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Schizophrenia (SCZ) is a complex neuropsychiatric disorder characterized by positive, negative, and cognitive symptoms. The neurodevelopmental methylazoxy-methanol acetate (MAM) rodent model replicates key neurobiological features of SCZ which includes hyperdopaminergic states in the ventral tegmental area (VTA) and cognitive deficits. Typical and atypical antipsychotics are primarily effective in treating the positive symptoms of SCZ but often fall short of addressing cognitive deficits. A promising therapeutic approach for treating all symptoms of SCZ has emerged through the inhibition of phosphodiesterase 10 A (PDE10A). Our study aim was to investigate the impact of acute and chronic THPP-1 (PDE10A inhibitor) treatment, in MAM rats, focusing on cognitive deficits and VTA dopamine (DA) activity. Adult offspring of pregnant rats treated with Saline or MAM (20 mg/kg) on gestational day 17 were treated with THPP-1 acutely (male/female rats; 3 mg/kg) at postnatal day (PD) 70-80 or chronically (males; 3 weeks; 2-3 mg/kg) from PD 70-91 and tested in the novel object recognition test and electrophysiological recording of DA neurons in the VTA. Acute THPP-1 treatment reversed cognitive impairments and normalized the increased number of active DA neurons in the VTA of male and female MAM rats, without affecting control rats. Also, chronic THPP-1 treatment reversed cognitive deficits and normalized DA hyperactivity in the VTA of male MAM rats. The efficacy of THPP-1 in reversing MAM-induced impairments underscores its ability to target disease-specific circuitry without affecting normal regulated systems in control rats. Our findings highlight the therapeutic potential of THPP-1 for addressing cognitive deficits and DA dysregulation in SCZ., Competing Interests: Declaration of competing interest Daniela L. Uliana and Angela Martinez have nothing to disclose. Anthony A. Grace has received consulting fees from Alkermes, Lundbeck, Takeda, Roche, and Lyra and Concert and research funding from Lundbeck, Newron, and Merck., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Maternal infection and stress exposure, especially during childhood and adolescence, have been implicated as risk factors for schizophrenia. Both insults induce an exacerbated inflammatory response, which could mediate disturbance of neurodevelopmental processes and, ultimately, malfunctioning of neural systems observed in this disorder. Thus, anti-inflammatory drugs, such as PPARγ agonists, may potentially be used to prevent the development of schizophrenia. Microglia culture was prepared from the offspring of saline or poly(I:C)-injected mice. The cells were pretreated with pioglitazone and then, stimulated by LPS. Proinflammatory mediators and phagocytic activity were measured. Also, pregnant rats were injected with saline or poly(I:C) on GD17. The offspring were subjected to footshock during adolescence and subsequently injected with pioglitazone or vehicle. At adulthood, behavior and dopaminergic activity were evaluated. Pioglitazone reduced proinflammatory mediators induced by poly(I:C) microglia stimulated by LPS without affecting their decreased phagocytic activity. The PPARγ agonist also prevented the emergence of social and cognitive impairments, as well as attenuated the increased number of spontaneously active dopamine neurons in the VTA, observed in both males and females from poly(I:C) and stress group. Therefore, pioglitazone could potentially prevent the emergence of the schizophrenia-like alterations induced by the two-hit model via reduction of microglial activation., Competing Interests: Declaration of competing interest AAG received funds from Merck, Newron, Alkermes, Lundbeck, Takeda, Roche, Lyra, Concert, and SynAgile. All other authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Post-Traumatic Stress Disorder (PTSD) is a debilitating psychiatric disorder that arises following exposure to an extreme stress. PTSD is characterized by five primary trauma-related symptom clusters, including symptoms of negative mood and hyperresponsivity to the traumatic event. Regrettably, the current therapy options are not highly effective. Therefore, prevention of PTSD is crucial and potentially applicable. Prazosin is an anti-adrenergic medication that is used to reduce nightmares in patient with PTSD, and can also mitigate the noradrenergic dysfunction caused by trauma. Here we show that administration of prazosin prior to the trauma prevented learned helplessness behavior in adult male rats. We show that the animals that were exposed to three days of inescapable foot shocks preceded by prazosin injections have fewer prazosin-treated animals showing learned helplessness compared to saline-treated animals. Nevertheless, there was no significant difference in anxiety-related behavior as measured in the elevated plus maze. Furthermore, the results of in vivo electrophysiological recordings of the ventral tegmental area shows that the prazosin group has a trend of increased number of active dopaminergic cells per track; this is significant when limited to central region of the ventral tegmental area. Our results demonstrate that prazosin has a potential for prevention of PTSD., Competing Interests: Declaration of competing interest A.A.G. received funds from following organizations: Merck, Newron, Alkermes, Lundbeck, Takeda, Roche, Lyra, Concert, and SynAgile. M.K. reports no conflicts of interest, (Copyright © 2024. Published by Elsevier B.V.)

The intricate balance between excitation and inhibition (E/I) in the brain plays a crucial role in normative information processing. Dysfunctions in the E/I balance have been implicated in various psychiatric disorders, including schizophrenia (SCZ). In particular, abnormalities in GABAergic signaling, specifically in parvalbumin (PV)-containing interneurons, have been consistently observed in SCZ pathophysiology. PV interneuron function is vital for maintaining an ideal E/I balance, and alterations in PV interneuron-mediated inhibition contribute to circuit deficits observed in SCZ, including hippocampus hyperactivity and midbrain dopamine system overdrive. While current antipsychotic medications primarily target D2 dopamine receptors and are effective primarily in treating positive symptoms, novel therapeutic strategies aiming to restore the E/I balance could potentially mitigate not only positive symptoms but also negative symptoms and cognitive deficits. This could involve, for instance, increasing the inhibitory drive onto excitatory neurons or decreasing the putative enhanced pyramidal neuron activity due to functional loss of PV interneurons. Compounds targeting the glycine site at glutamate NMDA receptors and muscarinic acetylcholine receptors on PV interneurons that can increase PV interneuron drive, as well as drugs that increase the postsynaptic action of GABA, such as positive allosteric modulators of α5-GABA-A receptors, and decrease glutamatergic output, such as mGluR2/3 agonists, represent promising approaches. Preventive strategies aiming at E/I balance also represent a path to reduce the risk of transitioning to SCZ in high-risk individuals. Therefore, compounds with novel mechanisms targeting E/I balance provide optimism for more effective and tailored interventions in the management of SCZ., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Daniela L. Uliana, Joao Roberto F. Lisboa and Felipe V. Gomes: no interest to disclosure. Anthony A. Grace has received consulting fees from Alkermes, Lundbeck, Takeda, Roche, and Lyra and Concert and research funding from Lundbeck, Newron, and Merck., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The ventral pallidum (VP) receives its primary inputs from the nucleus accumbens (NAC) and the basolateral amygdala (BLA). We demonstrated recently that in the VP, the D2 DA receptor (D 2 R) agonist quinpirole dose-dependently facilitates memory consolidation in inhibitory avoidance and spatial learning. In the VP, D 2 R can be found both on NAC and BLA terminals. According to our hypothesis, quinpirole microinjected into the VP can facilitate memory consolidation via modulation of synaptic plasticity on NAC and/or BLA terminals. The effect of intra-VP quinpirole on BLA-VP and NAC shell-VP synapses was investigated via a high frequency stimulation (HFS) protocol. Quinpirole was administered in three doses into the VP of male Sprague-Dawley rats after HFS; controls received vehicle. To examine whether an interaction between the NAC shell and the BLA at the level of the VP was involved, tetrodotoxin (TTX) was microinjected into one of the nuclei while stimulating the other nucleus. Our results showed that quinpirole dose-dependently modulates BLA-VP and NAC shell-VP synapses, similar to those observed in inhibitory avoidance and spatial learning, respectively. The lower dose inhibits BLA inputs, while the larger doses facilitates NAC shell inputs. The experiments with TTX demonstrates that the two nuclei do not influence each others' evoked responses in the VP. Power spectral density analysis demonstrated that independent from the synaptic facilitation, intra-VP quinpirole increases the amplitude of gamma frequency band after NAC HFS, and BLA tonically suppresses the NAC's HFS-induced gamma facilitation. In contrast, HFS of the BLA results in a delayed, transient increase in the amplitude of the gamma frequency band correlating with the LTP of the P1 component of the VP response to BLA stimulation. Furthermore, our results demonstrate that the BLA plays a prominent role in the generation of the delta oscillations: HFS of the BLA leads to a gradually increasing delta frequency band facilitation over time, while BLA inhibition blocks the NAC's HFS induced strong delta facilitation. These findings demonstrate that there is a complex interaction between the NAC shell region and the VP, as well as the BLA and the VP, and support the important role of VP D 2 Rs in the regulation of limbic information flow., Competing Interests: Declaration of competing interest Anthony A. Grace has received funds from Lundbeck, Pfizer, Lilly, Roche, Janssen, Alkermes, Newron, Takeda and Merck. The other author declares no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The widespread problem of burnout among healthcare workers is not only common but also a significant concern that impacts the entire healthcare system in Uganda. It is essential to understand the connection between burnout and quality of life among healthcare workers in the specific context of central Uganda, where healthcare professionals face high patient volumes, limited resources, exposure to infectious diseases, and socioeconomic challenges. This study examined the relationship between burnout and quality of life among healthcare workers in central Uganda., Methods: This research utilized a cross-sectional study conducted across various healthcare settings in central Uganda. The data were analyzed at descriptive, bivariate, and multivariate levels. The relationship between dependent and independent variables was evaluated using an independent t-test for binary variables and a one-way analysis of variance (ANOVA) for categorical variables. Significance was determined with a reported p-value, with relationships deemed significant at p < 0.2. For multivariable analysis, multiple linear regression was employed using a forward selection method, with significance set at 5% (p < 0.05)., Results: Our findings indicate that nearly 40% of healthcare workers reported experiencing high levels of burnout. The average score for overall quality of life was 10.71 (±4.89), with variations observed across different domains. The study reveals a significant connection between socio-demographic factors, burnout, and overall quality of life, emphasizing the impact of job category, supervisory support, sleep quality, and burnout on the well-being of healthcare workers. Predictive analysis illustrates how these factors influence both overall quality of life scores and scores in specific domains. Particularly noteworthy is that nurses and technicians tend to have a lower quality of life compared to physicians., Conclusion: The results underscore the relationship between socio-demographic factors, burnout, and particular aspects of quality of life. Notably, job category, supervisory support, sleep quality, and burnout stand out as significant factors shaping the well-being of healthcare workers. Nurses and technicians encounter distinct challenges, suggesting the need for interventions tailored to their needs. Addressing issues such as inadequate supervisory support, burnout, and sleep-related problems is recognized as a potential approach to improving the overall quality of life among healthcare workers., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kabunga et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Elevated hippocampal perfusion has been observed in people at clinical high risk for psychosis (CHR-P). Preclinical evidence suggests that hippocampal hyperactivity is central to the pathophysiology of psychosis, and that peripubertal treatment with diazepam can prevent the development of psychosis-relevant phenotypes. The present experimental medicine study examined whether diazepam can normalize hippocampal perfusion in CHR-P individuals. Using a randomized, double-blind, placebo-controlled, crossover design, 24 CHR-P individuals were assessed with magnetic resonance imaging (MRI) on two occasions, once following a single oral dose of diazepam (5 mg) and once following placebo. Regional cerebral blood flow (rCBF) was measured using 3D pseudo-continuous arterial spin labeling and sampled in native space using participant-specific hippocampus and subfield masks (CA1, subiculum, CA4/dentate gyrus). Twenty-two healthy controls (HC) were scanned using the same MRI acquisition sequence, but without administration of diazepam or placebo. Mixed-design ANCOVAs and linear mixed-effects models were used to examine the effects of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on rCBF in the hippocampus as a whole and by subfield. Under the placebo condition, CHR-P individuals (mean [±SD] age: 24.1 [±4.8] years, 15 F) showed significantly elevated rCBF compared to HC (mean [±SD] age: 26.5 [±5.1] years, 11 F) in the hippocampus (F(1,41) = 24.7, p FDR  < 0.001) and across its subfields (all p FDR  < 0.001). Following diazepam, rCBF in the hippocampus (and subfields, all p FDR  < 0.001) was significantly reduced (t(69) = -5.1, p FDR  < 0.001) and normalized to HC levels (F(1,41) = 0.4, p FDR  = 0.204). In conclusion, diazepam normalized hippocampal hyperperfusion in CHR-P individuals, consistent with evidence implicating medial temporal GABAergic dysfunction in increased vulnerability for psychosis., (© 2024. The Author(s).)

Background: Psychiatric disorders often emerge during late adolescence/early adulthood, a period with increased susceptibility to socioenvironmental factors that coincides with incomplete parvalbumin interneuron (PVI) development. Stress during this period causes functional loss of PVIs in the ventral hippocampus (vHip), which has been associated with dopamine system overdrive. This vulnerability persists until the appearance of perineuronal nets (PNNs) around PVIs. We assessed the long-lasting effects of adolescent or adult stress on behavior, ventral tegmental area dopamine neuron activity, and the number of PVIs and their associated PNNs in the vHip. Additionally, we tested whether PNN removal in the vHip of adult rats, proposed to reset PVIs to a juvenile-like state, would recreate an adolescent-like phenotype of stress susceptibility., Methods: Male rats underwent a 10-day stress protocol during adolescence or adulthood. Three to 4 weeks poststress, we evaluated behaviors related to anxiety, sociability, and cognition, ventral tegmental area dopamine neuron activity, and the number of PV + and PNN + cells in the vHip. Furthermore, adult animals received intra-vHip infusion of ChABC (chondroitinase ABC) to degrade PNNs before undergoing stress., Results: Unlike adult stress, adolescent stress induced anxiety responses, reduced sociability, cognitive deficits, ventral tegmental area dopamine system overdrive, and decreased PV + and PNN + cells in the vHip. However, intra-vHip ChABC infusion caused the adult stress to produce changes similar to the ones observed after adolescent stress., Conclusions: Our findings underscore adolescence as a period of heightened vulnerability to the long-lasting impact of stress and highlight the protective role of PNNs against stress-induced damage in PVIs., (© 2024 The Authors.)

Background: The escalating global prevalence of burnout among healthcare professionals poses a serious health concern. Recent studies focus on prevalence and predictors of burnout among healthcare providers, emphasizing the need for well-being interventions. This study investigates burnout and coping mechanisms among healthcare professionals in central Uganda, addressing the dearth of knowledge about coping strategies specific to the region., Methods: An analytical facility cross-sectional study was conducted in five healthcare facilities in central Uganda between June to July 2023. Participants included physicians, nurses, and technicians actively engaged in direct patient care. Data were collected using socio-demographic surveys, the Professional Quality of Life (ProQOL-5), and the Brief-COPE tools., Results: The study revealed a high prevalence of burnout, with 39.8% of participants experiencing significant levels. Active coping, positive reframing, and denial were negatively correlated with low burnout levels. Dysfunctional coping, specifically self-distraction and denial, showed positive correlations with average and high burnout levels. Emotion-focused coping mechanisms were not employed across burnout levels., Conclusions: The results emphasize the demanding nature of healthcare roles in the region and highlight the need for comprehensive, context-specific interventions to address burnout globally. While some healthcare professionals utilized adaptive strategies such as seeking social support, engaging in self-care activities, and utilizing problem-solving skills, others resorted to maladaptive coping mechanisms such as substance use and avoidance behaviors. This dichotomy highlights the need for targeted interventions to promote adaptive coping strategies and mitigate the negative impact of maladaptive behaviors on individual well-being and patient care., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kabunga, Kigongo, Okalo, Udho, Grace, Tumwesigye, Akello, Musinguzi, Acup, Nabaziwa, Shikanga and Namata.)

Background and Hypothesis: Animal models indicate GABAergic dysfunction in the development of psychosis, and that benzodiazepine (BDZ) exposure can prevent the emergence of psychosis-relevant phenotypes. However, whether BDZ exposure influences real-world clinical outcomes in individuals at clinical high risk for psychosis (CHR-P) is unknown., Study Design: This observational cohort study used electronic health record data from CHR-P individuals to investigate whether BDZ exposure (including hypnotics, eg, zopiclone) reduces the risk of developing psychosis and adverse clinical outcomes. Cox proportional-hazards models were employed in both the whole-unmatched sample, and a propensity score matched (PSM) subsample., Study Results: 567 CHR-P individuals (306 male, mean[±SD] age = 22.3[±4.9] years) were included after data cleaning. The BDZ-exposed (n = 105) and BDZ-unexposed (n = 462) groups differed on several demographic and clinical characteristics, including psychotic symptom severity. In the whole-unmatched sample, BDZ exposure was associated with increased risk of transition to psychosis (HR = 1.61; 95% CI: 1.03-2.52; P = .037), psychiatric hospital admission (HR = 1.93; 95% CI: 1.13-3.29; P = .017), home visit (HR = 1.64; 95% CI: 1.18-2.28; P = .004), and Accident and Emergency department attendance (HR = 1.88; 95% CI: 1.31-2.72; P < .001). However, after controlling for confounding-by-indication through PSM, BDZ exposure did not modulate the risk of any outcomes (all P > .05). In an analysis restricted to antipsychotic-naïve individuals, BDZ exposure reduced the risk of transition to psychosis numerically, although this was not statistically significant (HR = 0.59; 95% CI: 0.32-1.08; P = .089)., Conclusions: BDZ exposure in CHR-P individuals was not associated with a reduction in the risk of psychosis transition or adverse clinical outcomes. Results in the whole-unmatched sample suggest BDZ prescription may be more likely in CHR-P individuals with higher symptom severity., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Schizophrenia is a neurodevelopmental psychiatric disorder that often emerges in adolescence, is characterized by social dysfunction, and has an earlier onset in men. These features have been replicated in rats exposed to the mitotoxin methylazoxymethanol acetate (MAM) on gestational day (GD) 17, which as adults exhibit behavioral impairments and dopamine (DA) system changes consistent with a schizophrenia-relevant rodent model. In humans, social withdrawal is a negative symptom that often precedes disease onset and DA system dysfunction and is more pronounced in men. Children and adolescents at high-risk for schizophrenia exhibit social deficits prior to psychotic symptoms (i.e., prodromal phase), which can be used as a predictive marker for future psychopathology. Adult MAM rats also exhibit deficient social interaction, but less is known regarding the emergence of social dysfunction in this model, whether it varies by sex, and whether it is linked to disrupted DA function. To this end, we characterized the ontogeny of social and DA dysfunction in male and female MAM rats during the prepubertal period (postnatal days 33-43) and found sex-specific changes in motivated social behaviors (play, approach) and DA function. Male MAM rats exhibited reduced social approach and increased VTA DA neuron activity compared to saline-treated (SAL) males, whereas female MAM rats exhibited enhanced play behaviors compared to SAL females but no changes in social approach or VTA population activity during this period. These findings demonstrate sex differences in the emergence of social and DA deficits in the MAM model, in which females exhibit delayed emergence., Competing Interests: Declaration of competing interest MRC has no competing financial interests. AAG received funds from the following organizations: Newron, Merck, SynAgile, Alkermes, Lundbeck, Takeda, Roche, and Lyra., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Therapeutic intervention for schizophrenia relies on blockade of dopamine D2 receptors in the associative striatum; however, there is little evidence for baseline overdrive of the dopamine system. Instead, the dopamine system is in a hyper-responsive state due to excessive drive by the hippocampus. This causes more dopamine neurons to be in a spontaneously active, hyper-responsive state. Antipsychotic drugs alleviate this by causing depolarization block, or excessive depolarization-induced dopamine neuron inactivation. Indeed, both first- and second-generation antipsychotic drugs cause depolarization block in the ventral tegmentum to relieve positive symptoms, whereas first-generation drugs also cause depolarization in the nigrostriatal dopamine system to lead to extrapyramidal side effects. However, by blocking dopamine receptors, these drugs are activating multiple synapses downstream from the proposed site of pathology: the loss of inhibitory influence over the hippocampus. An overactive hippocampus not only drives the dopamine-dependent positive symptoms, but via its projections to the amygdala and the neocortex can also drive negative and cognitive symptoms, respectively. On this basis, a novel class of drugs that can reverse schizophrenia at the site of pathology, i.e., the hippocampal overdrive, could be effective in alleviating all three classes of symptoms of schizophrenia while also being better tolerated.

Background: The medial prefrontal cortex (mPFC) is necessary for cognitive flexibility and projects to medial septum (MS). MS activation improves strategy switching, a common measure of cognitive flexibility, likely via its ability to regulate midbrain dopamine (DA) neuron population activity. We hypothesized that the mPFC to MS pathway (mPFC-MS) may be the mechanism by which the MS regulates strategy switching and DA neuron population activity., Methods: Male and female rats learned a complex discrimination strategy across 2 different training time points: a constant length (10 days) and a variable length that coincided with each rat meeting an acquisition-level performance threshold (males: 5.3 ± 0.3 days, females: 3.8 ± 0.3 days). We then chemogenetically activated or inhibited the mPFC-MS pathway and measured each rat's ability to inhibit the prior learned discrimination strategy and switch to a prior ignored discrimination strategy (strategy switching)., Results: Activation of the mPFC-MS pathway improved strategy switching after 10 days of training in both sexes. Inhibition of the pathway produced a modest improvement in strategy switching that was quantitatively and qualitatively different from pathway activation. Neither activation nor inhibition of the mPFC-MS pathway affected strategy switching following the acquisition-level performance threshold training regimen. Activation, but not inhibition, of the mPFC-MS pathway bidirectionally regulated DA neuron activity in the ventral tegmental area and substantia nigra pars compacta, similar to general MS activation., Conclusions: This study presents a potential top-down circuit from the prefrontal cortex to the midbrain by which DA activity can be manipulated to promote cognitive flexibility., (© The Author(s) 2023. Published by Oxford University Press on behalf of CINP.)

Purpose of Review: Schizophrenia is a psychiatric disorder that has a significant socioeconomic impact worldwide. Antipsychotic drugs targeting dopamine transmission alleviate psychotic symptoms but with limited efficacy and tolerability. Animal models have long proven useful for drug discovery. The continued need for new treatment highlights the importance of animal models to study schizophrenia. The lack of new therapeutic compounds combined with the shortcomings of clinical design studies potentially decreased the enthusiasm for animal model use., Recent Findings: In the current review, we discuss the central role of animal models for schizophrenia in providing new insights into neurobiological features and therapeutic development. The US National Institute of Mental Health released the Research Domain Criteria to guide preclinical model studies. Here, we point out the advances of this approach and debate its potential limitations when using animal models to study schizophrenia from the drug discovery perspective., Summary: Cross-validated animal models for schizophrenia are crucial to comprehend the cause, pathophysiology, and behavioral and biological features of the disease, to advance prevention and treatment, and the need to carefully evaluate and select appropriate paradigms when investigating novel therapeutic targets., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Adolescent stress is a risk factor for schizophrenia. Emerging evidence suggests that age-dependent sensitive windows for childhood trauma are associated more strongly with adult psychosis, but the neurobiological basis and potential sex differences are unknown.Using in vivo electrophysiology and immunohistology in rats, we systematically compared the effects of two age-defined adolescent stress paradigms, prepubertal (postnatal day [PD] 21-30; PreP-S) and postpubertal (PD41-50; PostP-S) foot-shock and restraint combined stress, on ventral tegmental area (VTA) dopaminergic activity, pyramidal neuron activity in the ventral hippocampus (vHipp) and the basolateral amygdala (BLA), corticoamygdalar functional inhibitory control, and vHipp and BLA parvalbumin interneuron (PVI) impairments. These endpoints were selected based on their well-documented roles in the pathophysiology of psychosis.Overall, we found distinct sex- and exposure age-dependent stress vulnerability. Specifically, while males were selectively vulnerable to PreP-S-induced adult VTA dopamine neuron and vHipp hyperactivities, females were selectively vulnerable to PostP-S. These male selective PreP-S effects were correlated with stress-induced aberrant persistent BLA hyperactivity, dysfunctional prefrontal inhibitory control of BLA neurons, and vHipp/BLA PVI impairments. In contrast, female PostP-S only produced vHipp PVI impairments in adults, with the BLA structure and functions largely unaffected.Our results indicated distinct adolescent-sensitive periods during which stress can sex-dependently confer maximal risks to corticolimbic systems to drive dopamine hyperactivity, which provide critical insights into the neurobiological basis for sex-biased stress-related psychopathologies emphasizing but not limited to schizophrenia. Furthermore, our work also provides a framework for future translational research on age-sensitive targeted interventions., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background and Hypothesis: Stress during adolescence is a major risk factor for schizophrenia. We have found previously in rats that adolescent stress caused, in adulthood, behavioral changes and enhanced ventral tegmental area (VTA) dopamine system activity, which were associated with dysregulation of the excitatory-inhibitory (E/I) balance in the ventral hippocampus (vHip). Levetiracetam, an anticonvulsant drug, regulates the release of neurotransmitters, including glutamate, via SV2A inhibition. It also modulates parvalbumin interneuron activity via Kv3.1 channels. Therefore, levetiracetam could ameliorate deficits in the E/I balance. We tested whether levetiracetam attenuate the adolescent stress-induced behavioral changes, vHip hyperactivity, and enhanced VTA dopamine system activity in adult rats., Study Design: Male Sprague-Dawley rats were subjected to a combination of daily footshock (postnatal day [PD] 31-40), and three 1 h-restraint stress sessions (at PD31, 32, and 40). In adulthood (PD62), animals were tested for anxiety responses (elevated plus-maze and light-dark box), social interaction, and cognitive function (novel object recognition test). The activity of vHip pyramidal neurons and VTA dopamine neurons was also recorded., Study Results: Adolescent stress produced anxiety-like responses and impaired sociability and cognitive function. Levetiracetam (10 mg/kg) reversed these changes. Levetiracetam also reversed the increased VTA dopamine neuron population activity and the enhanced firing rate of vHip pyramidal neurons induced by adolescent stress., Conclusions: These findings suggest that levetiracetam attenuates the adverse outcomes associated with schizophrenia caused by stress during adolescence., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Postpartum depression (PPD) is the most common psychiatric disorder following childbirth and is characterized by maternal mood disturbances, impaired maternal responses, and disrupted caregiving- all of which negatively impact offspring development. Since PPD has detrimental consequences for both mother and child, clinical and preclinical research has focused on identifying brain changes associated with this disorder. In humans, PPD is linked to dysregulated mesolimbic dopamine (DA) system function and altered neural responses (i.e., decreased reward-related activity) to infant-related cues, which are considered hallmark features of PPD. In accordance, rodent models employing translational risk factors useful for the study of PPD have demonstrated alterations in mesolimbic DA system structure and function, and these changes are reviewed here. We also present two novel rodent models based on postpartum adversity exposure (i.e., pup removal, scarcity-adversity) which result in PPD-relevant behavioral changes (e.g., disrupted mother-infant interactions, deficits in maternal behavior, depressive-like phenotypes) and attenuated ventral tegmental area (VTA) DA neuron activity consistent with a hypodopaminergic state. Furthermore, we highlight open questions and future directions for these rodent models. In sum, human and rodent studies converge in showing blunted mesolimbic DA function (i.e., DA downregulation) in PPD. We propose that reduced activity of VTA DA neurons, resulting in downregulation of the mesolimbic DA system, interferes with reward-related processes necessary for maternal motivation and responsiveness. Thus, the mesolimbic DA system may constitute a therapeutic target for ameliorating reward-related deficits in PPD., Competing Interests: AAG has received funds from Alkermes, Lundbeck, Takeda, Roche, Lyra, Concert, Merck, and SynAgile. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rincón-Cortés and Grace.)

Strategy switching is a form of cognitive flexibility that requires inhibiting a previously successful strategy and switching to a new strategy of a different categorical modality. It is dependent on dopamine (DA) receptor activation and release in ventral striatum and prefrontal cortex, two primary targets of ventral tegmental area (VTA) DA projections. Although the circuitry that underlies strategy switching early in learning has been studied, few studies have examined it after extended discrimination training. This may be important as DA activity and release patterns change across learning, with several studies demonstrating a critical role for substantia nigra pars compacta (SNc) DA activity and release once behaviors are well-learned. We have demonstrated that medial septum (MS) activation simultaneously increased VTA and decreased SNc DA population activity, as well as improved reversal learning via these actions on DA activity. We hypothesized that MS activation would improve strategy switching both early in learning and after extended training through its ability to increase VTA DA population activity and decrease SNc DA population activity, respectively. We chemogenetically activated the MS of male and female rats and measured their performance on an operant-based strategy switching task following 1, 10, or 15 days of discrimination training. Contrary to our hypothesis, MS activation did not affect strategy switching after 1 day of discrimination training. MS activation improved strategy switching after 10 days of training, but only in females. MS activation improved strategy switching in both sexes after 15 days of training. Infusion of bicuculline into the ventral subiculum (vSub) inhibited the MS-mediated decrease in SNc DA population activity and attenuated the improvement in strategy switching. Intra-vSub infusion of scopolamine inhibited the MS-mediated increase in VTA DA population activity but did not affect the improvement in strategy switching. Intra-vSub infusion of both bicuculline and scopolamine inhibited the MS-mediated effects on DA population activity in both the SNc and VTA and completely prevented the improvement in strategy switching. These data indicate that MS activation improves strategy switching once the original strategy has been sufficiently well-learned, and that this may occur via the MS's regulation of DA neuron responsivity., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Despite strong evidence of the neurodevelopmental origins of psychosis, current pharmacological treatment is not usually initiated until after a clinical diagnosis is made, and is focussed on antagonising striatal dopamine receptors. These drugs are only partially effective, have serious side effects, fail to alleviate the negative and cognitive symptoms of the disorder, and are not useful as a preventive treatment. In recent years, attention has turned to upstream brain regions that regulate striatal dopamine function, such as the hippocampus. This review draws together these recent data to discuss why the hippocampus may be especially vulnerable in the pathophysiology of psychosis. First, we describe the neurodevelopmental trajectory of the hippocampus and its susceptibility to dysfunction, exploring this region's proneness to structural and functional imbalances, metabolic pressures, and oxidative stress. We then examine mechanisms of hippocampal dysfunction in psychosis and in individuals at high-risk for psychosis and discuss how and when hippocampal abnormalities may be targeted in these groups. We conclude with future directions for prospective studies to unlock the discovery of novel therapeutic strategies targeting hippocampal circuit imbalances to prevent or delay the onset of psychosis., (© 2022. The Author(s).)

Animal models of psychiatric disorders have been highly effective in advancing the field, identifying circuits related to pathophysiology, and identifying novel therapeutic targets. In this review, we show how animal models, particularly those based on development, have provided essential information regarding circuits involved in disorders, disease progression, and novel targets for intervention and potentially prevention. Nonetheless, in recent years there has been a pushback, largely driven by the US National Institute of Mental Health (NIMH), to shift away from animal models and instead focus on circuits in normal subjects. This has been driven primarily from a lack of discovery of new effective therapeutic targets, and the failure of targets based on preclinical research to show efficacy. We discuss why animal models of complex disorders, when strongly cross-validated by clinical research, are essential to understand disease etiology as well as pathophysiology, and direct new drug discovery. Issues related to shortcomings in clinical trial design that confound translation from animal models as well as the failure to take patient pharmacological history into account are proposed to be a source of the failure of what are likely effective compounds from showing promise in clinical trials., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Uliana, Zhu, Gomes and Grace.)

The nucleus accumbens shell (NAcSh) is a key brain region where environmental cues acquire incentive salience to reinforce motivated behaviors. Principal medium spiny neurons (MSNs) in the NAcSh receive extensive glutamatergic projections from limbic regions, among which, the ventral hippocampus (vH) transmits information enriched in contextual cues, and the basolateral amygdala (BLA) encodes real-time arousing states. The vH and BLA project convergently to NAcSh MSNs, both activated in a time-locked manner on a cue-conditioned motivational action. In brain slices prepared from male and female mice, we show that co-activation of the two projections induces long-term potentiation (LTP) at vH-to-NAcSh synapses without affecting BLA-to-NAcSh synapses, revealing a heterosynaptic mechanism through which BLA signals persistently increase the temporally contingent vH-to-NAcSh transmission. Furthermore, this LTP is more prominent in dopamine D1 receptor-expressing (D1) MSNs than D2 MSNs and can be prevented by inhibition of either D1 receptors or dopaminergic terminals in NAcSh. This heterosynaptic LTP may provide a dopamine-guided mechanism through which vH-encoded cue inputs that are contingent to BLA activation acquire increased circuit representation to reinforce behavior. SIGNIFICANCE STATEMENT In motivated behaviors, environmental cues associated with arousing stimuli acquire increased incentive salience, processes mediated in part by the nucleus accumbens (NAc). NAc principal neurons receive glutamatergic projections from the ventral hippocampus (vH) and basolateral amygdala (BLA), which transmit information encoding contextual cues and affective states, respectively. Our results show that co-activation of the two projections induces long-term potentiation (LTP) at vH-to-NAc synapses without affecting BLA-to-NAc synapses, revealing a heterosynaptic mechanism through which BLA signals potentiate the temporally contingent vH-to-NAc transmission. Furthermore, this LTP is prevented by inhibition of either D1 receptors or dopaminergic axons. This heterosynaptic LTP may provide a dopamine-guided mechanism through which vH-encoded cue inputs that are contingent to BLA activation acquire increased circuit representation to reinforce behavior., (Copyright © 2022 the authors.)

Monoamine oxidase (MAO) activity is reduced in cigarette smokers and this may promote the reinforcing actions of nicotine, thereby enhancing the addictive properties of cigarettes. At present, it is unclear how cigarette smoking leads to MAO inhibition, but preclinical studies in rodents show that MAO inhibition increases nicotine self-administration, especially at low doses of nicotine. This effect of MAO inhibition develops slowly, likely due to plasticity of brain monoamine systems; studies relying on acute MAO inhibition are unlikely to replicate what happens with smoking. Given that MAO inhibition may reduce the threshold level at which nicotine becomes reinforcing, it is important to consider this in the context of very low nicotine content (VLNC) cigarettes and potential tobacco product regulation. It is also important to consider how this interaction between MAO inhibition and the reinforcing actions of nicotine may be modified in populations that are particularly vulnerable to nicotine dependence. In the context of these issues, we show that the MAO-inhibiting action of cigarette smoke extract (CSE) is similar in VLNC cigarettes and cigarettes with a standard nicotine content. In addition, we present evidence that in a rodent model of schizophrenia the effect of MAO inhibition to enhance nicotine self-administration is absent, and speculate how this may relate to brain serotonin systems. These issues are relevant to the MAO-inhibiting effect of cigarette smoking and its implications to tobacco product regulation., Competing Interests: AG received funding from the organizations of Lundbeck, Pfizer, Otsuka, Asubio, Autofony, Janssen, Alkermes, SynAgile, Merck, and Newron outside of this work, but these funders were not involved in any way in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication., (Copyright © 2022 Sved, Weeks, Grace, Smith and Donny.)

Background: The ventral pallidum (VP) is a dopaminoceptive forebrain structure regulating the ventral tegmental area (VTA) dopaminergic population activity. We have recently demonstrated that in the VP, the D2-like dopamine (DA) receptor agonist quinpirole dose dependently facilitates memory consolidation in inhibitory avoidance and spatial learning. According to our hypothesis, quinpirole microinjected into the VP can modulate the VTA DAergic activity and influence motivation and learning processes of rats., Methods: Quinpirole was microinjected at 3 different doses into the VP of male rats, and controls received vehicle. Single unit recordings were employed to assess VTA DAergic activity. To investigate the possible reinforcing or aversive effect of quinpirole in the VP, the conditioned place preference paradigm was used., Results: Our results showed that intra-VP quinpirole microinjection regulates VTA DAergic neurons according to an inverted U-shaped dose-response curve. The largest dose of quinpirole decreased the population activity and strongly reduced burst activity of the DAergic neurons in the first hour after its application. In contrast, the 2 smaller doses increased DA population activity, but their effect started with a delay 1 hour after their microinjection. The CPP experiments revealed that the largest dose of quinpirole in the VP induced place aversion in the rats. Furthermore, the largest dose of quinpirole induced an acute locomotor activity reduction, while the medium dose led to a long-duration increase in locomotion., Conclusions: In summary, quinpirole dose dependently regulates VTA DAergic activity as well as the motivation and motor behavior of the rats at the level of the VP., (© The Author(s) 2022. Published by Oxford University Press on behalf of CINP.)

Antipsychotic drugs are the mainstay in the treatment of schizophrenia. However, one-third of patients do not show adequate improvement in positive symptoms with non-clozapine antipsychotics. Additionally, approximately half of them show poor response to clozapine, electroconvulsive therapy, or other augmentation strategies. However, the development of novel treatment for these conditions is difficult due to the complex and heterogenous pathophysiology of treatment-resistant schizophrenia (TRS). Therefore, this review provides key findings, potential treatments, and a roadmap for future research in this area. First, we review the neurobiological pathophysiology of TRS, particularly the dopaminergic, glutamatergic, and GABAergic pathways. Next, the limitations of existing and promising treatments are presented. Specifically, this article focuses on the therapeutic potential of neuromodulation, including electroconvulsive therapy, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation. Finally, we propose multivariate analyses that integrate various perspectives of the pathogenesis, such as dopaminergic dysfunction and excitatory/inhibitory imbalance, thereby elucidating the heterogeneity of TRS that could not be obtained by conventional statistics. These analyses can in turn lead to a precision medicine approach with closed-loop neuromodulation targeting the detected pathophysiology of TRS., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The nucleus reuniens of the thalamus (RE) is a pivotal area responsible for the connectivity of the prefrontal-hippocampus pathway that regulates cognitive, executive, and fear learning processes. Recently, it was proposed that the RE participates in the pathophysiological states related to affective dysregulation. We investigated the role of RE in motivational behavioral and electrophysiological dysregulation induced by stress. Adult Sprague-Dawley rats were exposed to a combination of stressors (restraint stress+footshock) for 10 days and tested one to two weeks later in the forced swim test (FST), ventral tegmental area (VTA)dopamine (DA) neuron electrophysiological activity, and hippocampal-nucleus accumbens plasticity. The RE was inactivated by injecting TTX prior to the procedures. The stress exposure increased the immobility in the FST and decreased VTA DA neuron population activity. Whereas an early long-term potentiation (e-LTP) in the ventral hippocampus-nucleus accumbens pathway was found after fimbria high-frequency stimulation in naïve animals, stressed animals showed an early long-term depression (e-LTD). Inactivation of the RE reversed the stress-induced changes in the FST and restored dopaminergic activity. RE inactivation partially recovered the stress-induced abnormal hippocampal-accumbens plasticity observed in controls. Our findings support the role of the RE in regulating affective dysregulation and blunted VTA DA system function induced by stress. Also, it points to the hippocampal-accumbens pathway as a potential neural circuit through which RE could modulate activity. Therefore, RE may represent a key brain region involved in the neurobiology of amotivational states and may provide insights into circuit dysfunction and markers of the maladaptive stress response., (© 2022. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Mapping for AF focuses on the identification of regions of interest that may guide management and - in particular - ablation therapy. Mapping may point to specific mechanisms associated with localised scar or fibrosis, or electrical features, such as localised repetitive, rotational or focal activation. In patients in whom AF is caused by disorganised waves with no spatial predilection, as proposed in the multiwavelet theory for AF, mapping would be of less benefit. The role of AF mapping is controversial at the current time in view of the debate over the underlying mechanisms. However, recent clinical expansions of mapping technologies confirm the importance of understanding the state of the art, including limitations of current approaches and potential areas of future development., Competing Interests: Disclosure: AAG and SMN are section editors on the Arrhythmia & Electrophysiology Review editorial board; this did not influence peer review. JABZ has no conflicts of interest to declare., (Copyright © 2022, Radcliffe Cardiology.)

Stress is a major risk factor for the development of both schizophrenia and depression, and comorbidity between the two is common in schizoaffective disorders. However, the effects of stress exposure (i.e. chronic mild stress-CMS) on depression-related phenotypes in a neurodevelopmental model relevant to schizophrenia (i.e. methylazoxymethanol acetate-MAM) have yet to be explored and could provide insight into shared mechanisms of disease. To this end, we combined the prenatal MAM model with adult CMS exposure and explored the resultant pathophysiology using the social approach test (SAT), immobility in the forced swim test (FST) and amphetamine-induced hyperlocomotion (AIH) as depression- and schizophrenia-related endophenotypes and performed extracellular recordings of ventral tegmental area (VTA) DA neurons. MAM rats exhibited a reduction in social approach and increased VTA DA neuron activity compared to SAL rats or CMS groups. Separate cohorts of MAM animals were subjected to FST and AIH testing (counterbalanced order) or FST only. CMS groups exhibited increased FST immobility. Post-FST, both MAM groups (MAM-CON, MAM-CMS) exhibited blunted locomotor response to amphetamine compared with their SAL counterparts exposed to the same tests. Post-FST, MAM rats exhibited comparable VTA population activity to SAL rats, and CMS groups exhibited attenuated VTA population activity. Apomorphine administration results were consistent with the model suggesting that reductions in VTA DA neuron activity in MAM rats following FST exposure resulted from over-excitation, or depolarization block. These data suggest stress-induced DA downregulation in MAM rats, as FST exposure was sufficient to block the DA hyperresponsivity phenotype., (© 2022. The Author(s).)

Here, we present a protocol for delivering environmental enrichment (EE) in discrete postnatal windows to prevent long-term dopamine neuron dysfunctions in a neurodevelopmental rat model of schizophrenia risk. We describe generation of the schizophrenia model through prenatal treatment of rats with methylazoxymethanol acetate (the MAM model) and the saline-treated controls. We then detail the 10-day or 20-day EE paradigms applied on male rats at different ages. This protocol also includes preparation of control groups in regular environment (RE) cages for comparison. For complete details on the use and execution of this protocol, please refer to Zhu and Grace (2021)., Competing Interests: A.A.G. has received consulting fees from Alkermes, Lundbeck, Takeda, Roche, Lyra, Concert, and SynAgile, and research funding from Lundbeck. X.Z. reports no biomedical financial interests or potential conflicts of interest., (© 2022 The Author(s).)

Hippocampal hyperactivity driven by GABAergic interneuron deficits and NMDA receptor hypofunction is associated with the hyperdopaminergic state often observed in schizophrenia. Furthermore, previous research in the methylazoxymethanol acetate (MAM) rat model has demonstrated that repeated peripubertal diazepam administration can prevent the emergence of adult hippocampal hyperactivity, dopamine-system hyperactivity, and associated psychosis-relevant behaviors. Here, we sought to characterize hippocampal GABA A and NMDA receptors in MAM-treated rats and to elucidate the receptor mechanisms underlying the promising effects of peripubertal diazepam exposure. Quantitative receptor autoradiography was used to measure receptor density in the dorsal hippocampus CA1, ventral hippocampus CA1, and ventral subiculum. Specifically, [ 3 H]-Ro15-4513 was used to quantify the density of α5GABA A receptors (α5GABA A R), [ 3 H]-flumazenil to quantify α1-3;5GABA A R, and [ 3 H]-MK801 to quantify NMDA receptors. MAM rats exhibited anxiety and schizophrenia-relevant behaviors as measured by elevated plus maze and amphetamine-induced hyperlocomotion (AIH), although diazepam only partially rescued these behaviors. α5GABA A R density was reduced in MAM-treated rats in all hippocampal sub-regions, and negatively correlated with AIH. Ventral hippocampus CA1 α5GABA A R density was positively correlated with anxiety-like behavior. Dorsal hippocampus CA1 NMDA receptor density was increased in MAM-treated rats, and positively correlated with AIH. [ 3 H]-flumazenil revealed no significant effects. Finally, we found no significant effect of diazepam treatment on receptor densities, potentially related to the only partial rescue of schizophrenia-relevant phenotypes. Overall, our findings provide first evidence of α5GABA A R and NMDA receptor abnormalities in the MAM model, suggesting that more selective pharmacological agents may become a novel therapeutic mechanism in schizophrenia., (© 2021. The Author(s).)

Postpartum adversity is among the strongest predictors for the emergence of postpartum depression (PPD) in humans and a translational risk factor employed in rodent models. Parental care is disturbed under conditions of environmental adversity, including low resource environments, and in PPD. Nonetheless, the neural changes associated with these adversity-induced maladaptive behavioral states remain poorly understood. Postpartum scarcity-adversity can be modeled in rats by providing the dam with limited bedding and nesting (LBN) materials, which mimics the effects of a stressful low resource environment in potentiating maltreatment/neglect in humans. Indeed, LBN exposure from postpartum days (PD) 2-9 increased adverse maternal behaviors, impaired pup retrieval, and increased passive stress coping responses. Since mesolimbic dopamine (DA) activity is an important mechanism for motivated maternal behavior and is implicated in PPD, we assessed the impact of postpartum scarcity-adversity on in vivo electrophysiological properties of ventral tegmental area (VTA) DA neurons at two timepoints. We found reduced numbers of active VTA DA neurons in LBN dams at PD 9-10 but not PD-21, suggesting a transient impact on VTA population activity in LBN dams. Finally, we assessed the impact of early life scarcity-adversity on VTA DA function by conducting VTA recordings in adult female offspring and found a long-lasting attenuation in DA activity. These findings highlight a link between adversity-induced deficits in DA function and disrupted maternal behavior, suggesting the VTA/mesolimbic DA system as a potential mechanism by which postpartum scarcity-adversity drives aberrant maternal behavior, and early postnatal programming of adult VTA function in the offspring., (© 2021. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Background: The present study utilized the methylazoxymethanol (MAM) neurodevelopmental rodent model of schizophrenia (SCZ) to evaluate the hypothesis that individuals with SCZ smoke in an attempt to "self-medicate" their symptoms through nicotine (NIC) intake., Methods: To explore this question, we examined the effects of acute and chronic administration of NIC in 2 established behavioral tests known to be disrupted in the MAM model: prepulse inhibition of startle and novel object recognition. Additionally, we assessed the effects of acute and chronic NIC on 2 indices of the pathophysiology of SCZ modeled by MAM, elevated dopamine neuron population activity in the ventral tegmental area and neuronal activity in the ventral hippocampus, using in vivo electrophysiological recordings., Results: Our findings demonstrated that both acute and chronic administration of NIC significantly improved deficits in prepulse inhibition of startle and novel object recognition among MAM rats and normalized elevated ventral tegmental area and ventral hippocampal neuronal activity in these animals., Conclusion: Together, these findings of NIC-induced improvement of deficits lend support for a "self-medication" hypothesis behind increased cigarette smoking in SCZ and illustrate the potential utility of nicotinic modulation in future pharmacotherapies for certain SCZ symptoms., (© The Author(s) 2021. Published by Oxford University Press on behalf of CINP.)

Recent evidence showed thalamic abnormalities in schizophrenia involving disruptions to the parvalbumin neurons in the thalamic reticular nucleus (TRN). However, their functional consequences, as well as a potential linkage to oxidative stress, are unclear. The TRN is posited to gate prefrontal control of dopamine neuron activity in the ventral tegmental area (VTA). Thus, we hypothesized that schizophrenia-related TRN abnormalities might contribute to dopamine dysregulation, a well-known feature of the disorder. To test this, in adult rats exposed prenatally to methylazoxymethanol acetate (MAM rats), oxidative impairments to the parvalbumin neurons in the anterior TRN were assessed by immunohistochemistry. Using in vivo electrophysiology, we investigated whether inactivation of the prefrontal cortex would produce differential effects on VTA dopamine neurons in MAM rats. We show that MAM rats displayed reduced markers of parvalbumin and wisteria floribunda agglutinin-labeled perineuronal nets, correlating with increased markers of oxidative stress (8-oxo-7, 8-dihydro-20-deoxyguanosine, and 3-nitrotyrosine). Moreover, MAM rats displayed heightened baseline and abnormal prefrontal control of VTA dopamine neuron activity, as tetrodotoxin-induced inactivation of the infralimbic prefrontal cortex decreased the dopamine population activity, contrary to the normal increase in controls. Such dopamine neuron dysregulation was recapitulated by enzymatic perineuronal net digestion in the TRN of normal rats. Furthermore, juvenile (postnatal day 11-25) antioxidant treatment (N-acetyl-cysteine, 900 mg/L drinking water) prevented all these impairments in MAM rats. Our findings suggest that early accumulation of oxidative stress in the TRN may shape the later onset of schizophrenia pathophysiology, highlighting redox regulation as a potential target for early intervention., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Preclinical rodent models suggest that psychosis involves alterations in the activity and glutamatergic function in the hippocampus, driving dopamine activity through projections to the striatum. The extent to which this model applies to the onset of psychosis in clinical subjects is unclear. We assessed whether interactions between hippocampal glutamatergic function and activity/striatal connectivity are associated with adverse clinical outcomes in people at clinical high-risk (CHR) for psychosis. We measured functional Magnetic Resonance Imaging of hippocampal activation/connectivity, and 1 H-Magnetic Resonance Spectroscopy of hippocampal glutamatergic metabolites in 75 CHR participants and 31 healthy volunteers. At follow-up, 12 CHR participants had transitioned to psychosis and 63 had not. Within the clinical high-risk cohort, at follow-up, 35 and 17 participants had a poor or a good functional outcome, respectively. The onset of psychosis (p peakFWE  = 0.003, t = 4.4, z = 4.19) and a poor functional outcome (p peakFWE  < 0.001, t = 5.52, z = 4.81 and p peakFWE  < 0.001, t = 5.25, z = 4.62) were associated with a negative correlation between the hippocampal activation and hippocampal Glx concentration at baseline. In addition, there was a negative association between hippocampal Glx concentration and hippocampo-striatal connectivity (p peakFWE  = 0.016, t = 3.73, z = 3.39, p peakFWE  = 0.014, t = 3.78, z = 3.42, p peakFWE  = 0.011, t = 4.45, z = 3.91, p peakFWE  = 0.003, t = 4.92, z = 4.23) in the total CHR sample, not seen in healthy volunteers. As predicted by preclinical models, adverse clinical outcomes in people at risk for psychosis are associated with altered interactions between hippocampal activity and glutamatergic function., (© 2021. The Author(s).)

Background: Pulmonary hypertension (PH) is a potentially devastating clinical condition with a poor long-term prognosis. Cardiac arrhythmias are frequent in PH, and pulmonary hypertensives are particularly susceptible to the adverse haemodynamic effects of heart rhythm disorders. However, arrhythmia management in PH patients can be more challenging than in the general population due to the particular physiological idiosyncrasies associated with the condition. Here, we summarise and appraise the data pertaining to multimodality treatment of cardiac arrhythmias in PH to help refine the management strategy for this vulnerable patient group., Results: The majority of our understanding of the safety and effectiveness of different arrhythmia treatments in PH is based on observational and retrospective data. Rhythm control is the overall goal, and for atrial and ventricular tachyarrhythmias, referral for catheter ablation, ideally using electroanatomical mapping technology in specialist centres, is the preferable means of achieving this. Contradictory viewpoints are expounded regarding the safety of beta blocker use in PH, though in three small prospective clinical trials and at least six animal models they appear to be well-tolerated. Nevertheless, amiodarone remains the preferred pharmacological treatment. Direct current cardioversion can be carried out effectively to terminate tachyarrhythmias in both the emergency and elective setting, though mechanistic studies demonstrate a higher recurrence rate in PH patients. Individual reports and series suggest that device implantation may be technically challenging and associated with a higher complication rate due to anatomical distortion and chamber enlargement. Modulation of sympathetic input to the heart appears to reduce arrhythmia vulnerability in canine models of PH, and its clinical application in humans is a worthwhile area of further study., Conclusion: Prompt restoration of sinus rhythm improves outcomes in PH, and at present, the most reliable and safest strategy for long-term rhythm control is amiodarone and, where possible, ablation. Reinforcement of the evidence base with randomised prospective trials is necessary. This would be particularly beneficial to clarify the role of atrial fibrillation ablation and the safety and efficacy of beta-blockers. In addition, a more comprehensive assessment of the vulnerability of PH patients to potentially fatal brady- and ventricular tachyarrhythmias may help guide recommendations for provision of primary prevention device therapy., (© 2021. Springer Science+Business Media, LLC, part of Springer Nature.)

Pomaglumetad methionil (POM), a group 2 metabotropic glutamate receptor (mGluR2/3) agonist, showed promise as a novel antipsychotic in preclinical research but failed to show efficacy in clinical trials, though it has been suggested that it may be effective in certain patient populations, including early in disease patients. We used the methyazoxymethanol acetate (MAM) rat model of schizophrenia to determine whether POM may prevent the development of dopamine (DA) system dysfunction in a model representative of the hyperdopaminergic state thought to underlie psychosis, compared to control (SAL) rats. MAM and SAL rats were administered either POM (3 mg/kg, i.p.), vehicle (1 ml/kg), or no injection during postnatal day (PD) 31-40. In either late adolescence (PD 47-56) or adulthood (PD 83-96), novel object recognition (NOR) was tested, followed by anesthetized in vivo electrophysiological recordings of VTA DA neuron activity or ventral hippocampal (vHPC) pyramidal neuron activity. MAM rats treated with POM demonstrated increased NOR in adulthood compared to no injection MAM rats, but not compared to vehicle-treated MAM rats. POM-treated MAM rats demonstrated normalized DA neuron population activity and vHPC pyramidal neuron activity compared to vehicle and no injection MAM rats in both late adolescence and adulthood. No significant differences were observed across treatment groups in SAL rats. These results suggest that peripubertal mGluR2/3 agonist administration can prevent the emergence of vHPC pyramidal neuron hyperactivity and increased DA neuron population activity in adult MAM rats., (Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center 2021.)

Offspring interaction is among the most highly motivated behaviors in maternal mammals and is mediated by mesolimbic dopamine (DA) system activation. Disruption or loss of significant social relationships is among the strongest individual predictors of affective dysregulation and depression onset in humans. However, little is known regarding the effects of disrupted mother-infant attachment (pup removal) in rat dams. Here, we tested the effects of permanent pup removal in rat dams, which were assigned to one of three groups on postpartum day (PD) 1: pups; pups removed, single-housed; or pups removed, co-housed with another dam who also had pups removed; and underwent a behavioral test battery during PD 21-23. In vivo electrophysiological recordings of ventral tegmental area (VTA) DA neurons were performed on PD 22 and 23 in a subset of animals. Pup removal did not impact sucrose consumption or anxiety-like behavior, but increased passive forced swim test (FST) coping responses. Pup-removal effects on social behavior and VTA activity were sensitive to social buffering: only single-housed dams exhibited reduced social motivation and decreased numbers of active DA neurons. Dams that had pups removed and were co-housed did not exhibit changes in social behavior or VTA function. Moreover, no changes in social behavior, FST coping, or VTA activity were found in socially isolated adult virgin females, indicating that effects observed in dams are specific to pup loss. This study showed that deprivation of species-expected social relationships (pups) during the postpartum precipitates an enduring negative affect state (enhanced passive coping, blunted social motivation) and attenuated VTA DA function in the dam, and that a subset of these effects is partially ameliorated through social buffering., Competing Interests: Conflict of Interest: AG received consultant fees from Lundbeck, Pfizer, Otsuka, Asubio, Autofony, Alkermes, Concert, and Janssen, and is on the advisory board for Alkermes, Newron, and Takeda. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Preclinical models propose that increased hippocampal activity drives subcortical dopaminergic dysfunction and leads to psychosis-like symptoms and behaviors. Here, we used multimodal neuroimaging to examine the relationship between hippocampal regional cerebral blood flow (rCBF) and striatal dopamine synthesis capacity in people at clinical high risk (CHR) for psychosis and investigated its association with subsequent clinical and functional outcomes. Ninety-five participants (67 CHR and 28 healthy controls) underwent arterial spin labeling MRI and 18 F-DOPA PET imaging at baseline. CHR participants were followed up for a median of 15 months to determine functional outcomes with the global assessment of function (GAF) scale and clinical outcomes using the comprehensive assessment of at-risk mental states (CAARMS). CHR participants with poor functional outcomes (follow-up GAF < 65, n = 25) showed higher rCBF in the right hippocampus compared to CHRs with good functional outcomes (GAF ≥ 65, n = 25) (p fwe  = 0.026). The relationship between rCBF in this right hippocampal region and striatal dopamine synthesis capacity was also significantly different between groups (p fwe  = 0.035); the association was negative in CHR with poor outcomes (p fwe  = 0.012), but non-significant in CHR with good outcomes. Furthermore, the correlation between right hippocampal rCBF and striatal dopamine function predicted a longitudinal increase in the severity of positive psychotic symptoms within the total CHR group (p = 0.041). There were no differences in rCBF, dopamine, or their associations in the total CHR group relative to controls. These findings indicate that altered interactions between the hippocampus and the subcortical dopamine system are implicated in the pathophysiology of adverse outcomes in the CHR state.

Treatment of schizophrenia (SCZ) historically relies on the use of antipsychotic drugs to treat psychosis, with all of the currently available antipsychotics acting through the antagonism of dopamine D2 receptors. Although antipsychotics reduce psychotic symptoms in many patients, they induce numerous undesirable effects and are not effective against negative and cognitive symptoms. These highlight the need to develop new drugs to treat SCZ. An advanced understanding of the circuitry of SCZ has pointed to pathological origins in the excitation/inhibition balance in regions such as the hippocampus, and restoring function in this region, particularly as a means to compensate for parvalbumin (PV) interneuron loss and resultant hippocampal hyperactivity, may be a more efficacious approach to relieve a broad range of SCZ symptoms. Other targets, such as cholinergic receptors and the trace amine-associated receptor 1 (TAAR1), have also shown some promise for the treatment of SCZ. Importantly, assessing efficacy of novel compounds must take into consideration treatment history of the patient, as preclinical studies suggest prior antipsychotic treatment may interfere with the efficacy of these novel agents. However, while novel therapeutic targets may be more effective in treating SCZ, a more effective approach would be to prevent the transition to SCZ in susceptible individuals. A focus on stress, which has been shown to be a predisposing factor in risk for SCZ, is a possible avenue that has shown promise in preclinical studies. Therefore, therapeutic approaches based on our current understanding of the circuitry of SCZ and its etiology are likely to enable development of more effective therapeutic interventions for this complex disorder.

Stress is a socio-environmental risk factor for the development of psychiatric disorders, with the age of exposure potentially determining the outcome. Several brain regions mediate stress responsivity, with a prominent role of the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) and their reciprocal inhibitory connectivity. Here we investigated the impact of stress exposure during adolescence and adulthood on the activity of putative pyramidal neurons in the BLA and corticoamygdalar plasticity using in vivo electrophysiology. 155 male Sprague-Dawley rats were subjected to a combination of footshock/restraint stress in either adolescence (postnatal day 31-40) or adulthood (postnatal day 65-74). Both adolescent and adult stress increased the number of spontaneously active putative BLA pyramidal neurons 1-2 weeks, but not 5-6 weeks post stress. High-frequency stimulation (HFS) of BLA and mPFC depressed evoked spike probability in the mPFC and BLA, respectively, in adult but not adolescent rats. In contrast, an adult-like BLA HFS-induced decrease in spike probability of mPFC neurons was found 1-2 weeks post-adolescent stress. Changes in mPFC and BLA neuron discharge were found 1-2 weeks post-adult stress after BLA and mPFC HFS, respectively. All these changes were transient since they were not found 5-6 weeks post adolescent or adult stress. Our findings indicate that stress during adolescence may accelerate the development of BLA-PFC plasticity, probably due to BLA hyperactivity, which can also disrupt the reciprocal communication of BLA-mPFC after adult stress. Therefore, precocious BLA-mPFC connectivity alterations may represent an early adaptive stress response that ultimately may contribute to vulnerability to adult psychiatric disorders.

The ability to identify biomarkers of psychosis risk is essential in defining effective preventive measures to potentially circumvent the transition to psychosis. Using samples of people at clinical high risk for psychosis (CHR) and Healthy controls (HC) who were administered a task fMRI paradigm, we used a framework for labelling time windows of fMRI scans as 'integrated' FC networks to provide a granular representation of functional connectivity (FC). Periods of integration were defined using the 'cartographic profile' of time windows and k-means clustering, and sub-network discovery was carried out using Network Based Statistics (NBS). There were no network differences between CHR and HC groups. Within the CHR group, using integrated FC networks, we identified a sub-network negatively associated with longitudinal changes in the severity of psychotic symptoms. This sub-network comprised brain areas implicated in bottom-up sensory processing and in integration with motor control, suggesting it may be related to the demands of the fMRI task. These data suggest that extracting integrated FC networks may be useful in the investigation of biomarkers of psychosis risk., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Schizophrenia (SCZ) is a neurodevelopmental disorder with a progressive, prolonged course. Early prevention for SCZ is promising but overall lacks support from preclinical evidence. Previous studies have tested environmental enrichment (EE) in certain models of SCZ and discovered a broadly beneficial effect in preventing behavioral abnormalities relevant, yet not specific, to the disorder. Nonetheless, whether EE can prevent dopamine (DA) dysregulation, a hallmark of psychosis and SCZ, had not been tested., Methods: Using the MAM (methylazoxymethanol acetate) rat model of schizophrenia and saline-treated control animals, we investigated the long-term electrophysiological effects of prepubertal (postnatal day 21-40) EE on DA neurons, pyramidal neurons in the ventral hippocampus, and projection neurons in the basolateral amygdala. Anxiety-related behaviors in the elevated plus maze and locomotor responses to amphetamine were also analyzed., Results: Prepubertal EE prevented the increased population activity of DA neurons and the associated increase in locomotor response to amphetamine. Prepubertal EE also prevented hyperactivity in the ventral hippocampus but did not prevent hyperactivity in the basolateral amygdala. Anxiety-like behaviors in MAM rats were not ameliorated by prepubertal exposure to EE., Conclusions: Twenty-day prepubertal EE is sufficient to prevent DA hyperresponsivity in the MAM model, measured by electrophysiological recordings and locomotor response to amphetamine. This effect is potentially mediated by normalizing excessive firing in the ventral hippocampus without affecting anxiety-like behaviors and basolateral amygdala firing. This study identified EE as a useful preventative approach that may protect against the pathophysiological development of SCZ., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The GABA B receptor (GABA B R) agonist baclofen has been used to treat alcohol and several other substance use disorders (AUD/SUD), yet its underlying neural mechanism remains unclear. The present study aimed to investigate cortical GABA B R dynamics following chronic alcohol exposure. Ex vivo brain slice recordings from mice chronically exposed to alcohol revealed a reduction in GABA B R-mediated currents, as well as a decrease of GABA B1/2 R and G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2) activities in the motor cortex. Moreover, our data indicated that these alterations could be attributed to dephosphorylation at the site of serine 783 (ser-783) in GABA B2 subunit, which regulates the surface expression of GABA B R. Furthermore, a human study using paired-pulse-transcranial magnetic stimulation (TMS) analysis further demonstrated a reduced cortical inhibition mediated by GABA B R in patients with AUD. Our findings provide the first evidence that chronic alcohol exposure is associated with significantly impaired cortical GABA B R function. The ability to promote GABA B R signaling may account for the therapeutic efficacy of baclofen in AUD.

Background: During adolescence, neuronal circuits exhibit plasticity in response to physiological changes and to adapt to environmental events. Nigrostriatal dopaminergic pathways are in constant flux during development. Evidence suggests a relationship between early use of cannabinoids and psychiatric disorders characterized by altered dopaminergic systems, such as schizophrenia and addiction. However, the impact of adolescent exposure to cannabinoids on nigrostriatal dopaminergic pathways in adulthood remains unclear. The aim of this research was to determine the effects of repeated activation of cannabinoid receptors during adolescence on dopaminergic activity of nigrostriatal pathways and the mechanisms underlying this impact during adulthood., Methods: Male Sprague-Dawley rats were treated with 1.2 mg/kg WIN 55212-2 daily from postnatal day 40 to 65. Then no-net flux microdialysis of dopamine in the dorsolateral striatum, electrophysiological recording of dopaminergic neuronal activity, and microdialysis measures of gamma-aminobutyric acid (GABA) and glutamate in substantia nigra par compacta were carried out during adulthood (postnatal days 72-78)., Results: Repeated activation of cannabinoid receptors during adolescence increased the release of dopamine in dorsolateral striatum accompanied by increased population activity of dopamine neurons and decreased extracellular GABA levels in substantia nigra par compacta in adulthood. Furthermore, perfusion of bicuculline, a GABAa antagonist, into the ventral pallidum reversed the increased dopamine neuron population activity in substantia nigra par compacta induced by adolescent cannabinoid exposure., Conclusions: These results suggest that adolescent exposure to cannabinoid agonists produces disinhibition of nigrostriatal dopamine transmission during adulthood mediated by decreased GABAergic input from the ventral pallidum., (© The Author(s) 2020. Published by Oxford University Press on behalf of CINP.)