Insomnia-related rodent models in drug discovery.

Despite the widespread prevalence and important medical impact of insomnia, effective agents with few side effects are lacking in clinics. This is most likely due to relatively poor understanding of the etiology and pathophysiology of insomnia, and the lack of appropriate animal models for screening new compounds. As the main homeostatic, circadian, and neurochemical modulations of sleep remain essentially similar between humans and rodents, rodent models are often used to elucidate the mechanisms of insomnia and to develop novel therapeutic targets. In this article, we focus on several rodent models of insomnia induced by stress, diseases, drugs, disruption of the circadian clock, and other means such as genetic manipulation of specific neuronal activity, respectively, which could be used to screen for novel hypnotics. Moreover, important advantages and constraints of some animal models are discussed. Finally, this review highlights that the rodent models of insomnia may play a crucial role in novel drug development to optimize the management of insomnia.

Trihexyphenidyl increases delta activity in non-rapid eye movement sleep without impairing cognitive function in rodent models.

Both human and rodent studies suggest the link between non-rapid eye movement (NREM) sleep and cognition. Recent study indicated that selective activation of cholinergic neurons in basal forebrain inhibits electroencephalogram (EEG) delta power and shortens NREM sleep. In the current study, we aimed to test the pharmacological effect of trihexyphenidyl (THP), a selective muscarinic M1 receptor antagonist, on EEG power spectra and sleep with or without the selective activation of basal forebrain cholinergic neurons. THP (1, 2, and 3 mg/kg) was administrated intraperitoneally in natural sleep phase. Basal forebrain cholinergic neurons expressing modified G protein-coupled muscarinic receptors (hM3Dq) were activated by intraperitoneal injection of clozapine-N-oxide in ChAT-IRES-Cre mice. EEG and electromyogram (EMG) signals were recorded in freely moving mice to analyze EEG power spectrum and sleep hypnogram. Y-maze and novel object recognition tests were used for testing cognition. THP 1 mg/kg significantly increased EEG delta power and facilitated NREM sleep in wildtype mice, while THP 3 mg/kg was required in ChAT-IRES-Cre mice treated with clozapine-N-oxide. THP with dosage up to 8 mg/kg did not induce cognitive impairments in wildtype mice. EEG delta power of NREM sleep is often used as an indicator of sleep depth or sleep quality, which tightly link with sleep-dependent cognition. Taken together, the data collected from rodents hinted that, THP could possibly be used as the NREM sleep facilitator in humans.

Whole-Brain Monosynaptic Inputs to Hypoglossal Motor Neurons in Mice.

Hypoglossal motor neurons (HMNs) innervate tongue muscles and play key roles in a variety of physiological functions, including swallowing, mastication, suckling, vocalization, and respiration. Dysfunction of HMNs is associated with several diseases, such as obstructive sleep apnea (OSA) and sudden infant death syndrome. OSA is a serious breathing disorder associated with the activity of HMNs during different sleep-wake states. Identifying the neural mechanisms by which the state-dependent activities of HMNs are controlled may be helpful in providing a theoretical basis for effective therapy for OSA. However, the presynaptic partners governing the activity of HMNs remain to be elucidated. In the present study, we used a cell-type-specific retrograde tracing system based on a modified rabies virus along with a Cre/loxP gene-expression strategy to map the whole-brain monosynaptic inputs to HMNs in mice. We identified 53 nuclei targeting HMNs from six brain regions: the amygdala, hypothalamus, midbrain, pons, medulla, and cerebellum. We discovered that GABAergic neurons in the central amygdaloid nucleus, as well as calretinin neurons in the parasubthalamic nucleus, sent monosynaptic projections to HMNs. In addition, HMNs received direct inputs from several regions associated with respiration, such as the pre-Botzinger complex, parabrachial nucleus, nucleus of the solitary tract, and hypothalamus. Some regions engaged in sleep-wake regulation (the parafacial zone, parabrachial nucleus, ventral medulla, sublaterodorsal tegmental nucleus, dorsal raphe nucleus, periaqueductal gray, and hypothalamus) also provided primary inputs to HMNs. These results contribute to further elucidating the neural circuits underlying disorders caused by the dysfunction of HMNs.

Genetic polymorphisms, forensic efficiency and phylogenetic analysis of 17 autosomal STR loci in the Han population of Wuxi, Eastern China.

The autosomal short tandem repeat (STR) plays a unique role in population comparisons, phylogenetic reconstruction and migration history tracing. This study investigated the frequencies of 17 autosomal STR loci in the Han population from Wuxi, Eastern China, with the aim of expanding the available population information in human genetic databases and for forensic DNA analysis. The genetic polymorphisms of 17 STR loci were analysed in 5358 individuals of the Han population from Wuxi, Eastern China. Population comparisons including genetic distances, the neighbour-joining tree and multidimensional scaling plot were carried out between the Wuxi Han population and different ethnic groups. A total of 777 alleles at 17 autosomal STR loci were observed, with the corresponding allelic frequencies ranging from 0.0001-0.5210. The combined power of discrimination and exclusion for the 17 autosomal STR loci were 0.0000 and 0.000, respectively. Moreover, the phylogenetic analysis was performed between the Wuxi Han population and other relevant populations. The neighbour-joining tree and multidimensional scaling plot were generated based on Nei's standard genetic distance. Population comparisons indicated that the Wuxi Han population had the closest genetic relationship with the Hubei Han population, relative to the other populations, which mirrors the historical and geographical background of the populations compared.

Dopamine D1 and D2 receptors mediate analgesic and hypnotic effects of l-tetrahydropalmatine in a mouse neuropathic pain model.

RATIONALE: Levo-tetrahydropalmatine (l-THP), an active ingredient of Corydalis yanhusuo, has been reported to be a partial agonist for dopamine D1 receptors (D1R) and an antagonist for D2R. Although it has been safely used clinically in China for decades as an analgesic with sedative/hypnotic properties, there are few studies that address the mechanisms by which l-THP exerts its beneficial effects in chronic pain-induced sleep disturbance. OBJECTIVES: To investigate the effects and mechanisms of l-THP on sleep disturbance in a neuropathic pain-like condition. METHODS: A mouse model of chronic neuropathic pain induced by partial sciatic nerve ligation (PSNL) was employed. The antinociceptive and hypnotic effects of l-THP were evaluated by measurement of mechanical allodynia, thermal hyperalgesia, and electroencephalogram (EEG) recordings in PSNL mice. Pharmacological approaches and c-Fos expression were used to clarify the mechanisms of l-THP. RESULTS: Intraperitoneal injection of l-THP at 5 and 10 mg/kg not only significantly increased the mechanical threshold by 134.4% and 174.8%, and prolonged the thermal latency by 49.4% and 69.2%, but also increased non-rapid eye movement sleep by 17.5% and 29.6%, and decreased sleep fragmentation in PSNL mice, compared with the vehicle control. Moreover, the antinociceptive effect of l-THP was prevented by D1R antagonist SCH23390 or D2R agonist quinpirole; meanwhile, the hypnotic effect of l-THP was blocked by quinpirole rather than by SCH23390. Immunohistochemistry demonstrated that l-THP inhibited c-Fos overexpression induced by PSNL in the cingulate cortex and the periaqueductal gray. CONCLUSIONS: These findings indicated that l-THP exerted analgesic effects by agonism D1R and antagonism D2R, and the antagonism of D2R mediated the hypnotic effect of l-THP in PSNL mice.