Animal Models Of Neuropsychiatric Disorders Research Articles

Environmental enrichment reduces innate anxiety with no effect on depression-like behaviour in mice lacking the serotonin transporter.

Along with being the main target of many antidepressant medications, the serotonin transporter (5-HTT) is known to be involved in the pathophysiology of depression and anxiety disorders. In line with this, mice with varying 5-HTT genotypes are invaluable tools to study depression- and anxiety-like behaviours as well as the mechanisms mediating potential therapeutics. There is clear evidence that both genetic and environmental factors play a role in the aetiology of psychiatric disorders. In that regard, housing paradigms which seek to enhance cognitive stimulation and physical activity have been shown to exert beneficial effects in animal models of neuropsychiatric disorders. In the present study, we examined the effects of environmental enrichment on affective-like behaviours and sensorimotor gating function of 5-HTT knock-out (KO) mice. Using the elevated-plus maze and the light-dark box, we found that environmental enrichment ameliorated the abnormal innate anxiety of 5-HTT KO mice on both tests. In contrast, environmental enrichment did not rescue the depression-like behaviour displayed by 5-HTT KO mice in the forced-swim test. Finally, measuring pre-pulse inhibition, we found no effect of genotype or treatment on sensorimotor gating. In conclusion, our data suggest that environmental enrichment specifically reduces innate anxiety of 5-HTT KO mice with no amelioration of the depression-like behaviour. This has implications for the current use of clinical interventions for patients with symptoms of both anxiety and depression.

Introduction to special issue on animal models of neuropsychiatric disorders and substance use disorders: Progress and gaps.

This is an introduction to the special issue, "Animal Models of Neuropsychiatric Disorders and Substance Use Disorders: Progress and Gaps." This issue presents 6 original research reports describing the use of mice and rats to model neurodevelopmental disorders, depressive disorders, anxiety disorders, and substance use disorders. Collectively, these studies demonstrate the progress of the field and the gaps and challenges that remain. They also illustrate the range of conditions that are informed by animal models and identify the clinical populations that stand to benefit from their use in preclinical research. (PsycINFO Database Record

Preserved cognition and reduced age-related cognitive decline during treatment with angiotensin II receptor blockers: A 20-year follow-up study

IntroductionModulators of the brain renin-angiotensin system (RAS) have been shown to improve cognitive functioning in several animal models of neuropsychiatric disorders. Moreover, the brain RAS has been considered a new target for the treatment of Alzheimer's disease (AD). However, there are no population-based follow-up studies supporting this hypothesis.ObjectivesCross-sectional and prospective relationships between cognitive decline and ARB treatment were examined in the population-based Kuopio Ischemic Heart Disease Risk Factor Study.AimsTo evaluate procognitive/antidementia capacity of orally delivered angiotensin II receptor blockers (ARB).MethodsThe study was conducted on a sample of 1774 subjects (920 females, 854 males; age range at baseline: 42–61 years) from Eastern Finland. An established cutoff score of at least 2-point decrease in the Mini Mental State Examination over a 9-year follow-up was used to detect age-related cognitive decline in the cross-sectional setting. In the prospective setting, a hospital discharge diagnosis of dementia/AD was used as outcome variable. Cross-sectional relationships were determined with logistic regression and prospective analyses were conducted with the Cox proportional hazards model (both adjusted for relevant background variables).ResultsCross-sectional analysis displayed a decrease of the odds of cognitive decline (n = 87; 4.9% of participants) in those with ARB treatment; OR = 0.445, 95% CI: 0.22–0.90, P = 0.024. Furthermore, in the prospective setting, the risk of dementia/AD diagnosis (n = 149; 8.4% of participants) was significantly reduced in ARB treated participants; HR = 0.621, 95% CI: 0.40–0.98, P = 0.038.ConclusionsARB treatment is associated with a decreased risk for age-related cognitive decline and dementia/AD manifestation.Disclosure of interestThe authors have not supplied their declaration of competing interest.

M40 - Effect of Chronic Treatment With Psychiatric Medications Aripiprazole And Riluzole on Dna Methylation Profiles In The Rat Striatum And Prefrontal Cortex

Background One of the main epigenetic mechanisms is DNA methylation. It mostly occurs in CpG islands in the promoters by addition of a methyl group to a cytosine that may inhibit gene expression. It is known that many developmental disorders are characterized by alterations in epigenetic mechanisms. Moreover, studies in animal models of neuropsychiatric disorders have shown that epigenetics may play an important role in pathogenesis and therapy. The aim of this study is to investigate the effect of drugs used in different psychiatric diseases including Tourette Syndrome (TS) on DNA methylation to find epigenetic targets that may influence the efficacy of treatment. Methods Treatment: Wistar Kyoto rats were chronically treated from post-natal day (PND) 35 to PND50 by intraperitoneal injection of either aripiprazole or riluzole or vehicle. Metabolite changes during the treatment were quantified by magnetic resonance spectroscopy in the striatum and prefrontal cortex. Samples: DNA isolated from striatum and prefrontal cortex was used for methylation studies. Reduced Representation Bisulfite Sequencing (RRBS): RRBS is a high-throughput technique used to analyze genome-wide methylation profiles at the single nucleotide level. It provides information of the most relevant genomic regions which are likely to influence gene expression. We analyzed striatum and prefrontal cortex of 2 rats in each group treated with aripiprazole (a dopaminergic neuroleptic) or riluzole (a glutamatergic anxiolytic) or vehicle in order to identify DNA methylation changes due to these drug treatments. Mass-Spectrometry: The analysis was performed by LC-MS/MS on striatum and prefrontal cortex in order to quantify the amount of 5-methyl-Cytosine (mC) and 5-HydroxyMethylCytosine (5hmC) after drug treatment. Results Mass-Spectrometry: LC-MS/MS showed significant differences in 5hmC levels in prefrontal cortex after treatment with aripiprazole and riluzole. The same trend was also observed for mC levels. We found no differences in methylation or hydroxy-methylation levels in striatal samples. RRBS: we observed differences in overall methylation levels between treatment using the two drugs and the vehicle. We identified differentially methylated CpG sites (DMS) and characterized their distribution across the genome (eg. promoter, intron, exon, UTR, etc.). Treatment with riluzole led to identification of 156 DMS in striatum and 346 DMS in prefrontal cortex. Treatment with aripiprazole yielded 117 DMS in striatum and 466 DMS in prefrontal cortex. The identified CpG sites were annotated, a candidate gene list was created and pathway analysis was also performed on these genes. Interestingly, most of the changes occurred in intergenic regions far from TSS suggesting that enhancers are the regions most prone to undergo methylation changes. Moreover, several genes (eg. OXTR, DRD2, etc.) have been associated with brain disorders or functions. Discussion The known functions of implicated genes suggest that some of the observed epigenetic changes might underlie the amelioration of symptoms by these drugs and some may account for certain adverse effects. Data on differential DNA methylation will be compared with imaging data on the respective brain regions. The results give insights into the mechanism of action of aripiprazole and riluzole as well as the side effects, not just in TS, but also in a broader context regarding these psychiatric medications.

Connecting Brain Proteomics with Behavioural Neuroscience in Translational Animal Models of Neuropsychiatric Disorders.

Modelling psychiatric disorders in animals has been hindered by several challenges related to our poor understanding of the disease causes. This chapter describes recent advances in translational research which may lead to animal models and relevant proteomic biomarkers that can be informative about disease mechanisms and potential new therapeutic targets. The review focuses on the behavioural and molecular correlates in models of schizophrenia and major depressive disorder, as guided by recently established Research Domain Criteria (RDoC). This approach is based on providing proteomic data for aetiologically driven, behaviourally well-characterised animal models to link discovered biomarker candidates with the human disease.

Optogenetics: Applications in neurobiology

Commonly used neuromodulation techniques such as electrical stimulation or pharmacologic intervention have some technical limitations that preclude dissecting particular cell- or pathway-specific functions in the brain, which is composed of billions of neurons. An advancement of molecular genetics techniques has provided a novel method in neuroscience called optogenetics. Optogenetics uses a combination of genetic and optical methods that provide a means to, with great temporal precision, experimentally control the activation or suppression of specific neuronal sub-populations in heterogeneous brain regions where multiple neuronal subtypes exist; this approach can be performed even on freely moving animals. Thus, this tool can uniquely assist in establishing causality between the disorder and the underlying pathology. Ongoing exploration of pathological mechanisms in various animal models of neuropsychiatric disorders with precise tools such as optogenetics can provide significant advances in the development of more focused approaches to treatment of these disorders. Here, we selectively highlight the major advancements gained by the use of optogenetic tools to uncover at circuit levels mechanisms relevant to neuropsychiatric disorders.

Re-evaluating the link between neuropsychiatric disorders and dysregulated adult neurogenesis.

People diagnosed with neuropsychiatric disorders such as depression, anxiety, addiction or schizophrenia often have dysregulated memory, mood, pattern separation and/or reward processing. These symptoms are indicative of a disrupted function of the dentate gyrus (DG) subregion of the brain, and they improve with treatment and remission. The dysfunction of the DG is accompanied by structural maladaptations, including dysregulation of adult-generated neurons. An increasing number of studies using modern inducible approaches to manipulate new neurons show that the behavioral symptoms in animal models of neuropsychiatric disorders can be produced or exacerbated by the inhibition of DG neurogenesis. Thus, here we posit that the connection between neuropsychiatric disorders and dysregulated DG neurogenesis is beyond correlation or epiphenomenon, and that the regulation of adult-generated DG neurogenesis merits continued and focused attention in the ongoing effort to develop novel treatments for neuropsychiatric disorders.

Neural changes induced by antipsychotic administration in adolescence: A review of studies in laboratory rodents.

Adolescence is characterized by major remodelling processes in the brain. Use of antipsychotic drugs (APDs) in adolescents has increased dramatically in the last 20 years; however, our understanding of the neurobiological consequences of APD treatment on the adolescent brain has not kept the same pace and significant concerns have been raised. In this review, we examined currently available preclinical studies of the effects of APDs on the adolescent brain. In animal models of neuropsychiatric disorders, adolescent APD treatment appears to be protective against selected structural, behavioural and neurochemical phenotypes. In "neurodevelopmentally normal" adolescent animals, a range of short- and long-term alterations in behaviour and neurochemistry have been reported. In particular, the adolescent brain appears to be sensitive to long-term locomotor/reward effects of chronic atypical APDs in contrast with the outcomes in adults. Long-lasting changes in dopaminergic, glutamatergic and gamma-amino butyric acid-ergic systems induced by adolescent APD administration have been observed in the nucleus accumbens. A detailed examination of other potential target regions such as striatum, prefrontal cortex and ventral tegmental area is still required. Through identification of specific neural pathways targeted by adolescent APD treatment, future studies will expand the current knowledge on long-term neural outcomes which are of translational value.

Spontaneous Gamma Activity in Schizophrenia.

A major goal of translational neuroscience is to identify neural circuit abnormalities in neuropsychiatric disorders that can be studied in animal models to facilitate the development of new treatments. Oscillations in the gamma band (30-100 Hz) of the electroencephalogram have received considerable interest as the basic mechanisms underlying these oscillations are understood, and gamma abnormalities have been found in schizophrenia (SZ). Animal models of SZ based on hypofunction of the N-methyl-d-aspartate receptor (NMDAR) demonstrate increased spontaneous broadband gamma power, but this phenomenon has not been identified clearly in patients with SZ. To examine spontaneous gamma power and its relationship to evoked gamma oscillations in the auditory cortex of patients with SZ. We performed a cross-sectional study including 24 patients with chronic SZ and 24 matched healthy control participants at the Veterans Affairs Boston Healthcare System from January 1, 2009, through December 31, 2012. Electroencephalograms were obtained during auditory steady-state stimulation at multiple frequencies (20, 30, and 40 Hz) and during a resting state in 18 participants in each group. Electroencephalographic activity in the auditory cortex was estimated using dipole source localization. Auditory steady-state response (ASSR) measures included the phase-locking factor and evoked power. Spontaneous gamma power was measured as induced (non-phase-locked) gamma power in the ASSR data and as total gamma power in the resting-state data. The ASSR phase-locking factor was reduced significantly in patients with SZ compared with controls for the 40-Hz stimulation (mean [SD], 0.075 [0.028] vs 0.113 [0.065]; F1,46 = 6.79 [P = .012]) but not the 20- or the 30-Hz stimulation (0.042 [0.038] vs 0.043 [0.034]; F1,46 = 0.006 [P = .938] and 0.084 [0.040] vs 0.098 [0.050]; F1,46 = 1.605 [P = .212], respectively), repeating previous findings. The mean [SD] broadband-induced (30-100 Hz) gamma power was increased in patients with SZ compared with controls during steady-state stimulation (6.579 [3.783] vs 3.984 [1.843]; F1,46 = 9.128 [P = .004]; d = 0.87) but not during rest (0.006 [0.003] vs 0.005 [0.002]; F1,34 = 1.067 [P = .309]; d = 0.35). Induced gamma power in the left hemisphere of the patients with SZ during the 40-Hz stimulation was positively correlated with auditory hallucination symptoms (tangential, ρ = 0.587 [P = .031]; radial, ρ = 0.593 [P = .024]) and negatively correlated with the ASSR phase-locking factor (baseline: ρ = -0.572 [P = .024]; ASSR: ρ = -0.568 [P = .032]). Spontaneous gamma activity is increased during auditory steady-state stimulation in SZ, reflecting a disruption in the normal balance of excitation and inhibition. This phenomenon interacts with evoked oscillations, possibly contributing to the gamma ASSR deficit found in SZ. The similarity of increased spontaneous gamma power in SZ to the findings of increased spontaneous gamma power in animal models of NMDAR hypofunction suggests that spontaneous gamma power could serve as a biomarker for the integrity of NMDARs on parvalbumin-expressing inhibitory interneurons in humans and in animal models of neuropsychiatric disorders.

The Biomaterial Relevance of Oxytocin in Some Zebrafish Studies

Oxytocin is a nonapeptide hormone that is involved, besides its classical functions, in linking social signals with cognition, behaviors and reward. Also, it seems to have a critical role in the regulation of brain-mediated processes that are strongly relevant to many neuropsychiatric disorders. In this way, in the present paper we will try to describe the most important and modern aspects regarding the relevance of oxytocin administration in various animal models of neuropsychiatric disorders, as well as in human patients. Also, the relevance of zebrafish studies in this context will be extensively discussed.

Association of brain immune genes with social behavior of inbred mouse strains.

BackgroundSocial deficit is one of the core symptoms of neuropsychiatric diseases, in which immune genes play an important role. Although a few immune genes have been shown to regulate social and emotional behaviors, how immune gene network(s) may jointly regulate sociability has not been investigated so far.MethodsTo decipher the potential immune-mediated mechanisms underlying social behavior, we first studied the brain microarray data of eight inbred mouse strains with known variations in social behavior and retrieved the differentially expressed immune genes. We then made a protein-protein interaction analysis of them to find the major networks and explored the potential association of these genes with the behavior and brain morphology in the mouse phenome database. To validate the expression and function of the candidate immune genes, we selected the C57BL/6 J and DBA/2 J strains among the eight inbred strains, compared their social behaviors in resident-intruder and 3-chambered social tests and the mRNA levels of these genes, and analyzed the correlations of these genes with the social behaviors.ResultsA group of immune genes were differentially expressed in the brains of these mouse strains. The representative C57BL/6 J and DBA/2 J strains displayed significant differences in social behaviors, DBA/2 J mice being less active in social dominance and social interaction than C57BL/6 J mice. The mRNA levels of H2-d1 in the prefrontal cortex, hippocampus, and hypothalamus and C1qb in the hippocampus of the DBA/2 J strain were significantly down-regulated as compared to those in the C57BL/6 J strain. In contrast, Polr3b in the hippocampus and Tnfsf13b in the prefrontal cortex of the DBA/2 J strain were up-regulated. Furthermore, C1qb, Cx3cl1, H2-d1, H2-k1, Polr3b, and Tnfsf13b were predicted to be associated with various behavioral and brain morphological features across the eight inbred strains. Importantly, the C1qb mRNA level was confirmed to be significantly correlated with the sociability in DBA/2 J but not in C57BL/6 J mice.ConclusionsOur study provided evidence on the association of immune gene network(s) with the brain development and behavior in animals and revealed neurobiological functions of novel brain immune genes that may contribute to social deficiency in animal models of neuropsychiatric disorders.

Neural correlates of sensorimotor gating: a metabolic positron emission tomography study in awake rats.

Impaired sensorimotor gating occurs in neuropsychiatric disorders such as schizophrenia and can be measured using the prepulse inhibition (PPI) paradigm of the acoustic startle response. This assay is frequently used to validate animal models of neuropsychiatric disorders and to explore the therapeutic potential of new drugs. The underlying neural network of PPI has been extensively studied with invasive methods and genetic modifications. However, its relevance for healthy untreated animals and the functional interplay between startle- and PPI-related areas during a PPI session is so far unknown. Therefore, we studied awake rats in a PPI paradigm, startle control and background noise control, combined with behavioral [18F]fluoro-2-deoxyglucose positron emission tomography (FDG-PET). Subtractive analyses between conditions were used to identify brain regions involved in startle and PPI processing in well-hearing Black hooded rats. For correlative analysis with regard to the amount of PPI we also included hearing-impaired Lister hooded rats that startled more often, because their hearing threshold was just below the lowest prepulses. Metabolic imaging showed that the brain areas proposed for startle and PPI mediation are active during PPI paradigms in healthy untreated rats. More importantly, we show for the first time that the whole PPI modulation network is active during “passive” PPI sessions, where no selective attention to prepulse or startle stimulus is required. We conclude that this reflects ongoing monitoring of stimulus significance and constant adjustment of sensorimotor gating.

Comprehensive Behavioural Analysis of Long Evans and Sprague-Dawley Rats Reveals Differential Effects of Housing Conditions on Tests Relevant to Neuropsychiatric Disorders

Genetic (G) and environmental (E) manipulations are known to alter behavioural outcomes in rodents, however many animal models of neuropsychiatric disorders only use a restricted selection of strain and housing conditions. The aim of this study was to examine GxE interactions comparing two outbred rat strains, which were housed in either standard or enriched cages. The strains selected were the albino Sprague-Dawley rat, commonly used for animal models, and the other was the pigmented Long Evans rat, which is frequently used in cognitive studies. Rats were assessed using a comprehensive behavioural test battery and included well-established tests frequently employed to examine animal models of neuropsychiatric diseases, measuring aspects of anxiety, exploration, sensorimotor gating and cognition. Selective strain and housing effects were observed on a number of tests. These included increased locomotion and reduced pre-pulse inhibition in Long Evans rats compared to Sprague Dawley rats; and rats housed in enriched cages had reduced anxiety-like behaviour compared to standard housed rats. Long Evans rats required fewer sessions than Sprague Dawley rats to learn operant tasks, including a signal detection task and reversal learning. Furthermore, Long Evans rats housed in enriched cages acquired simple operant tasks faster than standard housed Long Evans rats. Cognitive phenotypes in animal models of neuropsychiatric disorders would benefit from using strain and housing conditions where there is greater potential for both enhancement and deficits in performance.

Introduction. Animal models of neuropsychiatric disorders.

Introduction. Animal models of neuropsychiatric disorders.

Neurotransmitters, Psychotropic Drugs and Microglia: Clinical Implications for Psychiatry

Psychiatric disorders have long and dominantly been regarded to be induced by disturbances of neuronal networks including synapses and neurotransmitters. Thus, the effects of psychotropic drugs such as antipsychotics and antidepressants have been understood to modulate synaptic regulation via receptors and transporters of neurotransmitters such as dopamine and serotonin. Recently, microglia, immunological/inflammatory cells in the brain, have been indicated to have positive links to psychiatric disorders. Positron emission tomography (PET) imaging and postmortem studies have revealed microglial activation in the brain of neuropsychiatric disorders such as schizophrenia, depression and autism. Animal models of neuropsychiatric disorders have revealed the underlying microglial pathologies. In addition, various psychotropic drugs have been suggested to have direct effects on microglia. Until now, the relationship between microglia, neurotransmitters and psychiatric disorders has not been well understood. Therefore, in this review, at first, we summarize recent findings of interaction between microglia and neurotransmitters such as dopamine, serotonin, norepinephrine, acetylcholine and glutamate. Next, we introduce up-to-date knowledge of the effects of psychotropic drugs such as antipsychotics, antidepressants and antiepileptics on microglial modulation. Finally, we propose the possibility that modulating microglia may be a key target in the treatment of various psychiatric disorders. Further investigations and clinical trials should be conducted to clarify this perspective, using animal in vivo studies and imaging studies with human subjects.

S.18.04 Animal models of neuropsychiatric disorders: ketamine and related drugs

S.18.04 Animal models of neuropsychiatric disorders: ketamine and related drugs

Expanding Potential Drug Targets Could Refill Research Pipeline

Expanding Potential Drug Targets Could Refill Research Pipeline

Immediate and Sustained Improvements in Working Memory After Selective Stimulation of α7 Nicotinic Acetylcholine Receptors

Nicotine improves cognition in humans and animal models of neuropsychiatric disorders. Here, we sought to establish whether selective stimulation of the neuronal nicotinic α7 receptor could improve spatial working memory in nonhuman primates. Beginning with an estimated dose range from rodent studies, the dose of the α7 agonist AZD0328 was titrated for a significant impact on working memory in rhesus macaques after acute administration. After training to stability on the spatial delayed response task, subjects were administered AZD0328 (1.6 ng/kg-.48 mg/kg; intramuscular) or vehicle 30 min before cognitive testing. AZD0328 (1 ng/kg-1.0 μg/kg; intramuscular) was then administered in a repeated, intermittent ascending dose regimen where each dose was given in two bouts for 4 days with a 1-week washout in between bouts, followed by 2-week washout. Acute AZD0328 improved cognitive performance when the dose was titrated down to .0016 and .00048 mg/kg from a cognitively impairing dose of .48 mg/kg. In a subgroup, sustained enhancement of working memory was evident for 1 month or more after acute treatment. Immediate and sustained cognitive enhancement was also found during and after repeated administration of AZD0328 at .001 mg/kg. These findings demonstrate that extremely low doses of a nicotinic α7 agonist can have profound acute and long-lasting beneficial consequences for cognition, dependent upon the integrity of dorsolateral prefrontal cortex. Thus, the α7 receptor might have a fundamental role in the neural circuitry of working memory and in the synaptic plasticity upon which it might depend.

Animal models of neuropsychiatric disorders

Modeling of human neuropsychiatric disorders in animals is extremely challenging given the subjective nature of many symptoms, the lack of biomarkers and objective diagnostic tests, and the early state of the relevant neurobiology and genetics. Nonetheless, progress in understanding pathophysiology and in treatment development would benefit greatly from improved animal models. Here we review the current state of animal models of mental illness, with a focus on schizophrenia, depression and bipolar disorder. We argue for areas of focus that might increase the likelihood of creating more useful models, at least for some disorders, and for explicit guidelines when animal models are reported.

Effect of alpha1-adrenergic antagonist prazosin on behavioral alterations induced by MK-801 in a spatial memory task in Long-Evans rats

Animal models of neuropsychiatric disorders are current topics in behavioral neuroscience. Application of non-competitive antagonists of NMDA receptors (such as MK-801) was proposed as a model of schizophrenia, as it leads to specific behavioral alterations, which are partly analogous to human psychotic symptoms. This study examined an animal model of schizophrenia induced by a systemic application of MK-801 (0.15 and 0.20 mg/kg) into rats tested in the active allothetic place avoidance (AAPA) task. Previous studies suggested that MK-801 may interact in vivo with other neurotransmitter systems, including noradrenergic system. Our experiments therefore evaluated the hypothesis that both locomotor stimulation and deficit in avoidance behavior in AAPA task induced by this drug would be reversible by application of alpha(1)-adrenergic antagonist prazosin (1 and 2 mg/kg). The results showed that both doses of prazosin partially reversed hyperlocomotion induced by higher doses of MK-801 and an avoidance deficit measured as number of entrances into the shock sector. Interestingly, no effect of prazosin on the MK-801-induced decrease of maximum time between two entrances (another measure of cognitive performance) was observed. These results support previous data showing that prazosin can compensate for the hyperlocomotion induced by MK-801 and newly show that this partial reduction sustains even in the forced locomotor conditions, which are involved in the AAPA task. The study also shows that certain parameters of avoidance efficiency may be closely related to locomotor activity, whereas other measures of cognition may more selectively reflect cognitive changes.