Models Of Psychiatric Diseases Research Articles

Mice with deficiency in Pcdh15, a gene associated with bipolar disorders, exhibit significantly elevated diurnal amplitudes of locomotion and body temperature

Genetic factors significantly affect the pathogenesis of psychiatric disorders. However, the specific pathogenic mechanisms underlying these effects are not fully understood. Recent extensive genomic studies have implicated the protocadherin-related 15 (PCDH15) gene in the onset of psychiatric disorders, such as bipolar disorder (BD). To further investigate the pathogenesis of these psychiatric disorders, we developed a mouse model lacking Pcdh15. Notably, although PCDH15 is primarily identified as the causative gene of Usher syndrome, which presents with visual and auditory impairments, our mice with Pcdh15 homozygous deletion (Pcdh15-null) did not exhibit observable structural abnormalities in either the retina or the inner ear. The Pcdh15-null mice showed very high levels of spontaneous motor activity which was too disturbed to perform standard behavioral testing. However, the Pcdh15 heterozygous deletion mice (Pcdh15-het) exhibited enhanced spontaneous locomotor activity, reduced prepulse inhibition, and diminished cliff avoidance behavior. These observations agreed with the symptoms observed in patients with various psychiatric disorders and several mouse models of psychiatric diseases. Specifically, the hyperactivity may mirror the manic episodes in BD. To obtain a more physiological, long-term quantification of the hyperactive phenotype, we implanted nano tag® sensor chips in the animals, to enable the continuous monitoring of both activity and body temperature. During the light-off period, Pcdh15-null exhibited elevated activity and body temperature compared with wild-type (WT) mice. However, we observed a decreased body temperature during the light-on period. Comprehensive brain activity was visualized using c-Fos mapping, which was assessed during the activity and temperature peak and trough. There was a stark contrast between the distribution of c-Fos expression in Pcdh15-null and WT brains during both the light-on and light-off periods. These results provide valuable insights into the neural basis of the behavioral and thermal characteristics of Pcdh15-deletion mice. Therefore, Pcdh15-deletion mice can be a novel model for BD with mania and other psychiatric disorders, with a strong genetic component that satisfies both construct and surface validity.

Integrative metabolomics-genomics analysis identifies key networks in a stem cell-based model of schizophrenia

Schizophrenia (SCZ) is a neuropsychiatric disorder, caused by a combination of genetic and environmental factors. The etiology behind the disorder remains elusive although it is hypothesized to be associated with the aberrant response to neurotransmitters, such as dopamine and glutamate. Therefore, investigating the link between dysregulated metabolites and distorted neurodevelopment holds promise to offer valuable insights into the underlying mechanism of this complex disorder. In this study, we aimed to explore a presumed correlation between the transcriptome and the metabolome in a SCZ model based on patient-derived induced pluripotent stem cells (iPSCs). For this, iPSCs were differentiated towards cortical neurons and samples were collected longitudinally at various developmental stages, reflecting neuroepithelial-like cells, radial glia, young and mature neurons. The samples were analyzed by both RNA-sequencing and targeted metabolomics and the two modalities were used to construct integrative networks in silico. This multi-omics analysis revealed significant perturbations in the polyamine and gamma-aminobutyric acid (GABA) biosynthetic pathways during rosette maturation in SCZ lines. We particularly observed the downregulation of the glutamate decarboxylase encoding genes GAD1 and GAD2, as well as their protein product GAD65/67 and their biochemical product GABA in SCZ samples. Inhibition of ornithine decarboxylase resulted in further decrease of GABA levels suggesting a compensatory activation of the ornithine/putrescine pathway as an alternative route for GABA production. These findings indicate an imbalance of cortical excitatory/inhibitory dynamics occurring during early neurodevelopmental stages in SCZ. Our study supports the hypothesis of disruption of inhibitory circuits to be causative for SCZ and establishes a novel in silico approach that enables for integrative correlation of metabolic and transcriptomic data of psychiatric disease models.

Microbial short-chain fatty acids regulate drug seeking and transcriptional control in a model of cocaine seeking.

Cocaine use disorder represents a public health crisis with no FDA-approved medications for its treatment. A growing body of research has detailed the important connections between the brain and the resident population of bacteria in the gut, the gut microbiome, in psychiatric disease models. Acute depletion of gut bacteria results in enhanced reward in a mouse cocaine place preference model, and repletion of bacterially-derived short-chain fatty acid (SCFA) metabolites reverses this effect. However, the role of the gut microbiome and its metabolites in modulating cocaine-seeking behavior after prolonged abstinence is unknown. Given that relapse prevention is the most clinically challenging issue in treating substance use disorders, studies examining the effects of microbiome manipulations in relapse-relevant models are critical. Here, male Sprague-Dawley rats received either untreated water or antibiotics to deplete the gut microbiome and its metabolites. Rats were trained to self-administer cocaine and subjected to either within-session threshold testing to evaluate motivation for cocaine or 21 days of abstinence followed by a cue-induced cocaine-seeking task to model relapse behavior. Microbiome depletion did not affect cocaine acquisition on an fixed-ratio 1 schedule. However, microbiome-depleted rats exhibited significantly enhanced motivation for low dose cocaine on a within-session threshold task. Similarly, microbiome depletion increased cue-induced cocaine-seeking following prolonged abstinenceand altered transcriptional regulation in the nucleus accumbens. In the absence of a normal microbiome, repletion of bacterially-derived SCFA metabolites reversed the behavioral and transcriptional changes associated with microbiome depletion. These findings suggest that gut bacteria, via their metabolites, are key regulators of drug-seeking behaviors, positioning the microbiome as a potential translational research target.

The Role of Metabotropic Glutamate Receptor Subtype 5 in Mouse Models of Cocaine Addiction

Cocaine is a psychostimulant that is one of the most widely used illicit drugs, particularly in America. Cocaine addiction is a chronic relapsing disease that is characterized by drug craving and loss of inhibitory control. Animal models of psychiatric diseases are essential to identify underlying neural circuitry and to test the effectiveness of novel pharmacotherapies to prevent relapse. Current research using animal models indicates that type 5 metabotropic glutamate receptors may be of particular importance to the onset and maintenance of cocaine addiction. This literature review provides a general overview of the glutamate system, and the animal models frequently used in the study of addiction and summarizes peer-reviewed research focused on cocaine-induced adaptations to the type 5 metabotropic glutamate receptors in mice. Cocaine administration in mouse models induces a range of neural changes in the brain, reflecting the neuroadaptations associated with cocaine addiction. Cocaine-induced adaptations to type 5 metabotropic glutamate receptor vary by brain region and by methodological constraints. Key neural changes that occur in the mouse brain following cocaine administration include adaptations in the dopaminergic and glutamatergic systems. The interplay between mGluR5 and the dopamine system plays a significant role in the neurobiological adaptations that drive cocaine addiction. Lastly, we cover the potential efficacy of targeting this receptor as a novel therapeutic option to prevent cocaine relapse. Selective antagonists of this receptor have been studied for their potential therapeutic effects in mouse models of cocaine addiction. These compounds reduce the conditioned responses to drug-associated cues and reduce the motivation to seek cocaine, thereby inhibiting relapse-like behavior, and have been found to modulate synaptic plasticity in brain regions involved in addiction, such as the nucleus accumbens and prefrontal cortex. Overall, these compounds demonstrate promising effects in mouse models of cocaine addiction.

The Difficult Path to the Discovery of Novel Treatments in Psychiatric Disorders.

CNS diseases, including psychiatric disorders, represent a significant opportunity for the discovery and development of new drugs and therapeutic treatments with the potential to have a significant impact on human health. CNS diseases, however, present particular challenges to therapeutic discovery efforts, and psychiatric diseases/disorders may be among the most difficult. With specific exceptions such as psychostimulants for ADHD, a large number of psychiatric patients are resistant to existing treatments. In addition, clinicians have no way of knowing which psychiatric patients will respond to which drugs. By definition, psychiatric diagnoses are syndromal in nature; determinations of efficacy are often self-reported, and drug discovery is largely model-based. While such models of psychiatric disease are amenable to screening for new drugs, whether cellular or whole-animal based, they have only modest face validity and, more importantly, predictive validity. Multiple academic, pharmaceutical industry, and government agencies are dedicated to the translation of new findings about the neurobiology of major psychiatric disorders into the discovery and advancement of novel therapies. The collaboration of these agencies provide a pathway for developing new therapeutics. These efforts will be greatly helped by recent advances in understanding the genetic bases of psychiatric disorders, the ongoing search for diagnostic and therapy-responsive biomarkers, and the validation of new animal models.

Translational cognitive systems: focus on attention.

Cognitive dysfunction, particularly attentional impairment, is a core feature of many psychiatric disorders, yet is inadequately addressed by current treatments. Development of targeted therapeutics for the remediation of attentional deficits requires knowledge of underlying neurocircuit, cellular, and molecular mechanisms that cannot be directly assayed in the clinic. This level of detail can only be acquired by testing animals in cross-species translatable attentional paradigms, in combination with preclinical neuroscience techniques. The 5-choice continuous performance test (5C-CPT) and rodent continuous performance test (rCPT) represent the current state of the art of preclinical assessment of the most commonly studied subtype of attention: sustained attention, or vigilance. These tasks present animals with continuous streams of target stimuli to which they must respond (attention), in addition to non-target stimuli from which they must withhold responses (behavioral inhibition). The 5C-CPT and rCPT utilize the same measures as gold-standard clinical continuous performance tests and predict clinical efficacy of known pro-attentional drugs. They also engage common brain regions across species, although efforts to definitively establish neurophysiological construct validity are ongoing. The validity of these tasks as translational vigilance assessments enables their use in characterizing the neuropathology underlying attentional deficits of animal models of psychiatric disease, and in determining therapeutic potential of drugs ahead of clinical testing. Here, we briefly review the development and validation of such tests of attentional functioning, as well as the data they have generated pertaining to inattention, disinhibition, and impulsivity in psychiatric disorders.

All-optical approaches to studying psychiatric disease.

Improvements in all-optical means of monitoring and manipulating neural activity have generated new ways of studying psychiatric disease. The combination of calcium imaging techniques with optogenetics to concurrently record and manipulate neural activity has been used to create new disease models that link distinct circuit abnormalities to specific disease dimensions. These approaches represent a new path towards the development of more effective treatments, as they allow researchers to identify circuit manipulations that normalize pathological network activity. In this review we highlight the utility of all-optical approaches to generate new psychiatric disease models where the specific circuit abnormalities associated with disease symptomology can be assessed in vivo and in response to manipulations designed to normalize disease states. We then outline the principles underlying all-optical interrogations of neural circuits and discuss practical considerations for experimental design.

The Consequences of Structural Racism on Gray and White Matter in Threat-Relevant Brain Regions

Limited research has investigated racial/ethnic disparities in childhood adversity that often disproportionately burden Black and other minoritized groups and are relevant neurobiological models of psychiatric disease. The present analyses assessed gray matter volume (GMV) and fractional anisotropy (FA) of threat-related brain circuitry in Black and White children and their relationship with early life adversity.

Impaired discrimination of a subanesthetic dose of ketamine in a maternal immune activation model of schizophrenia risk.

Animal models of psychiatric diseases suffer from a lack of reliable methods for accurate assessment of subjective internal states in nonhumans. This gap makes translation of results from animal models to patients particularly challenging. Here, we used the drug-discrimination paradigm to allow rats that model a risk factor for schizophrenia (maternal immune activation, MIA) to report on the subjective internal state produced by a subanesthetic dose of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. The MIA rats' discrimination of ketamine was impaired relative to controls, both in the total number of rats that acquired and the asymptotic level of discrimination accuracy. This deficit was not due to a general inability to learn to discriminate an internal drug cue or internal state generally, as MIA rats were unimpaired in the learning and acquisition of a morphine drug discrimination and were as sensitive to the internal state of satiety as controls. Furthermore, the deficit was not due to a decreased sensitivity to the physiological effects of ketamine, as MIA rats showed increased ketamine-induced locomotor activity. Finally, impaired discrimination of ketamine was only seen at subanesthetic doses which functionally correspond to psychotomimetic doses in humans. These data link changes in NMDA responses to the MIA model. Furthermore, they confirm the utility of the drug-discrimination paradigm for future inquiries into the subjective internal state produced in models of schizophrenia and other developmental diseases.

Vortioxetine Improves Mood and Cognitive Function in Animal Models of Psychiatric Disease: Relevance of 5-HT3 Receptor-Mediated Regulation of GABA and Glutamate Neurotransmission

Vortioxetine is a multimodal antidepressant that improves mood and some cognitive functions major depressive disorder (MDD). Vortioxetine has a complex pharmacological profile that includes 5-HT3 receptor antagonism, which is thought to induce regionally selective increases glutamatergic neurotransmission by suppressing activity in GABAergic interneurons. In the present work, the relevance of 5-HT3 receptor antagonism for improving mood and cognition will be evaluated in animal models of MDD and schizophrenia.

PsyCoP - A Platform for Systematic Semi-Automated Behavioral and Cognitive Profiling Reveals Gene and Environment Dependent Impairments of Tcf4 Transgenic Mice Subjected to Social Defeat.

Recently, hundreds of risk genes associated with psychiatric disorders have been identified. These are thought to interact with environmental stress factors in precipitating pathological behaviors. However, the individual phenotypes resulting from specific genotype by environment (G×E) interactions remain to be determined. Toward a more systematic approach, we developed a novel standardized and partially automatized platform for systematic behavioral and cognitive profiling (PsyCoP). Here, we assessed the behavioral and cognitive disturbances in Tcf4 transgenic mice (Tcf4tg) exposed to psychosocial stress by social defeat during adolescence using a “two-hit” G×E mouse model. Notably, TCF4 has been repeatedly identified as a candidate risk gene for different psychiatric diseases and Tcf4tg mice display behavioral endophenotypes such as fear memory impairment and hyperactivity. We use the Research Domain Criteria (RDoC) concept as framework to categorize phenotyping results in a translational approach. We propose two methods of dimension reduction, clustering, and visualization of behavioral phenotypes to retain statistical power and clarity of the overview. Taken together, our results reveal that sensorimotor gating is disturbed by Tcf4 overexpression whereas both negative and positive valence systems are primarily influenced by psychosocial stress. Moreover, we confirm previous reports showing that deficits in the cognitive domain are largely dependent on the interaction between Tcf4 and psychosocial stress. We recommend that the standardized analysis and visualization strategies described here should be applied to other two-hit mouse models of psychiatric diseases and anticipate that this will help directing future preclinical treatment trials.

Optogenetically-inspired neuromodulation: Translating basic discoveries into therapeutic strategies.

Optogenetic tools allow for the selective activation, inhibition or modulation of genetically-defined neural circuits with incredible temporal precision. Over the past decade, application of these tools in preclinical models of psychiatric disease has advanced our understanding the neural circuit basis of maladaptive behaviors in these disorders. Despite their power as an investigational tool, optogenetics cannot yet be applied in the clinical for the treatment of neurological and psychiatric disorders. To date, deep brain stimulation (DBS) is the only clinical treatment that can be used to achieve circuit-specific neuromodulation in the context of psychiatric. Despite its increasing clinical indications, the mechanisms underlying the therapeutic effects of DBS for psychiatric disorders are poorly understood, which makes optimization difficult. We discuss the variety of optogenetic tools available for preclinical research, and how these tools have been leveraged to reverse-engineer the mechanisms underlying DBS for movement and compulsive disorders. We review studies that have used optogenetics to induce plasticity within defined basal ganglia circuits, to alter neural circuit function and evaluate the corresponding effects on motor and compulsive behaviors. While not immediately applicable to patient populations, the translational power of optogenetics is in inspiring novel DBS protocols by providing a rationale for targeting defined neural circuits to ameliorate specific behavioral symptoms, and by establishing optimal stimulation paradigms that could selectively compensate for pathological synaptic plasticity within these defined neural circuits.

Early-life stress effects on BDNF DNA methylation in first-episode psychosis and in rats reared in isolation

Stressful events during early-life are risk factors for psychiatric disorders. Brain-derived neurotrophic factor (BDNF) is implicated in psychosis pathophysiology and deficits in BDNF mRNA in animal models of psychiatric disease are reported. DNA methylation can control gene expression and may be influenced by environmental factors such as early-life stress. We investigated BDNF methylation in first-episode psychosis (FEP) patients (n = 58), their unaffected siblings (n = 29) and community-based controls (n = 59), each of whom completed the Childhood Trauma Questionnaire (CTQ); BDNF methylation was also tested in male Wistar rats housed isolated or grouped from weaning. DNA was extracted from human blood and rat brain (prefrontal cortex and hippocampus), bisulphite-converted and the methylation of equivalent sequences within BDNF exon IV determined by pyrosequencing. BDNF methylation did not differ significantly between diagnostic groups; however, individuals who had experienced trauma presented higher levels of methylation. We found association between the mean BDNF methylation and total CTQ score in FEP, as well as between individual CpG sites and subtypes of trauma. No significant correlations were found for controls or siblings with child trauma. These results were independent of age, gender, body mass index, BDNF genotype or LINE-1, a measure of global methylation, which showed no significant association with trauma. Isolation rearing resulted in increased BDNF methylation in both brain regions compared to group-housed animals, a correlate of previously reported changes in gene expression. Our results suggest that childhood maltreatment may result in increased BDNF methylation, providing a mechanism underlying the association between early-life stress and psychosis.

Computational Analysis of Multidimensional Behavioral Alterations After Chronic Social Defeat Stress

BackgroundThe study of depression in humans depends on animal models that attempt to mimic specific features of the human syndrome. Most studies focus on one or a few behavioral domains, with time and practical considerations prohibiting a comprehensive evaluation. Although machine learning has enabled unbiased analysis of behavior in animals, this has not yet been applied to animal models of psychiatric disease. MethodsWe performed chronic social defeat stress (CSDS) in mice and evaluated behavior with PsychoGenics’ SmartCube, a high-throughput unbiased automated phenotyping platform that collects >2000 behavioral features based on machine learning. We evaluated group differences at several times post-CSDS and after administration of the antidepressant medication imipramine. ResultsSmartCube analysis after CSDS successfully separated control and defeated-susceptible mice, and defeated-resilient mice more resembled control mice. We observed a potentiation of CSDS effects over time. Treatment of susceptible mice with imipramine induced a 40.2% recovery of the defeated-susceptible phenotype as assessed by SmartCube. ConclusionsHigh-throughput analysis can simultaneously evaluate multiple behavioral alterations in an animal model for the study of depression, which provides a more unbiased and holistic approach to evaluating group differences after CSDS and perhaps can be applied to other mouse models of psychiatric disease.

Noradrenergic circuits in the forebrain control affective responses to novelty

In rodents, exposure to novel environments elicits initial anxiety-like behavior (neophobia) followed by intense exploration (neophilia) that gradually subsides as the environment becomes familiar. Thus, innate novelty-induced behaviors are useful indices of anxiety and motivation in animal models of psychiatric disease. Noradrenergic neurons are activated by novelty and implicated in exploratory and anxiety-like responses, but the role of norepinephrine (NE) in neophobia has not been clearly delineated. We sought to define the role of central NE transmission in neophilic and neophobic behaviors. We assessed dopamine β-hydroxylase knockout (Dbh -/-) mice lacking NE and their NE-competent (Dbh +/-) littermate controls in neophilic (novelty-induced locomotion; NIL) and neophobic (novelty-suppressed feeding; NSF) behavioral tests with subsequent quantification of brain-wide c-fos induction. We complimented the gene knockout approach with pharmacological interventions. Dbh -/- mice exhibited blunted locomotor responses in the NIL task and completely lacked neophobia in the NSF test. Neophobia was rescued in Dbh -/- mice by acute pharmacological restoration of central NE with the synthetic precursor L-3,4-dihydroxyphenylserine (DOPS), and attenuated in control mice by the inhibitory α2-adrenergic autoreceptor agonist guanfacine. Following either NSF or NIL, Dbh -/- mice demonstrated reduced c-fos in the anterior cingulate cortex, medial septum, ventral hippocampus, bed nucleus of the stria terminalis, and basolateral amygdala. These findings indicate that central NE signaling is required for the expression of both neophilic and neophobic behaviors. Further, we describe a putative noradrenergic novelty network as a potential therapeutic target for treating anxiety and substance abuse disorders.

Perspective: Classifying Orthorexia Nervosa as a New Mental Illness—Much Discussion, Little Evidence

Significant prevalence rates of pathological healthful eating and its extreme form, orthorexia nervosa (ON), the pathological obsession with healthy eating, have led to increased efforts to understand this phenomenon's clinical relevance. This narrative review qualitatively summarizes existing evidence on the (psycho-)pathology and consequences of ON and offers an interpretation within the frame of existing theories and models of psychiatric disease. Adding to the controversy in the field of ON, this review offers important critiques and identifies gaps in our current understanding of ON as a (distinct) mental illness.

T166. VISUALIZATION OF AMPA RECEPTORS IN PATIENTS WITH SCHIZOPHRENIA AND DEPRESSION: THE FIRST PET IMAGING STUDY

BackgroundEvidence on physiological roles of AMPA receptors in psychiatric conditions, including schizophrenia, has been accumulated, which mainly derives from psychiatric disease model animals as well as post-mortem brain tissues. However, its clinical translation was limited due to lack of any tool to visualize AMPA receptors in living human brain. We have recently developed a new positron emission tomography (PET) probe for AMPA receptors (Miyazaki et al. Nature Medicine, in press). Here, we used the first PET probe that specifically binds to AMPA receptors and successfully visualized these receptors in living human brain of patients with schizophrenia.MethodsWe developed a novel PET probe for AMPARs, named [11C]K-2 (Miyazaki et al. Nature Medicine, in press). Male patients aged 30–49 with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) underwent a [11C]K-2 PET scan and an MRI scan for co-registration of the PET image and received clinical assessments for symptomatology, including the Positive and Negative Syndrome Scale (PANSS) (registration number: UMIN000025132).[11C]K-2 was synthesized at Yokohama City University Hospital in accordance with GMP ordinance and was certified by the Japanese Society of Nuclear Medicine. PET imaging was performed with a TOSHIBA Aquiduo scanner (TOSHIBA Medical), which provided an axial FOV of 240 mm, and 80 contiguous 2.0 mm thick slices. Standardized uptake value ratio (SUVR)30–50 min with the whole brain and white matter as a reference was calculated, respectively.ResultsTen subjects with schizophrenia (mean±SD age, 43.1±3.1 years; duration of illness, 16.8±8.0 years; PANSS total score, 61.7±13.4) participated in this study. There were negative correlations between SUVR30-50 min with the whole brain as a reference in the cingulate gyrus and parahippocampus and PANSS total scores according to the voxel-wise analysis. These correlations were not observed when the while matter was used as a reference.Discussion[11C]K-2 has revealed distinct distribution patterns of AMPA receptors for schizophrenia. Thus, [11C]K-2 is proven to be a potent PET tracer that can be used to visualize AMPARs with high contrast, leading to the elucidation of the molecular mechanisms of schizophrenia.

Antipsychotic lurasidone: Behavioural and pharmacokinetic data in C57BL/6 mice

Lurasidone is an atypical antipsychotic that has been shown to be effective in reversing schizophrenia-related cognitive impairment. The development of new preclinical models of schizophrenia is a key for improving treatments of cognitive symptoms. This study investigated the effects of chronic lurasidone treatment in C57BL/6 male mice via intraperitoneal injection (1 mg/kg daily at 5 p.m. for 5 weeks). A large battery of behavioural tests was performed (between 9 a.m. and 5 p.m.), which is currently used to assess face validity in animal models of psychiatric diseases. Overall, lurasidone did not interfere with behavioural performances, which characterises very good tolerance to such a high dose. Moreover, pharmacokinetic parameters after i.p. and oral administration were measured. Mean transit time (MTT) values were 1.91 h (1 mg/kg acute i.p.) and 1.74 h (8.3 mg/kg acute oral), respectively, and relative bioavailability comparing these two routes of administration was of 19.8%. This last result gives important data to adapt oral chronic administration of lurasidone with a more ethical perspective in comparison with chronic i.p. injections. This study brings tools to improve pharmacological validity of preclinical models of psychiatric diseases, and to adapt dosage of antipsychotics according to the route used.

High fidelity: Assessing zebrafish (Danio rerio) responses to social stimuli across several levels of realism

Behavioral assays of zebrafish shoaling have recently been employed to investigate social behavior in zebrafish models of psychiatric disease. Many studies have developed simulated models of conspecifics to serve as alternatives to live shoals in order to examine specific cues that contribute to shoaling behavior. However, no studies have investigated the extent to which zebrafish prefer one stimulus over another when given the choice between two conspecific alternatives (live or simulated). In the present study, we employed a new, four-quadrant choice preference task that allowed zebrafish to swim freely between a live shoal and a motorized mobile shoal, a live shoal and playback of a video-recorded shoal, or a motorized mobile shoal and playback of a video-recorded shoal. Behavior tracking software was used to track subjects’ movements in upper and lower quadrants on either side of the test arena. Subjects spent more time near the live shoal, especially in the lower quadrant, and exhibited different swim patterns in response to each simulated conspecific alternative, suggesting that zebrafish prefer a live shoal over models of lower fidelity.

Ectopic Mossy Fiber Pathfinding in the Hippocampus Caused the Abnormal Neuronal Transmission in the Mouse Models of Psychiatric Disease.

Appropriate axonal pathfinding is a necessary step for the function of neuronal circuits. The mossy fibers (MFs) in the hippocampus of CaMKIIα heterozygous knockout (CaMKIIα-hKO) psychiatric model mice project onto not only the stratum lucidum but also the stratum oriens region in the CA3, which is a projection pattern distinct from that in normal mice. Thus, we examined the electrophysiological properties of the MF-CA3 connection in this mutant mouse on field recordings and found a lower synaptic connection. This study suggested that the phenotype of abnormal MF pathfindings could induce aberrant neuronal functions, which may link to cognition and memory.