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Comment on Heilig et al.: The centrality of the brain and the fuzzy line of addiction
Justin C. Strickland & Kirsten E. Smith
doi : 10.1038/s41386-021-01000-x
Neuropsychopharmacology volume 46, pages1703–1704 (2021)
Adding dopamine to the complexity of sex differences in opioid reinforcement
Hannah L. Robinson & Matthew L. Banks
doi : 10.1038/s41386-021-01060-z
Neuropsychopharmacology volume 46, pages1705–1706 (2021)
A dubious distinction for females: rapid achievement of prefrontal cortical hypoactivity and cognitive deficit upon remifentanil self-administration
Shannon L. Gourley
doi : 10.1038/s41386-021-01053-y
Neuropsychopharmacology volume 46, pages1707–1708 (2021)
Being counted: LGBTQ+ representation within the American College of Neuropsychopharmacology (ACNP)
Hayley Fisher
doi : 10.1038/s41386-021-01047-w
Neuropsychopharmacology volume 46, pages1709–1711 (2021)
No level has primacy in what is called addiction: “addiction is a social disease” would be just as tenable
Robin Room
doi : 10.1038/s41386-021-01015-4
Neuropsychopharmacology volume 46, page1712 (2021)
Response to “Addiction is a social disease: just as tenable as calling it a brain disease”
Markus Heilig, James MacKillop, Diana Martinez, Jürgen Rehm, Lorenzo Leggio & Louk J. M. J. Vanderschuren
doi : 10.1038/s41386-021-01037-y
Neuropsychopharmacology volume 46, pages1713–1714 (2021)
Addiction as a brain disease revised: why it still matters, and the need for consilience
Markus Heilig, James MacKillop, Diana Martinez, Jürgen Rehm, Lorenzo Leggio & Louk J. M. J. Vanderschuren
doi : 10.1038/s41386-020-00950-y
Neuropsychopharmacology volume 46, pages1715–1723 (2021)
The view that substance addiction is a brain disease, although widely accepted in the neuroscience community, has become subject to acerbic criticism in recent years. These criticisms state that the brain disease view is deterministic, fails to account for heterogeneity in remission and recovery, places too much emphasis on a compulsive dimension of addiction, and that a specific neural signature of addiction has not been identified. We acknowledge that some of these criticisms have merit, but assert that the foundational premise that addiction has a neurobiological basis is fundamentally sound. We also emphasize that denying that addiction is a brain disease is a harmful standpoint since it contributes to reducing access to healthcare and treatment, the consequences of which are catastrophic. Here, we therefore address these criticisms, and in doing so provide a contemporary update of the brain disease view of addiction. We provide arguments to support this view, discuss why apparently spontaneous remission does not negate it, and how seemingly compulsive behaviors can co-exist with the sensitivity to alternative reinforcement in addiction. Most importantly, we argue that the brain is the biological substrate from which both addiction and the capacity for behavior change arise, arguing for an intensified neuroscientific study of recovery. More broadly, we propose that these disagreements reveal the need for multidisciplinary research that integrates neuroscientific, behavioral, clinical, and sociocultural perspectives.
Enhanced heroin self-administration and distinct dopamine adaptations in female rats
Brianna E. George, Samuel H. Barth, Lindsey B. Kuiper, Katherine M. Holleran, Ryan T. Lacy, Kimberly F. Raab-Graham & Sara R. Jones
doi : 10.1038/s41386-021-01035-0
Neuropsychopharmacology volume 46, pages1724–1733 (2021)
Increasing evidence suggests that females are more vulnerable to the harmful effects of drugs of abuse, including opioids. Additionally, rates of heroin-related deaths substantially increased in females from 1999 to 2017 [1], underscoring the need to evaluate sex differences in heroin vulnerability. Moreover, the neurobiological substrates underlying sexually dimorphic responding to heroin are not fully defined. Thus, we evaluated male and female Long Evans rats on acquisition, dose-responsiveness, and seeking for heroin self-administration (SA) as well as using a long access model to assess escalation of intake at low and high doses of heroin, 0.025 and 0.1?mg/kg/inf, respectively. We paired this with ex vivo fast-scan cyclic voltammetry (FSCV) in the medial nucleus accumbens (NAc) shell and quantification of mu-opioid receptor (MOR) protein in the ventral tegmental area (VTA) and NAc. While males and females had similar heroin SA acquisition rates, females displayed increased responding and intake across doses, seeking for heroin, and escalation on long access. However, we found that males and females had similar expression levels of MORs in the VTA and NAc, regardless of heroin exposure. FSCV results revealed that heroin exposure did not change single-pulse elicited dopamine release, but caused an increase in dopamine transporter activity in both males and females compared to their naïve counterparts. Phasic-like stimulations elicited robust increases in dopamine release in heroin-exposed females compared to heroin-naïve females, with no differences seen in males. Together, our results suggest that differential adaptations of dopamine terminals may underlie the increased heroin SA behaviors seen in females.
Remifentanil self-administration in mice promotes sex-specific prefrontal cortex dysfunction underlying deficits in cognitive flexibility
Eden M. Anderson, Annabel Engelhardt, Skyler Demis, Elissa Porath & Matthew C. Hearing
doi : 10.1038/s41386-021-01028-z
Neuropsychopharmacology volume 46, pages1734–1745 (2021)
Opioid-based drugs are frequently used for pain management in both males and females despite the known risk of prefrontal cortex dysfunction and cognitive impairments. Although poorly understood, loss of cognitive control following chronic drug use has been linked to decreased activation of frontal cortex regions. Here, we show that self-administration of the potent opioid, remifentanil, causes a long-lasting hypoactive basal state evidenced by a decrease in ex vivo excitability that is paralleled by an increase in firing capacity of layer 5/6 pyramidal neurons in the prelimbic, but not infralimbic region of the medial prefrontal cortex. This phenomenon was observed in females after as few as 5 days and up to 25–30 days of self-administration. In contrast, pyramidal neurons in males showed increased excitability following 10–16 days of self-administration, with hypoactive states arising only following 25–30 days of self-administration. The emergence of a hypoactive, but not hyperactive basal state following remifentanil self-administration aligned with deficits in cognitive flexibility as assessed using an operant-based attentional set-shifting task. In females, the hypoactive basal state is driven by a reduction in excitatory synaptic transmission mediated by AMPA-type glutamate receptors. Alternatively, hyper- and hypoactive states in males align selectively with decreased and increased GABAB signaling, respectively. Chemogenetic compensation for this hypoactive state prior to testing restored cognitive flexibility, basal hypoactive state, and remifentanil-induced plasticity. These data define cellular and synaptic mechanisms by which opioids impair prefrontal function and cognitive control; indicating that interventions aimed at targeting opioid-induced adaptations should be tailored based on biological sex.
Sex-specific nicotine sensitization and imprinting of self-administration in rats inform GWAS findings on human addiction phenotypes
Alena Kozlova, Robert R. Butler III, Siwei Zhang, Thomas Ujas, Hanwen Zhang, Stephan Steidl, Alan R. Sanders, Zhiping P. Pang, Paul Vezina & Jubao Duan
doi : 10.1038/s41386-021-01027-0
Neuropsychopharmacology volume 46, pages1746–1756 (2021)
Repeated nicotine exposure leads to sensitization (SST) and enhances self-administration (SA) in rodents. However, the molecular basis of nicotine SST and SA and their biological relevance to the mounting genome-wide association study (GWAS) loci of human addictive behaviors are poorly understood. Considering a gateway drug role of nicotine, we modeled nicotine SST and SA in F1 progeny of inbred rats (F344/BN) and conducted integrative genomics analyses. We unexpectedly observed male-specific nicotine SST and a parental effect of SA only present in paternal F344 crosses. Transcriptional profiling in the ventral tegmental area (VTA) and nucleus accumbens (NAc) core and shell further revealed sex- and brain region-specific transcriptomic signatures of SST and SA. We found that genes associated with SST and SA were enriched for those related to synaptic processes, myelin sheath, and tobacco use disorder or chemdependency. Interestingly, SST-associated genes were often downregulated in male VTA but upregulated in female VTA, and strongly enriched for smoking GWAS risk variants, possibly explaining the male-specific SST. For SA, we found widespread region-specific allelic imbalance of expression (AIE), of which genes showing AIE bias toward paternal F344 alleles in NAc core were strongly enriched for SA-associated genes and for GWAS risk variants of smoking initiation, likely contributing to the parental effect of SA. Our study suggests a mechanistic link between transcriptional changes underlying the NIC SST and SA and human nicotine addiction, providing a resource for understanding the neurobiology basis of the GWAS findings on human smoking and other addictive phenotypes.
Individual differences in dopamine uptake in the dorsomedial striatum prior to cocaine exposure predict motivation for cocaine in male rats
Jessica K. Shaw, I. Pamela Alonso, Stacia I. Lewandowski, Marion O. Scott, Bethan M. O’Connor, Shaili Aggarwal, Mariella De Biasi, Ole V. Mortensen & Rodrigo A. España
doi : 10.1038/s41386-021-01009-2
Neuropsychopharmacology volume 46, pages1757–1767 (2021)
A major theme of addiction research has focused on the neural substrates of individual differences in the risk for addiction; however, little is known about how vulnerable populations differ from those that are relatively protected. Here, we prospectively measured dopamine (DA) neurotransmission prior to cocaine exposure to predict the onset and course of cocaine use. Using in vivo voltammetry, we first generated baseline profiles of DA release and uptake in the dorsomedial striatum (DMS) and nucleus accumbens of drug-naïve male rats prior to exposing them to cocaine using conditioned place preference (CPP) or operant self-administration. We found that the innate rate of DA uptake in the DMS strongly predicted motivation for cocaine and drug-primed reinstatement, but not CPP, responding when “price” was low, or extinction. We then assessed the impact of baseline variations in DA uptake on cocaine potency in the DMS using ex vivo voltammetry in naïve rats and in rats with DA transporter (DAT) knockdown. DA uptake in the DMS of naïve rats predicted the neurochemical response to cocaine, such that rats with innately faster rates of DA uptake demonstrated higher cocaine potency at the DAT and rats with DAT knockdown displayed reduced potency compared to controls. Together, these data demonstrate that inherent variability in DA uptake in the DMS predicts the behavioral response to cocaine, potentially by altering the apparent potency of cocaine.
Cocaine induces paradigm-specific changes to the transcriptome within the ventral tegmental area
Rianne R. Campbell, Siwei Chen, Joy H. Beardwood, Alberto J. López, Lilyana V. Pham, Ashley M. Keiser, Jessica E. Childs, Dina P. Matheos, Vivek Swarup, Pierre Baldi & Marcelo A. Wood
doi : 10.1038/s41386-021-01031-4
Neuropsychopharmacology volume 46, pages1768–1779 (2021)
During the initial stages of drug use, cocaine-induced neuroadaptations within the ventral tegmental area (VTA) are critical for drug-associated cue learning and drug reinforcement processes. These neuroadaptations occur, in part, from alterations to the transcriptome. Although cocaine-induced transcriptional mechanisms within the VTA have been examined, various regimens and paradigms have been employed to examine candidate target genes. In order to identify key genes and biological processes regulating cocaine-induced processes, we employed genome-wide RNA-sequencing to analyze transcriptional profiles within the VTA from male mice that underwent one of four commonly used paradigms: acute home cage injections of cocaine, chronic home cage injections of cocaine, cocaine-conditioning, or intravenous-self administration of cocaine. We found that cocaine alters distinct sets of VTA genes within each exposure paradigm. Using behavioral measures from cocaine self-administering mice, we also found several genes whose expression patterns corelate with cocaine intake. In addition to overall gene expression levels, we identified several predicted upstream regulators of cocaine-induced transcription shared across all paradigms. Although distinct gene sets were altered across cocaine exposure paradigms, we found, from Gene Ontology (GO) term analysis, that biological processes important for energy regulation and synaptic plasticity were affected across all cocaine paradigms. Coexpression analysis also identified gene networks that are altered by cocaine. These data indicate that cocaine alters networks enriched with glial cell markers of the VTA that are involved in gene regulation and synaptic processes. Our analyses demonstrate that transcriptional changes within the VTA depend on the route, dose and context of cocaine exposure, and highlight several biological processes affected by cocaine. Overall, these findings provide a unique resource of gene expression data for future studies examining novel cocaine gene targets that regulate drug-associated behaviors.
Dopamine release and its control over early Pavlovian learning differs between the NAc core and medial NAc shell
Claire E. Stelly, Kasey S. Girven, Merridee J. Lefner, Kaitlyn M. Fonzi & Matthew J. Wanat
doi : 10.1038/s41386-020-00941-z
Neuropsychopharmacology volume 46, pages1780–1787 (2021)
Dopamine neurons respond to cues to reflect the value of associated outcomes. These cue-evoked dopamine responses can encode the relative rate of reward in rats with extensive Pavlovian training. Specifically, a cue that always follows the previous reward by a short delay (high reward rate) evokes a larger dopamine response in the nucleus accumbens (NAc) core relative to a distinct cue that always follows the prior reward by a long delay (low reward rate). However, it was unclear if these reward rate dopamine signals are evident during early Pavlovian training sessions and across NAc subregions. To address this, we performed fast-scan cyclic voltammetry recordings of dopamine levels to track the pattern of cue- and reward-evoked dopamine signals in the NAc core and medial NAc shell. We identified regional differences in the progression of cue-evoked dopamine signals across training. However, the dopamine response to cues did not reflect the reward rate in either the NAc core or the medial NAc shell during early training sessions. Pharmacological experiments found that dopamine-sensitive conditioned responding emerged in the NAc core before the medial NAc shell. Together, these findings illustrate regional differences in NAc dopamine release and its control over behavior during early Pavlovian learning.
Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics
Max Lam, Chia-Yen Chen, Tian Ge, Yan Xia, David W. Hill, Joey W. Trampush, Jin Yu, Emma Knowles, Gail Davies, Eli A. Stahl, Laura Huckins, David C. Liewald, Srdjan Djurovic, Ingrid Melle, Andrea Christoforou, Ivar Reinvang, Pamela DeRosse, Astri J. Lundervold, Vidar M. Steen, Thomas Espeseth, Katri Räikkönen, Elisabeth Widen, Aarno Palotie, Johan G. Eriksson, Ina Giegling, Bettina Konte, Annette M. Hartmann, Panos Roussos, Stella Giakoumaki, Katherine E. Burdick, Antony Payton, William Ollier, Ornit Chiba-Falek, Deborah C. Koltai, Anna C. Need, Elizabeth T. Cirulli, Aristotle N. Voineskos, Nikos C. Stefanis, Dimitrios Avramopoulos, Alex Hatzimanolis, Nikolaos Smyrnis, Robert M. Bilder, Nelson B. Freimer, Tyrone D. Cannon, Edythe London, Russell A. Poldrack, Fred W. Sabb, Eliza Congdon, Emily Drabant Conley, Matthew A. Scult, Dwight Dickinson, Richard E. Straub, Gary Donohoe, Derek Morris, Aiden Corvin, Michael Gill, Ahmad R. Hariri, Daniel R. Weinberger, Neil Pendleton, Panos Bitsios, Dan Rujescu, Jari Lahti, Stephanie Le Hellard, Matthew C. Keller, Ole A. Andreassen, Ian J. Deary, David C. Glahn, Hailiang Huang, Chunyu Liu, Anil K. Malhotra & Todd Lencz -Show fewer authors
doi : 10.1038/s41386-021-01023-4
Neuropsychopharmacology volume 46, pages1788–1801 (2021)
Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify “druggable” targets. Using our meta-analytic data set (N?=?373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.
Genome-wide association study accounting for anticholinergic burden to examine cognitive dysfunction in psychotic disorders
Seenae Eum, S. Kristian Hill, Ney Alliey-Rodriguez, James M. Stevenson, Leah H. Rubin, Adam M. Lee, Lauren J. Mills, James L. Reilly, Rebekka Lencer, Sarah K. Keedy, Elena Ivleva, Richard S. E. Keefe, Godfrey D. Pearlson, Brett A. Clementz, Carol A. Tamminga, Matcheri S. Keshavan, Elliot S. Gershon, John A. Sweeney & Jeffrey R. Bishop
doi : 10.1038/s41386-021-01057-8
Neuropsychopharmacology volume 46, pages1802–1810 (2021)
Identifying genetic contributors to cognitive impairments in psychosis-spectrum disorders can advance understanding of disease pathophysiology. Although CNS medications are known to affect cognitive performance, they are often not accounted for in genetic association studies. In this study, we performed a genome-wide association study (GWAS) of global cognitive performance, measured as composite z-scores from the Brief Assessment of Cognition in Schizophrenia (BACS), in persons with psychotic disorders and controls (N?=?817; 682 cases and 135 controls) from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Analyses accounting for anticholinergic exposures from both psychiatric and non-psychiatric medications revealed five significantly associated variants located at the chromosome 3p21.1 locus, with the top SNP rs1076425 in the inter-alpha-trypsin inhibitor heavy chain 1 (ITIH1) gene (P?=?3.25×E?9). The inclusion of anticholinergic burden improved association models (P?<?0.001) and the number of significant SNPs identified. The effect sizes and direction of effect of the top variants remained consistent when investigating findings within individuals receiving specific antipsychotic drugs and after accounting for antipsychotic dose. These associations were replicated in a separate study sample of untreated first-episode psychosis. The chromosome 3p21.1 locus was previously reported to have association with the risk for psychotic disorders and cognitive performance in healthy individuals. Our findings suggest that this region may be a psychosis risk locus that is associated with cognitive mechanisms. Our data highlight the general point that the inclusion of medication exposure information may improve the detection of gene-cognition associations in psychiatric genetic research.
Transcriptome-wide association study of post-trauma symptom trajectories identified GRIN3B as a potential biomarker for PTSD development
Adriana Lori, Katharina Schultebraucks, Isaac Galatzer-Levy, Nikolaos P. Daskalakis, Seyma Katrinli, Alicia K. Smith, Amanda J. Myers, Ryan Richholt, Matthew Huentelman, Guia Guffanti, Stefan Wuchty, Felicia Gould, Philip D. Harvey, Charles B. Nemeroff, Tanja Jovanovic, Ekaterina S. Gerasimov, Jessica L. Maples-Keller, Jennifer S. Stevens, Vasiliki Michopoulos, Barbara O. Rothbaum, Aliza P. Wingo & Kerry J. Ressler
doi : 10.1038/s41386-021-01073-8
Neuropsychopharmacology volume 46, pages1811–1820 (2021)
Biomarkers that predict symptom trajectories after trauma can facilitate early detection or intervention for posttraumatic stress disorder (PTSD) and may also advance our understanding of its biology. Here, we aimed to identify trajectory-based biomarkers using blood transcriptomes collected in the immediate aftermath of trauma exposure. Participants were recruited from an Emergency Department in the immediate aftermath of trauma exposure and assessed for PTSD symptoms at baseline, 1, 3, 6, and 12 months. Three empirical symptom trajectories (chronic-PTSD, remitting, and resilient) were identified in 377 individuals based on longitudinal symptoms across four data points (1, 3, 6, and 12 months), using latent growth mixture modeling. Blood transcriptomes were examined for association with longitudinal symptom trajectories, followed by expression quantitative trait locus analysis. GRIN3B and AMOTL1 blood mRNA levels were associated with chronic vs. resilient post-trauma symptom trajectories at a transcriptome-wide significant level (N?=?153, FDR-corrected p value?=?0.0063 and 0.0253, respectively). We identified four genetic variants that regulate mRNA blood expression levels of GRIN3B. Among these, GRIN3B rs10401454 was associated with PTSD in an independent dataset (N?=?3521, p?=?0.04). Examination of the BrainCloud and GTEx databases revealed that rs10401454 was associated with brain mRNA expression levels of GRIN3B. While further replication and validation studies are needed, our data suggest that GRIN3B, a glutamate ionotropic receptor NMDA type subunit-3B, may be involved in the manifestation of PTSD. In addition, the blood mRNA level of GRIN3B may be a promising early biomarker for the PTSD manifestation and development.
Transcriptome-wide association study of treatment-resistant depression and depression subtypes for drug repurposing
Chiara Fabbri, Oliver Pain, Saskia P. Hagenaars, Cathryn M. Lewis & Alessandro Serretti
doi : 10.1038/s41386-021-01059-6
Neuropsychopharmacology volume 46, pages1821–1829 (2021)
Major depressive disorder (MDD) is the single largest contributor to global disability and up to 20–30% of patients do not respond to at least two antidepressants (treatment-resistant depression, TRD). This study leveraged imputed gene expression in TRD to perform a drug repurposing analysis. Among those with MDD, we defined TRD as having at least two antidepressant switches according to primary care records in UK Biobank (UKB). We performed a transcriptome-wide association study (TWAS) of TRD (n?=?2165) vs healthy controls (n?=?11,188) using FUSION and gene expression levels from 21 tissues. We identified compounds with opposite gene expression signatures (ConnectivityMap data) compared to our TWAS results using the Kolmogorov-Smirnov test, Spearman and Pearson correlation. As symptom patterns are routinely assessed in clinical practice and could be used to provide targeted treatments, we identified MDD subtypes associated with TRD in UKB and analysed them using the same pipeline described for TRD. Anxious MDD (n?=?14,954) and MDD with weight gain (n?=?4697) were associated with TRD. In the TWAS, two genes were significantly dysregulated (TMEM106B and ATP2A1 for anxious and weight gain MDD, respectively). A muscarinic receptor antagonist was identified as top candidate for repurposing in TRD; inhibition of heat shock protein 90 was the main mechanism of action identified for anxious MDD, while modulators of metabolism such as troglitazone showed promising results for MDD with weight gain. This was the first TWAS of TRD and associated MDD subtypes. Our results shed light on possible pharmacological approaches in individuals with difficult-to-treat depression.
Dissociating default mode network resting state markers of suicide from familial risk factors for depression
Henry W. Chase, Randy P. Auerbach, David A. Brent, Jonathan Posner, Myrna M. Weissman & Ardesheer Talati
doi : 10.1038/s41386-021-01022-5
Neuropsychopharmacology volume 46, pages1830–1838 (2021)
Neural signatures of suicide risk likely reflect a combination of specific and non-specific factors, and clarifying specific factors may facilitate development of novel treatments. Previously, we demonstrated an altered pattern of resting state connectivity between the dorsal and ventral posterior cingulate cortex (d/vPCC) and the dorsal anterior cingulate cortex (dACC), as well as altered low frequency oscillations in these regions, in individuals with a history of suicidal thoughts and behaviors (STBs) compared to healthy controls. It remains uncertain, however, whether these markers were directly related to STBs or, more generally, reflect a trait-level risk factor for depression. Here, we examined data from a 3-generational longitudinal study of depression where resting state fMRI data were analyzed from 2nd and 3rd generation offspring of probands with (FH+?=?44: STB+?=?32, STB??=?12) and without (FH??=?25: STB+?=?15, STB??=?10) a family history of major depressive disorder (MDD). Standard seed-based methods and a frequency-based analysis of intrinsic neural activity (ALFF/fALFF) were employed. FH of MDD, but not a personal history of STBs or MDD, was associated with relatively reduced dPCC-dACC, and enhanced vPCC-dACC functional connectivity. FH of MDD showed a pattern of reduced ALFF in the dPCC whereas an STB history was associated with an increase. All findings were invariant to confounding by lifetime MDD and current depression severity. Overall, contrary to predictions, resting state functional connectivity within the default mode network (DMN) was associated with FH of depression rather than STBs. These findings confirm the relevance of DMN functional connectivity for mood disorders and underscore the importance of disambiguating biological factors that differentially relate to mental disorders versus STBs.
Interactive relations between maternal prenatal stress, fetal brain connectivity, and gestational age at delivery
Moriah E. Thomason, Jasmine L. Hect, Rebecca Waller & Paul Curtin
doi : 10.1038/s41386-021-01066-7
Neuropsychopharmacology volume 46, pages1839–1847 (2021)
Studies reporting significant associations between maternal prenatal stress and child outcomes are frequently confounded by correlates of prenatal stress that influence the postnatal rearing environment. The major objective of this study is to identify whether maternal prenatal stress is associated with variation in human brain functional connectivity prior to birth. We utilized fetal fMRI in 118 fetuses [48 female; mean age 32.9 weeks (SD?=?3.87)] to evaluate this association and further addressed whether fetal neural differences were related to maternal health behaviors, social support, or birth outcomes. Community detection was used to empirically define networks and enrichment was used to isolate differential within- or between-network connectivity effects. Significance for ?2 enrichment was determined by randomly permuting the subject pairing of fetal brain connectivity and maternal stress values 10,000 times. Mixtures modelling was used to test whether fetal neural differences were related to maternal health behaviors, social support, or birth outcomes. Increased maternal prenatal negative affect/stress was associated with alterations in fetal frontoparietal, striatal, and temporoparietal connectivity (??=?0.82, p?<?0.001). Follow-up analysis demonstrated that these associations were stronger in women with better health behaviors, more positive interpersonal support, and lower overall stress (??=?0.16, p?=?0.02). Additionally, magnitude of stress-related differences in neural connectivity was marginally correlated with younger gestational age at delivery (??=??0.18, p?=?0.05). This is the first evidence that negative affect/stress during pregnancy is reflected in functional network differences in the human brain in utero, and also provides information about how positive interpersonal and health behaviors could mitigate prenatal brain programming.
Behavioral and accumbens synaptic plasticity induced by cues associated with restraint stress
Constanza Garcia-Keller, Jordan S. Carter, Anna Kruyer, Angela M. Kearns, Jordan L. Hopkins, Ritchy Hodebourg, Peter W. Kalivas & Carmela M. Reichel
doi : 10.1038/s41386-021-01074-7
Neuropsychopharmacology volume 46, pages1848–1856 (2021)
Exposure to acute stress can increase vulnerability to develop or express many psychiatric disorders, including post-traumatic stress disorder. We hypothesized that stress-induced psychiatric vulnerability is associated with enduring neuroplasticity in the nucleus accumbens core because stress exposure can alter drug addiction-related behaviors that are associated with accumbens synaptic plasticity. We used a single 2-h stress session and 3 weeks later exposed male and female rats to stress-conditioned odors in a modified defensive burying task, and quantified both active and avoidant coping strategies. We measured corticosterone, dendritic spine and astrocyte morphology in accumbens, and examined reward sensitivity using a sucrose two-bottle choice and operant sucrose self-administration. Exposure to stress odor increased burying (active coping) and immobility (avoidant coping) in the defensive burying task in female and male rats. Systemic corticosterone was transiently increased by both ongoing acute restraint stress and stress-conditioned odors. Three weeks after administering acute restraint stress, we observed increased dendritic spine density and head diameter, and decreased synaptic association with astroglia and the astroglial glutamate transporter, GLT-1. Exposure to conditioned stress further increased head diameter without affecting spine density or astroglial morphology, and this increase by conditioned stress was correlated with burying behavior. Finally, we found that stress-exposed females have a preference for sweet solutions and higher motivation to seek sucrose than stressed male rats. We conclude that acute stress produced enduring plasticity in accumbens postsynapses and associated astroglia. Moreover, conditioned stress odors induced active behavioral coping strategies that were correlated with dendritic spine morphology.
Correction to: Progressive subcortical volume loss in treatment-resistant schizophrenia patients after commencing clozapine treatment
Giulia Tronchin, Theophilus N. Akudjedu, Mohamed Ahmed, Laurena Holleran, Brian Hallahan, Dara M. Cannon & Colm McDonald
doi : 10.1038/s41386-021-01062-x
Neuropsychopharmacology volume 46, pages1857–1858 (2021)
