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Neuropsychopharmacology (NPP): update on relationships between online attention and citation counts
Chloe J. Jordan, Keri Martinowich & William A. Carlezon Jr.
doi : 10.1038/s41386-021-00983-x
Neuropsychopharmacology volume 46, pages1061–1063(2021)
The social and winding road between inflammation and PTSD
Gianluca Ursini & Giovanna Punzi
doi : 10.1038/s41386-021-00979-7
Neuropsychopharmacology volume 46, pages1064–1065(2021)
Differentiating effort-related aspects of motivation from reinforcement learning: commentary on Soder et al. “Dose–response effects of d-amphetamine on effort-based decision-making and reinforcement learning”
John D. Salamone
doi : 10.1038/s41386-020-00930-2
Neuropsychopharmacology volume 46, pages1066–1067(2021)
Telemedicine for treating mental health and substance use disorders: reflections since the pandemic
Alisa B. Busch, Dawn E. Sugarman, Lisa E. Horvitz & Shelly F. Greenfield
doi : 10.1038/s41386-021-00960-4
Neuropsychopharmacology volume 46, pages1068–1070(2021)
Dissecting the genetic association of C-reactive protein with PTSD, traumatic events, and social support
Carolina Muniz Carvalho, Frank R. Wendt, Adam X. Maihofer, Dan J. Stein, Murray B. Stein, Jennifer A. Sumner, Sian M. J. Hemmings, Caroline M. Nievergelt, Karestan C. Koenen, Joel Gelernter, Sintia I. Belangero & Renato Polimanti
doi : 10.1038/s41386-020-0655-6
Neuropsychopharmacology volume 46, pages1071–1077(2021)
Inflammatory markers like C-reactive protein (CRP) have been associated with post-traumatic stress disorder (PTSD) and traumatic experiences, but the underlying mechanisms are unclear. We investigated the relationship among serum CRP, PTSD, and traits related to traumatic events and social support using genetic association data from the Psychiatric Genomics Consortium (23,185 PTSD cases and 151,309 controls), the UK Biobank (UKB; up to 117,900 individuals), and the CHARGE study (Cohorts for Heart and Aging Research in Genomic Epidemiology, 148,164 individual). Linkage disequilibrium score regression, polygenic risk scoring, and two-sample Mendelian randomization (MR) analyses were used to investigate genetic overlap and causal relationships. Genetic correlations of CRP were observed with PTSD (rg?=?0.16, p?=?0.026) and traits related to traumatic events, and the presence of social support (?0.28?<?rg?<?0.20; p?<?0.008). We observed a bidirectional association between CRP and PTSD (CRP???PTSD: ??=?0.065, p?=?0.015; PTSD???CRP: ??=?0.008, p?=?0.009). CRP also showed a negative association with the “felt loved as a child” trait (UKB, ??=??0.017, p?=?0.008). Owing to the known association of socioeconomic status (SES) on PTSD, a multivariable MR was performed to investigate SES as potential mediator. We found that household income (univariate MR: ??=??0.22, p?=?1.57?×?10?7; multivariate MR: ??=??0.17, p?=?0.005) and deprivation index (univariate MR: ??=?0.38, p?=?1.63?×?10?9; multivariate MR: ??=?0.27, p?=?0.016) were driving the causal estimates of “felt loved as a child” and CRP on PTSD. The present findings highlight a bidirectional genetic association between PTSD and CRP, also suggesting a potential role of SES in the interplay between childhood support and inflammatory processes with respect to PTSD risk.
Dose-response effects of d-amphetamine on effort-based decision-making and reinforcement learning
Heather E. Soder, Jessica A. Cooper, Paula Lopez-Gamundi, Jennifer K. Hoots, Cecilia Nunez, Victoria M. Lawlor, Scott D. Lane, Michael T. Treadway & Margaret C. Wardle
doi : 10.1038/s41386-020-0779-8
Neuropsychopharmacology volume 46, pages1078–1085(2021)
Effort-related decision-making and reward learning are both dopamine-dependent, but preclinical research suggests they depend on different dopamine signaling dynamics. Therefore, the same dose of a dopaminergic medication could have differential effects on effort for reward vs. reward learning. However, no study has tested how effort and reward learning respond to the same dopaminergic medication within subjects. The current study aimed to test the effect of therapeutic doses of d-amphetamine on effort for reward and reward learning in the same healthy volunteers. Participants (n?=?30) completed the Effort Expenditure for Reward Task (EEfRT) measure of effort-related decision-making, and the Probabilistic Reward Task (PRT) measure of reward learning, under placebo and two doses of d-amphetamine (10?mg, and 20?mg). Secondarily, we examined whether the individual characteristics of baseline working memory and willingness to exert effort for reward moderated the effects of d-amphetamine. d-Amphetamine increased willingness to exert effort, particularly at low to intermediate expected values of reward. Computational modeling analyses suggested this was due to decreased effort discounting rather than probability discounting or decision consistency. Both baseline effort and working memory emerged as moderators of this effect, such that d-amphetamine increased effort more in individuals with lower working memory and lower baseline effort, also primarily at low to intermediate expected values of reward. In contrast, d-amphetamine had no significant effect on reward learning. These results have implications for treatment of neuropsychiatric disorders, which may be characterized by multiple underlying reward dysfunctions.
Long-term antibiotic use during early life and risks to mental traits: an observational study and gene–environment-wide interaction study in UK Biobank cohort
Xiao Liang, Jing Ye, Yan Wen, Ping Li, Bolun Cheng, Shiqiang Cheng, Li Liu, Lu Zhang, Mei Ma, Xin Qi, Chujun Liang, Xiaomeng Chu, Om Prakash Kafle, Yumeng Jia & Feng Zhang
doi : 10.1038/s41386-020-00798-2
Neuropsychopharmacology volume 46, pages1086–1092(2021)
The relationships between long-term antibiotic use during early life and mental traits remain elusive now. A total of 158,444 subjects from UK Biobank were used in this study. Linear regression analyses were first conducted to assess the correlations between long-term antibiotic use during early life and mental traits. Gene–environment-wide interaction study (GEWIS) was then performed by PLINK2.0 to detect the interaction effects between long-term antibiotic use during early life and genes on the risks of mental traits. Finally, DAVID tool was used to conduct gene ontology (GO) analysis of the identified genes interacting with long-term antibiotic use during early life. We found negative associations of long-term antibiotic use during early life with remembrance (p value=1.74?×?10?6, b?=??0.10) and intelligence (p value=2.64?×?10?26, b?=??0.13), and positive associations of long-term antibiotic use during early life with anxiety (p value?=?2.75?×?10?47, b?=?0.12) and depression (p value=2.01?×?10?195, b?=?0.25). GEWIS identified multiple significant genes-long-term antibiotic use during early life interaction effects, such as ANK3 (rs773585997, p value?=?1.78?×?10?8) for anxiety and STRN (rs140049205, p value?=?1.88?×?10?8) for depression. GO enrichment analysis detected six GO terms enriched in the identified genes interacting with long-term antibiotic use during early life for anxiety, such as GO:0030425~dendrite (p value?=?3.41?×?10?2) and GO:0005886~plasma membrane (p value?=?3.64?×?10?3). Our study results suggest the impact of long-term antibiotic use during early life on the development of mental traits.
Investigation of glycaemic traits in psychiatric disorders using Mendelian randomisation revealed a causal relationship with anorexia nervosa
Danielle M. Adams, William R. Reay, Michael P. Geaghan & Murray J. Cairns
doi : 10.1038/s41386-020-00847-w
Neuropsychopharmacology volume 46, pages1093–1102(2021)
Data from observational studies have suggested an involvement of abnormal glycaemic regulation in the pathophysiology of psychiatric illness. This may be an attractive target for clinical intervention as glycaemia can be modulated by both lifestyle factors and pharmacological agents. However, observational studies are inherently confounded, and therefore, causal relationships cannot be reliably established. We employed genetic variants rigorously associated with three glycaemic traits (fasting glucose, fasting insulin, and glycated haemoglobin) as instrumental variables in a two-sample Mendelian randomisation analysis to investigate the causal effect of these measures on the risk for eight psychiatric disorders. A significant protective effect of a natural log transformed pmol/L increase in fasting insulin levels was observed for anorexia nervosa after the application of multiple testing correction (OR?=?0.48 [95% CI: 0.33-0.71]—inverse-variance weighted estimate). There was no consistently strong evidence for a causal effect of glycaemic factors on the other seven psychiatric disorders considered. The relationship between fasting insulin and anorexia nervosa was supported by a suite of sensitivity analyses, with no statistical evidence of instrument heterogeneity or horizontal pleiotropy. Further investigation is required to explore the relationship between insulin levels and anorexia.
Independent replications and integrative analyses confirm TRANK1 as a susceptibility gene for bipolar disorder
Wenqiang Li, Xin Cai, Hui-Juan Li, Meng Song, Chu-Yi Zhang, Yongfeng Yang, Luwen Zhang, Lijuan Zhao, Weipeng Liu, Lu Wang, Minglong Shao, Yan Zhang, Chen Zhang, Jun Cai, Dong-Sheng Zhou, Xingxing Li, Li Hui, Qiu-Fang Jia, Na Qu, Bao-Liang Zhong, Shu-Fang Zhang, Jing Chen, Bin Xia, Yi Li, Xueqin Song, Weixing Fan, Wei Tang, Wenxin Tang, Jinsong Tang, Xiaogang Chen, Weihua Yue, Dai Zhang, Yiru Fang, Xiao Xiao, Ming Li, Luxian Lv & Hong Chang
doi : 10.1038/s41386-020-00788-4
Neuropsychopharmacology volume 46, pages1103–1112(2021)
Genetic analyses for bipolar disorder (BD) have achieved prominent success in Europeans in recent years, whereas its genetic basis in other populations remains relatively less understood. We herein report that the leading risk locus for BD in European genome-wide association studies (GWAS), the single-nucleotide polymorphism (SNP) rs9834970 near TRANK1 at 3p22 region, is also genome-wide significantly associated with BD in a meta-analysis of four independent East Asian samples including 5748 cases and 65,361 controls (p?=?2.27?×?10?8, odds ratio?=?1.136). Expression quantitative trait loci (eQTL) analyses and summary data-based Mendelian randomization (SMR) analyses in multiple human brain samples suggest that lower TRANK1 mRNA expression is a principal BD risk factor explaining its genetic risk signals at 3p22. We also identified another SNP rs4789 in the 3? untranslated region (3?UTR) of TRANK1 showing stronger eQTL associations as well as genome-wide significant association with BD. Despite the relatively unclear neuronal function of TRANK1, our mRNA expression analyses in the human brains and in rat primary cortical neurons reveal that genes highly correlated with TRANK1 are significantly enriched in the biological processes related to dendritic spine, synaptic plasticity, axon guidance and circadian entrainment, and are also more likely to exhibit strong associations in psychiatric GWAS (e.g., the CACNA1C gene). Overall, our results support that TRANK1 is a potential BD risk gene. Further studies elucidating its roles in this illness are needed.
Change in prefrontal activity and executive functions after action-based cognitive remediation in bipolar disorder: a randomized controlled trial
Caroline V. Ott, Julian Macoveanu, Christopher R. Bowie, Patrick M. Fisher, Gitte M. Knudsen, Lars V. Kessing & Kamilla W. Miskowiak
doi : 10.1038/s41386-020-00901-7
Neuropsychopharmacology volume 46, pages1113–1121(2021)
Cognitive impairment is prevalent in bipolar disorder (BD) but treatments with pro-cognitive effects are lacking. Insight concerning the neurocircuitry of cognitive improvement could provide a biomarker for pro-cognitive effects to advance treatment development. The dorsal prefrontal cortex (dPFC) is a promising region for such treatment target engagement. The aim of this functional magnetic resonance imaging (fMRI) study was to examine the effects of action-based cognitive remediation (ABCR) on early change in the dPFC blood-oxygen-level-dependent response in patients with BD in remission, and whether the observed neural change predicted improved executive functions following 10 weeks of treatment. Forty-five participants with remitted BD (ABCR: n?=?26, control treatment: n?=?19) completed a spatial n-back working memory task during fMRI and executive function tasks outside the scanner before and after two weeks of ABCR/control treatment, and an additional assessment of executive function at treatment completion. Thirty-four healthy controls underwent a single fMRI and executive function assessment for baseline comparisons. We found an early reversal of pretreatment hypo-activity in the dorsolateral prefrontal cortex (dlPFC) following ABCR vs. control during both high-load (2-back?>?1-back) working memory (WM) (F(1,43)?=?5.69, p?=?0.02, ?2?=?0.12) and general WM (2-back?>?0-back) (F(1,43)?=?5.61, p?=?0.02, ?2?=?0.12). This dlPFC activity increase predicted improved executive functions at treatment completion (high-load WM: B?=??0.45, p?=?0.01, general WM: B?=??0.41, p?<?0.01), independent of changes in subsyndromal symptoms. In conclusion, early dPFC increase may provide a neurocircuitry-based biomarker for pro-cognitive effects. Future cognition trials should include fMRI assessments to confirm the validity of this putative biomarker model across disorders with cognitive impairment.
A potential biomarker for treatment stratification in psychosis: evaluation of an [18F] FDOPA PET imaging approach
Mattia Veronese, Barbara Santangelo, Sameer Jauhar, Enrico D’Ambrosio, Arsime Demjaha, Hugh Salimbeni, Jin Huajie, Paul McCrone, Federico Turkheimer & Oliver Howes
doi : 10.1038/s41386-020-00866-7
Neuropsychopharmacology volume 46, pages1122–1132(2021)
[18F]FDOPA PET imaging has shown dopaminergic function indexed as Kicer differs between antipsychotic treatment responders and non-responders. However, the theragnostic potential of this biomarker to identify non-responders has yet to be evaluated. In view of this, we aimed to evaluate this as a theragnostic test using linear and non-linear machine-learning (i.e., Bernoulli, support vector, random forest and Gaussian processes) analyses and to develop and evaluate a simplified approach, standardised uptake value ratio (SUVRc). Both [18F]FDOPA PET approaches had good test-rest reproducibility across striatal regions (Kicer ICC: 0.68–0.94, SUVRc ICC: 0.76–0.91). Both our linear and non-linear classification models showed good predictive power to distinguish responders from non-responders (receiver operating curve area under the curve for region-of-interest approach: Kicer?=?0.80, SUVRc?=?0.79; for voxel-wise approach using a linear support vector machine: 0.88) and similar sensitivity for identifying treatment non-responders with 100% specificity (Kicer: ~50%, SUVRc: 40–60%). Although the findings were replicated in two independent datasets, given the total sample size (n?=?84) and single setting, they warrant testing in other samples and settings. Preliminary economic analysis of [18F]FDOPA PET to fast-track treatment-resistant patients with schizophrenia to clozapine indicated a potential healthcare cost saving of ~£3400 (equivalent to $4232 USD) per patient. These findings indicate [18F]FDOPA PET dopamine imaging has potential as biomarker to guide treatment choice.
Reduced GABA/glutamate in the thalamus of individuals at clinical high risk for psychosis
Gonzalo M. Qui?ones, Ahmad Mayeli, Victor E. Yushmanov, Hoby P. Hetherington & Fabio Ferrarelli
doi : 10.1038/s41386-020-00920-4
Neuropsychopharmacology volume 46, pages1133–1139(2021)
Youth at clinical high risk (CHR) are a unique population enriched for precursors of major psychiatric disorders, especially schizophrenia (SCZ). Recent neuroimaging findings point to abnormalities in the thalamus of patients with SCZ, including chronic and early course patients, as well as in CHR individuals relative to healthy comparison groups, thus suggesting that thalamic dysfunctions are present even before illness onset. Furthermore, modeling data indicate that alteration between excitatory and inhibitory control, as reflected by alteration in GABAergic and glutamatergic balance (i.e., GABA/Glu), may underlie thalamic deficits linked to the risk and development of psychosis. There is, however, a lack of in vivo evidence of GABA/Glu thalamic abnormalities in the CHR state. Magnetic resonance spectroscopic imaging (MRSI) 7?Tesla (7?T) provides enhanced resolution to quantify GABA and Glu levels in the thalamus of CHR individuals. In this study, we performed 7?T MRSI in 15 CHR and 20 healthy control (HC) participants. We found that GABA/Glu was significantly reduced in the right medial anterior and right medial posterior thalamus of CHR relative to HC groups. The GABA/Glu reduction was negatively correlated with general symptoms in the right medial anterior thalamus, as well as with disorganization symptoms in the right medial posterior thalamus. Altogether, these findings indicate that GABA/Glu abnormalities are present in the thalamus before the onset of full-blown psychosis and are associated with symptom severity, thus providing putative molecular and neuronal targets for early interventions in youth at CHR.
Complement component C4 levels in the cerebrospinal fluid and plasma of patients with schizophrenia
Juan A. Gallego, Emily A. Blanco, Christopher Morell, Todd Lencz & Anil K. Malhotra
doi : 10.1038/s41386-020-00867-6
Neuropsychopharmacology volume 46, pages1140–1144(2021)
Abnormalities in the complement system have been described in patients with schizophrenia, with those individuals having greater frequency of complement component 4A (C4A) alleles and higher C4A transcript levels in postmortem brain tissue. Importantly, abnormalities in C4A and other complement molecules have been associated with synaptic pruning abnormalities that occur during neurodevelopment. A few studies have investigated C4 levels in living patients with schizophrenia, but all of them did so using peripheral blood samples. No studies have examined C4 levels in cerebrospinal fluid (CSF), presumably a better biofluid choice given its intimate contact with the brain. Therefore, we report for the first time on C4 levels in CSF and plasma of patients with schizophrenia. In this study, we obtained CSF in 32 patients with schizophrenia spectrum disorders and 32 healthy volunteers and peripheral blood samples in 33 SSD and 31 healthy volunteers. C4 levels were measured using Abcam ELISA assays. Univariate analysis did not show a statistically significant difference in CSF C4 values between groups. However, a multivariable analysis showed a statistically significant increase in CSF C4 levels between groups after adjusting for sex and age. We also observed a high correlation between CSF C4 levels and age. By contrast, plasma C4 levels were not significantly different between groups. CSF and plasma C4 levels were not significantly correlated. Therefore, the use of CSF samples is critical and should be complementary to the use of peripheral blood samples to allow for a comprehensive understanding of complement C4 abnormalities in schizophrenia.
Phase 1 randomized study on the safety, tolerability, and pharmacodynamic cognitive and electrophysiological effects of a dopamine D1 receptor positive allosteric modulator in patients with schizophrenia
Amit Desai, Lauren Benner, Ruishan Wu, Lev Gertsik, Paul Maruff, Gregory A. Light, Tolga Uz, Gerard J. Marek & Tong Zhu
doi : 10.1038/s41386-020-00908-0
Neuropsychopharmacology volume 46, pages1145–1151(2021)
ASP4345, a novel dopamine D1 receptor positive allosteric modulator, is being evaluated for the treatment of cognitive impairment associated with schizophrenia (CIAS). This phase 1 multiple ascending-dose study (NCT02720263) assessed the safety, tolerability, and pharmacodynamics of ASP4345 in patients with schizophrenia/schizoaffective disorder. Pharmacodynamic assessments were Cogstate cognitive tests and electrophysiological biomarkers, including gamma-band power and phase synchronization in response to 40-Hz auditory steady-state stimulation, as well as mismatch negativity (MMN) and P3a event-related potentials. The sample size determination was based on standard practice in assessing safety and tolerability of a new chemical entity. Data were summarized by conversion of this data into effect sizes using descriptive and inferential statistics. A total of 36 randomized patients received ASP4345 (3, 15, 50, and 150?mg; n?=?9 each dose) and 12 patients received placebo. Patients in the ASP4345 group experienced 73 treatment-emergent adverse events (TEAEs) and 34 TEAEs were reported for the placebo group. The most common TEAEs were headache and somnolence and nearly all TEAEs were mild in severity. No changes in mood or self-reports of suicidal ideation/behavior were observed. Improvements in performance on cognitive tests were noted, which suggests a potential improvement in psychomotor function and visual attention. Furthermore, positive changes in neurophysiological biomarkers (auditory steady-state response [ASSR] and MMN) suggest improvement in information processing. The findings need to be confirmed in studies with a larger patient population. Nonetheless, the trends in safety and pharmacodynamic data support further clinical development of ASP4345 for the treatment of CIAS.
Schizophrenia and bipolar disorder are associated with opposite brain reward anticipation-associated response
Jason Smucny, Laura M. Tully, Amber M. Howell, Tyler A. Lesh, Sheri L. Johnson, Randall C. O?Reilly, Michael J. Minzenberg, Stefan Ursu, Jong H. Yoon, Tara A. Niendam, J. Daniel Ragland & Cameron S. Carter
doi : 10.1038/s41386-020-00940-0
Neuropsychopharmacology volume 46, pages1152–1160(2021)
Blunted and exaggerated neuronal response to rewards are hypothesized to be core features of schizophrenia spectrum disorders (SZ) and bipolar disorder (BD), respectively. Nonetheless, direct tests of this hypothesis, in which response between SZ and BD is compared in the same study, are lacking. Here we examined the functional correlates of reward processing during the Incentivized Control Engagement Task (ICE-T) using 3T fMRI. Reward-associated activation was examined in 49 healthy controls (HCs), 52 recent-onset individuals with SZ, and 22 recent-onset individuals with Type I BD using anterior cingulate (ACC), anterior insula, and ventral striatal regions of interest. Significant group X reward condition (neutral vs. reward) interactions were observed during reward anticipation in the dorsal ACC (F(2,120)?=?4.21, P?=?0.017) and right insula (F(2,120)?=?4.77, P?=?0.010). The ACC interaction was driven by relatively higher activation in the BD group vs. HCs (P?=?0.007) and vs. individuals with SZ (P?=?0.010). The insula interaction was driven by reduced activation in the SZ group relative to HCs (P?=?0.018) and vs. people with BD (P?=?0.008). A composite of reward anticipation-associated response across all associated ROIs also differed significantly by diagnosis (F(1,120)?=?5.59, P?=?0.02), BD?>?HC?>?SZ. No effects of group or group X reward interactions were observed during reward feedback. These results suggest that people with SZ and BD have opposite patterns of activation associated with reward anticipation but not reward receipt. Implications of these findings in regard to Research Domain Criteria-based classification of illness and the neurobiology of reward in psychosis are discussed.
Antioxidant treatment ameliorates prefrontal hypomyelination and cognitive deficits in a rat model of schizophrenia
D. A. Maas, V. D. Eijsink, J. A. van Hulten, R. Panic, P. De Weerd, J. R. Homberg, A. Vallès, B. Nait-Oumesmar & G. J. M. Martens
doi : 10.1038/s41386-021-00964-0
Neuropsychopharmacology volume 46, pages1161–1171(2021)
Cognitive dysfunction in schizophrenia (SZ) is thought to arise from neurodevelopmental abnormalities that include interneuron hypomyelination in the prefrontal cortex (PFC). Here we report that RNA-sequencing of the medial (m)PFC of the APO-SUS rat model with SZ-relevant cognitive inflexibility revealed antioxidant metabolism as the most-enriched differentially expressed pathway. Antioxidant-related gene expression was altered throughout postnatal development and preceded hypomyelination. Furthermore, reduced glutathione levels and increased mitochondria numbers were observed in the mPFC. Strikingly, chronic treatment with the glutathione precursor N-acetylcysteine (NAC) from postnatal days 5–90 restored not only antioxidant-related mRNA expression and mitochondria numbers, but also myelin-related mRNA expression and mPFC-dependent cognitive dysfunction, while blood glutathione levels remained unaffected. The promyelinating effect of NAC was at least partly due to a positive effect on oligodendrocyte lineage progression. Together, our findings highlight that oxidative stress may contribute to cognitive symptoms in the APO-SUS rat model of SZ and encourage antioxidant therapy in early phases of SZ.
The medial entorhinal cortex mediates basolateral amygdala effects on spatial memory and downstream activity-regulated cytoskeletal-associated protein expression
Krista L. Wahlstrom, Amanda C. Alvarez-Dieppa, Christa K. McIntyre & Ryan T. LaLumiere
doi : 10.1038/s41386-020-00875-6
Neuropsychopharmacology volume 46, pages1172–1182(2021)
The basolateral amygdala (BLA) modulates the consolidation of dorsal hippocampus (DH)-dependent spatial and dorsolateral striatum (DLS)-dependent cued-response memories, often in competition with one another. Evidence suggests that a critical mechanism for BLA influences on memory consolidation is via effects on activity-regulated cytoskeletal-associated protein (ARC) in downstream brain regions. However, the circuitry by which the BLA modulates ARC in multiple competing memory systems remains unclear. Prior evidence indicates that optogenetic stimulation of BLA projections to the medial entorhinal cortex (mEC) enhances the consolidation of spatial learning and impairs the consolidation of cued-response learning, suggesting this pathway provides a circuit for favoring one system over another. Therefore, we hypothesized the BLA-mEC pathway mediates effects on downstream ARC-based synaptic plasticity related to these competing memory systems. To address this, male and female Sprague–Dawley rats underwent spatial or cued-response Barnes maze training and, 45?min later, were sacrificed for ARC analysis in synaptoneurosomes from the DH and DLS. Initial experiments found that spatial training alone increased ARC levels in the DH above those observed in control rats and rats that underwent a cued-response version of the task. Postspatial training optogenetic stimulation of the BLA–mEC pathway altered the balance of ARC expression in the DH vs. DLS, specifically shifting the balance in favor of the DH-based spatial memory system, although the precise region of ARC changes differed by sex. These findings suggest that BLA–mEC pathway influences on ARC in downstream regions are a mechanism by which the BLA can favor one memory system over another.
Prelimbic cortex glucocorticoid receptors regulate the stress-mediated inhibition of pain contagion in male mice
Navdeep K. Lidhar, Soroush Darvish-Ghane, Sivaani Sivaselvachandran, Sana Khan, Fatima Wasif, Holly Turner, Meruba Sivaselvachandran, Neil M. Fournier & Loren J. Martin
doi : 10.1038/s41386-020-00912-4
Neuropsychopharmacology volume 46, pages1183–1193(2021)
Experiencing pain with a familiar individual can enhance one’s own pain sensitivity, a process known as pain contagion. When experiencing pain with an unfamiliar individual, pain contagion is suppressed in males by activating the endocrine stress response. Here, we coupled a histological investigation with pharmacological and behavioral experiments to identify enhanced glucocorticoid receptor activity in the prelimbic subdivision of the medial prefrontal cortex as a candidate mechanism for suppressing pain contagion in stranger mice. Acute inhibition of glucocorticoid receptors in the prelimbic cortex was sufficient to elicit pain contagion in strangers, while their activation prevented pain contagion in cagemate dyads. Slice physiology recordings revealed enhanced excitatory transmission in stranger mice, an effect that was reversed by pre-treating mice with the corticosterone synthesis inhibitor metyrapone. Following removal from dyadic testing, stranger mice displayed enhanced affective-motivational pain behaviors when placed on an inescapable thermal stimulus, which were reversed by metyrapone. Together, our data suggest that the prelimbic cortex may play an integral role in modulating pain behavior within a social context and provide novel evidence towards the neural mechanism underlying the prevention of pain contagion.
The M1/M4 preferring muscarinic agonist xanomeline modulates functional connectivity and NMDAR antagonist-induced changes in the mouse brain
Caterina Montani, Carola Canella, Adam J. Schwarz, Jennifer Li, Gary Gilmour, Alberto Galbusera, Keith Wafford, Daniel Gutierrez-Barragan, Andrew McCarthy, David Shaw, Karen Knitowski, David McKinzie, Alessandro Gozzi & Christian Felder
doi : 10.1038/s41386-020-00916-0
Neuropsychopharmacology volume 46, pages1194–1206(2021)
Cholinergic drugs acting at M1/M4 muscarinic receptors hold promise for the treatment of symptoms associated with brain disorders characterized by cognitive impairment, mood disturbances, or psychosis, such as Alzheimer’s disease or schizophrenia. However, the brain-wide functional substrates engaged by muscarinic agonists remain poorly understood. Here we used a combination of pharmacological fMRI (phMRI), resting-state fMRI (rsfMRI), and resting-state quantitative EEG (qEEG) to investigate the effects of a behaviorally active dose of the M1/M4-preferring muscarinic agonist xanomeline on brain functional activity in the rodent brain. We investigated both the effects of xanomeline per se and its modulatory effects on signals elicited by the NMDA-receptor antagonists phencyclidine (PCP) and ketamine. We found that xanomeline induces robust and widespread BOLD signal phMRI amplitude increases and decreased high-frequency qEEG spectral activity. rsfMRI mapping in the mouse revealed that xanomeline robustly decreased neocortical and striatal connectivity but induces focal increases in functional connectivity within the nucleus accumbens and basal forebrain. Notably, xanomeline pre-administration robustly attenuated both the cortico-limbic phMRI response and the fronto-hippocampal hyper-connectivity induced by PCP, enhanced PCP-modulated functional connectivity locally within the nucleus accumbens and basal forebrain, and reversed the gamma and high-frequency qEEG power increases induced by ketamine. Collectively, these results show that xanomeline robustly induces both cholinergic-like neocortical activation and desynchronization of functional networks in the mammalian brain. These effects could serve as a translatable biomarker for future clinical investigations of muscarinic agents, and bear mechanistic relevance for the putative therapeutic effect of these class of compounds in brain disorders.
Effects of classical PKC activation on hippocampal neurogenesis and cognitive performance: mechanism of action
Samuel Dom?nguez-Garc?a, Ricardo G?mez-Oliva, Noelia Geribaldi-Dold?n, Carmen Hierro-Bujalance, Marta Sendra, Félix A. Ruiz, Livia Carrascal, Antonio J. Mac?as-S?nchez, Cristina Ver?stegui, Rosario Hern?ndez-Gal?n, M?nica Garc?a-Alloza, Pedro Nunez-Abades & Carmen Castro
doi : 10.1038/s41386-020-00934-y
Neuropsychopharmacology volume 46, pages1207–1219(2021)
Hippocampal neurogenesis has widely been linked to memory and learning performance. New neurons generated from neural stem cells (NSC) within the dentate gyrus of the hippocampus (DG) integrate in hippocampal circuitry participating in memory tasks. Several neurological and neuropsychiatric disorders show cognitive impairment together with a reduction in DG neurogenesis. Growth factors secreted within the DG promote neurogenesis. Protein kinases of the protein kinase C (PKC) family facilitate the release of several of these growth factors, highlighting the role of PKC isozymes as key target molecules for the development of drugs that induce hippocampal neurogenesis. PKC activating diterpenes have been shown to facilitate NSC proliferation in neurogenic niches when injected intracerebroventricularly. We show in here that long-term administration of diterpene ER272 promotes neurogenesis in the subventricular zone and in the DG of mice, affecting neuroblasts differentiation and neuronal maturation. A concomitant improvement in learning and spatial memory tasks performance can be observed. Insights into the mechanism of action reveal that this compound facilitates classical PKC? activation and promotes transforming growth factor alpha (TGF?) and, to a lesser extent, neuregulin release. Our results highlight the role of this molecule in the development of pharmacological drugs to treat neurological and neuropsychiatric disorders associated with memory loss and a deficient neurogenesis.
Pharmacokinetic neuroimaging to study the dose-related brain kinetics and target engagement of buprenorphine in vivo
Sylvain Auvity, Sébastien Goutal, Fabien Caillé, Dominique Vodovar, Alain Pruvost, Catriona Wimberley, Claire Leroy, Matteo Tonietto, Michel Bottlaender & Nicolas Tournier
doi : 10.1038/s41386-021-00976-w
Neuropsychopharmacology volume 46, pages1220–1228(2021)
A wide range of buprenorphine doses are used for either pain management or maintenance therapy in opioid addiction. The complex in vitro profile of buprenorphine, with affinity for µ-, ?-, and ?-opioid receptors (OR), makes it difficult to predict its dose-related neuropharmacology in vivo. In rats, microPET imaging and pretreatment by OR antagonists were performed to assess the binding of radiolabeled buprenorphine (microdose 11C-buprenorphine) to OR subtypes in vivo (n?=?4 per condition). The µ-selective antagonist naloxonazine (10?mg/kg) and the non-selective OR antagonist naloxone (1?mg/kg) blocked the binding of 11C-buprenorphine, while pretreatment by the ?-selective (naltrindole, 3?mg/kg) or the ?-selective antagonist (norbinaltorphimine, 10?mg/kg) did not. In four macaques, PET imaging and kinetic modeling enabled description of the regional brain kinetics of 11C-buprenorphine, co-injected with increasing doses of unlabeled buprenorphine. No saturation of the brain penetration of buprenorphine was observed for doses up to 0.11?mg/kg. Regional differences in buprenorphine-associated receptor occupancy were observed. Analgesic doses of buprenorphine (0.003 and 0.006?mg/kg), respectively, occupied 20% and 49% of receptors in the thalamus while saturating the low but significant binding observed in cerebellum and occipital cortex. Occupancy >90% was achieved in most brain regions with plasma concentrations >7?µg/L. PET data obtained after co-injection of an analgesic dose of buprenorphine (0.003?mg/kg) predicted the binding potential of microdose 11C-buprenorphine. This strategy could be further combined with pharmacodynamic exploration or pharmacological MRI to investigate the neuropharmacokinetics and neuroreceptor correlate, at least at µ-OR, of the acute effects of buprenorphine in humans.
In memoriam professor Philip Seeman (February 8, 1934-January 9, 2021)
Bertha Madras & Susan George
doi : 10.1038/s41386-021-00975-x
Neuropsychopharmacology volume 46, pages1229–1230(2021)
