Neuropsychopharmacology

Although sex differences in psychiatric disorders abound, few neuropsychopharmacology (NPP) studies consider sex as a biological variable (SABV). We conducted a scoping review of this literature in humans by systematically searching PubMed to identify peer-reviewed journal articles published before March 2020 that (1) studied FDA-approved medications used to treat psychiatric disorders (or related symptoms) and (2) adequately evaluated sex differences using in vivo neuroimaging methodologies. Of the 251 NPP studies that included both sexes and considered SABV in analyses, 80% used methodologies that eliminated the effect of sex (e.g., by including sex as a covariate to control for its effect). Only 20% (50 studies) adequately evaluated sex differences either by testing for an interaction involving sex or by stratifying analyses by sex. Of these 50 studies, 72% found statistically significant sex differences in at least one outcome. Sex differences in neural and behavioral outcomes were studied more often in drugs indicated for conditions with known sex differences. Likewise, the majority of studies conducted in those drug classes noted sex differences: antidepressants (13 of 16), antipsychotics (10 of 12), sedative-hypnotics (6 of 10), and stimulants (6 of 10). In contrast, only two studies of mood stabilizers evaluated SABV, with one noting a sex difference. By mapping this literature, we bring into sharp relief how few studies adequately evaluate sex differences in NPP studies. Currently, all NIH-funded studies are required to consider SABV. We urge scientific journals, peer reviewers, and regulatory agencies to require researchers to consider SABV in their research. Continuing to ignore SABV in NPP research has ramifications both in terms of rigor and reproducibility of research, potentially leading to costly consequences and unrealized benefits.

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Increased responsiveness to punishment of cocaine self-administration after experience with high punishment

Audrey Durand, Paul Girardeau, Luana Freese & Serge H. Ahmed

doi : 10.1038/s41386-021-01159-3

Neuropsychopharmacology volume 47, pages444–453 (2022)

One behavioral feature of drug addiction is continued drug use despite awareness that this causes negative consequences. Attempts to model this feature in animals typically involve punishing drug self-administration with electrical footshock to identify individuals whose drug use is differently suppressed by punishment. Here we sought to further study individual responsiveness of drug use to punishment in rats self-administering intravenous cocaine. Rats were first trained during several weeks to self-administer cocaine under a fixed-ratio 3 schedule of reinforcement. Then, their self-administration behavior was punished with increasing intensity of footshock (i.e., from 0.1?mA to 0.9?mA, every 30?min). With increasing intensity of punishment, rats first continued to self-administer cocaine before eventually stopping near completely. When retested, however, drug use became more responsive to punishment and was suppressed by a low and initially ineffective footshock intensity (i.e., 0.1?mA). This increase in responsiveness to punishment was seen in all individuals tested, albeit with varying degrees, and was acquired after one single experience with an intensity of punishment that near completely suppressed drug self-administration. Mere passive, non-contingent exposure to the same intensity, however, had no such effect. Once acquired, increased responsiveness to punishment persisted during at least one month when rats were tested every week, but not every day. Finally, increased responsiveness to punishment was not observed after exposure to a non-painful form of punishment (i.e., histamine). Overall, this study reveals that initial responsiveness of drug use to punishment can change rapidly and persistently with experience. We discuss several possible mechanisms that may account for this change in punishment responsiveness and also draw some of the implications and future perspectives for research on animal models of compulsion-like behavior.

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Dorsal striatal dopamine induces fronto-cortical hypoactivity and attenuates anxiety and compulsive behaviors in rats

Agata Casado-Sainz, Frederik Gudmundsen, Simone L. Baerentzen, Denise Lange, Annemette Ringsted, Isabel Martinez-Tejada, Siria Medina, Hedok Lee, Claus Svarer, Sune H. Keller, Martin Schain, Celia Kjaerby, Patrick M. Fisher, Paul Cumming & Mikael Palner

doi : 10.1038/s41386-021-01207-y

Neuropsychopharmacology volume 47, pages454–464 (2022)

Dorsal striatal dopamine transmission engages the cortico-striato-thalamo-cortical (CSTC) circuit, which is implicated in many neuropsychiatric diseases, including obsessive-compulsive disorder (OCD). Yet it is unknown if dorsal striatal dopamine hyperactivity is the cause or consequence of changes elsewhere in the CSTC circuit. Classical pharmacological and neurotoxic manipulations of the CSTC and other brain circuits suffer from various drawbacks related to off-target effects and adaptive changes. Chemogenetics, on the other hand, enables a highly selective targeting of specific neuronal populations within a given circuit. In this study, we developed a chemogenetic method for selective activation of dopamine neurons in the substantia nigra, which innervates the dorsal striatum in the rat. We used this model to investigate effects of targeted dopamine activation on CSTC circuit function, especially in fronto-cortical regions. We found that chemogenetic activation of these neurons increased movement (as expected with increased dopamine release), rearings and time spent in center, while also lower self-grooming. Furthermore, this activation increased prepulse inhibition of the startle response in females. Remarkably, we observed reduced [18F]FDG metabolism in the frontal cortex, following dopamine activation in the dorsal striatum, while total glutamate levels- in this region were increased. This result is in accord with clinical studies of increased [18F]FDG metabolism and lower glutamate levels in similar regions of the brain of people with OCD. Taken together, the present chemogenetic model adds a mechanistic basis with behavioral and translational relevance to prior clinical neuroimaging studies showing deficits in fronto-cortical glucose metabolism across a variety of clinical populations (e.g. addiction, risky decision-making, compulsivity or obesity).

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Impulsivity and risk-seeking as Bayesian inference under dopaminergic control

John G. Mikhael & Samuel J. Gershman

doi : 10.1038/s41386-021-01125-z

Neuropsychopharmacology volume 47, pages465–476 (2022)

Bayesian models successfully account for several of dopamine (DA)’s effects on contextual calibration in interval timing and reward estimation. In these models, tonic levels of DA control the precision of stimulus encoding, which is weighed against contextual information when making decisions. When DA levels are high, the animal relies more heavily on the (highly precise) stimulus encoding, whereas when DA levels are low, the context affects decisions more strongly. Here, we extend this idea to intertemporal choice and probability discounting tasks. In intertemporal choice tasks, agents must choose between a small reward delivered soon and a large reward delivered later, whereas in probability discounting tasks, agents must choose between a small reward that is always delivered and a large reward that may be omitted with some probability. Beginning with the principle that animals will seek to maximize their reward rates, we show that the Bayesian model predicts a number of curious empirical findings in both tasks. First, the model predicts that higher DA levels should normally promote selection of the larger/later option, which is often taken to imply that DA decreases ‘impulsivity,’ and promote selection of the large/risky option, often taken to imply that DA increases ‘risk-seeking.’ However, if the temporal precision is sufficiently decreased, higher DA levels should have the opposite effect—promoting selection of the smaller/sooner option (higher impulsivity) and the small/safe option (lower risk-seeking). Second, high enough levels of DA can result in preference reversals. Third, selectively decreasing the temporal precision, without manipulating DA, should promote selection of the larger/later and large/risky options. Fourth, when a different post-reward delay is associated with each option, animals will not learn the option-delay contingencies, but this learning can be salvaged when the post-reward delays are made more salient. Finally, the Bayesian model predicts correlations among behavioral phenotypes: Animals that are better timers will also appear less impulsive.

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Optogenetic inhibition of indirect pathway neurons in the dorsomedial striatum reduces excessive grooming in Sapap3-knockout mice

Kathia I. Ramírez-Armenta, Hector Alatriste-León, Anil K. Verma-Rodríguez, Argelia Llanos-Moreno, Josué O. Ramírez-Jarquín & Fatuel Tecuapetla

doi : 10.1038/s41386-021-01161-9

Neuropsychopharmacology volume 47, pages477–487 (2022)

Excessive grooming of Sapap3-KO mice has been used as a model of obsessive-compulsive disorder (OCD). Previous studies suggest that dysregulation of cortico-striatal circuits is critically important in the generation of compulsive behaviors, and it has been proposed that the alteration in the activity patterns of striatal circuitry underlies the excessive grooming observed in Sapap3-KO mice. To test this hypothesis, we used in-vivo calcium imaging of individual cells to record striatal activity in these animals and optogenetic inhibition to manipulate this activity. We identified striatal neurons that are modulated during grooming behavior and found that their proportion is significantly larger in Sapap3-KO mice compared to wild-type littermates. Inhibition of striatal cells in Sapap3-KO mice increased the number of grooming episodes observed. Remarkably, the specific inhibition of indirect pathway neurons decreased the occurrence of grooming events. Our results indicate that there is striatal neural activity related to excessive grooming engagement in Sapap3-KO mice. We also demonstrate, for the first time, that specific inhibition of striatal indirect pathway neurons reduces this compulsive phenotype, suggesting that treatments that alleviate compulsive symptoms in OCD patients may exert their effects through this specific striatal population.

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Postpartum scarcity-adversity disrupts maternal behavior and induces a hypodopaminergic state in the rat dam and adult female offspring

Millie Rincón-Cortés & Anthony A. Grace

doi : 10.1038/s41386-021-01210-3

Neuropsychopharmacology volume 47, pages488–496 (2022)

Postpartum adversity is among the strongest predictors for the emergence of postpartum depression (PPD) in humans and a translational risk factor employed in rodent models. Parental care is disturbed under conditions of environmental adversity, including low resource environments, and in PPD. Nonetheless, the neural changes associated with these adversity-induced maladaptive behavioral states remain poorly understood. Postpartum scarcity-adversity can be modeled in rats by providing the dam with limited bedding and nesting (LBN) materials, which mimics the effects of a stressful low resource environment in potentiating maltreatment/neglect in humans. Indeed, LBN exposure from postpartum days (PD) 2–9 increased adverse maternal behaviors, impaired pup retrieval, and increased passive stress coping responses. Since mesolimbic dopamine (DA) activity is an important mechanism for motivated maternal behavior and is implicated in PPD, we assessed the impact of postpartum scarcity-adversity on in vivo electrophysiological properties of ventral tegmental area (VTA) DA neurons at two timepoints. We found reduced numbers of active VTA DA neurons in LBN dams at PD 9-10 but not PD-21, suggesting a transient impact on VTA population activity in LBN dams. Finally, we assessed the impact of early life scarcity-adversity on VTA DA function by conducting VTA recordings in adult female offspring and found a long-lasting attenuation in DA activity. These findings highlight a link between adversity-induced deficits in DA function and disrupted maternal behavior, suggesting the VTA/mesolimbic DA system as a potential mechanism by which postpartum scarcity-adversity drives aberrant maternal behavior, and early postnatal programming of adult VTA function in the offspring.

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Sensitive period-regulating genetic pathways and exposure to adversity shape risk for depression

Yiwen Zhu, Min-Jung Wang, Katherine M. Crawford, Juan Carlos Ramírez-Tapia, Alexandre A. Lussier, Kathryn A. Davis, Christiaan de Leeuw, Anne E. Takesian, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Takao K. Hensch, Jordan W. Smoller & Erin C. Dunn

doi : 10.1038/s41386-021-01172-6

Neuropsychopharmacology volume 47, pages497–506 (2022)

Animal and human studies have documented the existence of developmental windows (or sensitive periods) when experience can have lasting effects on brain structure or function, behavior, and disease. Although sensitive periods for depression likely arise through a complex interplay of genes and experience, this possibility has not yet been explored in humans. We examined the effect of genetic pathways regulating sensitive periods, alone and in interaction with common childhood adversities, on depression risk. Guided by a translational approach, we: (1) performed association analyses of three gene sets (60 genes) shown in animal studies to regulate sensitive periods using summary data from a genome-wide association study of depression (n?=?807,553); (2) evaluated the developmental expression patterns of these genes using data from BrainSpan (n?=?31), a transcriptional atlas of postmortem brain samples; and (3) tested gene-by-development interplay (dGxE) by analyzing the combined effect of common variants in sensitive period genes and time-varying exposure to two types of childhood adversity within a population-based birth cohort (n?=?6254). The gene set regulating sensitive period opening associated with increased depression risk. Notably, 6 of the 15 genes in this set showed developmentally regulated gene-level expression. We also identified a statistical interaction between caregiver physical or emotional abuse during ages 1–5 years and genetic risk for depression conferred by the opening genes. Genes involved in regulating sensitive periods are differentially expressed across the life course and may be implicated in depression vulnerability. Our findings about gene-by-development interplay motivate further research in large, more diverse samples to further unravel the complexity of depression etiology through a sensitive period lens.

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Infralimbic BDNF signaling is necessary for the beneficial effects of extinction on set shifting in stressed rats

Denisse Paredes, Anna R. Knippenberg & David A. Morilak

doi : 10.1038/s41386-021-01171-7

Neuropsychopharmacology volume 47, pages507–515 (2022)

Current pharmacotherapies for posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) are ineffective for many patients, and often do not restore cognitive dysfunction associated with these disorders. Behavioral therapies, such as exposure therapy, can be effective for treatment-resistant patients. The mechanisms underlying exposure therapy are not well-understood. Fear extinction as an intervention after chronic stress can model the beneficial effects of exposure therapy in rats. Extinction requires neuronal activity and protein synthesis in the infralimbic (IL) cortex for its beneficial effects. We hypothesized that extinction requires Brain-Derived Neurotrophic Factor (BDNF) activity in the IL cortex to reverse stress-induced cognitive flexibility impairments. Extinction learning reversed set-shifting deficits induced by Chronic Unpredictable Stress (CUS), tested 24?h after extinction. Blocking BDNF signaling in the IL cortex during extinction by local administration of a neutralizing antibody prevented the beneficial effects of extinction on set shifting after stress. Extinction induced activation of the BDNF TrkB receptor, and signaling pathways associated with BDNF (Akt and Erk). Administration of exogenous BDNF into IL cortex in the absence of extinction was sufficient to reverse the effects of stress on set shifting. The effects of extinction were prevented by blocking either Erk or Akt signaling in the IL cortex, whereas the effects of exogenous BDNF were dependent on Erk, but not Akt, signaling. Our observations suggest that BDNF-Erk signaling induced by extinction underlies plastic changes that can reverse or counteract the effects of chronic stress in the IL cortex.

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Stress-induced generalization of negative memories is mediated by an extended hippocampal circuit

Lynn Y. Ren, Mariah A. A. Meyer, Viktoriya S. Grayson, Pan Gao, Anita L. Guedea & Jelena Radulovic

doi : 10.1038/s41386-021-01174-4

Neuropsychopharmacology volume 47, pages516–523 (2022)

Memories of negative experiences exert important control of behavior in the face of actual or anticipated threat. Sometimes, however, this control extends to non-threatening situations, a phenomenon known as overgeneralization of negative memories. Overgeneralization is a reliable cognitive phenotype of major depressive disorder, generalized anxiety disorder, and post-traumatic stress disorder. We therefore sought to develop an animal model to study stress-induced generalization of negative memories (SIG) and determine its dependence on the episodic-like memory circuit. We found that male and female mice, which were trained to differentiate a threatening from neutral context, exhibited robust SIG in response to subsequent social stress. Using chemogenetic circuit manipulations during memory retrieval, we demonstrated that both excitatory afferents to the dorsal hippocampus (DH) from the ventral tegmental area (VTA), and excitatory efferents from the DH to the retrosplenial cortex (RSC) contribute to SIG. Based on the known roles of these projections, we suggest that (1) by targeting subcortical VTA circuits that provide valence signals to the DH, stress prioritizes the retrieval of negative over neutral memories, and (2) by forwarding such information to the RSC, stress engages cortical mechanisms that support the retrieval of general relative to specific memory features. Altogether, these results suggest that various components of the extended hippocampal circuit can serve as treatment targets for memory overgeneralization.

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The association of matrix metalloproteinase 9 (MMP9) with hippocampal volume in schizophrenia: a preliminary MRI study

Johanna Seitz-Holland, Magdalena Seethaler, Nikos Makris, Jarrett Rushmore, Kang-Ik K. Cho, Elizabeth Rizzoni, Mark Vangel, Olcay Senay Sahin, Carina Heller, Ofer Pasternak, Filip Szczepankiewicz, Carl-Fredrik Westin, Jan Lošák, Libor Ustohal, Josef Tomandl, Lubomír Vojtíšek, Petr Kudli?ka, Martin Jáni, T. Wilson Woo, Tomáš Kašpárek, Zora Kikinis & Marek Kubicki

doi : 10.1038/s41386-021-00997-5

Neuropsychopharmacology volume 47, pages524–530 (2022)

Matrix metalloproteinases 9 (MMP9) are enzymes involved in regulating neuroplasticity in the hippocampus. This, combined with evidence for disrupted hippocampal structure and function in schizophrenia, has prompted our current investigation into the relationship between MMP9 and hippocampal volumes in schizophrenia. 34 healthy individuals (mean age?=?32.50, male?=?21, female?=?13) and 30 subjects with schizophrenia (mean age?=?33.07, male?=?19, female?=?11) underwent a blood draw and T1-weighted magnetic resonance imaging. The hippocampus was automatically segmented utilizing FreeSurfer. MMP9 plasma levels were measured with ELISA. ANCOVAs were conducted to compare MMP9 plasma levels (corrected for age and sex) and hippocampal volumes between groups (corrected for age, sex, total intracranial volume). Spearman correlations were utilized to investigate the relationship between symptoms, medication, duration of illness, number of episodes, and MMP9 plasma levels in patients. Last, we explored the correlation between MMP9 levels and hippocampal volumes in patients and healthy individuals separately. Patients displayed higher MMP9 plasma levels than healthy individuals (F(1, 60)?=?21.19, p?<?0.0001). MMP9 levels correlated with negative symptoms in patients (R?=?0.39, p?=?0.035), but not with medication, duration of illness, or the number of episodes. Further, patients had smaller left (F(1,59)?=?9.12, p?=?0.0040) and right (F(1,59)?=?6.49, p?=?0.013) hippocampal volumes. Finally, left (R?=??0.39, p?=?0.034) and right (R?=??0.37, p?=?0.046) hippocampal volumes correlated negatively with MMP9 plasma levels in patients. We observe higher MMP9 plasma levels in SCZ, associated with lower hippocampal volumes, suggesting involvement of MMP9 in the pathology of SCZ. Future studies are needed to investigate how MMP9 influences the pathology of SCZ over the lifespan, whether the observed associations are specific for schizophrenia, and if a therapeutic modulation of MMP9 promotes neuroprotective effects in SCZ.

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Organization of the social cognition network predicts future depression and interpersonal impairment: a prospective family-based study

Eyal Abraham, Yun Wang, Connie Svob, David Semanek, Marc J. Gameroff, Stewart A. Shankman, Myrna M. Weissman, Ardesheer Talati & Jonathan Posner

doi : 10.1038/s41386-021-01065-8

Neuropsychopharmacology volume 47, pages531–542 (2022)

Deficits in social cognition and functioning are common in major depressive disorder (MDD). Still, no study into the pathophysiology of MDD has examined the social cognition-related neural pathways through which familial risk for MDD leads to depression and interpersonal impairments. Using resting-state fMRI, we applied a graph theoretical analysis to quantify the influence of nodes within the fronto-temporo-parietal cortical social cognition network in 108 generation 2 and generation 3 offspring at high and low-risk for MDD, defined by the presence or absence, respectively, of moderate to severe MDD in generation 1. New MDD episodes, future depressive symptoms, and interpersonal impairments were tested for associations with social cognition nodal influence, using regression analyses applied in a generalized estimating equations approach. Increased familial risk was associated with reduced nodal influence within the network, and this predicted new depressive episodes, worsening depressive symptomatology, and interpersonal impairments, 5–8 years later. Findings remained significant after controlling for current depressive/anxiety symptoms and current/lifetime MDD and anxiety disorders. Path-analysis models indicate that increased familial risk impacted offspring’s brain function in two ways. First, high familial risk was indirectly associated with future depression, both new MDD episodes and symptomatology, via reduced nodal influence of the right posterior superior temporal gyrus (pSTG). Second, high familial risk was indirectly associated with future interpersonal impairments via reduced nodal influence of right inferior frontal gyrus (IFG). Finally, reduced nodal influence was associated with high familial risk in (1) those who had never had MDD at the time of scanning and (2) a subsample (n?=?52) rescanned 8 years later. Together, findings reveal a potential pathway for the intergenerational transmission of vulnerability via the aberrant social cognition network organization and suggest using the connectome of neural network related to social cognition to identify intervention and prevention targets for those particularly at risk.

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Lower synaptic density is associated with psychiatric and cognitive alterations in obesity

Ruth H. Asch, Sophie E. Holmes, Ania M. Jastreboff, Marc N. Potenza, Stephen R. Baldassarri, Richard E. Carson, Robert H. Pietrzak & Irina Esterlis

doi : 10.1038/s41386-021-01111-5

Neuropsychopharmacology volume 47, pages543–552 (2022)

Obesity is a serious medical condition that often co-occurs with stress-related psychiatric disorders. It is recognized that the brain plays a key role in the (patho)physiology of obesity and that there is a bidirectional relationship between obesity and psychopathology, yet molecular mechanisms altered in obesity have not been fully elucidated. Thus, we investigated relationships between obesity and synaptic density in vivo using the radioligand [11C]UCB-J (which binds to synaptic glycoprotein SV2A) and positron emission tomography in individuals with obesity, and with or without stress-related psychiatric disorders. Regions of interest were the dorsolateral prefrontal cortex, orbitofrontal cortex, ventromedial, amygdala, hippocampus, and cerebellum. Forty individuals with a body mass index (BMI)???25?kg/m2 (overweight/obese), with (n?=?28) or without (n?=?12) psychiatric diagnosis, were compared to 30 age- and sex-matched normal weight individuals (BMI?<?25), with (n?=?14) or without (n?=?16) psychiatric diagnosis. Overall, significantly lower synaptic density was observed in overweight/obese relative to normal weight participants (?p2?=?0.193, F?=?2.35, p?=?0.042). Importantly, in participants with stress-related psychiatric diagnoses, we found BMI to be negatively correlated with synaptic density in all regions of interest (p???0.03), but no such relationship observed for mentally healthy controls (p???0.68). In the stress-related psychiatric groups, dorsolateral prefrontal cortex synaptic density was negatively associated with measures of worry (r?=??0.46, p?=?0.01), tension/anxiety (r?=??0.38, p?=?0.04), fatigue (r?=??0.44, p?=?0.02), and attentional difficulties (r?=??0.44, p?=?0.02). In summary, the findings of this novel in vivo experiment suggest compounding effects of obesity and stress-related psychopathology on the brain and the associated symptomatology that may impact functioning. This offers a novel biological mechanism for the relationship between overweight/obesity and stress-related psychiatric disorders that may guide future intervention development efforts.

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BDNF controls GABAAR trafficking and related cognitive processes via autophagic regulation of p62

Toshifumi Tomoda, Akiko Sumitomo, Rammohan Shukla, Yuki Hirota-Tsuyada, Hitoshi Miyachi, Hyunjung Oh, Leon French & Etienne Sibille

doi : 10.1038/s41386-021-01116-0

Neuropsychopharmacology volume 47, pages553–563 (2022)

Reduced brain-derived neurotrophic factor (BDNF) and gamma-aminobutyric acid (GABA) neurotransmission co-occur in brain conditions (depression, schizophrenia and age-related disorders) and are associated with symptomatology. Rodent studies show they are causally linked, suggesting the presence of biological pathways mediating this link. Here we first show that reduced BDNF and GABA also co-occur with attenuated autophagy in human depression. Using mice, we then show that reducing Bdnf levels (Bdnf+/?) leads to upregulated sequestosome-1/p62, a key autophagy-associated adaptor protein, whose levels are inversely correlated with autophagic activity. Reduced Bdnf levels also caused reduced surface presentation of ?5 subunit-containing GABAA receptor (?5-GABAAR) in prefrontal cortex (PFC) pyramidal neurons. Reducing p62 gene dosage restored ?5-GABAAR surface expression and rescued PFC-relevant behavioral deficits of Bdnf+/? mice, including cognitive inflexibility and reduced sensorimotor gating. Increasing p62 levels was sufficient to recreate the molecular and behavioral profiles of Bdnf+/? mice. Collectively, the data reveal a novel mechanism by which deficient BDNF leads to targeted reduced GABAergic signaling through autophagic dysregulation of p62, potentially underlying cognitive impairment across brain conditions.

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Association between polygenic risk for Alzheimer’s disease, brain structure and cognitive abilities in UK Biobank

Rachana Tank, Joey Ward, Kristin E. Flegal, Daniel J. Smith, Mark E. S. Bailey, Jonathan Cavanagh & Donald M. Lyall

doi : 10.1038/s41386-021-01190-4

Neuropsychopharmacology volume 47, pages564–569 (2022)

Previous studies testing associations between polygenic risk for late-onset Alzheimer’s disease (LOAD-PGR) and brain magnetic resonance imaging (MRI) measures have been limited by small samples and inconsistent consideration of potential confounders. This study investigates whether higher LOAD-PGR is associated with differences in structural brain imaging and cognitive values in a relatively large sample of non-demented, generally healthy adults (UK Biobank). Summary statistics were used to create PGR scores for n?=?32,790 participants using LDpred. Outcomes included 12 structural MRI volumes and 6 concurrent cognitive measures. Models were adjusted for age, sex, body mass index, genotyping chip, 8 genetic principal components, lifetime smoking, apolipoprotein (APOE) e4 genotype and socioeconomic deprivation. We tested for statistical interactions between APOE e4 allele dose and LOAD-PGR vs. all outcomes. In fully adjusted models, LOAD-PGR was associated with worse fluid intelligence (standardised beta [?]?=??0.080 per LOAD-PGR standard deviation, p?=?0.002), matrix completion (??=??0.102, p?=?0.003), smaller left hippocampal total (??=??0.118, p?=?0.002) and body (??=??0.069, p?=?0.002) volumes, but not other hippocampal subdivisions. There were no significant APOE x LOAD-PGR score interactions for any outcomes in fully adjusted models. This is the largest study to date investigating LOAD-PGR and non-demented structural brain MRI and cognition phenotypes. LOAD-PGR was associated with smaller hippocampal volumes and aspects of cognitive ability in healthy adults and could supplement APOE status in risk stratification of cognitive impairment/LOAD.

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The efficacy and safety of zolpidem and zopiclone to treat insomnia in Alzheimer’s disease: a randomized, triple-blind, placebo-controlled trial

Luciana L. Louzada, Flávio V. Machado, Juliana L. Quintas, Guilherme A. Ribeiro, Mônica V. Silva, Dayde L. Mendonça-Silva, Bruno S. B. Gonçalves, Otávio T. Nóbrega & Einstein F. Camargos

doi : 10.1038/s41386-021-01191-3

Neuropsychopharmacology volume 47, pages570–579 (2022)

No prior studies have evaluated the efficacy and safety of zolpidem and zopiclone to treat insomnia of demented patients. This randomized, triple-blind, placebo-controlled clinical trial used these drugs to treat patients with probable, late onset Alzheimer’s dementia (AD) (DSM V and NINCDS-ADRDA criteria) exhibiting insomnia (DSM V criteria and nocturnal NPI scores???2). Actigraphic records were performed for 7 days at baseline and for 14 days during the treatment period in 62 patients aged 80.5 years in average and randomized at a 1:1:1 ratio for administration of zolpidem 10?mg/day, zopiclone 7.5?mg/day or placebo. Primary endpoint was the main nocturnal sleep duration (MNSD), whereas secondary outcomes were the proportion of the night time slept, awake time after sleep onset (WASO), nocturnal awakenings, total daytime sleep time and daytime naps. Cognitive and functional domains were tested before and after drug/placebo use. Three participants under zopiclone use had intervention interrupted due to intense daytime sedation and worsened agitation with wandering. Zopiclone produced an 81?min increase in MNSD (95% confidence interval (CI): ?0.8, 163.2), a 26?min reduction in WASO (95% CI: ?56.2, 4.8) and a 2-episode decrease in awakening per night (95% CI: ?4.0, 0.4) in average compared to placebo. Zolpidem yielded no significant difference in MNSD despite a significant 22?min reduction in WASO (95% CI: ?52.5, 8.3) and a reduction of 1 awakening each night (95% CI: ?3.4, 1.2) in relation to placebo. There was a 1-point reduction in mean performance in the symbols search test among zolpidem users (95% CI: ?4.1, 1.5) and an almost eight-point reduction in average scores in the digit-symbol coding test among zopiclone users (95% CI: ?21.7, 6.2). In summary, short-term use of zolpidem or zopiclone by older insomniacs with AD appears to be clinically helpful, even though safety and tolerance remain issues to be personalized in healthcare settings and further investigated in subsequent trials. This trial was registered in ClinicalTrials.gov Identifier: NCT03075241.

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Late-life depression accentuates cognitive weaknesses in older adults with small vessel disease

Lauren E. Oberlin, Matteo Respino, Lindsay Victoria, Lila Abreu, Matthew J. Hoptman, George S. Alexopoulos & Faith M. Gunning

doi : 10.1038/s41386-021-00973-z

Neuropsychopharmacology volume 47, pages580–587 (2022)

Neuroimaging features of small vessel disease (SVD) are highly prevalent in older adulthood and associated with significant variability in clinical symptoms, yet the factors predicting these symptom disparities are poorly understood. We employed a novel metric of SVD, peak width of skeletonized mean diffusivity (PSMD), to elucidate the relationship of late-life depression (LLD) to the cognitive presentation of vascular pathology. A total of 109 older adults without a diagnosis of a neurocognitive disorder were enrolled in the study; 44 with major depressive disorder and 65 age-matched controls. Subjects completed neuropsychological testing and magnetic resonance imaging including FLAIR and diffusion tensor imaging sequences, from which white matter hyperintensity volume and diffusion metrics (fractional anisotropy, mean diffusivity, PSMD) were quantified. In hierarchical models, the relationship between vascular burden and cognitive performance varied as a function of diagnostic status, such that the negative association between PSMD and processing speed was significantly stronger in participants with LLD compared to controls. Greater PSMD also predicted poorer performance on delayed memory and executive function tasks specifically among those with LLD, while there were no associations between PSMD and task performance among controls. PSMD outperformed conventional SVD and diffusion markers in predicting cognitive performance and dysexecutive behaviors in participants with LLD. These data suggest that LLD may confer a vulnerability to the cognitive manifestations of white matter abnormalities in older adulthood. PSMD, a novel biomarker of diffuse microstructural changes in SVD, may be a more sensitive marker of subtle cognitive deficits stemming from vascular pathology in LLD.

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Proof of concept study to develop a novel connectivity-based electric-field modelling approach for individualized targeting of transcranial magnetic stimulation treatment

Nicholas L. Balderston, Joanne C. Beer, Darsol Seok, Walid Makhoul, Zhi-De Deng, Tommaso Girelli, Marta Teferi, Nathan Smyk, Marc Jaskir, Desmond J. Oathes & Yvette I. Sheline

doi : 10.1038/s41386-021-01110-6

Neuropsychopharmacology volume 47, pages588–598 (2022)

Resting state functional connectivity (rsFC) offers promise for individualizing stimulation targets for transcranial magnetic stimulation (TMS) treatments. However, current targeting approaches do not account for non-focal TMS effects or large-scale connectivity patterns. To overcome these limitations, we propose a novel targeting optimization approach that combines whole-brain rsFC and electric-field (e-field) modelling to identify single-subject, symptom-specific TMS targets. In this proof of concept study, we recruited 91 anxious misery (AM) patients and 25 controls. We measured depression symptoms (MADRS/HAMD) and recorded rsFC. We used a PCA regression to predict symptoms from rsFC and estimate the parameter vector, for input into our e-field augmented model. We modeled 17 left dlPFC and 7 M1 sites using 24 equally spaced coil orientations. We computed single-subject predicted ?MADRS/HAMD scores for each site/orientation using the e-field augmented model, which comprises a linear combination of the following elementwise products (1) the estimated connectivity/symptom coefficients, (2) a vectorized e-field model for site/orientation, (3) rsFC matrix, scaled by a proportionality constant. In AM patients, our connectivity-based model predicted a significant decrease depression for sites near BA9, but not M1 for coil orientations perpendicular to the cortical gyrus. In control subjects, no site/orientation combination showed a significant predicted change. These results corroborate previous work suggesting the efficacy of left dlPFC stimulation for depression treatment, and predict better outcomes with individualized targeting. They also suggest that our novel connectivity-based e-field modelling approach may effectively identify potential TMS treatment responders and individualize TMS targeting to maximize the therapeutic impact.

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Fentanyl-induced hyperalgesia and analgesic tolerance in male rats: common underlying mechanisms and prevention by a polyamine deficient diet

Emilie Laboureyras, Meric Ben Boujema, Annie Mauborgne, John Simmers, Michel Pohl & Guy Simonnet

doi : 10.1038/s41386-021-01200-5

Neuropsychopharmacology volume 47, pages599–608 (2022)

Opioids are a mainstay of pain management but can induce unwanted effects, including analgesic tolerance and paradoxical hyperalgesia, either of which leads to increased pain. Clinically, however, the relationship between these two phenomena remains elusive. By evaluating changes in mechanical nociceptive threshold in male rats, we found that in contrast to a purely analgesic control response to a single subcutaneous administration of fentanyl (25??g/kg), in rats subjected to inflammatory pain 2 weeks previously (Day0), the same test dose (D13) induced a bi-phasic response: initial decreased analgesia (tolerance) followed by hyperalgesia lasting several hours. Both the tolerance and hyperalgesia were further enhanced in rats that had additionally received fentanyl on D0. The dose-response profiles (5?fg to 50??g/kg) of pain- and opioid-experienced rats were very different from pain/drug-naive rats. At ultra-low fentanyl doses (<5?ng/kg and <500?ng/kg for naïve control and pain/drug-experienced rats, respectively), solely hyperalgesia was observed in all cases. At higher doses, which now produced analgesia alone in naive rats, reduced analgesia (tolerance) coupled with hyperalgesia occurred in pain/fentanyl-experienced rats, with both phases increasing with dose. Transcriptomic and pharmacological data revealed that an overactivation of the spinal N-methyl-D-aspartate receptor-inducible NO synthase cascade plays a critical role in both acute tolerance and hyperalgesia, and together with the finding that the magnitudes of analgesia and associated hyperalgesia are negatively correlated, is indicative of closely related phenomena. Finally, a polyamine deficient diet prevented inducible NO synthase transcript upregulation, restored fentanyl’s analgesic efficacy and suppressed the emergence of hyperalgesia.

خرید پکیج و مشاهده آنلاین مقاله

Correction: Prefrontal cortex and depression

Diego A. Pizzagalli & Angela C. Roberts

doi : 10.1038/s41386-021-01160-w

Neuropsychopharmacology volume 47, page609 (2022)

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Correction to: Brain sex differences: the androgynous brain is advantageous for mental health and well-being

Qiang Luo & Barbara J. Sahakian

doi : 10.1038/s41386-021-01202-3

Neuropsychopharmacology volume 47, page610 (2022)

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Correction to: Biological sex classification with structural MRI data shows increased misclassification in transgender women

Claas Flint, Katharina Förster, Sophie A. Koser, Carsten Konrad, Pienie Zwitserlood, Klaus Berger, Marco Hermesdorf, Tilo Kircher, Igor Nenadic, Axel Krug, Bernhard T. Baune, Katharina Dohm, Ronny Redlich, Nils Opel, Volker Arolt, Tim Hahn, Xiaoyi Jiang, Udo Dannlowski & Dominik Grotegerd

doi : 10.1038/s41386-021-01203-2

Neuropsychopharmacology volume 47, page611 (2022)

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Correction: Organization of the social cognition network predicts future depression and interpersonal impairment: a prospective family-based study

Eyal Abraham, Yun Wang, Connie Svob, David Semanek, Marc J. Gameroff, Stewart A. Shankman, Myrna M. Weissman, Ardesheer Talati & Jonathan Posner

doi : 10.1038/s41386-021-01105-3

Neuropsychopharmacology volume 47, page612 (2022)

خرید پکیج و مشاهده آنلاین مقاله

IN MEMORIAM José Miguel Cañive, MD

Javier I. Escobar

doi : 10.1038/s41386-021-01206-z

Neuropsychopharmacology volume 47, page613 (2022)

خرید پکیج و مشاهده آنلاین مقاله

In memoriam—Stephen I. Szára, D.Sc., M.D. (1923–2021)

Anna Wirz-Justice

doi : 10.1038/s41386-021-01208-x

Neuropsychopharmacology volume 47, pages614–615 (2022)

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