Modulation Of Histamine/Central Histaminergic Systems On Neuronal Activities Of Subthalamic Nucleus And Cerebellar Nuclei

The central histaminergic system originates from tuberomammillary nucleus (TMN) of the hypothalamus and widely innervates to almost all regions of the brain including spinal cord. Histamine receptors are expressed in abundance in the whole brain. Studies from our laboratory and others have demonstrated that histamine may influence neuronal activities of some subcortical motor structures such as cerebellum, basal ganglia, red nucleus and lateral vestibular nuclei and also modulate animal’s motor abilities such as motor balance and coordination via these structures.In addition to the spinal cord, brainstem, and cerebral cortex in the three motor control hierarchies, the two parts of the brain (the cerebellum and basal ganglia) also involved in motor control. Cerebellum improve the accuracy of movement through comparing motor instructions issued by cerebral cortex and the feedback of actual execution of movement. Cerebellar damage could cause uncoordinated muscle activity, a variety of movement disorders and physical imbalance. Basal ganglia receives input fibers from all cerebral cortical regions, and its major output project to the frontal cortex related to motor programming. Basal ganglia disorders could lead to a series of movement disorders, including decrease and abnormal in voluntary movements and balance disorders such as Parkinson’s disease (PD) and Huntington’s disease (HD).Previous studies in our and other laboratories have revealed both the cerebellum and subthalamic nucleus of the basal ganglia receive histaminergic projection from tuberomammillary nucleus of the hypothalamus, and histamine receptors are also expressed in the cerebellum and subthalamic nucleus. However, effects of histamine/central histaminergic system on neuronal activities of the cerebellum and subthalamic nucleus are still largely unknown. Therefore, in this study effects of histamine/central histaminergic system on the cerebellum and subthalamic nucleus neuronal activities and underlying mechanisms as well as the consequent behavioral influences on the cerebellum and subthalamic nucleus mediated motor control were investigated by using in vitro and in vivo electrophysiological, immunofluorescence, and behavioral methods.1. Histaming/central histaminergic system 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 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 received the hypothalamic histaminergic innervations, and histamine H1receptors and H2receptors were 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 were 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 Hi or 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 Hi or 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 histochemical 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 models of PD rather than normal rats, besides increasing neuronal firing rates of subthalamic nucleus, histamine also significantly decreased coefficient of variation of interspike interval of neuronal firing (n=40), 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 of 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.2. Histamine/Central histaminergic system on the neuronal activity of the cerebellar nuclei and its related ionic mechanismsThe cerebellum is the largest motor structure under the cerebral cortex, which controls the movement being carried and ensures the accuracy in space and time in the process of motor execution. The cerebellar nuclei (fastigial nucleus, interpositus nucleus and the dentate nucleus) are the output nodes of the cerebellum, which play important role in the cerebellar mediated motor control and coordination. Our previous studies using extracellular electrophysiological recording have revealed that histamine excites rat interpositus nucleus and fastigial nucleus neurons. It has been known that local circuits in the cerebellar nuclei are composed by two types of neurons-projection neurons and interneurons. In this study, using brain slice preparation and whole-cell patch clamp technique, and on the basis of identifying these two types of cerebellar nuclear neurons, effects of histamine on the project neurons and interneurons were studied and the results are as follows:(i) The projection neurons and interneurons of cerebellar nuclei were identified combining morphological and electrophysiological methods. (ii) Histamine selectively excited rat projection neurons rather than interneruons in the cerebellar nuclei.(in) The excitatory effect of histamine on the projection neurons was elicited by a direct postsynaptic membrane potential depolarization, which was mediated by the activations of histamine H2receptors in the rat cerebellar nuclei.(iv) Immunofluorescence single and double labeling results showed that histamine H2receptors were expressed in the projection neurons rather than interneurons in the rat cerebellar nuclei.(v) The excitatory effect of histamine on the cerebellar nuclear projection neurons was mediated by the downstream hyperpolarization-activated cation channels after activating histamine H2receptors, but did not affect the small conductance calcium-activated potassium channels.The present study demonstrated that histamine selectively excited rat projection neurons rather than interneruons of the cerebellar nuclei. The excitatory effect of histamine on the cerebellar projection neurons was elicited by a direct postsynaptic membrane potential depolarization, which was mediated by the activations of histamine H2receptors and downstream hyperpolarization-activated cation channels. These findings suggest that on the level of the cerebellar nuclei, the ultimate origins of the outputs of cerebellum, the hypothalamocerebellar histaminergic fibers may directly modulate the final output of the cerebellum via their exclusive innervations on the projection neurons. These direct excitatory histaminergic innervations on the cerebellar projection neurons may regulate the excitability of the cerebellar nuclei that cause the neurons proper responses to inputs from the Purkinje cells as well as mossy fibers and climbing fibers. Thus, through the direct not indirect modulation on the cerebellar nuclear projection neurons, the central histaminergic system may consequently influence the cerebellum-mediated sensorimotor integration and modulate motor behavior through its role on the cerebellar circuits.