Neuropsychopharmacology

It has been proposed that binge eating reflects a pathological compulsion driven by the “addictive” properties of foods. Proponents of this argument highlight the large degree of phenomenological and diagnostic overlap between binge eating disorder (BED) and substance use disorders (SUDs), including loss of control over how much is consumed and repeated unsuccessful attempts to abstain from consumption, as well as commonalities in brain structures involved in food and drug craving. To date, very little attention has been given to an additional behavioral symptom that BED shares with SUDs—sleep dysregulation—and the extent to which this may contribute to the pathophysiology of BED. Here, we review studies examining sleep outcomes in patients with BED, which collectively point to a heightened incidence of sleep abnormalities in BED. We identify the orexin (hypocretin) system as a potential neurobiological link between compulsive eating and sleep dysregulation in BED, and provide a comprehensive update on the evidence linking this system to these processes. Finally, drawing on evidence from the SUD literature indicating that the orexin system exhibits significant plasticity in response to drugs of abuse, we hypothesize that chronic palatable food consumption likewise increases orexin system activity, resulting in dysregulated sleep/wake patterns. Poor sleep, in turn, is predicted to exacerbate binge eating, contributing to a cycle of uncontrolled food consumption. By extension, we suggest that pharmacotherapies normalizing orexin signaling, which are currently being trialed for the treatment of SUDs, might also have utility in the clinical management of BED.

خرید پکیج و مشاهده آنلاین مقاله

Alterations in microbiome composition and metabolic byproducts drive behavioral and transcriptional responses to morphine

Rebecca S. Hofford, Nicholas L. Mervosh, Tanner J. Euston, Katherine R. Meckel, Amon T. Orr & Drew D. Kiraly

doi : 10.1038/s41386-021-01043-0

Neuropsychopharmacology volume 46, pages2062–2072 (2021)

Recent evidence has demonstrated that the gut microbiome has marked effects on neuronal function and behavior. Disturbances to microbial populations within the gut have been linked to myriad models of neuropsychiatric disorders. However, the role of the microbiome in substance use disorders remains understudied. Here we show that male mice with their gut microbiome depleted by nonabsorbable antibiotics (Abx) exhibit decreased formation of morphine conditioned place preference across a range of doses (2.5–15?mg/kg), have decreased locomotor sensitization to morphine, and demonstrate marked changes in gene expression within the nucleus accumbens (NAc) in response to high-dose morphine (20?mg/kg?×?7 days). Replacement of short-chain fatty acid (SCFA) metabolites, which are reduced by microbiome knockdown, reversed the behavioral and transcriptional effects of microbiome depletion. This identifies SCFA as the crucial mediators of microbiome–brain communication responsible for the effects on morphine reward caused by microbiome knockdown. These studies add important new behavioral, molecular, and mechanistic insight to the role of gut–brain signaling in substance use disorders.

خرید پکیج و مشاهده آنلاین مقاله

Selective serotonin reuptake inhibitor treatment retunes emotional valence in primate ventral striatum

Benjamin Pasquereau, Guillaume Drui, Yosuke Saga, Augustin Richard, Mathilde Millot, Elise Météreau, Véronique Sgambato, Philippe N. Tobler & Léon Tremblay

doi : 10.1038/s41386-021-00991-x

Neuropsychopharmacology volume 46, pages2073–2082 (2021)

Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat psychiatric disorders with affective biases such as depression and anxiety. How SSRIs exert a beneficial action on emotions associated with life events is still unknown. Here we ask whether and how the effectiveness of the SSRI fluoxetine is underpinned by neural mechanisms in the ventral striatum. To address these issues, we studied the spiking activity of neurons in the ventral striatum of monkeys during an approach-avoidance task in which the valence assigned to sensory stimuli was manipulated. Neural responses to positive and negative events were measured before and during a 4-week treatment with fluoxetine. We conducted PET scans to confirm that fluoxetine binds within the ventral striatum at a therapeutic dose. In our monkeys, fluoxetine facilitated approach of rewards and avoidance of punishments. These beneficial effects were associated with changes in tonic and phasic activities of striatal neurons. Fluoxetine increased the spontaneous firing rate of striatal neurons and amplified the number of cells responding to rewards versus punishments, reflecting a drug-induced positive shift in the processing of emotionally valenced information. These findings reveal how SSRI treatment affects ventral striatum neurons encoding positive and negative valence and striatal signaling of emotional information. In addition to a key role in appetitive processing, our results shed light on the involvement of the ventral striatum in aversive processing. Together, the ventral striatum appears to play a central role in the action of SSRIs on emotion processing biases commonly observed in psychiatric disorders.

خرید پکیج و مشاهده آنلاین مقاله

Functional connectivity of the anterior insula during withdrawal from cigarette smoking

Dara G. Ghahremani, Jean-Baptiste Pochon, Maylen Perez Diaz, Rachel F. Tyndale, Andy C. Dean & Edythe D. London

doi : 10.1038/s41386-021-01036-z

Neuropsychopharmacology volume 46, pages2083–2089 (2021)

Currently available therapies for smoking cessation have limited efficacy, and potential treatments that target specific brain regions are under evaluation, with a focus on the insula. The ventral and dorsal anterior subregions of the insula serve distinct functional networks, yet our understanding of how these subregions contribute to smoking behavior is unclear. Resting-state functional connectivity (RSFC) provides a window into network-level function associated with smoking-related internal states. The goal of this study was to determine potentially distinct relationships of ventral and dorsal anterior insula RSFC with cigarette withdrawal after brief abstinence from smoking. Forty-seven participants (24 women; 18–45 years old), who smoked cigarettes daily and were abstinent from smoking overnight (~12?h), provided self-reports of withdrawal and underwent resting-state fMRI before and after smoking the first cigarette of the day. Correlations between withdrawal and RSFC were computed separately for ventral and dorsal anterior insula seed regions in whole-brain voxel-wise analyses. Withdrawal was positively correlated with RSFC of the right ventral anterior insula and dorsal anterior cingulate cortex (dACC) before but not after smoking. The correlation was mainly due to a composite effect of craving and physical symptoms of withdrawal. These results suggest a role of right ventral anterior insula-dACC connectivity in the internal states that maintain smoking behavior (e.g., withdrawal) and present a specific neural target for brain-based therapies seeking to attenuate withdrawal symptoms in the critical early stages of smoking cessation.

خرید پکیج و مشاهده آنلاین مقاله

Preclinical evidence to support repurposing everolimus for craving reduction during protracted drug withdrawal

Alvin S. Chiu, Matthew C. Kang, Laura L. Huerta Sanchez, Anne M. Fabella, Kalysta N. Holder, Brooke D. Barger, Kristina N. Elias, Christina B. Shin, C. Leonardo Jimenez Chavez, Tod E. Kippin & Karen K. Szumlinski

doi : 10.1038/s41386-021-01064-9

Neuropsychopharmacology volume 46, pages2090–2100 (2021)

Cue-elicited drug-craving is a cardinal feature of addiction that intensifies (incubates) during protracted withdrawal. In a rat model, these addiction-related behavioral pathologies are mediated, respectively, by time-dependent increases in PI3K/Akt1 signaling and reduced Group 1 metabotropic glutamate receptor (mGlu) expression, within the ventromedial prefrontal cortex (vmPFC). Herein, we examined the capacity of single oral dosing with everolimus, an FDA-approved inhibitor of the PI3K/Akt effector mTOR, to reduce incubated cocaine-craving and reverse incubation-associated changes in vmPFC kinase activity and mGlu expression. Rats were trained to lever-press for intravenous infusions of cocaine or delivery of sucrose pellets and then subjected to tests for cue-reinforced responding during early (3 days) or late (30–46 days) withdrawal. Rats were gavage-infused with everolimus (0–1.0?mg/kg), either prior to testing to examine for effects upon reinforcer-seeking behavior, or immediately following testing to probe effects upon the consolidation of extinction learning. Single oral dosing with everolimus dose-dependently blocked cocaine-seeking during late withdrawal and the effect lasted at least 24?h. No everolimus effects were observed for cue-elicited sucrose-seeking or cocaine-seeking in early withdrawal. In addition, everolimus treatment, following initial cue-testing, reduced subsequent cue hyper-responsivity exhibited observed during late withdrawal, arguing a facilitation of extinction memory consolidation. everolimus’ “anti-incubation” effect was associated with a reversal of withdrawal-induced changes in indices of PI3K/Akt1/mTOR activity, as well as Homer protein and mGlu1/5 expression, within the prelimbic (PL) subregion of the prefrontal cortex. Our results indicate mTOR inhibition as a viable strategy for interrupting heightened cocaine-craving and facilitating addiction recovery during protracted withdrawal.

خرید پکیج و مشاهده آنلاین مقاله

Exploring cannabidiol effects on inflammatory markers in individuals with cocaine use disorder: a randomized controlled trial

Florence Morissette, Violaine Mongeau-Pérusse, Elie Rizkallah, Paméla Thébault, Stéphanie Lepage, Suzanne Brissette, Julie Bruneau, Simon Dubreucq, Emmanuel Stip, Jean-François Cailhier & Didier Jutras-Aswad

doi : 10.1038/s41386-021-01098-z

Neuropsychopharmacology volume 46, pages2101–2111 (2021)

Cocaine use disorder (CUD) is a major public health issue associated with physical, social, and psychological problems. Excessive and repeated cocaine use induces oxidative stress leading to a systemic inflammatory response. Cannabidiol (CBD) has gained substantial interest for its anti-inflammatory properties, safety, and tolerability profile. However, CBD anti-inflammatory properties have yet to be confirmed in humans. This exploratory study is based on a single-site randomized controlled trial that enrolled participants with CUD between 18 and 65 years, randomized (1:1) to daily receive either CBD (800?mg) or placebo for 92 days. The trial was divided into a 10-day detoxification (phase I) followed by a 12-week outpatient follow-up (phase II). Blood samples were collected from 48 participants at baseline, day 8, week 4, and week 12 and were analyzed to determine monocytes and lymphocytes phenotypes, and concentrations of various inflammatory markers such as cytokines. We used generalized estimating equations to detect group differences. Participants treated with CBD had lower levels of interleukin-6 (p?=?0.017), vascular endothelial growth factor (p?=?0.032), intermediate monocytes CD14+CD16+ (p?=?0.024), and natural killer CD56negCD16hi (p?=?0.000) compared with participants receiving placebo. CD25+CD4+T cells were higher in the CBD group (p?=?0.007). No significant group difference was observed for B lymphocytes. This study suggests that CBD may exert anti-inflammatory effects in individuals with CUD.

خرید پکیج و مشاهده آنلاین مقاله

Exploring regulation and function of dopamine D3 receptors in alcohol use disorder. A PET [11C]-(+)-PHNO study

Chidera C. Chukwueke, Christina N. Nona, Matthew D. McPhee, Esmaeil Mansouri, Dafna S. Rubin-Kahana, Diana Martinez, Isabelle Boileau, Christian S. Hendershot & Bernard Le Foll

doi : 10.1038/s41386-021-01095-2

Neuropsychopharmacology volume 46, pages2112–2120 (2021)

Preclinical studies support an important role of dopamine D3 receptors (DRD3s) in alcohol use disorder (AUD). In animals, voluntary alcohol consumption increases DRD3 expression, and pharmacological blockade of DRD3s attenuates alcohol self-administration and reinstatement of alcohol seeking. However, these findings have yet to be translated in humans. This study used positron emission tomography (PET) and [11C]-(+)-PHNO to compare receptor levels in several dopamine D2 receptor (DRD2) and DRD3 regions of interest between AUD subjects in early abstinence (n?=?17; 6.59?±?4.14 days of abstinence) and healthy controls (n?=?18). We recruited non-treatment seeking subjects meeting DSM-5 criteria for AUD. We examined the relationship between DRD2/3 levels and both alcohol craving and alcohol motivation/wanting, using a cue reactivity procedure and an intravenous alcohol self-administration (IVASA) paradigm, respectively. [11C]-(+)-PHNO binding levels in AUD subjects were significantly lower than binding in HCs when looking at all DRD2/3 ROIs jointly (Wilk’s ??=?.58, F(6,28) =3.33, p?=?0.013, ?2p?=?0.42), however there were no region-specific differences. Binding values demonstrate ?12.3% and ?16.1% lower [11C]-(+)-PHNO binding in the SMST and SN respectively, though these differences did not withstand Bonferroni corrections. There was a positive association between [11C]-(+)-PHNO binding in the SN (almost exclusively reflective of DRD3) and alpha (lower values reflect higher alcohol demand) in the APT after Bonferroni corrections (r?=?0.66, p?=?0.0080). This demonstrates that AUD subjects with lower DRD3 levels in the SN exhibit increased demand for alcohol. These results replicate previous findings demonstrating reduced DRD2/3 levels while also supporting a lack of DRD3 upregulation and potential downregulation in early abstinent AUD. Furthermore, the finding that binding in the SN is associated with alcohol demand warrants further examination.

خرید پکیج و مشاهده آنلاین مقاله

NOP receptor antagonism attenuates reinstatement of alcohol-seeking through modulation of the mesolimbic circuitry in male and female alcohol-preferring rats

Anna Maria Borruto, Yannick Fotio, Serena Stopponi, Michele Petrella, Sara De Carlo, Ana Domi, Massimo Ubaldi, Friedbert Weiss & Roberto Ciccocioppo

doi : 10.1038/s41386-021-01096-1

Neuropsychopharmacology volume 46, pages2121–2131 (2021)

In patients suffering from alcohol use disorder (AUD), stress and environmental stimuli associated with alcohol availability are important triggers of relapse. Activation of the nociceptin opioid peptide (NOP) receptor by its endogenous ligand Nociceptin/Orphanin FQ (N/OFQ) attenuates alcohol drinking and relapse in rodents, suggesting that NOP agonists may be efficacious in treating AUD. Intriguingly, recent data demonstrated that also blockade of NOP receptor reduced alcohol drinking in rodents. To explore further the potential of NOP antagonism, we investigated its effects on the reinstatement of alcohol-seeking elicited by administration of the ?2 antagonist yohimbine (1.25?mg/kg, i.p.) or by environmental conditioning factors in male and female genetically selected alcohol-preferring Marchigian Sardinian (msP) rats. The selective NOP receptor antagonist LY2817412 (0.0, 3.0, 10.0, and 30.0?mg/kg) was first tested following oral (p.o.) administration. We then investigated the effects of LY2817412 (1.0, 3.0, 6.0??g/?l/rat) microinjected into three candidate mesolimbic brain regions: the ventral tegmental area (VTA), the central nucleus of the amygdala (CeA), and the nucleus accumbens (NAc). We found that relapse to alcohol seeking was generally stronger in female than in male rats and oral administration of LY2817412 reduced yohimbine- and cue-induced reinstatement in both sexes. Following site-specific microinjections, LY2817412 reduced yohimbine-induced reinstatement of alcohol-seeking when administered into the VTA and the CeA, but not in the NAc. Cue-induced reinstatement was suppressed only when LY2817412 was microinjected into the VTA. Infusions of LY2817412 into the VTA and the CeA did not alter saccharin self-administration. These results demonstrate that NOP receptor blockade prevents the reinstatement of alcohol-seeking through modulation of mesolimbic system circuitry, providing further evidence of the therapeutic potential of NOP receptor antagonism in AUD.

خرید پکیج و مشاهده آنلاین مقاله

Genetic contributions to alcohol use disorder treatment outcomes: a genome-wide pharmacogenomics study

Joanna M. Biernacka, Brandon J. Coombes, Anthony Batzler, Ada Man-Choi Ho, Jennifer R. Geske, Josef Frank, Colin Hodgkinson, Michelle Skime, Colin Colby, Lea Zillich, Sofia Pozsonyiova, Ming-Fen Ho, Falk Kiefer, Marcella Rietschel, Richard Weinshilboum, Stephanie S. O’Malley, Karl Mann, Ray Anton, David Goldman & Victor M. Karpyak

doi : 10.1038/s41386-021-01097-0

Neuropsychopharmacology volume 46, pages2132–2139 (2021)

Naltrexone can aid in reducing alcohol consumption, while acamprosate supports abstinence; however, not all patients with alcohol use disorder (AUD) benefit from these treatments. Here we present the first genome-wide association study of AUD treatment outcomes based on data from the COMBINE and PREDICT studies of acamprosate and naltrexone, and the Mayo Clinic CITA study of acamprosate. Primary analyses focused on treatment outcomes regardless of pharmacological intervention and were followed by drug-stratified analyses to identify treatment-specific pharmacogenomic predictors of acamprosate and naltrexone response. Treatment outcomes were defined as: (1) time until relapse to any drinking (TR) and (2) time until relapse to heavy drinking (THR;???5 drinks for men, ?4 drinks for women in a day), during the first 3 months of treatment. Analyses were performed within each dataset, followed by meta-analysis across the studies (N?=?1083 European ancestry participants). Single nucleotide polymorphisms (SNPs) in the BRE gene were associated with THR (min p?=?1.6E?8) in the entire sample, while two intergenic SNPs were associated with medication-specific outcomes (naltrexone THR: rs12749274, p?=?3.9E?8; acamprosate TR: rs77583603, p?=?3.1E?9). The top association signal for TR (p?=?7.7E?8) and second strongest signal in the THR (p?=?6.1E?8) analysis of naltrexone-treated patients maps to PTPRD, a gene previously implicated in addiction phenotypes in human and animal studies. Leave-one-out polygenic risk score analyses showed significant associations with TR (p?=?3.7E?4) and THR (p?=?2.6E?4). This study provides the first evidence of a polygenic effect on AUD treatment response, and identifies genetic variants associated with potentially medication-specific effects on AUD treatment response.

خرید پکیج و مشاهده آنلاین مقاله

Effectiveness of spironolactone dispensation in reducing weekly alcohol use: a retrospective high-dimensional propensity score-matched cohort study

Vanessa A. Palzes, Mehdi Farokhnia, Andrea H. Kline-Simon, Joseph Elson, Stacy Sterling, Lorenzo Leggio, Constance Weisner & Felicia W. Chi

doi : 10.1038/s41386-021-01117-z

Neuropsychopharmacology volume 46, pages2140–2147 (2021)

There is a need to increase the armamentarium of pharmacotherapies for alcohol use disorder (AUD). Recent research suggests that mineralocorticoid receptor (MR) antagonism via spironolactone may represent a novel pharmacological treatment for AUD. We conducted a pharmacoepidemiologic retrospective cohort study (June 1, 2014 to May 31, 2018) to examine whether spironolactone dispensation (?90 continuous days), for any indication, is associated with changes in weekly alcohol use about 6 months later. We compared 523 spironolactone-treated adults and 2305 untreated adults, matched on high-dimensional propensity scores created from a set of predefined (sociodemographic and health characteristics, diagnoses, and service utilization) and empirical electronic health record-derived covariates. The sample was 57% female and 27% non-White with a mean age of 59.2 years (SD?=?19.3). Treated patients reduced their weekly alcohol use by 3.50 drinks (95% CI?=??4.22, ?2.79), while untreated patients reduced by 2.74 drinks (95% CI?=??3.22, ?2.26), yielding a significant difference of 0.76 fewer drinks (95% CI?=??1.43, ?0.11). Among those who drank >7 drinks/week at baseline, treated patients, compared to untreated patients, reported a greater reduction in weekly alcohol use by 4.18 drinks (95% CI?=??5.38, ?2.97), while there was no significant difference among those who drank less. There was a significant dose-response relationship between spironolactone dosage and change in drinks/week. Pending additional evidence on its safety and efficacy in individuals with AUD, spironolactone (and MR blockade, at large) may hold promise as a pharmacotherapy for AUD.

خرید پکیج و مشاهده آنلاین مقاله

Frontal cortex genetic ablation of metabotropic glutamate receptor subtype 3 (mGlu3) impairs postsynaptic plasticity and modulates affective behaviors

Max E. Joffe, Chiaki I. Santiago, Sheryl Anne D. Vermudez, Nicole M. Fisher, Shalini Dogra, Colleen M. Niswender & P. Jeffrey Conn

doi : 10.1038/s41386-021-01041-2

Neuropsychopharmacology volume 46, pages2148–2157 (2021)

Clinical and translational studies suggest that prefrontal cortex (PFC) dysregulation is a hallmark feature of several affective disorders. Thus, investigating the mechanisms involved in the regulation of PFC function and synaptic plasticity could aid in developing new medications. In recent years, the mGlu2 and mGlu3 subtypes of metabotropic glutamate (mGlu) receptors have emerged as exciting potential targets for the treatment of affective disorders, as mGlu2/3 antagonists exert antidepressant-like effects across many rodent models. Several recent studies suggest that presynaptic mGlu2 receptors may contribute to these effects by regulating excitatory transmission at synapses from the thalamus to the PFC. Interestingly, we found that mGlu3 receptors also inhibit excitatory drive to the PFC but act by inducing long-term depression (LTD) at amygdala-PFC synapses. It remains unclear, however, whether blockade of presynaptic, postsynaptic, or glial mGlu3 receptors contribute to long-term effects on PFC circuit function and antidepressant-like effects of mGlu2/3 antagonists. To address these outstanding questions, we leveraged transgenic Grm3fl/fl mice and viral-mediated gene transfer to genetically ablate mGlu3 receptors from pyramidal cells in the frontal cortex of adult mice of all sexes. Consistent with a role for mGlu3 in PFC pyramidal cells, mGlu3-dependent amygdala-cortical LTD was eliminated following mGlu3 receptor knockdown. Furthermore, knockdown mice displayed a modest, task-specific anxiolytic phenotype and decreased passive coping behaviors. These studies reveal that postsynaptic mGlu3 receptors are critical for mGlu3-dependent LTD and provide convergent genetic evidence suggesting that modulating cortical mGlu3 receptors may provide a promising new approach for the treatment of mood disorders.

خرید پکیج و مشاهده آنلاین مقاله

Suppression of pyramidal neuron G protein-gated inwardly rectifying K+?channel signaling impairs prelimbic cortical function and underlies stress-induced deficits in cognitive flexibility in male, but not female, mice

Eden M. Anderson, Steven Loke, Benjamin Wrucke, Annabel Engelhardt, Skyler Demis, Kevin O’Reilly, Evan Hess, Kevin Wickman & Matthew C. Hearing

doi : 10.1038/s41386-021-01063-w

Neuropsychopharmacology volume 46, pages2158–2169 (2021)

Imbalance in prefrontal cortical (PFC) pyramidal neuron excitation:inhibition is thought to underlie symptomologies shared across stress-related disorders and neuropsychiatric disease, including dysregulation of emotion and cognitive function. G protein-gated inwardly rectifying K+ (GIRK/Kir3) channels mediate excitability of medial PFC pyramidal neurons, however, the functional role of these channels in mPFC-dependent regulation of affect, cognition, and cortical dynamics is unknown. We used a viral-cre approach in male and female mice harboring a “floxed” version of the kcnj3 (Girk1) gene, to disrupt GIRK1-containing channel expression in pyramidal neurons within the prelimbic cortex (PrL). In males, loss of pyramidal GIRK1-dependent signaling differentially impacted measures of affect and impaired working memory and cognitive flexibility. Unexpectedly, ablation of PrL GIRK1-dependent signaling did not impact affect or cognition in female mice. Additional studies used a model of chronic unpredictable stress (CUS) to determine the impact on PrL GIRK-dependent signaling and cognitive function. CUS exposure in male mice produced deficits in cognition that paralleled a reduction in PrL pyramidal GIRK-dependent signaling akin to viral approaches whereas CUS exposure in female mice did not alter cognitive flexibility performance. Stress-induced behavioral deficits in male mice were rescued by systemic injection of a novel, GIRK1-selective agonist, ML297. In conclusion, GIRK1-dependent signaling in male mice, but not females, is critical for maintaining optimal PrL function and behavioral control. Disruption of this inhibition may underlie stress-related dysfunction of the PrL and represent a therapeutic target for treating stress-induced deficits in affect regulation and impaired cognition that reduce quality of life.

خرید پکیج و مشاهده آنلاین مقاله

Enduring glucocorticoid-evoked exacerbation of synaptic plasticity disruption in male rats modelling early Alzheimer’s disease amyloidosis

Yingjie Qi, Igor Klyubin, Tomas Ondrejcak, Neng-Wei Hu & Michael J. Rowan

doi : 10.1038/s41386-021-01056-9

Neuropsychopharmacology volume 46, pages2170–2179 (2021)

Synaptic dysfunction is a likely proximate cause of subtle cognitive impairment in early Alzheimer’s disease. Soluble oligomers are the most synaptotoxic forms of amyloid ß-protein (Aß) and mediate synaptic plasticity disruption in Alzheimer’s disease amyloidosis. Because the presence and extent of cortisol excess in prodromal Alzheimer’s disease predicts the onset of cognitive symptoms we hypothesised that corticosteroids would exacerbate the inhibition of hippocampal synaptic long-term potentiation in a rat model of Alzheimer’s disease amyloidosis. In a longitudinal experimental design using freely behaving pre-plaque McGill-R-Thy1-APP male rats, three injections of corticosterone or the glucocorticoid methylprednisolone profoundly disrupted long-term potentiation induced by strong conditioning stimulation for at least 2 months. The same treatments had a transient or no detectible detrimental effect on synaptic plasticity in wild-type littermates. Moreover, corticosterone-mediated cognitive dysfunction, as assessed in a novel object recognition test, was more persistent in the transgenic animals. Evidence for the involvement of pro-inflammatory mechanisms was provided by the ability of the selective the NOD-leucine rich repeat and pyrin containing protein 3 (NLRP3) inflammasome inhibitor Mcc950 to reverse the synaptic plasticity deficit in corticosterone-treated transgenic animals. The marked prolongation of the synaptic plasticity disrupting effects of brief corticosteroid excess substantiates a causal role for hypothalamic-pituitary-adrenal axis dysregulation in early Alzheimer’s disease.

خرید پکیج و مشاهده آنلاین مقاله

Default mode network dissociation linking cerebral beta amyloid retention and depression in cognitively normal older adults

Sheng-Min Wang, Nak-Young Kim, Yoo Hyun Um, Dong Woo Kang, Hae-Ran Na, Chang Uk Lee & Hyun Kook Lim

doi : 10.1038/s41386-021-01072-9

Neuropsychopharmacology volume 46, pages2180–2187 (2021)

Cerebral beta amyloid (A?) deposition and late-life depression (LLD) are known to be associated with the trajectory of Alzheimer’s disease (AD). However, their neurobiological link is not clear. Previous studies showed aberrant functional connectivity (FC) changes in the default mode network (DMN) in early A? deposition and LLD, but its mediating role has not been elucidated. This study was performed to investigate the distinctive association pattern of DMN FC linking LLD and A? retention in cognitively normal older adults. A total of 235 cognitively normal older adults with (n?=?118) and without depression (n?=?117) underwent resting-state functional magnetic resonance imaging and 18F-flutemetamol positron emission tomography to investigate the associations between A? burden, depression, and DMN FC. Independent component analysis showed increased anterior DMN FC and decreased posterior DMN FC in the depression group compared with the no depression group. Global cerebral A? retention was positively correlated with anterior and negatively correlated with posterior DMN FC. Anterior DMN FC was positively correlated with severity of depression, whereas posterior DMN FC was negatively correlated with cognitive function. In addition, the effects of global cerebral A? retention on severity of depression were mediated by subgenual anterior cingulate FC. Our results of anterior and posterior DMN FC dissociation pattern may be pivotal in linking cerebral A? pathology and LLD in the course of AD progression. Further longitudinal studies are needed to confirm the causal relationships between cerebral A? retention and LLD.

خرید پکیج و مشاهده آنلاین مقاله

Reductions in rostral anterior cingulate GABA are associated with stress circuitry in females with major depression: a multimodal imaging investigation

Maria Ironside, Amelia D. Moser, Laura M. Holsen, Chun S. Zuo, Fei Du, Sarah Perlo, Christine E. Richards, Jessica M. Duda, Xi Chen, Lisa D. Nickerson, Kaylee E. Null, Nara Nascimento, David J. Crowley, Madhusmita Misra, Jill M. Goldstein & Diego A. Pizzagalli

doi : 10.1038/s41386-021-01127-x

Neuropsychopharmacology volume 46, pages2188–2196 (2021)

The interplay between cortical and limbic regions in stress circuitry calls for a neural systems approach to investigations of acute stress responses in major depressive disorder (MDD). Advances in multimodal imaging allow inferences between regional neurotransmitter function and activation in circuits linked to MDD, which could inform treatment development. The current study investigated the role of the inhibitory neurotransmitter GABA in stress circuitry in females with current and remitted MDD. Multimodal imaging data were analyzed from 49 young female adults across three groups (current MDD, remitted MDD (rMDD), and healthy controls). GABA was assessed at baseline using magnetic resonance spectroscopy, and functional MRI data were collected before, during, and after an acute stressor and analyzed using a network modeling approach. The MDD group showed an overall lower cortisol response than the rMDD group and lower rostral anterior cingulate cortex (ACC) GABA than healthy controls. Across groups, stress decreased activation in the frontoparietal network (FPN) but increased activation in the default mode network (DMN) and a network encompassing the ventromedial prefrontal cortex–striatum–anterior cingulate cortex (vmPFC–Str–ACC). Relative to controls, the MDD and rMDD groups were characterized by decreased FPN and salience network (SN) activation overall. Rostral ACC GABA was positively associated with connectivity between an overlapping limbic network (Temporal–Insula–Amygdala) and two other circuits (FPN and DMN). Collectively, these findings indicate that reduced GABA in females with MDD was associated with connectivity differences within and across key networks implicated in depression. GABAergic treatments for MDD might alleviate stress circuitry abnormalities in females.

خرید پکیج و مشاهده آنلاین مقاله

?2-containing ?-aminobutyric acid type A receptors promote stress resiliency in male mice

Rebecca S. Benham, Catherine Choi, Nathaniel W. Hodgson, Nishani B. Hewage, Rahel Kastli, Rachel J. Donahue, John W. Muschamp, Elif Engin, William A. Carlezon Jr., Takao K. Hensch & Uwe Rudolph

doi : 10.1038/s41386-021-01144-w

Neuropsychopharmacology volume 46, pages2197–2206 (2021)

Brain ?2-containing GABAA receptors play a critical role in the modulation of anxiety- and fear-like behavior. However, it is unknown whether these receptors also play a role in modulating resilience to chronic stress, and in which brain areas and cell types such an effect would be mediated. We evaluated the role of ?2-containing GABAA receptors following chronic social defeat stress using male mice deficient in the ?2 subunit globally or conditionally in dopamine D1- or D2-receptor-expressing neurons, e.g., within the nucleus accumbens (NAc). In addition, we examined the effect of the lack of the ?2 subunit on intermediates of the glutathione synthesis pathway. We found that ?2-containing GABAA receptors on D2-receptor-positive but not on D1-receptor-positive neurons promote resiliency to chronic social defeat stress, as reflected in social interaction tests. The pro-resiliency effects of ?2-containing GABAA receptors on D2-receptor-positive neurons do not appear to be directly related to alterations in anxiety-like behavior, as reflected in the elevated plus-maze, light–dark box, and novel open field tests. Increases in indices of oxidative stress—reflected by increases in cystathionine levels and reductions in GSH/GSSG ratios—were found in the NAc and prefrontal cortex but not in the hippocampus of mice lacking ?2-containing GABAA receptors. We conclude that ?2-containing GABAA receptors within specific brain areas and cell populations promote stress resiliency independently of direct effects on anxiety-like behaviors. A potential mechanism contributing to this increased resiliency is the protection that ?2-containing GABAA receptors provide against oxidative stress in NAc and the prefrontal cortex.

خرید پکیج و مشاهده آنلاین مقاله

Differentiating white matter measures that protect against vs. predispose to bipolar disorder and other psychopathology in at-risk youth

Renata Rozovsky, Amelia Versace, Lisa K. Bonar, Michele Bertocci, Cecile D. Ladouceur, Jay Fournier, Kelly Monk, Halimah Abdul-waalee, Genna Bebko, Danella Hafeman, Dara Sakolsky, Tina Goldstein, Boris Birmaher & Mary L. Phillips

doi : 10.1038/s41386-021-01088-1

Neuropsychopharmacology volume 46, pages2207–2216 (2021)

Bipolar disorder (BD) is highly heritable. Identifying objective biomarkers reflecting pathophysiological processes predisposing to, versus protecting against BD, can help identify BD risk in offspring of BD parents. We recruited 21 BD participants with a first-degree relative with BD, 25 offspring of BD parents, 27 offspring of comparison parents with non-BD psychiatric disorders, and 32 healthy offspring of healthy parents. In at-risk groups, 23 had non-BD diagnoses and 29, no Axis-I diagnoses(healthy). Five at-risk offspring who developed BD post scan(Converters) were included. Diffusion imaging(dMRI) analysis with tract segmentation identified between-group differences in the microstructure of prefrontal tracts supporting emotional regulation relevant to BD: forceps minor, anterior thalamic radiation(ATR), cingulum bundle(CB), and uncinate fasciculus(UF). BD participants showed lower fractional anisotropy (FA) in the right CB (anterior portion) than other groups (q?<?0.05); and in bilateral ATR (posterior portion) versus at-risk groups (q?<?0.001). Healthy, but not non-BD, at-risk participants showed significantly higher FA in bilateral ATR clusters than healthy controls (qs?<?0.05). At-risk groups showed higher FA in these clusters than BD participants (qs?<?0.05). Non-BD versus healthy at-risk participants, and Converters versus offspring of BD parents, showed lower FA in the right ATR cluster (qs?<?0.05). Low anterior right CB FA in BD participants versus other groups might result from having BD. High bilateral ATR FA in at-risk groups, and in healthy at-risk participants, versus healthy controls might protect against BD/other psychiatric disorders. Absence of elevated right ATR FA in non-BD versus healthy at-risk participants, and in Converters versus non-converter offspring of BD parents, might lower protection against BD in at-risk groups.

خرید پکیج و مشاهده آنلاین مقاله

Pediatric PTSD is characterized by age- and sex-related abnormalities in structural connectivity

Justin D. Russell, Sara A. Heyn, Doug C. Dean III & Ryan J. Herringa

doi : 10.1038/s41386-021-01083-6

Neuropsychopharmacology volume 46, pages2217–2223 (2021)

Pediatric post-traumatic stress disorder (pPTSD) is a prevalent and pervasive form of mental illness comprising a disparate constellation of psychiatric symptoms. Emerging evidence suggests that pPTSD may be characterized by alterations in functional networks traversing the brain. Yet, little is known about pathological changes in the structural tracts underlying functional connectivity. In adults, PTSD is linked to widespread change in white matter integrity throughout the brain, yet similar studies with youth populations have yet to be conducted. Current understanding of the nature and treatment of pPTSD may be enhanced by examining alterations in white matter, while further untangling effects of age and sex. Here, we assess the microstructure of 12 major white matter tracts in a sample of well-phenotyped youth with PTSD. Measures of fractional anisotropy were derived from diffusion tensor images acquired from 82 unmediated youth (ages 8–18), of whom 39 met criteria for pPTSD. Diagnosis of pPTSD was linked to remarkable age- and sex-linked differences in the microstructure of major white matter tracts including the uncinate fasciculus, cingulum bundle, and inferior longitudinal fasciculus. In each case, youth with PTSD show an absence of increased white matter integrity with age, suggesting an altered pattern of neurodevelopment that may contribute to persistence or worsening of illness. Broadly, our results suggest abnormal white matter development in pediatric PTSD, a finding which may contribute to illness persistence, comorbidity with other disorders, and poorer prognosis across time. Critically, these findings further speak to the nature of pPTSD as a ‘whole-brain’ disorder.

خرید پکیج و مشاهده آنلاین مقاله

Correction to: Selective kappa-opioid antagonism ameliorates anhedonic behavior: evidence from the Fast-fail Trial in Mood and Anxiety Spectrum Disorders (FAST-MAS)

Diego A. Pizzagalli, Moria Smoski, Yuen-Siang Ang, Alexis E. Whitton, Gerard Sanacora, Sanjay J. Mathew, John Nurnberger Jr, Sarah H. Lisanby, Dan V. Iosifescu, James W. Murrough, Hongqiu Yang, Richard D. Weiner, Joseph R. Calabrese, Wayne Goodman, William Z. Potter & Andrew D. Krystal

doi : 10.1038/s41386-021-01145-9

Neuropsychopharmacology volume 46, page2224 (2021)

خرید پکیج و مشاهده آنلاین مقاله