| 1. |
- Barlow, Rebecca L., et al.
(författare)
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Markers of Serotonergic Function in the Orbitofrontal Cortex and Dorsal Raphe Nucleus Predict Individual Variation in Spatial-Discrimination Serial Reversal Learning
- 2015
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Ingår i: Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 0893-133X .- 1740-634X. ; 40:7, s. 1619-1630
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Tidskriftsartikel (refereegranskat)abstract
- Dysfunction of the orbitofrontal cortex (OFC) impairs the ability of individuals to flexibly adapt behavior to changing stimulus-reward (S-R) contingencies. Impaired flexibility also results from interventions that alter serotonin (5-HT) and dopamine (DA) transmission in the OFC and dorsomedial striatum (DMS). However, it is unclear whether similar mechanisms underpin naturally occurring variations in behavioral flexibility. In the present study, we used a spatial-discrimination serial reversal procedure to investigate interindividual variability in behavioral flexibility in rats. We show that flexibility on this task is improved following systemic administration of the 5-HT reuptake inhibitor citalopram and by low doses of the DA reuptake inhibitor GBR12909. Rats in the upper quintile of the distribution of perseverative responses during repeated S-R reversals showed significantly reduced levels of the 5-HT metabolite, 5-hydroxy-indoleacetic acid, in the OFC. Additionally, 5-HT2A receptor binding in the OFC of mid-and high-quintile rats was significantly reduced compared with rats in the low-quintile group. These perturbations were accompanied by an increase in the expression of monoamine oxidase-A (MAO-A) and MAO-B in the lateral OFC and by a decrease in the expression of MAO-A, MAO-B, and tryptophan hydroxylase in the dorsal raphe nucleus of highly perseverative rats. We found no evidence of significant differences in markers of DA and 5-HT function in the DMS or MAO expression in the ventral tegmental area of low-vs high-perseverative rats. These findings indicate that diminished serotonergic tone in the OFC may be an endophenotype that predisposes to behavioral inflexibility and other forms of compulsive behavior.
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| 2. |
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| 3. |
- Mar, Adam C., et al.
(författare)
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MAM-E17 rat model impairments on a novel continuous performance task : effects of potential cognitive enhancing drugs
- 2017
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Ingår i: Psychopharmacology. - : SPRINGER. - 0033-3158 .- 1432-2072. ; 234:19, s. 2837-2857
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Tidskriftsartikel (refereegranskat)abstract
- Impairments in attention and inhibitory control are endophenotypic markers of neuropsychiatric disorders such as schizophrenia and represent key targets for therapeutic management. Robust preclinical models and assays sensitive to clinically relevant treatments are crucial for improving cognitive enhancement strategies. We assessed a rodent model with neural and behavioral features relevant to schizophrenia (gestational day 17 methylazoxymethanol acetate treatment (MAM-E17)) on a novel test of attention and executive function, and examined the impact of putative nootropic drugs. MAM-E17 and sham control rats were trained on a novel touchscreen-based rodent continuous performance test (rCPT) designed to closely mimic the human CPT paradigm. Performance following acute, systemic treatment with an array of pharmacological compounds was investigated. Two cohorts of MAM-E17 rats were impaired on rCPT performance including deficits in sensitivity (d') and increased false alarm rates (FARs). Sulpiride (0-30 mg/kg) dose-dependently reduced elevated FAR in MAM-E17 rats whereas low-dose modafinil (8 mg/kg) only improved d' in sham controls. ABT-594 (5.9-19.4 mu g/kg) and modafinil (64 mg/kg) showed expected stimulant-like effects, while LSN2463359 (5 mg/kg), RO493858 (10 mg/kg), atomoxetine (0.3-1 mg/kg), and sulpiride (30 mg/kg) showed expected suppressant effects on performance across all animals. Donepezil (0.1-1 mg/kg) showed near-significant enhancements in d', and EVP-6124 (0.3-3 mg/kg) exerted no effects in the rCPT paradigm. The MAM-E17 model exhibits robust and replicable impairments in rCPT performance that resemble attention and inhibitory control deficits seen in schizophrenia. Pharmacological profiles were highly consistent with known drug effects on cognition in preclinical and clinical studies. The rCPT is a sensitive and reliable tool with high translational potential for understanding the etiology and treatment of disorders affecting attention and executive dysfunction.
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| 4. |
- Nilsson, Simon R O, et al.
(författare)
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A mouse model of the 15q13.3 microdeletion syndrome shows prefrontal neurophysiological dysfunctions and attentional impairment
- 2016
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Ingår i: Psychopharmacologia. - : Springer Science and Business Media LLC. - 0033-3158. ; 233:11, s. 2151-2163
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: A microdeletion at locus 15q13.3 is associated with high incidence rates of psychopathology, including schizophrenia. A mouse model of the 15q13.3 microdeletion syndrome has been generated (Df[h15q13]/+) with translational utility for modelling schizophrenia-like pathology. Among other deficits, schizophrenia is characterised by dysfunctions in prefrontal cortical (PFC) inhibitory circuitry and attention. Objectives: The objective of this study is to assess PFC-dependent functioning in the Df(h15q13)/+ mouse using electrophysiological, pharmacological, and behavioural assays. Method: Experiments 1–2 investigated baseline firing and auditory-evoked responses of PFC interneurons and pyramidal neurons. Experiment 3 measured pyramidal firing in response to intra-PFC GABAAreceptor antagonism. Experiments 4–6 assessed PFC-dependent attentional functioning through the touchscreen 5-choice serial reaction time task (5-CSRTT). Experiments 7–12 assessed reversal learning, paired-associate learning, extinction learning, progressive ratio, trial-unique non-match to sample, and object recognition. Results: In experiments 1–3, the Df(h15q13)/+ mouse showed reduced baseline firing rate of fast-spiking interneurons and in the ability of the GABAAreceptor antagonist gabazine to increase the firing rate of pyramidal neurons. In assays of auditory-evoked responses, PFC interneurons in the Df(h15q13)/+ mouse had reduced detection amplitudes and increased detection latencies, while pyramidal neurons showed increased detection latencies. In experiments 4–6, the Df(h15q13)/+ mouse showed a stimulus duration-dependent decrease in percent accuracy in the 5-CSRTT. The impairment was insensitive to treatment with the partial α7nAChR agonist EVP-6124. The Df(h15q13)/+ mouse showed no cognitive impairments in experiments 7–12. Conclusion: The Df(h15q13)/+ mouse has multiple dysfunctions converging on disrupted PFC processing as measured by several independent assays of inhibitory transmission and attentional function.
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| 5. |
- Pickering, Chris, et al.
(författare)
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Ethanol impairment of spontaneous alternation behaviour and associated changes in medial prefrontal glutamatergic gene expression precede putative markers of dependence
- 2015
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Ingår i: Pharmacology, Biochemistry and Behavior. - : Elsevier BV. - 0091-3057 .- 1873-5177. ; 132, s. 63-70
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Tidskriftsartikel (refereegranskat)abstract
- Cognitive impairments are observable in over half of cases with alcoholism, deficits in spatial working memory being particularly common. Previously we observed that rats make more alternation errors in a Y-maze test of spontaneous alternation behaviour/spatial working memory after 5-day intermittent ethanol. Here we used qPCR to quantify changes in gene expression accompanying this behavioural impairment. Male Wistar rats were treated with either saline or ethanol (1 or 2.5 g/kg) for 5 days followed by 2 drug-free days. Brains were dissected after Y-maze analysis and RNA was extracted from the medial prefrontal cortex, hippocampus and nucleus accumbens. Using the Qiagen GABA & Glutamate PCR array we measured changes in these two neurotransmitter systems. A dose of 1 g/kg ethanol did not affect spontaneous alternation behaviour or any other behavioural variable. 2.5 g/kg significantly decreased % correct alternations (p = 0.028) without affecting total distance (p = 0.54) and increased time in the choice area (p = 0.023) at the Y-maze centre, indicating a possible impairment in decision-making. In the medial prefrontal cortex, 2.5 g/kg ethanol decreased mRNA expression of brain-derived neurotrophic factor, NMDA NR2A subunit, mGluR8 receptor, Homer1, the glutamate transporters SLC1a1 and SLC1a6 and Srr. In the nucleus accumbens this dose did not affect mRNA expression of the dopamine D1 or D2 receptors but did upregulate the GABA transporter GAT-3. Even if only correlational, these data suggest that gene expression changes in the medial prefrontal cortex and associated cognitive impairment occur before adaptation of the dopaminergic system and, presumably, drug dependence.
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| 6. |
- Ruggeri, Barbara, et al.
(författare)
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Association of Protein Phosphatase PPM1G With Alcohol Use Disorder and Brain Activity During Behavioral Control in a Genome-Wide Methylation Analysis
- 2015
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Ingår i: American Journal of Psychiatry. - : American Psychiatric Association Publishing. - 0002-953X .- 1535-7228. ; 172:6, s. 543-552
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The genetic component of alcohol use disorder is substantial, but monozygotic twin discordance indicates a role for nonheritable differences that could be mediated by epigenetics. Despite growing evidence associating epigenetics and psychiatric disorders, it is unclear how epigenetics, particularly DNA methylation, relate to brain function and behavior, including drinking behavior. Method: The authors carried out a genome-wide analysis of DNA methylation of 18 monozygotic twin pairs discordant for alcohol use disorder and validated differentially methylated regions. After validation, the authors characterized these differentially methylated regions using personality trait assessment and functional MRI in a sample of 499 adolescents. Results: Hypermethylation in the 3'-protein-phosphatase-1G (PPM1G) gene locus was associated with alcohol use disorder. The authors found association of PPM1G hypermethylation with early escalation of alcohol use and increased impulsiveness. They also observed association of PPM1G hypermethylation with increased blood-oxygen-level-dependent response in the right subthalamic nucleus during an impulsiveness task. Conclusions: Overall, the authors provide first evidence for an epigenetic marker associated with alcohol consumption and its underlying neurobehavioral phenotype.
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| 7. |
- Tyagi, Himanshu, et al.
(författare)
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A randomized trial directly comparing ventral capsule and anteromedial subthalamic nucleus stimulation in obsessive-compulsive disorder : Clinical and imaging evidence for dissociable effects
- 2022
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Ingår i: FOCUS. - : American Psychiatric Association Publishing. - 1541-4094 .- 1541-4108. ; 20:1, s. 160-169
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Tidskriftsartikel (refereegranskat)abstract
- Background: Deep brain stimulation (DBS) is an emerging treatment for severe obsessive-compulsive disorder (OCD). We compared the efficacy of ventral capsule/ventral striatal (VC/VS) and anteromedial subthalamic nucleus (amSTN) DBS in the same patients and tested for mechanistic differences on mood and cognitive flexibility and associated neural circuitry. The possible synergistic benefit of DBS at both sites and cognitive behavioral therapy was explored.Methods: Six patients with treatment-refractory OCD (5 men; Yale-Brown Obsessive Compulsive Scale score >32) entered double-blind counterbalanced phases of 12-week amSTN or VC/VS DBS, followed by 12-week open phases when amSTN and VC/VS were stimulated together, in which optimal stimulation parameters were achieved and adjunctive inpatient cognitive behavioral therapy was delivered. OCD and mood were assessed with standardized scales and cognitive flexibility with the Cambridge Neuropsychological Test Automated Battery Intra-Extra Dimensional Set-Shift task. Diffusion-weighted and intraoperative magnetic resonance imaging scans were performed for tractography from optimally activated electrode contacts.Results: DBS at each site significantly and equivalently reduced OCD symptoms with little additional gain following combined stimulation. amSTN but not VC/VS DBS significantly improved cognitive flexibility, whereas VC/VS DBS had a greater effect on mood. The VC/VS effective site was within the VC. VC DBS connected primarily to the medial orbitofrontal cortex, and amSTN DBS to the lateral orbitofrontal cortex, dorsal anterior cingulate cortex, and dorsolateral prefrontal cortex. No further improvement followed cognitive behavioral therapy, reflecting a floor effect of DBS on OCD.Conclusions: Both the VC/VS and amSTN are effective targets for severe treatment-refractory OCD. Differential improvements in mood and cognitive flexibility and their associated connectivity suggest that DBS at these sites modulates distinct brain networks.
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| 8. |
- Zhukovsky, Peter, et al.
(författare)
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Perseveration in a spatial-discrimination serial reversal learning task is differentially affected by MAO-A and MAO-B inhibition and associated with reduced anxiety and peripheral serotonin levels
- 2017
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Ingår i: Psychopharmacology. - : SPRINGER. - 0033-3158 .- 1432-2072. ; 234:9-10, s. 1557-1571
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Tidskriftsartikel (refereegranskat)abstract
- Impairments in behavioral flexibility lie at the core of anxiety and obsessive-compulsive disorders. Few studies, however, have investigated the neural substrates of natural variation in behavioral flexibility and whether inflexible behavior is linked to anxiety and peripheral markers of stress and monoamine function. The objective of the study was to investigate peripheral and central markers associated with perseverative behavior on a spatial-discrimination serial reversal learning task. Rats were trained on a reversal learning task prior to blood sampling, anxiety assessment, and the behavioral evaluation of selective monoamine oxidase-A (MAO-A) and MAO-B inhibitors, which block the degradation of serotonin (5-HT), dopamine (DA), and noradrenaline (NA). Perseveration correlated positively with 5-HT levels in blood plasma and inversely with trait anxiety, as measured on the elevated plus maze. No significant relationships were found between perseveration and the stress hormone corticosterone or the 5-HT precursor tryptophan. Reversal learning was significantly improved by systemic administration of the MAO-A inhibitor moclobemide but not by the MAO-B inhibitor lazabemide. Moclobemide also increased latencies to initiate a new trial following an incorrect response suggesting a possible role in modulating behavioral inhibition to negative feedback. MAO-A but not MAO-B inhibition resulted in pronounced increases in 5-HT and NA content in the orbitofrontal cortex and dorsal raph, nuclei and increased 5-HT and DA content in the basolateral amygdala and dorsomedial striatum. These findings indicate that central and peripheral monoaminergic mechanisms underlie inter-individual variation in behavioral flexibility, which overlaps with trait anxiety and depends on functional MAO-A activity.
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