Deep brain stimulation of the thalamic centromedian-parafascicular nucleus improves behavioural and neuronal traits in a rat model of Tourette.

Deficient prepulse inhibition (PPI) of the acoustic startle reaction after injection of the dopamine receptor agonist apomorphine has been experimentally used to model certain aspects of Tourette syndrome (TS) in rats. Deep brain stimulation (DBS) of the centromedian-parafascicular (CM-Pf) complex alleviates tics in patients with TS. The CM-Pf projects to striatal regions, which might mediate the effect of DBS via the cortico basal-ganglia circuitry implicated in the pathophysiology of TS. We tested the effect of CM-Pf DBS on apomorphine-induced deficient PPI and on striatal neuronal activity in rats. Electrodes were stereotaxically implanted bilaterally in the CM-Pf of adult male Sprague Dawley rats. Thereafter, rats were stimulated (150 µA and 130 Hz) or sham-stimulated (no application of current) to test the effect on apomorphine-induced deficient PPI (vehicle and 1.0 mg/kg). Additionally, the neuronal activity of the dorsomedial striatum (DMS) and the nucleus accumbens (NAC), as well as its coherence with the sensorimotor cortex (SM-Ctx) was recorded after apomorphine injection and CM-Pf DBS. CM-Pf DBS prevented the apomorphine-induced PPI-deficit. In striatal neurons apomorphine enhanced burst activity, as well as oscillatory theta band coherence with SM-Ctx electrocorticogram (SM-Ctx ECoG), which was reduced by CM-Pf DBS. Overall, the effect was stronger in the NAC than in the DMS. Modulation of neuronal activity in striatal regions may mediate the effects of CM-Pf DBS on PPI. This model may be used to test and improve novel neuro-modulation strategies.

Alcohol Withdrawal and Proopiomelanocortin Neuropeptides in an Animal Model of Alcohol Dependence.

BACKGROUND: Alcohol is one of the leading threats to health worldwide. Craving for alcohol makes abstinence a difficult challenge by maintaining alcohol dependence. Many studies suppose the hypothalamic-pituitary-adrenal axis, especially the proopiomelanocortin (POMC)-derived neuropeptides, to mediate craving during withdrawal in alcohol dependence. Evidence is available that the two POMC proteins, α-melanocyte-stimulating hormone (α-MSH) and ß-endorphin (ß-END) are altered by alcohol consumption and influence alcohol consumption, respectively. OBJECTIVES: We investigated the dynamics of α-MSH and ß-END during alcohol withdrawal and the influence of intraperitoneal administration of either α-MSH or ß-END in an established rodent model (Wistar rats) for alcohol dependence. RESULTS: After long-term alcohol self-administration over 12 months and repeated deprivation periods for 3 days, we found a significant decrease in α-MSH levels during withdrawal in rodents (p = 0.006) compared to controls, while ß-END levels remained unchanged. Treatment with intraperitoneally administered α-MSH and ß-END did not affect alcohol drinking behavior after deprivation. CONCLUSION: We demonstrate the effects of alcohol deprivation on α-MSH in alcohol-dependent rodents, which appear to mimic α-MSH alteration found after fasting periods during appetite regulation. Therefore, low α-MSH levels are a possible indicator for craving in alcohol-dependent individuals and hence would be a potential target for anti-craving treatment.

Long-term impairment of social behavior, vocalizations and motor activity induced by bilateral lesions of the fastigial nucleus in juvenile rats.

The cerebellum is increasingly recognized to be involved in limbic and cognitive-associative functioning. Cerebellar cognitive affective syndromes may result from various types of injuries. Cerebellar mutism may occur in children after resection of midline tumors in the posterior fossa, which has been thought to be related to damage to the cerebellar vermis. Here, we investigated whether bilateral lesions of the fastigial nucleus, which is located within the upper vermis, would affect social behavior in a rat model. Juvenile male Sprague-Dawley rats, aged 23 days, underwent bilateral thermocoagulation of the fastigial nucleus via stereotaxically implanted electrodes under general anesthesia. Electrodes were inserted without application of electric current in a sham-lesion group and naïve rats served as additional controls. All groups underwent standardized examination before surgery and on specific time points up to 49 days after surgery to investigate locomotor activity, motor coordination, social behavior, and ultrasound vocalizations during social interaction. Finally, lesions were verified histologically. Playing behavior and vocalizations were reduced up to 4 weeks after surgery in rats of the lesion group compared to rats with sham-lesions and controls. After surgery in rats of the lesion group, locomotor activity was disturbed for 3 days as compared to sham-lesion rats, but for 4 weeks as compared to controls. Motor coordination measured by the rotarod and balance beam test was compromised until adulthood. Bilateral lesions of the fastigial nucleus in juvenile rats cause a severe and long-lasting reduction of social interaction and motor coordination in juvenile rats, which has some similarities to cerebellar cognitive affective syndromes in the human context. This indicates a modulating role of the fastigial nucleus with regard to neural circuitries relevant for social behavior, such as the limbic system and the prefrontal cortex.

Intracranial rat glioma model for tumor resection and local treatment.

BACKGROUND: Although tumor resection is among the most important prognostic factors, high grade gliomas regrow in most cases. Also, resection of glial tumors in eloquent brain regions is not or only partially possible. Despite these severe restraints, however, only a few in-vivo models have been established to investigate tumor recurrence and local treatment. Here we characterize the intracranial BT4Ca rat glioma as a model for these aspects. NEW METHOD: BT4Ca cells were stereotaxically implanted into the frontal cortex of BDIX rats. Rats were than allocated to (1) a control group, which received no further treatment; (2) a catheter group, where a catheter was implanted for repeated microinjection of vehicle every 3rd day as catheter-control; (3) a resection group, where the tumor was microsurgically removed eight days after cell injection. Postoperatively, survival time, weight and general health condition were scored and the tumor size was histologically assessed. RESULTS: Injection of BT4Ca cells induced fast-growing tumors with a mean survival time of 16 days in the control and catheter groups. Resection significantly prolonged survival time whereby the tumor regrew in all rats. Tumor size was similar between all groups. COMPARISON WITH EXISTING METHOD(S): We here present a robust and reliable intracranial rat glioma model, which is suitable to simulate tumor recurrence after surgical resection and local treatment. Importantly, this model does not require advanced imaging or elaborate surgical techniques. CONCLUSIONS: The intracranial BT4Ca glioma model appears to be a feasible tool to investigate tumor recurrence after resection and to test local treatment.

Cortical electroconvulsive stimulation alleviates breeding-induced prepulse inhibition deficit in rats.

In patients with medical-refractory schizophrenia electroconvulsive therapy (ECT), i.e., the induction of therapeutic seizures via cortical surface electrodes, is effectively used. Electroconvulsive stimulation (ECS) in rodents simulates ECT in humans and is applied to investigate the mechanisms underlying this treatment. Experimentally-induced reduced prepulse inhibition (PPI) of the acoustic startle response (ASR), i.e., the reduction of the startle response to an intense acoustic stimulus when this stimulus is shortly preceded by a weaker not-startling stimulus, serves as an endophenotype for neuropsychiatric disorders that are accompanied by disturbed sensorimotor gating, such as schizophrenia. Here we used rats selectively bred for high and low PPI to evaluate whether bifrontal cortical ECS would affect PPI. For this purpose, cortical screw electrodes were stereotactically implanted above the frontal cortex. After recovery ECS was applied for five consecutive days with stimuli of 1 ms pulse-width, 100 pulses/s, 1 s duration, ranging from 5.5 mA to 10 mA. PPI of ASR was measured one day before ECS, and on days 1, 7, and 14 after the last ECS. In rats with breeding-induced low PPI ECS increased PPI one week after stimulation. In contrast, ECS decreased PPI in rats with high PPI on the first day after stimulation. The reaction to the startle impulse was reduced by ECS without difference between groups. This work provides evidence that rats with breeding-induced high or low PPI could be used to further investigate the underlying mechanisms of ECT in neuropsychiatric disorders with disturbed sensorimotor gating like schizophrenia.

The rotenone-induced rat model of Parkinson's disease: behavioral and electrophysiological findings.

Exposure to rotenone leads to parkinsonian features, such as loss of dopaminergic neurons in the substantia nigra and motor impairment, however, the validity of this model has recently been questioned. In rodent and monkey models of Parkinson's disease (PD) abnormal neuronal activity in the basal ganglia motor loop has been described, with hyperactivity of the subthalamic nucleus (STN) similar to that found in PD. The present study aims at providing new and more specific evidence for the validity of the rotenone rat model of PD by examining whether neuronal activity in the STN is altered. Male Sprague Dawley rats were treated with rotenone injections (2.5mg/kg bodyweight intraperitoneally) for 60 days. Behavioral analysis showed an impairment in the rotarod and hanging wire test in the rotenone group (p<0.05), accompanied by a decline in tyrosine hydroxylase immunoreactive neurons in the nigro-striatal region (p<0.001). Thereafter, single unit (SU) activities and local field potentials were recorded in the STN in urethane anesthetized rats. The SU analysis revealed a higher neuronal discharge rate (p<0.001), more bursts per minute (p=0.006) and a higher oscillatory activity (p=0.008) in the STN of rotenone treated rats. Spectral analysis showed an increase of relative beta power in the STN as well as in the motor cortex. We found electrophysiological key features of PD pathology and pathophysiology in the STN of rotenone treated rats. Therefore, the rotenone-induced rat model of PD deserves further attention since it covers more aspects than dopamine depletion and implies the reproducibility of PD specific features.