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1.
Muscle Nerve ; 55(3): 316-322, 2017 03.
Article in English | MEDLINE | ID: mdl-27422849

ABSTRACT

INTRODUCTION: In severely affected inherited polyneuropathy patients, primary demyelination can be difficult to determine by routine extremity limb nerve conduction studies (NCS). Blink reflexes may help classify severe polyneuropathies as either axonal or demyelinating. However, blink reflex studies have not been studied systematically in any genetically confirmed cohort. METHODS: Patients with a genetic diagnosis who had undergone blink reflex testing and extremity NCS were identified retrospectively. Blink reflex R1 latency, extremity NCS, and severity were compared. RESULTS: We identified 26 demyelinating and 23 axonal, genetically confirmed cases, including 20 with PMP22 duplications. In 12 (25%), the ulnar CMAP amplitude was ≤0.5 mV making electrophysiological classification difficult. However, the R1-latency cutoff of >13 ms (demyelinating) robustly classified all patients regardless of severity. CONCLUSIONS: We show that blink reflex studies are reliable for identification of inherited demyelinating polyneuropathy regardless of severity and can facilitate algorithmic decisions in genetic testing. Muscle Nerve 55: 316-322, 2017.


Subject(s)
Algorithms , Blinking/genetics , Genetic Testing , Mutation/genetics , Myelin Proteins/genetics , Polyneuropathies/genetics , Polyneuropathies/physiopathology , Adolescent , Adult , Aged , Child , Child, Preschool , Cohort Studies , Electromyography , Female , Humans , Male , Middle Aged , Myelin P0 Protein/genetics , Neural Conduction/genetics , Nuclear Proteins/genetics , Regression Analysis , Transcription Factors/genetics , Young Adult
2.
Int J Psychophysiol ; 115: 57-64, 2017 05.
Article in English | MEDLINE | ID: mdl-27666795

ABSTRACT

Startle reflex and affect-modified startle reflex are used as indicators of defensive reactivity and emotional processing, respectively. The present study investigated the heritability of both the startle blink reflex and affect modification of this reflex in a community sample of 772 twins ages 14-15years old. Subjects were shown affective picture slides falling in three valence categories: negative, positive and neutral; crossed with two arousal categories: high arousal and low arousal. Some of these slides were accompanied with a loud startling noise. Results suggested sex differences in mean levels of startle reflex as well as in proportions of variance explained by genetic and environmental factors. Females had higher mean startle blink amplitudes for each valence-arousal slide category, indicating greater baseline defensive reactivity compared to males. Startle blink reflex in males was significantly heritable (49%), whereas in females, variance was explained primarily by shared environmental factors (53%) and non-shared environmental factors (41%). Heritability of affect modified startle (AMS) was found to be negligible in both males and females. These results suggest sex differences in the etiology of startle reactivity, while questioning the utility of the startle paradigm for understanding the genetic basis of emotional processing.


Subject(s)
Blinking/genetics , Reflex, Startle/genetics , Sex Characteristics , Acoustic Stimulation , Adolescent , Analysis of Variance , Arousal/physiology , Child , Electromyography , Environment , Female , Humans , Male , Models, Genetic , Photic Stimulation , Twins, Dizygotic , Twins, Monozygotic
3.
Psychoneuroendocrinology ; 73: 133-141, 2016 11.
Article in English | MEDLINE | ID: mdl-27497153

ABSTRACT

BACKGROUND: Corticotropin-releasing hormone receptor 1 (CRH-R1) in the amygdala and the stria terminalis plays an important role in the activation of central stress circuits. Genetic factors may contribute to the hyperresponsiveness of these circuits in irritable bowel syndrome (IBS). AIMS: To determine if CRH-R1 SNPs are associated with: (1) a diagnosis of IBS, (2) gastrointestinal (GI) symptoms, and (3) acoustic startle response (ASR) to threat, which is mediated by the amygdala via CRH. METHODS: Three CRH-R1 SNPS (rs110402, rs242924, and rs7209436) were genotyped using salivary DNA from IBS and healthy control subjects (HCs). Eye blink ASR was obtained during safe (no shock), anticipation (abdominal shock may soon occur) and threat (abdominal shock likely) conditions in a subset of subjects. Associations between each SNP with IBS status, clinical traits and ASR were measured. RESULTS: 235 IBS patients (mean age 37.5 yrs, 74% F) and 264 HCs (mean age 32.1 yrs, 70% F) were studied. Of these, 57 IBS and 41 HCs underwent the ASR protocol. The presence of IBS was associated with the major allele for all three CRH-R1 SNPs (p=0.009-0.025). Within IBS, the major allele for all three SNPs (p=0.017-0.065) was associated with GI symptom anxiety scores. Within subjects with at least one copy of the major allele for the CRH-R1 SNPs, IBS had significantly lower ASR compared to HCs during threat conditions (p=0.001-0.002). Within IBS, CRH-R1 SNPs were associated with a graded increase in ASR to threat (p=0.007-0.008). CONCLUSION: These findings support that CRH-R1 contributes to the dysregulated stress responsiveness in IBS.


Subject(s)
Blinking/genetics , Irritable Bowel Syndrome/genetics , Receptors, Corticotropin-Releasing Hormone/genetics , Reflex, Acoustic/genetics , Reflex, Startle/genetics , Adult , Female , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide
4.
Neuroreport ; 27(14): 1046-9, 2016 Sep 28.
Article in English | MEDLINE | ID: mdl-27508977

ABSTRACT

The aim of this study is to evaluate the brainstem function in DYT1 carriers manifesting clinical dystonia (MDYT1) and those without clinical symptoms (NMDYT1). Motor cortical inhibition and plasticity were found to be abnormal in MDYT1, whereas these were less abnormal in NMDYT1. However, the spinal reciprocal inhibition was abnormal in MDYT1, but normal in NMDYT1. Moreover, protein accumulation and perinuclear inclusion bodies were found in the brainstem, but not in other brain areas, in DYT1 patients. Therefore, we designed this study to investigate the brainstem physiology using the blink reflex (BR) recovery cycle test in MDYT1 and NMDYT1. We recruited eight MDYT1, five NMDYT1, and nine age-matched healthy controls. The BR recovery cycle was assessed with paired stimuli that induced the BR in a random order at interstimulus intervals of 250, 500, and 1000 ms. A two-way analysis of variance showed a significant difference between MDYT1, NMDYT1, and the healthy control (P=0.004). Post-hoc analysis showed that this was because of a significantly lower inhibition of R2 in MDYT1 and NMDYT1 compared with the controls (two-way analysis of variance: P=0.003 and 0.021, respectively). There was no difference between MDYT1 and NMDYT1 (P=0.224). The tested brainstem circuits were equally involved in MDYT1 and NMDYT1. The finding is in agreement with the pathological findings in DYT1 carriers. Together with previous findings in the motor cortex and the spinal cord, the brainstem may lie closer to the pathogenesis of dystonia than the motor cortex in DYT1 gene carriers.


Subject(s)
Blinking/genetics , Dystonic Disorders/genetics , Dystonic Disorders/physiopathology , Molecular Chaperones/genetics , Mutation/genetics , Recovery of Function/genetics , Adult , Analysis of Variance , Electromyography , Female , Humans , Male , Middle Aged
5.
Sci Rep ; 5: 8658, 2015 Mar 02.
Article in English | MEDLINE | ID: mdl-25729002

ABSTRACT

Spontaneous eyeblink rates greatly vary among individuals from several blinks to a few dozen blinks per minute. Because dopamine agonists immediately increase the blink rate, individual differences in blink rate are used as a behavioral index of central dopamine functioning. However, an association of the blink rate with polymorphisms in dopamine-related genes has yet not been found. In this study, we demonstrated that a genetic variation of the nicotinic acetylcholine receptor CHRNA4 (rs1044396) increased the blink rate while watching a video. A receiver operating characteristic analysis revealed that the blink rate predicts a genetic variation in the nicotinic receptor gene with a significant discrimination level (0.66, p < 0.004). The present study suggests that differences in sensitivity to acetylcholine because of the genetic variation of the nicotinic receptor are associated with individual differences in spontaneous eye blink rate.


Subject(s)
Blinking/genetics , Genetic Association Studies , Polymorphism, Single Nucleotide/genetics , Receptors, Nicotinic/genetics , Adult , Alleles , Female , Gene Frequency/genetics , Humans , Male , Young Adult
6.
J Neurophysiol ; 108(1): 101-11, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22490558

ABSTRACT

Previously, we proposed a two-stage model for an in vitro neural correlate of eyeblink classical conditioning involving the initial synaptic incorporation of glutamate receptor A1 (GluA1)-containing α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid type receptors (AMPARs) followed by delivery of GluA4-containing AMPARs that support acquisition of conditioned responses. To test specific elements of our model for conditioning, selective knockdown of GluA4 AMPAR subunits was used using small-interfering RNAs (siRNAs). Recently, we sequenced and characterized the GluA4 subunit and its splice variants from pond turtles, Trachemys scripta elegans (tGluA4). Analysis of the relative abundance of mRNA expression by real-time RT-PCR showed that the flip/flop variants of tGluA4, tGluA4c, and a novel truncated variant tGluA4trc1 are major isoforms in the turtle brain. Here, transfection of in vitro brain stem preparations with anti-tGluA4 siRNA suppressed conditioning, tGluA4 mRNA and protein expression, and synaptic delivery of tGluA4-containing AMPARs but not tGluA1 subunits. Significantly, transfection of abducens motor neurons by nerve injections of tGluA4 flop rescue plasmid prior to anti-tGluA4 siRNA application restored conditioning and synaptic incorporation of tGluA4-containing AMPARs. In contrast, treatment with rescue plasmids for tGluA4 flip or tGluA4trc1 failed to rescue conditioning. Finally, treatment with a siRNA directed against GluA1 subunits inhibited conditioning and synaptic delivery of tGluA1-containing AMPARs and importantly, those containing tGluA4. These data strongly support our two-stage model of conditioning and our hypothesis that synaptic incorporation of tGluA4-containing AMPARs underlies the acquisition of in vitro classical conditioning. Furthermore, they suggest that tGluA4 flop may have a critical role in conditioning mechanisms compared with the other tGluA4 splice variants.


Subject(s)
Blinking/physiology , Conditioning, Classical/physiology , Gene Expression Regulation/physiology , RNA Splicing/physiology , Receptors, AMPA/metabolism , Animals , Blinking/genetics , COS Cells , Chlorocebus aethiops , Conditioning, Classical/drug effects , Cranial Nerves/physiology , Gene Expression Regulation/drug effects , In Vitro Techniques , Microscopy, Confocal , Mutation/genetics , Pons/drug effects , Pons/physiology , Protein Transport/drug effects , Protein Transport/genetics , RNA, Messenger , RNA, Small Interfering/metabolism , RNA, Small Interfering/pharmacology , Receptors, AMPA/genetics , Synaptophysin/metabolism , Transfection , Turtles
7.
Int J Neuropsychopharmacol ; 15(9): 1205-15, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22078257

ABSTRACT

Recently, the neuropeptide S (NPS) neurotransmitter system has been identified as a promising psychopharmacological drug target given that NPS has shown anxiolytic-like and stress-reducing properties and memory-enhancing effects in rodent models. NPS binds to the G-protein-coupled receptor encoded by the neuropeptide S receptor gene (NPSR1). A functional variant within this gene leads to an amino-acid exchange (rs324981, Asn107Ile) resulting in a gain-of-function in the Ile107 variant which was recently associated with panic disorder in two independent studies. A potential psychopharmacological effect of NPS on schizophrenia psychopathology was demonstrated by showing that NPS can block NMDA antagonist-induced deficits in prepulse inhibition. We therefore explored a potential role of the NPSR1 Asn107Ile variation in schizophrenia. A case-control sample of 778 schizophrenia patients and 713 healthy control subjects was successfully genotyped for NPSR1 Asn107Ile. Verbal declarative memory and acoustic startle response were measured in subsamples of the schizophrenia patients. The case-control comparison revealed that the low-functioning NPSR1 Asn107 variant was significantly associated with schizophrenia (OR 1.19, p=0.017). Moreover, specifically decreased verbal memory consolidation was found in homozygous Asn107 carriers while memory acquisition was unaffected by NPSR1 genotype. The schizophrenia patients carrying the Ile107 variant demonstrated significantly reduced startle amplitudes but unaffected prepulse inhibition and habituation. The present study confirms findings from rodent models demonstrating an effect of NPS on memory consolidation and startle response in schizophrenia patients. Based on these findings, we consider NPS as a promising target for antipsychotic drug development.


Subject(s)
Asparagine/genetics , Isoleucine/genetics , Memory/physiology , Receptors, G-Protein-Coupled/genetics , Reflex, Startle/genetics , Schizophrenia/genetics , Acoustic Stimulation , Adult , Algorithms , Amino Acid Substitution/genetics , Amino Acid Substitution/physiology , Analysis of Variance , Blinking/genetics , Blinking/physiology , DNA/genetics , Diagnostic and Statistical Manual of Mental Disorders , Female , Genotype , Humans , Male , Neuropsychological Tests , Polymorphism, Single Nucleotide , Reflex, Startle/physiology , Schizophrenic Psychology , Sensory Gating/drug effects
8.
Neurosci Lett ; 506(1): 155-9, 2012 Jan 06.
Article in English | MEDLINE | ID: mdl-22085694

ABSTRACT

Eyeblink conditioning has been used for assessing cognitive performance in cases of human neurodegenerative diseases including Alzheimer's disease (AD). Here, we tested and compared the delay and long-trace interval (TI=500ms) eyeblink conditionings in a Tg2576 mouse model of AD, at the age of 3, 6, and 12 months. Tg2576 mice exhibited significant impairment in trace conditioning at 6 months of age. In contrast, delay conditioning was not impaired in Tg2576 mice even at 12 months. These findings indicate that the long-TI eyeblink conditioning is more susceptible to age-related cognitive deterioration than delay conditioning in Tg2576 mice. The long-trace eyeblink conditioning could be a potential tool for detecting early cognitive deficits in AD mouse model.


Subject(s)
Alzheimer Disease/complications , Blinking/physiology , Conditioning, Classical/physiology , Learning Disabilities/etiology , Age Factors , Alzheimer Disease/genetics , Amyloid beta-Protein Precursor/genetics , Analysis of Variance , Animals , Blinking/genetics , Disease Models, Animal , Electromyography , Humans , Learning Disabilities/genetics , Mice , Mice, Inbred C57BL , Mice, Transgenic , Motor Activity/genetics , Mutation/genetics , Reaction Time/genetics
9.
J Cogn Neurosci ; 23(11): 3576-85, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21563886

ABSTRACT

The attentional blink (AB)--a deficit in reporting the second of two target stimuli presented in close succession in a rapid sequence of distracters--has been related to processing limitations in working memory. Given that dopamine (DA) plays a crucial role working memory, the present study tested whether individual differences in the size of the AB can be predicted by differences in genetic predisposition related to the efficiency of dopaminergic pathways. Polymorphisms related to mesocortical and nigrostriatal dopaminergic pathways were considered, as well as polymorphisms related to norepinephrine (NE), a transmitter system that has also been suspected to play a role in the AB. In a sample of 157 healthy adults, we studied the dependency of the individual magnitude of the AB and the C957T polymorphism at the DRD2 gene (associated with striatal DA/D2 receptors), the DARPP32 polymorphism (associated with striatal DA/D1), the COMT Val(158)Met polymorphism (associated with frontal DA), DBH444 g/a and DBH5'-ins/del polymorphisms (polymorphisms strongly correlated with DA beta hydroxylase, the enzyme catalyzing the DA-NE conversion) and NET T-182C (a polymorphism related to the NE transporter). DRD2 C957T T/T homozygotes showed a significantly smaller AB, whereas polymorphisms associated with frontal DA and NE were unrelated to performance. This outcome pattern suggests a crucial role of the nigrostriatal dopaminergic pathway and of nigrostriatal D2 receptors, in particular, in the management of attentional resources.


Subject(s)
Attention/physiology , Blinking/genetics , Individuality , Polymorphism, Single Nucleotide/genetics , Receptors, Dopamine D2/genetics , Adolescent , Adult , Analysis of Variance , Catechol O-Methyltransferase/genetics , DNA Mutational Analysis , Dopamine and cAMP-Regulated Phosphoprotein 32/genetics , Dopamine beta-Hydroxylase/genetics , Female , Genotype , Humans , Male , Photic Stimulation/methods , Predictive Value of Tests , Reaction Time/genetics , Regression Analysis , Young Adult
10.
Psychophysiology ; 47(5): 857-62, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20374544

ABSTRACT

Difficulty down-regulating negative affect has been linked with anxiety and depression. In addition, recent studies have identified specific polymorphisms of the MAOA gene related to affective psychopathology. Here we examined whether genetic variation in MAOA was associated with the time course of responses to affective stimuli. Emotion-modulation of the startle blink response was measured during and after affective pictures. Women with the G/G genotype of the MAOA T941G single nucleotide polymorphism showed sustained reactivity to unpleasant stimuli, as evidenced by continued blink potentiation during the picture-offset period. These data suggest that the MAOA T941G polymorphism, which has been previously linked with mood disorders, is associated with a maladaptive pattern of affective responding in women.


Subject(s)
Emotions/physiology , Monoamine Oxidase/genetics , Adolescent , Alleles , Blinking/genetics , Blinking/physiology , Electromyography , Female , Gene Frequency , Genotype , Humans , Photic Stimulation , Polymorphism, Genetic/genetics , Reflex, Startle/genetics , Reflex, Startle/physiology , Young Adult
11.
Exp Neurol ; 221(1): 225-30, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19913014

ABSTRACT

Facial nerve axotomy is a well-described injury paradigm for peripheral nerve regeneration and facial motoneuron (FMN) survival. We have previously shown that CD4(+) T helper (Th) 1 and 2 effector subsets develop in the draining cervical lymph node, and that the IL-4/STAT-6 pathway of Th2 development is critical for FMN survival after transection axotomy. In addition, delayed behavioral recovery time in immunodeficient mice may be due to the absence of T and B cells. This study utilized a crush axotomy paradigm to evaluate FMN survival and functional recovery in WT, STAT-6 KO (impaired Th2 response), T-Bet KO (impaired Th1 response), and RAG-2 KO (lacking mature T and B cells) mice to elucidate the contributions of specific CD4(+) T cell subsets in motoneuron survival and recovery mechanisms. STAT-6 KO and RAG-2 KO mice exhibited decreased FMN survival after crush axotomy compared to WT, supporting a critical role for the Th2 effector cell in motoneuron survival before target reconnection. Long term FMN survival was sustained through 10 wpo after crush axotomy in both WT and RAG-2 KO mice, indicating that target derived neurotrophic support maintains FMN survival after target reconnection. In addition, RAG-2 KO mice exhibited delayed functional recovery compared to WT mice. Both STAT-6 and T-Bet KO mice exhibited partially delayed functional recovery compared to WT, though not to the extent of RAG-2 KO mice. Collectively, our findings indicate that both pro- and anti-inflammatory CD4(+) T cell responses contribute to optimal functional recovery from axotomy-induced facial paralysis, while FMN survival is supported by the anti-inflammatory Th2 response alone.


Subject(s)
B-Lymphocytes/physiology , Facial Nerve Injuries/pathology , Facial Nerve Injuries/physiopathology , Motor Neurons/physiology , Recovery of Function/physiology , T-Lymphocytes/physiology , Animals , Axotomy/methods , Blinking/genetics , Blinking/physiology , Cell Count/methods , DNA-Binding Proteins/deficiency , Disease Models, Animal , Female , Functional Laterality , Mice , Mice, Inbred C57BL , Mice, Knockout , Movement/physiology , Recovery of Function/genetics , STAT Transcription Factors/deficiency , T-Box Domain Proteins/deficiency , Vibrissae/innervation
12.
Neuroscience ; 162(3): 723-31, 2009 Sep 01.
Article in English | MEDLINE | ID: mdl-19344639

ABSTRACT

The cerebellar circuitry consists of two main excitatory glutamatergic pathways. The inputs of mossy fibers and climbing fibers converge on Purkinje cells and deep cerebellar nuclei. In this circuitry, Golgi interneurons suppress granule cell excitability via the inhibitory GABA transmitter. A novel technique termed reversible neurotransmission blocking (RNB) was genetically established, in which granule cell transmission to Purkinje cells was selectively and reversibly blocked in the mouse cerebellar circuitry. This study revealed that Purkinje cells are essential for expression of conditioned eye-blink motor learning but that this memory is acquired and stored in deep cerebellar nuclei. A different technique termed immunotoxin-mediated cell targeting (IMCT) was developed to selectively ablate Golgi cells from the mouse cerebellar network. The study disclosed that excitatory glutamate receptors and inhibitory GABA receptors cooperatively act at Golgi cell-mossy fiber-granule cell synapses and are indispensable for motor coordination and adaptation. Finally, gene targeting of mGluR2 displayed that the metabotropic glutamate receptor acts collaboratively with the ionotropic AMPA receptors at granule cell-Golgi cell synapses and is crucial for the spatiotemporal regulation in the mouse cerebellar circuitry. The neural information is thus hierarchically regulated and integrated at different levels of the cerebellar network.


Subject(s)
Cerebellum/anatomy & histology , Genetic Techniques , Neural Pathways/physiology , Synaptic Transmission/genetics , Animals , Blinking/genetics , Cerebellum/physiology , Gene Expression Regulation/genetics , Mice , Mice, Transgenic , Models, Biological , Nerve Fibers/physiology , Nerve Net/physiology , Neural Inhibition/genetics , Neural Inhibition/physiology , Neurons/classification , Neurons/physiology , Purkinje Cells/physiology , Receptors, Metabotropic Glutamate/deficiency , Synapses/genetics , Synapses/physiology
13.
Behav Neurosci ; 123(2): 438-42, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19331466

ABSTRACT

The calcium/calmodulin-dependent protein kinase type IV (CaMKIV) is highly expressed in cerebellar cortical granule cells and deep nuclear neurons in the cerebellum. It mediates the phosphorylation and activation of the cAMP-dependent response element binding protein (CREB). In several paradigms CREB-dependent transcription is required for cellular events underlying long-term memory processes. Also, CaMKIV deficiency results in impaired long-term depression (LTD) induction in cerebellar cortex. To investigate the function of CaMKIV in the cerebellum, Wild-type (WT) and CaMKIV KO mice were tested with delay eyeblink conditioning. KO and WT mice did not differ in acquisition, but the KO mice showed a significantly lower conditioned response (CR) percentage than the WT mice in the retention testing and retraining period. The CR peak latencies for the two groups did not differ in acquisition but were shorter for the KO mice in the testing period. No significant differences were found between KO and WT mice in spontaneous eyeblink activity, auditory brainstem response (ABR) amplitudes, and tail-flick latency. The results suggest an important role for CaMKIV in long-term memory in the cerebellum.


Subject(s)
Blinking/genetics , Calcium-Calmodulin-Dependent Protein Kinase Type 4/deficiency , Conditioning, Eyelid/physiology , Memory Disorders/genetics , Acoustic Stimulation/methods , Analysis of Variance , Animals , Calcium-Calmodulin-Dependent Protein Kinase Type 4/genetics , Cerebellum/physiology , Evoked Potentials, Auditory, Brain Stem/genetics , Male , Mice , Mice, Knockout , Reaction Time/genetics
14.
Acta Neurol Belg ; 108(2): 44-7, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18795595

ABSTRACT

UNLABELLED: The aim of the present study was to investigate the subclinical involvement of the central nervous system (CNS) in an X-linked Charcot-Marie-Toth (CMTX) family. MATERIAL AND METHODS: Seven subjects, all members of one family with a C.462T > G connexin 32 (Cx32) mutation were investigated by Blink reflex, Somatosensory evoked potentials (SEP) and Transcranial magnetic stimulation (TMS). There were five clinically symptomatic for CMT neuropathy (four male and one female) and two asymptomatic (female) subjects. RESULTS: Subclinical CNS involvement was observed in all, symptomatic and asymptomatic subjects. CONCLUSION: This is the largest CMTX neuropathy family investigated for CNS involvement. Electrophysiological involvement of the CNS in every examined member of this family was observed, raising the question of a more systematic involvement of the CNS in CMTX disease.


Subject(s)
Central Nervous System/physiopathology , Charcot-Marie-Tooth Disease/physiopathology , Genetic Diseases, X-Linked/physiopathology , Adult , Blinking/genetics , Charcot-Marie-Tooth Disease/genetics , Evoked Potentials, Motor/genetics , Evoked Potentials, Somatosensory/genetics , Female , Humans , Male , Middle Aged , Pedigree , Point Mutation , Transcranial Magnetic Stimulation
15.
Behav Brain Res ; 187(2): 428-32, 2008 Mar 05.
Article in English | MEDLINE | ID: mdl-18037170

ABSTRACT

There is plenty of evidence from schizophrenia research and psychopharmacological experiments showing the influence of the dopaminergic neurotransmission on the prepulse inhibition (PPI). A lot of insights into the underlying neural mechanisms of the PPI have been gained from animal models, which are in need to be validated in humans. Due to new technological advances, findings from psychopharmacological challenge tests can now be verified with techniques from molecular genetics which provide an elegant non-invasive approach. To close the gap between animal research and research in humans in this field a molecular genetic approach was applied to investigate the neural mechanisms of the PPI in healthy subjects. In N=96 female participants recruited out of a sample of N=800 subjects according to their genotypes we tested the association between the DRD2 Taq Ia and the COMT Val158Met polymorphisms, and the magnitude of the eye-blink reflex in an acoustic PPI paradigm. Neither significant influences of both dopaminergic single nucleotide polymorphisms nor an epistasis effect could be detected. Although findings do not support the hypothesis that two of the most prominent dopaminergic candidate loci (DRD2 Taq Ia and COMT Val158Met) effect PPI the study does not exclude the relevance of the dopaminergic system in general. Further molecular genetic studies investigating other variants on dopaminergic genes have to be conducted.


Subject(s)
Blinking/genetics , Catechol O-Methyltransferase/genetics , Inhibition, Psychological , Neural Inhibition/genetics , Receptors, Dopamine D2/genetics , Reflex, Startle/genetics , Acoustic Stimulation , Adolescent , Adult , Analysis of Variance , Conditioning, Classical/physiology , Female , Humans , Menstrual Cycle/physiology , Polymorphism, Single Nucleotide , Reaction Time/genetics , Reference Values
17.
Brain Res ; 1131(1): 155-62, 2007 Feb 02.
Article in English | MEDLINE | ID: mdl-17156756

ABSTRACT

Converging evidence suggests a modulatory role of dopamine in cognitive control. We investigated the influence of two correlates of dopaminergic activity, the spontaneous eyeblink rate and the DRD4 exon III polymorphism, and the potential impact of gender on flexibility in an attentional set-shifting paradigm. The objective of the study was to confirm previous findings of an association between high eyeblink rates and increased cognitive flexibility. These findings were replicated in 87 healthy volunteers this time using a continuous variable for eyeblink rates instead of a dichotomized variable. The interaction between eyeblink rate and DRD4 found in the previous study was lower and failed significance. Analysis of the collapsed sample of n=150 revealed a main effect of gender and an interaction of gender and eyeblink rate on cognitive control. The complete prediction model explained 26% of the total variance. These data suggest that (1) the eyeblink rate is a reliable predictor of dopamine-mediated flexibility of cognitive control and (2) it is useful to include gender as predictor in future studies of dopaminergic modulation of cognitive control.


Subject(s)
Blinking/genetics , Brain Chemistry/genetics , Cognition/physiology , Dopamine/metabolism , Receptors, Dopamine D4/genetics , Sex Characteristics , Adolescent , Adult , Attention/physiology , Brain/metabolism , Female , Humans , Male , Neuropsychological Tests , Polymorphism, Genetic , Synaptic Transmission/genetics
18.
J Intellect Disabil Res ; 49(Pt 9): 647-56, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16108982

ABSTRACT

BACKGROUND: Dopamine, a neurotransmitter involved in motor and cognitive functioning, can be non-invasively measured via observation of spontaneous blink rates. Blink rates have been studied in a number of clinical conditions including schizophrenia, autism, Parkinsons, and attention deficit/hyperactivity disorder with results implicating either hyper or hypo dopaminergic states. METHODS: This study examined spontaneous blink rate in boys with fragile X syndrome (FXS). Blink rates of boys (4-8 years old) with FXS (n = 6) were compared with those of age-matched typically developing boys (n = 6) during active and passive tasks. Blink rates (blinks per minute) for each task were compared between the two groups. Then, the relation between blink measures and core FXS-related features [problem behaviours, arousal, fmr 1 protein (FMRP)] were examined within the group of boys with FXS. RESULTS: Blink rate in boys with FXS was significantly higher than typically developing boys during passive tasks. Within the FXS group, there were significant correlations between blink rate and problem behaviours and physiological arousal (i.e. heart activity) but not with FMRP. CONCLUSIONS: Observed differences in spontaneous blink rate between boys with and without FXS and the relation between blink rate and physiological and behavioural measures in boys with FXS suggests that further work examining dopamine dysfunction as a factor in the pathophysiology of FXS may be warranted.


Subject(s)
Blinking/genetics , Dopamine/physiology , Fragile X Syndrome/genetics , Arousal/physiology , Attention/physiology , Blinking/physiology , Child , Child Behavior Disorders/genetics , Child Behavior Disorders/physiopathology , Fragile X Mental Retardation Protein/genetics , Fragile X Syndrome/physiopathology , Humans , Male , Phenotype , Reference Values , Statistics as Topic
19.
Neuropsychology ; 19(4): 437-45, 2005 Jul.
Article in English | MEDLINE | ID: mdl-16060818

ABSTRACT

Patients with Alzheimer's disease (AD) demonstrate slowed acquisition of the conditioned response (CR) in eyeblink classical conditioning paradigms (EBCC), although it is unknown how early in the course of the disease CR acquisition is affected. This study investigated whether changes in the rate of CR acquisition were apparent in nondemented older adults at greater genetic risk for developing AD (i.e., carriers of the apolipoprotein E [APOE] epsilon 4 allele). Both epsilon 4+ and epsilon 4- participants demonstrated CR acquisition to auditory and olfactory CSs; however, rate of acquisition to the olfactory CS was significantly slower in epsilon 4+ persons. Both groups acquired the CR to an auditory CS at the same rate. Results support olfactory compromise in the earliest stages of the AD disease process. ((c) 2005 APA, all rights reserved).


Subject(s)
Alzheimer Disease/physiopathology , Apolipoproteins E/genetics , Blinking/physiology , Conditioning, Classical/physiology , Acoustic Stimulation/methods , Aged , Alzheimer Disease/genetics , Analysis of Variance , Apolipoprotein E4 , Blinking/genetics , Female , Humans , Male , Odorants , Olfactory Pathways/physiopathology , Reaction Time/physiology , Sensory Thresholds/physiology
20.
Neurosci Lett ; 364(1): 43-7, 2004 Jun 24.
Article in English | MEDLINE | ID: mdl-15193753

ABSTRACT

It has been proposed that the N-methyl-d-aspartate (NMDA)-type glutamate receptor (GluR) plays an important role in synaptic plasticity, learning, and memory. The four GluRepsilon (NR2) subunits, which constitute NMDA receptors with a GluRzeta (NR1) subunit, differ both in their expression patterns in the brain and in their functional properties. In order to specify the distinct participation of each of these subunits, we focused on the GluRepsilon2 subunits, which are expressed mainly in the forebrain. We investigated delay and trace eyeblink conditioning in GluRepsilon2 heterozygous mutant mice whose content of GluRepsilon2 protein was decreased to about half of that in wild-type mice. GluRepsilon2 mutant mice exhibited severe impairment of the attained level of conditioned response (CR) in the delay paradigm, for which the cerebellum is essential and modulation by the forebrain has been suggested. Moreover, GluRepsilon2 mutant mice showed no trend toward CR acquisition in the trace paradigm with a trace interval of 500 ms, in which the forebrain is critically involved in successful learning. On the other hand, the reduction of GluRepsilon2 proteins did not disturb any basic sensory and motor functions which might have explained the observed impairment. These results are different from those obtained with GluRepsilon1 null mutant mice, which attain a normal level of the CR but at a slower rate in the delay paradigm, and showed a severe impairment in the trace paradigm. Therefore, the NMDA receptor GluRepsilon2 plays a more critical role than the GluRepsilon1 subunit in classical eyeblink conditioning.


Subject(s)
Blinking/physiology , Conditioning, Psychological/physiology , Learning Disabilities/physiopathology , Receptors, N-Methyl-D-Aspartate/physiology , Analysis of Variance , Animals , Behavior, Animal , Blinking/genetics , Female , Learning Disabilities/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Motor Activity/genetics , Motor Activity/physiology , Psychomotor Performance/physiology , Reaction Time/genetics , Reaction Time/physiology , Receptors, N-Methyl-D-Aspartate/genetics
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