Periaqueductal grey stimulation induced panic-like behaviour is accompanied by deactivation of the deep cerebellar nuclei.

Until recently, the cerebellum was primarily considered to be a structure involved in motor behaviour. New anatomical and clinical evidence has shown that the cerebellum is also involved in higher cognitive functions and non-motor behavioural changes. Functional imaging in patients with anxiety disorders and in cholecystokinin tetrapeptide-induced panic-attacks shows activation changes in the cerebellum. Deep brain stimulation of the dorsolateral periaqueductal grey (dlPAG) and the ventromedial hypothalamus (VMH) in rats has been shown to induce escape behaviour, which mimics a panic attack in humans. We used this animal model to study the neuronal activation in the deep cerebellar nuclei (DCbN) using c-Fos immunohistochemistry. c-Fos expression in the DCbN decreased significantly after inducing escape behaviour by stimulation of the dlPAG and the VMH, indicating that the DCbN were deactivated. This study demonstrates that the DCbN are directly or indirectly involved in panic attacks. We suggest that the cerebellum plays a role in the selection of relevant information, and that deactivation of the cerebellar nuclei is required to allow inappropriate behaviour to occur, such as panic attacks.

Sustained Reduction of Cerebellar Activity in Experimental Epilepsy.

Clinical and experimental evidence suggests a role for the cerebellum in seizure control, while no data are available on cerebellar activity between seizures. We hypothesized that interictal regional activity of the deep cerebellar nuclei is reduced in epilepsy and tested this in an animal model by using ΔFosB and cytochrome oxidase (COX) (immuno)histochemistry. The expression of these two markers of neuronal activity was analysed in the dentate nucleus (DN), interpositus nucleus (IN), and fastigial nucleus (FN) of the cerebellum of fully amygdala kindled rats that were sacrificed 48 hours after their last seizure. The DN and FN of kindled rats exhibited 25 to 29% less ΔFosB immunopositive cells than their respective counterpart in sham controls (P < 0.05). COX expression in the DN and FN of kindled animals was reduced by 32 to 33% compared to respective control values (P < 0.05). These results indicate that an epileptogenic state is characterized by decreased activity of deep cerebellar nuclei, especially the DN and FN. Possible consequences may include a decreased activation of the thalamus, contributing to further seizure spread. Restoration of FN activity by low frequency electrical stimulation is suggested as a possible treatment option in chronic epilepsy.

Premature responding following bilateral stimulation of the rat subthalamic nucleus is amplitude and frequency dependent.

The subthalamic nucleus (STN), a key component of the basal ganglia circuitry, functions as an internal clock that regulates the correct sequence of movements in a motor response. The importance of the STN in motor function is evidenced by its involvement in Parkinson disease (PD). This nucleus has also been associated with the attentional and emotional aspects of motor behavior through its connections with the limbic and prefrontal areas of the brain. As lesions of the STN have been shown to increase premature responding in a serial reaction time task in rats, indicative of its involvement in cognitive performance, the present study aimed to investigate whether bilateral deep brain stimulation (DBS) of the STN, in non-lesioned rats, affects cognitive functions and whether these are dependent on certain stimulation parameters. Rats were trained in a choice reaction time task and implanted bilaterally with electrodes. Stimulation parameters (amplitude, frequency and pulse width) were varied during the test procedure, after which rats were sacrificed and the brains processed for histochemical staining. Results show no change in reaction times or motor times during stimulation. However, a linear decrease in premature responses was observed with decreasing amplitudes and at high frequencies only. These results are the first to demonstrate that bilateral STN HFS has a positive effect on cognition in freely moving rats. This latter result is in contrast to findings following lesions of the STN, and suggests that current strength and frequency of stimulation are parameters that are integral to the mediation of stimulation effects. Furthermore, the overall effects of DBS on neuronal cells cannot be classified simply as being "inhibitory" and evidently mediates its effects by more complex mechanisms than lesions of the same brain area.

Cerebellar nuclei are activated by high-frequency stimulation of the subthalamic nucleus.

The cerebellum, primarily considered a pure motor structure, is increasingly considered to play a role in behaviour and cognition. In a similar manner, there is increasing evidence that the basal ganglia are involved in non-motor processes. Recently a direct connection between the cerebellum and the basal ganglia has been shown to exist. High-frequency stimulation (HFS) of the subthalamic nucleus (STN) has become an accepted treatment in advanced Parkinson's disease (PD). We performed HFS of the STN in rats to evaluate the neuronal activation in the deep cerebellar nuclei (DCbN) using c-Fos immunohistochemistry. We found an increased c-Fos expression in the DCbN. Previously, we have shown that STN HFS in rats leads to decreased impulsive behaviour and our findings now suggest a link with increased DCbN activity. This is in line with our previous work showing that decreased DCbN activity is accompanied by disruptive behaviour. We suggest that the DCbN play a role in the selection of relevant information on which a behavioural response is based. The connection between the cerebellum and the basal ganglia may imply a role for the cerebellum in behavioural aspects of disorders of the basal ganglia.

Cerebellar nuclei are involved in impulsive behaviour.

Recent anatomical and clinical evidence has shown that the cerebellum, primarily considered a motor control structure, is also involved in higher cognitive functions and behavioural changes, such as impulsive behaviour. Impulsive behaviour has been shown in several studies to be increased by lesions of the mediodorsal (MD) thalamic nucleus. We performed deep brain stimulation (DBS) of the mediodorsal and ventrolateral (VL) thalamic nuclei in rats, clinically mimicking such a lesion, and tested them for changes in impulsive behaviour in a choice reaction time test. We then analysed the effects of this stimulation on c-Fos expression in both the deep cerebellar nuclei (DCbN) and the prefrontal cortex (PFC), and correlated these outcomes to the measured changes in impulsive behaviour. DBS of the MD thalamic nucleus increased impulsive behaviour without changing motor parameters. This was accompanied by a decrease in the c-Fos expression in all cerebellar nuclei; with a corresponding increase in c-Fos expression in the PFC. DBS of the VL thalamic nucleus caused no significant change in behaviour or c-Fos expression in either region. The present study demonstrates that impulsive behaviour involves the cerebellar nuclei, possibly through a decreased selective attention caused by a disruption of the cerebello-thalamo-cortical pathways through the MD thalamic nucleus.