ABSTRACT
AIM: To investigate the influence of apolipoprotein E (APOE) genotype on cortical activity, using the event-related potential P300 in healthy older adults and individuals with Alzheimer's disease (AD). METHODS: A cohort of 37 healthy older adults and 48 with AD participated in this study and completed an auditory oddball task using electroencephalographic equipment with 21 channels (10-20 system). APOE genotyping was obtained by real-time PCR. RESULTS: AD presented increased P300 latency and lower P300 amplitude, compared to healthy older adults. AD APOE ε4 carriers presented increased P300 latency in F3 (420.7 ± 65.8 ms), F4 (412.0 ± 49.0 ms), C4 (413.0 ± 41.1 ms) and P3 (420.4 ± 55.7 ms) compared to non-carriers (F3 = 382.5 ± 56.8 ms, p < 0.01; F4 = 372.2 ± 56.7 ms, p < 0.01; C4 = 374.2 ± 51.7 ms, p < 0.01; P3 = 384.4 ± 44.4 ms, p < 0.01). Healthy older adults APOE ε4 carriers presented lower Fz amplitude (2.6 ± 1.5 µV) compared to non-carriers (4.9 ± 2.9 µV; p = 0.02). Linear regression analysis showed that being a carrier of APOE ε4 allele remained significantly associated with P300 latency even after adjusting for sex, age, and cognitive grouping. APOE ε4 allele increases P300 latency (95% CI 0.11-0.98; p = 0.02). CONCLUSION: APOE ε4 allele negatively impacts cortical activity in both healthy older adults and AD individuals.
Subject(s)
Alzheimer Disease/genetics , Apolipoprotein E4/genetics , Evoked Potentials/genetics , Healthy Aging/genetics , Aged , Alleles , Apolipoproteins E/genetics , Case-Control Studies , Cognition , Cross-Sectional Studies , Electroencephalography , Female , Genotype , Humans , Male , Middle AgedABSTRACT
The cell-cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.
Subject(s)
Attention Deficit Disorder with Hyperactivity/genetics , Cadherins/genetics , Memory, Short-Term/physiology , Adult , Attention Deficit Disorder with Hyperactivity/physiopathology , Attention Deficit Disorder with Hyperactivity/psychology , Brain/physiopathology , Case-Control Studies , Electroencephalography , Evoked Potentials/genetics , Executive Function/physiology , Female , Humans , Male , Personality , Polymorphism, Single NucleotideABSTRACT
Zebrafish are an excellent model organism to study many aspects of vertebrate sensory encoding and behavior. Their escape responses begin with a C-shaped body bend followed by several swimming bouts away from the potentially threatening stimulus. This highly stereotyped motor behavior provides a model for studying startle reflexes and the neural circuitry underlying multisensory encoding and locomotion. Channelrhodopsin (ChR2) can be expressed in the lateral line and ear hair cells of zebrafish and can be excited in vivo to elicit these rapid forms of escape. Here we review our methods for studying transgenic ChR2-expressing zebrafish larvae, including screening for positive expression of ChR2 and recording field potentials and high-speed videos of optically evoked escape responses. We also highlight important features of the acquired data and provide a brief review of other zebrafish research that utilizes or has the potential to benefit from ChR2 and optogenetics.
Subject(s)
Channelrhodopsins/genetics , Evoked Potentials/genetics , Neurons/metabolism , Optogenetics/methods , Animals , Animals, Genetically Modified/genetics , Channelrhodopsins/physiology , Evoked Potentials/physiology , Hair Cells, Auditory/metabolism , Larva/physiology , Locomotion/genetics , Locomotion/physiology , Neurons/pathology , Reflex, Startle/physiology , Swimming/physiology , Zebrafish/genetics , Zebrafish/physiologyABSTRACT
Slow maturation of visual pathways transmitting low spatial frequency (LSF) information may contribute to inaccurate facial emotion recognition in adolescence. We recorded ERPs from adolescents and adults to upright and inverted happy faces, fearful faces, and chairs, which were unfiltered, contained only LSFs, or only high spatial frequencies. P100s and N170s were larger for adolescents than adults, with the greatest effect size for LSF stimuli. For LSFs only, adolescents showed a larger N170 inversion effect for happy than for fearful faces, but adults showed the opposite response. Thus, immaturities in LSF pathways appear to impact facial expression processing in adolescents.
Subject(s)
Evoked Potentials/genetics , Facial Recognition/physiology , Orientation, Spatial/physiology , Adolescent , Adult , Child , Female , Humans , Male , Young AdultABSTRACT
Each vestibular sensory epithelium in the inner ear is divided morphologically and physiologically into two zones, called the striola and extrastriola in otolith organ maculae, and the central and peripheral zones in semicircular canal cristae. We found that formation of striolar/central zones during embryogenesis requires Cytochrome P450 26b1 (Cyp26b1)-mediated degradation of retinoic acid (RA). In Cyp26b1 conditional knockout mice, formation of striolar/central zones is compromised, such that they resemble extrastriolar/peripheral zones in multiple features. Mutants have deficient vestibular evoked potential (VsEP) responses to jerk stimuli, head tremor and deficits in balance beam tests that are consistent with abnormal vestibular input, but normal vestibulo-ocular reflexes and apparently normal motor performance during swimming. Thus, degradation of RA during embryogenesis is required for formation of highly specialized regions of the vestibular sensory epithelia with specific functions in detecting head motions.
Subject(s)
Otolithic Membrane/embryology , Retinoic Acid 4-Hydroxylase/metabolism , Tretinoin/metabolism , Animals , Evoked Potentials/genetics , Evoked Potentials/physiology , Female , Gene Expression Regulation, Developmental , Head/physiopathology , Mice, Inbred C57BL , Mice, Knockout , Osteopontin/metabolism , Otolithic Membrane/cytology , Otolithic Membrane/metabolism , Retinal Dehydrogenase/genetics , Retinal Dehydrogenase/metabolism , Retinoic Acid 4-Hydroxylase/genetics , Saccule and Utricle/cytology , Saccule and Utricle/embryology , Tremor/genetics , Tremor/physiopathology , Vestibular Function Tests , Vestibule, Labyrinth/embryology , Vestibule, Labyrinth/metabolismABSTRACT
The own name is a salient stimulus, used by others to initiate social interaction. Typically developing infants orient towards the sound of their own name and exhibit enhanced event-related potentials (ERP) at 5 months. The lack of orientation to the own name is considered to be one of the earliest signs of autism spectrum disorder (ASD). In this study, we investigated ERPs to hearing the own name in infants at high and low risk for ASD, at 10 and 14 months. We hypothesized that low-risk infants would exhibit enhanced frontal ERP responses to their own name compared to an unfamiliar name, while high-risk infants were expected to show attenuation or absence of this difference in their ERP responses. In contrast to expectations, we did not find enhanced ERPs to own name in the low-risk group. However, the high-risk group exhibited attenuated frontal positive-going activity to their own name compared to an unfamiliar name and compared to the low-risk group, at the age of 14 months. These results suggest that infants at high risk for ASD start to process their own name differently shortly after one year of age, a period when frontal brain development is happening at a fast rate.
Subject(s)
Autism Spectrum Disorder/complications , Child Development/physiology , Evoked Potentials/genetics , Hearing/genetics , Social Change , Autism Spectrum Disorder/pathology , Child, Preschool , Female , Humans , Infant , Male , NamesABSTRACT
KCC2 regulates neuronal transmembrane chloride gradients and thereby controls GABA signaling in the brain. KCC2 downregulation is observed in numerous neurological and psychiatric disorders. Paradoxical, excitatory GABA signaling is usually assumed to contribute to abnormal network activity underlying the pathology. We tested this hypothesis and explored the functional impact of chronic KCC2 downregulation in the rat dentate gyrus. Although the reversal potential of GABAA receptor currents is depolarized in KCC2 knockdown neurons, this shift is compensated by depolarization of the resting membrane potential. This reflects downregulation of leak potassium currents. We show KCC2 interacts with Task-3 (KCNK9) channels and is required for their membrane expression. Increased neuronal excitability upon KCC2 suppression altered dentate gyrus rhythmogenesis, which could be normalized by chemogenetic hyperpolarization. Our data reveal KCC2 downregulation engages complex synaptic and cellular alterations beyond GABA signaling that perturb network activity thus offering additional targets for therapeutic intervention.
Subject(s)
Dentate Gyrus/metabolism , Neurons/metabolism , Potassium Channels, Tandem Pore Domain/metabolism , Potassium Channels/metabolism , Seizures/metabolism , Symporters/metabolism , Animals , Dentate Gyrus/drug effects , Evoked Potentials/genetics , Evoked Potentials/physiology , GABA Antagonists/pharmacology , Gene Knockdown Techniques , HEK293 Cells , Humans , Male , Membrane Potentials/genetics , Membrane Potentials/physiology , Potassium Channels/drug effects , Rats , Rats, Wistar , Seizures/chemically induced , Seizures/genetics , Symporters/genetics , gamma-Aminobutyric Acid/metabolism , K Cl- CotransportersABSTRACT
Williams-Beuren syndrome (WBS) is a microdeletion disorder with cognitive phenotype. NSUN5 gene, which encodes a cytosine-5 RNA methyltransferase, is located in WBS deletion locus. To investigate the influence of NSUN5 deletion on cognitive behaviors, we produced single-gene Nsun5 knockout (Nsun5-KO) mice. Here, we report that adult Nsun5-KO mice showed spatial cognitive deficits. Size of the brain and hippocampal structures and the number of CA1 or CA3 pyramidal cells in Nsun5-KO mice did not differ from WT mice. Basal properties of Schaffer collateral-CA1 synaptic transmission in Nsun5-KO mice were unchanged, but NMDA receptor (NMDAr)-dependent long-term potentiation (LTP) was not induced. The NMDA-evoked current in CA1 pyramidal cells was reduced in Nsun5-KO mice without the changes in expression and phosphorylation of NMDAr subunits NR2A and NR2B. Although the protein level of AMPA receptor subunit GluR2 was attenuated in Nsun5-KO mice, the AMPA-evoked current was not altered. Hippocampal immuno-staining showed the selective expression of Nsun5 in NG2 or PDGFRα labeled oligodendrocyte precursor cells (OPCs), but not in pyramidal cells or astrocytes. Analysis of RT-PCR determined the Nsun5 expression in purified populations of OPCs rather than neurons or astrocytes. The Nsun5 deficiency led to decreases in the number and neurite outgrowth of OPCs in the hippocampal CA1 and DG, with the decline in NG2 expression and OPCs proliferation. These findings indicate that the Nsun5 deletion suppresses NMDAr activity in neuronal cells probably through the disrupted development and function of OPCs, leading to deficits in NMDAr-dependent LTP and spatial cognitive abilities.
Subject(s)
Cognition Disorders/genetics , Cognition Disorders/pathology , DNA (Cytosine-5-)-Methyltransferases/deficiency , Oligodendrocyte Precursor Cells/pathology , Action Potentials/drug effects , Action Potentials/genetics , Animals , Brain/cytology , Brain/physiology , Cells, Cultured , DNA (Cytosine-5-)-Methyltransferases/genetics , Disease Models, Animal , Eating/genetics , Energy Metabolism/genetics , Evoked Potentials/drug effects , Evoked Potentials/genetics , Exploratory Behavior , Female , Male , Maze Learning/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Nerve Tissue Proteins/metabolism , Neurotransmitter Agents/pharmacologyABSTRACT
The partners of each pair must be able to pass the McGill Friendship Questionnaire without communicating. Each partner is then seated in front of a screen in one of two adjacent rooms. These rooms are separated by a glass window through which participants communicate to maintain feelings of togetherness while being fitted with the EEG cap. After checking for adequate EEG signals, the glass is covered by a curtain to prevent visual communication. Then, partners must be silent but are instructed to try to feel in the presence of their partner during the entire experiment. Just before it starts, participants are told that each of them will be presented with one image at a time and that these images will occur at the same time for both of them on their own screen. They are also instructed that, for each trial, the simultaneous images will always be different. However, unbeknownst to them, trials are randomized: only half of them are consistent with this instruction and actually include two different images. These trials form the DSC, that is, the different-stimuli condition. The other half of the trials are inconsistent with the instruction. They include two identical images and form the ISC (identical-stimuli condition). After the experiment, participants are sorted into two groups: those who reported that they felt in the presence of their partner during the majority of the trials and those who reported they did not. The impact of the stimulus processing of the partner is found by subtracting the mean voltages of the ERPs of the ISC (inconsistent with the instructions) from the ERPs of the DSC (consistent with the instructions) in at least two time windows (TWs): firstly, in the 75 to 150 ms TW, where the absolute values of these subtractions are greater, especially at right frontal sites, in those who felt in the presence of their partner than in those who did not; secondly, in the LPP time window (i.e., from 650 to 950 ms post onset), where ERPs are significantly less positive in the DSC than in the ISC in those in whom the raw results of the early (75-150ms) subtractions are negative.
Subject(s)
Brain/physiopathology , Electroencephalography/methods , Evoked Potentials/genetics , Photic Stimulation/methods , Adult , Female , Humans , Male , Young AdultABSTRACT
Mature granule cells are poorly excitable neurons that were recently shown to fire action potentials, preferentially in bursts. It is believed that the particularly pronounced short-term facilitation of mossy fiber synapses makes granule cell bursting a very effective means of properly transferring information to CA3. However, the mechanism underlying the unique bursting behavior of mature granule cells is currently unknown. Here, we show that Cav3.2 T-type channels at the axon initial segment are responsible for burst firing of mature granule cells in rats and mice. Accordingly, Cav3.2 knockout mice fire tonic spikes and exhibit impaired bursting, synaptic plasticity and dentate-to-CA3 communication. The data show that Cav3.2 channels are strong modulators of bursting and can be considered a critical molecular switch that enables effective information transfer from mature granule cells to the CA3 pyramids.
Subject(s)
Action Potentials/genetics , Calcium Channels, T-Type/deficiency , Dentate Gyrus/cytology , Neurons/physiology , Animals , Biophysics , Calcium Channel Blockers/pharmacology , Calcium Channels, T-Type/genetics , Electric Stimulation , Evoked Potentials/drug effects , Evoked Potentials/genetics , In Vitro Techniques , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neurotransmitter Agents/pharmacology , Patch-Clamp Techniques , Perforant Pathway/physiology , Rats , Rats, Wistar , Synaptic Potentials/drug effects , Synaptic Potentials/geneticsABSTRACT
Diabetes mellitus is associated with sensory abnormalities, including exacerbated responses to painful (hyperalgesia) or non-painful (allodynia) stimuli. These abnormalities are symptoms of diabetic peripheral neuropathy (DPN), which is the most common complication that affects approximately 50% of diabetic patients. Yet, the underlying mechanisms linking hyperglycemia and symptoms of DPN remain poorly understood. The transient receptor potential vanilloid 1 (TRPV1) channel plays a central role in such sensory abnormalities and shows elevated expression levels in animal models of diabetes. Here, we investigated the function of TRPV1 channels in sensory neurons cultured from the dorsal root ganglion (DRG) of neonatal mice, under control (5mM) and high glucose (25mM) conditions. After maintaining DRG neurons in high glucose for 1 week, we observed a significant increase in capsaicin (CAP)-evoked currents and CAP-evoked depolarizations, independent of TRPV1 channel expression. These functional changes were largely dependent on the expression of the receptor for Advanced Glycation End-products (RAGE), calcium influx, cytoplasmic ROS accumulation, PKC, and Src kinase activity. Like cultured neurons from neonates, mature neurons from adult mice also displayed a similar potentiation of CAP-evoked currents in the high glucose condition. Taken together, our data demonstrate that under the diabetic condition, DRG neurons are directly affected by elevated levels of glucose, independent of vascular or glial signals, and dependent on RAGE expression. These early cellular and molecular changes to sensory neurons in vitro are potential mechanisms that might contribute to sensory abnormalities that can occur in the very early stages of diabetes.
Subject(s)
Diabetic Neuropathies/metabolism , Ganglia, Spinal/metabolism , Glucose/pharmacology , Long-Term Potentiation/drug effects , Receptor for Advanced Glycation End Products/metabolism , Sensory Receptor Cells/metabolism , TRPV Cation Channels/metabolism , Animals , Calcium Signaling/drug effects , Calcium Signaling/genetics , Capsaicin/pharmacology , Diabetic Neuropathies/genetics , Diabetic Neuropathies/pathology , Diabetic Neuropathies/physiopathology , Evoked Potentials/drug effects , Evoked Potentials/genetics , Ganglia, Spinal/pathology , Ganglia, Spinal/physiopathology , Glucose/metabolism , Humans , Long-Term Potentiation/genetics , Mice , Mice, Knockout , Reactive Oxygen Species/metabolism , Receptor for Advanced Glycation End Products/genetics , Sensory Receptor Cells/pathology , TRPV Cation Channels/geneticsABSTRACT
Mutations in the HGPRT1 gene, which encodes hypoxanthine-guanine phosphoribosyltransferase (HGprt), housekeeping enzyme responsible for recycling purines, lead to Lesch-Nyhan disease (LND). Clinical expression of LND indicates that HGprt deficiency has adverse effects on gastrointestinal motility. Therefore, we aimed to evaluate intestinal motility in HGprt knockout mice (HGprt¯). Spontaneous and neurally evoked mechanical activity was recorded in vitro as changes in isometric tension in circular muscle strips of distal colon. HGprt¯ tissues showed a lower in amplitude spontaneous activity and atropine-sensitivity neural contraction compared to control mice. The responses to carbachol and to high KCl were reduced, demonstrating a widespread impairment of contractility. L-NAME was not able in the HGprt¯ tissues to restore the large amplitude contractile activity typical of control. In HGprt¯ colon, a reduced expression of dopaminergic D1 receptor was observed together with the loss of its tonic inhibitory activity present in control-mice. The analysis of inflammatory and oxidative stress in colonic tissue of HGprt¯ mice revealed a significant increase of lipid peroxidation associated with over production of oxygen free radicals. In conclusion, HGprt deficiency in mice is associated with a decrease in colon contractility, not dependent upon reduction of acetylcholine release from the myenteric plexus or hyperactivity of inhibitory signalling. By contrast the increased levels of oxidative stress could partially explain the reduced colon motility in HGprt¯ mice. Colonic dysmotility observed in HGprt¯ mice may mimic the gastrointestinal dysfunctions symptoms of human syndrome, providing a useful animal model to elucidate the pathophysiology of this problem in the LND.
Subject(s)
Gastrointestinal Motility/genetics , Gene Expression Regulation/genetics , Lesch-Nyhan Syndrome/complications , Muscle, Smooth/physiopathology , Animals , Atropine/pharmacology , Benzazepines/pharmacology , Brain/drug effects , Brain/metabolism , Carbachol/pharmacology , Cytokines/metabolism , Disease Models, Animal , Dopamine/metabolism , Enzyme Inhibitors/pharmacology , Evoked Potentials/drug effects , Evoked Potentials/genetics , Face , Gastrointestinal Motility/drug effects , Gene Expression Regulation/drug effects , Hypoxanthine Phosphoribosyltransferase/deficiency , Hypoxanthine Phosphoribosyltransferase/metabolism , In Vitro Techniques , Lesch-Nyhan Syndrome/genetics , Lesch-Nyhan Syndrome/pathology , Lesch-Nyhan Syndrome/physiopathology , Lipid Peroxidation/drug effects , Lipid Peroxidation/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Muscle, Smooth/drug effects , NG-Nitroarginine Methyl Ester/pharmacology , Neurotransmitter Agents/pharmacology , Reactive Oxygen Species/metabolism , Tyrosine 3-Monooxygenase/genetics , Tyrosine 3-Monooxygenase/metabolismABSTRACT
Brain-derived neurotrophic factor (BDNF) heterozygous knockout mice (BDNF+/- mice) show fear learning deficits from 3 months of age onwards. Here, we addressed the question how this learning deficit correlates with altered long-term potentiation (LTP) in the cortical synaptic input to the lateral amygdala (LA) and at downstream intra-amygdala synapses in BDNF+/- mice. Our results reveal that the fear learning deficit in BDNF+/- mice was not paralleled by a loss of LTP, neither at cortical inputs to the LA nor at downstream intra-amygdala glutamatergic synapses. As we did observe early fear memory (30 min after training) in BDNF+/- mice while long-term memory (24 h post-training) was absent, the stable LTP in cortico-LA and downstream synapses is in line with the intact acquisition of fear memories. Ex vivo recordings in acute slices of fear-conditioned wildtype (WT) mice revealed that fear learning induces long-lasting changes at cortico-LA synapses that occluded generation of LTP 4 and 24 h after training. Overall, our data show that the intact LTP in the tested amygdala circuits is consistent with intact acquisition of fear memories in both WT and BDNF+/- mice. In addition, the lack of learning-induced long-term changes at cortico-LA synapses in BDNF+/- mice parallels the observed deficit in fear memory consolidation.
Subject(s)
Amygdala/cytology , Brain-Derived Neurotrophic Factor/deficiency , Fear/physiology , Glutamic Acid/metabolism , Learning/physiology , Long-Term Potentiation/genetics , Animals , Brain-Derived Neurotrophic Factor/genetics , Carbazoles/pharmacology , Cerebral Cortex/physiology , Electric Stimulation , Enzyme Inhibitors/pharmacology , Evoked Potentials/genetics , GABA Antagonists/pharmacology , Indole Alkaloids/pharmacology , Long-Term Potentiation/drug effects , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neurons/cytology , Neurons/drug effects , Patch-Clamp Techniques , Pyridazines/pharmacologyABSTRACT
Neuroligin-4 (Nlgn4) is a cell adhesion protein that regulates synapse organization and function. Mutations in human NLGN4 are among the causes of autism spectrum disorders. In mouse, Nlgn4 knockout (KO) perturbs GABAergic synaptic transmission and oscillatory activity in hippocampus, and causes social interaction deficits. The complex profile of cellular and circuit changes that are caused by Nlgn4-KO is still only partly understood. Using Nlgn4-KO mice, we found that Nlgn4-KO increases the power in the alpha frequency band of spontaneous network activity in the barrel cortex under urethane anesthesia in vivo. Nlgn4-KO did not affect single-whisker-induced local field potentials, but suppressed the late evoked multiunit activity in vivo. Although Nlgn4-KO did not affect evoked EPSCs in layer 4 (L4) spiny stellate cells in acute thalamocortical slices elicited by electrical stimulation of thalamocortical inputs, it caused a lower frequency of both miniature (m) IPSCs and mEPSCs, and a decrease in the number of readily releasable vesicles at GABAergic and glutamatergic connections, weakening both excitatory and inhibitory transmission. However, Nlgn4 deficit strongly suppresses glutamatergic activity, shifting the excitation-inhibition balance to inhibition. We conclude that Nlgn4-KO does not influence the incoming whisker-mediated sensory information to the barrel cortex, but modifies intracortical information processing.
Subject(s)
Cell Adhesion Molecules, Neuronal/deficiency , Evoked Potentials/genetics , Neocortex/pathology , Nerve Net/physiopathology , Neurons/physiology , Afferent Pathways/pathology , Afferent Pathways/physiopathology , Animals , Animals, Newborn , Cell Adhesion Molecules, Neuronal/genetics , Electric Stimulation , Evoked Potentials/drug effects , In Vitro Techniques , Mice , Mice, Knockout , Neocortex/growth & development , Nerve Net/drug effects , Nerve Net/pathology , Neurons/drug effects , Neurotransmitter Agents/pharmacology , Vibrissae/innervation , Voltage-Sensitive Dye ImagingABSTRACT
Background: Failure of procognitive drug trials in schizophrenia may reflect the clinical heterogeneity of schizophrenia, underscoring the need to identify biomarkers of treatment sensitivity. We used an experimental medicine design to test the procognitive effects of a putative procognitive agent, tolcapone, using an electroencephalogram-based cognitive control task in healthy subjects. Methods: Healthy men and women (n=27; ages 18-35 years), homozygous for either the Met/Met or Val/Val rs4680 genotype, received placebo and tolcapone 200 mg orally across 2 test days separated by 1 week in a double-blind, randomized, counterbalanced, within-subject design. On each test day, neurocognitive performance was assessed using the MATRICS Consensus Cognitive Battery and an electroencephalogram-based 5 Choice-Continuous Performance Test. Results: Tolcapone enhanced visual learning in low-baseline MATRICS Consensus Cognitive Battery performers (d=0.35) and had an opposite effect in high performers (d=0.5), and enhanced verbal fluency across all subjects (P=.03) but had no effect on overall MATRICS Consensus Cognitive Battery performance. Tolcapone reduced false alarm rate (d=0.8) and enhanced frontal P200 amplitude during correctly identified nontarget trials (d=0.6) in low-baseline 5 Choice-Continuous Performance Test performers and had opposite effects in high performers (d=0.5 and d=0.25, respectively). Tolcapone's effect on frontal P200 amplitude and false alarm rate was correlated (rs=-0.4, P=.05). All neurocognitive effects of tolcapone were independent of rs4680 genotype. Conclusion: Tolcapone enhanced neurocognition and engaged electroencephalogram measures relevant to cognitive processes in specific subgroups of healthy individuals. These findings support an experimental medicine model for identifying procognitive treatments and provide a strong basis for future biomarker-informed procognitive studies in schizophrenia patients.
Subject(s)
Benzophenones/pharmacology , Brain Mapping , Brain/drug effects , Catechol O-Methyltransferase Inhibitors/pharmacology , Cognition/drug effects , Evoked Potentials/drug effects , Nitrophenols/pharmacology , Adolescent , Adult , Brain/physiology , Catechol O-Methyltransferase/genetics , Choice Behavior/drug effects , Cross-Over Studies , Double-Blind Method , Evoked Potentials/genetics , Female , Genotype , Healthy Volunteers , Humans , Learning/drug effects , Male , Neuropsychological Tests , Photic Stimulation , Tolcapone , Young AdultABSTRACT
The mammalian main olfactory epithelium (MOE) modifies its activities in response to changes in the chemical environment. This process is essential for maintaining the functions of the olfactory system and the upper airway. However, mechanisms involved in this functional maintenance, especially those occurring via paracrine regulatory pathways within the multicellular MOE, are poorly understood. Previously, a population of non-neuronal, transient receptor potential M5-expressing microvillous cells (TRPM5-MCs) was identified in the MOE, and the initial characterization of these cells showed that they are cholinergic and responsive to various xenobiotics including odorants at high concentrations. Here, we investigated the role of TRPM5-MCs in maintaining olfactory function using transcription factor Skn-1a knockout (Skn-1a-/-) mice, which lack TRPM5-MCs in the MOE. Under our standard housing conditions, Skn-1a-/- mice do not differ significantly from control mice in odor-evoked electro-olfactogram (EOG) responses and olfactory-guided behaviors, including finding buried food and preference reactions to socially and sexually relevant odors. However, after a 2-wk exposure to high-concentration odor chemicals and chitin powder, Skn-1a-/- mice exhibited a significant reduction in their odor and pheromone-evoked EOG responses. Consequently, their olfactory-guided behaviors were impaired compared with vehicle-exposed Skn-1a-/- mice. Conversely, the chemical exposure did not induce significant changes in the EOG responses and olfactory behaviors of control mice. Therefore, our physiological and behavioral results indicate that TRPM5-MCs play a protective role in maintaining the olfactory function of the MOE.
Subject(s)
Gene Expression Regulation/genetics , Olfactory Mucosa/cytology , Olfactory Receptor Neurons/metabolism , Smell/physiology , TRPM Cation Channels/deficiency , Animals , Choice Behavior/physiology , Evoked Potentials/genetics , Feeding Behavior , Female , GAP-43 Protein/metabolism , Gene Expression Regulation/drug effects , Male , Maze Learning/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Octamer Transcription Factors/genetics , Octamer Transcription Factors/metabolism , Odorants , Olfactory Marker Protein/metabolism , Olfactory Receptor Neurons/physiology , Stimulation, Chemical , TRPM Cation Channels/geneticsABSTRACT
Previous research on the association between intra-subject variability (ISV) in reaction times (RTs) and the Val158Met polymorphism of the catechol-o-methyltransferase gene (COMT; rs4680) has yielded mixed results. The present study compared the associations between COMT genotype and ISV in P3b latency measured during working and secondary memory tasks using residue iteration decomposition (RIDE) of single trial latencies. We compared the outcome of the present analyses with a previous analysis of the same data (N=70, n-back tasks) using an alternative single-trial method. Additionally, we used RIDE to analyse the association between COMT genotype and ISV in an independent sample performing a different task (N=91, face-recognition task). Analyses reconfirmed previous results from the n-back tasks, showing that Val alleles are associated with lower ISV. In the face recognition tasks, genotype interacted with task conditions, so Val homozygotes had higher ISV to unfamiliar faces than familiar ones but Met carriers showed no effect of familiarity. Moreover, in both datasets trial-by-trial RTs were predicted by P3b latencies. Therefore, the present data suggests that associations between COMT genotype and ISV depend on the type of cognitive processes, which may explain heterogeneity in previous results.
Subject(s)
Catechol O-Methyltransferase/genetics , Cognition/physiology , Evoked Potentials/genetics , Genotype , Memory/physiology , Adult , Alleles , Facial Recognition/physiology , Female , Humans , Male , Polymorphism, Single Nucleotide , Reaction Time/genetics , Young AdultABSTRACT
Chronic pain and hyperalgesia, as well as pain resulting from episodes of vaso-occlusion, are characteristic features of sickle cell disease (SCD) and are difficult to treat. Since there is growing evidence that increasing local levels of endocannabinoids can decrease hyperalgesia, we examined the effects of URB597, a fatty acid amide hydrolase (FAAH) inhibitor, which blocks the hydrolysis of the endogenous cannabinoid anandamide, on hyperalgesia and sensitization of cutaneous nociceptors in a humanized mouse model of SCD. Using homozygous HbSS-BERK sickle mice, we determined the effects of URB597 on mechanical hyperalgesia and on sensitization of C-fiber nociceptors in vivo. Intraplantar administration of URB597 (10 µg in 10 µL) decreased the frequency of withdrawal responses evoked by a von Frey monofilament (3.9 mN bending force) applied to the plantar hind paw. This was blocked by the CB1 receptor antagonist AM281 but not by the CB2 receptor antagonist AM630. Also, URB597 decreased hyperalgesia in HbSS-BERK/CB2R sickle mice, further confirming the role of CB1 receptors in the effects produced by URB597. Electrophysiological recordings were made from primary afferent fibers of the tibial nerve in anesthetized mice. The proportion of Aδ- and C-fiber nociceptors that exhibited spontaneous activity and responses of C-fibers to mechanical and thermal stimuli were greater in HbSS-BERK sickle mice as compared to control HbAA-BERK mice. Spontaneous activity and evoked responses of nociceptors were decreased by URB597 via CB1 receptors. It is suggested that enhanced endocannabinoid activity in the periphery may be beneficial in alleviating chronic pain associated with SCD.
Subject(s)
Anemia, Sickle Cell/pathology , Arachidonic Acids/metabolism , Endocannabinoids/metabolism , Hydrolysis/drug effects , Nerve Fibers, Unmyelinated/metabolism , Nociceptors/metabolism , Polyunsaturated Alkamides/metabolism , Anemia, Sickle Cell/genetics , Anemia, Sickle Cell/metabolism , Animals , Benzamides/therapeutic use , Carbamates/therapeutic use , Disease Models, Animal , Enzyme Inhibitors/therapeutic use , Evoked Potentials/drug effects , Evoked Potentials/genetics , Hemoglobins/genetics , Hemoglobins/metabolism , Humans , Hyperalgesia/drug therapy , Hyperalgesia/physiopathology , Indoles/therapeutic use , Male , Mice , Mice, Transgenic , Morpholines/therapeutic use , Nerve Fibers, Unmyelinated/drug effects , Nerve Fibers, Unmyelinated/pathology , Nociceptors/drug effects , Pain Threshold/drug effects , Pain Threshold/physiology , Pyrazoles/therapeutic use , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Receptor, Cannabinoid, CB2/antagonists & inhibitors , Receptor, Cannabinoid, CB2/genetics , Receptor, Cannabinoid, CB2/metabolismABSTRACT
Previous studies have suggested that the neurokinin-1 receptor (NK-1R) expressing neurons in the globus pallidus (GP) receive substance P (SP), presumably released by axon collaterals of striatal direct neurons. However, the effect of SP on the GP remains unclear. In this study, we identified that the SP-responsive cells comprise a highly specific cell type in the GP with regard to immunofluorescence, electrophysiology, and projection properties. Morphologically, NK-1R-immunoreactive neurons occasionally co-expressed parvalbumin (PV) and/or Lim-homeobox 6 (Lhx6), but not Forkhead box protein P2 (FoxP2), which is mainly expressed by arkypallidal neurons. Retrograde tracing experiments also showed that some of GP neurons projecting to the subthalamic nucleus (namely prototypic neurons) expressed NK-1R as well as Lhx6 and/or PV, but not FoxP2. In vitro electrophysiological study revealed that, among 48 GP neurons, the SP agonist induced inward current in 21 neurons. The response was prevented by bath application of the NK-1R antagonist. Based on the firing properties, 92 recorded GP neurons were classified into three distinct types, i.e., CL1, 2, and 3. Interestingly, all the SP-responsive neurons were found to be in CL2 and CL3 types, but not in CL1. Moreover, active and passive membrane properties of the neurons in those clusters and immunofluorescent identification suggested that CL1 and CL2/3 could be considered as arkypallidal and prototypic neurons, respectively. Therefore, SP-responsive neurons were one of the populations of prototypic neurons based on both anatomical and electrophysiological results. Altogether, the striatal direct pathway neurons could affect the indirect pathway in the way of prototypic neurons, via the action of SP to NK-1R.
Subject(s)
Globus Pallidus/cytology , Neurons/drug effects , Neurons/metabolism , Substance P/pharmacology , Action Potentials/drug effects , Age Factors , Animals , Animals, Newborn , Cholera Toxin/metabolism , Choline O-Acetyltransferase/metabolism , Evoked Potentials/drug effects , Evoked Potentials/genetics , Female , Globus Pallidus/growth & development , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , In Vitro Techniques , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Nerve Tissue Proteins/metabolism , Neurokinin-1 Receptor Antagonists/pharmacology , Neurotransmitter Agents/pharmacology , Parvalbumins/genetics , Parvalbumins/metabolism , Physical Stimulation , Receptors, Neurokinin-1/metabolismABSTRACT
The ability to inhibit prepotent but context- or goal-inappropriate responses is essential for adaptive self-regulation of behavior. Deficits in response inhibition, a key component of impulsivity, have been implicated as a core dysfunction in a range of neuropsychiatric disorders such as ADHD and addictions. Identification of genetically transmitted variation in the neural underpinnings of response inhibition can help to elucidate etiological pathways to these disorders and establish the links between genes, brain, and behavior. However, little is known about genetic influences on the neural mechanisms of response inhibition during adolescence, a developmental period characterized by weak self-regulation of behavior. Here we investigated heritability of ERPs elicited in a Go/No-Go task in a large sample of adolescent twins assessed longitudinally at ages 12, 14, and 16. Genetic analyses showed significant heritability of inhibition-related frontal N2 and P3 components at all three ages, with 50 to 60% of inter-individual variability being attributable to genetic factors. These genetic influences included both common genetic factors active at different ages and novel genetic influences emerging during development. Finally, individual differences in the rate of developmental changes from age 12 to age 16 were significantly influenced by genetic factors. In conclusion, the present study provides the first evidence for genetic influences on neural correlates of response inhibition during adolescence and suggests that ERPs elicited in the Go/No-Go task can serve as intermediate neurophysiological phenotypes (endophenotypes) for the study of disinhibition and impulse control disorders.