Thalamic and basal ganglia regions are involved in attentional processing of behaviorally significant events: evidence from simultaneous depth and scalp EEG.

Extensive descriptions exist on cortical responses to change in the acoustic environment. However, the involvement of subcortical regions is not well understood. Here we present simultaneous recordings of cortical and subcortical event-related potentials (ERPs) to different pure tones in patients undergoing surgery for deep brain stimulation (DBS). These patients had externalized electrodes in the subthalamic nucleus (STN), the ventrolateral posterior thalamus (VLp) or the globus pallidus internus (GPi). Subcortical and cortical ERPs were analyzed upon presentation of one frequent non-target stimulus and two infrequent stimuli, either being a target or a distractor stimulus. The results revealed that amplitudes of scalp-recorded P3 and subcortical late attention-modulated responses (AMR) were largest upon presentation of target stimuli compared with distractor stimuli. This suggests that thalamic and basal ganglia regions are sensitive to behaviorally relevant auditory events. Comparison of the subcortical structures showed that responses in VLp have shorter latency than in GPi and STN. Further, the subcortical responses in VLp and STN emerged significantly prior to the cortical P3 response. Our findings point to higher-order cognitive functions already at a subcortical level. Auditory events are categorized as behaviorally relevant in subcortical loops involving basal ganglia and thalamic regions. This label is then distributed to cortical regions by ascending projections.

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.

Neuronal activity of the prefrontal cortex is reduced in rats selectively bred for deficient sensorimotor gating.

Rats selectively bred for deficient prepulse inhibition (PPI), an operant measure of sensorimotor gating in which a weak prepulse stimulus attenuates the response to a subsequent startling stimulus, may be used to study certain pathophysiological mechanisms and therapeutic strategies for neuropsychiatric disorders with abnormalities in information processing, such as schizophrenia and Tourette's syndrome (TS). Little is known about neuronal activity in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAC), which are involved in the modulation of PPI. Here, we examined neuronal activity in these structures, and also in the entopeduncular nucleus (EPN), since lesions of this region alleviate the PPI deficit. Male rats with breeding-induced high and low expression of PPI (n=7, each) were anesthetized with urethane (1.4 mg/kg). Single-unit activity and local field potentials were recorded in the mPFC, the NAC and in the EPN. In the mPFC discharge rate, measures of irregularity and burst activity were significantly reduced in PPI low compared to PPI high rats (P<0.05), while analysis in the NAC showed approximately inverse behavior. In the EPN no difference between groups was found. Additionally, the oscillatory theta band activity (4-8 Hz) was enhanced and the beta band (13-30 Hz) and gamma band (30-100 Hz) activity was reduced in the NAC in PPI low rats. Reduced neuronal activity in the mPFC and enhanced activity in the NAC of PPI low rats, together with altered oscillatory behavior are clearly associated with reduced PPI. PPI low rats may thus be used to study the pathophysiology and therapeutic strategies for neuropsychiatric disorders accompanied by deficient sensorimotor gating.

Effect of deep brain stimulation in rats selectively bred for reduced prepulse inhibition.

BACKGROUND: Sensorimotor gating, measured as prepulse inhibition (PPI) of the acoustic startle reaction (ASR), is disturbed in certain neuropsychiatric disorders, such as schizophrenia, obsessive compulsive disorder, and Tourette's syndrome (TS). Deep brain stimulation (DBS) of the centromedian-parafascicular complex (CM-Pf), globus pallidus internus (in rats the entopeduncular nucleus - EPN), and the ventral striatum (in rats the nucleus accumbens - NAC) has been used for treatment in TS. OBJECTIVE: We tested whether DBS of these regions would alleviate breeding-induced low PPI in rats. METHODS: Rats with breeding-induced low and high PPI were bilaterally implanted with electrodes in the CM-Pf, the EPN, or the NAC. After two weeks, they were stimulated or sham stimulated for epochs of 6 days (in the EPN with a current of 20% below the individual threshold for stimulation-induced side effects, in the NAC or CM-Pf with 100 µA and 150 µA). On the 6th day the rats were tested for PPI of ASR. RESULTS: Stimulation in the CM-Pf with 150 µA significantly alleviated PPI, while NAC stimulation was less effective. In PPI low rats electrode implantation in the EPN already improved PPI, while subsequent stimulation had no additional effect. Startle reaction of PPI low rats was not affected by stimulation of either region. CONCLUSION: The CM-Pf and the EPN are important for the modulation of sensorimotor gating in rats with breeding-induced low PPI. These rats may therefore be useful to further investigate the pathophysiological mechanisms of deficient sensorimotor gating and also mechanisms of action of DBS in these circumstances.

Deep brain stimulation of the entopeduncular nucleus in rats prevents apomorphine-induced deficient sensorimotor gating.

Pharmacologically induced stereotypies and deficient sensorimotor gating, measured as prepulse inhibition (PPI) of the acoustic startle response (ASR), are used as endophenotypes for certain symptoms common to neuropsychiatric disorders, such as schizophrenia and Tourette's syndrome (TS) among others. We here investigated whether high frequency deep brain stimulation (DBS) of the rat's entopeduncular nucleus (EPN), the equivalent to the human globus pallidus internus (GPi), would improve PPI-deficits and stereotypies induced by the dopamine receptor agonist apomorphine. Electrodes were stereotactically implanted bilaterally in the EPN of 13 Sprague-Dawley rats. After one week of recovery the rats were stimulated with an amplitude 20% below their individual threshold for side effects (130 Hz, 80 µs pulse width) or sham-stimulated for epochs of five days. At the end of each epoch the effect of ongoing stimulation or sham-stimulation on apomorphine-induced stereotypies (vehicle and 0.5 mg/kg) and deficient PPI (vehicle and 1.0 mg/kg) were tested. In nine rats, in which the full protocol could be applied and in which the electrode position was histologically confirmed in the target, EPN DBS did not affect baseline PPI but counteracted the apomorphine-induced PPI-deficit, while apomorphine-induced stereotypies were not affected by DBS. This work indicates an important role of the EPN in the modulation of apomorphine-induced deficient prepulse inhibition. This model may be useful to further investigate the pathophysiological of deficient sensorimotor gating and mechanisms of action of DBS in certain neuropsychiatric disorders.

Deep brain stimulation of the subthalamic nucleus in the 6-hydroxydopamine rat model of Parkinson's disease: effects on sensorimotor gating.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effectively used to treat motor symptoms in Parkinson's disease (PD). Recently more attention has been paid to behavioral disturbances caused by PD itself and by STN DBS. In the 6-hydroxydopamine (6-OHDA) PD rat model we investigated the effect of STN DBS on deficient prepulse inhibition (PPI) induced by the dopamine (DA) receptor agonist apomorphine, which is an operative measure for disturbed sensorimotor gating seen in certain neuropsychiatric disturbances. Male Sprague Dawley rats with bilateral lesions of the nigrostriatal DA system (striatal injection of 6-OHDA or vehicle for sham-lesion) were bilaterally implanted with electrodes for DBS into the STN. After determination of individual thresholds rats were stimulated (130Hz, 80µs pulse width) or sham-stimulated for epochs of six days. On the sixth day of each epoch rats were tested for PPI of the acoustic startle response after apomorphine or vehicle injection in a within randomized cross-over design. Stimulation of the STN improved PPI in vehicle-treated (control) rats, but deteriorated PPI after apomorphine treatment. This effect was more pronounced in sham-lesioned rats. Furthermore, in lesioned rats the startle reaction was marginally enhanced without effect of stimulation or apomorphine treatment. These data suggest that STN DBS interacts with dopaminergic action. With respect to functional neurosurgery, STN DBS alone may improve certain aspects of psychiatric disturbances, but may have a different impact when combined with dopaminergic medication.

Lesions of the rat entopeduncular nucleus further deteriorate N-methyl-D-aspartate receptor antagonist-induced deficient prepulse inhibition.

Lesions of the rat entopeduncular nucleus (EPN), the equivalent to the human globus pallidus internus (GPi), have been shown to improve deficient prepulse inhibition (PPI) induced by the dopamine agonist apomorphine. We here tested the effect of EPN lesions on the PPI-disruptive effect of the non-competitive NMDA receptor antagonist dizocilpine in rats. Neurotoxic bilateral lesions of the EPN were induced by ibotenic acid (4 µg in 0.4 µl). Rats were tested for PPI and locomotor activity after systemic injection of dizocilpine (vehicle and 0.15 mg/kg). Bilateral EPN lesions further deteriorated the PPI deficit induced by dizocilpine, while locomotion was not affected. This work indicates that the EPN is an important brain region within the neuronal circuit responsible for NMDA receptor antagonist-induced PPI deficits.

Lesions of the entopeduncular nucleus in rats prevent apomorphine-induced deficient sensorimotor gating.

Dopamine-induced hyperactivity and deficient sensorimotor gating, measured as prepulse inhibition (PPI) of the acoustic startle response (ASR), are used as animal models for neuropsychiatric disorders such as schizophrenia and Tourette's syndrome. We here investigated whether excitotoxic lesions of the rat entopeduncular nucleus (EPN), the equivalent to the human globus pallidus internus (GPi), would improve apomorphine-induced PPI-deficits and hyperactivity. Additionally, we investigated the effect of EPN lesions on cognition, motivation and motor skills. In male Sprague Dawley rats bilateral EPN lesions were induced by stereotactic injection of ibotenate (4 µg in 0.4 µl phosphate buffered saline, PBS) or sham-lesions by injection of vehicle PBS. After one week, rats were tested for learning and memory (continuous and delayed alternation, T-maze), for motivation (progressive ratio test with breakpoint of 3 min inactivity, Skinner box), and for motor skills (rotating rod). Thereafter, rats were tested for PPI of ASR (startle response system) after subcutaneous injection of apomorphine (1.0mg/kg and vehicle) and for locomotor activity (0.5mg/kg and vehicle). Ibotenate-induced EPN lesions did not affect learning and memory, motivation or motor skills. Basal locomotor activity and PPI was also not affected, but EPN lesions ameliorated apomorphine-induced hyperlocomotion and deficient PPI. This work indicates an important role of the EPN for the modulation of dopamine agonist-induced deficient sensorimotor gating and hyperlocomotion, without affecting normal behavioral function.

Decreased density of amygdaloid parvalbumin-positive interneurons and behavioral changes in dystonic hamsters (Mesocricetus auratus).

The dtsz hamster represents a model of primary paroxysmal nonkinesiogenic dyskinesia in which dystonic episodes can be induced by stress and anxious stimuli. This disease is regarded as a basal ganglia disorder. In fact, a deficit of striatal interneurons could play a key role in the pathophysiology in dystonic hamsters. Because the involvement of limbic structures cannot be excluded so far, the density of parvalbumin-immunoreactive (PV+) interneurons was determined in the basolateral amygdala in the present study. Compared with nondystonic hamsters, the density of PV+ interneurons was moderately decreased in the dtsz mutant. The functional consequence of this finding was examined by behavioral analyses. Examinations in the elevated plus maze and in a modified open field failed to disclose an enhanced anxiety-related behavior in dtsz hamsters (Mesocricetus auratus). A lower acoustic startle response and a stronger habituation in mutant hamsters than in controls correlated with a decreased body weight. Interestingly, prepulse inhibition was absent in mutant hamsters. The latter finding suggests a disturbed sensorimotor gating that can be related to alterations in both the basal ganglia nuclei and in limbic structures.

Disturbed social behavior and motivation in rats selectively bred for deficient sensorimotor gating.

Deficient prepulse inhibition (PPI) of startle reflects disturbed sensorimotor gating found in certain neuropsychiatric disorders. We here tested whether rats selectively bred for deficient PPI are deteriorated in behavioral paradigms used to model negative symptoms of schizophrenia. Rats with low PPI preferred standard rat-chow when having the choice between lever-pressing for reward-pellets or freely available rat-chow, suggesting reduced motivation. Additionally, these rats show deteriorated social behavior during interaction with a juvenile rat. Rats selectively bred for low PPI may therefore be used as a model to study the biological mechanisms and therapeutic strategies of negative symptoms of schizophrenia.

Selective breeding of reduced sensorimotor gating in Wistar rats.

Prepulse inhibition (PPI) of startle is an operational measure of sensorimotor gating that is reduced in some neuropsychiatric disorders (e.g. schizophrenia). Animal models have revealed insight into the neuronal and pharmacological underpinnings of PPI-deficits. Recent work has shown that a PPI-deficit can be selectively bred in Wistar rats and is already stable in the second filial generation. We here report on developmental and parametric characteristics of sensorimotor gating deficits in the 4th and 6th filial generation of male rats selectively bred for low PPI (low PPI) compared to rats with normal levels of PPI (high PPI). Low PPI rats showed significantly reduced PPI and variable startle magnitude (in pulse alone trials) along with reduced short-term habituation of startle as adults. Reduced PPI in the low PPI rats was found throughout development (tested on postnatal days 21, 35, 49, 70). PPI-deficits in the low PPI rats were evident at prepulse intensities ranging from 62-86 dB and for interstimulus intervals ranging between 30-1000 ms. These behavioral data add to a growing body of knowledge about the genetic basis of sensorimotor gating deficits and suggest that low PPI rats have potential use as an intermediate phenotype in schizophrenia research. The stable phenotype of breeding-induced PPI-deficits and reduced startle habituation indicates that PPI has strong genetic determinants and that selectively bred rats can be used for future neurophysiological, anatomical, pharmacological, and genomic analyses.

Deficient prepulse inhibition induced by selective breeding of rats can be restored by the dopamine D2 antagonist haloperidol.

Deficient sensorimotor gating, measured as prepulse inhibition (PPI) of startle, reflects disturbed information processing found in neuropsychiatric disorders. Examining the ability to selectively breed rats for high and low PPI, results showed significant differences of PPI scores within two generations. Comparing antipsychotics to restore PPI of the low group, haloperidol was shown more effective than clozapine. This suggests low PPI rats may be useful models for neuropsychiatric disorders and screening antipsychotics.