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RationaleSmoking is the leading cause of preventable death in the USA, but quit attempts result in withdrawal-induced cognitive dysfunction and predicts relapse. Greater understanding of the neural mechanism(s) underlying these cognitive deficits is required to develop targeted treatments to aid quit attempts.ObjectivesWe examined nicotine withdrawal-induced inattention in mice lacking the α7 nicotinic acetylcholine receptor (nAChR) using the five-choice continuous performance test (5C-CPT).MethodsMice were trained in the 5C-CPT prior to osmotic minipump implantation containing saline or nicotine. Experiment 1 used 40 mg kg-1 day-1 nicotine treatment and tested C57BL/6 mice 4, 28, and 52 h after pump removal. Experiment 2 used 14 and 40 mg kg-1 day-1 nicotine treatment in α7 nAChR knockout (KO) and wildtype (WT) littermates tested 4 h after pump removal. Subsets of WT mice were killed before and after pump removal to assess changes in receptor expression associated with nicotine administration and withdrawal.ResultsNicotine withdrawal impaired attention in the 5C-CPT, driven by response inhibition and target detection deficits. The overall attentional deficit was absent in α7 nAChR KO mice despite response disinhibition in these mice. Synaptosomal glutamate mGluR5 and dopamine D4 receptor expression were reduced during chronic nicotine but increased during withdrawal, potentially contributing to cognitive deficits.ConclusionsThe α7 nAChR may underlie nicotine withdrawal-induced deficits in target detection but is not required for response disinhibition deficits. Alterations to the glutamatergic and dopaminergic pathways may also contribute to withdrawal-induced attentional deficits, providing novel targets to alleviate the cognitive symptoms of withdrawal during quit attempts.

Serious mental illness occurs in 25% of the general population, with many disorders being neurodevelopmental, lifelong, and debilitating. The wide variation and overlap in symptoms across disorders increases the difficulty of research and treatment development. The NIMH Research Domain of Criteria initiative aims to improve our understanding of the molecular and behavioral consequences of specific neurodevelopmental mechanisms across disorders, enabling targeted treatment development. The transcription factor Specificity Protein 4 (SP4) is important for neurodevelopment and is genetically associated with both schizophrenia and bipolar disorder. Reduced Sp4 expression in mice (hypomorphic) reproduces several characteristics of psychiatric disorders. We further tested the utility of Sp4 hypomorphic mice as a model organism relevant to psychiatric disorders by assessing cognitive control plus effort and decision-making aspects of approach motivation using cross-species-relevant tests. Sp4 hypomorphic mice exhibited impaired attention as measured by the 5-Choice Continuous Performance Test, an effect that was attenuated by glycine type-1 transporter (GlyT-1) inhibition. Hypomorphic mice also exhibited reduced motivation to work for a reward and impaired probabilistic learning. These deficits may stem from affected anticipatory reward, analogous to anhedonia in patients with schizophrenia and other psychiatric disorders. Neither positive valence deficit was attenuated by GlyT-1 treatment, suggesting that these and the attentional deficits stem from different underlying mechanisms. Given the association of SP4 gene with schizophrenia and bipolar disorder, the present studies provide support that personalized GlyT-1 inhibition may treat attentional deficits in neuropsychiatric patients with low SP4 levels.

BackgroundPosttraumatic Stress Disorder (PTSD) is a major public health concern, especially given the recent wars in Iraq and Afghanistan. Nevertheless, despite a sharp increase in the incidence of psychiatric disorders in returning veterans, empirically based prevention strategies are still lacking. To develop effective prevention and treatment strategies, it is necessary to understand the underlying biological mechanisms contributing to PTSD and other trauma related symptoms.MethodsThe "Marine Resiliency Study II" (MRS-II; October 2011-October 2013) Neurocognition project is an investigation of neurocognitive performance in Marines about to be deployed to Afghanistan. As part of this investigation, 1195 Marines and Navy corpsmen underwent a fear conditioning and extinction paradigm and psychiatric symptom assessment prior to deployment. The current study assesses (1) the effectiveness of the fear potentiated startle paradigm in producing fear learning and extinction and (2) the association of performance in the paradigm with baseline psychiatric symptom classes (healthy: n=923, PTSD symptoms: n=42, anxiety symptoms: n=37, and depression symptoms: n=12).ResultsResults suggest that the task was effective in producing differential fear learning and fear extinction in this cohort. Further, distinct patterns emerged differentiating the PTSD and anxiety symptom classes from both healthy and depression classes. During fear acquisition, the PTSD symptom group was the only group to show deficient discrimination between the conditioned stimulus (CS+) and safety cue (CS-), exhibiting larger startle responses during the safety cue compared to the healthy group. During extinction learning, the PTSD symptom group showed significantly less reduction in their CS+ responding over time compared to the healthy group, as well as reduced extinction of self-reported anxiety to the CS+ by the end of the extinction session. Conversely, the anxiety symptom group showed normal safety signal discrimination and extinction of conditioned fear, but exhibited increased baseline startle reactivity and potentiated startle to CS+, as well as higher self-reported anxiety to both cues. The depression symptom group showed similar physiological and self-report measures as the healthy group.DiscussionThese data are consistent with the idea that safety signal discrimination is a relatively specific marker of PTSD symptoms compared to general anxiety and depression symptoms. Further research is needed to determine if deficits in fear inhibition vs. exaggerated fear responding are separate biological "domains" across anxiety disorders that may predict differential biological mechanisms and possibly treatment needs. Future longitudinal analyses will examine whether poor learning of safety signals provides a marker of vulnerability to develop PTSD or is specific to symptom state.

Attentional dysfunction in schizophrenia (SZ) is a core deficit that contributes to multiple cognitive deficits and the resulting functional disability. However, developing procognitive therapeutics for neuropsychiatric disorders have been limited by a 'translational gap'--a lack of cognitive paradigms having cross-species translational validity and relevance. The present study was designed to perform an initial validation of the cross-species homology of the 5-choice Continuous Performance Test (5C-CPT) in healthy nonpsychiatric comparison subjects (NCS), SZ patients and mice under pharmacologic challenge. The 5C-CPT performance in SZ patients (n=20) was compared with age-matched NCS (n=23). The effects of the general muscarinic receptor antagonist scopolamine on mice (n=21) performing the 5C-CPT were also assessed. SZ subjects exhibited significantly impaired attention in the 5C-CPT, driven by reduced target detection over time and nonsignificantly increased impulsive responding. Similarly, scopolamine significantly impaired attention in mice, driven by reduced target detection and nonsignificantly increased impulsive responding. Scopolamine also negatively affected accuracy and speed of responding in mice, although these measures failed to differentiate SZ vs. NCS. Thus, mice treated with scopolamine exhibited similar impairments in vigilance as seen in SZ, although the differences between the behavioral profiles warrant further study. The availability of rodent and human versions of this paradigm provides an opportunity to: (1) investigate the neuroanatomic, neurochemical and genomic architecture of abnormalities in attention observed in clinical populations such as SZ; (2) develop and refine animal models of cognitive impairments; and (3) improve cross-species translational testing for the development of treatments for these impairments.

Anxiety disorders are prevalent and disabling yet understudied from a genetic standpoint, compared with other major psychiatric disorders such as bipolar disorder and schizophrenia. The fact that they are more common, diverse and perceived as embedded in normal life may explain this relative oversight. In addition, as for other psychiatric disorders, there are technical challenges related to the identification and validation of candidate genes and peripheral biomarkers. Human studies, particularly genetic ones, are susceptible to the issue of being underpowered, because of genetic heterogeneity, the effect of variable environmental exposure on gene expression, and difficulty of accrual of large, well phenotyped cohorts. Animal model gene expression studies, in a genetically homogeneous and experimentally tractable setting, can avoid artifacts and provide sensitivity of detection. Subsequent translational integration of the animal model datasets with human genetic and gene expression datasets can ensure cross-validatory power and specificity for illness. We have used a pharmacogenomic mouse model (involving treatments with an anxiogenic drug--yohimbine, and an anti-anxiety drug--diazepam) as a discovery engine for identification of anxiety candidate genes as well as potential blood biomarkers. Gene expression changes in key brain regions for anxiety (prefrontal cortex, amygdala and hippocampus) and blood were analyzed using a convergent functional genomics (CFG) approach, which integrates our new data with published human and animal model data, as a translational strategy of cross-matching and prioritizing findings. Our work identifies top candidate genes (such as FOS, GABBR1, NR4A2, DRD1, ADORA2A, QKI, RGS2, PTGDS, HSPA1B, DYNLL2, CCKBR and DBP), brain-blood biomarkers (such as FOS, QKI and HSPA1B), pathways (such as cAMP signaling) and mechanisms for anxiety disorders--notably signal transduction and reactivity to environment, with a prominent role for the hippocampus. Overall, this work complements our previous similar work (on bipolar mood disorders and schizophrenia) conducted over the last decade. It concludes our programmatic first pass mapping of the genomic landscape of the triad of major psychiatric disorder domains using CFG, and permitted us to uncover the significant genetic overlap between anxiety and these other major psychiatric disorders, notably the under-appreciated overlap with schizophrenia. PDE10A, TAC1 and other genes uncovered by our work provide a molecular basis for the frequently observed clinical co-morbidity and interdependence between anxiety and other major psychiatric disorders, and suggest schizo-anxiety as a possible new nosological domain.

Schizophrenia is a life-long debilitating mental disorder affecting tens of millions of people worldwide. The serendipitous discovery of antipsychotics focused pharmaceutical research on developing a better antipsychotic. Our understanding of the disorder has advanced however, with the knowledge that cognitive enhancers are required for patients in order to improve their everyday lives. While antipsychotics treat psychosis, they do not enhance cognition and hence are not antischizophrenics. Developing pro-cognitive therapeutics has been extremely difficult, however, especially when no approved treatment exists. In lieu of stumbling on an efficacious treatment, developing targeted compounds can be facilitated by understanding the neural mechanisms underlying altered cognitive functioning in patients. Equally importantly, these cognitive domains will need to be measured similarly in animals and humans so that novel targets can be tested prior to conducting expensive clinical trials. To date, the limited similarity of testing across species has resulted in a translational bottleneck. In this review, we emphasize that schizophrenia is a disorder characterized by abnormal cognitive behavior. Quantifying these abnormalities using tasks having cross-species validity would enable the quantification of comparable processes in rodents. This approach would increase the likelihood that the neural substrates underlying relevant behaviors will be conserved across species. Hence, we detail cross-species tasks which can be used to test the effects of manipulations relevant to schizophrenia and putative therapeutics. Such tasks offer the hope of providing a bridge between non-clinical and clinical testing that will eventually lead to treatments developed specifically for patients with deficient cognition. [ABSTRACT FROM PUBLISHER]

HF-1B/SP4:, a member of the Sp1 family of transcription factors, is expressed restrictively in the developing nervous system and most abundantly in adult hippocampus in mice. Here, we report the generation of hypomorphic Sp4 allele mice, in which the Sp4 deficiency can be rescued by the expression of Cre recombinase. Vacuolization was detected in the hippocampal gray matter of the mutant Sp4-deficient mice. Expression analysis of Sp4 mutant hippocampi revealed an age-dependent decrease in neurotrophin-3 expression in the dentate granule cells. Hypomorphic Sp4 mutant mice displayed robust deficits in both sensorimotor gating and contextual memory. The restoration of Sp4 expression, via a Cre-dependent rescue strategy, completely rescued all the observed molecular, histological and behavioral abnormalities. Our studies thus reveal a novel Sp4 pathway that is essential for hippocampal integrity and modulates behavioral processes relevant to psychiatric disorders.Molecular Psychiatry (2005) 10, 393-406. doi:10.1038/sj.mp.4001621 Published online 23 November 2004 [ABSTRACT FROM AUTHOR]

OBJECTIVE: The plasticity of the startle reflex, including prepulse inhibition (PPI) and habituation, provides operational measures of information processing that are abnormal in several neuropsychiatric disorders characterized by deficits in suppression or inhibition of intrusive or irrelevant stimuli. Clinically, patients with panic disorder (PD) have been described as having difficulties in the inhibition of their response to sensory and cognitive events. Because such difficulties may be the result of failures in early stages of information processing, we hypothesized that startle reactivity, PPI and habituation are deficient in unmedicated patients with PD. Moreover, we tested whether there was a relation between startle reflex measures and dysfunctional cognition. METHODS: Fourteen unmedicated patients with PD (7 men, 7 women) and 28 healthy comparison subjects (14 men, 14 women) were recruited. Acoustic startle reactivity, habituation and PPI (30-ms, 60-ms, 120-ms, 240-ms and 2000-ms interstimulus intervals) were assessed in the patients with PD and the age-matched and sex-matched healthy controls. These data for unmedicated patients with PD were compared with those for 24 medicated patients with PD. Moreover, dysfunctional cognition in patients with PD was measured using the Body Sensations Questionnaire. RESULTS: Unmedicated patients with PD exhibited increased startle reactivity, reduced habituation and significantly reduced PPI in the 30-ms, 60-ms, 120-ms and 240-ms prepulse conditions. Furthermore, in unmedicated patients with PD, increased startle response and decreased habituation were correlated significantly with higher cognitive dysfunction scores, but this was not the case for PPI. CONCLUSIONS: These data indicate that the early stages of sensory information processing are abnormal in patients with PD in the absence of medication. The observed deficits in PPI and habituation could reflect a more generalized difficulty in suppressing or gating information in PD. The correlation between cognitive symptoms and higher startle response and deficient habituation supports the hypothesis that subjects with PD have abnormalities in the early stages of information processing that lead to a cascade of downstream effects on cognition. [ABSTRACT FROM AUTHOR]

Abstract Background The Nef protein of HIV facilitates virus replication and disease progression in infected patients. This role as pathogenesis factor depends on several genetically separable Nef functions that are mediated by interactions of highly conserved protein-protein interaction motifs with different host cell proteins. By studying the functionality of a series of nef alleles from clinical isolates, we identified a dysfunctional HIV group O Nef in which a highly conserved valine-glycine-phenylalanine (VGF) region, which links a preceding acidic cluster with the following proline-rich motif into an amphipathic surface was deleted. In this study, we aimed to study the functional importance of this VGF region. Results The dysfunctional HIV group O8 nef allele was restored to the consensus sequence, and mutants of canonical (NL4.3, NA-7, SF2) and non-canonical (B2 and C1422) HIV-1 group M nef alleles were generated in which the amino acids of the VGF region were changed into alanines (VGF→AAA) and tested for their capacity to interfere with surface receptor trafficking, signal transduction and enhancement of viral replication and infectivity. We found the VGF motif, and each individual amino acid of this motif, to be critical for downregulation of MHC-I and CXCR4. Moreover, Nef’s association with the cellular p21-activated kinase 2 (PAK2), the resulting deregulation of cofilin and inhibition of host cell actin remodeling, and targeting of Lck kinase to the trans-golgi-network (TGN) were affected as well. Of particular interest, VGF integrity was essential for Nef-mediated enhancement of HIV virion infectivity and HIV replication in peripheral blood lymphocytes. For targeting of Lck kinase to the TGN and viral infectivity, especially the phenylalanine of the triplet was essential. At the molecular level, the VGF motif was required for the physical interaction of the adjacent proline-rich motif with Hck. Conclusion Based on these findings, we propose that this highly conserved three amino acid VGF motif together with the acidic cluster and the proline-rich motif form a previously unrecognized amphipathic surface on Nef. This surface appears to be essential for the majority of Nef functions and thus represents a prime target for the pharmacological inhibition of Nef.

Abstract Background Executive dysfunction may play a major role in cognitive decline with aging because frontal lobe structures are particularly vulnerable to advancing age. Lesion studies in rats and mice have suggested that intradimensional shifts (IDSs), extradimensional shifts (EDSs), and reversal learning are mediated by the anterior cingulate cortex, the medial prefrontal cortex, and the orbitofrontal cortex, respectively. We hypothesized that the latent structure of cognitive performance would reflect functional localization in the brain and would be altered by aging. Methods Young (4 months, n = 16) and aged (23 months, n = 18) C57BL/6N mice performed an attentional set-shifting task (ASST) that evaluates simple discrimination (SD), compound discrimination (CD), IDS, EDS, and reversal learning. The performance data were subjected to an exploratory factor analysis to extract the latent structures of ASST performance in young and aged mice. Results The factor analysis extracted two- and three-factor models. In the two-factor model, the factor associated with SD and CD was clearly separated from the factor associated with the rest of the ASST stages in the young mice only. In the three-factor model, the SD and CD loaded on distinct factors. The three-factor model also showed a separation of factors associated with IDS, EDS, and CD reversal. However, the other reversal learning variables, ID reversal and ED reversal, had somewhat inconsistent factor loadings. Conclusions The separation of performance factors in aged mice was less clear than in young mice, which suggests that aged mice utilize neuronal networks more broadly for specific cognitive functions. The result that the factors associated with SD and CD were separated in the three-factor model may suggest that the introduction of an irrelevant or distracting dimension results in the use of a new/orthogonal strategy for better discrimination.

Abstract Introduction Wegener's Granulomatosis is a vasculitis of uncertain aetiology. Affected patients usually present with disease of the respiratory and renal tracts. Classic symptoms and clinical findings, together with serology titres positive for anti-neutrophil cytolplasmic antibody against proteinase 3 confirm the diagnosis. Wegener's Granulomatosis can occasionally involve other organs, but solitary parotid gland disease is uncommon; patients generally also have systemic disease. Case Presentation We report a case of Wegener's Granulomatosis in a 69-year-old Caucasian female presenting initially with an isolated parotid abscess and only subsequently developing nasal, paranasal sinus and respiratory symptoms. We describe the clinical course, diagnostic difficulties, imaging and histopathology of this case. Conclusion Major salivary gland infection is not an uncommon ENT disorder, but the clinician should be wary of the patient who fails to respond appropriately to adequate therapy. In such cases a differential diagnosis of Wegener's Granulomatosis should be considered, as early recognition and treatment of this potentially fatal disease is paramount.

Abstract Background The positive transcription elongation factor b (P-TEFb) is an essential cellular co-factor for the transcription of the human immunodeficiency virus type 1 (HIV-1). The cyclin T1 (CycT1) subunit of P-TEFb associates with a viral protein, Tat, at the transactivation response element (TAR). This represents a critical and necessary step for the stimulation of transcriptional elongation. Therefore, CycT1 may serve as a potential target for the development of anti-HIV therapies. Results To create effective inhibitors of HIV transcription, mutant CycT1 proteins were constructed based upon sequence similarities between CycT1 and other cyclin molecules, as well as the defined crystal structure of CycT1. One of these mutants, termed CycT1-U7, showed a potent dominant negative effect on Tat-dependent HIV transcription despite a remarkably low steady-state expression level. Surprisingly, the expression levels of Tat proteins co-expressed with CycT1-U7 were significantly lower than Tat co-expressed with wild type CycT1. However, the expression levels of CycT1-U7 and Tat were restored by treatment with proteasome inhibitors. Concomitantly, the dominant negative effect of CycT1-U7 was abolished by these inhibitors. Conclusion These results suggest that CycT1-U7 inhibits HIV transcription by promoting a rapid degradation of Tat. These mutant CycT1 proteins represent a novel class of specific inhibitors for HIV transcription that could potentially be used in the design of anti-viral therapy.

Abstract Background The Nef protein of Human Immunodeficiency Viruses optimizes viral spread in the infected host by manipulating cellular transport and signal transduction machineries. Nef also boosts the infectivity of HIV particles by an unknown mechanism. Recent studies suggested a correlation between the association of Nef with lipid raft microdomains and its positive effects on virion infectivity. Furthermore, the lipidome analysis of HIV-1 particles revealed a marked enrichment of classical raft lipids and thus identified HIV-1 virions as an example for naturally occurring membrane microdomains. Since Nef modulates the protein composition and function of membrane microdomains we tested here if Nef also has the propensity to alter microdomain lipid composition. Results Quantitative mass spectrometric lipidome analysis of highly purified HIV-1 particles revealed that the presence of Nef during virus production from T lymphocytes enforced their raft character via a significant reduction of polyunsaturated phosphatidylcholine species and a specific enrichment of sphingomyelin. In contrast, Nef did not significantly affect virion levels of phosphoglycerolipids or cholesterol. The observed alterations in virion lipid composition were insufficient to mediate Nef's effect on particle infectivity and Nef augmented virion infectivity independently of whether virus entry was targeted to or excluded from membrane microdomains. However, altered lipid compositions similar to those observed in virions were also detected in detergent-resistant membrane preparations of virus producing cells. Conclusion Nef alters not only the proteome but also the lipid composition of host cell microdomains. This novel activity represents a previously unrecognized mechanism by which Nef could manipulate HIV-1 target cells to facilitate virus propagation in vivo.

Classical serotonergic psychedelics such as lysergic acid diethylamide or the naturally occurring compounds psilocybin and mescaline produce profound changes in mood, thought, intuition, sensory perception, the experience of time and space, and even the experience of self. Research examining psychedelic compounds has had a complex and turbulent evolution. Many cultures throughout the world have used psychedelic plants not only for mystical, ritualistic, or divinatory purposes but also for curing illnesses. Much of the genesis and progress of modern investigations into the effects and underlying mechanisms of action of psychedelics have been intertwined with studies of the neurotransmitter serotonin. Early hypotheses that serotonergic systems mediate psychedelic effects were supported initially by preclinical animal studies and subsequently confirmed by pharmacological studies in healthy humans. The use of psychedelic compounds as putative psychotomimetics that reproduce some features of naturally occurring psychotic disorders met with some limited success. More recent studies are exploring psychedelics as potential psychotherapeutic agents. Recent indications that even 1 or 2 psychedelic treatments produce robust and sustained reductions in clinical symptoms in a variety of psychiatric disorders have prompted an enormous resurgence of interest in the nature and mechanisms contributing to their effects., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The balance between exploration and exploitation is essential for decision-making. The present study investigated the role of ventromedial orbitofrontal cortex (vmOFC) glutamate neurons in mediating value-based decision-making by first using optogenetics to manipulate vmOFC glutamate activity in rats during a probabilistic reversal learning (PRL) task. Rats that received vmOFC activation during informative feedback completed fewer reversals and exhibited reduced reward sensitivity relative to rats. Analysis with a Q-learning computational model revealed that increased vmOFC activity did not affect the learning rate but instead promoted maladaptive exploration. By contrast, vmOFC inhibition increased the number of completed reversals and increased exploitative behavior. In a separate group of animals, calcium activity of vmOFC glutamate neurons was recorded using fiber photometry. Complementing our results above, we found that suppression of vmOFC activity during the latter part of rewarded trials was associated with improved PRL performance, greater win-stay responding and selecting the correct choice on the next trial. These data demonstrate that excessive vmOFC activity during reward feedback disrupted value-based decision-making by increasing the maladaptive exploration of lower-valued options. Our findings support the premise that pharmacological interventions that normalize aberrant vmOFC glutamate activity during reward feedback processing may attenuate deficits in value-based decision-making., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Human immunodeficiency virus (HIV) continues to infect millions worldwide, negatively impacting neurobehavioral function. Further understanding of the combined effects of HIV and methamphetamine use is crucial, as methamphetamine use is prevalent in people with HIV. The HIV-associated protein Tat may contribute to cognitive dysfunction, modeled preclinically in mice using doxycycline (DOX)-inducible Tat expression (iTat). Tat may exert its effects on cognitive function via disruption of the dopamine transporter, similar to the action of methamphetamine. Additionally, Tat and methamphetamine both decrease interneuron populations, including those expressing calbindin. It is important to understand the combined effects of Tat and methamphetamine in preclinical models of HIV infection. Here, we used iTat transgenic mice and a chronic binge regimen of methamphetamine exposure to determine their combined impact on reward learning and motivation. We also measured calbindin expression in behavior-relevant brain regions. Before induction with DOX, iTat mice exhibited no differences in behavior. Chronic methamphetamine exposure before Tat induction impaired initial reward learning but did not affect motivation. Furthermore, DOX-induced Tat expression did not alter behavior, but slowed latencies to retrieve rewards. This effect of Tat, however, was not observed in methamphetamine-treated mice, indicative of a potential protective effect. Finally, Tat expression was associated with an increase in calbindin-expressing cells in the VTA, while methamphetamine exposure did not alter calbindin numbers. These findings may indicate a protective role of methamphetamine in HIV neuropathology, which in turn may help in our understanding of why people with HIV use methamphetamine at disproportionately higher rates., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Although antiretroviral therapy (ART) has increased the quality of life and lifespan in people living with HIV (PWH), millions continue to suffer from the neurobehavioral effects of the virus. Additionally, the abuse of illicit drugs (methamphetamine in particular) is significantly higher in PWH compared to the general population, which may further impact their neurological functions. The HIV regulatory protein, Tat, has been implicated in the neurobehavioral impacts of HIV and is purported to inhibit dopamine transporter (DAT) function in a way similar to methamphetamine. Thus, we hypothesized that a combination of Tat expression and methamphetamine would exert synergistic deleterious effects on behavior and DAT expression. We examined the impact of chronic methamphetamine exposure on exploration in transgenic mice expressing human Tat (iTat) vs. their wildtype littermates using the behavioral pattern monitor (BPM). During baseline, mice exhibited sex-dependent differences in BPM behavior, which persisted through methamphetamine exposure, and Tat activation with doxycycline. We observed a main effect of methamphetamine, wherein exposure, irrespective of genotype, increased locomotor activity and decreased specific exploration. After doxycycline treatment, mice continued to exhibit drug-dependent alterations in locomotion, with no effect of Tat, or methamphetamine interactions. DAT levels were higher in wildtype, saline-exposed males compared to all other groups. These data support stimulant-induced changes of locomotor activity and exploration, and suggest that viral Tat and methamphetamine do not synergistically interact to alter these behaviors in mice. These findings are important for future studies attempting to disentangle the effect of substances that impact DAT on HAND-relevant behaviors using such transgenic animals., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Little is understood about cognitive mechanisms that confer risk and resiliency for posttraumatic stress disorder (PTSD). Prepulse Inhibition (PPI) is a measure of pre-attentional response inhibition that is a stable cognitive trait disrupted in many neuropsychiatric disorders characterized by poor behavioral or cognitive inhibition, including PTSD. Differentiating between PTSD-related phenotypes that are pre-existing factors vs. those that emerge specifically after trauma is critical to understanding PTSD etiology and can only be addressed by prospective studies. This study tested the hypothesis that sensorimotor gating performance is associated with risk/resiliency for combat-related PTSD. As part of a prospective, longitudinal study, 1226 active duty Marines and Navy Corpsman completed a PPI test as well as a clinical interview to assess PTSD symptoms both before,  and 3 and 6 months after a combat deployment. Participants that developed PTSD 6 months following deployment (N=46)  showed lower PPI across pre and post-deployment time points compared to participants who did not develop PTSD (N=1182) . Examination of the distribution of PTSD across PPI performance revealed a lower than expected number of cases in the highest performing quartile compared to the rest of the distribution (p < 0.04). When controlling for other factors that predict PTSD in this population, those in the top 25% of PPI performance showed a >50% reduction in chance to develop PTSD (OR = 0.32). Baseline startle reactivity and startle habituation were not significantly different between PTSD risk and control groups. These findings suggest that robust sensorimotor gating may represent a resiliency factor for development of PTSD following trauma., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: HIV-associated neurocognitive disorder (HAND) is commonly observed in persons living with HIV (PWH) and is characterized by cognitive deficits implicating disruptions of fronto-striatal neurocircuitry. Such circuitry is also susceptible to alteration by cannabis and other drugs of abuse. PWH use cannabis at much higher rates than the general population, thus prioritizing the characterization of any interactions between HIV and cannabinoids on cognitively relevant systems. Prepulse inhibition (PPI) of the startle response, the process by which the motor response to a startling stimulus is attenuated by perception of a preceding non-startling stimulus, is an operational assay of fronto-striatal circuit integrity that is translatable across species. PPI is reduced in PWH. The HIV transgenic (HIVtg) rat model of HIV infection mimics numerous aspects of HAND, although to date the PPI deficit observed in PWH has yet to be fully recreated in animals., Methods: PPI was measured in male and female HIVtg rats and wild-type controls following acute, nonconcurrent treatment with the primary constituents of cannabis: Δ 9-tetrahydrocannabinol (THC; 1 and 3 mg/kg, s.c.) and cannabidiol (1, 10, and 30 mg/kg, i.p.)., Results: HIVtg rats exhibited a significant PPI deficit relative to wild-type controls. THC reduced PPI in controls but not HIVtg rats. Cannabidiol exerted only minor, genotype-independent effects on PPI., Conclusions: HIVtg rats exhibit a relative insensitivity to the deleterious effects of THC on the fronto-striatal function reflected by PPI, which may partially explain the higher rates of cannabis use among PWH., (© The Author(s) 2021. Published by Oxford University Press on behalf of CINP.)

Autism spectrum disorder (ASD) is often signaled by atypical cries during infancy. Copy number variants (CNVs) provide genetically identifiable cases of ASD, but how early atypical cries predict a later onset of ASD among CNV carriers is not understood in humans. Genetic mouse models of CNVs have provided a reliable tool to experimentally isolate the impact of CNVs and identify early predictors for later abnormalities in behaviors relevant to ASD. However, many technical issues have confounded the phenotypic characterization of such mouse models, including systematically biased genetic backgrounds and weak or absent behavioral phenotypes. To address these issues, we developed a coisogenic mouse model of human proximal 16p11.2 hemizygous deletion and applied computational approaches to identify hidden variables within neonatal vocalizations that have predictive power for postpubertal dimensions relevant to ASD. After variables of neonatal vocalizations were selected by least absolute shrinkage and selection operator (Lasso), random forest, and Markov model, regression models were constructed to predict postpubertal dimensions relevant to ASD. While the average scores of many standard behavioral assays designed to model dimensions did not differentiate a model of 16p11.2 hemizygous deletion and wild-type littermates, specific call types and call sequences of neonatal vocalizations predicted individual variability of postpubertal reciprocal social interaction and olfactory responses to a social cue in a genotype-specific manner. Deep-phenotyping and computational analyses identified hidden variables within neonatal social communication that are predictive of postpubertal behaviors., (© 2021. The Author(s).)

Background: Older adults (≥50 years) represent the fastest-growing population of people who use cannabis, potentially due to the increasing promotion of cannabis as medicine by dispensaries and cannabis websites. Given healthy aging and cannabis use are both associated with cognitive decline, it is important to establish the effects of cannabis on cognition in healthy aging., Objective: This systematic scoping review used preferred reporting items for systematic reviews and meta-analyses guidelines to critically examine the extent of literature on this topic and highlight areas for future research., Method: A search of six databases (PubMed, EMBASE, PsycINFO, Web of Science, Family and Society Studies Worldwide, and CINAHL) for articles published by September 2019, yielded 1,014 unique results., Results: Six articles reported findings for older populations (three human and three rodent studies), highlighting the paucity of research in this area. Human studies revealed largely null results, likely due to several methodological limitations. Better-controlled rodent studies indicate that the relationship between ∆9-tetrahydrocannabinol (THC) and cognitive function in healthy aging depends on age and level of THC exposure. Extremely low doses of THC improved cognition in very old rodents. Somewhat higher chronic doses improved cognition in moderately aged rodents. No studies examined the effects of cannabidiol (CBD) or high-CBD cannabis on cognition., Conclusions: This systematic scoping review provides crucial, timely direction for future research on this emerging issue. Future research that combines neuroimaging and cognitive assessment would serve to advance understanding of the effects of age and quantity of THC and CBD on cognition in healthy aging., (Published by Oxford University Press 2020.)

Background: Bipolar disorder is a life-threatening disorder linked to dopamine transporter (DAT) polymorphisms, with reduced DAT levels seen in positron emission tomography and postmortem brains., Aims: The purpose of this study was to examine the effects of approved antipsychotics on DAT dysfunction-mediated mania behavior in mice., Methods: DAT knockdown mice received either D 2 -family receptor antagonist risperidone or asenapine and mania-related behaviors were assessed in the clinically-relevant behavioral pattern monitor to assess spontaneous exploration., Results: Chronic risperidone did not reverse mania-like behavior in DAT knockdown mice. Chronic asenapine reduced mania behavior but this effect was more pronounced in wild-type littermates than in DAT knockdown mice., Conclusion: Taken together, these findings suggest that while acute antipsychotic treatment may be beneficial in management of bipolar mania, more targeted therapeutics may be necessary for long-term treatment. Specific investigation into DAT-targeting drugs could improve future treatment of bipolar mania., (Copyright © 2021. Published by Elsevier B.V.)

Bipolar disorder (BD) and cannabis use are highly comorbid and are each associated with cognitive impairment.  Given the prevalence of cannabis use in people with BD, it is important to understand whether the two interact to impact cognitive function. We performed a systematic scoping review to determine what is currently known in this field. We systematically searched PubMed, Embase, CINAHL, Web of Science, and PsycINFO for studies on the relationship between cannabis use and cognition in people with BD or relevant animal models. Six observational human studies and no animal studies met inclusion criteria. Two studies found cannabis use in BD was associated with better performance in some cognitive domains, while three studies found no association. One study found cannabis use in BD was associated with worse overall cognition. Overall, most identified studies suggest cannabis use is not associated with significant cognitive impairment in BD; however, the scope of knowledge in this field is limited, and more systematic studies are clearly required. Future studies should focus on longitudinal and experimental trials, and well-controlled observational studies with rigorous quantification of the onset, frequency, quantity, duration, and type of cannabis use, as well as BD illness features., (Copyright © 2020. Published by Elsevier B.V.)

Background: Human immunodeficiency virus (HIV)-associated neurocognitive disorders persist in the era of antiretroviral therapy. One factor that is elevated among persons with HIV (PWH) and independently associated with neurocognitive impairment is methamphetamine dependence (METH). Such dependence may further increase cognitive impairment among PWH, by delaying HIV diagnosis (and thus, antiretroviral therapy initiation), which has been posited to account for persistent cognitive impairment among PWH, despite subsequent treatment-related viral load suppression (VLS; <50 copies of the virus per milliliter in plasma or cerebrospinal fluid). This study examined the main and interactive (additive versus synergistic) effects of HIV and history of METH on the sustained attention and vigilance cognitive domain, while controlling for VLS., Methods: Participants included 205 (median age = 44 years; 77% males; HIV-/METH- n = 67; HIV+/METH - n = 49; HIV-/METH+ n = 36; HIV+/METH+ n = 53) individuals enrolled in the Translational Methamphetamine AIDS Research Center, who completed Conners' and the 5-Choice continuous performance tests (CPTs)., Results: METH participants exhibited deficits in sustained attention and vigilance; however, these effects were not significant after excluding participants who had a positive urine toxicology screen for methamphetamine. Controlling for VLS, PWH did not have worse sustained attention and vigilance, but consistently displayed slower reaction times across blocks, relative to HIV- participants. There was no HIV x METH interaction on sustained attention and vigilance., Conclusions: Recent methamphetamine use among METH people and detectable viral loads are detrimental to sustained attention and vigilance. These findings highlight the need for prompt diagnosis of HIV and initiation of antiretroviral therapy, and METH use interventions., (Copyright © 2020 Elsevier B.V. All rights reserved.)

To reveal post-traumatic stress disorder (PTSD) genetic risk influences on tissue-specific gene expression, we use brain and non-brain transcriptomic imputation. We impute genetically regulated gene expression (GReX) in 29,539 PTSD cases and 166,145 controls from 70 ancestry-specific cohorts and identify 18 significant GReX-PTSD associations corresponding to specific tissue-gene pairs. The results suggest substantial genetic heterogeneity based on ancestry, cohort type (military versus civilian), and sex. Two study-wide significant PTSD associations are identified in European and military European cohorts; ZNF140 is predicted to be upregulated in whole blood, and SNRNP35 is predicted to be downregulated in dorsolateral prefrontal cortex, respectively. In peripheral leukocytes from 175 marines, the observed PTSD differential gene expression correlates with the predicted differences for these individuals, and deployment stress produces glucocorticoid-regulated expression changes that include downregulation of both ZNF140 and SNRNP35. SNRNP35 knockdown in cells validates its functional role in U12-intron splicing. Finally, exogenous glucocorticoids in mice downregulate prefrontal Snrnp35 expression., Competing Interests: Declaration of Interests J.W.S. is an unpaid member of the Bipolar/Depression Research Community Advisory Panel of 23andMe. D.J.S. has received research grants and/or consultancy honoraria from Biocodex, Lundbeck, and Sun. R.Y. is a co-inventor of the following patent: “Genes associated with posttraumatic-stress disorder, WO 2010029176 A1.” I.L. has been a consultant for ARMGO Pharmaceuticals, Sunovion Pharmaceuticals, and Trimaran Pharma. K.J.R. has received consulting income from Alkermes and is on scientific advisory boards for Janssen, Verily, and Resilience Therapeutics. He has also received sponsored research support from Takeda and Brainsway. N.P.D. has held a part-time paid position at Cohen Veteran Bioscience. He has also been a consultant for Sunovion Pharmaceuticals., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Bipolar disorder (BD) is a debilitating psychiatric illness affecting 2%-5% of the population. Although mania is the cardinal feature of BD, inattention and related cognitive dysfunction are observed across all stages. Since cognitive dysfunction confers poor functional outcome in patients, understanding the relevant neural mechanisms remains key to developing novel-targeted therapeutics., Methods: The 5-choice continuous performance test (5C-CPT) is a mouse and fMRI-compatible human attentional task, requiring responding to target stimuli while inhibiting responding to nontarget stimuli, as in clinical CPTs. This task was used to delineate systems-level neural deficits in BD contributing to inattentive performance in human subjects with BD as well as mouse models with either parietal cortex (PC) lesions or reduced dopamine transporter (DAT) expression., Results: Mania BD participants exhibited severe 5C-CPT impairment. Euthymic BD patients exhibited modestly impaired 5C-CPT. High impulsivity BD subjects exhibited reduced PC activation during target and nontarget responding compared with healthy participants. In mice, bilateral PC lesions impaired both target and nontarget responding. In the DAT knockdown mouse model of BD mania, knockdown mice exhibited severely impaired 5C-CPT performance versus wildtype littermates., Conclusions: These data support the role of the PC in inattention in BD-specifically regarding identifying the appropriate response to target vs nontarget stimuli. Moreover, the findings indicate that severely reduced DAT function/hyperdopaminergia recreates the attentional deficits observed in BD mania patients. Determining the contribution of DAT in the PC to attention may provide a future target for treatment development., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Efforts to replicate results from both basic and clinical models have highlighted problems with reproducibility in science. In psychiatry, reproducibility issues are compounded because the complex behavioral syndromes make many disorders challenging to model. We develop translatable tasks that quantitatively measure psychiatry-relevant behaviors across species. The behavioral pattern monitor (BPM) was designed to analyze exploratory behaviors, which are altered in patients with bipolar disorder (BD), especially during mania episodes. We have repeatedly assessed the behavioral effects of reduced dopamine transporter (DAT) expression in the BPM using a DAT knockdown (KD) mouse line (~10% normal expression). DAT KD mice exhibit a profile in the BPM consistent with acutely manic BD patients in the human version of the task-hyperactivity, increased exploratory behavior, and reduced spatial d (Perry et al., 2009). We collected data from multiple DAT KD BPM experiments in our laboratory to assess the reproducibility of behavioral outcomes across experiments. The four outcomes analyzed were: 1) transitions (amount of locomotor activity); 2) rearings (exploratory activity); 3) holepokes (exploratory activity); and 4) spatial d (geometrical pattern of locomotor activity). By comparing DAT KD mice to wildtype (WT) littermates in every experiment, we calculated effect sizes for each of the four outcomes and then calculated a mean effect size using a random effects model. DAT KD mice exhibited robust, reproducible changes in each of the four outcomes, including increased transitions, rearings, and holepokes, and reduced spatial d, vs. WT littermates. Our results demonstrate that the DAT KD mouse line in the BPM is a consistent, reproducible model of mania-relevant behaviors. More work must be done to assess reproducibility of behavioral outcomes across experiments in order to advance the field of psychiatry and develop more effective therapeutics for patients., (Copyright © 2017. Published by Elsevier Inc.)

Background: There is evidence that mGlu2/3 receptors regulate 5-HT 2A signaling, interactions that have been theorized to play a role in the antipsychotic-like effects of mGlu2/3 agonists as well as the hallucinogenic effects of 5-HT 2A agonists. One approach to unraveling this interaction is through the chronic administration of agonists at the two receptors, which should influence the functional properties of the targeted receptor due to receptor downregulation or desensitization and thereby alter crosstalk between the two receptors. In this study, we investigated whether chronic treatment with the mGlu2/3 agonist LY379268 would alter the behavioral response to a phenethylamine hallucinogen, 25CN-NBOH, which acts as a selective 5-HT 2A agonist., Methods: We first conducted a dose response of 25CN-NBOH (0.1, 0.3, 1, 3, or 10 mg/kg) to confirm the effects on head-twitch response (HTR) and then blockade studies with either the M100907 (0.1 mg/kg) or SB242084 (0.1, 0.3, or 1 mg/kg) to determine the contribution of 5-HT2A and 5-HT2C to 25CN-NBOH-induced HTR, respectively. To determine whether an mGlu2/3 agonist could block 25CN-NBOH-induced HTR, mice were pretreated with vehicle or LY379268 (0.1, 1, or 10 mg/kg) prior to 25CN-NBOH, and HTR was assessed. The effects of chronic LY379268 on 5-HT2A agonist-induced HTR were evaluated by treating mice with either vehicle or LY379268 (10 mg/kg) for 21 days and measuring 25CN-NBOH-induced HTR 48 h after the final LY379268 treatment. The following day (72 h after the final LY379268 treatment), the ability of acute LY379268 to block PCP-induced locomotor activity was assessed., Results: 25CN-NBOH dose-dependently increased the HTR, a 5-HT 2A -mediated behavior, in mice. The selective 5-HT 2A antagonist M100907 completely blocked the HTR induced by 25CN-NBOH, whereas the selective 5-HT 2C antagonist SB242084 had no effect on the HTR. Administration of LY379268 (10 mg/kg SC) attenuated the HTR induced by 1 mg/kg 25CN-NBOH by ~ 50%. Chronic treatment (21 days) with LY379268 also attenuated the HTR response to 25CN-NBOH when tested 48 h after the last dose of LY379268. In locomotor tests, acute LY379268 significantly attenuated PCP-induced locomotor activity in the chronic vehicle treatment group; by contrast, there was only a trend for an overall interaction in the chronic LY379268 group, with LY379268 blocking the locomotor-stimulating effects of PCP only during the last 20 min., Conclusions: These data are consistent with a functional interaction between mGlu2/3 and 5-HT 2A receptors, although the specific mechanism for the interaction is not known. These data support the hypothesis that mGlu2/3 receptors play a prominent role in modulating the behavioral response to 5-HT 2A receptor activation.

Cognitive impairments, e.g., reward learning, are present in various psychiatric disorders and warrant treatment. Improving reward-related learning could synergistically enhance psychosocial treatments and cognition generally. A critical first step is to understand the mechanisms underlying reward learning. The dopamine system has been implicated in such learning, but less known is how indirect activation of this system may affect reward learning. We determined the role of alpha7 nicotinic acetylcholine receptors (nAChR) on a probabilistic reversal learning task (PRLT) in mice that includes reward and punishment. Male alpha7 knockout (KO), heterozygous (HT), and wildtype (WT) littermate mice (n = 84) were treated with vehicle, 0.03, or 0.3 mg/kg nicotine. Two cohorts of C57BL/6NJ male mice were treated with various alpha7 nAChR ligands, including the full agonists PNU282877 and AR-R-17779, the positive allosteric modulator CCMI, the partial agonist SSR180711, and the antagonist methyllycaconitine. All mice were then tested in the PRLT. Nicotine (0.3 mg/kg) significantly improved initial reward learning in alpha7 WT and HT mice but did not improve learning in KO mice, suggesting an involvement of the alpha7 nAChR in the pro-learning effects of nicotine. Neither alpha7 nAChR treatments (PNU282987, AR-R-17779, CCMI, SSR180711, nor methyllycaconitine) affected mouse PRLT performance however. Nicotine improved reward learning via a mechanism that may include alpha7 nAChRs. This improvement unlikely relied solely on alpha7 nAChRs however, since no alpha7 nAChR ligand improved reward learning in normal mice. Future assessments of the effects of other nAChR subtypes on reward learning are needed., (Copyright © 2018 Elsevier B.V. and European College of Neuropsychopharmacology. All rights reserved.)

Non-medical use of prescription stimulants amongst college students is common, with claims of cognitive and academic benefits. The mechanism, magnitude, and pervasiveness of the cognitive enhancing effects of stimulants in healthy adults remain poorly understood however. The present study determined the effects of dextroamphetamine (D-amp) on the 5-choice continuous performance test (5C-CPT) of attention in healthy young adult humans and mice. A mixed gender sample received placebo (n = 29), 10 (n = 17) or 20 mg D-amp (n = 25) in a double-blind fashion before 5C-CPT testing. In addition, male C57BL/6J mice were trained on a touchscreen adaptation of the 5C-CPT and tested after receiving saline or D-amp (0.1, 0.3, 1.0 mg/kg; n = 8/dose). In humans, D-amp significantly improved 5C-CPT performance. Both doses improved signal detection driven by increased hit rate (reduced omissions). Both doses also improved response accuracy and reduced hit reaction time (HRT) variability. In mice, similar effects (improved signal detection, hit rate, and response accuracy) were observed at the moderate dose (0.3 mg/kg). In contrast to human participants however, no effect on HRT variability was detected in mice, with no effect on HRT in either species. Human 5C-CPT performance was consistent with prior studies and consistent with alternative CPT paradigms. The performance of C57BL/6J mice on the touchscreen 5C-CPT mirrored performance of this strain on 5-hole operant chambers. Importantly, comparable facilitation of attention with D-amp was observed in both species. The 5C-CPT provides a cross-species paradigm by which the cognitive enhancing properties of stimulants and the neural underpinnings of attention can be assessed., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Athina Markou and others argue forcefully for the adoption of a "translational-back translational strategy" for central nervous system drug discovery involving novel application of drugs with established safety profiles in proof-of-principle studies in humans, which in turn encourage parallel studies using experimental animals to provide vital data on the neural systems and neuropharmacological mechanisms related to the actions of the candidate drugs. Encouraged by the increasing adoption of drug-development strategies involving reciprocal information exchange between preclinical animal studies and related clinical research programs, this review presents additional compelling examples related to the following: 1) the treatment of cognitive deficits that define attention-deficit/hyperactivity disorder; 2) the development of fast-acting antidepressants based on promising clinical effects with low doses of the anesthetic ketamine; and 3) new and effective medications for the treatment of substance misuse. In the context of addressing the unmet medical need for new and effective drugs for treatment of mental ill health, now may be the time to launch major new academic-industry consortia committed to open access of all preclinical and clinical data generated by this research., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objectives: Amphetamine improves vigilance as assessed by continuous performance tests (CPT) in children and adults with attention deficit hyperactivity disorder (ADHD). Less is known, however, regarding amphetamine effects on vigilance in healthy adults. Thus, it remains unclear whether amphetamine produces general enhancement of vigilance or if these effects are constrained to the remediation of deficits in patients with ADHD., Methods: We tested 69 healthy adults (35 female) on a standardized CPT (Conner's CPT-2) after receiving 10- or 20-mg d-amphetamine or placebo. To evaluate potential effects on learning, impulsivity, and perseveration, participants were additionally tested on the Iowa Gambling Task (IGT) and Wisconsin Card Sorting Task (WCST)., Results: Participants receiving placebo exhibited the classic vigilance decrement, demonstrated by a significant reduction in attention (D') across the task. This vigilance decrement was not observed, however, after either dose of amphetamine. Consistent with enhanced vigilance, the 20-mg dose also reduced reaction time variability across the task and the ADHD confidence index. The effects of amphetamine appeared to be selective to vigilance since no effects were observed on the IGT, WCST, or response inhibition/perseveration measures from the CPT., Conclusions: The present data support the premise that amphetamine improves vigilance irrespective of disease state. Given that amphetamine is a norepinephrine/dopamine transporter inhibitor and releaser, these effects are informative regarding the neurobiological substrates of attentional control. (JINS, 2018, 24, 283-293).

PTSD has been associated consistently with abnormalities in fear acquisition and extinction learning and retention. Fear acquisition refers to learning to discriminate between threat and safety cues. Extinction learning reflects the formation of a new inhibitory-memory that competes with a previously learned threat-related memory. Adjudicating the competition between threat memory and the new inhibitory memory during extinction may rely, in part, on cognitive processes such as working memory (WM). Despite significant shared neural circuits and signaling pathways the relationship between WM, fear acquisition, and extinction is poorly understood. Here, we analyzed data from a large sample of healthy Marines who underwent an assessment battery including tests of fear acquisition, extinction learning, and WM (N-back). Fear potentiated startle (FPS), fear expectancy ratings, and self-reported anxiety served as the primary dependent variables. High WM ability (N = 192) was associated with greater CS + fear inhibition during the late block of extinction and greater US expectancy change during extinction learning compared to individuals with low WM ability (N = 204). WM ability was not associated with magnitude of fear conditioning/expression. Attention ability was unrelated to fear acquisition or extinction supporting specificity of WM associations with extinction. These results support the conclusion that individual differences in WM may contribute to regulating fear responses., (Copyright © 2018. Published by Elsevier Ltd.)

Background: The catechol-O-methyltransferase (COMT) Val158Met gene influences cognition and behavior in psychiatric illnesses; its low-activity allele, methionine (Met), may be associated with behavior reflecting catecholamine overactivity. Heightened motor activity and increased positive valence are central features of bipolar disorder (BD) and have been quantified in the human Behavioral Pattern Monitor (hBPM), an exploration paradigm based upon the rodent open field. We examined whether hBPM behavior was related to the COMT gene in a small sample of manic BD patients., Methods: Twenty-six acutely hospitalized manic BD patients were genotyped for the COMT Val158Met polymorphism and tested in the hBPM, an unfamiliar room containing novel objects. Movements around the hBPM and object interactions were video-recorded for 15 min and rated., Results: Met homozygote BD patients demonstrated significantly more interactions with multiple objects and more time spent with objects in the hBPM. Valine (Val) homozygote patients exhibited the least object exploration, while heterozygote patients demonstrated intermediate levels., Conclusion: This preliminary study suggests that arousal and positive valence are influenced in a linear fashion by COMT, presumably due to increased catecholamine in frontal regions, but these findings require replication in a larger sample. The hBPM can enable cross-species and transdiagnostic studies to inform neurobiology of psychiatric disorders.

Because of the ethical and regulatory hurdles associated with human studies, much of what is known about the psychopharmacology of hallucinogens has been derived from animal models. However, developing reliable animal models has proven to be a challenging task due to the complexity and variability of hallucinogen effects in humans. This chapter focuses on three animal models that are frequently used to test the effects of hallucinogens on unconditioned behavior: head twitch response (HTR), prepulse inhibition of startle (PPI), and exploratory behavior. The HTR has demonstrated considerable utility in the neurochemical actions of hallucinogens. However, the latter two models have clearer conceptual bridges to human phenomenology. Consistent with the known mechanism of action of hallucinogens in humans, the behavioral effects of hallucinogens in rodents are mediated primarily by activation of 5-HT 2A receptors. There is evidence, however, that other receptors may play secondary roles. The structure-activity relationships (SAR) of hallucinogens are reviewed in relation to each model, with a focus on the HTR in rats and mice.

Background: Risk for posttraumatic stress disorder (PTSD) is thought to be mediated by gene × environment (G × E) interactions that affect core cognitive processes such as fear learning. The catechol-O-methyltransferase (COMT) val158met polymorphism has been associated with risk for PTSD and impaired fear inhibition. We used a large, relatively homogenous population to (1) replicate previous findings of poor fear inhibition in COMT Met/Met carriers with PTSD; (2) determine if COMT association with fear inhibition is moderated by childhood trauma (CT), an environmental risk factor for PTSD; and (3) determine if COMT is associated with altered fear processes after recent exposure to combat trauma., Methods: Male Marines and Navy Corpsmen of European-American ancestry were assessed prior to (n = 714) and 4-6 months after deployment to Afghanistan (n = 452). Acquisition and extinction of fear-potentiated startle, childhood and combat trauma history, and PTSD diagnosis were assessed at both time points., Results: Before deployment, Met/Met genotype was associated with fear inhibition deficits in participants with current PTSD; however, this association was dependent on CT exposure. After deployment, combat trauma was associated with a modest reduction in fear extinction in Met/Met compared with Val/Val carriers. There were no associations of COMT genotype with fear extinction within healthy and non-traumatized individuals., Conclusions: These findings support the hypothesis that G × E interactions underlie associations of COMT val158met with fear inhibition deficits. These studies confirm that Met/Met carriers with PTSD have poor fear inhibition, and support further research in understanding how this polymorphism might impact response to extinction-based therapies., (© 2017 Wiley Periodicals, Inc.)

The wake-promoting drug modafinil is frequently used off-label to improve cognition in psychiatric and academic populations alike. The domain-specific attentional benefits of modafinil have yet to be quantified objectively in healthy human volunteers using tasks validated for comparison across species. Further, given that modafinil is a low-affinity inhibitor for the dopamine and norepinephrine transporters (DAT/NET respectively) it is unclear if any effects are attributable to a non-specific increase in arousal, a feature of many catecholamine reuptake inhibitors (e.g., cocaine, amphetamine). These experiments were designed to test for domain-specific enhancement of attention and cognitive control by modafinil (200 and 400 mg) in healthy volunteers using the 5-choice continuous performance task (5C-CPT) and Wisconsin Card Sort Task (WCST). An additional cross-species assessment of arousal and hyperactivity was performed in this group and in mice (3.2, 10, or 32 mg/kg) using species-specific versions of the behavioral pattern monitor (BPM). Modafinil significantly enhanced attention (d prime) in humans performing the 5C-CPT at doses that did not affect WCST performance or induce hyperactivity in the BPM. In mice, only the highest dose elicited increased activity in the BPM. These results indicate that modafinil produces domain-specific enhancement of attention in humans not driven by hyperarousal, unlike other drugs in this class, and higher equivalent doses were required for hyperarousal in mice. Further, these data support the utility of using the 5C-CPT across species to more precisely determine the mechanism(s) underlying the pro-cognitive effects of modafinil and potentially other pharmacological treatments., (Copyright © 2017 Elsevier Ltd. All rights reserved.)