflow directly toward to the midbrain of the brainstem (basal ganglia-brainstem system; BG-BS system) has been recently recognized with respect to the regulation of muscle tone and posture-gait synergy (Takakusaki et al, 2003a(Takakusaki et al, , 2004c. It has been suggested that the BG-BS may also contribute to the modulation of vigilance states (Takakusaki et al, 2004c(Takakusaki et al, , 2005. Fundamental structures involved in the control of posture and locomotion and those in the muscle tone regulation during awake-sleep states exist in the brainstem and spinal cord (Chase & Morales 1990;Takakusaki et al, 1993Takakusaki et al, , 1994Takakusaki et al, , 2004aTakakusaki et al, , 2006.…”

Central functions of the orexinergic system

“…The latter contains the mesencephalic locomotor region and pedunculopontine nucleus, both of which are involved in the initiation and modulation of locomotion and other stereotyped movements. in decerebrate cats, injecting orexin A into the mesencephalic locomotor region reduces the intensity of electrical stimulation required to induce locomotion on a treadmill or even elicits locomotor movements without electrical stimulation [46] . on the other hand, microinjection of orexin A into the pedunculopontine nucleus increases the stimulus intensity required to induce muscle atonia [46] .…”