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  • Latent variable analysis of negative affect and its contributions to neural responses during shock anticipation
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-08-22
    Namik Kirlic, Robin L. Aupperle, Jamie L. Rhudy, Masaya Misaki, Rayus Kuplicki, Anne Sutton, Ruben P. Alvarez

    Negative affect is considered an important factor in the etiology of depression and anxiety, and is highly related to pain. However, negative effect is not a unitary construct. To identify specific targets for treatment development, we aimed to derive latent variables of negative affect and test their unique contributions to affective processing during anticipation of unpredictable, painful shock. Eighty-three subjects (43 with depression and anxiety spectrum disorders and 40 healthy controls) completed self-report measures of negative valence and underwent neuroimaging while exploring computer-simulated contexts with and without the threat of a painful, but tolerable, shock. Principal component analysis (PCA) extracted distinct components of general negative affect (GNA) and pain-related negative affect (PNA). While elevated GNA and PNA were both indicative of depression and anxiety disorders, greater PNA was more strongly related to task-specific anxious reactivity during shock anticipation. GNA was associated with increased precuneus and middle frontal gyrus activity, whereas PNA was related to increased bilateral anterior insula activity. Anterior insula activity mediated the relationship between PNA and task-specific anxious reactivity. In conclusion, GNA and PNA have distinct neural signatures and uniquely contribute to anxious anticipation. PNA, via insula activity, may relate to arousal in ways that could contribute to affective dysregulation, and thus may be an important treatment target.

    更新日期:2018-08-22
  • CB1R regulates CDK5 signaling and epigenetically controls Rac1 expression contributing to neurobehavioral abnormalities in mice postnatally exposed to ethanol
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-08-22
    Vikram Joshi, Shivakumar Subbanna, Madhu Shivakumar, Balapal S. Basavarajappa

    Fetal alcohol spectrum disorders (FASD) represent a wide array of defects that arise from ethanol exposure during development. However, the underlying molecular mechanisms are limited. In the current report, we aimed to further evaluate the cannabinoid receptor type 1 (CB1R)-mediated mechanisms in a postnatal ethanol-exposed animal model. We report that the exposure of postnatal day 7 (P7) mice to ethanol generates p25, a CDK5-activating peptide, in a time- and CB1R-dependent manner in the hippocampus and neocortex brain regions. Pharmacological inhibition of CDK5 activity before ethanol exposure prevented accumulation of cleaved caspase-3 (CC3) and hyperphosphorylated tau (PHF1) (a marker for neurodegeneration) in neonatal mice and reversed cAMP response element-binding protein (CREB) activation and activity-regulated cytoskeleton-associated protein (Arc) expression. We also found that postnatal ethanol exposure caused a loss of RhoGTPase-related, Rac1, gene expression in a CB1R and CDK5 activity-dependent manner, which persisted to adulthood. Our epigenetic analysis of the Rac1 gene promoter suggested that persistent suppression of Rac1 expression is mediated by enhanced histone H3 lysine 9 dimethylation (H3K9me2), a repressive chromatin state, via G9a recruitment. The inhibition of CDK5/p25 activity before postnatal ethanol exposure rescued CREB activation, Arc, chromatin remodeling and Rac1 expression, spatial memory, and long-term potentiation (LTP) abnormalities in adult mice. Together, these findings propose that the postnatal ethanol-induced CB1R-mediated activation of CDK5 suppresses Arc and Rac1 expression in the mouse brain and is responsible for persistent synaptic plasticity and learning and memory defects in adult mice. This CB1R-mediated activation of CDK5 signaling during active synaptic development may slow down the maturation of synaptic circuits and may cause neurobehavioral defects, as found in this FASD animal model.

    更新日期:2018-08-22
  • Parental smartphone use and children’s mental outcomes: a neuroscience perspective
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-08-21
    Tallie Z. Baram, Jessica L. Bolton

    Parental smartphone use and children’s mental outcomes: a neuroscience perspectiveParental smartphone use and children’s mental outcomes: a neuroscience perspective, Published online: 21 August 2018; doi:10.1038/s41386-018-0184-8Parental smartphone use and children’s mental outcomes: a neuroscience perspective

    更新日期:2018-08-21
  • Maternal immune activation: reporting guidelines to improve the rigor, reproducibility, and transparency of the model
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-08-21
    Amanda C. Kentner, Staci D. Bilbo, Alan S. Brown, Elaine Y. Hsiao, A. Kimberley McAllister, Urs Meyer, Brad D. Pearce, Mikhail V. Pletnikov, Solomon H. Snyder, Robert H. Yolken, Melissa D. Bauman

    The 2017 American College of Neuropychopharmacology (ACNP) conference hosted a Study Group on 4 December 2017, Establishing best practice guidelines to improve the rigor, reproducibility, and transparency of the maternal immune activation (MIA) animal model of neurodevelopmental abnormalities. The goals of this session were to (a) evaluate the current literature and establish a consensus on best practices to be implemented in MIA studies, (b) identify remaining research gaps warranting additional data collection and lend to the development of evidence-based best practice design, and (c) inform the MIA research community of these findings. During this session, there was a detailed discussion on the importance of validating immunogen doses and standardizing the general design (e.g., species, immunogenic compound used, housing) of our MIA models both within and across laboratories. The consensus of the study group was that data does not currently exist to support specific evidence-based model selection or methodological recommendations due to lack of consistency in reporting, and that this issue extends to other inflammatory models of neurodevelopmental abnormalities. This launched a call to establish a reporting checklist focusing on validation, implementation, and transparency modeled on the ARRIVE Guidelines and CONSORT (scientific reporting guidelines for animal and clinical research, respectively). Here we provide a summary of the discussions in addition to a suggested checklist of reporting guidelines needed to improve the rigor and reproducibility of this valuable translational model, which can be adapted and applied to other animal models as well.

    更新日期:2018-08-21
  • Nicotine effects on associative learning in human non-smokers
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-08-17
    Britta Hahn, Ashleigh K. Wells, Agatha Lenartowicz, Marie B. Yuille

    Tobacco smoking is the most common preventable cause of death in the US. Nicotine is considered the primary constituent responsible for tobacco addiction. Its paradoxically high abuse potential may reflect behavioral control by drug-associated stimuli, which appears to play a larger role for tobacco dependence than for other abused drugs. We tested a potential explanation, hypothesizing that nicotine enhances associative learning, the mechanism underlying the conditioning of drug-associated stimuli. Thirty-two non-smokers were exposed to transdermal nicotine (7 mg/24 h) and placebo in a double-blind cross-over study and tested with behavioral paradigms designed to isolate incidental stimulus–stimulus or stimulus–response learning. The stop signal task required speeded gender judgments of face stimuli. A tone signaled when to withhold the response. Unbeknownst to participants, some faces were always paired with stop trials. Nicotine enhanced the facilitation of stop-responses to these stimuli, and the slowing of go-responses when previously stop-associated stimuli were paired with go trials, indicating stronger associations between paired stimuli and the stop signal/stop response. Another task required feedback-based learning of associations between pairs of shape stimuli. Five pairs were made from either ten different stimuli, or from different combinations of two identical sets of five stimuli with correct associations depending on contextual information. Nicotine increased incorrect choices of stimuli that were associated in a different context, indicating stronger stimulus–stimulus associations at the expense of flexible context-adaptive behavior. The results indicate that nicotine can enhance incidental associative learning, a mechanism that may promote the formation of smoking-associated stimuli and habitual, cue-controlled drug-taking.

    更新日期:2018-08-17
  • Striato-cortical tracts predict 12-h abstinence-induced lapse in smokers
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-08-15
    Kai Yuan, Meng Zhao, Dahua Yu, Peter Manza, Nora D. Volkow, Gene-Jack Wang, Jie Tian

    Striatal circuit dysfunction is implicated in smoking behaviors and lapses during abstinence attempts. However, little is known about whether the structural connectivity of striatal tracts can be used to predict abstinence-induced craving and lapses. The tract strengths of striatal circuits were compared in 53 male nicotine-dependent cigarette smokers and 58 matched nonsmokers, using seed-based classification by diffusion tensor imaging (DTI) probabilistic tractography with 10 a priori target masks. A 12-h abstinence procedure was then employed, after which 31 individuals abstained and 22 lapsed. Linear regression and binary logistic regression was conducted to test whether the tract strength of frontostriatal circuits was associated with craving changes in abstainers and predicted lapse in smokers. Compared with nonsmokers, in the left hemisphere, smokers showed weaker tract strength in striatum-medial orbitofrontal cortex (mOFC), striatum-ventral lateral prefrontal cortex (vlPFC), striatum-inferior frontal gyrus (IFG) and striatum-posterior cingulate cortex (PCC) (Bonferroni corrected, p < 0.05/20 = 0.0025). In abstainers, the abstinence-induced increases in craving were associated with the tract strength of the left striatum-mOFC and striatum-vlPFC. The tract strength of left striatum-dorsolateral PFC (dlPFC) predicted lapse in smokers with an accuracy of 68.3%. These results provide system-level insights into the weaker tract strength of frontostriatal circuits in male smokers and their potential roles as neuroimaging markers for abstinence-induced craving and risk of lapse. Future studies in female smokers are needed to determine if this generalizes across genders.

    更新日期:2018-08-15
  • Do baseline sub-threshold hypomanic symptoms affect acute-phase antidepressant outcome in outpatients with major depressive disorder? Preliminary findings from the randomized CO-MED trial
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-08-15
    Manish K. Jha, Ashley L. Malchow, Bruce D. Grannemann, A. John Rush, Madhukar H. Trivedi

    Sub-threshold hypomanic symptoms are common in major depressive disorder. This study evaluated the prevalence, the clinical and sociodemographic correlates, and the overall and differential effects of the presence/absence of sub-threshold hypomanic symptoms at baseline on acute-phase treatment outcomes with bupropion-plus-escitalopram, escitalopram monotherapy, and venlafaxine-plus-mirtazapine combination. Combining medications to enhance depression outcomes (CO-MED) trial participants (n = 665) were designated as sub-threshold hypomanic symptoms present (Altman Self-Rating Mania Scale score (ASRM) ≥ 1) or absent (ASRM = 0) and compared on clinical and sociodemographic features and remission rates. Participants with sub-threshold hypomanic symptoms (n = 335/665, 50.4%) were more likely to be black and non-Hispanic, have comorbid medical and psychiatric disorders, experience longer index episodes, and report lower depression severity and psychosocial impairment. Intent-to-treat remission rates were lower overall (absent = 42.7%, present = 34.0%, p = 0.02), with escitalopram monotherapy (absent = 45.8%, present = 31.6%, p = 0.03), and with venlafaxine-XR-plus-mirtazapine (absent = 44.4%, present = 30.1%, p = 0.03) but not with bupropion-plus-escitalopram (absent = 37.7%, present = 40.0%, p = 0.73). Participants without sub-threshold hypomanic symptoms were more likely to remit than those with such symptoms overall [odds ratio (OR) = 1.49], with escitalopram monotherapy (OR = 1.71), and with venlafaxine-plus-mirtazapine (OR = 1.97) but not with bupropion-plus-escitalopram (OR = 0.96), even after controlling for baseline depression severity, psychosocial impairment, and number of comorbid psychiatric disorders. Sub-threshold hypomanic symptoms (found in about 50% of patients in this report) were associated with lower remission rates with escitalopram monotherapy and with a venlafaxine-plus-mirtazapine combination but not with the bupropion-plus-escitalopram combination.

    更新日期:2018-08-15
  • Memory enhancing effects of BPN14770, an allosteric inhibitor of phosphodiesterase-4D, in wild-type and humanized mice
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-08-14
    Chong Zhang, Ying Xu, Anirudh Chowdhary, David Fox 3rd, Mark E. Gurney, Han-Ting Zhang, Benjamin D. Auerbach, Richard J. Salvi, Mingxin Yang, Gaowen Li, James M. O’Donnell

    Inhibitors of phosphodiesterase-4 (PDE4) have beneficial effects on memory in preclinical and clinical studies. Development of these drugs has stalled due to dose-limiting side effects of nausea and emesis. While use of subtype-selective inhibitors (i.e., for PDE4A, B, or D) could overcome this issue, conservation of the catalytic region, to which classical inhibitors bind, limits this approach. The present study examined the effects of BPN14770, an allosteric inhibitor of PDE4D, which binds to a primate-specific, N-terminal region. In mice engineered to express PDE4D with this primate-specific sequence, BPN14770 was 100-fold more potent for improving memory than in wild-type mice; meanwhile, it exhibited low potency in a mouse surrogate model for emesis. BPN14770 also antagonized the amnesic effects of scopolamine, increased cAMP signaling in brain, and increased BDNF and markers of neuronal plasticity associated with memory. These data establish a relationship between PDE4D target engagement and effects on memory for BPN14770 and suggest clinical potential for PDE4D-selective inhibitors.

    更新日期:2018-08-14
  • Let’s call the whole thing off: evaluating gender and sex differences in executive function
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-08-14
    Nicola M. Grissom, Teresa M. Reyes

    The executive functions allow for purposeful, deliberate, and intentional interactions with the world—attention and focus, impulse control, decision making, and working memory. These measures have been correlated with academic outcomes and quality of life, and are impacted by deleterious environmental events throughout the life span, including gestational and early life insults. This review will address the topic of sex differences in executive function including a discussion of differences arising in response to developmental programming. Work on gender differences in human studies and sex differences in animal research will be reviewed. Overall, we find little support for significant gender or sex differences in executive function. An important variable that factors into the interpretation of potential sex differences include differing developmental trajectories. We conclude by discussing future directions for the field and a brief discussion of biological mechanisms.

    更新日期:2018-08-14
  • JHU-083 selectively blocks glutaminase activity in brain CD11b+ cells and prevents depression-associated behaviors induced by chronic social defeat stress
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-08-13
    Xiaolei Zhu, Michael T. Nedelcovych, Ajit G. Thomas, Yuto Hasegawa, Aisa Moreno-Megui, Wade Coomer, Varun Vohra, Atsushi Saito, Gabriel Perez, Ying Wu, Jesse Alt, Eva Prchalova, Lukáš Tenora, Pavel Majer, Rana Rais, Camilo Rojas, Barbara S. Slusher, Atsushi Kamiya

    There are a number of clinically effective treatments for stress-associated psychiatric diseases, including major depressive disorder (MDD). Nonetheless, many patients exhibit resistance to first-line interventions calling for novel interventions based on pathological mechanisms. Accumulating evidence implicates altered glutamate signaling in MDD pathophysiology, suggesting that modulation of glutamate signaling cascades may offer novel therapeutic potential. Here we report that JHU-083, our recently developed prodrug of the glutaminase inhibitor 6-diazo-5-oxo-l-norleucine (DON) ameliorates social avoidance and anhedonia-like behaviors in mice subjected to chronic social defeat stress (CSDS). JHU-083 normalized CSDS-induced increases in glutaminase activity specifically in microglia-enriched CD11b+ cells isolated from the prefrontal cortex and hippocampus. JHU-083 treatment also reverses the CSDS-induced inflammatory activation of CD11b+ cells. These results support the importance of altered glutamate signaling in the behavioral abnormalities observed in the CSDS model, and identify glutaminase in microglia-enriched CD11b+ cells as a pharmacotherapeutic target implicated in the pathophysiology of stress-associated psychiatric conditions such as MDD.

    更新日期:2018-08-14
  • Alteration of BDNF in the medial prefrontal cortex and the ventral hippocampus impairs extinction of avoidance
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-08-11
    Luis E. Rosas-Vidal, Valeria Lozada, Yisel Cantres-Rosario, Alexis Vega-Medina, Loyda Melendez, Gregory J. Quirk

    Brain-derived neurotrophic factor (BDNF) is critical for establishing activity-related neural plasticity. There is increasing interest in the mechanisms of active avoidance and its extinction, but little is known about the role of BDNF in these processes. Using the platform-mediated avoidance task combined with local infusions of an antibody against BDNF, we show that blocking BDNF in either prelimbic (PL) or infralimbic (IL) medial prefrontal cortex impairs subsequent recall of extinction of avoidance, differing from extinction of conditioned freezing. By combining retrograde tracers with BDNF immunohistochemistry, we show that extinction of avoidance increases BDNF expression in ventral hippocampal (vHPC) neurons, but not amygdala neurons, projecting to PL and IL. Using the CRISPR/Cas9 system, we further show that reducing BDNF production in vHPC neurons impairs recall of avoidance extinction. Thus, the vHPC may mediate behavioral flexibility in avoidance by driving plasticity via BDNFergic projections to both PL and IL. These findings add to the growing body of knowledge implicating the hippocampal-prefrontal pathway in anxiety-related disorders and extinction-based therapies.

    更新日期:2018-08-13
  • A transdiagnostic neuroanatomical signature of psychiatric illness
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-08-08
    Qiyong Gong, Cristina Scarpazza, Jing Dai, Manxi He, Xin Xu, Yan Shi, Baiwan Zhou, Sandra Vieira, Eamon McCrory, Yuan Ai, Cheng Yang, Feifei Zhang, Su Lui, Andrea Mechelli

    Despite an increasing focus on transdiagnostic approaches to mental health, it remains unclear whether different diagnostic categories share a common neuronatomical basis. The current investigation sought to investigate whether a transdiagnostic set of structural alterations characterized schizophrenia, depression, post-traumatic stress disorder, and obsessive-compulsive disorder, and determine whether any such alterations reflected markers of psychiatric illness or pre-existing familial vulnerability. A total of 404 patients with a psychiatric diagnosis were recruited (psychosis, n = 129; unipolar depression, n = 92; post-traumatic stress disorder, n = 91; obsessive-compulsive disorder, n = 92) alongside n = 201 healthy controls and n = 20 unaffected first-degree relatives. We collected structural magnetic resonance imaging scans from each participant, and tested for transdiagnostic alterations using Voxel-based morphometry. Inferences were made at p < 0.05 after family-wise error correction for multiple comparisons. The four psychiatric groups relative to healthy controls were all characterized by significantly greater gray matter volume in the putamen (right: z-score: 5.97, p-value < 0.001; left: z-score: 4.97, p-value = 0.001); the volume of this region was positively correlated with severity of symptoms across groups (r = 0.313; p < 0.001). Putamen enlargement was also evident in unaffected relatives compared to healthy controls (right: z-score: 8.13, p-value < 0.001; left: z-score: 9.38, p-value < 0.001). Taken collectively, these findings indicate that increased putamen volume may reflect a transdiagnostic marker of familial vulnerability to psychopathology. This is consistent with emerging conceptualizations of psychiatric illness, in which each disorder is understood as a combination of diagnosis-specific features and a transdiagnostic factor reflecting general psychopathology.

    更新日期:2018-08-08
  • High-dose ondansetron reduces activation of interoceptive and sensorimotor brain regions
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-08-08
    Emily R. Stern, Rebbia Shahab, Stephanie J. Grimaldi, Evan Leibu, James W. Murrough, Lazar Fleysher, Michael K. Parides, Barbara J. Coffey, Katherine E. Burdick, Wayne K. Goodman

    Several psychiatric disorders involve abnormalities of interoception and associated neural circuitry centered on the insula. The development of interventions modulating interoceptive circuits could lead to novel treatment approaches for these disorders. The 5-HT3 receptor antagonist ondansetron is a good candidate for the modulation of interoceptive circuits, as 5-HT3 receptors are located abundantly on sensory pathways and ondansetron has shown some clinical utility in disorders characterized by sensory and interoceptive abnormalities. The present study tested the ability of three different doses of ondansetron to engage neural regions involved in interoception to determine the drug’s utility as a therapeutic agent to target circuit abnormalities in patients. Fifty-three healthy subjects were randomized to receive a single 8-mg (n = 18), 16-mg (n = 17), or 24-mg (n = 18) dose of ondansetron and placebo before MRI scanning on separate days. Subjects performed an fMRI task previously shown to engage interoceptive circuitry in which they viewed videos depicting body movements/sensation and control videos. The results revealed a highly significant relationship between dosage and activation in bilateral insula, somatosensory and premotor regions, cingulate cortex, and temporal cortex for control but not body-focused videos. These effects were driven by a robust reduction in activation for ondansetron compared to placebo for the 24-mg group, with weaker effects for the 16-mg and 8-mg groups. In conclusion, high-dose ondansetron reduces activation of several areas important for interoception, including insula and sensorimotor cortical regions. This study reveals the potential utility of this drug in modulating hyperactivity in these regions in patients.

    更新日期:2018-08-08
  • The olfactory bulb is a source of high-frequency oscillations (130–180 Hz) associated with a subanesthetic dose of ketamine in rodents
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-08-08
    Mark Jeremy Hunt, Natalie E Adams, Władysław Średniawa, Daniel K Wójcik, Anna Simon, Stefan Kasicki, Miles Adrian Whittington

    High-frequency neuronal population oscillations (HFO, 130–180 Hz) are robustly potentiated by subanesthetic doses of ketamine. This frequency band has been recorded in functionally and neuroanatomically diverse cortical and subcortical regions, notably ventral striatal areas. However, the locus of generation remains largely unknown. There is compelling evidence that olfactory regions can drive oscillations in distant areas. Here we tested the hypothesis that the olfactory bulb (OB) is a locus for the generation of HFO following a subanesthetic dose of ketamine. The effect of ketamine on the electrophysiological activity of the OB and ventral striatum of male Wistar rats was examined using field potential and unit recordings, local inhibition, naris blockade, current source density and causality estimates. Ketamine-HFO was of larger magnitude and was phase-advanced in the OB relative to ventral striatum. Granger causality analysis was consistent with the OB as the source of HFO. Unilateral local inhibition of the OB and naris blockade both attenuated HFO recorded locally and in the ventral striatum. Within the OB, current source density analysis revealed HFO current dipoles close to the mitral layer and unit firing of mitral/tufted cells was phase locked to HFO. Our results reveal the OB as a source of ketamine-HFO which can contribute to HFO in the ventral striatum, known to project diffusely to many other brain regions. These findings provide a new conceptual understanding on how changes in olfactory system function may have implications for neurological disorders involving NMDA receptor dysfunction such as schizophrenia and depression.

    更新日期:2018-08-08
  • Oxytocin attenuates phencyclidine hyperactivity and increases social interaction and nucleus accumben dopamine release in rats
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-08-07
    Shivali Kohli, Madeleine V. King, Stuart Williams, Adele Edwards, Theresa M. Ballard, Lucinda J. Steward, Daniella Alberati, Kevin C. F. Fone

    The pituitary neuropeptide oxytocin promotes social behavior, and is a potential adjunct therapy for social deficits in schizophrenia and autism. Oxytocin may mediate pro-social effects by modulating monoamine release in limbic and cortical areas, which was investigated herein using in vivo microdialysis, after establishing a dose that did not produce accompanying sedative or thermoregulatory effects that could concomitantly influence behavior. The effects of oxytocin (0.03–0.3 mg/kg subcutaneous) on locomotor activity, core body temperature, and social behavior (social interaction and ultrasonic vocalizations) were examined in adult male Lister-hooded rats, using selective antagonists to determine the role of oxytocin and vasopressin V1a receptors. Dopamine and serotonin efflux in the prefrontal cortex and nucleus accumbens of conscious rats were assessed using microdialysis. In all, 0.3 mg/kg oxytocin modestly reduced activity and caused hypothermia but only the latter was attenuated by the V1a receptor antagonist, SR49059 (1 mg/kg intraperitoneal). Oxytocin at 0.1 mg/kg, which did not alter activity and had little effect on temperature, significantly attenuated phencyclidine-induced hyperactivity and increased social interaction between unfamiliar rats without altering the number or pattern of ultrasonic vocalizations. In the same rats, oxytocin (0.1 mg/kg) selectively elevated dopamine overflow in the nucleus accumbens, but not prefrontal cortex, without influencing serotonin efflux. Systemic oxytocin administration attenuated phencyclidine-induced hyperactivity and increased pro-social behavior without decreasing core body temperature and selectively enhanced nucleus accumbens dopamine release, consistent with activation of mesocorticolimbic circuits regulating associative/reward behavior being involved. This highlights the therapeutic potential of oxytocin to treat social behavioral deficits seen in psychiatric disorders such as schizophrenia.

    更新日期:2018-08-08
  • Digital devices and continuous telemetry: opportunities for aligning psychiatry and neuroscience
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-08-02
    Justin T. Baker, Laura T. Germine, Kerry J. Ressler, Scott L. Rauch, William A. Carlezon Jr.

    Digital devices and continuous telemetry: opportunities for aligning psychiatry and neuroscienceDigital devices and continuous telemetry: opportunities for aligning psychiatry and neuroscience, Published online: 02 August 2018; doi:10.1038/s41386-018-0172-zDigital devices and continuous telemetry: opportunities for aligning psychiatry and neuroscience

    更新日期:2018-08-02
  • Altered ErbB4 splicing and cortical parvalbumin interneuron dysfunction in schizophrenia and mood disorders
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-08-02
    Daniel W. Chung, Youjin Chung, H. Holly Bazmi, David A. Lewis

    Working memory requires the activity of parvalbumin (PV) interneurons in the dorsolateral prefrontal cortex (DLPFC). Impaired working memory and lower PV expression in the DLPFC are reported in schizophrenia and to a lesser degree in mood disorders. We previously proposed that activity-dependent PV expression is lower in schizophrenia due to a shift in the splicing of erb-b2 receptor tyrosine kinase 4 (ErbB4) transcripts from major to inactive minor variants that reduces excitatory drive to PV interneurons. Here, we tested the hypothesis that the degree of major-to-minor shift in ErbB4 splicing predicts the level of PV expression across schizophrenia and mood disorders. Levels of ErbB4 splice variants and PV mRNA were quantified by PCR in the DLPFC from 40 matched tetrads (N = 160 subjects) of schizophrenia, bipolar disorder (BD), major depressive disorder (MDD), and unaffected comparison subjects. Relative to unaffected comparisons subjects, the magnitude of increases in minor variant levels and decreases in major variant levels was greatest in schizophrenia, intermediate in BD, and least in MDD. The same rank order was present for the magnitude of increases in the composite splicing score, which reflects the degree of major-to-minor shift across all ErbB4 splice loci, and for the magnitude of deficient PV expression. Finally, the composite splicing score negatively predicted PV expression across all subject groups. Together, these findings demonstrate a shared relationship between ErbB4 splicing and PV expression and suggest that scaling of the major-to-minor shift in ErbB4 splicing may influence the severity of deficient PV interneuron activity across diagnoses.

    更新日期:2018-08-02
  • PKMζ in the nucleus accumbens acts to dampen cocaine seeking
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-08-01
    Anna G. McGrath, Jeffrey D. Lenz, Lisa A. Briand

    The constitutively active, atypical protein kinase C, protein kinase M-ζ (PKMζ), is exclusively expressed in the brain and its expression increases following exposure to drugs of abuse. However, the limitations of currently available tools have made it difficult to examine the role of PKMζ in cocaine self-administration and relapse. The current study demonstrates that constitutive deletion of PKMζ potentiates cue-induced reinstatement of cocaine seeking and increases both food and cocaine self-administration, without affecting cue-driven food seeking in both male and female mice. Conditional deletion of PKMζ within the nucleus accumbens recapitulated the increase in cocaine taking and seeking seen in the constitutive knockout mice, but only in male animals. Site-specific knockdown of PKMζ in the nucleus accumbens had no effect on cocaine taking or seeking in female mice. Additionally, neither male nor female mice exhibited any alterations in food self-administration or cue-induced reinstatement of food seeking following accumbal deletion of PKMζ. Taken together these results indicate that PKMζ may act to dampen cocaine taking and seeking. Furthermore, these results indicate that PKMζ is playing divergent roles in reward seeking in males and females.

    更新日期:2018-08-02
  • TAK-071, a novel M1 positive allosteric modulator with low cooperativity, improves cognitive function in rodents with few cholinergic side effects
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-08-01
    Yuu Sako, Emi Kurimoto, Takao Mandai, Atsushi Suzuki, Maiko Tanaka, Motohisa Suzuki, Yuji Shimizu, Masami Yamada, Haruhide Kimura

    The muscarinic M1 receptor (M1R) is a promising target for treating cognitive impairment associated with cholinergic deficits in disorders such as Alzheimer’s disease and schizophrenia. We previously reported that cooperativity (α-value) was key to lowering the risk of diarrhea by M1R positive allosteric modulators (M1 PAMs). Based on this, we discovered a low α-value M1 PAM, TAK-071 (α-value: 199), and characterized TAK-071 using T-662 as a reference M1 PAM with high α-value of 1786. Both TAK-071 and T-662 were potent and highly selective M1 PAMs, with inflection points of 2.7 and 0.62 nM, respectively. However, T-662 but not TAK-071 augmented isolated ileum motility. TAK-071 and T-662 increased hippocampal inositol monophosphate production through M1R activation and improved scopolamine-induced cognitive deficits in rats at 0.3 and 0.1 mg/kg, respectively. TAK-071 and T-662 also induced diarrhea at 10 and 0.1 mg/kg, respectively, in rats. Thus, taking into consideration the fourfold lower brain penetration ratio of T-662, TAK-071 had a wider margin between cognitive improvement and diarrhea induction than T-662. Activation of M1R increases neural excitability via membrane depolarization, reduced afterhyperpolarization, and generation of afterdepolarization in prefrontal cortical pyramidal neurons. T-662 induced all three processes, whereas TAK-071 selectively induced afterdepolarization. Combining sub-effective doses of TAK-071, but not T-662, with an acetylcholinesterase inhibitor, significantly ameliorated scopolamine-induced cognitive deficits in rats. TAK-071 may therefore provide therapeutic opportunities for cognitive dysfunction related to cholinergic deficits or reduced M1R expression, while minimizing peripheral cholinergic side effects.

    更新日期:2018-08-01
  • Sex differences in the hypothalamic–pituitary–adrenal axis’ response to stress: an important role for gonadal hormones
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-08-01
    Ashley L. Heck, Robert J. Handa

    The hypothalamic–pituitary–adrenal (HPA) axis, a neuroendocrine network that controls hormonal responses to internal and external challenges in an organism’s environment, exhibits strikingly sex-biased activity. In adult female rodents, acute HPA function following a stressor is markedly greater than it is in males, and this difference has largely been attributed to modulation by the gonadal hormones testosterone and estradiol. These gonadal hormones are produced by the hypothalamic–pituitary–gonadal (HPG) axis and have been shown to determine sex differences in adult HPA function after acute stress via their activational and organizational effects. Although these actions of gonadal hormones are well supported, the possibility that sex chromosomes similarly influence HPA activity is unexplored. Moreover, questions remain regarding sex differences in the activity of the HPA axis following chronic stress and the underlying contributions of gonadal hormones and sex chromosomes. The present review examines what is currently known about sex differences in the neuroendocrine response to stress, as well as outstanding questions regarding this sex bias. Although it primarily focuses on the rodent literature, a brief discussion of sex differences in the human HPA axis is also included.

    更新日期:2018-08-01
  • Striatal activity correlates with stimulant-like effects of alcohol in healthy volunteers
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-08-01
    Jessica Weafer, Thomas J. Ross, Sean O’Connor, Elliot A. Stein, Harriet de Wit, Emma Childs

    Individuals who experience greater stimulation and less sedation from alcohol are at increased risk for alcohol-related problems. However, little is known regarding the neurobiological mechanisms underlying subjective response to alcohol. The current study examined the degree to which alcohol-induced brain activation correlates with ratings of stimulation and sedation, using a within-subjects, double-blind, placebo-controlled design. Participants (N = 34 healthy adults with no history of alcohol use disorder) completed three sessions: a calibration session to determine the duration of infusion needed to bring the breath alcohol to 80 mg/dl for each subject, and two counterbalanced fMRI sessions with placebo and alcohol administration. During the fMRI sessions, participants underwent 50 min scans, which included a 10 min baseline period, the IV infusion period needed to bring breath alcohol concentration (BrAC) to a peak 80 mg/dl (on the alcohol session), followed by a post-peak decline period. Participants rated their subjective stimulation and sedation at regular intervals throughout the scan. A priori VOI analyses showed that the time course of stimulation correlated with BOLD signal in the striatum. The time course of sedation did not correlate with BOLD signal in any VOIs. There were no correlations in primary visual cortex, which served as a control. These findings are the first to show that alcohol effects in the striatum are linked to the positive, stimulant-like effects of the drug and advance our understanding of the neurobiological mechanisms underlying individual differences in subjective responses to alcohol, and more broadly, risk for alcohol use disorders.

    更新日期:2018-08-01
  • The best defense is a strong offense: preventing alcohol abstinence-induced depression
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-30
    Kara K. Cover, Willa G. Kerkhoff, Brian N. Mathur

    The best defense is a strong offense: preventing alcohol abstinence-induced depressionThe best defense is a strong offense: preventing alcohol abstinence-induced depression, Published online: 30 July 2018; doi:10.1038/s41386-018-0152-3The best defense is a strong offense: preventing alcohol abstinence-induced depression

    更新日期:2018-07-30
  • Hippocampal glutamate metabolites and glial activation in clinical high risk and first episode psychosis
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-28
    Shima Shakory, Jeremy J. Watts, Sina Hafizi, Tania Da Silva, Saad Khan, Michael Kiang, R. Michael Bagby, Sofia Chavez, Romina Mizrahi

    Alterations in glutamate neurotransmission have been implicated in the pathophysiology of schizophrenia, as well as in symptom severity and cognitive deficits. The hippocampus, in particular, is a site of key functional and structural abnormalities in schizophrenia. Yet few studies have investigated hippocampal glutamate in antipsychotic-naïve first episode psychosis patients or in individuals at clinical high risk (CHR) of developing psychosis. Using proton magnetic resonance spectroscopy (1H-MRS), we investigated glutamate metabolite levels in the left hippocampus of 25 CHR (19 antipsychotic-naïve), 16 patients with first-episode psychosis (13 antipsychotic-naïve) and 31 healthy volunteers. We also explored associations between hippocampal glutamate metabolites and glial activation, as indexed by [18F]FEPPA positron emission tomography (PET); symptom severity; and cognitive function. Groups differed significantly in glutamate plus glutamine (Glx) levels (F(2, 69) = 6.39, p = 0.003). Post-hoc analysis revealed that CHR had significantly lower Glx levels than both healthy volunteers (p = 0.003) and first-episode psychosis patients (p = 0.050). No associations were found between glutamate metabolites and glial activation. Our findings suggest that glutamate metabolites are altered in CHR.

    更新日期:2018-07-29
  • Interneuronal δ-GABAA receptors regulate binge drinking and are necessary for the behavioral effects of early withdrawal
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-28
    Laverne C. Melón, James T. Nasman, Ashley St. John, Kenechukwu Mbonu, Jamie L. Maguire

    Extensive evidence points to a role for GABAergic signaling in the amygdala in mediating the effects of alcohol, including presynaptic changes in GABA release, suggesting effects on GABAergic neurons. However, the majority of studies focus solely on the effects of alcohol on principal neurons. Here we demonstrate that δ-GABAARs, which have been suggested to confer ethanol sensitivity, are expressed at a high density on parvalbumin (PV) interneurons in the basolateral amygdala (BLA). Thus, we hypothesized that δ-GABAARs on PV interneurons may represent both an initial pharmacological target for alcohol and a site for plasticity associated with the expression of various behavioral maladaptations during withdrawal from binge drinking. To investigate this, we used a mouse model of voluntary alcohol intake (Drinking-in-the-Dark-Multiple Scheduled Access) to induce escalating heavy binge drinking and anxiety-like behavior in mice. This pattern of intake was associated with increased δ protein expression on parvalbumin positive interneurons in both the BLA and hippocampus. Loss of δ-GABAARs specifically in PV interneurons (PV:δ−/−) increased binge drinking behavior, reduced sensitivity to alcohol-induced motor incoordination, enhanced sensitivity to alcohol-induced hyperlocomotion and blocked the expression of withdrawal from binge drinking. This study is the first to demonstrate a role for δGABAARs specifically in PV-expressing interneurons in modulating binge alcohol intake and withdrawal-induced anxiety.

    更新日期:2018-07-28
  • A dose-finding study of oxytocin using neurophysiological measures of social processing
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-28
    Jonathan K. Wynn, Michael F. Green, Gerhard Hellemann, Eric A. Reavis, Stephen R. Marder

    Recent interest has focused on oxytocin (OT), a neurotransmitter that promotes social processing, to improve social functioning in people with schizophrenia. However, little information is available regarding the doses of OT that are effective for influencing social processing in the brain (i.e., target engagement). In this study, we conducted a double-blind, placebo-controlled, cross-over dose ranging study of OT. In total 47 patients with schizophrenia were randomly assigned to one of eight doses of OT (8, 12, 24, 36, 48, 60, 72, or 84 IU). Patients completed two social processing tasks: one electroencephalography (EEG) task, a biological motion Mu-suppression task (i.e., identifying the gender, emotion, or direction of walking of point-light animations of human movement); and one pupillometry task, pupil dilation in response to viewing affective faces. Participants completed these tasks twice, one week apart, and were randomly administered drug or placebo intranasally 30 min prior to each session. Mu-suppression, i.e., suppression of oscillations in the 8–12 Hz range over central electrodes in response to social stimuli, was significantly enhanced at doses of 36 and 48 IU in comparison to placebo, but not at other doses. Significant pupil dilation was observed in response to faces vs. non-face stimuli, though there were no drug effects at any dose. Results suggest that OT affects central measures of social information processing in patients with schizophrenia and is optimal at a mid-range dose (36–48 IU). These results provide dosing guidance for future studies of OT to be used to enhance social processing in people with schizophrenia.

    更新日期:2018-07-28
  • TPA-023 attenuates subchronic phencyclidine-induced declarative and reversal learning deficits via GABAA receptor agonist mechanism: possible therapeutic target for cognitive deficit in schizophrenia
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-23
    Lakshmi Rajagopal, Mei Huang, Eric Michael, Sunoh Kwon, Herbert Y. Meltzer

    GABAergic drugs are of interest for the treatment of anxiety, depression, bipolar disorder, pain, cognitive impairment associated with schizophrenia (CIAS), and other neuropsychiatric disorders. Some evidence suggests that TPA-023, (7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b] pyridazine), a GABAA α2,3 subtype-selective GABAA partial agonist and α1/5 antagonist, and the neurosteroid, pregnenolone sulfate, a GABAA antagonist, may improve CIAS in pilot clinical trials. The goal of this study was to investigate the effect of TPA-023 in mice after acute or subchronic (sc) treatment with the N-methyl-d-aspartate receptor (NMDAR) antagonist, phencyclidine (PCP), on novel object recognition (NOR), reversal learning (RL), and locomotor activity (LMA) in rodents. Acute TPA-023 significantly reversed scPCP-induced NOR and RL deficits. Co-administration of sub-effective dose (SED) TPA-023 with SEDs of the atypical antipsychotic drug, lurasidone, significantly potentiated the effect of TPA-023 in reversing the scPCP-induced NOR deficit. Further, scTPA-023 co-administration significantly prevented scPCP-induced NOR deficit for 5 weeks. Also, administration of TPA-023 for 7 days following scPCP reversed the NOR deficit for 1 week. However, TPA-023 did not blunt acute PCP-induced hyperactivity, suggesting lack of efficacy as a treatment for psychosis. Systemic TPA-023 significantly blocked lurasidone-induced increases in cortical acetylcholine, dopamine, and glutamate without affecting increases in norepinephrine and with minimal effect on basal release of these neurotransmitters. TPA-023 significantly inhibited PCP-induced cortical and striatal dopamine, serotonin, norepinephrine, and glutamate efflux. These results suggest that TPA-023 and other GABAA agonists may be of benefit to treat CIAS.

    更新日期:2018-07-24
  • Efficacy of typical and atypical antipsychotic medication on hostility in patients with psychosis-spectrum disorders: a review and meta-analysis
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-23
    Margo D. M. Faay, Pál Czobor, Iris E. Sommer

    As violence against self and others is an important outcome in the treatment of patients with psychosis-spectrum disorders and hostility is an important indicator for violence, we set out to evaluate the effects of different types of antipsychotic agents in reducing hostility. We performed a systematic literature search, which provided 18 suitable randomized studies comparing typical to atypical antipsychotics for at least 4 weeks in patients with psychotic disorders. Results showed a small (0.26) but significant effect for atypical as compared to typical antipsychotics, with high heterogeneity, even though the mean dose of typical antipsychotics was higher. This effect size remained similar when separately analyzing sponsored and non-sponsored studies. When differentiating between high and low-dose studies, the high-dose group showed a significant difference between typical and atypical antipsychotics whereas the low-dose group did not. An analysis comparing clozapine to typical antipsychotics showed a moderate effect size (0.415), with low heterogeneity. These results are important for clinicians to help their shared decision making with patients when choosing maintenance treatment, as next to efficacy for psychosis and tolerability, safety for the patient and their environment is an important outcome.

    更新日期:2018-07-24
  • Disentangling the genetic overlap between cholesterol and suicide risk
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-23
    Emma E. M. Knowles, Joanne E. Curran, Peter J. Meikle, Kevin Huynh, Samuel R. Mathias, Harald H. H. Goring, John L. VandeBerg, Michael C. Mahaney, Maria Jalbrzikowski, Marian K. Mosior, Laura F. Michael, Rene L. Olvera, Ravi Duggirala, Laura Almasy, David C. Glahn, John Blangero

    Suicide is major public health concern; one million individuals worldwide die by suicide each year of which there are many more attempts. Thus, it is imperative that robust and reliable indicators, or biomarkers, of suicide risk be identified so that individuals at risk can be identified and provided appropriate interventions as quickly as possible. Previous work has revealed a relationship between low levels of circulating cholesterol and suicide risk, implicating cholesterol level as one such potential biomarker, but the factors underlying this relationship remain unknown. In the present study, we applied a combination of bivariate polygenic and coefficient-of-relatedness analysis, followed by mediation analysis, in a large sample of Mexican-American individuals from extended pedigrees [N = 1897; 96 pedigrees (average size = 19.17 individuals, range = 2–189) 60% female; mean age = 42.58 years, range = 18–97 years, sd = 15.75 years] with no exclusion criteria for any given psychiatric disorder. We observed that total esterified cholesterol measured at the time of psychiatric assessment shared a significant genetic overlap with risk for suicide attempt (ρg = −0.64, p = 1.24 × 10−04). We also found that total unesterified cholesterol measured around 20 years prior to assessment varied as a function of genetic proximity to an affected individual (h2 = 0.21, se = 0.10, p = 8.73 × 10−04; βsuicide = −0.70, se = 0.25, p = 8.90 × 10−03). Finally, we found that the relationship between total unesterified cholesterol and suicide risk was significantly mediated by ABCA-1-specific cholesterol efflux capacity (βsuicide-efflux = −0.45, p = 0.039; βefflux-cholexterol = −0.34, p < 0.0001; βindirect = −0.15, p = 0.044). These findings suggest that the relatively well-delineated process of cholesterol metabolism and associated molecular pathways will be informative for understanding the neurobiological underpinnings of risk for suicide attempt.

    更新日期:2018-07-23
  • Methylation in OTX2 and related genes, maltreatment, and depression in children
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-21
    Joan Kaufman, Nicholas F. Wymbs, Janitza L. Montalvo-Ortiz, Catherine Orr, Matthew D. Albaugh, Robert Althoff, Kerry O’Loughlin, Hannah Holbrook, Hugh Garavan, Catherine Kearney, Bao-Zhu Yang, Hongyu Zhao, Catherine Peña, Eric J. Nestler, Richard S. Lee, Stewart Mostofsky, Joel Gelernter, James Hudziak

    Through unbiased transcriptomics and multiple molecular tools, transient downregulation of the Orthodenticle homeobox 2 (OTX2) gene was recently causatively associated with the development of depressive-like behaviors in a mouse model of early life stress. The analyses presented in this manuscript test the translational applicability of these findings by examining the peripheral markers of methylation of OTX2 and OTX2-regulated genes in relation to measures of depression and resting-state functional connectivity data collected as part of a larger study examining risk and resilience in maltreated children. The sample included 157 children between the ages of 8 and 15 years (χ = 11.4, SD = 1.9). DNA specimens were derived from saliva samples and processed using the Illumina 450 K beadchip. A subset of children (N = 47) with DNA specimens also had resting-state functional MRI data. After controlling for demographic factors, cell heterogeneity, and three principal components, maltreatment history and methylation in OTX2 significantly predicted depression in children. In terms of the imaging data, increased OTX2 methylation was found to be associated with increased functional connectivity between the right vmPFC and bilateral regions of the medial frontal cortex and the cingulate, including the subcallosal gyrus, frontal pole, and paracingulate gyrus—key structures implicated in depression. Mouse models of early stress hold significant promise in helping to unravel the mechanisms by which child adversity confers risk for psychopathology, with data presented in this manuscript supporting a potential role for OTX2 and OTX2-related (e.g., WNT1, PAX6) genes in the pathophysiology of stress-related depressive disorders in children.

    更新日期:2018-07-21
  • Phosphoproteomic approach for agonist-specific signaling in mouse brains: mTOR pathway is involved in κ opioid aversion
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-20
    Jeffrey J. Liu, Yi-Ting Chiu, Kelly M. DiMattio, Chongguang Chen, Peng Huang, Taylor A. Gentile, John W. Muschamp, Alan Cowan, Matthias Mann, Lee-Yuan Liu-Chen

    Kappa opioid receptor (KOR) agonists produce analgesic and anti-pruritic effects, but their clinical application was limited by dysphoria and hallucinations. Nalfurafine, a clinically used KOR agonist, does not cause dysphoria or hallucinations at therapeutic doses in humans. We found that in CD-1 mice nalfurafine produced analgesic and anti-scratch effects dose-dependently, like the prototypic KOR agonist U50,488H. In contrast, unlike U50,488H, nalfurafine caused no aversion, anhedonia, sedation or motor incoordination at the effective analgesia and anti-scratch doses. Thus, we established a mouse model that recapitulated important aspects of the clinical observations. We then employed a phosphoproteomics approach to investigate mechanisms underlying differential KOR-mediated effects. A large-scale mass spectrometry (MS)-based analysis on brains revealed that nalfurafine perturbed phosphoproteomes differently from U50,488H in a brain-region specific manner after 30-min treatment. In particular, U50,488H and nalfurafine imparted phosphorylation changes to proteins found in different cellular components or signaling pathways in different brain regions. Notably, we observed that U50,488H, but not nalfurafine, activated the mammalian target of rapamycin (mTOR) pathway in the striatum and cortex. Inhibition of the mTOR pathway by rapamycin abolished U50,488H-induced aversion, without affecting analgesic, anti-scratch, and sedative effects and motor incoordination. The results indicate that the mTOR pathway is involved in KOR agonist-induced aversion. This is the first demonstration that phosphoproteomics can be applied to agonist-specific signaling of G protein-coupled receptors (GPCRs) in mouse brains to unravel pharmacologically important pathways. Furthermore, this is one of the first two reports that the mTOR pathway mediates aversion caused by KOR activation.

    更新日期:2018-07-21
  • Striatal dopamine D2 receptors regulate effort but not value-based decision making and alter the dopaminergic encoding of cost
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-20
    Ina Filla, Matthew R. Bailey, Elke Schipani, Vanessa Winiger, Chris Mezias, Peter D. Balsam, Eleanor H. Simpson

    Deficits in goal-directed motivation represent a debilitating symptom for many patients with schizophrenia. Impairments in motivation can arise from deficits in processing information about effort and or value, disrupting effective cost-benefit decision making. We have previously shown that upregulated dopamine D2 receptor expression within the striatum (D2R-OE mice) decreases goal-directed motivation. Here, we determine the behavioral and neurochemical mechanisms behind this deficit. Female D2R-OE mice were tested in several behavioral paradigms including recently developed tasks that independently assess the impact of Value or Effort manipulations on cost-benefit decision making. In vivo microdialysis was used to measure extracellular dopamine in the striatum during behavior. In a value-based choice task, D2R-OE mice show normal sensitivity to changes in reward value and used reward value to guide their actions. In an effort-based choice task, D2R-OE mice evaluate the cost of increasing the number of responses greater relative to the effort cost of longer duration responses compared to controls. This shift away from choosing to repeatedly execute a response is accompanied by a dampening of extracellular dopamine in the striatum during goal-directed behavior. In the ventral striatum, extracellular dopamine level negatively correlates with response cost in controls, but this relationship is lost in D2R-OE mice. These results show that D2R signaling in the striatum, as observed in some patients with schizophrenia, alters the relationship between effort expenditure and extracellular dopamine. This dysregulation produces motivation deficits that are specific to effort but not value-based decision making, paralleling the effort-based motivational deficits observed in schizophrenia.

    更新日期:2018-07-21
  • Genome-wide transcriptional profiling of central amygdala and orbitofrontal cortex during incubation of methamphetamine craving
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-20
    Hannah M. Cates, Xuan Li, Immanuel Purushothaman, Pamela J. Kennedy, Li Shen, Yavin Shaham, Eric J. Nestler

    Methamphetamine (Meth) seeking progressively increases after withdrawal (incubation of Meth craving), but the transcriptional mechanisms that contribute to this incubation are unknown. Here we used RNA-sequencing to analyze transcriptional profiles associated with incubation of Meth craving in central amygdala (CeA) and orbitofrontal cortex (OFC), two brain areas previously implicated in relapse to drug seeking. We trained rats to self-administer either saline (control condition) or Meth (10 days; 9 h/day, 0.1 mg/kg/infusion). Next, we collected brain tissue from CeA and OFC on withdrawal day 2 (when Meth seeking is low and non-incubated) and on day 35 (when Meth seeking is high and incubated), for subsequent RNA-sequencing. In CeA, we identified 10-fold more differentially expressed genes (DEGs) on withdrawal day 35 than day 2. These genes were enriched for several biological processes, including protein ubiquitination and histone methylation. In OFC, we identified much fewer expression changes than in CeA, with more DEGs on withdrawal day 2 than on day 35. There was a significant overlap between upregulated genes on withdrawal day 2 and downregulated genes on withdrawal day 35 in OFC. Our analyses highlight the CeA as a key region of transcriptional regulation associated with incubation of Meth seeking. In contrast, transcriptional regulation in OFC may contribute to Meth seeking during early withdrawal. Overall, these findings provide a unique resource of gene expression data for future studies examining transcriptional mechanisms in CeA that mediate Meth seeking after prolonged withdrawal.

    更新日期:2018-07-21
  • Sex differences in antidepressant efficacy
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-20
    Tara A. LeGates, Mark D. Kvarta, Scott M. Thompson

    Sex differences have been observed across many psychiatric diseases, especially mood disorders. For major depression, the most prevalent psychiatric disorder, females show a roughly two-fold greater risk as compared to males. Depression is sexually dimorphic with males and females exhibiting differences in clinical presentation, course, and response to antidepressant treatment. In this review, we first discuss sex differences observed in depressed patients, as well as animal models that reveal potential underlying mechanisms. We then discuss antidepressant treatments including their proposed mechanism of action and sex differences observed in treatment response. We include possible mechanisms underlying these sex differences with particular focus on synaptic transmission.

    更新日期:2018-07-21
  • Sound of silent synapses from the addicted hippocampus
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-20
    Eisuke Koya, Yan Dong

    Sound of silent synapses from the addicted hippocampus Sound of silent synapses from the addicted hippocampus, Published online: 20 July 2018; doi:10.1038/s41386-018-0142-5 Sound of silent synapses from the addicted hippocampus

    更新日期:2018-07-21
  • Sex differences in psychiatric disorders: what we can learn from sex chromosome aneuploidies
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-16
    Tamar Green, Shira Flash, Allan L. Reiss

    The study of sexual dimorphism in psychiatric and neurodevelopmental disorders is challenging due to the complex interplay of diverse biological, psychological, and social factors. Males are more susceptible to neurodevelopmental disorders including intellectual disability, autism spectrum disorder, and attention-deficit activity disorder. Conversely, after puberty, females are more prone to major depressive disorder and anxiety disorders compared to males. One major biological factor contributing to sex differences is the sex chromosomes. First, the X and Y chromosomes have unique and specific genetic effects as well as downstream gonadal effects. Second, males have one X chromosome and one Y chromosome, while females have two X chromosomes. Thus, sex chromosome constitution also differs between the sexes. Due to this complexity, determining genetic and downstream biological influences on sexual dimorphism in humans is challenging. Sex chromosome aneuploidies, such as Turner syndrome (X0) and Klinefelter syndrome (XXY), are common genetic conditions in humans. The study of individuals with sex chromosome aneuploidies provides a promising framework for studying sexual dimorphism in neurodevelopmental and psychiatric disorders. Here we will review and contrast four syndromes caused by variation in the number of sex chromosomes: Turner syndrome, Klinefelter syndrome, XYY syndrome, and XXX syndrome. Overall we describe an increased rate of attention-deficit hyperactivity disorder and autism spectrum disorder, along with the increased rates of major depressive disorder and anxiety disorders in one or more of these conditions. In addition to contributing unique insights about sexual dimorphism in neuropsychiatric disorders, awareness of the increased risk of neurodevelopmental and psychiatric disorders in sex chromosome aneuploidies can inform appropriate management of these common genetic disorders.

    更新日期:2018-07-16
  • Resolution of inflammation-induced depression requires T lymphocytes and endogenous brain interleukin-10 signaling
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-16
    Geoffroy Laumet, Jules Daniel Edralin, Angie Chi-An Chiang, Robert Dantzer, Cobi J. Heijnen, Annemieke Kavelaars

    In humans, depression is often associated with low-grade inflammation, activation of the tryptophan/kynurenine pathway, and mild lymphopenia. Preclinical research confirms that inflammation induces depression-like behavior through activation of the tryptophan/kynurenine pathway. However, the mechanisms governing recovery from depression are unknown. Understanding the pathways leading to resolution of depression will likely lead to identification of novel targets for treatment. We investigated the contribution of T lymphocytes to the resolution of lipopolysaccharide-induced depression-like behavior. Duration of depression-like behavior was markedly prolonged in mice without mature T or B lymphocytes (Rag1−/− mice). This prolonged depression-like behavior was associated with persistent upregulation of the tryptophan-metabolizing enzyme indoleamine-2,3-dioxygenase (Ido)1 in the prefrontal cortex (PFC). Reconstitution of Rag1−/− mice with T lymphocytes normalized resolution of depression-like behavior and expression of Ido1 in the PFC. During resolution of inflammation-induced depression-like behavior, T lymphocytes accumulated in the meninges and were required for induction of interleukin (IL)-10 in the meninges and the PFC. Inhibition of IL-10 signaling by nasal administration of neutralizing anti–IL-10 antibody to WT mice led to persistent upregulation of Ido1 in the PFC and prolonged depression-like behavior. Conversely, nasal administration of recombinant IL-10 in Rag1−/− mice normalized Ido1 expression and resolution of depression-like behavior. In conclusion, the present data show for the first time that resolution of inflammation-induced depression is an active process requiring T lymphocytes acting via an IL-10–dependent pathway to decrease Ido1 expression in the brain. We propose that targeting the T lymphocyte/IL-10 resolution pathway could represent a novel approach to promote recovery from major depressive disorder.

    更新日期:2018-07-16
  • Isoform-selective phosphoinositide 3-kinase inhibition ameliorates a broad range of fragile X syndrome-associated deficits in a mouse model
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-13
    Christina Gross, Anwesha Banerjee, Durgesh Tiwari, Francesco Longo, Angela R. White, A. G. Allen, Lindsay M. Schroeder-Carter, Joseph C. Krzeski, Nada A. Elsayed, Rosemary Puckett, Eric Klann, Ralph A. Rivero, Shannon L. Gourley, Gary J. Bassell

    Defects in the phosphoinositide 3-kinase (PI3K) pathway are shared characteristics in several brain disorders, including the inherited intellectual disability and autism spectrum disorder, fragile X syndrome (FXS). PI3K signaling therefore could serve as a therapeutic target for FXS and other brain disorders. However, broad inhibition of such a central signal transduction pathway involved in essential cellular functions may produce deleterious side effects. Pharmacological strategies that selectively correct the overactive components of the PI3K pathway while leaving other parts of the pathway intact may overcome these challenges. Here, we provide the first evidence that disease mechanism-based PI3K isoform-specific inhibition may be a viable treatment option for FXS. FXS is caused by loss of the fragile X mental retardation protein (FMRP), which translationally represses specific messenger RNAs, including the PI3K catalytic isoform p110β. FMRP deficiency increases p110β protein levels and activity in FXS mouse models and in cells from subjects with FXS. Here, we show that a novel, brain-permeable p110β-specific inhibitor, GSK2702926A, ameliorates FXS-associated phenotypes on molecular, cellular, behavioral, and cognitive levels in two different FMRP-deficient mouse models. Rescued phenotypes included increased PI3K downstream signaling, protein synthesis rates, and dendritic spine density, as well as impaired social interaction and higher-order cognition. Several p110β-selective inhibitors, for example, a molecule from the same chemotype as GSK2702926A, are currently being evaluated in clinical trials to treat cancer. Our results suggest that repurposing p110β inhibitors to treat cognitive and behavioral defects may be a promising disease-modifying strategy for FXS and other brain disorders.

    更新日期:2018-07-14
  • Ventral midbrain astrocytes display unique physiological features and sensitivity to dopamine D2 receptor signaling
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-13
    Wendy Xin, Kornel E. Schuebel, Kamwing Jair, Raffaello Cimbro, Lindsay M. De Biase, David Goldman, Antonello Bonci

    Astrocytes are ubiquitous CNS cells that support tissue homeostasis through ion buffering, neurotransmitter recycling, and regulation of CNS vasculature. Yet, despite the essential functional roles they fill, very little is known about the physiology of astrocytes in the ventral midbrain, a region that houses dopamine-releasing neurons and is critical for reward learning and motivated behaviors. Here, using a combination of whole-transcriptome sequencing, histology, slice electrophysiology, and calcium imaging, we performed the first functional and molecular profiling of ventral midbrain astrocytes and observed numerous differences between these cells and their telencephalic counterparts, both in their gene expression profile and in their physiological properties. Ventral midbrain astrocytes have very low membrane resistance and inward-rectifying potassium channel-mediated current, and are extensively coupled to surrounding oligodendrocytes through gap junctions. They exhibit calcium responses to glutamate but are relatively insensitive to norepinephrine. In addition, their calcium activity can be dynamically modulated by dopamine D2 receptor signaling. Taken together, these data indicate that ventral midbrain astrocytes are physiologically distinct from astrocytes in cortex and hippocampus. This work provides new insights into the extent of functional astrocyte heterogeneity within the adult brain and establishes the foundation for examining the impact of regional astrocyte differences on dopamine neuron function and susceptibility to degeneration.

    更新日期:2018-07-14
  • Dopamine in the oval bed nucleus of the stria terminalis contributes to compulsive responding for sucrose in rats
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-10
    Amanda C. Maracle, Catherine P. Normandeau, Éric C. Dumont, Mary C. Olmstead

    Binge eating disorder (BED) is characterized by periods of excessive food intake combined with subjective feelings of loss of control. We examined whether sucrose bingeing itself leads to uncontrolled or compulsive responding and whether this effect is magnified following a period of abstinence. We then assessed dopamine (DA) modulation of inhibitory synaptic transmission in the oval bed nucleus of the stria terminalis (ovBNST) as a neural correlate of compulsive responding and whether this behavioral effect could be disrupted by DA blockade in the ovBNST. Over 28 days, male Long–Evans rats (n = 8–16 per group) had access to 10% sucrose and food (12 or 24 h), 0.1% saccharin and food (12 h), or food alone (12 h). Compulsive responding was assessed following 1 or 28 days of sucrose abstinence using a conditioned suppression paradigm. Only rats given 12 h access to sucrose developed binge-like intake, manifested as copious intake within the first hour; compulsive responding was significantly elevated in this group following 28 days of abstinence. In parallel, the effect of DA on ovBNST inhibitory transmission switched from a reduction to a potentiation; the effect, although observable after 1 day, was more pronounced and sustained following 28 days of abstinence. Intra-ovBNST infusions of a DA D1 receptor antagonist (0.8 µg/µl SCH-23390) reversed the blockade of conditioned suppression, thereby confirming the causal relationship between ovBNST DA modulation of γ-aminobutyric acid transmission and alterations in conditioned suppression following binge-like intake of sucrose.

    更新日期:2018-07-12
  • Sex differences and the neurobiology of affective disorders
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-09
    David R. Rubinow, Peter J. Schmidt

    Observations of the disproportionate incidence of depression in women compared with men have long preceded the recent explosion of interest in sex differences. Nonetheless, the source and implications of this epidemiologic sex difference remain unclear, as does the practical significance of the multitude of sex differences that have been reported in brain structure and function. In this article, we attempt to provide a framework for thinking about how sex and reproductive hormones (particularly estradiol as an example) might contribute to affective illness. After briefly reviewing some observed sex differences in depression, we discuss how sex might alter brain function through hormonal effects (both organizational (programmed) and activational (acute)), sex chromosome effects, and the interaction of sex with the environment. We next review sex differences in the brain at the structural, cellular, and network levels. We then focus on how sex and reproductive hormones regulate systems implicated in the pathophysiology of depression, including neuroplasticity, genetic and neural networks, the stress axis, and immune function. Finally, we suggest several models that might explain a sex-dependent differential regulation of affect and susceptibility to affective illness. As a disclaimer, the studies cited in this review are not intended to be comprehensive but rather serve as examples of the multitude of levels at which sex and reproductive hormones regulate brain structure and function. As such and despite our current ignorance regarding both the ontogeny of affective illness and the impact of sex on that ontogeny, sex differences may provide a lens through which we may better view the mechanisms underlying affective regulation and dysfunction.

    更新日期:2018-07-09
  • Neuropsychopharmacology of JNJ-55308942: evaluation of a clinical candidate targeting P2X7 ion channels in animal models of neuroinflammation and anhedonia
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-09
    Anindya Bhattacharya, Brian Lord, Jan-Sebastian Grigoleit, Yingbo He, Ian Fraser, Shannon N. Campbell, Natalie Taylor, Leah Aluisio, Jason C. O’Connor, Mariusz Papp, Christa Chrovian, Nicholas Carruthers, Timothy W. Lovenberg, Michael A. Letavic

    Emerging data continues to point towards a relationship between neuroinflammation and neuropsychiatric disorders. ATP-induced activation of P2X7 results in IL-1β release causing neuroinflammation and microglial activation. This study describes the in-vitro and in-vivo neuropharmacology of a novel brain-penetrant P2X7 antagonist, JNJ-55308942, currently in clinical development. JNJ-55308942 is a high-affinity, selective, brain-penetrant (brain/plasma of 1) P2X7 functional antagonist. In human blood and in mouse blood and microglia, JNJ-55308942 attenuated IL-1β release in a potent and concentration-dependent manner. After oral dosing, the compound exhibited both dose and concentration-dependent occupancy of rat brain P2X7 with an ED50 of 0.07 mg/kg. The P2X7 antagonist (3 mg/kg, oral) blocked Bz-ATP-induced brain IL-1β release in conscious rats, demonstrating functional effects of target engagement in the brain. JNJ-55308942 (30 mg/kg, oral) attenuated LPS-induced microglial activation in mice, assessed at day 2 after a single systemic LPS injection (0.8 mg/kg, i.p.), suggesting a role for P2X7 in microglial activation. In a model of BCG-induced depression, JNJ-55308942 dosed orally (30 mg/kg), reversed the BCG-induced deficits of sucrose preference and social interaction, indicating for the first time a role of P2X7 in the BCG model of depression, probably due to the neuroinflammatory component induced by BCG inoculation. Finally, in a rat model of chronic stress induced sucrose intake deficit, JNJ-55308942 reversed the deficit with concurrent high P2X7 brain occupancy as measured by autoradiography. This body of data demonstrates that JNJ-55308942 is a potent P2X7 antagonist, engages the target in brain, modulates IL-1β release and microglial activation leading to efficacy in two models of anhedonia in rodents.

    更新日期:2018-07-09
  • Chronic clozapine treatment restrains via HDAC2 the performance of mGlu2 receptor agonism in a rodent model of antipsychotic activity
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-07
    Mario de la Fuente Revenga, Daisuke Ibi, Travis Cuddy, Rudy Toneatti, Mitsumasa Kurita, Maryum K. Ijaz, Michael F. Miles, Jennifer T. Wolstenholme, Javier González-Maeso

    Preclinical findings in rodent models pointed toward activation of metabotropic glutamate 2/3 (mGlu2/3) receptors as a new pharmacological approach to treat psychosis. However, more recent studies failed to show clinical efficacy of mGlu2/3 receptor agonism in schizophrenia patients. We previously proposed that long-term antipsychotic medication restricted the therapeutic effects of these glutamatergic agents. However, little is known about the molecular mechanism underlying the potential repercussion of previous antipsychotic exposure on the therapeutic performance of mGlu2/3 receptor agonists. Here we show that this maladaptive effect of antipsychotic treatment is mediated mostly via histone deacetylase 2 (HDAC2). Chronic treatment with the antipsychotic clozapine led to a decrease in mouse frontal cortex mGlu2 mRNA, an effect that required expression of both HDAC2 and the serotonin 5-HT2A receptor. This transcriptional alteration occurred in association with HDAC2-dependent repressive histone modifications at the mGlu2 promoter. We found that chronic clozapine treatment decreased via HDAC2 the capabilities of the mGlu2/3 receptor agonist LY379268 to activate G-proteins in the frontal cortex of mice. Chronic clozapine treatment blunted the antipsychotic-related behavioral effects of LY379268, an effect that was not observed in HDAC2 knockout mice. More importantly, co-administration of the class I and II HDAC inhibitor SAHA (vorinostat) preserved the antipsychotic profile of LY379268 and frontal cortex mGlu2/3 receptor density in wild-type mice. These findings raise concerns on the design of previous clinical studies with mGlu2/3 agonists, providing the rationale for the development of HDAC2 inhibitors as a new epigenetic-based approach to improve the currently limited response to treatment with glutamatergic antipsychotics.

    更新日期:2018-07-08
  • Sex differences in major depression and comorbidity of cardiometabolic disorders: impact of prenatal stress and immune exposures
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-07
    Jill M. Goldstein, Taben Hale, Simmie L. Foster, Stuart A. Tobet, Robert J. Handa

    Major depressive disorder topped ischemic heart disease as the number one cause of disability worldwide in 2012, and women have twice the risk of men. Further, the comorbidity of depression and cardiometabolic disorders will be one of the primary causes of disability worldwide by 2020, with women at twice the risk. Thus, understanding the sex-dependent comorbidities has public health consequences worldwide. We propose here that sex differences in MDD-cardiometabolic comorbidity originate, in part, from pathogenic processes initiated in fetal development that involve sex differences in shared pathophysiology between the brain, the vascular system, the CNS control of the heart and associated hormonal, immune, and metabolic physiology. Pathways implicate neurotrophic and angiogenic growth factors, gonadal hormone receptors, and neurotransmitters (such as GABA) on neuronal and vascular development of HPA axis regions, such as the PVN, in addition to blood pressure, in part through the renin–angiotensin system, and insulin and glucose metabolism. We show that the same prenatal exposures have consequences for sex differences across multiple organ systems that, in part, share common pathophysiology. Thus, we believe that applying a sex differences lens to understanding shared biologic substrates underlying these comorbidities will provide novel insights into the development of sex-dependent therapeutics. Further, taking a lifespan perspective beginning in fetal development provides the opportunity to target abnormalities early in the natural history of these disorders in a sex-dependent way.

    更新日期:2018-07-08
  • Genetic association of the cytochrome c oxidase-related genes with Alzheimer’s disease in Han Chinese
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-06
    Rui Bi, Wen Zhang, Deng-Feng Zhang, Min Xu, Yu Fan, Qiu-Xiang Hu, Hong-Yan Jiang, Liwen Tan, Tao Li, Yiru Fang, Chen Zhang, Yong-Gang Yao

    Alzheimer’s disease (AD) is the most common cause of dementia. Mitochondrial dysfunction has been widely reported in AD due to its important role in cellular metabolism and energy production. Complex IV (cytochrome c oxidase, COX) of mitochondrial electron transport chain, is particularly vulnerable in AD. Defects of COX in AD have been well documented, but there is little evidence to support the genetic association of the COX-related genes with AD. In this study, we investigated the genetic association between 17 nuclear-encoded COX-related genes and AD in 1572 Han Chinese. The whole exons of these genes were also screened in 107 unrelated AD patients with a high probability of hereditarily transmitted AD. Variants in COX6B1, NDUFA4, SURF1, and COX10 were identified to be associated with AD. An integrative analysis with data of eQTL, expression and pathology revealed that most of the COX-related genes were significantly downregulated in AD patients and mouse models, and the AD-associated variants in COX6B1, SURF1, and COX10 were linked to altered mRNA levels in brain tissues. Furthermore, mRNA levels of Ndufa4, Cox5a, Cox10, Cox6b2, Cox7a2, and Lrpprc were significantly correlated with Aβ plaque burden in hippocampus of AD mice. Convergent functional genomics analysis revealed strong supportive evidence for the roles of COX6B1, COX10, NDUFA4, and SURF1 in AD. As the result of our comprehensive analysis of the COX-related genes at the genetic, expression, and pathology levels, we have been able to provide a systematic view for understanding the relationships of the COX-related genes in the pathology of AD.

    更新日期:2018-07-08
  • In vivo biased agonism at 5-HT1A receptors: characterisation by simultaneous PET/MR imaging
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-06
    Benjamin Vidal, Sylvain Fieux, Jérôme Redouté, Marjorie Villien, Frédéric Bonnefoi, Didier Le Bars, Adrian Newman-Tancredi, Nicolas Costes, Luc Zimmer

    In neuropharmacology, the recent concept of 'biased agonism' denotes the capacity of certain agonists to target-specific intracellular pathways of a given receptor in specific brain areas. In the context of serotonin pharmacotherapy, 5-HT1A receptor-biased agonists could be of great interest in several neuropsychiatric disorders. The aim of this study was to determine whether biased agonists could be differentiated in terms of regional targeting by use of simultaneous functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) brain imaging. We compared two 5-HT1A-biased agonists, NLX-112 and NLX-101, injected at three different doses in anaesthetised cats (n = 4). PET imaging was acquired for 90 min after bolus administration followed by constant infusion of the 5-HT1A radiotracer, [18F]MPPF. Drug occupancy was evaluated after injection at 40 min and BOLD fMRI was simultaneously acquired to evaluate subsequent brain activation patterns. 5-HT1A receptor occupancy was found to be dose-dependent for both agonists, but differed in magnitude and spatial distribution at equal doses with distinct BOLD patterns. Functional connectivity, as measured by BOLD signal temporal correlations between regions, was also differently modified by NLX-112 or NLX-101. Voxel-based correlation analyses between PET and fMRI suggested that NLX-112 stimulates both 5-HT1A autoreceptors and post-synaptic receptors, whereas NLX-101 preferentially stimulates post-synaptic cortical receptors. In cingulate cortex, the agonists induced opposite BOLD signal changes in response to receptor occupancy. These data constitute the first simultaneous exploration of 5-HT1A occupancy and its consequences in terms of brain activation, and demonstrates differential signalling by two 5-HT1A-biased agonists. Combined PET/fMRI represents a powerful tool in neuropharmacology, and opens new ways to address the concept of biased agonism by translational approaches.

    更新日期:2018-07-08
  • What has sex got to do with it? the role of hormones in the transgender brain
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-05
    Hillary B. Nguyen, James Loughead, Emily Lipner, Liisa Hantsoo, Sara L. Kornfield, C. Neill Epperson

    Sex differences and hormonal effects in presumed cisgender individuals have been well-studied and support the concept of a mosaic of both male and female “characteristics” in any given brain. Gonadal steroid increases and fluctuations during peri-puberty and across the reproductive lifespan influence the brain structure and function programmed by testosterone and estradiol exposures in utero. While it is becoming increasingly common for transgender and gender non-binary individuals to block their transition to puberty and/or use gender-affirming hormone therapy (GAHT) to obtain their desired gender phenotype, little is known about the impact of these manipulations on brain structure and function. Using sex differences and the effects of reproductive hormones in cisgender individuals as the backdrop, we summarize here the existing nascent neuroimaging and behavioral literature focusing on potential brain and cognitive differences in transgender individuals at baseline and after GAHT. Research in this area has the potential to inform our understanding of the developmental origins of gender identity and sex difference in response to gonadal steroid manipulations, but care is needed in our research questions and methods to not further stigmatize sex and gender minorities.

    更新日期:2018-07-08
  • Role of gamma-amino-butyric acid in the dorsal anterior cingulate in age-associated changes in cognition
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-03
    Stefano Marenco, Christian Meyer, Jan Willem van der Veen, Yan Zhang, Ryan Kelly, Jun Shen, Daniel R. Weinberger, Dwight Dickinson, Karen F. Berman

    GABAergic mechanisms have been shown to contribute to cognitive aging in animal models, but there is currently limited in vivo evidence to support this relationship in humans. It is also unclear whether aging is associated with changes in GABA levels measured with proton magnetic resonance spectroscopy (MRS). Spectral-editing MRS at 3 T was used to measure GABA in the dorsal anterior cingulate cortex (dACC) for a large sample of healthy volunteers (N = 229) aged 18–55. In a subset of 171 participants, age effects on several cognitive tasks were studied. We formally tested whether the MRS measures mediated the relationship between age and cognition. Robust associations of age with performance were found for the Wisconsin Card Sorting Test ([WCST], p < 0.0001). Age was also significantly associated with declining levels of GABA in the dACC (p < 0.001), and GABA levels significantly predicted WCST performance (p < 0.0004). Mediation analysis revealed that GABA in the dACC mediated the effect of age on WCST performance (p < 0.01). Other metabolites were similarly associated with age, but only GABA and creatine levels were significantly associated with WCST performance. No association with age or cognitive performance was found in a frontal white matter control region in a subset of participants. The association of GABA with WCST performance was not related to the amount of brain atrophy associated with aging as measured by the proportion of CSF, gray, and white matter in the MRS voxel. These results implicate GABAergic and possibly energetic metabolism in the dACC as mechanisms of age effects in executive function.

    更新日期:2018-07-04
  • Overnight memory consolidation facilitates rather than interferes with new learning of similar materials—a study probing NMDA receptors
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-07-02
    M. Alizadeh Asfestani, E. Braganza, J. Schwidetzky, J. Santiago, S. Soekadar, J. Born, G. B. Feld

    Although sleep-dependent consolidation and its neurochemical underpinnings have been strongly researched, less is known about how consolidation during sleep affects subsequent learning. Since sleep enhances memory, it can be expected to pro-actively interfere with learning after sleep, in particular of similar materials. This pro-active interference should be enhanced by substances that benefit consolidation during sleep, such as d-cycloserine. We tested this hypothesis in two groups (Sleep, Wake) of young healthy participants receiving on one occasion d-cycloserine (175 mg) and on another occasion placebo, according to a double-blind balanced crossover design. Treatment was administered after participants had learned a set of word pairs (A–B list) and before nocturnal retention periods of sleep vs. wakefulness. After d-cycloserine blood plasma levels had dropped to negligible amounts, i.e., the next day in the evening, participants learned, in three sequential runs, new sets of word pairs. One list—to enhance interference—consisted of the same cue words as the original set paired with a new target word (A–C list) and the other of completely new cue words (D–E set). Unexpectedly, during post-retention learning the A–C interference list was generally better learned than the completely new D–E list, which suggests that consolidation of previously encoded similar material enhances memory integration rather than pro-active interference. Consistent with this view, new learning of word pairs was better after sleep than wakefulness. Similarly, d-cycloserine generally enhanced learning of new word pairs, compared to placebo. This effect being independent of sleep or wakefulness, leads us to speculate that d-cycloserine, in addition to enhancing sleep-dependent consolidation, might mediate a time-dependent process of active forgetting.

    更新日期:2018-07-03
  • Sex differences in stress reactivity in arousal and attention systems
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-06-29
    Debra A. Bangasser, Samantha R. Eck, Evelyn Ordoñes Sanchez

    Women are more likely than men to suffer from psychiatric disorders with hyperarousal symptoms, including posttraumatic stress disorder (PTSD) and major depression. In contrast, women are less likely than men to be diagnosed with schizophrenia and attention deficit hyperactivity disorder (ADHD), which share attentional impairments as a feature. Stressful events exacerbate symptoms of the aforementioned disorders. Thus, researchers are examining whether sex differences in stress responses bias women and men towards different psychopathology. Here, we review the preclinical literature suggesting that, compared to males, females are more vulnerable to stress-induced hyperarousal, while they are more resilient to stress-induced attention deficits. Specifically described are sex differences in receptors for the stress neuropeptide, corticotropin-releasing factor (CRF), that render the locus coeruleus arousal system of females more vulnerable to stress and less adaptable to CRF hypersecretion, a condition found in patients with PTSD and depression. Studies on the protective effects of ovarian hormones against CRF-induced deficits in sustained attention are also detailed. Importantly, we highlight how comparing males and females in preclinical studies can lead to the development of novel therapeutics to improve treatments for psychiatric disorders in both women and men.

    更新日期:2018-06-30
  • How uncertainty sensitizes dopamine neurons and invigorates amphetamine-related behaviors
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-06-29
    Mike J. F. Robinson, Patrick Anselme

    How uncertainty sensitizes dopamine neurons and invigorates amphetamine-related behaviors How uncertainty sensitizes dopamine neurons and invigorates amphetamine-related behaviors, Published online: 29 June 2018; doi:10.1038/s41386-018-0130-9 How uncertainty sensitizes dopamine neurons and invigorates amphetamine-related behaviors

    更新日期:2018-06-30
  • Sex differences in neuroimmunity as an inherent risk factor
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-06-29
    Margaret M. McCarthy

    Identifying and understanding the sources of inherent risk to neurodevelopmental disorders is a fundamental goal of neuroscience. Being male or being exposed to inflammation early in life are two known risk factors, but they are only infrequently associated with each other. Cellular and molecular mechanisms mediating the masculinization of the brain in animal models reveal a consistent role for inflammatory signaling molecules and immune cells in the healthy male brain. Why this is so remains in the realm of speculation but may have its origins in the maternal immune system. Masculinization of the brain occurs during a restricted critical period that begins in utero and overlaps with the sensitive period during which maternal immune activation negatively impacts the developing brain. The convergence of maleness and early life inflammation as risk factors for neuropsychiatric disorders compels us to consider whether sexual differentiation of the brain in males creates an inherent and greater risk than that experienced by females.

    更新日期:2018-06-30
  • Regulation of monoamine transporters and receptors by lipid microdomains: implications for depression
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-06-28
    Joanne J. Liu, Adrienne Hezghia, Saame Raza Shaikh, Joshua F. Cenido, Ruth E. Stark, J. John Mann, M. Elizabeth Sublette

    Lipid microdomains (“rafts”) are dynamic, nanoscale regions of the plasma membrane enriched in cholesterol and glycosphingolipids, that possess distinctive physicochemical properties including higher order than the surrounding membrane. Lipid microdomain integrity is thought to affect neurotransmitter signaling by regulating membrane-bound protein signaling. Among the proteins potentially affected are monoaminergic receptors and transporters. As dysfunction of monoaminergic neurotransmission is implicated in major depressive disorder and other neuropsychiatric conditions, interactions with lipid microdomains may be of clinical importance. This systematic review evaluates what is known about the molecular relationships of monoamine transporter and receptor regulation to lipid microdomains. The PubMed/MeSH database was searched for original studies published in English through August 2017 concerning relationships between lipid microdomains and serotonin, dopamine and norepinephrine transporters and receptors. Fifty-seven publications were identified and assessed. Strong evidence implicates lipid microdomains in the regulation of serotonin and norepinephrine transporters; serotonin-1A, 2A, 3A, and 7A receptors; and dopamine D1 and β2 adrenergic receptors. Results were conflicting or more complex regarding lipid microdomain associations with the dopamine transporter, D2, D3, and D5 receptors; and negative with respect to β1 adrenergic receptors. Indirect evidence suggests that antidepressants, lipid-lowering drugs, and polyunsaturated fatty acids may exert effects on depression and suicide by altering the lipid milieu, thereby affecting monoaminergic transporter and receptor signaling. The lipid composition of membrane subdomains is involved in localization and trafficking of specific monoaminergic receptors and transporters. Elucidating precise mechanisms whereby lipid microdomains modulate monoamine neurotransmission in clinical contexts can have critical implications for pharmacotherapeutic targeting.

    更新日期:2018-06-30
  • The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-06-28
    Chadi G. Abdallah, Henk M. De Feyter, Lynnette A. Averill, Lihong Jiang, Christopher L. Averill, Golam M. I. Chowdhury, Prerana Purohit, Robin A. de Graaf, Irina Esterlis, Christoph Juchem, Brian P. Pittman, John H. Krystal, Douglas L. Rothman, Gerard Sanacora, Graeme F. Mason

    The ability of ketamine administration to activate prefrontal glutamate neurotransmission is thought to be a key mechanism contributing to its transient psychotomimetic effects and its delayed and sustained antidepressant effects. Rodent studies employing carbon-13 magnetic resonance spectroscopy (13C MRS) methods have shown ketamine and other N-methyl-D-aspartate (NMDA) receptor antagonists to transiently increase measures reflecting glutamate–glutamine cycling and glutamate neurotransmission in the frontal cortex. However, there are not yet direct measures of glutamate neurotransmission in vivo in humans to support these hypotheses. The current first-level pilot study employed a novel prefrontal 13C MRS approach similar to that used in the rodent studies for direct measurement of ketamine effects on glutamate–glutamine cycling. Twenty-one participants (14 healthy and 7 depressed) completed two 13C MRS scans during infusion of normal saline or subanesthetic doses of ketamine. Compared to placebo, ketamine increased prefrontal glutamate–glutamine cycling, as indicated by a 13% increase in 13C glutamine enrichment (t = 2.4, p = 0.02). We found no evidence of ketamine effects on oxidative energy production, as reflected by 13C glutamate enrichment. During ketamine infusion, the ratio of 13C glutamate/glutamine enrichments, a putative measure of neurotransmission strength, was correlated with the Clinician-Administered Dissociative States Scale (r = −0.54, p = 0.048). These findings provide the most direct evidence in humans to date that ketamine increases glutamate release in the prefrontal cortex, a mechanism previously linked to schizophrenia pathophysiology and implicated in the induction of rapid antidepressant effects.

    更新日期:2018-06-28
  • Activity-dependent neuroprotective protein (ADNP) is an alcohol-responsive gene and negative regulator of alcohol consumption in female mice
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-06-27
    Yarden Ziv, Nofar Rahamim, Noa Lezmy, Oren Even-Chen, Ohad Shaham, Anna Malishkevich, Eliezer Giladi, Ran Elkon, Illana Gozes, Segev Barak

    Neuroadaptations in the brain reward system caused by excessive alcohol intake, lead to drinking escalation and alcohol use disorder phenotypes. Activity-dependent neuroprotective protein (ADNP) is crucial for brain development, and is implicated in neural plasticity in adulthood. Here, we discovered that alcohol exposure regulates Adnp expression in the mesolimbic system, and that Adnp keeps alcohol drinking in moderation, in a sex-dependent manner. Specifically, Sub-chronic alcohol treatment (2.5 g/kg/day for 7 days) increased Adnp mRNA levels in the dorsal hippocampus in both sexes, and in the nucleus accumbens of female mice, 24 h after the last alcohol injection. Long-term voluntary excessive alcohol consumption (~10–15 g/kg/24 h, 5 weeks) increased Adnp mRNA in the hippocampus of male mice immediately after an alcohol-drinking session, but the level returned to baseline after 24 h of withdrawal. In contrast, excessive alcohol consumption in females led to long-lasting reduction in hippocampal Adnp expression. We further tested the regulatory role of Adnp in alcohol consumption, using the Adnp haploinsufficient mouse model. We found that Adnp haploinsufficient female mice showed higher alcohol consumption and preference, compared to Adnp intact females, whereas no genotype difference was observed in males. Interestingly, daily intranasal administration of the ADNP-snippet drug candidate NAP normalized alcohol consumption in Adnp haploinsufficient females. Finally, female Adnp haploinsufficient mice showed a sharp increase in alcohol intake after abstinence, suggesting that Adnp protects against relapse in females. The current data suggest that ADNP is a potential novel biomarker and negative regulator of alcohol drinking-behaviors.

    更新日期:2018-06-28
  • Role of endocannabinoids in the hippocampus and amygdala in emotional memory and plasticity
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-06-27
    Amir Segev, Nachshon Korem, Tomer Mizrachi Zer-Aviv, Hila Abush, Rachel Lange, Garrett Sauber, Cecilia J. Hillard, Irit Akirav

    Posttraumatic stress disorder (PTSD) is characterized by the reexperiencing of a traumatic event and is associated with slower extinction of fear responses. Impaired extinction of fearful associations to trauma-related cues may interfere with treatment response, and extinction deficits may be premorbid risk factors for the development of PTSD. We examined the effects of exposure to a severe footshock followed by situational reminders (SRs) on extinction, plasticity, and endocannabinoid (eCB) content and activity in the hippocampal CA1 area and basolateral amygdala (BLA). We also examined whether enhancing eCB signaling before extinction, using the fatty acid amide hydrolase (FAAH) inhibitor URB597, could prevent the shock/SRs-induced effects on fear response and plasticity. URB597 administered systemically (0.3 mg/kg) or locally into the CA1 or BLA (0.1 µg/side) prior to extinction decreased fear retrieval and this effect persisted throughout extinction training and did not recuperate during spontaneous recovery. A low dose of the CB1 receptor antagonist AM251 (0.3 mg/kg i.p. or 0.01 µg/0.5 µl intra-CA1 or intra-BLA) blocked these effects suggesting that the effects of URB597 were CB1 receptor-dependent. Exposure to shock and reminders induced behavioral metaplasticity with opposite effects on long-term potentiation (LTP) in the hippocampus (impairment) and the BLA (enhancement). URB597 was found to prevent the opposite shock/SR-induced metaplasticity in hippocampal and BLA-LTP. Exposure to shock and reminders might cause variation in endogenous cannabinoid levels that could affect fear-circuit function. Indeed, exposure to shock and SRs affected eCB content: increased 2-arachidonoyl-glycerol (2-AG) and N-arachidonylethanolamine (AEA) levels in the CA1, decreased serum and BLA AEA levels while shock exposure increased FAAH activity in the CA1 and BLA. FAAH inhibition before extinction abolished fear and modulated LTP in the hippocampus and amygdala, brain regions pertinent to emotional memory. The findings suggest that targeting the eCB system before extinction may be beneficial in fear memory attenuation and these effects may involve metaplasticity in the CA1 and BLA.

    更新日期:2018-06-28
  • Ronald R Fieve
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-06-26
    David L Dunner

    Ronald R FieveRonald R Fieve, Published online: 26 June 2018; doi:10.1038/s41386-018-0045-5Ronald R Fieve

    更新日期:2018-06-27
  • Genetic loss of GluN2B in D1-expressing cell types enhances long-term cocaine reward and potentiation of thalamo-accumbens synapses
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-06-25
    Max E. Joffe, Brandon D. Turner, Eric Delpire, Brad A. Grueter

    Transient upregulation of GluN2B-containing NMDA receptors (R) in the nucleus accumbens (NAc) is proposed as an intermediate to long-term AMPAR plasticity associated with persistent cocaine-related behaviors. However, cell type- and input-specific contributions of GluN2B underlying lasting actions of cocaine remain to be elucidated. We utilized GluN2B cell type-specific knockouts and optogenetics to deconstruct the role of GluN2B in cocaine-induced NAc synaptic and behavioral plasticity. While reward learning was unaffected, loss of GluN2B in D1 dopamine receptor-expressing cells (D1) led to prolonged retention of reward memory. In control mice, prefrontal cortex (PFC)-D1(+) NAc AMPAR function was unaffected by cocaine exposure, while midline thalamus (mThal)-D1(+) NAc AMPAR function was potentiated but diminished after withdrawal. In D1-GluN2B−/− mice, the potentiation of mThal-D1(+) NAc AMPAR function persisted following withdrawal, corresponding with continued expression of cocaine reward behavior. These data suggest NAc GluN2B-containing NMDARs serve a feedback role and may weaken reward-related memories.

    更新日期:2018-06-27
  • Sex-dependent regulation of social reward by oxytocin: an inverted U hypothesis
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-06-23
    Johnathan M. Borland, James K. Rilling, Kyle J. Frantz, H. Elliott Albers

    The rewarding properties of social interactions are essential for the expression of social behavior and the development of adaptive social relationships. Here, we review sex differences in social reward, and more specifically, how oxytocin (OT) acts in the mesolimbic dopamine system (MDS) to mediate the rewarding properties of social interactions in a sex-dependent manner. Evidence from rodents and humans suggests that same-sex social interactions may be more rewarding in females than in males. We propose that there is an inverted U relationship between OT dose, social reward, and neural activity within structures of the MDS in both males and females, and that this dose–response relationship is initiated at lower doses in females than males. As a result, depending on the dose of OT administered, OT could reduce social reward in females, while enhancing it in males. Sex differences in the neural mechanisms regulating social reward may contribute to sex differences in the incidence of a large number of psychiatric and neurodevelopmental disorders. This review addresses the potential significance of a sex-dependent inverted U dose–response function for OT’s effects on social reward and in the development of gender-specific therapies for these disorders.

    更新日期:2018-06-25
  • Neuronal and glial factors contributing to sex differences in opioid modulation of pain
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-06-23
    Dayna L. Averitt, Lori N. Eidson, Hillary H. Doyle, Anne Z. Murphy

    Morphine remains one of the most widely prescribed opioids for alleviation of persistent and/or severe pain; however, multiple preclinical and clinical studies report that morphine is less efficacious in females compared to males. Morphine primarily binds to the mu opioid receptor, a prototypical G-protein coupled receptor densely localized in the midbrain periaqueductal gray. Anatomical and physiological studies conducted in the 1960s identified the periaqueductal gray, and its descending projections to the rostral ventromedial medulla and spinal cord, as an essential descending inhibitory circuit mediating opioid-based analgesia. Remarkably, the majority of studies published over the following 30 years were conducted in males with the implicit assumption that the anatomical and physiological characteristics of this descending inhibitory circuit were comparable in females; not surprisingly, this is not the case. Several factors have since been identified as contributing to the dimorphic effects of opioids, including sex differences in the neuroanatomical and neurophysiological characteristics of the descending inhibitory circuit and its modulation by gonadal steroids. Recent data also implicate sex differences in opioid metabolism and neuroimmune signaling as additional contributing factors. Here we cohesively present these lines of evidence demonstrating a neural basis for sex differences in opioid modulation of pain, with a focus on the PAG as a sexually dimorphic core of descending opioid-induced inhibition and argue for the development of sex-specific pain therapeutics.

    更新日期:2018-06-25
  • Fear extinction disruption in a developmental rodent model of schizophrenia correlates with an impairment in basolateral amygdala-medial prefrontal cortex plasticity
    Neuropsychopharmacology (IF 6.544) Pub Date : 2018-06-23
    D. L. Uliana, L. B. M. Resstel, A. A. Grace

    Schizophrenia patients typically exhibit prominent negative symptoms associated with deficits in extinction recall and decreased ventromedial prefrontal cortex activity (vmPFC, analogous to medial PFC infralimbic segment in rodents). mPFC activity modulates the activity of basolateral amygdala (BLA) and this connectivity is related to extinction. mPFC and BLA activity has been shown to be altered in the methylazoxymethanol acetate (MAM) developmental disruption model of schizophrenia. However, it is unknown if there are alterations in extinction processes in this model. Therefore, we investigated extinction and the role of mPFC-BLA balance in MAM rats. Male offspring of pregnant rats treated with Saline or MAM (20 mg/kg; i.p.) on gestational day 17 were used in fear conditioning (contextual/tone) and electrophysiological experiments (mPFC-BLA plasticity). No difference was observed in conditioning, extinction, and test sessions in contextual fear conditioning. However, MAM-treated rats demonstrated impairment in extinction learning and recall in tone fear conditioning. Furthermore, high frequency stimulation (HFS) of the BLA decreased spike probability in the mPFC of saline-treated rats but not in MAM rats. NMDA antagonist microinjected into the BLA disrupted extinction learning and recall in control rats, resulting in a similar deficit as that observed in MAM-treated rats. These data demonstrate extinction impairment in the MAM model that is analogous to that observed in schizophrenia patients, that was probably due to disruption in the regulation of mPFC activity by glutamatergic neurotransmission in the BLA.

    更新日期:2018-06-25
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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