Psychosis superspectrum II: neurobiology, treatment, and implications.

Alternatives to traditional categorical diagnoses have been proposed to improve the validity and utility of psychiatric nosology. This paper continues the companion review of an alternative model, the psychosis superspectrum of the Hierarchical Taxonomy of Psychopathology (HiTOP). The superspectrum model aims to describe psychosis-related psychopathology according to data on distributions and associations among signs and symptoms. The superspectrum includes psychoticism and detachment spectra as well as narrow subdimensions within them. Auxiliary domains of cognitive deficit and functional impairment complete the psychopathology profile. The current paper reviews evidence on this model from neurobiology, treatment response, clinical utility, and measure development. Neurobiology research suggests that psychopathology included in the superspectrum shows similar patterns of neural alterations. Treatment response often mirrors the hierarchy of the superspectrum with some treatments being efficacious for psychoticism, others for detachment, and others for a specific subdimension. Compared to traditional diagnostic systems, the quantitative nosology shows an approximately 2-fold increase in reliability, explanatory power, and prognostic accuracy. Clinicians consistently report that the quantitative nosology has more utility than traditional diagnoses, but studies of patients with frank psychosis are currently lacking. Validated measures are available to implement the superspectrum model in practice. The dimensional conceptualization of psychosis-related psychopathology has implications for research, clinical practice, and public health programs. For example, it encourages use of the cohort study design (rather than case-control), transdiagnostic treatment strategies, and selective prevention based on subclinical symptoms. These approaches are already used in the field, and the superspectrum provides further impetus and guidance for their implementation. Existing knowledge on this model is substantial, but significant gaps remain. We identify outstanding questions and propose testable hypotheses to guide further research. Overall, we predict that the more informative, reliable, and valid characterization of psychopathology offered by the superspectrum model will facilitate progress in research and clinical care.

Amphetamine increases motivation of humans and mice as measured by breakpoint, but does not affect an Electroencephalographic biomarker.

Translation of drug targets from preclinical studies to clinical trials has been aided by cross-species behavioral tasks, but evidence for brain-based engagement during task performance is still required. Cross-species progressive ratio breakpoint tasks (PRBTs) measure motivation-related behavior and are pharmacologically and clinically sensitive. We recently advanced elevated parietal alpha power as a cross-species electroencephalographic (EEG) biomarker of PRBT engagement. Given that amphetamine increases breakpoint in mice, we tested its effects on breakpoint and parietal alpha power in both humans and mice. Twenty-three healthy participants performed the PRBT with EEG after amphetamine or placebo in a double-blind design. C57BL/6J mice were trained on PRBT with EEG (n = 24) and were treated with amphetamine or vehicle. A second cohort of mice was trained on PRBT without EEG (n = 40) and was treated with amphetamine or vehicle. In humans, amphetamine increased breakpoint. In mice, during concomitant EEG, 1 mg/kg of amphetamine significantly decreased breakpoint. In cohort 2, however, 0.3 mg/kg of amphetamine increased breakpoint consistent with human findings. Increased alpha power was observed in both species as they reached breakpoint, replicating previous findings. Amphetamine did not affect alpha power in either species. Amphetamine increased effort in humans and mice. Consistent with previous reports, elevated parietal alpha power was observed in humans and mice as they performed the PRBT. Amphetamine did not affect this EEG biomarker of effort. Hence, these findings support the pharmacological predictive validity of the PRBT to measure effort in humans and mice and suggest that this EEG biomarker is not directly reflective of amphetamine-induced changes in effort.

The Impact of Cannabis Use on Cognition in People with HIV: Evidence of Function-Dependent Effects and Mechanisms from Clinical and Preclinical Studies.

PURPOSE OF REVIEW: Cannabis may have beneficial anti-inflammatory effects in people with HIV (PWH); however, given this population's high burden of persisting neurocognitive impairment (NCI), clinicians are concerned they may be particularly vulnerable to the deleterious effects of cannabis on cognition. Here, we present a systematic scoping review of clinical and preclinical studies evaluating the effects of cannabinoid exposure on cognition in HIV. RECENT FINDINGS: Results revealed little evidence to support a harmful impact of cannabis use on cognition in HIV, with few eligible preclinical data existing. Furthermore, the beneficial/harmful effects of cannabis use observed on cognition were function-dependent and confounded by several factors (e.g., age, frequency of use). Results are discussed alongside potential mechanisms of cannabis effects on cognition in HIV (e.g., anti-inflammatory), and considerations are outlined for screening PWH that may benefit from cannabis interventions. We further highlight the value of accelerating research discoveries in this area by utilizing translatable cross-species tasks to facilitate comparisons across human and animal work.

Modulation of ventromedial orbitofrontal cortical glutamatergic activity affects the explore-exploit balance and influences value-based decision-making.

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 Role of Cannabis and The Endocannabinoid System in Sleep Regulation and Cognition: A Review of Human and Animal Studies.

OBJECTIVES: Both sleep and cognition are partially modulated by the endocannabinoid (ECB) system. Cannabis has been reported to have effects on sleep and cognition. This review aims to summarize the recent literature on the ECB system, the role of cannabis and the ECB system on sleep regulation and cognition. Further, this review will identify existing gaps in knowledge and suggest potential targets for future research. METHODS: We performed this review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Reports were identified by searching PubMed/MEDLINE, Embase, CINAHL, Web of Science, and PsycINFO for articles published through September 2021 for studies with data available on aspects of cognition, cannabis, or the ECB system, and sleep or circadian rhythms (CRs). RESULTS: We identified 6 human and 6 animal studies to be eligible for inclusion in this review. Several human studies found that cannabis use is not associated with changes in sleep quality or cognitive function. However, individual cannabinoids appeared to have independent effects on cognition and sleep; THC alone decreased cognitive performance and increased daytime sleepiness, whereas CBD alone had no effect on sleep or cognition. Animal studies demonstrated that manipulation of the ECB system altered activity and cognitive function, some of which appeared to be dependent on the light/dark cycle. CONCLUSION: The sleep-wake cycle and CRs are both likely modulated by the ECB system, potentially resulting in effects on cognition, however this area is critically understudied.

A Pilot Assessment of the Effects of HIV and Methamphetamine Dependence on Socially Dysregulated Behavior in the Human Behavioral Pattern Monitor.

Deficits in social cognition are seen in both people living with HIV (PWH) and people with a history of methamphetamine (METH) dependence. Dually affected individuals may experience additive negative effects on social cognition due to these conditions. We evaluated social cognition in 4 diagnostic groups (HIV-/METH-, HIV-/METH+, HIV+/METH-, HIV+/METH+). First, we used traditional social-emotional functioning assessments, the Difficulties in Emotion Regulation Scale and the Faux Pas Task, to determine any significant effects of METH dependence and HIV on social cognition. Next, we quantified social cognition using the Human Behavioral Pattern Monitor by evaluating social behavior represented by interaction with novel objects. METH dependence significantly affected social-emotional functions and HIV significantly affected on object interactions, however no significant additive effects were observed using these methods. The nuanced relationship between HIV and METH dependence suggests that other factors (i.e., adaptive life skills) likely mediate social cognition-related behaviors.

RESUMEN: Los déficits en la cognición social se observan tanto en las personas que viven con el VIH (PWH) como en las personas con antecedentes de dependencia de la metanfetamina (METH). Las personas con ambas condiciones pueden experimentar efectos negativos aditivos en la cognición social. Evaluamos la cognición social en 4 grupos de diagnóstico (VIH−/METH−, VIH−/METH+, VIH+/METH−, VIH+/METH+). En primer lugar, utilizamos evaluaciones tradicionales del funcionamiento socioemocional, la Escala de Dificultades en la Regulación Emocional y la Prueba de Faux Pas, para determinar efecto significativo debido a la dependencia de METH y el VIH en la cognición social. Entonces, cuantificamos la cognición social utilizando el Monitor de Patrones de comportamiento humano mediante la evaluación del comportamiento social representado por la interacción con objetos novedosos. La dependencia de METH afectó significativamente las funciones socioemocionales y el VIH afectó significativamente las interacciones con los objetos, sin embargo, no se observaron efectos aditivos significativos al usar estos métodos. La relación compleja entre el VIH y la dependencia de METH sugiere que otros factores (i.e., habilidades adaptativas) probablemente regulan los comportamientos relacionados con la cognición social.

Daily mood and cognitive performance of women with and without bipolar disorder: role of menopausal status.

We examined the role of menopausal status in daily mood and cognitive performance among women with bipolar disorder (BD) compared to healthy comparison women. We analyzed the association of menopausal status, bipolar diagnosis, and their interaction on daily mood assessed by mobile surveys and attentional performance measured multiple times over 2 weeks. Menopausal status was associated with more daily negative affect in women with BD, but not related to attentional performance.

HIV Transgenic Rats Demonstrate Superior Task Acquisition and Intact Reversal Learning in the Within-Session Probabilistic Reversal Learning Task.

The HIV transgenic (HIVtg) rat is a commonly used animal model of chronic HIV infection that exhibits a wide range of cognitive deficits. To date, relatively little work has been conducted on these rats' capacity for reversal learning, an assay of executive function and cognitive flexibility used in humans. The present study sought to determine the impact of HIV genotype on probabilistic reversal learning, effortful motivation, and spontaneous locomotion/exploration in rats. Male (n = 8) and female (n = 8) HIVtg rats and wildtype (WT) controls were utilized. Cognitive flexibility was assessed via the Probabilistic Reversal Learning Task (PRLT), which reinforced responses to two stimuli on differential probabilistic schedules that periodically reversed. Effortful motivation and locomotor/exploratory behavior were assessed via the Progressive Ratio Breakpoint Task (PRBT) and the Behavioral Pattern Monitor (BPM), respectively. Regardless of sex, HIVtg rats required fewer trials to ascertain initial PRLT reward schedules than WT rats, and completed the same number of reversals. Secondary behaviors suggested that HIVtg PRLT performance was facilitated by a speed-accuracy tradeoff strategy. No main or interactive effects of genotype were observed in the PRBT or BPM. Relative to WT controls, HIVtg rats exhibited superior probabilistic reinforcement learning. Reversal learning was unaffected by HIV genotype, as was effortful motivation and exploratory behavior. These findings contrast with previous characterizations of the HIVtg rat, thus indicating a nuanced cognitive profile that is dependent upon such task specifications as within- versus between-session assessment and probabilistic versus deterministic reward schedules.

HIV Transgenic Rats Demonstrate Impaired Sensorimotor Gating But Are Insensitive to Cannabinoid (Δ9-Tetrahydrocannabinol)-Induced Deficits.

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.

Converging evidence that short-active photoperiod increases acetylcholine signaling in the hippocampus.

Seasonal variations in environmental light influence switches between moods in seasonal affective disorder (SAD) and bipolar disorder (BD), with depression arising during short active (SA) winter periods. Light-induced changes in behavior are also seen in healthy animals and are intensified in mice with reduced dopamine transporter expression. Specifically, decreasing the nocturnal active period (SA) of mice increases punishment perseveration and forced swim test (FST) immobility. Elevating acetylcholine with the acetylcholinesterase inhibitor physostigmine induces depression symptoms in people and increases FST immobility in mice. We used SA photoperiods and physostigmine to elevate acetylcholine prior to testing in a probabilistic learning task and the FST, including reversing subsequent deficits with nicotinic and scopolamine antagonists and targeted hippocampal adeno-associated viral administration. We confirmed that physostigmine also increases punishment sensitivity in a probabilistic learning paradigm. In addition, muscarinic and nicotinic receptor blockade attenuated both physostigmine-induced and SA-induced phenotypes. Finally, viral-mediated hippocampal expression of human AChE used to lower ACh levels blocked SA-induced elevation of FST immobility. These results indicate that increased hippocampal acetylcholine neurotransmission is necessary for the expression of SA exposure-induced behaviors. Furthermore, these studies support the potential for cholinergic treatments in depression. Taken together, these results provide evidence for hippocampal cholinergic mechanisms in contributing to seasonally depressed affective states induced by short day lengths.

The D2-family receptor agonist bromocriptine but, not nicotine, reverses NMDA receptor antagonist-induced working memory deficits in the radial arm maze in mice.

Hypofunction of the NMDA receptor (NMDAr) may underlie cognitive deficits associated with schizophrenia and other psychiatric conditions including working memory (WM) impairments. Given that these deficits link closely to functional outcome, treatments remediating such deficits require identification. NMDAr hypofunction can be modeled via treatment with the antagonist MK-801. Hence, the present study determined whether cholinergic or dopaminergic agonists attenuate MK-801-induced WM deficits in mice. WM was assessed in male C57BL/6 mice trained on an automated 12-arm radial arm maze (RAM) paradigm, wherein rewards were delivered after the first but, not after subsequent entries into WM arms (8/12) and never delivered for entries into reference memory (RM) arms (4/12). Mice were then treated with MK-801 (vehicle or 0.3 mg/kg) and nicotine (vehicle, 0.03 or 0.30 mg/kg) in a cross-over design. After a 2-week washout, mice were then retested with MK-801 and the dopamine D2-family receptor agonist bromocriptine (vehicle, 3 or 10 mg/kg). In both experiments, MK-801 reduced WM span and increased RM and WM error rates. Nicotine did not attenuate these deficits. In contrast, a bromocriptine/MK-801 interaction was observed on WM error rate, where bromocriptine attenuated MK-801 induced deficits without affecting MK-801-induced RM errors. Additionally, bromocriptine produced the main effect of slowing latency to collect rewards. Hence, while NMDAr hypofunction-induced deficits in WM was unaffected by nicotine, it was remediated by treatment with the dopamine D2-family agonist bromocriptine. Future studies should determine whether selective activation of dopamine D2, D3, or D4 receptors remediate this NMDAr hypofunction-induced WM deficit.

Convergent neural substrates of inattention in bipolar disorder patients and dopamine transporter-deficient mice using the 5-choice CPT.

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.

Transgenic mice expressing HIV-1 envelope protein gp120 in the brain as an animal model in neuroAIDS research.

HIV-1 infection causes injury to the central nervous system (CNS) and is often associated with neurocognitive disorders. One model for brain damage seen in AIDS patients is the transgenic (tg) mouse expressing a soluble envelope protein gp120 of HIV-1 LAV in the brain in astrocytes under the control of the promoter of glial fibrillary acidic protein. These GFAP-gp120tg mice manifest several key neuropathological features observed in AIDS brains, such as decreased synaptic and dendritic density, increased numbers of activated microglia, and pronounced astrocytosis. Several recent studies show that brains of GFAP-gp120tg mice and neurocognitively impaired HIV patients share also a significant number of differentially regulated genes, activation of innate immunity and other cellular signaling pathways, disturbed neurogenesis, and learning deficits. These findings support the continued relevance of the GFAP-gp120tg mouse as a useful model to investigate neurodegenerative mechanisms and develop therapeutic strategies to mitigate the consequences associated with HIV infection of the CNS, neuroAIDS, and HAND.

Amphetamine Modestly Improves Conners' Continuous Performance Test Performance in Healthy Adults.

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).

Tolcapone-Enhanced Neurocognition in Healthy Adults: Neural Basis and Predictors.

Background: Failure of procognitive drug trials in schizophrenia may reflect the clinical heterogeneity of schizophrenia, underscoring the need to identify biomarkers of treatment sensitivity. We used an experimental medicine design to test the procognitive effects of a putative procognitive agent, tolcapone, using an electroencephalogram-based cognitive control task in healthy subjects. Methods: Healthy men and women (n=27; ages 18-35 years), homozygous for either the Met/Met or Val/Val rs4680 genotype, received placebo and tolcapone 200 mg orally across 2 test days separated by 1 week in a double-blind, randomized, counterbalanced, within-subject design. On each test day, neurocognitive performance was assessed using the MATRICS Consensus Cognitive Battery and an electroencephalogram-based 5 Choice-Continuous Performance Test. Results: Tolcapone enhanced visual learning in low-baseline MATRICS Consensus Cognitive Battery performers (d=0.35) and had an opposite effect in high performers (d=0.5), and enhanced verbal fluency across all subjects (P=.03) but had no effect on overall MATRICS Consensus Cognitive Battery performance. Tolcapone reduced false alarm rate (d=0.8) and enhanced frontal P200 amplitude during correctly identified nontarget trials (d=0.6) in low-baseline 5 Choice-Continuous Performance Test performers and had opposite effects in high performers (d=0.5 and d=0.25, respectively). Tolcapone's effect on frontal P200 amplitude and false alarm rate was correlated (rs=-0.4, P=.05). All neurocognitive effects of tolcapone were independent of rs4680 genotype. Conclusion: Tolcapone enhanced neurocognition and engaged electroencephalogram measures relevant to cognitive processes in specific subgroups of healthy individuals. These findings support an experimental medicine model for identifying procognitive treatments and provide a strong basis for future biomarker-informed procognitive studies in schizophrenia patients.

Inhibition of protein translation by the DISC1-Boymaw fusion gene from a Scottish family with major psychiatric disorders.

The t(1; 11) translocation appears to be the causal genetic lesion with 70% penetrance for schizophrenia, major depression and other psychiatric disorders in a Scottish family. Molecular studies identified the disruption of the disrupted-in-schizophrenia 1 (DISC1) gene by chromosome translocation at chromosome 1q42. Our previous studies, however, revealed that the translocation also disrupted another gene, Boymaw (also termed DISC1FP1), on chromosome 11. After translocation, two fusion genes [the DISC1-Boymaw (DB7) and the Boymaw-DISC1 (BD13)] are generated between the DISC1 and Boymaw genes. In the present study, we report that expression of the DB7 fusion gene inhibits both intracellular NADH oxidoreductase activities and protein translation. We generated humanized DISC1-Boymaw mice with gene targeting to examine the in vivo functions of the fusion genes. Consistent with the in vitro studies on the DB7 fusion gene, protein translation activity is decreased in the hippocampus and in cultured primary neurons from the brains of the humanized mice. Expression of Gad67, Nmdar1 and Psd95 proteins are also reduced. The humanized mice display prolonged and increased responses to the NMDA receptor antagonist, ketamine, on various mouse genetic backgrounds. Abnormal information processing of acoustic startle and depressive-like behaviors are also observed. In addition, the humanized mice display abnormal erythropoiesis, which was reported to associate with depression in humans. Expression of the DB7 fusion gene may reduce protein translation to impair brain functions and thereby contribute to the pathogenesis of major psychiatric disorders.

Early Adolescent Emergence of Reversal Learning Impairments in Isolation-Reared Rats.

Cognitive impairments appear early in the progression of schizophrenia, often preceding the symptoms of psychosis. Thus, the systems subserving these functions may be more vulnerable to, and mechanistically linked with, the initial pathology. Understanding the trajectory of behavioral and anatomical abnormalities relevant to the schizophrenia prodrome and their sensitivity to interventions in relevant models will be critical to identifying early therapeutic strategies. Isolation rearing of rats is an environmental perturbation that deprives rodents of social contact from weaning through adulthood and produces behavioral and neuronal abnormalities that mirror some pathophysiology associated with schizophrenia, e.g. frontal cortex abnormalities and prepulse inhibition (PPI) of startle deficits. Previously, we showed that PPI deficits in isolation-reared rats emerge in mid-adolescence (4 weeks after weaning; approx. postnatal day 52) but are not present when tested at 2 weeks after weaning (approx. postnatal day 38). Because cognitive deficits are reported during early adolescence, are relevant to the prodrome, and are linked to functional outcome, we examined the putative time course of reversal learning deficits in isolation-reared rats. Separate groups of male Sprague Dawley rats were tested in a two-choice discrimination task at 2 and 8 weeks after weaning, on postnatal day 38 and 80, respectively. The isolation-reared rats displayed impaired reversal learning at both time points. Isolation rearing was also associated with deficits in PPI at 4 and 10 weeks after weaning. The reversal learning deficits in the isolated rats were accompanied by reductions in parvalbumin immunoreactivity, a marker for specific subpopulations of GABAergic neurons, in the hippocampus. Hence, isolation rearing of rats may offer a unique model to examine the ontogeny of behavioral and neurobiological alterations that may be relevant to preclinical models of prodromal psychosis. © 2015 S. Karger AG, Basel.

Negative visuospatial priming in isolation-reared rats: Evidence of resistance to the disruptive effects of amphetamine.

Negative visuospatial priming (NP) represents a quantifiable measure of inhibitory information processing that is disrupted in several neurodevelopmental and psychiatric disorders, including schizophrenia. We developed a novel rodent NP task to investigate mechanisms underlying NP and its role in various disorders, and to test potential therapeutics. In the present studies, we further characterized this novel paradigm by investigating whether NP is disrupted in rats reared in isolation, a developmental manipulation that produces a range of abnormalities in behavior, neurochemistry, and brain structure that mirror aspects of schizophrenia pathology. We also further explored the role of monoaminergic signaling in NP and the effects of isolation rearing by challenging both socially reared and isolation-reared rats with D-amphetamine during the NP task. Although fewer isolation-reared animals learned the complex NP task, those that learned exhibited unaffected NP compared with socially reared rats. Consistent with previous reports, D-amphetamine impaired NP and increased motor impulsivity in socially reared rats. In contrast, D-amphetamine did not affect NP or motor impulsivity in isolation-reared rats. These data confirm a monoaminergic influence on NP behavior and indicate that rats reared in isolation have altered dopaminergic sensitivity.

Restoration of Sp4 in Forebrain GABAergic Neurons Rescues Hypersensitivity to Ketamine in Sp4 Hypomorphic Mice.

BACKGROUND: Ketamine produces schizophrenia-like behavioral phenotypes in healthy people. Prolonged ketamine effects and exacerbation of symptoms after the administration of ketamine have been observed in patients with schizophrenia. More recently, ketamine has been used as a potent antidepressant to treat patients with major depression. The genes and neurons that regulate behavioral responses to ketamine, however, remain poorly understood. Sp4 is a transcription factor for which gene expression is restricted to neuronal cells in the brain. Our previous studies demonstrated that Sp4 hypomorphic mice display several behavioral phenotypes relevant to psychiatric disorders, consistent with human SP4 gene associations with schizophrenia, bipolar disorder, and major depression. Among those behavioral phenotypes, hypersensitivity to ketamine-induced hyperlocomotion has been observed in Sp4 hypomorphic mice. METHODS: In the present study, we used the Cre-LoxP system to restore Sp4 gene expression, specifically in either forebrain excitatory or GABAergic inhibitory neurons in Sp4 hypomorphic mice. Mouse behavioral phenotypes related to psychiatric disorders were examined in these distinct rescue mice. RESULTS: Restoration of Sp4 in forebrain excitatory neurons did not rescue deficient sensorimotor gating nor ketamine-induced hyperlocomotion. Restoration of Sp4 in forebrain GABAergic neurons, however, rescued ketamine-induced hyperlocomotion, but did not rescue deficient sensorimotor gating. CONCLUSIONS: Our studies suggest that the Sp4 gene in forebrain GABAergic neurons regulates ketamine-induced hyperlocomotion.