Effects of Contralateral Deep Brain Stimulation and Levodopa on Subthalamic Nucleus Oscillatory Activity and Phase-Amplitude Coupling

BackgroundThe modulatory effects of medication and deep brain stimulation (DBS) on subthalamic nucleus (STN) neural activity in Parkinson's disease have been widely studied. However, effects on the contralateral side to the stimulated STN, in particular, changes in local field potential (LFP) oscillatory activity and phase-amplitude coupling (PAC), have not yet been reported.ObjectiveThe aim of this study was to examine changes in STN LFP activity across a range of frequency bands and STN PAC for different combinations of DBS and medication on/off on the side contralateral to the applied stimulation.Materials and MethodsWe examined STN LFPs that were recorded using externalized leads from eight parkinsonian patients during unilateral DBS from the side contralateral to the stimulation. LFP spectral power in alpha (5 to ～13 Hz), low beta (13 to ～20 Hz), high beta (20–30 Hz), and high gamma plus high-frequency oscillation (high gamma+HFO) (100–400 Hz) bands were estimated for different combinations of medication and unilateral stimulation (off/on). PAC between beta and high gamma+HFO in the STN LFPs was also investigated. The effect of the condition was examined using linear mixed models.ResultsPAC in the STN LFP was reduced by DBS when compared to the baseline condition (no medication and stimulation). Medication had no significant effect on PAC. Alpha power decreased with DBS, both alone and when combined with medication. Beta power decreased with DBS, medication, and DBS and medication combined. High gamma+HFO power increased during the application of contralateral DBS and was unaltered by medication.ConclusionsThe results provide new insights into the effects of DBS and levodopa on STN LFP PAC and oscillatory activity on the side contralateral to stimulation. These may have important implications in understanding mechanisms underlying motor improvements with DBS, including changes on both contralateral and ipsilateral sides, while suggesting a possible role for contralateral sensing during unilateral DBS.     

Effects of Environmental Tobacco Smoke on Adult Rat Brain Biochemistry

Environmental tobacco smoke (ETS) has been linked to deleterious health effects, particularly pulmonary and cardiac disease; yet, the general public considers ETS benign to brain function in adults. In contrast, epidemiological data have suggested that ETS impacts the brain and potentially modulates neurodegenerative disease. The present study begins to examine yet unknown biochemical effects of ETS on the adult mammalian brain. In the developed animal model, adult male rats were exposed to ETS 3 h a day for 3 weeks. Biochemical data showed altered glial fibrillary acid protein levels as a main treatment effect of ETS, suggestive of reactive astrogliosis. Yet, markers of oxidative and cell stress were unaffected by ETS exposure in the brain regions examined. Increased proteolytic degradation of αII-spectrin by caspase-3 and the dephosphorylation of serine₁₁₆ on PEA-15 indicated greater apoptotic cell death modulated by the extrinsic pathway in the brains of ETS-exposed animals. Further, β-synuclein was upregulated by ETS, a neuroprotective protein previously reported to exhibit anti-apoptotic and anti-fibrillogenic properties. These findings demonstrate that ETS exposure alters the neuroproteome of the adult rat brain, and suggest modulation of inflammatory and cell death processes.     

Effect of Deep Brain Stimulation on Levodopa-Induced Dyskinesias and Striatal Oscillatory Local Field Potentials in a Rat Model of Parkinson's Disease

BackgroundIn Parkinson's disease (PD) dyskinesias appear after long-term dopaminergic treatment. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the globus pallidus internus (GPi) is a well-established treatment option for both PD symptoms and complications of medication.ObjectiveTo elucidate physiological mechanisms of the effect of DBS on levodopa-induced dyskinesias (LID) we investigated both DBS in the GPi and the centromedian-parafascicular complex (CM-Pf), which are part of an internal basal ganglia loop connecting with the dorsolateral striatum. In particular, we focused on changes of oscillatory activity in the dorsolateral striatum, which also presents the entrance region of the basal ganglia (BG).Methods6-Hydroxydopamine (6-OHDA) hemiparkinsonian (HP) rats and 6-OHDA lesioned HP rats with LID (HP-LID) were used to compare the effect of DBS in the entopeduncular nucleus (EPN, the equivalent to the human GPi) and the thalamic parafascicular nucleus (Pf, the equivalent of the human CM-Pf) on dyskinesias and neuronal oscillatory activity of selected frequency bands in the dorsolateral striatum on and off levodopa.ResultsIn HP-LID rats the relative beta and gamma power was lower, while relative theta power was higher as compared to HP rats. Chronic DBS of either the EPN or the Pf improved dyskinesia scores in HP-LID rats, and no differences in oscillatory activity were observed between groups.ConclusionsStimulation of the Pf has a specific impact on dyskinesias, which is similar to that found after EPN stimulation, and which is accompanied by changes of oscillatory activity.     

Effects of Changes in Rat Brain Glucose on Serotonergic and Noradrenergic Neurons

Microdialysis was used in the freely moving rat to measure the effects of graded changes in brain glucose on the serotonergic and noradrenergic projections to the hippocampus. The concentration of glucose in the dialysate was monitored using an enzyme-based assay. A systemic injection of insulin caused a steep decline in glucose level which was restored to the control level by oral administration of glucose solution. The changes in 5-hydroxytryptamine (5-HT) and noradrenaline were a mirror image of the glucose changes: they rose after insulin injection and returned to control during glucose administration. A delayed increase was shown by 5-hydroxyindoleacetic acid (5-HIAA) which did not return to baseline on glucose administration. The metabolite dihydroxyphenylacetic acid (DOPAC) decreased after insulin administration and increased above control during glucose administration. While the responses of 5-HT, noradrenaline and 5-HIAA to hypoglycaemia resemble those to mild stress, the changes in DOPAC are the reverse of those produced by stress.     

Effect of Carbamazepine on Dopamine Release and Reuptake in Rat Striatal Slices

Carbamazepine has been shown to enhance dopaminergic agonist behavioral effects, but not to displace [3H]spiroperidol binding. To verify if carbamazepine acts presynaptically on dopaminergic neurons, reuptake and release of [3H]dopamine were measured in rat striatal slices in vitro. It was observed that carbamazepine blocked 20% of the reuptake of [3H]dopamine, while cocaine blocked 82% of the reuptake, compared with control. Carbamazepine released 62% and tyramine released 92% of the accumulated [3H]dopamine, compared with control. It was concluded that carbamazepine acts presynaptically on striatal neurons, mainly through enhancement of dopamine release. This finding can be related to some behavioral effects described for carbamazepine; however, the importance of its effects in epileptic and manic-depressive patients remains to be clarified.     

Protein SP40,40-like Immunoreactivity in the Rat Brain: Progressive Increase With Age

The pattern of distribution of SP40,40-like immunoreactive structures has been studied in the rat brain using a well-characterized polyclonal antibody raised against the SP40,40 protein. Protein SP40,40 is the human counterpart of the rat sulphated glycoprotein 2, whose mRNA shows widespread expression in the developing and mature brain. In young adult rats few immunoreactive structures were observed. Some immunoreactive neurons were found in the cingulate cortex, the arcuate and perifornical hypothalamic nuclei, as well as glial labelling in the hypothalamus. A striking increase in the number of immunoreactive cells was observed as a function of age. In 20–22-month-old rats, numerous immunoreactive cells were observed in the cingulate cortex, several thalamic and hypothalamic nuclei, the red nucleus, olivary nuclei, superior colliculus, and many cranial nerve nuclei. Whereas the immunoreactivity was restricted to a diffuse labelling of the cell bodies and processes in young rats, other forms of labelling were observed in aged rats: punctate cytoplasmic labelling and intensely stained granules with no visible cell membrane. A further increase in the density of the immunoreactive material was observed in 30–31-month-old rats. Double labelling experiments demonstrated that the SP40,40 immunoreactivity was almost exclusively located in neurons and not in glial cells (with the exception noted above). The distribution of SP40,40 immunoreactivity in aged rats did not coincide with the distribution of the microtubule-associated tau protein, OX42 or lipofuscin.     

Neurotoxic Effects of Kainic Acid on Substantia Nigra Neurons in Rat Brain Slices

Excitatory amino acids (EAAs) have been implicated as mediators of cell death in neurodegenerative diseases involving catecholamine neurons. Few studies, however, have examined the toxic effects of EAAs on identified catecholamine neuronsin vitro.We have investigated the neurotoxic effects of kainic acid in a rat brain substantia nigra (SN) slice preparation. Rats (60–80 g) were anesthetised with halothane and killed by cervical dislocation. SN slices, 300 μm thick, were incubated at 35°C in a modified Krebs solution in the presence or absence of kainic acid and then fixed and processed for either immunohistochemistry (IHC) or electron microscopy (EM). In IHC experiments, SN neurons were labeled using antibody to tyrosine hydroxylase (TH) coupled to diaminobenzidine. In control slices, the antibody labeled not only the cell body but also the prolific dendritic arbor of SN neurons. Treatment with 50 μMkainic acid for 15 min or 2 h resulted in loss of TH staining and apparent fragmentation of the dendrites. EM provided ultrastructural evidence for kainic acid-induced degeneration of the dendritic arbor of SN neurons. Typically, the dendritic membrane was broken, or diffuse and collapsed. Ultrastructural damage, including clumping and marginalization of chromatin and vacuolation of the cytoplasm, was also observed in cell bodies. Damage to the dendritic arbor may occur early in the neurotoxic events leading to cell death, preceding the loss of the cell body. Our observations are consistent with the postulated role of EAAs as mediators of catecholamine neuron death.     

Effects of Paced Mating on c-fos Gene Expression in the Female Rat Brain

When estrous female rats control or pace (P) their sexual contacts with males, several neuroendocrine and behavioral responses to mating occur that are not observed or are greatly attenuated after nonpaced mating. The present study examined whether the distribution and amount of FOS immunoreactivity (FOS-IR) induced in brain by mating would be altered in females receiving paced rather than nonpaced mating stimulation. In the first experiment, females received 5 or 15 intromissions during paced mating tests (5P and 15P), 5 or 15 intromissions during nonpaced mating tests (5NP and 15NP), 15 mounts-without-intromission (MO) or remained in their homecages (HC). Selective increases 1 h after paced mating stimulation were observed in the posterodorsal medial amygdala (MePD), where significantly more FOS-IR cells were present in the 5P and 15P groups than in the respective NP groups. The 5P, 5NP and 15NP had significantly more FOS-IR than the HC, MO, and 5NP groups, and the 5P group had levels of FOS-IR which were equivalent to that seen in the 15NP group. In the posteromedial portion of the bed nucleus of the stria terminalis (BNSTpm) and the ventrolateral portion of the ventromedial nucleus of the hypothalamus (VMHvl), paced mating induced significantly greater numbers of FOS-IR cells than did either MO or HC treatments; increases induced by nonpaced mating were not statistically greater than HC controls. No differences between groups were seen in the medial preoptic area (mPOA). In the second experiment, experimentally lengthening the interintromission interval (III) as well as increasing the intromission duration to mimic the characteristics of paced mating, resulted in significant increases in FOS-IR in the MePD but not in the other three brain regions. These results demonstrate that paced mating is more effective in inducing c-fos expression than nonpaced mating, and that the MePD is particularly sensitive to differing characteristics of the mating stimuli received.     

Functional Striatal Abnormalities:A Distinct Brain Signature of Schizophrenia

Schizophrenia is a severe and complex mental disorder 111.Neuroimaging offers a powerful window for identifying the brain biomarkers and investigating the neuropathological mechanisms of psychiatric disorders.A study led by Professors Jiang and Liu,published recently in Nature Medicine,developed a new neuroimaging biomarker to characterize striatal dysfunction based on a multi-site functional MRI dataset with>1000 individuals.They show that this biomarker can distinguish individuals with schizophrenia and predict the short-term effects of antipsychotic treatmem[2].     

Effects of Thyrotropin-Releasing Hormone on Catecholamine Concentration in Various Structures of the Rat Brain

Abstract: In an attempt to identify the site of TRH-action in the central nervous system (CNS), we have measured catecholamine levels in discrete brain regions of rats after an intravenous administration of TRH or a long-term intraventricular administration of TRH using Alzet's osmotic minipump. An intravenous administration of 50 μg TRH caused a rapid increase in dopamine (DA) concentration in the septal nucleus and then returned to the basal level at 30 min after injection. The concentration of DA in the septal nucleus after the long-term TRH intraventricular administration was also significantly higher than that in the controls. These results indicate that a long-term intraventricular administration of TRH as well as a bolus intravenous injection of TRH may affect the release or metabolism of DA in the septal nucleus.     

Methamphetamine Preconditioning: Differential Protective Effects on Monoaminergic Systems in the Rat Brain

Pretreatment with methamphetamine (METH) can attenuate toxicity due to acute METH challenges. The majority of previous reports have focused mainly on the effects of the drug on the striatal dopaminergic system. In the present study, we used a regimen that involves gradual increases in METH administration to rats in order to mimic progressively larger doses of the drug used by some human METH addicts. We found that this METH preconditioning was associated with complete protection against dopamine depletion caused by a METH challenge (5 mg/kg × 6 injections given 1 h apart) in the striatum and cortex. In contrast, there was no preconditioning-mediated protection against METH-induced serotonin depletion in the striatum and hippocampus, with some protection being observed in the cortex. There was also no protection against METH-induced norepinephrine (NE) depletion in the hippocampus. These results indicate that, in contrast to the present dogmas, there might be differences in the mechanisms involved in METH toxicity on monoaminergic systems in the rodent brain. Thus, chronic injections of METH might activate programs that protect against dopamine toxicity without influencing drug-induced pathological changes in serotoninergic systems. Further studies will need to evaluate the cellular and molecular bases for these differential responses.     

大鼠大脑缺血再灌注中PMNLs对脑组织cGRP表达及损伤程度的影响

目的:探讨多形核白细胞(ＰＭＮＬｓ)在大鼠大脑缺血再灌注中对大脑神经元降钙素基因相关肽(ｃＧＲＰ)表达及脑损伤程度的影响。方法:大鼠大脑中动脉(ＭＣＡ)缺血再灌注模型中,观察神经元的ｃＧＲＰ表达,对比各组大脑神经元超微结构变化。结果:未加注Ｍａｃ－１抗体组脑组织ＰＭＮＬｓ聚集较明显,相应区域的神经元呈ｃＧＲＰ弱阳性反应,电镜观察神经元、神经纤维及突触肿胀明显,神经毡结构间隙增大并常有变性或坏死。结论:大鼠大脑中动脉缺血再灌注期间,脑神经元的ｃＧＲＰ表达可反应性增加,而浸润到脑组织中的大量ＰＭＮＬｓ可干扰神经元的ｃＧＲＰ表达,并同时伴有脑组织超微结构的破坏性改变。     

Df—521巴曲酶对大鼠脑出血后脑水肿形成的影响

目的:观察Df-521巴曲酶对大鼠脑出血后脑水肿对血肿周边区脑组织ICAM-1表达的影响。方法:一侧基底节注射自体血制作大鼠脑出血模型,用干湿重法,测定脑组织含水量;用免疫组化法检测血肿周边水肿带ICAM-1的表达情况。结果:大鼠脑出血后,血肿侧脑组织含水量上升,同时水肿区ICAM-1的表达量增加;给予Df-521巴曲酶制剂处理后,血肿侧脑水肿减轻,脑组织ICAM-1的表达有所下降。结论:Df-521巴曲酶能下调脑出血后血肿周边组织ICAM-1的表达并减轻脑水肿的程度。     

Transplantation of Mesencephalic Cell Suspension in Dopamine-Denervated Striatum of the Rat: I. Effects on Spontaneous Activity of Striatal Neurons

These studies have examined the extent to which intrastriatal grafts of embryonic mesencephalic neurons induce recovery of normal discharge patterns in striatal neurons of rats after a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal dopamine (DA) pathway. Lesioned rats were tested for rotational behavior induced by amphetamine and apomorphine. Animals which responded positively to these tests received two suspensions of mesencephalic embryonic neurons into the dorsal striatum (ST) ipsilateral to the denervated side. Sham-grafted rats received the suspension medium only. The vitality of the graft was assessed by the disappearance or reversion of rotational movements induced by amphetamine. Extracellular recordings of neurons located throughout the ST were carried out 3 months after grafting, when the animals reached the age of 6 months. The 6-OHDA-induced nigral lesion caused a net increase both in the number of striatal neurons spontaneously active and in their discharging rates. The signs of increased neuronal activity were also present in sham-grafted animals. The grafting of embryonal cells strongly reduced the number of active neurons and decreased significantly their discharging rate. The effects of the intrastriatal graft appeared to be present within a radius of 1.5–2 mm from the core of the grafted area. The presence of tyrosine-hydroxylase-immunopositive neurons innervating the host ST confirmed the viability of the grafts at the time of electrophysiological recording. The results show that besides compensating motor asymmetries caused by DA denervation, intrastriatally grafted dopaminergic neurons are able to only partially restore the electrophysiological action of DA in discrete striatal domains.     

脑乙酰胆碱酯酶的PET显像剂[^11C]4-乙酰氧基-N-甲基哌啶在大鼠体内分布的研究

目的：研究脑乙酰胆碱酯酶（AChE）活性的正电子断层扫描（PET）诊断显像剂[^11C]4-乙酰氧基-N-甲基哌啶（[^11C]MP4A）在大鼠体内的摄取和分布。方法：正常雌性SD大鼠尾静脉注射[^11C]MP4A，按注射后5、15、25、35、45和60min时间点分组后断头处死动物，迅速取血，分离脏器和脑（大脑皮质、小脑和脑干），用自动γ放射性计数仪计算经衰变校正后不同时间点各脏器放射性摄取率，以％ID／g表示。结果：一次剂量的[^11C]MP4A静脉注射后，血中5min时％ID／g为（13．44±1．88），清除迅速，60min时接近于基线水平；各脏器组织中％ID／g 15-25min达到稳态；大脑皮质5min％ID／g为（2．26±0．29）。脑内各区域的摄取在注射后15～25min达到稳态。皮质的平均％ID/g〉小脑，两者比值范围为1．13～2．08；60min时小脑、脑干和皮质的％ID／g与其最高峰相比分别下降了77％、80％和40％；皮质放射活性清除最慢。结论：[^11C]MP4A血中清除迅速。脑各区域摄取在短时达到稳态，提示[^11C]MP4A有较好的脂溶性，易透过血脑屏障；皮质摄取比小脑高但清除慢，表明[^11C]MP4A能更好反映皮质AChE活性，适合作为脑AChE活性的PET诊断显像剂。     

腺苷对突触体^45Ca摄取的抑制作用

用同位素标记~(15)Ca法测定大鼠突触体内游离钙的浓度,探讨了腺苷对高钾、N-甲基-D-天冬氨酸(NMDA)谷氨酸(Glu)等刺激所致的Ca~(2 )内流增加的影响。结果发现腺苷在10nmol/L～0.1μmol/L范围内对高钾、NMDA、Glu等刺激所致的Ca~(2 )内流有抑制作用,并呈剂量依赖关系,最大抑制率分别为41.68±7.68％、31.32±6.17％、37.52±2.29％。这可能是腺苷对缺血性脑损伤保护作用的机理。