Dopamine is vital for coordinated motion and for association learning linked to behavioral reinforcement. Here we show that the precise overlap of striatal dopaminergic and cholinergic fibers underlies potent control of dopamine release by ongoing nicotinic receptor activity. In mouse striatal slices, nicotinic antagonists or depletion of endogenous acetylcholine decreased evoked dopamine release by 90%. Nicotine at the concentration experienced by smokers also regulated dopamine release. In mutant mice lacking the beta2 nicotinic subunit, evoked dopamine release was dramatically suppressed, and those mice did not show cholinergic regulation of dopamine release. The results offer new perspectives when considering nicotine addiction and the high prevalence of smoking in schizophrenics.

The dorsal striatum and the nucleus accumbens (NAc) shell of the ventral striatum have similar cellular components and are both richly innervated by dopamine neurons. Despite similarities that extend throughout the striatum, only the NAc shell has a conspicuous increase in basal dopamine upon the initial administration of psychostimulant drugs such as nicotine. As measured by microdialysis, the elevated dopamine in the NAc shell is considered an identifying functional characteristic of addictive drugs. To examine this general functional difference between nicotine's action on the dorsolateral striatum and NAc shell, we directly monitored dopamine release in rat striatal slices using fast-scan cyclic voltammetry. In addition, we separately monitored the in vivo unit firing activity of putative midbrain dopamine neurons from freely moving rats using chronic multiple tetrodes. Nicotine administration increased the firing frequency of dopamine neurons and specifically increased the number and the length of phasic burst firing. The frequency dependence for dopamine release in the dorsolateral striatum and NAc shell is fundamentally different, enabling mainly the NAc shell to capitalize on the nicotineinduced phasic burst firing by dopamine neurons. Although nicotine decreased low-frequency (tonic) dopamine release in both areas, the increased ratio of phasic bursts relative to tonic firing caused by nicotine boosted the basal dopamine concentration predominantly in the NAc shell. By favoring release from bursts while depressing release from tonic signals, nicotine spreads the range of dopamine signaling and effectively increases the signal-to-noise relationship along dopamine afferents.

The striatum receives rich dopaminergic and more moderate serotonergic innervation. After vesicular release, dopamine and serotonin (5-hydroxytryptamine, 5-HT) signaling is controlled by transporter-mediated reuptake. Dopamine is taken up by dopamine transporters (DATs), which are expressed at the highest density in the striatum. Although DATs also display a low affinity for 5-HT, that neurotransmitter is normally efficiently taken up by the 5-HT transporters. We found that when extracellular 5-HT is elevated by exogenous application or by using antidepressants (e.g., fluoxetine) to inhibit the 5-HT transporters, the extremely dense striatal DATs uptake 5-HT into dopamine terminals. Immunohistochemical results and measurements using fast cyclic voltammetry showed that elevated 5-HT is taken up by DATs into striatal dopamine terminals that subsequently release 5-HT and dopamine together. These results suggest that antidepressants that block serotonin transporters or other factors that elevate extracellular 5-HT alter the temporal and spatial relationship between dopamine and 5-HT signaling in the striatum.

Tobacco use is a major health problem that is estimated to cause 4 million deaths a year worldwide. Nicotine is the main addictive component of tobacco. It acts as an agonist to activate and desensitize nicotinic acetylcholine receptors (nAChRs). A component of nicotine's addictive power is attributable to actions on the mesolimbic dopaminergic system, which serves a fundamental role in the acquisition of behaviors that are inappropriately reinforced by addictive drugs. Here we show that nicotine, in the same concentration and time ranges as obtained from tobacco, has three main actions that regulate the activity of midbrain dopamine (DA) neurons. Nicotine first activates and then desensitizes nAChRs on the DA neurons. This process directly excites the DA neurons for a short period of time before the nAChRs desensitize. Nicotine also enhances glutamatergic excitation and decreases GABAergic inhibition onto DA neurons. These events increase the probability for synaptic plasticity, such as long-term potentiation. The short-lived direct excitation of the DA neurons coupled with the enhanced glutamatergic afferent activity provides the presynaptic and postsynaptic coincidence necessary to initiate synaptic potentiation. In total, these synaptic events lead to a relatively long-lasting heightened activity of midbrain DA neurons. Consistent with other summarized studies, this work indicates that the synaptic changes normally associated with learning and memory can be influenced and commandeered during the nicotine addiction process.

BRIT1 protein (also known as MCPH1) contains 3 BRCT domains which are conserved in BRCA1, BRCA2, and other important molecules involved in DNA damage signaling, DNA repair, and tumor suppression. BRIT1 mutations or aberrant expression are found in primary microcephaly patients as well as in cancer patients. Recent in vitro studies suggest that BRIT1/MCPH1 functions as a novel key regulator in the DNA damage response pathways. To investigate its physiological role and dissect the underlying mechanisms, we generated BRIT1 −/− mice and identified its essential roles in mitotic and meiotic recombination DNA repair and in maintaining genomic stability. Both BRIT1 −/− mice and mouse embryonic fibroblasts (MEFs) were hypersensitive to γ-irradiation. BRIT1 −/− MEFs and T lymphocytes exhibited severe chromatid breaks and reduced RAD51 foci formation after irradiation. Notably, BRIT1 −/− mice were infertile and meiotic homologous recombination was impaired. BRIT1-deficient spermatocytes exhibited a failure of chromosomal synapsis, and meiosis was arrested at late zygotene of prophase I accompanied by apoptosis. In mutant spermatocytes, DNA double-strand breaks (DSBs) were formed, but localization of RAD51 or BRCA2 to meiotic chromosomes was severely impaired. In addition, we found that BRIT1 could bind to RAD51/BRCA2 complexes and that, in the absence of BRIT1, recruitment of RAD51 and BRCA2 to chromatin was reduced while their protein levels were not altered, indicating that BRIT1 is involved in mediating recruitment of RAD51/BRCA2 to the damage site. Collectively, our BRIT1-null mouse model demonstrates that BRIT1 is essential for maintaining genomic stability in vivo to protect the hosts from both programmed and irradiation-induced DNA damages, and its depletion causes a failure in both mitotic and meiotic recombination DNA repair via impairing RAD51/BRCA2's function and as a result leads to infertility and genomic instability in mice.

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Breast cancer is the most common type of cancer among women worldwide, and metastasis represents the most devastating stage of the disease. Recent studies have revealed that microRNAs (miRNA) have critical roles to regulate cancer cell invasion and metastasis. Here we present evidence to show the role of miR-182 in breast cancer metastasis. miR-182 is upregulated in the malignant cell line variants of both human MCF10 and mouse 4T1 series. Ectopic expression of miR-182 enhanced breast cancer cell motility and invasiveness, whereas miR-182 inhibition resulted in opposite changes. In nude mice, miR-182 led to increased pulmonary colonization of cancer cells. We further demonstrated that miR-182 directly targets MIM (Missing in Metastasis), which suppresses metastasis by inhibiting ras homolog family member A (RhoA) activity and stress fiber formation in breast cancer cells. Restoring MIM expression completely blocked the pro-metastasis function of miR-182, while RhoA inhibition reversed the phenotypes of both miR-182 overexpression and MIM knockdown. In breast tumor samples, miR-182 induction is linked to downregulation of MIM, RhoA activation and poor prognosis. Hence, our data delineates the molecular pathway by which miR-182 promotes breast cancer invasion and metastasis, and may have important implication for the treatment of metastatic cancers.

BackgroundThere are few studies on associations between children’s respiratory heath and air pollution in schools in China. The industrial development and increased traffic may affect the indoor exposure to air pollutants in school environment. Moreover, there is a need to study respiratory effects of environmental tobacco smoke (ETS) and emissions from new building materials in homes in China.ObjectivesWe studied the associations between pupils’ asthmatic symptoms and indoor and outdoor air pollution in schools, as well as selected home exposures, in a coal-burning city in north China.MethodsA questionnaire survey was administered to pupils (11–15 years of age) in 10 schools in urban Taiyuan, collecting data on respiratory health and selected home environmental factors. Indoor and outdoor school air pollutants and climate factors were measured in winter.ResultsA total of 1,993 pupils (90.2%) participated; 1.8% had cumulative asthma, 8.4% wheezing, 29.8% had daytime attacks of breathlessness. The indoor average concentrations of sulfur dioxide, nitrogen dioxide, ozone, and formaldehyde by class were 264.8, 39.4, 10.1, and 2.3 μg/m3, respectively. Outdoor levels were two to three times higher. Controlling for possible confounders, either wheeze or daytime or nocturnal attacks of breathlessness were positively associated with SO2, NO2, or formaldehyde. In addition, ETS and new furniture at home were risk factors for wheeze, daytime breathlessness, and respiratory infections.ConclusionsIndoor chemical air pollutants of mainly outdoor origin could be risk factors for pupils’ respiratory symptoms at school, and home exposure to ETS and chemical emissions from new furniture could affect pupils’ respiratory health.