Influence of Musical Enculturation on Brain Responses to Metric Deviants.

The ability to recognize metric accents is fundamental in both music and language perception. It has been suggested that music listeners prefer rhythms that follow simple binary meters, which are common in Western music. This means that listeners expect odd-numbered beats to be strong and even-numbered beats to be weak. In support of this, studies have shown that listeners exposed to Western music show stronger novelty and incongruity related P3 and irregularity detection related mismatch negativity (MMN) brain responses to attenuated odd- than attenuated even-numbered metric positions. Furthermore, behavioral evidence suggests that music listeners' preferences can be changed by long-term exposure to non-Western rhythms and meters, e.g., by listening to African or Balkan music. In our study, we investigated whether it might be possible to measure effects of music enculturation on neural responses to attenuated tones on specific metric positions. We compared the magnetic mismatch negativity (MMNm) to attenuated beats in a "Western group" of listeners (n = 12) mainly exposed to Western music and a "Bicultural group" of listeners (n = 13) exposed for at least 1 year to both Sub-Saharan African music in addition to Western music. We found that in the "Western group" the MMNm was higher in amplitude to deviant tones on odd compared to even metric positions, but not in the "Bicultural group." In support of this finding, there was also a trend of the "Western group" to rate omitted beats as more surprising on odd than even metric positions, whereas the "Bicultural group" seemed to discriminate less between metric positions in terms of surprise ratings. Also, we observed that the overall latency of the MMNm was significantly shorter in the Bicultural group compared to the Western group. These effects were not biased by possible differences in rhythm perception ability or music training, measured with the Musical Ear Test (MET). Furthermore, source localization analyses suggest that auditory, inferior temporal, sensory-motor, superior frontal, and parahippocampal regions might be involved in eliciting the MMNm to the metric deviants. These findings suggest that effects of music enculturation can be measured on MMNm responses to attenuated tones on specific metric positions.

Acute in vivo effect of valproic acid on the GABAergic system in rat brain: A [11C]Ro15-4513 microPET study.

γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the nervous system acting mainly through GABAA receptors. In the presence of high levels of GABA, an allosteric shift in the GABAA receptors can change the affinity of benzodiazepine (BZD) ligands. Valproic acid (VPA) is an anticonvulsant that enhances the level of endogenous GABA in the brain. The BZD ligand, Ro15-4513 has a high affinity for GABAA receptors containing the α5 subunit and can be used to investigate the GABA shift in the brains of living rats after VPA exposure. Seven Wistar rats were scanned using a Mediso NanoScan PET/MRI. A baseline 90-min dynamic [11C]Ro15-4513 PET scan was acquired prior to an intravenous injection of 50 mg/kg VPA, and was followed by a second [11C]Ro15-4513 PET scan. Standardized uptake values were obtained for regions of high GABA binding, including the hippocampus and amygdala, and low GABA binding such as the cerebellum. We showed a significant increase in [11C]Ro15-4513 uptake in hippocampus and amygdala, but no significant differences in cerebellar uptake, after acute VPA exposure. In contrast to several in vitro studies, we demonstrated a positive allosteric change in the GABAA receptors after pharmacologically enhanced GABA levels resulting in enhanced Ro15-4513 uptake. Knowledge of how subtypes of the GABAA receptors react will provide us with information useful to fine-tune pharmacological interventions and design receptor subtype specific drugs.

Suppressed play behaviour and decreased oxytocin receptor binding in the amygdala after prenatal exposure to low-dose valproic acid.

To better understand the role of the neuropeptide oxytocin in autism spectrum disorder (ASD), we investigated potential deficits in social play behaviour and oxytocin receptor (OXTR) density alterations in the amygdala in a rodent model of ASD. Pregnant rats were injected daily with 20 or 100 mg/kg valproic acid (VPA) or saline from day 12 until the end of pregnancy. The number of pinning and pouncing events was assessed at postnatal days 29-34. Brains from male offspring (n=7/group) were removed at postnatal day 50. We performed quantitative autoradiography with an OXTR radioligand, the [I]-ornithine vasotocin analogue, in brain slices from the amygdala and other limbic brain regions involved in rat social behaviour. The results demonstrated a significant reduction in pinning behaviour and decreased OXTR density in the central nucleus of the amygdala in the 20 mg/kg VPA group. However, the 100 mg/kg VPA group had no significant changes in the number of play behaviour-related events or OXTR binding in the central nucleus of the amygdala. The reduction in OXTR density in the amygdala may be a critical disrupting mechanism affecting social behaviour in pervasive disorders such as ASD.

Increased GABAA receptor binding in amygdala after prenatal administration of valproic acid to rats.

OBJECTIVE: Prenatal exposure to valproic acid (VPA) enhances the risk for later development of autism spectrum disorders (ASD). An altered gamma-aminobutyric acid (GABA) system may be a key factor in ASD. Here we investigated possible changes in the GABA system in rats exposed to a low dose of prenatal VPA. METHOD: We performed autoradiography with [3H]muscimol, (a GABAA receptor agonist), and [11C]Ro15-4513 (a partial agonist of the GABAA α1+5 receptor subtypes), in brain sections containing amygdala, thalamus and hippocampus of rats treated prenatally with 20 mg/kg VPA or saline from the 12th day of gestation. Result Prenatal VPA significantly increased [11C]Ro15-4513 binding in the left amygdala compared with controls (p<0.05). This difference was not observed in the hippocampus, thalamus or right amygdala. No differences were observed in [3H]muscimol binding. CONCLUSION: We observed an asymmetric increase in GABAA receptor binding. Disturbances in the GABAA receptor system have also been detected in human autism with [11C]Ro15-4513.

The touchscreen operant platform for assessing cognitive functions in a rat model of depression.

In the present study we assessed alterations in cognitive functions in a chronic mild stress (CMS) rat model of depression. Cognitive functions were assessed in two different tasks applying the translational operant platform touchscreen technology; the visual discrimination/acquisition task was used to assess the ability to perceive and distinguish visual stimuli and to assess associative stimulus-reward learning. The visual discrimination/reversal learning task was used to assess functional brain plasticity or reprogramming of previously acquired stimulus-reward associations. These tasks permit the dissociation of multiple cognitive domains. The CMS model is a validated depression model with the useful feature that rats upon stress exposure show a graduated, individual stress response allowing the segregation of rats into different phenotypes including stress-resilient and anhedonic-like subgroups. Anhedonic-like rats are less likely to acquire the pairwise discrimination task, and they have a slower acquisition rate than controls. In the reversal learning task, resilient rats performed significantly better than anhedonic-like rats over time and 50% passed criterion as opposed to 25% for controls and only 14% for anhedonic-like rats. This indicates that resilient rats have higher cognitive flexibility than anhedonic-like rats. Thus they perform better in learning a novel task, which at the same time potentially implies an increased ability to inhibit previously rewarded behavior.

Hyperactivity and lack of social discrimination in the adolescent Fmr1 knockout mouse.

The aims of this study were to investigate behaviour relevant to human autism spectrum disorder (ASD) and the fragile X syndrome in adolescent Fmr1 knockout (KO) mice and to evaluate the tissue levels of striatal monoamines. Fmr1 KO mice were evaluated in the open field, marble burying and three-chamber test for the presence of hyperactivity, anxiety, repetitive behaviour, sociability and observation of social novelty compared with wild-type (WT) mice. The Fmr1 KO mice expressed anxiety and hyperactivity in the open field compared with WT mice. This increased level of hyperactivity was confirmed in the three-chamber test. Fmr1 KO mice spent more time with stranger mice compared with the WT. However, after a correction for hyperactivity, their apparent increase in sociability became identical to that of the WT. Furthermore, the Fmr1 KO mice could not differentiate between a familiar or a novel mouse. Monoamines were measured by HPLC: Fmr1 KO mice showed an increase in the striatal dopamine level. We conclude that the fragile X syndrome model seems to be useful for understanding certain aspects of ASD and may have translational interest for studies of social behaviour when hyperactivity coexists in ASD patients.

Corrigendum to "Long-term valproic acid exposure increases the number of neocortical neurons in the developing rat brain" [Neurosci.Lett. 580 (2014) 12­16] A possible new animal model of autism.

The aim of this study was to test the hypothesis that long-term fetal valproic acid (VPA) exposure at doses relevant to the human clinic interferes with normal brain development. Pregnant rats were given intraperitoneal injections of VPA (20 mg/kg or 100 mg/kg) continuously during the last 9­12 days of pregnancy and during the lactation period until sacrifice on the 23rd postnatal day. Total number of neocortical neurons was estimated using the optical fraction at or and frontal cortical thicknesses were sampled in VPA exposed pups compared with an unexposed control group. We found that pups exposed to 20 mg/kg and 100 mg/kg doses of VPA had statistically significant higher total number of neurons in neocortex by 15.8% and 12.3%, respectively, (p < 0.05) compared to controls amounting to 15.5??106 neocortical neurons (p < 0.01). There was no statistical difference between the two VPA groups. Pups exposed to 100 mg/kg, but not to 20 mg/kg VPA displayed a significant (p < 0.05) broader (7.5%) of frontal cortical thickness compared to controls. Our results support the hypothesis that fetal exposure of VPA may interfere with normal brain development by disturbing neocortical organization, resulting in overgrowth of frontal lobes and increased neuronal cell numbers. The results indirectly suggest that prenatal VPA may contribute as a causative factor in the brain developmental disturbances equivalent to those seen inhuman autism spectrum disorders. We therefore suggest that this version of the VPA model may provide a translational model of autism.

Long-term valproic acid exposure increases the number of neocortical neurons in the developing rat brain. A possible new animal model of autism.

The aim of this study was to test the hypothesis that long-term fetal valproic acid (VPA) exposure at doses relevant to the human clinic interferes with normal brain development. Pregnant rats were given intraperitoneal injections of VPA (20mg/kg or 100mg/kg) continuously during the last 9-12 days of pregnancy and during the lactation period until sacrifice on the 23rd postnatal day. Total number of neocortical neurons was estimated using the optical fractionator and frontal cortical thicknesses were sampled in VPA exposed pups compared with an unexposed control group. We found that pups exposed to 20mg/kg and 100mg/kg doses of VPA had statistically significant higher total number of neurons in neocortex by 15.8% and 12.3%, respectively (p<0.05) compared to controls amounting to 15.5×10(6) neocortical neurons (p<0.01). There was no statistical difference between the two VPA groups. Pups exposed to100mg/kg, but not to 20mg/kg VPA displayed a significant (p<0.05) broader (7.5%) of frontal cortical thickness compared to controls. Our results support the hypothesis that fetal exposure of VPA may interfere with normal brain development by disturbing neocortical organization, resulting in overgrowth of frontal lobes and increased neuronal cell numbers. The results indirectly suggest that prenatal VPA may contribute as a causative factor in the brain developmental disturbances equivalent to those seen in human autism spectrum disorders. We therefore suggest that this version of the VPA model may provide a translational model of autism.