Department of Morphology, Zlotowski Center for Neuroscience, Division of Basic Sciences, Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er Sheva, Israel.
Neuroscience. 2009 Nov 10;163(4):1012-23. doi: 10.1016/j.neuroscience.2009.07.040. Epub 2009 Jul 24.
The embryonic mid-hindbrain organizer, which is composed of a transient cell population in the brainstem, controls the development of dopaminergic and serotonergic neurons. Different genes determining the position and activity of this embryonic structure have been implicated in dopamine- and serotonin-associated disorders. Mouse mutants with a caudally shifted mid-hindbrain organizer, are hyperactive, show increased numbers of dopaminergic neurons and a reduction in serotonergic cells. In the present study we used these mutants to gain insights into the genetic and developmental mechanisms underlying motor activity and the response to psychostimulants. To this end, we studied the motor activity of these animals after exposure to methylphenidate and amphetamine and characterized their dopaminergic and serotonergic innervation. Saline-treated mutants showed increased locomotion, more stereotypic behavior and a decrease in rearing compared to wild-type mice. This baseline level of activity was similar to behaviors observed in wild-type animals treated with high doses of psychostimulants. In mutants methylphenidate (5 or 30 mg/kg) or amphetamine (2 or 4 mg/kg) did not further increase activity or even caused a decrease of locomotor activity, in contrast to wild-type mice. Fluoxetine (5 or 10 mg/kg) reduced hyperactivity of mutants to levels observed in wild-types. Transmitter measurements, dopamine and serotonin transporter binding assays and autoradiography, indicated a subtle increase in striatal dopaminergic innervation and a marked general decrease of serotonergic innervation in mutants. Taken together, our data suggest that mice with an aberrantly positioned mid-hindbrain organizer show altered sensitivity to psychostimulants and that an increase of serotonergic neurotransmission reverses their hyperactivity. We conclude that the mid-hindbrain organizer, by orchestrating the formation of dopaminergic and serotonergic neurons, is an essential developmental parameter of locomotor activity and psychostimulant response.
胚胎中后脑组织者，由脑干中的一个短暂细胞群组成，控制多巴胺能和血清素能神经元的发育。不同的基因决定了这个胚胎结构的位置和活性，这些基因与多巴胺和血清素相关的疾病有关。中后脑组织者尾部移位的小鼠突变体表现出过度活跃，多巴胺能神经元数量增加，血清素能细胞减少。在本研究中，我们使用这些突变体来深入了解运动活动和对精神兴奋剂反应的遗传和发育机制。为此，我们研究了这些动物在暴露于哌甲酯和安非他命后的运动活动，并描述了它们的多巴胺能和血清素能神经支配。与野生型小鼠相比，生理盐水处理的突变体显示出增加的运动、更多的刻板行为和减少的直立行为。这种基线活动水平与用高剂量精神兴奋剂处理的野生型动物观察到的行为相似。在突变体中，哌甲酯（5 或 30mg/kg）或安非他命（2 或 4mg/kg）没有进一步增加活动，甚至导致运动活动减少，与野生型小鼠相反。氟西汀（5 或 10mg/kg）将突变体的过度活跃降低到野生型观察到的水平。递质测量、多巴胺和血清素转运体结合测定和放射自显影表明，纹状体多巴胺能神经支配略有增加，而突变体的血清素能神经支配明显普遍减少。总之，我们的数据表明，中后脑组织者位置异常的小鼠对精神兴奋剂的敏感性发生改变，而血清素能神经传递的增加可逆转其过度活跃。我们得出结论，中后脑组织者通过协调多巴胺能和血清素能神经元的形成，是运动活动和精神兴奋剂反应的一个重要发育参数。
