Studies Of Interaction Between Hypothalamus And Central Motor Structures

The cerebellum is traditionally considered as a subcortical somatic motor center. However, accumulating experimental evidences have revealed that the cerebellum also participates in nonsomatic basic functions such as cardiovascular, respiratory, micturition, immune, learning and cognition. Recently, a series of neuroanatomical investigations have demonstrated the direct bidirectional connections between the cerebellum and the hypothalamus. Considering the hypothalamus being a high autonomic center, the cerebollohypothalamic projection is supposed to be potential pathways underlying the cerebellar autonomic modulation.Although the cerebellohypothalamic projection is clarified, its natural physiological function has not been well elucidated. Among the 3 cerebellar nuclei, the fastigial nucleus (FN) is the phylogenetically oldest nucleus, and has been found to modulate various gastrointestinal activities. Thus, in this paper, issue 1 focused on the FN and was undertaken to investigate the function of cerebellohypothalamic projection by means of in vivo electrophysiological recordings.Meanwhile, orexin system, originating uniquely from the lateral hypothalamus/perifornical area of the hypothalamus, projects extensively to almost whole brain including the central vestibular system. The central orexinergic system has been implicated in many basic nonsomatic functions, including the sleep/wake states, feeding, and reward processes. However, whether the system has a role in somatic motor control remains enigmatic.Orexin deficiency in humans, dogs and rodents results in cataplexy, a motor deficit characterized by sudden loss of muscle tone suggesting the possibility of a modulatory role for orexin in motor control. But, since cataplexy is closely related to narcolepsy and often triggered by strong emotions, the effect of orexin on the motor system may be secondary to its actions on the neural circuits controlling sleep or emotions. However, several lines of evidence indicate that the orexinergic system may directly participate in central motor control. First, essential subcortical motor structures, such as basal ganglia, cerebellum, and vestibular nuclei, receive direct innervation from the hypothalamic orexinergic neurons. Secondly, during movements, orexinergic neurons are particularly active and orexin release increases. Finally, injection of orexin into the midbrain locomotor region of decerebate cats triggers locomotion and facilitates muscle tone. Thus, the role of central orexinergic system in motor control needs to be clarified. In issue 2 of this paper, the exact relationship between the central orexinergic system and motor control was investigated by means of quantitative RT-PCR, immunocytochemistry, in vitro/in vivo electrophysiological recordings and behavioral techniques at molecular, cellular, and behavioral levels.1. Cerebellar fastigial nuclear inputs and peripheral feeding signals converge on neurons in the dorsomedial hypothalamic nucleusModulation of food intake is a highly complicated physiological process involving the integrative operation of various brain regions, discrete neural pathways as well as gastrointestinal and metabolic factors. Some behavioral studies revealed that the animals with lesions of cerebellar cortex showed an alteration in food intake behavior, a disturbance in nutritional utilization and a decrease in body weight. It is well known that the dorsomedial hypothalamic nucleus (DMN) is an important center that regulates food intake, energy homeostasis and body weight. The present study was designed to examine, by using extracellular recordings in vivo in rats, whether the cerebellar FN inputs could reach and converge with the feeding-associated gastric vagal, glycemia and leptin signals onto single DMN neurons.Of the 200 DMN neurons recorded,104 (52%) responded to the cerebellar FN stimulation, in which 95 (91.3%) were also showed a response to the gastric vagal stimulation, suggesting a convergence of cerebellar FN and gastric vagal inputs on the DMN neurons. Moreover, a summation of responses was observed (n= 10) when the cerebellar FN and gastric vagal nerve were simultaneously stimulated. Among the 18 DMN neurons receiving convergent inputs from the cerebellar FN and gastric vagal nerves,16 (88.9%) cells also responded to the systemic administration of glucose and leptin. These results demonstrated that cerebellar FN afferent inputs, together with the feeding signals from the gastric vagal nerves, blood glucose as well as leptin, converge onto single DMN neurons, suggesting that a somatic-visceral integration related to the feeding may occur in the DMN and the cerebellum may actively participate in the feeding regulation through the cerebellar FN-DMN projections.2. A role for orexin in central vestibular motor controlCentral orexinergic system originating from the hypothalamus but projecting extensively to almost the whole brain has been implicated in many basic functions. The present study was undertaken to reveal the exact relationship between the central orexinergic system and motor control, the effects of orexin on the motor system and the underlying mechanisms. Considering that cataplexy is characterized by sudden loss of muscle tone and the central vestibular system plays a critical role in control of muscle tone and postural control, we focused on the effects of orexin on the vestibular nuclear complex in the brainstem. Therefore, we concentrated on the lateral vestibular nucleus (LVN, or Deiters'nucleus) in the vestibular nuclear complex, to investigate the relationship between the orexinergic system and motor control. The results are as follows: (â…°) By using quantitative RT-PCR and immunocytochemistry, OXi and OX2 receptors were identified in the LVN, specifically in the giant Deiters'neurons in this nucleus.(â…±) Inward whole-cell currents of LVN neurons induced by orexin-A were mediated by activation of both OX] and OX2 receptors.(â…²) Orexin-A excited the LVN neurons via a dual ionic mechanism, including both activation of Na+-Ca2+exchangers and closure of inward rectifier K+channels.(â…³) Orexin-A directly increased activities and sensitivities of LVN neurons.(â…´) Orexin-A excited LVN neurons in vivo and improved rat motor performance in balance beam tests and negative geotaxis tests.(â…µ) Microinjection of OX1 antagonist SB334867 into LVN strongly attenuated rat performance in inclined blance beam and accelerating rota-rod.Therefore, orexin participates not only in sleep and emotion (nonsomatic) but also in motor (somatic) regulation, suggesting that the central orexinergic system plays an important role in somatic-nonsomatic integration. These findings may account for why the absence of orexin results in narcolepsy-cataplexy.Investigations of interaction between hypothalamus and central motor structures will help us not only in understanding the fine network of feeding regulation, motor control, the mechanisms of cataplexy and somatic-visceral integration, but also in offering therapeutic strategy to cure disturbance of ingestion (obesity and anorexia), cataplexy, and other somatic-visceral dysfunctions.