Matti Mintz

The cerebellum in action: a simulation and robotics study

The control or prediction of the precise timing of events are central aspects of the many tasks assigned to the cerebellum. Despite much detailed knowledge of its physiology and anatomy, it remains unclear how the cerebellar circuitry can achieve such an adaptive timing function. We present a computational model pursuing this question for one extensively studied type of cerebellar‐mediated learning: the classical conditioning of discrete motor responses. This model combines multiple current assumptions on the function of the cerebellar circuitry and was used to investigate whether plasticity in the cerebellar cortex alone can mediate adaptive conditioned response timing. In particular, we studied the effect of changes in the strength of the synapses formed between parallel fibres and Purkinje cells under the control of a negative feedback loop formed between inferior olive, cerebellar cortex and cerebellar deep nuclei. The learning performance of the model was evaluated at the circuit level in simulated conditioning experiments as well as at the behavioural level using a mobile robot. We demonstrate that the model supports adaptively timed responses under real‐world conditions. Thus, in contrast to many other models that have focused on cerebellar‐mediated conditioning, we investigated whether and how the suggested underlying mechanisms could give rise to behavioural phenomena.

Involvement of the amygdala in classical conditioning of eyeblink response in the rat

The two-factor theory postulates that classical conditioning proceeds through two stages, which support successive acquisition of emotional and motor responses. Emotional conditioning is thought to facilitate the subsequent acquisition of the motor response. This form of interaction between the two stages of learning can be investigated while considering the central role of the amygdala and the cerebellum in emotional and motor conditioning, respectively. Rats with bilateral lesions of the amygdala or the cerebellar interpositus or intact rats were subjected to a fear conditioning session followed by four eyeblink conditioning sessions. Another group of intact rats was subjected to eyeblink conditioning only. The CS in the fear conditioning session was a 73 dB tone, paired with a 100 dB noise-US. The same CS was paired with a periorbital electroshock-US during eyeblink conditioning. Results showed that fear preconditioning facilitated the subsequent eyeblink conditioning among the intact groups. Amygdaloid lesions abolished this facilitatory effect of fear conditioning. These findings demonstrate that amygdala-mediated emotional conditioning facilitates the subsequent acquisition of cerebellum-mediated motor responses.

Two-stage theory of conditioning: involvement of the cerebellum and the amygdala

Classical conditioning is thought to proceed through two successive stages: fast rate emotional conditioning followed by slower motor conditioning. To verify the involvement of the amygdala and the cerebellum in these two stages of learning, rats were subjected to paired tone-airpuff (CS-US) trials. Lick suppression to CS was used as an index of conditioned emotional response (emotional CRs) and head movement was used as an index of motor CRs. The results showed that the fast acquisition of emotional CRs was dependent on the integrity of the amygdala and the slow acquisition of motor CRs was dependent on the integrity of the cerebellar interpositus nucleus. Cerebellar lesions had no effect on the acquisition of the emotional CRs but prevented the extinction of the emotional CRs seen in intact rats after massive conditioning. These findings suggest that the amygdala and the cerebellum provide the neuronal substrates of the fast and slow conditioning systems, respectively, and that conditioning-related cerebellar output interacts with the amygdala-based emotional conditioning.

Behavioral and Anatomical Effects of Long-Term l-Dihydroxyphenylalanine (L-DOPA) Administration in Rats with Unilateral Lesions of the Nigrostriatal System

This study investigated behavioral and anatomical changes induced by long periods of L-DOPA treatment in the unilateral rat model of Parkinsons disease. After daily injections of L-DOPA (50 mg/kg, ip) given for 1, 4, 8, or 16 weeks, behavioral sensitization, expressed by contralateral turning and changes in its pattern, increased within the first week of treatment and remained unchanged thereafter. Dyskinetic movements, affecting the trunk and limbs of all treated rats, also developed within the first week of treatment and increased further during the 16 weeks of L-DOPA treatment. L-DOPA responsiveness was also accompanied by changes at the neuronal level, as shown by changes in the expression of c-fos in the dopamine-depleted striatum. Following 1 week of L-DOPA treatment there was a marked decrease in striatal c-fos expression, compared to single injections, especially evident in the medial and ventral regions and to a lesser extent in the dorsolateral regions of the striatum. This specific regional expression of c-fos was maintained throughout the 16 weeks of L-DOPA treatment. Overall, our results show that behavioral sensitization to L-DOPA starts relatively early during the treatment and include not only an increase in contralateral turning rate but also an increase in dyskinetic movements. Persisting c-fos expression in the dorsolateral striatum might be implicated in the development of dyskinesias when L-DOPA treatment is extended for periods longer than 1 week.

Unilateral inferior olive NMDA lesion leads to unilateral deficit in acquisition and retention of eyelid classical conditioning

New Zealand White rabbits (Oryctolagus cuniculus) were trained for acquisition (N = 21) or retention (N = 10) of classical eyelid conditioning with unilateral or bilateral N-methyl-DL-aspartate chemical lesions of the rostromedial dorsal accessory inferior olive (rmDAO; multiple injections totaling 76 to 342 nmol). In all instances, subjects were unable to learn or retain conditioning on the side contralateral to the lesion. Learning rates were comparable for lesions outside of the rmDAO and sham operates. These findings demonstrate a specific unilateral deficit whereas in previous research the answer to this question was ambiguous since electrolytic lesions effectively cause bilateral olivary lesions. This research agrees with the concept that the inferior olive projects essential information about the unconditioned stimulus to a cerebellar locus of learning and memory for classical conditioning.

The crossed nigrostriatal projection decussates in the ventral tegmental decussation

Horseradish peroxidase (HRP) tract-tracing techniques were used in 44 rats in order to establish the site of decussation of the crossed nigrostriatal projection. Somata in both the ipsilateral and the contralateral ventromedial mesencephalon were labelled after injection of HRP into the caudate nucleus. In agreement with previous studies, contralateral labelling constituted about 3% of the ipsilateral labelling. Midsagittal transection of the mesodiencephalic junction did not prevent the contralateral labelling. However, mid-sagittal transection of the ventral mesencephalon, or selective 6-hydroxydopamine (6-OHDA) lesions of the ventral tegmental decussation did prevent the contralateral labelling. Moreover, 6-OHDA lesions of the substantia nigra ipsilateral to the horseradish peroxidase injection also prevented contralateral labelling. We conclude that the crossed nigrostriatal projection decussates in the ventral tegmental decussation, and that this projection is susceptible to damage by standard 6-OHDA lesions located on the opposite side to the origin of the crossed pathway.

Convulsant-Speciflc Architecture of the Postictal Behavior Syndrome in the Rat

Summary: The postictal immobility syndrome was examined in five experimental grand mal epilepsy models in an attempt to analyze separately the behavioral and underlying neurochemical aspects of the rigid‐catatonic and flaccid‐cataleptic states. Catalepsy and analgesia were found in varying degrees after maximal electroshock (MES), metrazol, picrotoxin, and Ro 5–3663 activated seizures. Signs of rigidity were noticed after the MES and picrotoxin seizures. Kindled seizures were followed by explosive behavior without signs of rigidity, catalepsy, and analgesia. Naloxone reduced the duration but not the score (intensity) of catalepsy and failed to selectively antagonize analgesia. The relative representation of the tonic stage of convulsions seemed to be the major determinant of the development of catatonic‐cataleptic symptomatology. It is suggested that more than a single neurotransmitter system is involved in the postictal immobility syndrome and each epilepsy model has its unique neurochemical profile.

In the eye of the beholder: Internally driven uncertainty of danger recruits the amygdala and dorsomedial prefrontal cortex

Interpretation of emotional context is a pivotal aspect of understanding social situations. A critical component of this process is assessment of danger levels in the surrounding, which may have a direct effect on the organisms survival. The limbic system has been implicated in mediating this assessment. In situations of uncertainty, the evaluation process may also call for greater involvement of prefrontal cortex for decision-making and planning of an appropriate behavioral response. In the following study, morphed face images depicting emotional expressions were used to examine brain correlates of subjective uncertainty and perceptual ambiguity regarding danger. Fear and neutral expressions of 20 faces were morphed, and each of the face videos was divided into three sequences of equal length representing three levels of objective certainty regarding the expressions neutral, fear, and ambiguous. Sixteen subjects were scanned in a 1.5-T scanner while viewing 60 × 6-sec video sequences and were asked to report their subjective certainty regarding the level of danger surrounding the face on a four-level scale combining definite/maybe and danger/no-danger values. The individual responses were recorded and used as the basis for a “subjective protocol” versus an “objective protocol.” Significant activations of the amygdala, dorsomedial prefrontal cortex, and dorsolateral prefrontal cortex were observed under the subjective protocol of internally driven uncertainty, but not under objective stimuli-based ambiguity. We suggest that this brain network is involved in generating subjective assessment of social affective cues. This study provides further support to the “relevance detector” theory of the amygdala and implicates its importance to behavior relying heavily on subjective assessment of danger, such as in the security domain context.

Balance treatment ameliorates anxiety and increases self-esteem in children with comorbid anxiety and balance disorder.

Comorbidity between balance and anxiety disorders in adult population is a well-studied clinical entity. Children might be particularly prone to develop balance-anxiety comorbidity, but surprisingly they are practically neglected in this field of research. The consequence is that children are treated for what seems to be the primary disorder without noticing possible effects on the other disorder. In Study 1, children with balance dysfunction were compared to normally balanced controls on anxiety and self-esteem. In study 2, children with balance dysfunction were assigned to either balance training or a waiting-list control. Training consisted of 12 weekly sessions of balance treatment. Anxiety and self-esteem were tested before and after treatment/waiting. Study 1 confirmed significantly higher anxiety and lower self-esteem in the balance dysfunction group compared to the control group. Study 2 showed that treatment improved balance performance, reduced anxiety, and increased self-esteem relative to the control waiting list group. Taken together, the present findings are in accord with the observations of comorbidity between balance and anxiety disorders in adults and confirm their validity in children younger than 7 years of age. This profile of comorbidity between balance dysfunction and anxiety also include lower self-esteem.

Unilateral dopamine deficit and lateral EEG asymmetry: Sleep abnormalities in hemi-parkinson's patients

The hypothesis was tested that unilateral dopamine deficiency leading to the contralateral extrapyramidal syndrome (hemi-parkinsonism) would cause distinctly asymmetric EEG sleep patterns. In 7 hemi-Parkinsons patients 2 nights of sleep were monitored along with pre-sleep waking periods. No medication was given prior to the first night. The second night followed at least 2 months of L-DOPA medication. Although in all patients sleep architecture was disturbed, no statistically significant asymmetries of sleep patterns were obtained. L-DOPA medication improved the quality of sleep. Delta sleep was most visibly improved. Also, post-treatment enhancement of the mean delta power over the parkinsonian hemisphere was supported statistically. The role of dopamine in slow wave sleep control and mechanisms of contralateral hemisphere involvement are discussed.