scholarly journals Novel, non-nitrocatechol COMT inhibitors modulate dopamine neurotransmission in the frontal cortex and improve cognitive flexibility

2019 ◽  
Author(s):  
Spencer Byers ◽  
Ingrid P. Buchler ◽  
Michael DePasquale ◽  
Helen L. Rowley ◽  
Rajiv S. Kulkarni ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Frontal Cortex ◽  
Cognitive Flexibility ◽  
Severe Toxicity ◽  
Comt Inhibitors ◽  
Attentional Set ◽  
Comt Inhibitor ◽  
Attentional Set Shifting ◽  
Barrier Penetration

AbstractCognitive impairment is a primary feature of many neuropsychiatric disorders and there is a need for new therapeutic options. Catechol-O-methyltransferase (COMT) inhibitors modulate cortical dopaminergic function and have been proposed as potential cognitive enhancers. Unfortunately, currently available COMT inhibitors are not good candidates due to either poor blood-brain barrier penetration or severe toxicity. To address the need for safe, brain-penetrant COMT inhibitors, we tested multiple novel COMT inhibitors in a set of preclinical in vivo efficacy assays to determine their viability as potential clinical candidates. We found that multiple COMT inhibitors, exemplified by LIBD-1 and LIBD-3, significantly modulated dopaminergic function measured as decreases in homovanillic acid (HVA) and increases in 3,4-Dihydroxyphenylacetic acid (DOPAC), two dopamine metabolites, in cerebrospinal fluid (CSF) and the frontal cortex. Additionally, we found the LIBD-1 significantly improved cognitive flexibility in a rat attentional set-shifting assay (ASST), an effect previously seen with the COMT inhibitor tolcapone. These results demonstrate that LIBD-1 is a novel COMT inhibitor with promising in vivo activity and the potential to serve as a new therapy for cognitive impairment.

scholarly journals Mediodorsal thalamus is critical for updating during extra-dimensional shifts but not reversals in the attentional set-shifting task

2021 ◽  
Author(s):  
Zakaria Ouhaz ◽  
Brook AL Perry ◽  
Kouichi Nakamura ◽  
Anna S Mitchell
Keyword(s):  
Frontal Cortex ◽  
Cognitive Flexibility ◽  
Optimal Choice ◽  
Response Strategy ◽  
Choice Response ◽  
Set Shifting ◽  
Attentional Set ◽  
Mediodorsal Thalamus ◽  
Attentional Set Shifting ◽  
Set Shifting Task

AbstractCognitive flexibility, attributed to frontal cortex, is vital for navigating the complexities of everyday life. The mediodorsal thalamus (MD), interconnected to frontal cortex, may influence cognitive flexibility. Here rats performed an attentional set-shifting task measuring intra-dimensional and extra-dimensional shifts in sensory discriminations. MD lesion rats needed more trials to learn the rewarded sensory dimension. However, once the choice response strategy was established, learning further two-choice discriminations in the same sensory dimension, and reversals of the reward contingencies in the same dimension, were unimpaired. Critically though, MD lesion rats were impaired during the extra-dimensional shift, when they must rapidly update the optimal choice response strategy. Behavioral analyses showed MD lesion rats had significantly reduced ‘on-the-fly’ correct second choice responses. Diminshed c-Fos expression in the prelimbic and orbitofrontal cortex was also documented. This evidence shows transfer of information via the MD is critical when monitoring and rapid updates in established choice response strategies are required.

scholarly journals A psychiatric disease-related circular RNA controls synaptic gene expression and cognition

2020 ◽  
Vol 25 (11) ◽  
pp. 2712-2727 ◽  
Author(s):  
Amber J. Zimmerman ◽  
Alexander K. Hafez ◽  
Stephen K. Amoah ◽  
Brian A. Rodriguez ◽  
Michela Dell’Orco ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prefrontal Cortex ◽  
Frontal Cortex ◽  
Cognitive Flexibility ◽  
Rna Binding ◽  
Age Of Onset ◽  
Psychiatric Disease ◽  
Mammalian Brain ◽  
Neuronal Cultures

Abstract Although circular RNAs (circRNAs) are enriched in the mammalian brain, very little is known about their potential involvement in brain function and psychiatric disease. Here, we show that circHomer1a, a neuronal-enriched circRNA abundantly expressed in the frontal cortex, derived from Homer protein homolog 1 (HOMER1), is significantly reduced in both the prefrontal cortex (PFC) and induced pluripotent stem cell-derived neuronal cultures from patients with schizophrenia (SCZ) and bipolar disorder (BD). Moreover, alterations in circHomer1a were positively associated with the age of onset of SCZ in both the dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC). No correlations between the age of onset of SCZ and linear HOMER1 mRNA were observed, whose expression was mostly unaltered in BD and SCZ postmortem brain. Using in vivo circRNA-specific knockdown of circHomer1a in mouse PFC, we show that it modulates the expression of numerous alternative mRNA transcripts from genes involved in synaptic plasticity and psychiatric disease. Intriguingly, in vivo circHomer1a knockdown in mouse OFC resulted in specific deficits in OFC-mediated cognitive flexibility. Lastly, we demonstrate that the neuronal RNA-binding protein HuD binds to circHomer1a and can influence its synaptic expression in the frontal cortex. Collectively, our data uncover a novel psychiatric disease-associated circRNA that regulates synaptic gene expression and cognitive flexibility.

scholarly journals Medial Frontal Cortex Mediates Perceptual Attentional Set Shifting in the Rat

2000 ◽  
Vol 20 (11) ◽  
pp. 4320-4324 ◽  
Author(s):  
Jennifer M. Birrell ◽  
Verity J. Brown
Keyword(s):  
Frontal Cortex ◽  
Medial Frontal Cortex ◽  
Set Shifting ◽  
Attentional Set ◽  
Attentional Set Shifting

scholarly journals Fronto-striatal circuits for cognitive flexibility in far from onset Huntington’s disease: evidence from the Young Adult Study

2020 ◽  
pp. jnnp-2020-324104 ◽  
Author(s):  
Christelle Langley ◽  
Sarah Gregory ◽  
Katie Osborne-Crowley ◽  
Claire O'Callaghan ◽  
Paul Zeun ◽  
...  
Keyword(s):  
Young Adult ◽  
Functional Connectivity ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cognitive Flexibility ◽  
Study Cohort ◽  
Set Shifting ◽  
Attentional Set ◽  
Adult Study ◽  
Attentional Set Shifting

ObjectivesCognitive flexibility, which is key for adaptive decision-making, engages prefrontal cortex (PFC)-striatal circuitry and is impaired in both manifest and premanifest Huntington’s disease (pre-HD). The aim of this study was to examine cognitive flexibility in a far from onset pre-HD cohort to determine whether an early impairment exists and if so, whether fronto-striatal circuits were associated with this deficit.MethodsIn the present study, we examined performance of 51 pre-HD participants (mean age=29.22 (SD=5.71) years) from the HD Young Adult Study cohort and 53 controls matched for age, sex and IQ, on the Cambridge Neuropsychological Test Automated Battery (CANTAB) Intra-Extra Dimensional Set-Shift (IED) task. This cohort is unique as it is the furthest from disease onset comprehensively studied to date (mean years=23.89 (SD=5.96) years). The IED task measures visual discrimination learning, cognitive flexibility and specifically attentional set-shifting. We used resting-state functional MRI to examine whether the functional connectivity between specific fronto-striatal circuits was dysfunctional in pre-HD, compared with controls, and whether these circuits were associated with performance on the critical extradimensional shift stage.ResultsOur results demonstrated that the CANTAB IED task detects a mild early impairment in cognitive flexibility in a pre-HD group far from onset. Attentional set-shifting was significantly related to functional connectivity between the ventrolateral PFC and ventral striatum in healthy controls and to functional connectivity between the dorsolateral PFC and caudate in pre-HD participants.ConclusionWe postulate that this incipient impairment of cognitive flexibility may be associated with intrinsically abnormal functional connectivity of fronto-striatal circuitry in pre-HD.

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