Predicting neurodevelopmental outcomes in extremely preterm neonates with low-grade germinal matrix-intraventricular hemorrhage using synthetic MRI.

Objectives: This study aims to assess the predictive capability of synthetic MRI in assessing neurodevelopmental outcomes for extremely preterm neonates with low-grade Germinal Matrix-Intraventricular Hemorrhage (GMH-IVH). The study also investigates the potential enhancement of predictive performance by combining relaxation times from different brain regions. Materials and methods: In this prospective study, 80 extremely preterm neonates with GMH-IVH underwent synthetic MRI around 38 weeks, between January 2020 and June 2022. Neurodevelopmental assessments at 18 months of corrected age categorized the infants into two groups: those without disability (n = 40) and those with disability (n = 40), with cognitive and motor outcome scores recorded. T1, T2 relaxation times, and Proton Density (PD) values were measured in different brain regions. Logistic regression analysis was utilized to correlate MRI values with neurodevelopmental outcome scores. Synthetic MRI metrics linked to disability were identified, and combined models with independent predictors were established. The predictability of synthetic MRI metrics in different brain regions and their combinations were evaluated and compared with internal validation using bootstrap resampling. Results: Elevated T1 and T2 relaxation times in the frontal white matter (FWM) and caudate were significantly associated with disability (p < 0.05). The T1-FWM, T1-Caudate, T2-FWM, and T2-Caudate models exhibited overall predictive performance with AUC values of 0.751, 0.695, 0.856, and 0.872, respectively. Combining these models into T1-FWM + T1-Caudate + T2-FWM + T2-Caudate resulted in an improved AUC of 0.955, surpassing individual models (p < 0.05). Bootstrap resampling confirmed the validity of the models. Conclusion: Synthetic MRI proves effective in early predicting adverse outcomes in extremely preterm infants with GMH-IVH. The combination of T1-FWM + T1-Caudate + T2-FWM + T2-Caudate further enhances predictive accuracy, offering valuable insights for early intervention strategies.

Associations between diffusion kurtosis imaging metrics and neurodevelopmental outcomes in neonates with low-grade germinal matrix and intraventricular hemorrhage.

Diffusion Kurtosis Imaging (DKI)-derived metrics are recognized as indicators of maturation in neonates with low-grade germinal matrix and intraventricular hemorrhage (GMH-IVH). However, it is not yet known if these factors are associated with neurodevelopmental outcomes. The objective of this study was to acquire DKI-derived metrics in neonates with low-grade GMH-IVH, and to demonstrate their association with later neurodevelopmental outcomes. In this prospective study, neonates with low-grade GMH-IVH and control neonates were recruited, and DKI were performed between January 2020 and March 2021. These neonates underwent the Bayley Scales of Infant Development test at 18 months of age. Mean kurtosis (MK), radial kurtosis (RK) and gray matter values were measured. Spearman correlation analyses were conducted for the measured values and neurodevelopmental outcome scores. Forty controls (18 males, average gestational age (GA) 30 weeks ± 1.3, corrected GA at MRI scan 38 weeks ± 1) and thirty neonates with low-grade GMH-IVH (13 males, average GA 30 weeks ± 1.5, corrected GA at MRI scan 38 weeks ± 1). Neonates with low-grade GMH-IVH exhibited lower MK and RK values in the PLIC and the thalamus (P < 0.05). The MK value in the thalamus was associated with Mental Development Index (MDI) (r = 0.810, 95% CI 0.695-0.13; P < 0.001) and Psychomotor Development Index (PDI) (r = 0.852, 95% CI 0.722-0.912; P < 0.001) scores. RK value in the caudate nucleus significantly and positively correlated with MDI (r = 0.496, 95% CI 0.657-0.933; P < 0.001) and PDI (r = 0.545, 95% CI 0.712-0.942; P < 0.001) scores. The area under the curve (AUC) were used to assess diagnostic performance of MK and RK in thalamus (AUC = 0.866, 0.787) and caudate nucleus (AUC = 0.833, 0.671) for predicting neurodevelopmental outcomes. As quantitative neuroimaging markers, MK in thalamus and RK in caudate nucleus may help predict neurodevelopmental outcomes in neonates with low-grade GMH-IVH.

Assessment of brain structure and volume reveals neurodevelopmental abnormalities in preterm infants with low-grade intraventricular hemorrhage.

There is increasing evidence of abnormal neurodevelopmental outcomes in preterm infants with low-grade intraventricular hemorrhage (IVH). The purpose of the study was to explore whether brain microstructure and volume are associated with neuro-behavioral outcomes at 40 weeks corrected gestational age in preterm infants with low-grade IVH. MR imaging at term-equivalent age (TEA) was performed in 25 preterm infants with mild IVH (Papile grading I/II) and 40 control subjects without IVH. These subjects all had neonatal behavioral neurological assessment (NBNA) at 40 weeks' corrected age. Microstructure and volume evaluation of the brain were performed by using diffusion kurtosis imaging (DKI) and Synthetic MRI. Correlations among microstructure parameters, volume, and developmental outcomes were explored by using Spearman's correlation. In preterm infants with low-grade IVH, the volume of brain parenchymal fraction (BPF) was reduced. In addition, mean kurtosis (MK), fractional anisotropy (FA), radial kurtosis (RK), axial kurtosis (AK) in several major brain regions were reduced, while mean diffusivity (MD) was increased (P < 0.05). BPF, RK in the cerebellum, MK in the genu of the corpus callosum, and MK in the thalamus of preterm infants with low-grade IVH were associated with lower NBNA scores (r = 0.831, 0.836, 0.728, 0.772, P < 0.05). DKI and Synthetic MRI can quantitatively evaluate the microstructure alterations and brain volumes in preterm infants with low-grade IVH, which provides clinicians with a more comprehensive and accurate neurobehavioral assessment of preterm infants with low-grade IVH.

Bimetallic AuNR@AgNCs for ultrasensitive surface-enhanced Raman scattering sensing of dithianon in apple juice.

In this study, a bimetallic surfaced-enhanced Raman spectroscopy (SERS)-active substrate consisting of AuNR@AgNCs was proposed for the rapid detection of dithianon. Due to the significant synergistic enhancement of the core-shell nanocuboids, the obtained AuNR@AgNC substrate exhibited excellent SERS performance. The simulation findings supported the practical SERS results and demonstrated that interactions were mainly maintained by the nitrile functional group. The AuNR@AgNCs could be used to detect dithianon with an LOD value of 20 nM. Moreover, dithianon in river water and apple juice could be detected with recovery in the satisfactory ranges of 97.41%-98.35% and 97.77%-98.70%, respectively, by using this substrate under optimal conditions, indicating that the AuNR@AgNC substrate could serve as an excellent SERS detection platform for pesticide residues in fruit.

A direct Z-scheme BS/PtO2 van der Waals heterojunction for enhanced visible-light photocatalytic water splitting: a first-principles study.

A direct Z-scheme heterostructure holds a unique advantage in solar-driven overall water splitting, while the rational design of efficient photocatalysts for water splitting in such heterostructures remains a challenge. Based on first-principles calculations, this study proposes a novel direct Z-scheme two-dimensional (2D) van der Waals (vdW) heterostructure photocatalyst, denoted as BS/PtO2. Its band edges match the oxidation-reduction potentials of water, satisfying the conditions for the oxidation and reduction of water. Under acidic conditions (pH = 0), the results of the oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) indicate that BS/PtO2 can drive the OER without the need for an external bias, while the HER requires catalytic assistance. Interestingly, compared to single-layer materials, this heterostructure exhibits a significant enhancement in visible light absorption, implying a more efficient solar energy conversion capability. Therefore, the BS/PtO2 heterostructure holds the potential to become a promising direct Z-scheme photocatalyst with efficient visible light activity.

Evaluation of white matter microstructural alterations in premature infants with necrotizing enterocolitis.

Background: Preterm infants with necrotizing enterocolitis (NEC) are at high risk of adverse neurodevelopmental outcomes. The aim of this study was to explore the value of diffusion tensor imaging (DTI) combined with serum C-reactive protein (CRP) and procalcitonin (PCT) in evaluating alterations of white matter (WM) microstructure in preterm infants with NEC. Methods: A retrospective cross-sectional study was conducted in which all participants were consecutively enrolled at The Third Affiliated Hospital of Zhengzhou University from June 2017 and October 2021. Data from 30 preterm infants with NEC [mean gestational age at birth 31.41±1.15 weeks; mean age at magnetic resonance imaging (MRI) 37.53±3.08 weeks] and 40 healthy preterm infants with no NEC were recorded (mean gestational age at birth 32.27±2.09 weeks; mean age at MRI 37.15±3.23 weeks). WM was used to obtain the fractional anisotropy (FA) and mean diffusivity (MD) values of the regions of interest (ROIs). Additionally, serum levels of CRP and PCT were determined. Spearman correlation analysis was performed between the WM-derived parameters, CRP level, and the PCT serum index. Results: Preterm infants with NEC had reduced FA values and elevated MD values in WM regions [posterior limbs of the internal capsule (PLIC), lentiform nucleus (LN), frontal white matter (FWM)] compared to the control group (P<0.05). Additionally, the FA of the PLIC was negatively correlated with serum CRP (r=-0.846; P<0.05) and PCT (r=-0.843; P<0.05). Meanwhile, the MD of PLIC was positively correlated with serum CRP (r=0.743; P<0.05) and PCT (r=0.743; P<0.05, respectively). The area under the curve (AUC) of FA and MD combined with CRP and PCT in the diagnosis of WM microstructure alterations with NEC was 0.968, representing a considerable improvement in predicted efficacy over single indicators, including FA [AUC: 0.938; 95% confidence interval (CI): 0.840-0.950], MD (AUC: 0.807; 95% CI: 0.722-0.838), CRP (AUC: 0.867; 95% CI: 0.822-0.889), and PCT (AUC: 0.706; 95% CI: 0.701-0.758). Conclusions: WM can noninvasively and quantitatively assess the WM microstructure alterations in preterm infants with NEC. WM combined with serum CRP and PCT demonstrated superior performance in detecting and evaluating WM microstructure alterations in preterm infants with NEC.

Cortical gray-white matter contrast abnormalities in male children with attention deficit hyperactivity disorder.

Purpose: Presently, research concerning alterations in brain structure among individuals with attention deficit hyperactivity disorder (ADHD) predominantly focuses on entire brain volume and cortical thickness. In this study, we extend our examination to the cortical microstructure of male children with ADHD. To achieve this, we employ the gray-white matter tissue contrast (GWC) metric, allowing for an assessment of modifications in gray matter density and white matter microstructure. Furthermore, we explore the potential connection between GWC and the severity of disorder in male children by ADHD. Methods: We acquired 3DT1 sequences from the public ADHD-200 database. In this study, we conducted a comparative analysis between 43 male children diagnosed with ADHD and 50 age-matched male controls exhibiting typical development trajectories. Our investigation entailed assessing differences in GWC and cortical thickness. Additionally, we explored the potential correlation between GWC and the severity of ADHD. To delineate the cerebral landscape, each hemisphere was subdivided into 34 cortical regions using freesurfer 7.2.0. For quantification, GWC was computed by evaluating the intensity contrast of non-normalized T1 images above and below the gray-white matter interface. Results: Our findings unveiled elevated GWC within the bilateral lingual, bilateral insular, left transverse temporal, right parahippocampal and right pericalcarine regions in male children with ADHD when contrasted with their healthy counterparts. Moreover, the cortical thickness in the ADHD group no notable distinctions that of control group in all areas. Intriguingly, the GWC of left transverse temporal demonstrated a negative correlation with the extent of inattention experienced by male children with ADHD. Conclusion: Utilizing GWC as a metric facilitates a more comprehensive assessment of microstructural brain changes in children with ADHD. The fluctuations in GWC observed in specific brain regions might serve as a neural biomarker, illuminating structural modifications in male children grappling with ADHD. This perspective enriches our comprehension of white matter microstructure and cortical density in these children. Notably, the inverse correlation between the GWC of the left transverse temporal and inattention severity underscores the potential role of structural and functional anomalies within this region in ADHD progression. Enhancing our insight into ADHD-related brain changes holds significant promise in deciphering potential neuropathological mechanisms.

Magnetic resonance imaging radiomics to differentiate ovarian sex cord-stromal tumors and primary epithelial ovarian cancers.

Objective: To evaluate the diagnostic ability of magnetic resonance imaging (MRI) based radiomics and traditional characteristics to differentiate between Ovarian sex cord-stromal tumors (SCSTs) and epithelial ovarian cancers (EOCs). Methods: We consecutively included a total of 148 patients with 173 tumors (81 SCSTs in 73 patients and 92 EOCs in 75 patients), who were randomly divided into development and testing cohorts at a ratio of 8:2. Radiomics features were extracted from each tumor, 5-fold cross-validation was conducted for the selection of stable features based on development cohort, and we built radiomics model based on these selected features. Univariate and multivariate analyses were used to identify the independent predictors in clinical features and conventional MR parameters for differentiating SCSTs and EOCs. And nomogram was used to visualized the ultimately predictive models. All models were constructed based on the logistic regression (LR) classifier. The performance of each model was evaluated by the receiver operating characteristic (ROC) curve. Calibration and decision curves analysis (DCA) were used to evaluate the performance of models. Results: The final radiomics model was constructed by nine radiomics features, which exhibited superior predictive ability with AUCs of 0.915 (95%CI: 0.869-0.962) and 0.867 (95%CI: 0.732-1.000) in the development and testing cohorts, respectively. The mixed model which combining the radiomics signatures and traditional parameters achieved the best performance, with AUCs of 0.934 (95%CI: 0.892-0.976) and 0.875 (95%CI: 0.743-1.000) in the development and testing cohorts, respectively. Conclusion: We believe that the radiomics approach could be a more objective and accurate way to distinguish between SCSTs and EOCs, and the mixed model developed in our study could provide a comprehensive, effective method for clinicians to develop an appropriate management strategy.

The Value of Diffusion Kurtosis Imaging in Detecting Delayed Brain Development of Premature Infants.

Objective: Preterm infants are at high risk of the adverse neurodevelopmental outcomes. Our aim is to explore the value of diffusion kurtosis imaging (DKI) in diagnosing brain developmental disorders in premature infants. Materials and Methods: A total of 52 subjects were included in this study, including 26 premature infants as the preterm group, and 26 full-term infants as the control group. Routine MRI and DKI examinations were performed. Mean kurtosis (MK), radial kurtosis (RK), fractional anisotropy (FA), and mean diffusivity (MD) values were measured in the brain regions including posterior limbs of the internal capsule (PLIC), anterior limb of internal capsule (ALIC), parietal white matter (PWM), frontal white matter (FWM), thalamus (TH), caudate nucleus (CN), and genu of the corpus callosum (GCC). The chi-squared test, t-test, Spearman's correlation analysis, and receiver operating characteristic curve were used for data analyses. Results: In the premature infant group, the MK and RK values of PLIA, ALIC, and PWM were lower than those in the control group (p < 0.05). The FA values of PWM, FWM, and TH were also lower than those of the control group (p < 0.05). The area under curves of MK in PLIC and ALIC, MD in PWM, and FA in FWM were 0.813, 0.802, 0.842, and 0.867 (p < 0.05). In the thalamus and CN, the correlations between MK, RK values, and postmenstrual age (PMA) were higher than those between FA, MD values, and PMA. Conclusion: Diffusion kurtosis imaging can be used as an effective tool in detecting brain developmental disorders in premature infants.

Tyramine excites rat subthalamic neurons in vitro by a dopamine-dependent mechanism.

Tyramine, an endogenous ligand for mammalian trace amine-associated receptors, may act as a neuromodulator that regulates neuronal activity in basal ganglia. Using whole-cell patch recordings of subthalamic nucleus (STN) neurons in rat brain slices, we found that bath application of tyramine evoked an inward current in voltage-clamp in over 60% of all STN neurons. The inward current induced by tyramine was mimicked by the D(2)-like dopamine receptor agonist quinpirole, but was only partially blocked by the D(2)-like receptor antagonist sulpiride. In contrast, the D(1)-like receptor agonist SKF38393 evoked no current in STN neurons. Inward current evoked by tyramine was significantly reduced by the catecholamine uptake inhibitor nomifensine, and by exhausting catecholamines in the brain via pretreatment with reserpine. Tyramine also reduced the amplitude of GABA(A) receptor-mediated IPSCs that were evoked by focal electrical stimulation of the slice. Inhibition of IPSCs by tyramine was mimicked by quinpirole and was blocked by sulpiride but not by SCH23390, a D(1) receptor antagonist. Moreover, tyramine-induced inhibition of IPSCs was reduced in slices pretreated with reserpine, and this inhibition could be restored by briefly superfusing the slice with dopamine. These results suggest that tyramine acts as an indirect dopamine agonist in the STN. Although inhibition of IPSCs is mediated by D(2)-like receptors, the dopamine-dependent inward currents evoked by tyramine do not fit a typical dopamine receptor pharmacological profile.

NMDA enhances a depolarization-activated inward current in subthalamic neurons.

Previous studies have shown that N-methyl-D-aspartate (NMDA) receptor stimulation evokes Ca2+- and Na+-dependent burst firing in subthalamic nucleus (STN) neurons. Using whole-cell patch pipettes to record currents under voltage-clamp, we identified a time-dependent depolarization-activated inward current (DIC) that may underlie NMDA-induced burst firing in STN neurons in rat brain slices. Continuous superfusion with NMDA (20 microM) elicited a marked TTX-insensitive inward current when the membrane was depolarized to the level of -70 or -50 mV, from a holding potential of -100 mV. This current had a long duration, and its peak amplitude occurred at a test potential of -60 mV. DIC could not be evoked using the non-NMDA receptor agonist D,L-alpha-amino-3-hydroxy-5-methylisoxalone-4-propionic acid (AMPA). DIC was blocked by either intracellular BAPTA or by removal of extracellular Ca2+, but selective blockers of T-type (mibefradil), L-type (nifedipine) and N-type (omega-conotoxin GVIA) Ca2+ channels did not. Perfusing slices with a low extracellular concentration of sodium abolished the NMDA-induced DIC, implying that both Ca2+ and Na+ are necessary for the expression of DIC. Transient receptor potential (TRP) channel blockers flufenamic acid and SKF96365 severely reduced DIC amplitude, whereas NMDA-gated currents were either increased or were unchanged. These results suggest that the activation of NMDA receptors enhances a Ca2+-activated non-selective cation current that may be mediated by a member of the TRP channel family in STN neurons.

Biphasic firing response of nucleus accumbens neurons elicited by THPB-18 and its correlation with DA receptor subtypes.

AIM: To investigate the possibility whether THPB-18 (l-12-shloroscoulerine) possesses the D1 agonist-D2 antagonist action on meso-accumbens-mPFC DA system. METHODS: Single unit spontaneous firing activity was recorded in the nucleus accumbens (NAc) neurons of naive and unilateral-6-hydroxydopamine (6-OHDA)-lesioned Sprague-Dawley rats. The effects of drugs applied intravenously or iontophoretically were determined by the change of firing rates. RESULTS: Under normal conditions, the systemic administration of THPB-18 produced a decrease-increase biphasic firing pattern in the NAc neurons during cumulative doses. High dose of THPB-18 was capable of reversing the inhibition induced by both D2 agonist LY171555 and D1/D2 agonist APO on NAc firing activity. Spiperone pretreatment could not block the high dose of THPB-18-induced firing rate increase, which was reversed by the D1 selective antagonist SCH23390. The tested NAc neurons were effectively inhibited by iontophoretically applied THPB-18 in 90 % of 6-OHDA-lesioned rats, while THPB-18 caused variable effects on the firing of NAc neurons in the neurons of unlesioned rats. The inhibitory effect of THPB-18 was blocked by iontophoretic application of SCH23390, but not D2 antagonist spiperone. CONCLUSION: Similar to L-stepholidine, THPB-18 also possesses the D1 agonistic-D2 antagonistic dual action on the VTA-NAc DA system.

Calcium-dependent subthreshold oscillations determine bursting activity induced by N-methyl-D-aspartate in rat subthalamic neurons in vitro.

We used whole-cell patch recordings in current clamp to investigate the ionic dependence of burst firing induced by N-methyl-d-aspartate (NMDA) in neurons of the subthalamic nucleus (STN) in slices of rat brain. NMDA (20 microm) converted single-spike firing to burst firing in 87% of STN neurons tested. NMDA-induced bursting was blocked by AP5 (50 microm), and was not mimicked by the non-NMDA receptor agonist AMPA (0.6 microm). Tetrodotoxin (1 microm) converted bursts to oscillations of membrane potential, which were most robust when oscillations ranged between -50 and -70 mV. The NMDA bursts were blocked by an elevated extracellular concentration of Mg(2+), but superfusate containing no added Mg(2+) either reduced or increased burst firing, depending upon the amount of intracellular current injection. Block of K(+) conductances by apamin and tetraethylammonium prolonged burst duration, but iberiotoxin had no effect. NMDA-induced burst firing and membrane oscillations were completely blocked by superfusate containing no added Ca(2+), and they were significantly reduced when patch pipettes contained BAPTA. Selective antagonists for T-type (mibefradil, 10 microm), L-type (nifedipine, 3 microm), and N-type (omega-conotoxin GVIA, 1 micro m) Ca(2+) channels had no effect on NMDA burst firing. Superfusate containing a low concentration of Na(+) (20 mm) completely abolished NMDA-induced burst firing. Flufenamic acid (10 microm), which blocks current mediated by Ca(2+)-activated nonselective cation channels (I(CAN)), reversibly abolished NMDA-depended bursting. These results are consistent with the hypothesis that NMDA-induced burst firing in STN neurons requires activation of either an I(CAN) or a Na(+)-Ca(2+) exchanger.

Dopamine receptor supersensitivity in rat subthalamus after 6-hydroxydopamine lesions.

The subthalamic nucleus (STN) receives direct dopaminergic innervation from the substantia nigra pars compacta, but the importance of this input in the pathophysiology of parkinsonism remains to be determined. We used whole-cell patch-clamp recordings in brain slices to study presynaptic dopaminergic modulation of synaptic inputs to the STN in unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats. Here, we report that dopamine was more potent for inhibiting GABA IPSCs and glutamate EPSCs in the STN ipsilateral to the lesion, and was less potent for suppressing IPSCs and EPSCs in the STN contralateral to the lesion, compared with the effects of dopamine in control STN. Dopamine reduced IPSCs with an IC50 value of 20.9 +/- 3.6 microM in control STN, whereas IC50 values were 0.83 +/- 0.15 and 55.1 +/- 11.1 microM in STN ipsilateral and contralateral to 6-OHDA lesions, respectively. Dopamine also inhibited EPSCs with an IC50 value of 12.8 +/- 2.8 microM in control STN, whereas IC50 values were 4.5 +/- 0.9 and 41.6 +/- 9.8 microM in STN ipsilateral and contralateral to 6-OHDA lesions, respectively. Results with paired stimuli to evoke EPSCs and IPSCs suggest that endogenous dopamine acts presynaptically to inhibit transmitter release in the STN. These results show that chronic dopamine denervation significantly alters the regulation of synaptic input to the STN. Our results also suggest that the STN may be an important target for levodopa therapy in Parkinson's disease.

Synaptic plasticity in rat subthalamic nucleus induced by high-frequency stimulation.

The technique of deep brain stimulation (DBS) has become a preferred surgical choice for the treatment of advanced Parkinson's disease. The subthalamic nucleus (STN) is presently the most promising target for such DBS. In this study, whole-cell patch-clamp recordings were made from 46 STN neurons in rat brain slices to examine the effect of high-frequency stimulation (HFS) of the STN on glutamatergic synaptic transmission in STN neurons. HFS, consisting of trains of stimuli at a frequency of 100 Hz for 1 min, produced three types of synaptic plasticity in 17 STN neurons. First, HFS of the STN induced short-term potentiation (STP) of evoked postsynaptic current (EPSC) amplitude in four neurons. STP was associated with a reduction in the EPSC paired-pulse ratio, suggesting a presynaptic site of action. Second, HFS of the STN generated long-term potentiation (LTP) of EPSC amplitude in eight neurons. Although the EPSC paired-pulse ratio was reduced transiently in the first 2 min following HFS, ratios measured 6-20 min after HFS were unchanged from control. This suggests that LTP is maintained by a postsynaptic mechanism. Third, HFS produced long-term depression (LTD) of EPSC amplitude in five STN neurons. LTD was associated with a significant increase in EPSC paired-pulse ratios, indicating a presynaptic site of action. These results suggest that HFS can produce long-term changes in the efficacy of synaptic transmission in the STN. HFS-induced synaptic plasticity might be one mechanism underlying the effectiveness of DBS in the STN as a treatment of advanced Parkinson's disease.

Excitatory effects of dopamine on subthalamic nucleus neurons: in vitro study of rats pretreated with 6-hydroxydopamine and levodopa.

Increased output from the subthalamic nucleus (STN) following chronic dopamine depletion has been linked to the rigidity and tremor seen in Parkinson's disease (PD). We used extracellular microelectrode recordings from rat brain slices to investigate effects of dopamine on STN neurons. In brain slices prepared from rats that received unilateral 6-hydroxydopamine (6-OHDA) treatment, the spontaneous firing rate of STN neurons was reduced by 63%, and the firing pattern was more irregular, compared to STN neurons from normal rats. However, treatment with levodopa (50 mg/kg, i.p., daily) for 4 weeks normalized the firing rate and pattern of STN neurons in the 6-OHDA-treated rats. Dopamine (3-300 microM), added to the superfusate, significantly increased the firing rates of STN neurons in a concentration-dependent fashion, and also produced a more regular firing pattern in 6-OHDA-lesioned tissue. This excitatory effect of dopamine was mimicked by a D2 receptor agonist (quinpirole), and was reduced by the D2 antagonists haloperidol, clozapine and sulpiride. Antagonists of the D1 receptor (SCH-23390) and ionotropic glutamatergic receptors (CNQX and AP5) could not block the effect of dopamine on firing rate. These results suggest that dopamine exerts a direct excitatory influence on STN neurons via the activation of D2-like receptors.

Pharmacological identification of inward current evoked by dopamine in rat subthalamic neurons in vitro.

Dopaminergic mechanisms in the subthalamic nucleus (STN) are implicated in the pathophysiology of Parkinson's disease. Here, electrophysiological responses of STN neurons to dopamine (DA) were investigated by using whole-cell patch-clamp recordings in the rat brain slice preparation. Under current-clamp, DA depolarized membrane potential and increased the frequency of spontaneous action potentials of STN neurons. Under voltage-clamp, DA (3-300 microM) produced a reversible concentration-dependent inward current (I(DA); 6-40 pA) with an EC(50) of 13 microM. This DA-induced current had a negative slope conductance which reversed at -102 mV. It was partially reduced by barium and by superfusion with an elevated concentration of extracellular K(+). Moreover, TTX and glutamate receptor antagonists (CNQX and AP5) did not significantly affect the DA responses, indicating that I(DA) is not dependent upon afferent synaptic activity in the STN. Quinpirole, a D(2) receptor agonist, mimicked the DA action more effectively than did the D(1) agonist SKF-38393. The D(2) antagonist sulpiride, but not the D(1) antagonist SCH-23390, blocked responses induced by DA. Intracellular application of G-protein inhibitor GDP-beta-S also suppressed I(DA). GTP-gamma-S, added to the pipette solution, evoked a sustained inward shift in the absence of DA. These results suggest that DA increases the activity of STN neurons via activation of G-protein-coupled D(2)-like receptors which reduce a K(+) conductance.