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How nicotine withdrawal symptoms fight each other: interpeduncular GABA neuron activity dynamically controls negative affect vs. coping behavior
Alicia J. Avelar & Olivier George
doi : 10.1038/s41386-021-01185-1
Neuropsychopharmacology volume 47, pages617–618 (2022)
Deviating from the norm: cocaine-induced synaptic plasticity in the nucleus accumbens via ?1 receptors and endocannabinoid signaling
Daniel S. Copeland & Stephanie C. Gantz
doi : 10.1038/s41386-021-01198-w
Neuropsychopharmacology volume 47, pages619–620 (2022)
A scientific approach to navigating the academic job market
Sofia Beas & Kirstie A. Cummings
doi : 10.1038/s41386-021-01225-w
Neuropsychopharmacology volume 47, pages621–627 (2022)
The prediction-error hypothesis of schizophrenia: new data point to circuit-specific changes in dopamine activity
Samuel J. Millard, Carrie E. Bearden, Katherine H. Karlsgodt & Melissa J. Sharpe
doi : 10.1038/s41386-021-01188-y
Neuropsychopharmacology volume 47, pages628–640 (2022)
Schizophrenia is a severe psychiatric disorder affecting 21 million people worldwide. People with schizophrenia suffer from symptoms including psychosis and delusions, apathy, anhedonia, and cognitive deficits. Strikingly, schizophrenia is characterised by a learning paradox involving difficulties learning from rewarding events, whilst simultaneously ‘overlearning’ about irrelevant or neutral information. While dysfunction in dopaminergic signalling has long been linked to the pathophysiology of schizophrenia, a cohesive framework that accounts for this learning paradox remains elusive. Recently, there has been an explosion of new research investigating how dopamine contributes to reinforcement learning, which illustrates that midbrain dopamine contributes in complex ways to reinforcement learning, not previously envisioned. This new data brings new possibilities for how dopamine signalling contributes to the symptomatology of schizophrenia. Building on recent work, we present a new neural framework for how we might envision specific dopamine circuits contributing to this learning paradox in schizophrenia in the context of models of reinforcement learning. Further, we discuss avenues of preclinical research with the use of cutting-edge neuroscience techniques where aspects of this model may be tested. Ultimately, it is hoped that this review will spur to action more research utilising specific reinforcement learning paradigms in preclinical models of schizophrenia, to reconcile seemingly disparate symptomatology and develop more efficient therapeutics.
Dynamic activity of interpeduncular nucleus GABAergic neurons controls expression of nicotine withdrawal in male mice
Paul M. Klenowski, Rubing Zhao-Shea, Timothy G. Freels, Susanna Molas & Andrew R. Tapper
doi : 10.1038/s41386-021-01107-1
Neuropsychopharmacology volume 47, pages641–651 (2022)
A critical brain area implicated in nicotine dependence is the interpeduncular nucleus (IPN) located in the ventral midbrain and consisting primarily of GABAergic neurons. Previous studies indicate that IPN GABAergic neurons contribute to expression of somatic symptoms of nicotine withdrawal; however, whether IPN neurons are dynamically regulated during withdrawal in vivo and how this may contribute to both somatic and affective withdrawal behavior is unknown. To bridge this gap in knowledge, we expressed GCaMP in IPN GABAergic neurons and used in vivo fiber photometry to record changes in fluorescence, as a proxy for neuronal activity, in male mice during nicotine withdrawal. Mecamylamine-precipitated withdrawal significantly increased activity of IPN GABAergic neurons in nicotine-dependent, but not nicotine-naive mice. Analysis of GCaMP signals time-locked with somatic symptoms including grooming and scratching revealed reduced IPN GABAergic activity during these behaviors, specifically in mice undergoing withdrawal. In the elevated plus maze, used to measure anxiety-like behavior, an affective withdrawal symptom, IPN GABAergic neuron activity was increased during open-arm versus closed-arm exploration in nicotine-withdrawn, but not non-withdrawn mice. Optogenetic silencing IPN GABAergic neurons during withdrawal significantly reduced withdrawal-induced increases in somatic behavior and increased open-arm exploration. Together, our data indicate that IPN GABAergic neurons are dynamically regulated during nicotine withdrawal, leading to increased anxiety-like symptoms and somatic behavior, which inherently decrease IPN GABAergic neuron activity as a withdrawal-coping mechanism. These results provide a neuronal basis underlying the role of the IPN in the expression of somatic and affective behaviors of nicotine withdrawal.
Cocaine restricts nucleus accumbens feedforward drive through a monoamine-independent mechanism
Kevin M. Manz, Benjamin C. Coleman, Alexis N. Jameson, Dipanwita G. Ghose, Sachin Patel & Brad A. Grueter
doi : 10.1038/s41386-021-01167-3
Neuropsychopharmacology volume 47, pages652–663 (2022)
Parvalbumin-expressing fast-spiking interneurons (PV-INs) within feedforward microcircuits in the nucleus accumbens (NAc) coordinate goal-directed motivational behavior. Feedforward inhibition of medium spiny projection neurons (MSNs) is initiated by glutamatergic input from corticolimbic brain structures. While corticolimbic synapses onto MSNs are targeted by the psychostimulant, cocaine, it remains unknown whether cocaine also exerts acute neuromodulatory actions at collateralizing synapses onto PV-INs. Using whole-cell patch-clamp electrophysiology, optogenetics, and pharmacological tools in transgenic reporter mice, we found that cocaine decreases thalamocortical glutamatergic drive onto PV-INs by engaging a monoamine-independent mechanism. This mechanism relies on postsynaptic sigma-1 (?1) activity, leading to the mobilization of intracellular Ca2+ stores that trigger retrograde endocannabinoid signaling at presynaptic type-1 cannabinoid receptors (CB1R). Cocaine-evoked CB1R activity occludes the expression of CB1R-dependent long-term depression (LTD) at this synaptic locus. These findings provide evidence that acute cocaine exposure targets feedforward microcircuits in the NAc and extend existing models of cocaine action on mesolimbic reward circuits.
Metabolic adverse effects of off-label use of second-generation antipsychotics in the adult population: a systematic review and meta-analysis
Nicolette Stogios, Emily Smith, Sylvie Bowden, Veronica Tran, Roshanak Asgariroozbehani, William Brett McIntyre, Gary Remington, Dan Siskind, Sri Mahavir Agarwal & Margaret K. Hahn
doi : 10.1038/s41386-021-01163-7
Neuropsychopharmacology volume 47, pages664–672 (2022)
Prescription rates of second-generation antipsychotics (SGAs) are rapidly increasing for non-indicated (i.e., off-label) usage. SGAs used for approved indications are associated with significant metabolic adverse effects, including weight gain. The objective of this systematic review and meta-analysis is to evaluate the metabolic adverse effects of SGA use for off-label management of psychiatric illnesses in the adult population. We performed a systematic database search to identify randomized controlled trials (RCTs) that reported on weight and other metabolic outcomes with off-label use of SGAs among adults. Thirty-eight RCTs met inclusion criteria for this review; 35 of these studies, with a total of 4930 patients, were included in the quantitative meta-analysis. Patients treated with olanzapine, risperidone, and quetiapine were more likely to report weight gain as a side effect and experience clinically significant (?7%) weight gain compared to those treated with a placebo. Among studies that reported weight as a continuous outcome, olanzapine was associated with significantly greater weight gain across all disorders (mean difference (MD)?=?3.24?kg, 95% CI: 2.57–3.90 p?=?0.001, N?=?12 studies). Similar trends were noted with quetiapine and risperidone. A meta-regression analysis revealed a positive dose-response association between olanzapine dose and weight gain (regression coefficient: 0.36, p?=?0.001). This review demonstrates that off-label use of SGAs, and particularly olanzapine, is associated with significant weight gain among adult patients. Our findings are concerning given the widespread off-label use of SGAs. Further studies are required to better understand the effects of off-label SGA use on other metabolic parameters. The study was registered with the PROSPERO international database of prospectively registered systematic reviews (PROSPERO #143186).
Thalamocortical dysrhythmia in patients with schizophrenia spectrum disorder and individuals at clinical high risk for psychosis
Minah Kim, Tak Hyung Lee, Hyungyou Park, Sun-Young Moon, Silvia Kyungjin Lho & Jun Soo Kwon
doi : 10.1038/s41386-021-01180-6
Neuropsychopharmacology volume 47, pages673–680 (2022)
Thalamocortical dysrhythmia (TCD) is a model characterized by abnormal resting-state thalamic oscillatory patterns where the alpha rhythm is replaced by cross-frequency coupling of low- and high-frequency rhythms. Although disrupted thalamic function is a suggested important pathophysiological mechanism underlying schizophrenia, knowledge regarding the TCD model in schizophrenia spectrum disorder (SSD) patients and individuals at clinical high risk (CHR) for psychosis is limited. A total of 169 SSD patients, 106 individuals at CHR for psychosis, and 105 healthy controls (HCs) underwent resting-state electroencephalography recordings. We performed mean global field power (MGFP) spectral analysis between 1 and 49?Hz as well as source-level theta phase-gamma amplitude coupling (TGC) analysis and compared resting-state oscillatory patterns across groups. Correlations between altered TGC values and psychotic symptom severity in the patient group were investigated. Spectral MGFP of low- and high-frequencies was larger in the SSD and CHR groups than in the HC group. The TGC of SSD patients was greater than that of HCs in the right frontal, right parietal, and left and right limbic lobes. Greater TGC in the right frontal and limbic lobes was associated with positive symptom severity in SSD patients. However, TGC in the CHR group was comparable to that in the HCs and was smaller than that in the SSD group in widespread cortical regions. The TCD pattern may be apparent after frank psychotic disorder onset in tandem with overt positive symptoms. A psychosis-risk state without overt psychotic symptoms could be characterized by abnormally increased low- and high-frequency activities with relatively preserved TGC.
Impairment in acquisition of conditioned fear in schizophrenia
Lauri Tuominen, Liana Romaniuk, Mohammed R. Milad, Donald C. Goff, Jeremy Hall & Daphne J. Holt
doi : 10.1038/s41386-021-01193-1
Neuropsychopharmacology volume 47, pages681–686 (2022)
Individuals with schizophrenia show impairments in associative learning. One well-studied, quantifiable form of associative learning is Pavlovian fear conditioning. However, to date, studies of fear conditioning in schizophrenia have been inconclusive, possibly because they lacked sufficient power. To address this issue, we pooled data from four independent fear conditioning studies that included a total of 77 individuals with schizophrenia and 74 control subjects. Skin conductance responses (SCRs) to stimuli that were paired (the CS?+?) or not paired (CS?) with an aversive, unconditioned stimulus were measured, and the success of acquisition of differential conditioning (the magnitude of CS?+?vs. CS? SCRs) and responses to CS?+?and CS? separately were assessed. We found that acquisition of differential conditioned fear responses was significantly lower in individuals with schizophrenia than in healthy controls (Cohen’s d?=?0.53). This effect was primarily related to a significantly higher response to the CS? stimulus in the schizophrenia compared to the control group. Moreover, the magnitude of this response to the CS? in the schizophrenia group was correlated with the severity of delusional ideation (p?=?0.006). Other symptoms or antipsychotic dose were not associated with fear conditioning measures. In conclusion, individuals with schizophrenia who endorse delusional beliefs may be over-responsive to neutral stimuli during fear conditioning. This finding is consistent with prior models of abnormal associative learning in psychosis.
GABAA and NMDA receptor density alterations and their behavioral correlates in the gestational methylazoxymethanol acetate model for schizophrenia
Amanda Kiemes, Felipe V. Gomes, Diana Cash, Daniela L. Uliana, Camilla Simmons, Nisha Singh, Anthony C. Vernon, Federico Turkheimer, Cathy Davies, James M. Stone, Anthony A. Grace & Gemma Modinos
doi : 10.1038/s41386-021-01213-0
Neuropsychopharmacology volume 47, pages687–695 (2022)
Hippocampal hyperactivity driven by GABAergic interneuron deficits and NMDA receptor hypofunction is associated with the hyperdopaminergic state often observed in schizophrenia. Furthermore, previous research in the methylazoxymethanol acetate (MAM) rat model has demonstrated that repeated peripubertal diazepam administration can prevent the emergence of adult hippocampal hyperactivity, dopamine-system hyperactivity, and associated psychosis-relevant behaviors. Here, we sought to characterize hippocampal GABAA and NMDA receptors in MAM-treated rats and to elucidate the receptor mechanisms underlying the promising effects of peripubertal diazepam exposure. Quantitative receptor autoradiography was used to measure receptor density in the dorsal hippocampus CA1, ventral hippocampus CA1, and ventral subiculum. Specifically, [3H]-Ro15-4513 was used to quantify the density of ?5GABAA receptors (?5GABAAR), [3H]-flumazenil to quantify ?1-3;5GABAAR, and [3H]-MK801 to quantify NMDA receptors. MAM rats exhibited anxiety and schizophrenia-relevant behaviors as measured by elevated plus maze and amphetamine-induced hyperlocomotion (AIH), although diazepam only partially rescued these behaviors. ?5GABAAR density was reduced in MAM-treated rats in all hippocampal sub-regions, and negatively correlated with AIH. Ventral hippocampus CA1 ?5GABAAR density was positively correlated with anxiety-like behavior. Dorsal hippocampus CA1 NMDA receptor density was increased in MAM-treated rats, and positively correlated with AIH. [3H]-flumazenil revealed no significant effects. Finally, we found no significant effect of diazepam treatment on receptor densities, potentially related to the only partial rescue of schizophrenia-relevant phenotypes. Overall, our findings provide first evidence of ?5GABAAR and NMDA receptor abnormalities in the MAM model, suggesting that more selective pharmacological agents may become a novel therapeutic mechanism in schizophrenia.
Insulin and glucose metabolism with olanzapine and a combination of olanzapine and samidorphan: exploratory phase 1 results in healthy volunteers
Frederico G. S. Toledo, William F. Martin, Linda Morrow, Carine Beysen, Daiva Bajorunas, Ying Jiang, Bernard L. Silverman, David McDonnell, Mark N. Namchuk, John W. Newcomer & Christine Graham
doi : 10.1038/s41386-021-01244-7
Neuropsychopharmacology volume 47, pages696–703 (2022)
A combination of olanzapine and samidorphan (OLZ/SAM) received US Food and Drug Administration approval in May 2021 for the treatment of adults with schizophrenia or bipolar I disorder. OLZ/SAM provides the efficacy of olanzapine, while mitigating olanzapine-associated weight gain. This exploratory study characterized the metabolic profile of OLZ/SAM in healthy volunteers to gain mechanistic insights. Volunteers received once-daily oral 10?mg/10?mg OLZ/SAM, 10?mg olanzapine, or placebo for 21 days. Assessments included insulin sensitivity during an oral glucose tolerance test (OGTT), hyperinsulinemic-euglycemic clamp, other measures of glucose/lipid metabolism, and adverse event (AE) monitoring. Treatment effects were estimated with analysis of covariance. In total, 60 subjects were randomized (double-blind; placebo, n?=?12; olanzapine, n?=?24; OLZ/SAM, n?=?24). Olanzapine resulted in hyperinsulinemia and reduced insulin sensitivity during an OGTT at day 19, changes not observed with OLZ/SAM or placebo. Insulin sensitivity, measured by hyperinsulinemic-euglycemic clamp, was decreased in all treatment groups relative to baseline, but this effect was greatest with olanzapine and OLZ/SAM. Although postprandial (OGTT) glucose and fasting cholesterol concentrations were similarly increased with olanzapine or OLZ/SAM, other early metabolic effects were distinct, including post-OGTT C-peptide concentrations and aspects of energy metabolism. Forty-nine subjects (81.7%) experienced at least 1 AE, most mild or moderate in severity. OLZ/SAM appeared to mitigate some of olanzapine’s unfavorable postprandial metabolic effects (e.g., hyperinsulinemia, elevated C-peptide) in this exploratory study. These findings supplement the body of evidence from completed or ongoing OLZ/SAM clinical trials supporting its role in the treatment of schizophrenia and bipolar I disorder.
An examination of the relationships between attention/deficit hyperactivity disorder symptoms and functional connectivity over time
Luke J. Norman, Gustavo Sudre, Marine Bouyssi-Kobar, Wendy Sharp & Philip Shaw
doi : 10.1038/s41386-021-00958-y
Neuropsychopharmacology volume 47, pages704–710 (2022)
Previous cross-sectional work has demonstrated resting-state connectivity abnormalities in children and adolescents with attention/deficit hyperactivity disorder (ADHD) relative to typically developing controls. However, it is unclear to what extent these neural abnormalities confer risk for later symptoms of the disorder, or represent the downstream effects of symptoms on functional connectivity. Here, we studied 167 children and adolescents (mean age at baseline?=?10.74 years (SD?=?2.54); mean age at follow-up?=?13.3 years (SD?=?2.48); 56 females) with varying levels of ADHD symptoms, all of whom underwent resting-state functional magnetic resonance imaging and ADHD symptom assessments on two occasions during development. Resting-state functional connectivity was quantified using eigenvector centrality mapping. Using voxelwise cross-lag modeling, we found that less connectivity at baseline within right inferior frontal gyrus was associated with more follow-up symptoms of inattention (significant at an uncorrected cluster-forming threshold of p???0.001 and a cluster-level familywise error corrected threshold of p?<?0.05). Findings suggest that previously reported cross-sectional abnormalities in functional connectivity within inferior frontal gyrus in patients with ADHD may represent a longitudinal risk factor for the disorder, in line with efforts to target this region with novel therapeutic methods.
Mismatch negativity as an index of target engagement for excitation/inhibition-based treatment development: a double-blind, placebo-controlled, randomized, single-dose cross-over study of the serotonin type-3 receptor antagonist CVN058
Pejman Sehatpour, Daniel C. Javitt, Heloise M. De Baun, Marlene Carlson, Anna Beloborodova, David H. Margolin, Mark B. L. Carlton, Nicola L. Brice & Joshua T. Kantrowitz
doi : 10.1038/s41386-021-01170-8
Neuropsychopharmacology volume 47, pages711–718 (2022)
Serotonin type-3 receptor (5-HT3R) antagonists show potential as a treatment for cognitive deficits in schizophrenia. CVN058, a brain-penetrant, potent and selective 5-HT3R antagonist, shows efficacy in rodent models of cognition and was well-tolerated in Phase-1 studies. We evaluated the target engagement of CVN058 using mismatch negativity (MMN) in a randomized, double-blind, placebo-controlled, cross-over study. Subjects were stable outpatients with schizophrenia or schizoaffective disorder treated with antipsychotics. Subjects were not permitted to use other 5-HT3R modulators or serotonin reuptake inhibitors. Each subject received a high (150?mg) and low (15?mg or 75?mg) oral dose of CVN058 and placebo in a randomized order across 3 single-day treatment visits separated by at least 1 week. The primary pre-registered outcome was amplitude of duration MMN. Amplitude of other MMN deviants (frequency, intensity, frequency modulation, and location), P50, P300 and auditory steady-state response (ASSR) were exploratory endpoints. 19 of 22 randomized subjects (86.4%) completed the study. Baseline PANSS scores indicated moderate impairment. CVN058 150?mg led to significant improvement vs. placebo on the primary outcome of duration MMN (p?=?0.02, Cohen’s d?=?0.48). A significant treatment effect was also seen in a combined analysis across all MMN deviants (p?<?0.001, d?=?0.57). Effects on location MMN were independently significant (p?<?0.007, d?=?0.46). No other significant effects were seen for other deviants, doses or EEG measures. There were no clinically significant treatment related adverse effects. These results show MMN to be a sensitive target engagement biomarker for 5-HT3R, and support the potential utility of CVN058 in correcting the excitatory/inhibitory imbalance in schizophrenia.
Effects of the selective orexin-2 receptor antagonist JNJ-48816274 on sleep initiated in the circadian wake maintenance zone: a randomised trial
Victoria L. Revell, Ciro della Monica, Jeewaka Mendis, Hana Hassanin, Robin J. Halter, Sandra R. Chaplan & Derk-Jan Dijk
doi : 10.1038/s41386-021-01175-3
Neuropsychopharmacology volume 47, pages719–727 (2022)
The effects of orexinergic peptides are diverse and are mediated by orexin-1 and orexin-2 receptors. Antagonists that target both receptors have been shown to promote sleep initiation and maintenance. Here, we investigated the role of the orexin-2 receptor in sleep regulation in a randomised, double-blind, placebo-controlled, three-period crossover clinical trial using two doses (20 and 50?mg) of a highly selective orexin-2 receptor antagonist (2-SORA) (JNJ-48816274). We used a phase advance model of sleep disruption where sleep initiation is scheduled in the circadian wake maintenance zone. We assessed objective and subjective sleep parameters, pharmacokinetic profiles and residual effects on cognitive performance in 18 healthy male participants without sleep disorders. The phase advance model alone (placebo condition) resulted in disruption of sleep at the beginning of the sleep period compared to baseline sleep (scheduled at habitual time). Compared to placebo, both doses of JNJ-48816274 significantly increased total sleep time, REM sleep duration and sleep efficiency, and reduced latency to persistent sleep, sleep onset latency, and REM latency. All night EEG spectral power density for both NREM and REM sleep were unaffected by either dose. Participants reported significantly better quality of sleep and feeling more refreshed upon awakening following JNJ-48816274 compared to placebo. No significant residual effects on objective performance measures were observed and the compound was well tolerated. In conclusion, the selective orexin-2 receptor antagonist JNJ-48816274 rapidly induced sleep when sleep was scheduled earlier in the circadian cycle and improved self-reported sleep quality without impact on waking performance.
Optogenetic stimulation of lateral hypothalamic orexin/dynorphin inputs in the ventral tegmental area potentiates mesolimbic dopamine neurotransmission and promotes reward-seeking behaviours
Catherine S. Thomas, Aida Mohammadkhani, Madiha Rana, Min Qiao, Corey Baimel & Stephanie L. Borgland
doi : 10.1038/s41386-021-01196-y
Neuropsychopharmacology volume 47, pages728–740 (2022)
Reward and reinforcement processes are critical for survival and propagation of genes. While numerous brain systems underlie these processes, a cardinal role is ascribed to mesolimbic dopamine. However, ventral tegmental area (VTA) dopamine neurons receive complex innervation and various neuromodulatory factors, including input from lateral hypothalamic (LH) orexin/hypocretin neurons which also express and co-release the neuropeptide, dynorphin. Dynorphin in the VTA induces aversive conditioning through the Kappa opioid receptor (KOR) and decreases dopamine when administered intra-VTA. Exogenous application of orexin or orexin 1 receptor (oxR1) antagonists in the VTA bidirectionally modulates dopamine-driven motivation and reward-seeking behaviours, including the attribution of motivational value to primary rewards and associated conditioned stimuli. However, the effect of endogenous stimulation of LH orexin/dynorphin-containing projections to the VTA and the potential contribution of co-released dynorphin on mesolimbic dopamine and reward related processes remains uncharacterised. We combined optogenetic, electrochemical, and behavioural approaches to examine this. We found that optical stimulation of LH orexin/dynorphin inputs in the VTA potentiates mesolimbic dopamine neurotransmission in the nucleus accumbens (NAc) core, produces real time and conditioned place preference, and increases the food cue-directed orientation in a Pavlovian conditioning procedure. LH orexin/dynorphin potentiation of NAc dopamine release and real time place preference was blocked by an oxR1, but not KOR antagonist. Thus, rewarding effects associated with optical stimulation of LH orexin/dynorphin inputs in the VTA are predominantly driven by orexin rather than dynorphin.
Orexin-1 receptor signaling in ventral tegmental area mediates cue-driven demand for cocaine
Caroline B. Pantazis, Morgan H. James, Shayna O’Connor, Noah Shin & Gary Aston-Jones
doi : 10.1038/s41386-021-01173-5
Neuropsychopharmacology volume 47, pages741–751 (2022)
Drug-associated sensory cues increase motivation for drug and the orexin system is importantly involved in this stimulus-enhanced motivation. Ventral tegmental area (VTA) is a major target by which orexin signaling modulates reward behaviors, but it is unknown whether this circuit is necessary for cue-driven motivation for cocaine. Here, we investigated the role of VTA orexin signaling in cue-driven motivation for cocaine using a behavioral economics (BE) paradigm. We found that infusion of the orexin-1 receptor (Ox1R) antagonist SB-334867 (SB) into VTA prior to BE testing reduced motivation when animals were trained to self-administer cocaine with discrete cues and tested on BE with those cues. SB had no effect when animals were trained to self-administer cocaine without cues or tested on BE without cues, indicating that learning to associate cues with drug delivery during self-administration training was necessary for cues to recruit orexin signaling in VTA. These effects were specific to VTA, as injections of SB immediately dorsal had no effect. Moreover, intra-VTA SB did not have an impact on locomotor activity, or low- or high-effort consumption of sucrose. Finally, we microinjected a novel retrograde adeno-associated virus (AAVretro) containing an orexin-specific short hairpin RNA (OxshRNA) into VTA to knock down orexin in the hypothalamus-VTA circuit. These injections significantly reduced orexin expression in lateral hypothalamus (LH) and decreased cue-driven motivation. These studies demonstrate a role for orexin signaling in VTA, specifically when cues predict drug reward.
A three-factor model of common early onset psychiatric disorders: temperament, adversity, and dopamine
Maisha Iqbal, Sylvia Maria Leonarda Cox, Natalia Jaworska, Maria Tippler, Natalie Castellanos-Ryan, Sophie Parent, Alain Dagher, Frank Vitaro, Mara R. Brendgen, Michel Boivin, Robert O. Pihl, Sylvana M. Côté, Richard E. Tremblay, Jean R. Séguin & Marco Leyton
doi : 10.1038/s41386-021-01187-z
Neuropsychopharmacology volume 47, pages752–758 (2022)
Commonly comorbid early onset psychiatric disorders might reflect the varying expression of overlapping risk factors. The mediating processes remain poorly understood, but three factors show some promise: adolescent externalizing traits, early life adversity, and midbrain dopamine autoreceptors. To investigate whether these features acquire greater predictive power when combined, a longitudinal study was conducted in youth who have been followed since birth. Cohort members were invited to participate based on externalizing scores between 11 to 16?years of age. At age 18 (age 18.5?±?0.6 y.o.), 52 entry criteria meeting volunteers had a 90-min positron emission tomography scan with [18F]fallypride, completed the Childhood Trauma Questionnaire, and were assessed with the Structured Clinical Interview for DSM-5. The three-factor model identified those with a lifetime history of DSM-5 disorders with an overall accuracy of 90.4% (p?=?2.4?×?10?5) and explained 91.5% of the area under the receiver operating characteristic curve [95% CI: .824, 1.000]. Targeting externalizing disorders specifically did not yield a more powerful model than targeting all disorders (p?=?0.54). The model remained significant when including data from participants who developed their first disorders during a three-year follow-up period (p?=?3.5?×?10?5). Together, these results raise the possibility that a combination of temperamental traits, childhood adversity, and poorly regulated dopamine transmission increases risk for diverse, commonly comorbid, early onset psychiatric problems, predicting this susceptibility prospectively.
In utero exposure to antipsychotic medication and psychiatric outcomes in the offspring
Natalie C. Momen, Thalia Robakis, Xiaoqin Liu, Abraham Reichenberg, Veerle Bergink & Trine Munk-Olsen
doi : 10.1038/s41386-021-01223-y
Neuropsychopharmacology volume 47, pages759–766 (2022)
Information on neurodevelopmental effects of antenatal exposure to antipsychotics is limited to 10 studies, all examining children up to 5 years of age or less. The paper aimed to investigate the association between in utero exposure to antipsychotics and psychiatric outcomes in children using Danish nationwide registers. In total, 9011 liveborn singletons born 1998–2015 in Denmark whose mothers took antipsychotic medication before pregnancy were identified. Children whose mothers continued to take antipsychotics during pregnancy were compared with children of mothers who discontinued antipsychotics before pregnancy. As a negative control, paternal antipsychotic use in the same window was investigated. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression for the primary outcome of psychiatric disorders, as well for subcategories of psychiatric disorders. In total, 9.9% of children in the discontinuation group and 11.0% of children in the continuation group received a psychiatric disorder diagnosis during follow-up. The adjusted HR for psychiatric disorders among offspring in the continuation group compared to the discontinuation group was 1.10 (95% CI 0.93–1.30). For antipsychotic use in the fathers, the HR was 1.05 (95% CI 0.89–1.24). The study does not provide evidence of increased risk of psychiatric disorders among children of women who continue antipsychotic treatment during pregnancy. This was observed after accounting for the underlying risk conferred by maternal psychiatric disorders. This suggests women who need to continue antipsychotic medications during pregnancy can do so without adverse psychiatric outcomes for offspring.
A cross-species assay demonstrates that reward responsiveness is enduringly impacted by adverse, unpredictable early-life experiences
Brian D. Kangas, Annabel K. Short, Oanh T. Luc, Hal S. Stern, Tallie Z. Baram & Diego A. Pizzagalli
doi : 10.1038/s41386-021-01250-9
Neuropsychopharmacology volume 47, pages767–775 (2022)
Exposure to early-life adversity (ELA) is associated with several neuropsychiatric conditions, including major depressive disorder, yet causality is difficult to establish in humans. Recent work in rodents has implicated impaired reward circuit signaling in anhedonic-like behavior after ELA exposure. Anhedonia, the lack of reactivity to previously rewarding stimuli, is a transdiagnostic construct common to mental illnesses associated with ELA. Here, we employed an assay of reward responsiveness validated across species, the Probabilistic Reward Task (PRT). In the PRT, healthy participants reliably develop a response bias toward the more richly rewarded stimulus, whereas participants with anhedonia exhibit a blunted response bias that correlates with current and future anhedonia. In a well-established model of ELA that generates a stressful, chaotic, and unpredictable early-life environment, ELA led to blunted response biases in the PRT in two separate cohorts, recapitulating findings in humans with anhedonia. The same ELA rats had blunted sucrose preference, further supporting their anhedonic-like phenotypes. Probing the aspects of ELA that might provoke these deficits, we quantified the unpredictability of dam/pup interactions using entropy measures and found that the unpredictability of maternal care was significantly higher in the ELA groups in which PRT and sucrose preference reward deficits were present later in life. Taken together, these data position the PRT, established in clinical patient populations, as a potent instrument to assess the impact of ELA on the reward circuit across species. These findings also implicate the unpredictability of maternal signals during early life as an important driver of reward sensitivity deficits.
Nucleus accumbens dichotomically controls social dominance in male mice
Qiang Shan, You Hu, Shijie Chen & Yao Tian
doi : 10.1038/s41386-021-01220-1
Neuropsychopharmacology volume 47, pages776–787 (2022)
Social dominance versus social submissiveness is a basic behavioral trait of social animals such as human beings and laboratory mice. The brain regions associated with this behavior have been intensely investigated, and early neuroimaging research on human subjects implies that the nucleus accumbens (NAc) might be involved in encoding social dominance. However, the underlying circuitry and synaptic mechanism are largely unknown. In this study, by introducing lesions to both NAc subregions, the shell and core, a causal relationship is established between social dominance and both NAc subregions. A further electrophysiology investigation on the circuitry of these two subregions revealed that the postsynaptic strength of excitatory synapses onto the medium spiny neurons that express the D1 dopamine receptors in the shell is negatively correlated, and the postsynaptic strength of excitatory synapses onto the medium spiny neurons that express the D2 dopamine receptors in the core is positively correlated, with social dominance. Correspondingly, a DREADD investigation revealed that the activities of these respective medium spiny neurons suppress and promote social dominance. These findings identify a neural substrate for social dominance, implying the potential for a therapeutic strategy for treating related psychiatric disorders.
Structure and function differences in the prelimbic cortex to basolateral amygdala circuit mediate trait vulnerability in a novel model of acute social defeat stress in male mice
Yael S. Grossman, Clementine Fillinger, Alessia Manganaro, George Voren, Rachel Waldman, Tiffany Zou, William G. Janssen, Paul J. Kenny & Dani Dumitriu
doi : 10.1038/s41386-021-01229-6
Neuropsychopharmacology volume 47, pages788–799 (2022)
Stressful life events are ubiquitous and well-known to negatively impact mental health. However, in both humans and animal models, there is large individual variability in how individuals respond to stress, with some but not all experiencing long-term adverse consequences. While there is growing understanding of the neurobiological underpinnings of the stress response, much less is known about how neurocircuits shaped by lifetime experiences are activated during an initial stressor and contribute to this selective vulnerability versus resilience. We developed a model of acute social defeat stress (ASDS) that allows classification of male mice into “susceptible” (socially avoidant) versus “resilient” (expressing control-level social approach) one hour after exposure to six minutes of social stress. Using circuit tracing and high-resolution confocal imaging, we explored differences in activation and dendritic spine density and morphology in the prelimbic cortex to basolateral amygdala (PL?BLA) circuit in resilient versus susceptible mice. Susceptible mice had greater PL?BLA recruitment during ASDS and activated PL?BLA neurons from susceptible mice had more and larger mushroom spines compared to resilient mice. We hypothesized identified structure/function differences indicate an overactive PL?BLA response in susceptible mice and used an intersectional chemogenetic approach to inhibit the PL?BLA circuit during or prior to ASDS. We found in both cases that this blocked ASDS-induced social avoidance. Overall, we show PL?BLA structure/function differences mediate divergent behavioral responses to ASDS in male mice. These results support PL?BLA circuit overactivity during stress as a biomarker of trait vulnerability and potential target for prevention of stress-induced psychopathology.
IN MEMORIAM – Paula J Clayton, MD
Robert M. A. Hirschfeld
doi : 10.1038/s41386-021-01233-w
Neuropsychopharmacology volume 47, page800 (2022)
