Real-time decoding of dopamine concentration changes in the caudate-putamen during tonic and phasic firing

The fundamental process that underlies volume transmission in the brain is the extracellular diffusion of neurotransmitters from release sites to distal target cells. Dopaminergic neurons display a range of activity states, from low-frequency tonic firing to bursts of high-frequency action potentials (phasic firing). However, it is not clear how this activity affects volume transmission on a subsecond time scale. To evaluate this, we developed a finite-difference model that predicts the lifetime and diffusion of dopamine in brain tissue. We first used this model to decode in vivo amperometric measurements of electrically evoked dopamine, and obtained rate constants for release and uptake as well as the extent of diffusion. Accurate predictions were made under a variety of conditions including different regions, different stimulation parameters and with uptake inhibited. Second, we used the decoded rate constants to predict how heterogeneity of dopamine release and uptake sites would affect dopamine concentration fluctuations during different activity states in the absence of an electrode. These simulations show that synchronous phasic firing can produce spatially and temporally heterogeneous concentration profiles whereas asynchronous tonic firing elicits uniform, steady-state dopamine concentrations.     

慢性强直电刺激右侧尾壳核诱导大鼠癫痫样电图和行为发作特征

目的 :慢性强直电刺激右侧尾壳核 (CPu)诱导大鼠电图和行为癫痫点燃样现象 ,观察CPu或海马 (HPC)网络异常的靶向癫痫样行为表达特征。方法 :共用雄性SD大鼠 58只。强直电刺激 ( 60Hz ,0 .4～ 0 .6mA ,2s)大鼠右侧CPu或右侧前背HPC ,1time/d ,连续刺激 7～ 12d。结果 :①CPu电图节律性尖波样发放或HPC电图阵发性高幅失律。②CPu或HPC刺激组大鼠均可以出现原发性、继发性或点燃样湿狗样抖动 (wetdogshakes ,WEDS)、直立、洗面、好静、咀嚼和节律性点头等行为发作。③CPu刺激组大鼠原发性WEDS频率明显低于HPC刺激组大鼠( 2 .10± 0 .12和 2 .89± 0 .2 0times/min ,P <0 .0 1) ,继发性WEDS频率明显高于HPC刺激组大鼠 ( 1.2 3± 0 .11和0 .78± 0 .0 6times/min ,P <0 .0 1)。④CPu刺激组大鼠点燃样效应出现之前的行为静止天数较长。结论 :如同刺激HPC一样 ,慢性电刺激大鼠CPu可以出现类似的癫痫样行为发作。结果提示 :CPu功能异常有可能成为癫痫发作的起源病灶 ,与HPC类似 ,参与了颞叶癫痫电网络的重建 ,具有特征性的癫痫样靶行为表达     

Catecholamine exocytosis is diminished in R6/2 Huntington's disease model mice

In this work, the mechanisms responsible for dopamine (DA) release impairments observed previously in Huntington's disease model R6/2 mice were evaluated. Voltammetrically measured DA release evoked in striatal brain slices from 12-week old R6/2 mice by a single electrical stimulus pulse was only 19% of wild-type (WT) control mice. Iontophoresis experiments suggest that the concentration of released DA is not diluted by a larger striatal extracellular volume arising from brain atrophy, but, rather, that striatal dopaminergic terminals have a decreased capacity for DA release. This decreased capacity was not due to an altered requirement for extracellular Ca²⁺, and, as in WT mice, the release in R6/2 mice required functioning vesicular transporters. Catecholamine secretion from individual vesicles was measured during exocytosis from adrenal chromaffin cells harvested from R6/2 and WT mice. While the number of exocytotic events was unchanged, the amounts released per vesicle were significantly diminished in R6/2 mice, indicating that vesicular catecholamines are present in decreased amounts. Treatment of chromaffin cells with 3-nitropropionic acid decreased the vesicular release amount from WT cells by 50%, mimicking the release observed from untreated R6/2 cells. Thus, catecholamine release from tissues isolated from R6/2 mice is diminished because of impaired vesicle loading.     

Activation of the Rostral Intralaminar Thalamus Drives Reinforcement through Striatal Dopamine Release

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Adenosine transiently modulates stimulated dopamine release in the caudate–putamen via A1 receptors

Adenosine modulates dopamine in the brain via A₁ and A_2A receptors, but that modulation has only been characterized on a slow time scale. Recent studies have characterized a rapid signaling mode of adenosine that suggests a possible rapid modulatory role. Here, fast‐scan cyclic voltammetry was used to characterize the extent to which transient adenosine changes modulate stimulated dopamine release (5 pulses at 60 Hz) in rat caudate–putamen brain slices. Exogenous adenosine was applied and dopamine concentration monitored. Adenosine only modulated dopamine when it was applied 2 or 5 s before stimulation. Longer time intervals and bath application of 5 μM adenosine did not decrease dopamine release. Mechanical stimulation of endogenous adenosine 2 s before dopamine stimulation also decreased stimulated dopamine release by 41 ± 7%, similar to the 54 ± 6% decrease in dopamine after exogenous adenosine application. Dopamine inhibition by transient adenosine was recovered within 10 min. The A₁ receptor antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine blocked the dopamine modulation, whereas dopamine modulation was unaffected by the A_2A receptor antagonist SCH 442416. Thus, transient adenosine changes can transiently modulate phasic dopamine release via A₁ receptors. These data demonstrate that adenosine has a rapid, but transient, modulatory role in the brain.

     

Regional Differences in Striatal Dopamine Uptake and Release Associated with Recovery from MPTP-Induced Parkinsonism

Abstract : This study directly assessed striatal dopamine (DA) uptake rates and peak release in response to KCl in normal, symptomatic, and recovered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated cats using in vivo electrochemistry. DA uptake rates measured after direct application of known concentrations of DA to the striatum were slowed significantly in both dorsal and ventral striatum in symptomatic cats compared with rates recorded in normal animals. DA uptake rates remained significantly slowed in recovered cats and were not significantly different from the rates recorded in symptomatic animals. In symptomatic cats, both DA uptake rates and the signal recorded in response to KCl stimulation were significantly decreased from normal in all dorsal and ventral striatal regions sampled. Reduction/oxidation (redox) ratios recorded in response to KCl stimulation suggested DA to be the predominant electroactive species. In spontaneously recovered MPTP-treated cats, recordings in the ventral striatum subsequent to KCl stimulation again suggested DA to be the predominant electroactive species released, and peak levels were significantly higher than those recorded in symptomatic animals. In the dorsal striatum of recovered cats, redox ratios recorded subsequent to KCl stimulation suggested serotonin rather than DA to be the predominant electroactive species released. Peak levels of release in the dorsal striatum were not significantly greater than those recorded in symptomatic animals. These results suggest that in spontaneously recovered MPTP-treated cats, there is partial recovery of ventral striatal DAergic terminals, persistent loss of dorsal striatal DAergic terminals, and a down-regulation of DA transporter number/function throughout the striatum. These processes may contribute to volume transmission of DA in the striatum and promote functional recovery.     

成年大鼠纹状体、边缘区和苍白球的计算机三维结构重建

应用计算机图形技术在大鼠脑的连续冠状切片Nissl染色的基础上通过Onyx2超级图形工作站对大鼠脑的纹状体进行了三维重建。结果提示：大鼠纹状体由尾壳核、苍白球和边缘区三部分组成,其中边缘区位于尾壳核和苍白球之间,被二完全包绕;尾壳核呈近似的内凹半球形,嘴尾径最大的为6.2mm;背腹径最大为4.9mm;宽度（冠状平面上的内外径)为3.5mm。从嘴侧到尾侧随着脑平面的增宽,尾壳核逐渐向外侧（即靠近外轮廓的方向）移位。苍白球呈块形,嘴尾径最大为4.4mm,背腹径最大为2.6mm,宽度（冠状平面上的内外径）最大为1.5mm。位于尾壳核的内侧,除内侧外基它三个方向均被尾壳核包绕。边缘区呈现一个片状扇形结构,嘴侧背腹径大,最大为2.2mm,宽约0.17mm;尾侧背腹径小,为0.8mm,宽约0.13mm。同属壳核和苍白球一样,从嘴侧到尾侧随着脑平面的增宽边缘区亦逐渐向外侧（即靠近外轮廓的方向）移位,其移位的幅度亦明显大于脑平面增宽的幅度;整个边缘区从嘴侧到尾侧呈均匀变化,其片状逐渐变宽,长度（背腹径）逐渐变小,从而形成一个盘状结构。     

刺激大鼠右侧胼胝体激活对侧尾壳核-海马癫痫相关性神经网络

目的：探讨慢性激活右侧胼胝体(corpus callosum,CC)重建对侧尾壳核(caudate-putamen,CPu)-海马(hippocam-pus,HPC)癫痫网络的跨半球机制。方法：SD大鼠50只。慢性强直电刺激(60Hz,0．4～0．6mA,2s)右侧CC(chronic tetanization of the rignt CC,CTRCC),一天一次,8d后再次施加强直电刺激,同步记录左侧CPu(LCPu)和左侧HPC(LHPC)电图。结果：CTRCC①引起LCPu和LHPC出现深部电波的交互性抑制现象,LCPu电图出现持续尖波发放时交互抑制现象消失。②诱发LCPu和LHPC电图出现癫痫点燃现象。③未引起大鼠LCPu和LH-PC电图点燃时,急性强直电刺激可诱发LCPu出现高幅失律,压抑LHPC具有频率特征的尖波连续发放。④联合运用慢性和急性强直电刺激可诱导LCPu或LHPC电图出现原发性后放。结论：慢性激活ROC可促进对侧CPu-HPC癫痫网络的重建。形成新的癫痫病灶。     

Differential Regional Effects of Methamphetamine on the Activities of Tryptophan and Tyrosine Hydroxylase

Abstract : Administration of high doses of methamphetamine (METH) produces both short- and long-term enzymatic deficits in central monoaminergic systems. To determine whether a correlative relationship exists between these acute and long-term consequences of METH treatment, in the present study we examined the regional effects of METH on tryptophan hydroxylase (TPH) and tyrosine hydroxylase (TH) activities in various regions of the caudate nucleus, nucleus accumbens, and globus pallidus. A single METH administration decreased TPH activity 1 h after treatment in the globus pallidus, in the nucleus accumbens, and throughout the caudate ; in the anterior caudate, the ventral-medial was more affected than the dorsal-lateral region. In contrast, TH activity was not decreased in either the caudate or the globus pallidus after a single METH administration ; however, it was altered in the nucleus accumbens. Seven days after multiple METH administrations, TH and TPH activities were decreased in most caudate regions but not in the nucleus accumbens or globus pallidus. These data demonstrate that (1) the effects of METH on TPH and TH vary regionally ; and (2) the short-term and long-term regional responses of TPH to METH in the caudate and globus pallidus correlated. In contrast, METH-induced acute TH responses did not predict the long-term changes in TH activity.