| The hypothalamus is the high center for regulating visceral activities and endocrine. Recent studies revealed that hypothalamus connected with many subcortical motor structures such as cerebellum, basal ganglia and red nucleus through histaminergic fibers. These direct histaminergic projections from hypothalamus to subcortical motor structures suggest that central histaminergic nervous system may regulate the neuronal activity of subcortical motor structures and modulate motor behavior that mediated by those subcortical motor structures. Also, the system may play an important role in integrating/coordinating somatic-visceral response.The central histaminergic nervous system originates from the tuberomammillary nucleus of the hypothalamus widely innervates almost the whole brain including the cerebellum and other subcortical motor structures. Four types histamine receptors are also found extensively existent in the central nervous system by radioautography, immunohistochemistry, hybridization experiments, and all of them are metabotropic. The deficiency/disorder of central histaminergic nervous system may cause some motor diseases and behavioral abnormalities, suggesting the system plays an important role on central motor control.The cerebellum and basal ganglia are two most important subcortical motor structures in the central nervous system. It has been well known that the cerebellum plays a key role in regulating muscle tonus, motor balance and motor coordination, ensuring that movements are performed with spatial and temporal precision. The injury/disorder of the cerebellum may induce the abnormal muscle tone, motor balance and coordination. The basal ganglia also participates in central motor control. The injury/disorder of the basal ganglia may induce some motor disorders, for instance the Parkinson disease (PD) and Huntingdon disease (HD).The neuroanatomical studies have revealed the direct histaminergic projection from hypothalamus to cerebellum and the subthalamic nucleus (STN) of basal ganglia and histamine receptors have also been found on cerebellar and STN neurons. However, the physiological significance of the hypothalamic histaminergic projections on cerebellar fastigial nucleus (FN) and STN has been still unknown. In this study, the effects of histamine on cerebellar FN and STN neuronal activity were observed by using rat brain slice preparations and extracellular recordings. Also, behavioral tests were used to evaluate the effect of histamine on FN-and STN-mediated motor control.1. Histamine excites rat cerebellar fastigial nucleus neurons and promotes motor performances through H2receptorsThe cerebellar FN, together with the IN, constitutes the two final output nuclei of the spinocerebellum and holds an important role in motor control and body balance. Previous studies have revealed a direct histaminergic projection from the hypothalamus to the cerebellar nuclei and a postsynaptic excitatory effect of histamine on the cerebellar IN. However, the effect of histamine and physiological significance of hypothalamic histaminergic projection on the cerebellar FN has been still unknown. In this study, using rat brain slice preparations and extracellular recordings, we found that histamine elicited the cerebellar FN neurons a concentration-dependent excitatory response (65/77,84.4%). The low-Ca2+/high-Mg2+medium did not block the histamine-induced excitation (n=10), indicated a direct postsynaptic action of the amine. The excitation of histamine on FN neurons was not blocked by selective histamine H1receptor antagonist triprolidine (n=20) or chlorpheniramine (n=10), but was effectively suppressed by ranitidine (n=15), a selective histamine H2receptor antagonist. On the other hand, selective histamine H2receptor agonist dimaprit (n=30) instead of histamine H1receptor agonist2-pyridylethylamine (n=20) mimicked the excitatory effect of histamine on FN neurons. The dimaprit-induced FN neuronal excitation was effectively antagonized by ranitidine (n=13) but not triprolidine (n=15). These results demonstrate that histamine excites cerebellar FN cells via the histamine H2receptor mechanism.Furthermore, histaminergic agents were bilaterally microinjected into the cerebellar FN of adult male rats in vivo for observation of their effects on motor behavior. Although histamine did not influence general movements in an open field, it remarkably improved motor performances on both accelerating rota-rod and balance beam. Ranitidine considerably declined those motor performances, but triprolidine showed no effect. Dimaprit rather than2-pyridylethylamine mimicked the facilitation effect of histamine on the movements. Moreover, histamine reversed the inhibitory effects of ranitidine on motor performances. These results demonstrate that histamine enhances rat motor balance and coordination through modulation of cerebellar FN neurons by activation of histamine H2receptors, and suggest that the hypothalamocerebellar histaminergic projections originating from the hypothalamus may modulate the cerebellar final output nuclei and subsequently influence the cerebellar function of motor control.Considering the hypothalamus is a high center for regulating visceral activities, we speculate that during ongoing movements, the hypothalamocerebellar histaminergic pathway may help to generate an integrated and coordinated somatic-visceral response for adaption of the changes of internal and external environments.2. Histamine on the subthalamic nucleus neuronal activities and motor performanceThe subthalamic nucleus is the only excitatory glutamatergic nucleus in the basal ganglia motor circuit, and its widespread projections to other basal ganglia regions lead it to be viewed as a’driving force’or’control structure’in the integrative function of the basal ganglia circuitry. Numerous studies show that in Parkinson disease (PD) patients and PD animal models the spontaneous firing rate of subthalamic nucleus neurons increased with irregular β-synchronized oscillatory. Thus, the subthalamic nucleus has long been clinically regarded as an important target in deep brain stimulation for PD.A series of autoradiography, immunohistochemistry and in situ hybridization studies showed that the subthalamic nucleus of squirrels receive the hypothalamic histaminergic innervations, and histamine H1and H2receptors are present in the subthalamic nucleus of human and guinea pigs. Other studies demonstrated that the density of histaminergic fibers in the brain of PD patients and the concentration of histamine in their basal ganglia and the blood are significantly higher. However, research about effect of histamine on subthalamic nucleus neuron activities and role of the central histaminergic nervous system in PD is relatively rare. Thus, in this study, effects of histamine on the subthalamic nucleus neurons and on motor performance of normal rats and PD model rats were investigated.By using rat brain slice preparations and extracellular recordings,134subthalamic nucleus neurons were recorded in this study and all of the neurons (134/134,100%) were concentration-dependently excited by histamine. The histamine-induced excitation was not blocked by low-Ca2+/high-Mg2+medium (n=12), indicating that the action of histamine on the subthalamic nucleus neurons was a directly postsynaptic effect. Ranitidine (n=23), a selective histamine H2receptor antagonist, but not mepyramine (n=20) or JNJ7777120(n=18), a selective histamine H1or H4receptor antagonist, blocked the histamine-induced excitation. Dimaprit (n=32), a selective histamine H2receptor agonist, rather than2-pyridylethylamine (n=16) or UVF8430(n=15), a selective histamine H1or H4receptor agonists, mimicked the excitatory effect of histamine on the subthalamic nucleus neurons. Additionally, the dimaprit-induced subthalamic nucleus neuronal excitation was effectively antagonized by ranitidine (n=16). The results demonstrate that histamine excites the subthalamic nucleus neurons via H2receptors, which is consistent with our immunofluorescence results that only histamine H2receptors presented in the subthalamic nucleus. Interestingly, Behavioral tests showed that unilateral microinjection of histamine and high K+solution (n=12) to the subthalamic nucleus ipslateral to the lesioning side of the6-hydroxydopamine-lesioned rat considerably reduced the apomorphine-induced rotation, whereas unilateral microinjecting ranitidine (n=12) rather than mepyramine (n=12) considerably promoted the apomorphine-induced rotation. Moreover, in the6-hydroxydopamine-induced rat PD models rather than normal rats, besides increasing neuronal firing rates of subthalamic nucleus, histamine also significantly decreased coefficient of variation of interspike interval of the neuronal firing (n=30), indicating that histamine regularizes the firing pattern of subthalamic nucleus neurons. Further behavioral tests showed that histamine enhanced rats’motor ability through histamine H2receptors in the subthalamic nucleus.These results demonstrate that histamine restores motor performances of PD rat models by activation of H2receptors. Considering histamine also excites the substantia nigra, neostriatum and globus pallidus, we speculate that the central histaminergic system may actively modulate the balance between direct and indirect pathways in the basal ganglia through its direct parallel innervations on those structures as well as the subthalamic nucleus, and consequently regulate motor initiation, execution and termination. Presumably, histamine H2receptor in the basal ganglia is a potential target for clinical treatment of PD. |
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