Reinforcement omission effects in rats with bilateral lesions in the substantia nigra pars compacta and ventral tegmental area

Reinforcement omission effects (ROEs) are characterized by higher response rates after reinforcement omission than after reinforcement delivery. This pattern of behavior is interpreted in terms of motivational and attentional processes. Recent studies from our laboratory have shown that the amygdala, nucleus accumbens, and medial prefrontal cortex are involved in ROE modulation. Also, the literature has demonstrated a role of other areas such as substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) in processes related to surprising events, such as prediction error and presentation or omission of an event (exteroceptive stimulus and reinforcement). Since these structures send projections to areas related to ROE modulation such as the amygdala, nucleus accumbens, and prefrontal cortex, the objective of the present study was to determine whether the SNc and VTA also integrate the circuit involved in ROE modulation. Rats were trained on a fixed-interval 12 s with limited-hold 6 s signaled schedule of reinforcement (Pre-lesion training). After acquisition of stable performance, the rats received bilateral neurotoxic lesions of the SNc (Experiment 1) and VTA (Experiment 2). Following postoperative recovery, the rats were submitted to two refresher sessions (Post-lesion training). Subsequently, the training was changed from a 100 to a 50% schedule of reinforcement (Post-lesion testing). In both experiments, the results showed that there was no difference in performance between sham rats and rats with bilateral lesions of the SNc or the VTA.

Effect of pinealectomy and gonadectomy on dopaminergic neurons of mesencephalon in Parkinson's disease model rats / 中华行为医学与脑科学杂志

Objective To investigate the effect of PX and GDX on dopaminergic neurons of mesencephalon in Parkinson's disease model rats.Methods Eighty male Wistar rats were randomly divided into five groups:NS,N+6-OHDA,PX+6-OHDA,GDX+6-OHDA and PX+GDX+6-OHDA group;16 rats in each group.60 days after operation,6-OHDA was injected into SNc and VTA in the right side of the mesencephalon.Mter 14 days,the rats were sacrificed.HE staining was used to observe the proliferation of glial cells.The number of astrocytes was observed by GFAP staining.The number of apoptotic cells was observed by TUNEL staining.Immunohistochemical staining (S-P Method) was used to detect the changes of TH-positive cells and fiber,apoptosis-related proteins Bax and Bcl2.Results (1) The numbers of proliferated glial cells in SNc and VTA were significantly increased according to the following sequence:NS,N+6-OHDA,PX + 6-OHDA,GDX+ 6-OHDA,and PX+GDX+6-OHDA (HE staining:Hc =280.178,P＜0.01;Hc =334.260,P＜0.01) (GFAP staining:Hc=367.081,P＜0.01;Hc=376.049,P＜0.01).(2) The numbers of apoptotic cells in SNc and VTA were significantly increased according to the following sequence:NS,N+ 6-OHDA,PX+ 6-OHDA,GDX+6-OHDA,and PX+GDX+6-OHDA (Hc =344.401,P＜0.01;Hc =326.198,P＜0.01).(3) The numbers of TH (+) cells in SNc and VTA were significantly decreased according to the following sequence:NS,N+6-OHDA,PX+ 6-OHDA,GDX+ 6-OHDA,and PX+GDX+ 6-OHDA (Hc =366.532,P＜ 0.01;Hc =372.565,P＜0.01).(4) The gray values of TH(+) positive cells and fiber in SNc and VTA were significantly increased according to the following sequence:NS,N+6-OHDA,PX+6-OHDA,GDX+6-OHDA and PX+GDX+ 6-OHDA (F=517.239,P＜ 0.01;F=526.758,P＜ 0.01).(5) Bax expression:weakly positive in NS group,positive in N+6-OHDA group,and strongly positive in remaining three groups;Bcl2 expression:weakly positive in each group.Conclusion PX and GDX significantly aggravate neurotoxicity of 6-OHDA.And GDX is greater than PX,while PX + GDX is strongest.

Effect of pinealectomy and gonadectomy on dopaminergic neurons of mesencephalon in Parkinson's disease model rats / 中华行为医学与脑科学杂志

Objective To investigate the effect of PX and GDX on dopaminergic neurons of mesencephalon in Parkinson's disease model rats.Methods Eighty male Wistar rats were randomly divided into five groups:NS,N+6-OHDA,PX+6-OHDA,GDX+6-OHDA and PX+GDX+6-OHDA group;16 rats in each group.60 days after operation,6-OHDA was injected into SNc and VTA in the right side of the mesencephalon.Mter 14 days,the rats were sacrificed.HE staining was used to observe the proliferation of glial cells.The number of astrocytes was observed by GFAP staining.The number of apoptotic cells was observed by TUNEL staining.Immunohistochemical staining (S-P Method) was used to detect the changes of TH-positive cells and fiber,apoptosis-related proteins Bax and Bcl2.Results (1) The numbers of proliferated glial cells in SNc and VTA were significantly increased according to the following sequence:NS,N+6-OHDA,PX + 6-OHDA,GDX+ 6-OHDA,and PX+GDX+6-OHDA (HE staining:Hc =280.178,P＜0.01;Hc =334.260,P＜0.01) (GFAP staining:Hc=367.081,P＜0.01;Hc=376.049,P＜0.01).(2) The numbers of apoptotic cells in SNc and VTA were significantly increased according to the following sequence:NS,N+ 6-OHDA,PX+ 6-OHDA,GDX+6-OHDA,and PX+GDX+6-OHDA (Hc =344.401,P＜0.01;Hc =326.198,P＜0.01).(3) The numbers of TH (+) cells in SNc and VTA were significantly decreased according to the following sequence:NS,N+6-OHDA,PX+ 6-OHDA,GDX+ 6-OHDA,and PX+GDX+ 6-OHDA (Hc =366.532,P＜ 0.01;Hc =372.565,P＜0.01).(4) The gray values of TH(+) positive cells and fiber in SNc and VTA were significantly increased according to the following sequence:NS,N+6-OHDA,PX+6-OHDA,GDX+6-OHDA and PX+GDX+ 6-OHDA (F=517.239,P＜ 0.01;F=526.758,P＜ 0.01).(5) Bax expression:weakly positive in NS group,positive in N+6-OHDA group,and strongly positive in remaining three groups;Bcl2 expression:weakly positive in each group.Conclusion PX and GDX significantly aggravate neurotoxicity of 6-OHDA.And GDX is greater than PX,while PX + GDX is strongest.

Structural changes of substantia nigra in patients with unilateral Parkinson′s disease / 中华全科医师杂志

Magnetic resonance imaging ( MRI ) findings were studied in 19 patients with non-dementia Parkinson′s disease ( PD) Hoehn-Yahr Stage 1 and 1.5 and 38 healthy subjects.The width and area of pars compacta of substantia nigra ( SNc) , substantia nigra ( SN) and midbrain were measured.The width and area ratios of SNc to SN were calculated.Compared with controls, the widths of right SNc was narrower, bilateral ratios of SNc to SN width were decreased in PD group.As to the area of substantia nigra, there was no significant difference between PD and controls.The width of left SN and the ratio of right SNc to SN width was negatively correlation with age of patients.The ratio of left SNc to SN width, the area of bilateral SNc and left SN, as well as the ratio of right SNc to SN area had negative correlation with the disease duration;however, there was no correlation with gender, Hoehn-Yahr Stage, the Unified Parkinson disease rating scale score, mini mental state scale, education years, levodopa equivalent daily dose, Hamilton Depression Scale or Hamilton Anxiety Scale in PD group.The results indicate that there are bilateral structural changes of SN in unilateral PD patients, which may be more significant with increasing disease duration.The measurement of SNc width and SN area can be used as an objective indicator for diagnosis and disease progression monitoring of PD.

3.0T MR Susceptibility-weighted Imaging for Substantia Nigra Pars Compacta in Primary Parkinson’s Disease / 昆明医科大学学报

Objective To evaluate the application of measurement of T2*value,width of substantia nigra pars compacta (SNc) and the ratio of the width to the midbrain diameter in diagnosing Parkinson disease (PD) in early stage with susceptibility weighted imaging ( SWI) by 3T MR. Methods 59 patients with early stage idiopathic PD patients and 59 healthy controls,ranging in same ages and gender,had been scanned with routine sequences and SWI sequences by 3T MR. T2*value,width and the ratio of the width to the midbrain diameter of SNc were measured. The results of measurement were analyzed and compared. Results (1) The T2*values, width and the ratio of the width to the midbrain diameter was decreased in homolateral side SNc of symptoms of subjects with PD compared with the healthy controls ( 0.05) . Conclusion Measurement of T2*value, width and the ratio of the width to the midbrain diameter of SNc with SWI is reliable to diagnose PD.

Beneficial Effect of Vitamin E in Rotenone Induced Model of PD: Behavioural, Neurochemical and Biochemical Study

Parkinson's disease (PD) a neurodegenerative disorder for which no preventive or long-term effective treatment strategies are available. Epidemiologic studies have failed to identify specific environmental, dietary or lifestyle risk factors for PD. However, oxidative stress in the SN is the most broadly accepted hypothesis for the etiopathology of PD. The Symptoms do not appear until there is a decline of striatal dopamine levels by 80% making it difficult to have early therapeutic interventions. Thus, the present experiment was designed to track down the sequential changes starting from the initiation of motor dysfunction and associated biochemical abnormality in rotenone based PD model. The study also evaluated the neuroprotective efficacy of vitamin E. Rats were treated with rotenone 2 mg/kg b.wt (s.c.) for 35 days. The level of dopamine decreased by 70~80% which was in turn reflected by marked deterioration in motor function such as (Total locomotor activity and catalepsy). Along with these the level of GSH and SOD declined significantly which was associated with elevated lipid peroxidation levels as much as by 60%.Vitamin E co-administration at a dose of 100 I.U/kg b.wt (i.m.) ameliorated rotenone induced changes in motor functions i.e Total locomotor activity and Catalepsy at the end of 5th week. Further, vitamin E supplementation significantly decreased lipid peroxidation and improved associated biochemical parameters i.e SOD and GSH level. Most interestingly the changes appeared as early as 3rd week suggesting that supplementation of vitamin E right at the beginning should be neuroprotective in PD.

El núcleo pedunuulopontino y su relación con la fisiopatología de la enfermedad de parkinson / The Pedunculopontine Nucleus and its Relationship to the Pathophysiology of Parkinson's Disease

Varias décadas de investigaciones neuropatológicas e imagenológicas han proporcionado suficientes evidencias acerca de las alteraciones en la neurotransmisión colinérgica que acompañan a la disfunción dopaminérgica en la enfermedad de Parkinson (EP). El núcleo pedunculopontino tegmental laterodorsal (NPP) representa una de las fuentes principales de proyecciones colinérgicas en el cerebro y a su vez es el origen de la única proyección colinérgica que recibe la substantia nigra pars compacta (SNpc). Actualmente el estudio de la participación del NPP en la fisiopatología de la EP toma en cuenta dos vertientes: el impacto de la pérdida temprana de la influencia excitatoria pontina sobre la SNpc asociado a la degeneración temprana del NPP y la estimulación a baja frecuencia del NPP como tratamiento quirúrgico beneficioso para los signos axiales de la EP. El NPP ha emergido como una estructura esencial en la comprensión de la fisiopatología de la EP dado sus relaciones con los núcleos de los ganglios basales, el tálamo, la corteza motora y la médula espinal. La degeneración de algunas de sus poblaciones neuronales en etapas presintomáticas de la EP ha sugerido una relación causa-efecto entre este hallazgo y la muerte de las células dopaminérgicas nigrales. Por otra parte la estimulación del NPP tiene resultados favorables sobre los trastornos posturales y de la marcha, los cuales se presentan en etapas tardías de la EP y son refractarios a otros tratamientos farmacológicos y quirúrgicos.

Several decades of neuropathologic and imagenologic investigations have provided sufficient evidences about alterations in cholinergic neurotransmission that go together with the dopaminergic dysfunction in Parkinson s disease (PD). The laterodorsal tegmental pedunculopontine nucleus (PPN) represents one of the main sources of cholinergic projections into the brain and at the same time the origin of the only cholinergic projection that substantia nigra pars compacta (SNpc) receives. At present, the study of the PPN participation as part of the physiopathology of PD has two notions: the impact of the lack of pontine excitatory influence on SNpc, associated to the early degeneration of PPN as well as the low frequency stimulation in the PPN as a beneficial surgical treatment for the axial symptoms of PD. PPN has emerged as an essential structure in the comprehension of PD physiopathology, given by its relation with the basal ganglia nuclei, thalamus, motor cortex and the spinal cord. The degeneration of some of its neuronal populations in PD pre symptomatic steps, has suggested a cause- and-effect relation on this finding and the death of nigral dopaminergic cells. On the other hand, PPN stimulation has favorable results on postural and gait disorders, which present themselves in late PD stages and are refractory to other pharmacological and surgical treatments.

Lesion of the subthalamic nucleus reverses motor deficits but not death of nigrostriatal dopaminergic neurons in a rat 6-hydroxydopamine-lesion model of Parkinson's disease

The objective of the present study was to determine whether lesion of the subthalamic nucleus (STN) promoted by N-methyl-D-aspartate (NMDA) would rescue nigrostriatal dopaminergic neurons after unilateral 6-hydroxydopamine (6-OHDA) injection into the medial forebrain bundle (MFB). Initially, 16 mg 6-OHDA (6-OHDA group) or vehicle (artificial cerebrospinal fluid - aCSF; Sham group) was infused into the right MFB of adult male Wistar rats. Fifteen days after surgery, the 6-OHDA and SHAM groups were randomly subdivided and received ipsilateral injection of either 60 mM NMDA or aCSF in the right STN. Additionally, a control group was not submitted to stereotaxic surgery. Five groups of rats were studied: 6-OHDA/NMDA, 6-OHDA/Sham, Sham/NMDA, Sham/Sham, and Control. Fourteen days after injection of 6-OHDA, rats were submitted to the rotational test induced by apomorphine (0.1 mg/kg, ip) and to the open-field test. The same tests were performed again 14 days after NMDA-induced lesion of the STN. The STN lesion reduced the contralateral turns induced by apomorphine and blocked the progression of motor impairment in the open-field test in 6-OHDA-treated rats. However, lesion of the STN did not prevent the reduction of striatal concentrations of dopamine and metabolites or the number of nigrostriatal dopaminergic neurons after 6-OHDA lesion. Therefore, STN lesion is able to reverse motor deficits after severe 6-OHDA-induced lesion of the nigrostriatal pathway, but does not protect or rescue dopaminergic neurons in the substantia nigra pars compacta.

Gentle handling temporarily increases c-Fos in the substantia nigra pars compacta

Dopaminergic neurotransmission is involved in the regulation of sleep. In particular, the nigrostriatal pathway is an important center of sleep regulation. We hypothesized that dopaminergic neurons located in substantia nigra pars compacta (SNpc) could be activated by gentle handling, a method to obtain sleep deprivation (SD). Adult male C57/BL6J mice (N = 5/group) were distributed into non-SD (NSD) or SD groups. SD animals were subjected to SD once for 1 or 3 h by gentle handling. Two experiments were performed. The first determined the activation of SNpc neurons after SD, and the second examined the same parameters after pharmacologically induced dopaminergic depletion using intraperitoneal reserpine (2 mg/kg). After 1 or 3 h, SD and NSD mice were subjected to motor evaluation using the open field test. Immediately after the behavioral test, the mice were perfused intracardially to fix the brain and for immunohistochemical analysis of c-Fos protein expression within the SNpc. The open field test indicated that SD for 1 or 3 h did not modify motor behavior. However, c-Fos protein expression was increased after 1 h of SD compared with the NSD and 3-h SD groups. These immunohistochemistry data indicate that these periods of SD are not able to produce dopaminergic supersensitivity. Nevertheless, the increased expression of c-Fos within the SNpc suggests that dopaminergic nigral activation was triggered by SD earlier than motor responsiveness. Dopamine-depleted mice (experiment 2) exhibited a similar increase of c-Fos expression compared to control animals indicating that dopamine neurons are still activated in the 1-h SD group despite the exhaustion of dopamine. This finding suggests that this range (2-5-fold) of neuronal activation may serve as a marker of SD.

Changes in firing rate and firing pattern of midbrain dopaminergic neurons after lesioning of the dorsal raphe nucleus by 5,7-drhydroxytryptamine in adult rats / 西安交通大学学报·英文版

Objective: To study the effect of serotonergic efferent projection of the dorsal raphe nucleus (DRN) on the activity of substantia nigra pars compacta (SNc) and ventral tegmenta area (VTA) dopaminergic neurons after lesioning of the DRN by the neurotoxin 5,7-drhydroxytryptamine (5,7-DHT) in rat. Methods: The changes in the firing rate and firing pattern of SNc and VTA dopaminergic neurons were observed with extracellular recording in control and the lesioned rats. Results: The results showed that the mean firing rates of the fast-firing dopaminergic neurons of the SNc in control and the lesioned rats were (5.34±0.13) Hz (n=23) and (7.13±0.49) Hz (n=37), respectively. The mean firing rate of the fast-firing dopaminergic neurons of the SNc in the lesioned rats was significantly increased when compared to that of control rats (P<0.01), while the mean firing rate of the slow-firing dopaminergic neurons of the SNc did not change. The mean firing rates of dopaminergic neurons of the VTA in control and the lesioned rats were (5.27±0.38) Hz (n=35) and (3.6±0.2) Hz (n=52), respectively. Lesioning of the DRN induced a significant decrease in the mean firing rate of dopaminergic neurons of the VTA. The firing pattern of SNc and VTA dopaminergic neurons changed towards a more bursting or irrgular firing after the lesioning. Conclusion: These data suggest that the serotonergic efferent projections of the DRN significantly affect the activity of SNc and VTA dopaminergic neurons.

Changes in firing rate and firing pattern of midbrain dopaminergic neurons after lesioning of the dorsal raphe nucleus by 5,7-drhydroxytryptamine in adult rats / 药物分析学报

Objective To study the effect of serotonergic efferent projection of the dorsal rophe nucleus (DRN) on the activity of substantia nigro pars compacta (SNc) and ventral tegmenta area (VTA) dopaminergic neurons after lesioning of the DRN by the neurotoxin 5,7-drhydroxytryptamine (5,7-DHT) in rot. Methods The changes in the firing rote and firing pattern of SNc and VTA dopaminergic neurons were observed with extrocellular recording in control and the lesioned rats. Results The results showed that the mean firing rotes of the fast-firing dopaminergic neurons of the SNc in control and the lesioned rots were (5.34±0. 13 ) Hz (n = 23 ) and ( 7.13±0. 49 ) Hz (n=37), respectively. The mean firing rote of the fast-firing dopaminergic neurons of the SNc in the lesioned rats was significantly increased when compared to that of control rots (P<0.01), while the mean firing rote of the slow-firing dopaminergic neurons of the SNc did not change. The mean firing rotes of dopaminergic neurons of the VTA in control and the lesioned rots were (5.27±0. 38)Hz (n=35) and (3.6±0.2)Hz (n=52), respectively. Lesioning of the DRN induced a significant decrease in the mean firing rote of dopaminergic neurons of the VTA. The firing pattern of SNc and VTA dopaminergic neurons changed towards a more bursting or irrgular firing after the lesioning. Conlusion These data suggest that the serotonergic efferent projections of the DRN significantly affect the activity of SNe and VTA dopaminergic neurons.

The application of measurement of the width of pars compacta of substantia nigra in differential diagnosis on Parkinson's disease and vascular parkinsonism on MRI / 临床神经病学杂志

Objective To evaluate the value of measurement of the width of pars compacta of substantia nigra(SNc) and SNc's ratio to midbrain diameter in diagnosing Parkinson's disease(PD) and differentiating PD from vascular parkinsonism(VP) on routine MRI.Methods The width of SNc, midbrain diameter, and SNc's ratio to midbrain diameter were measured in 60 patients with PD (38 patients with Hoehn-Yahr stage Ⅰ～Ⅱ, 14 patients with Hoehn-Yahr stage Ⅲ, and 8 patients with Hoehn-Yahr stage Ⅳ), 60 patients with VP (26 patients with Hoehn-Yahr stage Ⅰ～Ⅱ, 20 patients with Hoehn-Yahr stage Ⅲ, and 14 patients with Hoehn-Yahr stage Ⅳ), and 60 age-matched heathly control subjects by means of routine axial T 2-weighted MRI. The results of measurement were analyzed and compared.Results Significant reduction was found in the width of SNc and SNc's ratio to midbrain diameter in PD compared those in VP and control subjects(P