A systematic scoping review of rodent models of catatonia: Clinical correlations, translation and future approaches.

Catatonia is a psychiatric disorder, which subsumes a plethora of affective, motor and behavioral symptoms. In the last two decades, the number of behavioral and neuroimaging studies on catatonia has steadily increased. The majority of behavioral and neuroimaging studies in psychiatric patients suggested aberrant higher-order frontoparietal networks which, on the biochemical level, are insufficiently modulated by gamma-aminobutyric acid (GABA)-ergic and glutamatergic transmission. However, the pathomechanisms of catatonic symptoms have rarely been studied using rodent models. Here, we performed a scoping review of literature available on PubMed for studies on rodent models of catatonia. We sought to identify what we could learn from pre-clinical animal models of catatonia-like symptoms, their underlying neuronal correlates, and the complex molecular (i.e. genes and neurotransmitter) mechanisms by which its modulation exerts its effects. What becomes evident is that although many transgenic models present catatonia-like symptoms, they have not been used to better understand the pathophysiological mechanisms underlying catatonia so far. However, the identified neuronal correlates of catatonia-like symptoms correlate to a great extent with findings from neuroscience research in psychiatric patients. This points us towards fundamental cortical-striatal-thalamocortical and associated networks modulated by white matter inflammation as well as aberrant dopaminergic, GABAergic, and glutamatergic neurotransmission that is involved in catatonia. Therefore, this scoping review opens up the possibility of finally using transgenic models to help with identifying novel target mechanisms for the development of new drugs for the treatment of catatonia.

Psilocybin does not induce the vulnerability marker HSP70 in neurons susceptible to Olney's lesions.

S-ketamine, a N-methyl-D-aspartate receptor (NMDAR) antagonist, and psilocybin, a 5-hydroxy-tryptamine (serotonin) 2A receptor (5-HT2AR) agonist, are reported as effective rapid-acting antidepressants. Both compounds increase glutamate signalling and evoke cortical hyperexcitation. S-ketamine induces neurotoxicity especially in the retrosplenial cortex (Olney's lesions). Whether psilocybin produces similar neurotoxic effects has so far not been investigated. We performed an immunohistochemical whole-brain mapping for heat shock protein 70 (HSP70) in rats treated with psilocybin, S-ketamine, and MK-801. In contrast to S-ketamine- and MK-801-treated animals, we did not detect any HSP70-positive neurons in retrosplenial cortex of rats treated with psilocybin. Our results suggest that psilocybin might be safer for clinical use compared to S-ketamine regarding neuronal damage.

Evidence-based severity assessment of the forced swim test in the rat.

The forced swim test (FST) is a traditional assay, which has been used for more than 40 years to assess antidepressant effects of novel drug candidates. In recent years, a debate about the test has focused on the assumption that the FST is highly aversive and burdening for the animals because of the earlier anthropomorphic interpretation and designation as a "behavioral despair test". The Directive 2010/63/EU and the German Animal Welfare law require a prospective severity classification of the planned experimental procedures. Still, an objective examination of the animals' burden in this test has not been performed yet. To fill this gap, we conducted an evidence-based severity assessment of the forced swim test in rats according to a 'standard protocol' with a water temperature of 25°C. We examined parameters representing the physiological and the affective state, and natural as well as locomotion-associated behaviors in three separate experiments to reflect as many dimensions as possible of the animal's condition in the test. Hypothermia was the only effect observed in all animals exposed to the FST when using this standard protocol. Additional adverse effects on body weight, food consumption, and fecal corticosterone metabolite concentrations occurred in response to administration of the antidepressant imipramine, which is frequently used as positive control when testing for antidepressant effects of new substances. We conclude that this version of the FST itself is less severe for the animals than assumed, and we suggest a severity classification of 'moderate' because of the acute and short-lasting effects of hypothermia. To refine the FST according to the 3Rs, we encourage confirming the predictive validity in warmer water temperatures to allow the rats to maintain physiological body temperature.

A systematic mapping review of the evolution of the rat Forced Swim Test: Protocols and outcome parameters.

As depression is projected to become the leading mental disease burden globally by 2030, understanding the underlying pathology, as well as screening potential anti-depressants with a higher efficacy, faster onset of action, and/or fewer side-effects is essential. A commonly used test for screening novel antidepressants and studying depression-linked aspects in rodents is the Porsolt Forced Swim Test. The present systematic mappping review gives a comprehensive overview of the evolution and of the most prevalently used set-ups of this test in rats, including the choice of animals (strain, sex, and age), technical aspects of protocol and environment, as well as reported outcome measures. Additionally, we provide an accessible list of all existing publications, to support informed decision-making for procedural and technical aspects of the test, to thereby enhance reproducibility and comparability. This should further contribute to reducing the number of unnecessarily replicated experiments, and consequently, reduce the number of animals used in future.

Chronic Lithium Treatment Alters NMDA and AMPA Receptor Synaptic Availability and Dendritic Spine Organization in the Rat Hippocampus.

BACKGROUND: The mechanisms underlying the action of lithium (LiCl) in bipolar disorder(BD) are still far from being completely understood. Previous evidence has revealed that BD is characterized by glutamate hyperexcitability, suggesting that LiCl may act, at least partially, by toning down glutamatergic signaling abnormalities. OBJECTIVE: In this study, taking advantage of western blot and confocal microscopy, we used a combination of integrative molecular and morphological approaches in rats exposed to repeated administration of LiCl at a therapeutic dose (between 0.6 and 1.2 mmol/l) and sacrificed at two different time points, i.e., 24 hours and 7 days after the last exposure. RESULTS: We report that repeated LiCl treatment activates multiple, parallel, but also converging forms of compensatory neuroplasticity related to glutamatergic signaling. More specifically, LiCl promoted a wave of neuroplasticity in the hippocampus, involving the synaptic recruitment of GluN2A-containing NMDA receptors, GluA1-containing AMPA receptors, and the neurotrophin BDNF that are indicative of a more plastic spine. The latter is evidenced by morphological analyses showing changes in dendritic spine morphology, such as increased length and head diameter of such spines. These changes may counteract the potentially negative extra-synaptic movements of GluN2B-containing NMDA receptors as well as the increase in the formation of GluA2-lacking Ca2+-permeable AMPA receptors. CONCLUSION: Our findings highlight a previously unknown cohesive picture of the glutamatergic implications of LiCl action that persist long after the end of its administration, revealing for the first time a profound and persistent reorganization of the glutamatergic postsynaptic density receptor composition and structure.

Comparative Severity Assessment of Genetic, Stress-Based, and Pharmacological Mouse Models of Depression.

The use of animals in neurosciences is pivotal to gaining insights into complex functions and dysfunctions of behavior. For example, various forms of physical and/or psychological stress are inherent to various animal models for psychiatric disorders, e.g., depression. Regarding animal welfare, it would be mandatory to use models that inflict the least amount of stress necessary to address the underlying scientific question. This study compared the severity of different approaches to induce depression in mice: mutagenesis in GluA1 knockout, immobilization stress, and stress-induction via stress hormone treatment. While genetic alterations potentially represent a lifelong burden, the temporary intervention only affects the animals for a limited time. Therefore, we used home cage-based behavioral and physiological parameters, including nest building, burrowing, body weight, and fecal corticosterone metabolites, to determine the well-being of male and female mice. In addition, we performed an evidence-based estimate of severity using a composite score for relative severity assessment (RELSA) with this data. We found that even though restraint stress and supplementation of corticosterone in the diet both aimed at depression-related precipitating stress effects, the latter affected the well-being much stronger, especially in females. Restraint leads to less noticeable well-being impairments but causes depression-associated anhedonic behavior. Mice of both sexes recovered well from the stress treatment. GluA1 KO and their littermates showed diminished well-being, comparable to the immobilization experiments. However, since this is a lifelong condition, this burden is not reversible and potentially accumulative. In line with the 3Rs (Replacement, Reduction, and Refinement), the process of choosing the most suitable model should ideally include an evidence-based severity assessment to be able to opt for the least severe alternative, which still induces the desired effect. Promoting refinement, in our study, this would be the restraint stress.

Dopamine Transporter Knockout Rats Show Impaired Wellbeing in a Multimodal Severity Assessment Approach.

In preclinical psychiatry research, animals are central to modeling and understanding biological mechanisms of behavior and psychiatric disorders. We here present the first multimodal severity assessment of a genetically modified rat strain used in psychiatric research, lacking the dopamine transporter (DAT) gene and showing endophenotypes of several dopamine-associated disorders. Absence of the DAT leads to high extracellular dopamine (DA) levels and has been associated with locomotor hyperactivity, compulsive behaviors and stereotypies in the past. The German Animal Welfare Law, which is based on the EU Directive (2010/63/EU), requires a prospective severity assessment for every animal experiment, depending on the extent of the expected degree of pain, suffering, distress or lasting harm that the animals will experience. This should consider all procedures but also the impact of the genotype on the phenotype. Therefore, we examined multiple parameters indicating animal welfare, like burrowing behavior, social interaction, saccharin preference, baseline stress hormone levels and nesting behavior. Additionally, a footprint analysis was performed and home cage activity was analyzed for a more detailed characterization of locomotion. DAT KO rats demonstrated reduced burrowing, social interaction and saccharin preference. We also found pronounced stereotypies and alterations in the gait analysis in DAT KO rats. Moreover, we confirmed the hyperactivity and the impaired sensorimotor gating mechanisms to assure that our rats are exhibiting the correct phenotype. In conclusion, we provide evidence that DAT KO rats show alterations in natural behavior patterns and deduce that the marked stereotypies are a sign for coping difficulties, both indicating a negative influence of the genotype on wellbeing. We suggest to assess further rat models in an objectified severity assessment as previously done in mice to create a relative severity assessment based on scientific evidence. Until then, we propose the classification of homozygous DAT KO rats as "moderate" in accordance with the criteria of the EU directive 2010/63.

Dopamine transporter silencing in the rat: systems-level alterations in striato-cerebellar and prefrontal-midbrain circuits.

Silencing of dopamine transporter (DAT), a main controlling factor of dopaminergic signaling, results in biochemical and behavioral features characteristic for neuropsychiatric diseases with presumed hyperdopaminergia including schizophrenia, attention deficit hyperactivity disorder (ADHD), bipolar disorder, and obsessive-compulsive disorder (OCD). Investigation of DAT silencing thus provides a transdiagnostic approach towards a systems-level understanding of common underlying pathways. Using a high-field multimodal imaging approach and a highly sensitive cryogenic coil, we integrated structural, functional and metabolic investigations in tandem with behavioral assessments on a newly developed preclinical rat model, comparing DAT homozygous knockout (DAT-KO, N = 14), heterozygous knockout (N = 8) and wild-type male rats (N = 14). We identified spatially distributed structural and functional brain alterations encompassing motor, limbic and associative loops that demonstrated strong behavioral relevance and were highly consistent across imaging modalities. DAT-KO rats manifested pronounced volume loss in the dorsal striatum, negatively correlating with cerebellar volume increase. These alterations were associated with hyperlocomotion, repetitive behavior and loss of efficient functional small-world organization. Further, prefrontal and midbrain regions manifested opposite changes in functional connectivity and local network topology. These prefrontal disturbances were corroborated by elevated myo-inositol levels and increased volume. To conclude, our imaging genetics approach provides multimodal evidence for prefrontal-midbrain decoupling and striato-cerebellar neuroplastic compensation as two key features of constitutive DAT blockade, proposing them as transdiagnostic mechanisms of hyperdopaminergia. Thus, our study connects developmental DAT blockade to systems-level brain changes, underlying impaired action inhibition control and resulting in motor hyperactivity and compulsive-like features relevant for ADHD, schizophrenia and OCD.

Dysregulation of Npas4 and Inhba expression and an altered excitation-inhibition balance are associated with cognitive deficits in DBA/2 mice.

Differences in the learning associated transcriptional profiles between mouse strains with distinct learning abilities could provide insight into the molecular basis of learning and memory. The inbred mouse strain DBA/2 shows deficits in hippocampus-dependent memory, yet the transcriptional responses to learning and the underlying mechanisms of the impairments are unknown. Comparing DBA/2J mice with the reference standard C57BL/6N mouse strain we verify an enhanced susceptibility to kainic acid induced seizures, confirm impairments in hippocampus-dependent spatial memory tasks and uncover additional behavioral abnormalities including deficits in hippocampus-independent learning. Surprisingly, we found no broad dysfunction of the DBA/2J strain in immediate early gene (IEG) activation but instead report brain region-specific and gene-specific alterations. The learning-associated IEGs Arc, c-Fos, and Nr4a1 showed no DBA/2J deficits in basal or synaptic activity induced gene expression in hippocampal or cortical primary neuronal cultures or in the CA1, CA3, or retrosplenial cortex following spatial object recognition (SOR) training in vivo. However, the parietal cortex showed reduced and the dentate gyrus showed enhanced SOR-evoked induction of most IEGs. All DBA/2J hippocampal regions exhibited elevated basal expression of inhibin ß A (Inhba) and a learning-associated superinduction of the transcription factor neuronal Per-Arnt-Sim domain protein 4 (Npas4) known to regulate the synaptic excitation-inhibition balance. In line with this, CA1 pyramidal neurons of DBA/2J mice showed fewer inhibitory and more excitatory miniature postsynaptic currents but no alteration in most other electrophysiological properties or gross dendritic morphology. The dysregulation of Npas4 and Inhba expression and synaptic connectivity may underlie the cognitive deficits and increased susceptibility to seizures of DBA/2J mice.

Cre-Activation in ErbB4-Positive Neurons of Floxed Grin1/NMDA Receptor Mice Is Not Associated With Major Behavioral Impairment.

Extensive evidence suggests a dysfunction of the glutamate NMDA receptor (NMDAR) in schizophrenia, a severe psychiatric disorder with putative early neurodevelopmental origins, but clinical onset mainly during late adolescence. On the other hand, pharmacological models using NMDAR antagonists and the clinical manifestation of anti-NMDAR encephalitis indicate that NMDAR blockade/hypofunction can trigger psychosis also at adult stages, without any early developmental dysfunction. Previous genetic models of NMDAR hypofunction restricted to parvalbumin-positive interneurons indicate the necessity of an early postnatal impairment to trigger schizophrenia-like abnormalities, whereas the cellular substrates of NMDAR-mediated psychosis at adolescent/adult stages are unknown. Neuregulin 1 (NRG1) and its receptor ErbB4 represent schizophrenia-associated susceptibility factors that closely interact with NMDAR. To determine the neuronal populations implicated in "late" NMDAR-driven psychosis, we analyzed the effect of the inducible ablation of NMDARs in ErbB4-expressing cells in mice during late adolescence using a pharmacogenetic approach. Interestingly, the tamoxifen-inducible NMDAR deletion during this late developmental stage did not induce behavioral alterations resembling depression, schizophrenia or anxiety. Our data indicate that post-adolescent NMDAR deletion, even in a wider cell population than parvalbumin-positive interneurons, is also not sufficient to generate behavioral abnormalities resembling psychiatric disorders. Other neuronal substrates that have to be revealed by future studies, may underlie post-adolescent NMDAR-driven psychosis.

The continued need for animals to advance brain research.

Policymakers aim to move toward animal-free alternatives for scientific research and have introduced very strict regulations for animal research. We argue that, for neuroscience research, until viable and translational alternatives become available and the value of these alternatives has been proven, the use of animals should not be compromised.

Correction: Social isolation in rats: Effects on animal welfare and molecular markers for neuroplasticity.

[This corrects the article DOI: 10.1371/journal.pone.0240439.].

Rapastinel alleviates the neurotoxic effect induced by NMDA receptor blockade in the early postnatal mouse brain.

Rapastinel is a novel psychoactive substance that acts as an N-methyl-D-aspartate-receptor (NMDAR) agonist and triggers antidepressant- and antipsychotic-like effects in animal models. However, it is unknown if rapastinel possesses a better side-effect profile than fast-acting glutamatergic antidepressants, like ketamine, which trigger neurotoxicity in the perinatal rodent cortex and protracted schizophrenia-like alterations. Here we found a remarkable neuroprotective effect of rapastinel against apoptosis induced by the NMDAR antagonist MK-801 in comparison to that elicited by clozapine and the mGlu2/3 agonist LY354740. These results suggest the potential therapeutic/prophylactic effect of rapastinel in ameliorating deleterious effects induced by NMDAR blockade during neurodevelopment.

Social isolation in rats: Effects on animal welfare and molecular markers for neuroplasticity.

Early life stress compromises brain development and can contribute to the development of mental illnesses. A common animal model used to study different facets of psychiatric disorders is social isolation from early life on. In rats, this isolation can induce long-lasting alterations in molecular expression and in behavior. Since social isolation models severe psychiatric symptoms, it is to be expected that it affects the overall wellbeing of the animals. As also promoted by the 3Rs principle, though, it is pivotal to decrease the burden of laboratory animals by limiting the number of subjects (reduce, replace) and by improving the animals' wellbeing (refine). The aim of this study was therefore to test possible refinement strategies such as resocialization and mere adult social isolation. We examined whether the alternatives still triggered the necessary phenotype while minimizing the stress load on the animals. Interestingly, we did not find reduced wellbeing-associated burrowing performance in isolated rats. The hyperactive phenotype seen in socially isolated animals was observed for rats undergoing the adult-only isolation, but resocializing ameliorated the locomotor abnormality. Isolation strongly affected markers of neuroplasticity in the prefrontal cortex independent of timing: mRNA levels of Arc, Bdnf and the pool of Bdnf transcripts with the 3' long UTR were reduced in all groups. Bdnf splice variant IV expression was reduced in lifelong-isolated animals. Some of these deficits normalized after resocialization; likewise, exon VI Bdnf mRNA levels were reduced only in animals persistently isolated. Conversely, social deprivation did not affect the expression of Gad67 and Pvb, two GABAergic markers, whereas changes occurred in the expression of dopamine d1 and d2 receptors. As adult isolation was sufficient to trigger the hyperactive phenotype and impaired neuroplasticity in the prefrontal cortex, it could be a candidate for a refinement strategy for certain research questions. To fully grade the severity of post-weaning social isolation and the alternatives, adult isolation and resocialization, a more profound and multimodal assessment approach is necessary.

The impact of handling technique and handling frequency on laboratory mouse welfare is sex-specific.

Handling is a well-known source of stress to laboratory animals and can affect variability of results and even compromise animal welfare. The conventional tail handling in mice has been shown to induce aversion and anxiety-like behaviour. Recent findings demonstrate that the use of alternative handling techniques, e.g. tunnel handling, can mitigate negative handling-induced effects. Here, we show that technique and frequency of handling influence affective behaviour and stress hormone release of subjects in a sex-dependent manner. While frequent tail handling led to a reduction of wellbeing-associated burrowing and increased despair-like behaviour in male mice, females seemed unaffected. Instead, they displayed a stress response to a low handling frequency, which was not detectable in males. This could suggest that in terms of refinement, the impact in handling could differ between the sexes. Independently from this observation, both sexes preferred to interact with the tunnel. Mice generally explored the tunnel more often than the tail-handling hands of the experimenter and showed more positively rated approaches, e.g. touching or climbing, and at the same time, less defensive burrowing, indicating a strong preference for the tunnel.

Systematic analysis of severity in a widely used cognitive depression model for mice.

Animal models in psychiatric research are indispensable for insights into mechanisms of behaviour and mental disorders. Distress is an important aetiological factor in psychiatric diseases, especially depression, and is often used to mimic the human condition. Modern bioethics requires balancing scientific progress with animal welfare concerns. Therefore, scientifically based severity assessment of procedures is a prerequisite for choosing the least compromising paradigm according to the 3Rs principle. Evidence-based severity assessment in psychiatric animal models is scarce, particularly in depression research. Here, we assessed severity in a cognitive depression model by analysing indicators of stress and well-being, including physiological (body weight and corticosterone metabolite concentrations) and behavioural (nesting and burrowing behaviour) parameters. Additionally, a novel approach for objective individualised severity grading was employed using clustering of voluntary wheel running (VWR) behaviour. Exposure to the paradigm evoked a transient elevation of corticosterone, but neither affected body weight, nesting or burrowing behaviour. However, the performance in VWR was impaired after recurrent stress exposure, and the individual severity level increased, indicating that this method is more sensitive in detecting compromised welfare. Interestingly, the direct comparison to a somatic, chemically induced colitis model indicates less distress in the depression model. Further objective severity assessment studies are needed to classify the severity of psychiatric animal models in order to balance validity and welfare, reduce the stress load and thus promote refinement.

Effects of Soy in Laboratory Rodent Diets on the Basal, Affective, and Cognitive Behavior of C57BL/6 Mice.

Soy is one of the most common sources of protein in many commercial formulas for laboratory rodent diets. Soy contains isoflavones, which are estrogenic. Therefore, soy-containing animal diets might influence estrogen-regulated systems, including basal behavioral domains, as well as affective behavior and cognition. Furthermore, the isoflavone content of soy varies, potentially unpredictably confounding behavioral results. Therefore researchers are increasingly considering completely avoiding dietary soy to circumvent this problem. Several animal studies have investigated the effects of soy free diets but produced inconsistent results. In addition, most of these previous studies were performed in outbred rat or mouse strains. In the current study, we assessed whether a soy-free diet altered locomotion, exploration, nesting, anxiety-related behaviors, learning, and memory in C57BL/6 mice, the most common inbred strain used in biomedical research. The parameters evaluated address measures of basic health, natural behavior, and affective state that also are landmarks for animal welfare. We found minor differences between feeding groups but no indications of altered welfare. We therefore suggest that a soy-free diet can be used as a standard diet to prevent undesirable side effects of isoflavones and to further optimize diet standardization, quality assurance, and ultimately increase the reproducibility of experiments.

Differential Neuroinflammatory Response in Male and Female Mice: A Role for BDNF.

A growing body of evidence supports the close relationship between major depressive disorder (MDD), a severe psychiatric disease more common among women than men, and alterations of the immune/inflammatory system. However, despite the large number of studies aimed at understanding the molecular bases of this association, a lack of information exists on the potential cross-talk between systems known to be involved in depression and components of the inflammatory response, especially with respect to sex differences. Brain-derived neurotrophic factor (BDNF) is a neurotrophin with a well-established role in MDD etiopathology: it is altered in depressed patients as well as in animal models of the disease and its changes are restored by antidepressant drugs. Interestingly, this neurotrophin is also involved in the inflammatory response. Indeed, it can be secreted by microglia, the primary innate immune cells in the central nervous system whose functions may be in turn regulated by BDNF. With these premises, in this study, we investigated the reciprocal impact of BDNF and the immune system by evaluating the neuroinflammatory response in male and female BDNF-heterozygous mutant mice acutely treated with the cytokine-inducer lipopolysaccharide (LPS). Specifically, we assessed the potential onset of an LPS-induced sickness behavior as well as changes of inflammatory mediators in the mouse hippocampus and frontal cortex, with respect to both genotype and sex. We found that the increased inflammatory response induced by LPS in the brain of male mice was independent of the genotype, whereas in the female, it was restricted to the heterozygous mice with no changes in the wild-type group, suggestive of a role for BDNF in the sex-dependent effect of the inflammatory challenge. Considering the involvement of both BDNF and neuroinflammation in several psychiatric diseases and the diverse incidence of such pathologies in males and females, a deeper investigation of the mechanisms underlying their interaction may have a critical translational relevance.

Altered prepulse inhibition of the acoustic startle response in BDNF-deficient mice in a model of early postnatal hypoxia: implications for schizophrenia.

The brain-derived neurotrophic factor (BDNF) is a major proliferative agent in the nervous system. Both BDNF-deficiency and perinatal hypoxia represent genetic/environmental risk factors for schizophrenia. Moreover, a decreased BDNF response to birth hypoxia was associated with the disease. BDNF expression is influenced by neuronal activity and environmental conditions such as hypoxia. Thus, it may partake in neuroprotective and reparative mechanisms in acute or chronic neuronal insults. However, the interaction of hypoxia and BDNF is insufficiently understood and the behavioral outcome unknown. Therefore, we conducted a battery of behavioral tests in a classical model of chronic early postnatal mild hypoxia (10% O2), known to significantly impair brain development, in BDNF-deficient mice. We found selective deficits in measures associated with sensorimotor gating, namely enhanced acoustic startle response (ASR) and reduced prepulse inhibition (PPI) of ASR in BDNF-deficient mice. Unexpectedly, the alterations of sensorimotor gating were caused only by BDNF-deficiency alone, whereas hypoxia failed to evoke severe deficits and even leads to a milder phenotype in BDNF-deficient mice. As deficits in sensorimotor gating are present in schizophrenia and animal models of the disease, our results are of relevance regarding the involvement of BDNF in its pathogenesis. On the other hand, they suggest that the effect of perinatal hypoxia on long-term brain abnormalities is complex, ranging from protective to deleterious actions, and may critically depend on the degree of hypoxia. Therefore, future studies may refine existing hypoxia protocols to better understand neurodevelopmental consequences associated with schizophrenia.

Neural Mechanisms of Early-Life Social Stress as a Developmental Risk Factor for Severe Psychiatric Disorders.

BACKGROUND: To explore the domain-general risk factor of early-life social stress in mental illness, rearing rodents in persistent postweaning social isolation has been established as a widely used animal model with translational relevance for neurodevelopmental psychiatric disorders such as schizophrenia. Although changes in resting-state brain connectivity are a transdiagnostic key finding in neurodevelopmental diseases, a characterization of imaging correlates elicited by early-life social stress is lacking. METHODS: We performed resting-state functional magnetic resonance imaging of postweaning social isolation rats (N = 23) 9 weeks after isolation. Addressing well-established transdiagnostic connectivity changes of psychiatric disorders, we focused on altered frontal and posterior connectivity using a seed-based approach. Then, we examined changes in regional network architecture and global topology using graph theoretical analysis. RESULTS: Seed-based analyses demonstrated reduced functional connectivity in frontal brain regions and increased functional connectivity in posterior brain regions of postweaning social isolation rats. Graph analyses revealed a shift of the regional architecture, characterized by loss of dominance of frontal regions and emergence of nonfrontal regions, correlating to our behavioral results, and a reduced modularity in isolation-reared rats. CONCLUSIONS: Our result of functional connectivity alterations in the frontal brain supports previous investigations postulating social neural circuits, including prefrontal brain regions, as key pathways for risk for mental disorders arising through social stressors. We extend this knowledge by demonstrating more widespread changes of brain network organization elicited by early-life social stress, namely a shift of hubness and dysmodularity. Our results highly resemble core alterations in neurodevelopmental psychiatric disorders such as schizophrenia, autism, and attention-deficit/hyperactivity disorder in humans.