痛情绪相关神经递质及神经环路研究进展＊

痛情绪是指因疼痛引发的情绪和情感体验，是疾病过程中最常见的一种情绪。痛情绪相关神经机制非常复杂，但主要与单胺类神经递质、神经肽和某些神经环路有关，笔者将结合目前研究现状分别从以上两方面展开，就痛情绪相关单胺类神经递质和神经肽在受体分类、脑区通路、共疾病以及各神经递质之间的联系和痛情绪相关神经环路中各个蛋白的作用机制等方面进行探讨。     

Model-Free and Model-Based Influences in Addiction-Related Behaviors

BackgroundDisruptions in the decision-making processes that guide action selection are a core feature of many psychiatric disorders, including addiction. Decision making is influenced by the goal-directed and habitual systems that can be computationally characterized using model-based and model-free reinforcement learning algorithms, respectively. Recent evidence suggests an imbalance in the influence of these reinforcement learning systems on behavior in individuals with substance dependence, but it is unknown whether these disruptions are a manifestation of chronic drug use and/or are a preexisting risk factor for addiction.MethodsWe trained adult male rats on a multistage decision-making task to quantify model-free and model-based processes before and after self-administration of methamphetamine or saline.ResultsIndividual differences in model-free, but not model-based, learning prior to any drug use predicted subsequent methamphetamine self-administration; rats with lower model-free behavior took more methamphetamine than rats with higher model-free behavior. This relationship was selective to model-free updating following a rewarded, but not unrewarded, choice. Both model-free and model-based learning were reduced in rats following methamphetamine self-administration, which was due to a decrement in the ability of rats to use unrewarded outcomes appropriately. Moreover, the magnitude of drug-induced disruptions in model-free learning was not correlated with disruptions in model-based behavior, indicating that drug self-administration independently altered both reinforcement learning strategies.ConclusionsThese findings provide direct evidence that model-free and model-based learning mechanisms are involved in select aspects of addiction vulnerability and pathology, and they provide a unique behavioral platform for conducting systems-level analyses of decision making in preclinical models of mental illness.     

Positive association between cerebral grey matter metabolism and dopamine D2/D3 receptor availability in healthy and schizophrenia subjects: An 18F-fluorodeoxyglucose and 18F-fallypride positron emission tomography study

Abstract

Objectives: Overlapping decreases in extrastriatal dopamine D₂/D₃-receptor availability and glucose metabolism have been reported in subjects with schizophrenia. It remains unknown whether these findings are physiologically related or coincidental.

Methods: To ascertain this, we used two consecutive ¹⁸F-fluorodeoxyglucose and ¹⁸F-fallypride positron emission tomography scans in 19 healthy and 25 unmedicated schizophrenia subjects. Matrices of correlations between ¹⁸F-fluorodeoxyglucose uptake and ¹⁸F-fallypride binding in voxels at the same xyz location and AFNI-generated regions of interest were evaluated in both diagnostic groups.

Results: ¹⁸F-fluorodeoxyglucose uptake and ¹⁸F-fallypride binding potential were predominantly positively correlated across the striatal and extrastriatal grey matter in both healthy and schizophrenia subjects. In comparison to healthy subjects, significantly weaker correlations in subjects with schizophrenia were confirmed in the right cingulate gyrus and thalamus, including the mediodorsal, lateral dorsal, anterior, and midline nuclei. Schizophrenia subjects showed decreased D₂/D₃-receptor availability in the hypothalamus, mamillary bodies, thalamus and several thalamic nuclei, and increased glucose uptake in three lobules of the cerebellar vermis.

Conclusions: Dopaminergic system may be involved in modulation of grey matter metabolism and neurometabolic coupling in both healthy human brain and psychopathology. Hyperdopaminergic state in untreated schizophrenia may at least partly account for the corresponding decreases in grey matter metabolism.     

Parkinson's disease may reduce sensitivity to visual-tactile asynchrony irrespective of dopaminergic treatment: Evidence from the rubber hand illusion

BackgroundThe feeling of body ownership relies on the binding of multisensory body-related signals. Various sensory abnormalities have been described in Parkinson's disease (PD).ObjectiveTo assess the rubber hand illusion (RHI) in patients with PD (PwPD) and age-matched healthy controls (CTRL). To evaluate the influence of the dopaminergic system in a PwPD subgroup OFF medication.MethodsThe RHI paradigm was applied to 42 PwPD and 48 CTRL. In this experimental setup, stroking a visible plastic hand simultaneously with the covered real hand elicits the feeling of ownership over the seen hand. Asynchronous stroking served as a control condition. Proprioceptive bias and an illusion score based on a questionnaire were used as measures of the RHI. Seventeen PwPD additionally underwent the experiments “OFF medication”.ResultsCompared to CTRL, PwPD showed higher proprioceptive bias independent of the stroking condition (p = 0.015), and had higher illusion scores in the asynchronous condition (p < 0.05). In PwPD, there were no significant differences between ON- and OFF-medication state.ConclusionIn PwPD, responses to the RHI are less specific with respect to the degree of synchronicity of brushstrokes. This might be attributed to a less stable body representation, internal “noise” during multisensory integration, or a blur of temporal discrimination in PD. The fact that RHI measures did not differ between ON- and OFF-medication states indicates an involvement of non-dopaminergic transmitter systems in this finding.     

Comparative study of the substantia nigra echogenicity and 123I-Ioflupane SPECT in patients with synucleinopathies with and without REM sleep behavior disorder

ObjectivesHyperechogenicity of the substantia nigra (SN) and abnormal dopamine transporter-single-photon emission computed tomography (DAT-SPECT) are biomarkers commonly used in the assessment of prodromal synucleinopathy. Our goals were as follows: (1) to compare echogenicity of SN in idiopathic rapid eye movement (REM) behavior disorder (iRBD), Parkinson's disease (PD) without RBD (PD-noRBD), PD with RBD (PD + RBD), and control subjects; and (2) to examine association between SN degeneration assessed by DAT-SPECT and SN echogenicity.Patients/methodsA total of 61 subjects with confirmed iRBD were examined using Movement Disorders Society-unified PD rating scale (MDS-UPDRS), TCS (transcranial sonography) and DAT-SPECT. The results were compared with 44 patients with PD (25% PD + RBD) and with 120 age-matched healthy subjects.Results and conclusionThe abnormal SN area was found in 75.5% PD, 23% iRBD and 7.3% controls. Median SN echogenicity area in PD (0.27 ± 0.22 cm²) was higher compared to iRBD (0.07 ± 0.07 cm²; p < 0.0001) and controls (0.05 ± 0.03 cm²; p < 0.0001). SN echogenicity in PD + RBD was not significantly different from PD-noRBD (0.30 vs. 0.22, p = 0.15).Abnormal DAT-SPECT was found in 16 iRBD (25.4%) and 44 PD subjects (100%). No correlation between the larger SN area and corresponding putaminal binding index was found in iRBD (r = −0.13, p = 0.29), nor in PD (r = −0.19, p = 0.22).The results of our study showed that: (1) SN echogenicity area in iRBD was higher compared to controls, but the hyperechogenicity was present only in a minority of iRBD patients; (2) SN echogenicity and DAT-SPECT binding index did not correlate in either group; and (3) SN echogenicity does not differ between PD with/without RBD.     

Neural mechanisms regulating different forms of risk-related decision-making: Insights from animal models

Over the past 20 years there has been a growing interest in the neural underpinnings of cost/benefit decision-making. Recent studies with animal models have made considerable advances in our understanding of how different prefrontal, striatal, limbic and monoaminergic circuits interact to promote efficient risk/reward decision-making, and how dysfunction in these circuits underlies aberrant decision-making observed in numerous psychiatric disorders. This review will highlight recent findings from studies exploring these questions using a variety of behavioral assays, as well as molecular, pharmacological, neurophysiological, and translational approaches. We begin with a discussion of how neural systems related to decision subcomponents may interact to generate more complex decisions involving risk and uncertainty. This is followed by an overview of interactions between prefrontal-amygdala-dopamine and habenular circuits in regulating choice between certain and uncertain rewards and how different modes of dopamine transmission may contribute to these processes. These data will be compared with results from other studies investigating the contribution of some of these systems to guiding decision-making related to rewards vs. punishment. Lastly, we provide a brief summary of impairments in risk-related decision-making associated with psychiatric disorders, highlighting recent translational studies in laboratory animals.     

Neural processing of reward in adolescent rodents

Immaturities in adolescent reward processing are thought to contribute to poor decision making and increased susceptibility to develop addictive and psychiatric disorders. Very little is known; however, about how the adolescent brain processes reward. The current mechanistic theories of reward processing are derived from adult models. Here we review recent research focused on understanding of how the adolescent brain responds to rewards and reward-associated events. A critical aspect of this work is that age-related differences are evident in neuronal processing of reward-related events across multiple brain regions even when adolescent rats demonstrate behavior similar to adults. These include differences in reward processing between adolescent and adult rats in orbitofrontal cortex and dorsal striatum. Surprisingly, minimal age related differences are observed in ventral striatum, which has been a focal point of developmental studies. We go on to discuss the implications of these differences for behavioral traits affected in adolescence, such as impulsivity, risk-taking, and behavioral flexibility. Collectively, this work suggests that reward-evoked neural activity differs as a function of age and that regions such as the dorsal striatum that are not traditionally associated with affective processing in adults may be critical for reward processing and psychiatric vulnerability in adolescents.     

Differential effects of vagus nerve stimulation paradigms guide clinical development for Parkinson’s disease

BackgroundVagus nerve stimulation (VNS) modifies brain rhythms in the locus coeruleus (LC) via the solitary nucleus. Degeneration of the LC in Parkinson’s disease (PD) is an early catalyst of the spreading neurodegenerative process, suggesting that stimulating LC output with VNS has the potential to modify disease progression. We previously showed in a lesion PD model that VNS delivered twice daily reduced neuroinflammation and motor deficits, and attenuated tyrosine hydroxylase (TH)-positive cell loss.ObjectiveThe goal of this study was to characterize the differential effects of three clinically-relevant VNS paradigms in a PD lesion model.MethodsEleven days after DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, noradrenergic lesion, administered systemically)/6-OHDA (6-hydroxydopamine, dopaminergic lesion, administered intrastriatally) rats were implanted with VNS devices, and received either low-frequency VNS, standard-frequency VNS, or high-frequency microburst VNS. After 10 days of treatment and behavioral assessment, rats were euthanized, right prefrontal cortex (PFC) was dissected for norepinephrine assessment, and the left striatum, bilateral substantia nigra (SN), and LC were sectioned for immunohistochemical detection of catecholamine neurons, α-synuclein, astrocytes, and microglia.ResultsAt higher VNS frequencies, specifically microburst VNS, greater improvements occurred in motor function, attenuation of TH-positive cell loss in SN and LC, and norepinephrine concentration in the PFC. Additionally, higher VNS frequencies resulted in lower intrasomal α-synuclein accumulation and glial density in the SN.ConclusionsThese data indicate that higher stimulation frequencies provided the greatest attenuation of behavioral and pathological markers in this PD model, indicating therapeutic potential for these VNS paradigms.     

多巴胺受体调节对新生大鼠缺氧缺血性脑损伤后焦虑样行为的影响

目的 观察缺氧缺血性脑损伤（HIBD）新生大鼠远期黑质酪氨酸羟化酶（TH）的表达及焦虑样行为的变化以及多巴胺（DA）受体拮抗剂干预对其远期焦虑样行为的影响。方法 将120 只7 日龄（P7）SD大鼠分为正常对照组、假手术组、HIBD 组及HIBD+DA 受体拮抗剂组。Rice 法制作HIBD 模型；假手术组予右侧颈总动脉分离，但不予结扎和低氧处理；HIBD+DA 受体拮抗剂组在造模前后予腹腔注射DA 受体拮抗剂，其余组予等量的生理盐水腹腔注射。各组分别于P14、P21 及P28（n=10）进行高架十字迷宫（EPM）实验检测动物的焦虑样行为及应用免疫组织化学方法测定其大脑黑质TH 的表达。结果 P21 及P28 时HIBD 组开放臂停留时间（OT）及开放臂次数比率较正常对照组、假手术组及HIBD+DAR 组增高（P<0.05），且HIBD+DAR 组OT较正常对照组增高（P<0.05）。P14、P21 及P28 时HIBD 组及HIBD+DAR 组TH 水平均低于正常对照组及假手术组，且HIBD 组低于HIBD+DAR 组（P<0.05）。结论 初生时给予DA 受体拮抗剂能改善HIDB 对青春期焦虑样行为的异常作用并能减轻多巴胺能神经元的损伤。     

Looking for reward in all the wrong places: dopamine receptor gene polymorphisms indirectly affect aggression through sensation-seeking

Individuals with genotypes that code for reduced dopaminergic brain activity often exhibit a predisposition toward aggression. However, it remains largely unknown how dopaminergic genotypes may increase aggression. Lower-functioning dopamine systems motivate individuals to seek reward from external sources such as illicit drugs and other risky experiences. Based on emerging evidence that aggression is a rewarding experience, we predicted that the effect of lower-functioning dopaminergic functioning on aggression would be mediated by tendencies to seek the environment for rewards. Caucasian female and male undergraduates (N = 277) were genotyped for five polymorphisms of the dopamine D2 receptor (DRD2) gene; they reported their previous history of aggression and their dispositional reward-seeking. Lower-functioning DRD2 profiles were associated with greater sensation-seeking, which then predicted greater aggression. Our findings suggest that lower-functioning dopaminergic activity puts individuals at risk for violence because it motivates them to experience aggression’s hedonically rewarding qualities.