Human Neuropsychiatric Disorders Research Articles

Pathological mechanisms of glial cell activation and neurodegenerative and neuropsychiatric disorders caused by Toxoplasma gondii infection.

Toxoplasma gondii is an intracellular opportunistic parasite that exists in a latent form within the human central nervous system (CNS), even in immune-competent hosts. During acute infection, T. gondii traverses the blood-brain barrier (BBB). In the subsequent chronic infection phase, the infiltration of immune cells into the brain, driven by T. gondii infection and the formation of parasitic cysts, leads to persistent activation and proliferation of astrocytes and microglia. This process results in neuronal damages that are fatal in some cases. Through inducing systemic immune responses, T. gondii infection can dramatically alter the behavior of rodents and increase the risk of various neuropsychiatric disorders in humans. In this review, we explore some recent research progress on the major events involved in BBB disruption, glial cell activation and neuronal damage following T. gondii infection in hosts. It further discusses potential pathological mechanisms and the feasible treatment approaches for the neurodegenerative and neuropsychiatric disorders caused by T. gondii infection to extend our understanding for pathogenesis and preventive control of toxoplasmosis in humans.

Time-on-task-related decrements in performance in the rodent continuous performance test are not caused by physical disengagement from the task.

Attention deficits, a hallmark of many neuropsychiatric disorders, significantly impair quality of life and functional outcome for patients. Continuous Performance Tests (CPTs) are widely used to assess attentional function in clinical settings and have been adapted for mice as the rodent Continuous Performance Test (rCPT). In this study, we combined traditional analyses of rCPT performance with markerless pose estimation using DeepLabCut and visual field analysis (VFA) to objectively measure the orientation of mice toward stimuli during rCPT sessions. Additionally, we extended session lengths to assess performance decrements over time. Our findings show that extending rCPT sessions from 45 to 90 minutes results in a significant decline in performance in male mice, which aligns with performance decrements observed in clinical research. Importantly, physical engagement with the task remained relatively stable throughout the session, even as performance deteriorated. This suggests that the performance decline specifically reflects a time-on-task (TOT)-dependent vigilance decrement rather than physical disengagement. We also investigated the effects of amphetamine, an FDA-approved treatment for attention-deficit/hyperactivity disorder (ADHD), on rCPT performance. Amphetamine significantly improved rCPT performance in male mice by reducing false alarms without modulating orientation or physical engagement with the task stimuli. Collectively, these findings validate a behavioral tracking platform for objectively measuring physical engagement in the rCPT and a task modification that accentuates TOT-dependent performance decrements, enhancing the translational value of the rCPT for studies related to human neuropsychiatric disorders.

Translational approaches to the neurobiological study of conditional discrimination and inhibition: Implications for psychiatric disease.

There is a growing number of studies investigating discriminatory fear conditioning and conditioned inhibition of fear to assess safety learning, in addition to extinction of cued fear. Despite all of these paradigms resulting in a reduction in fear expression, there are nuanced differences among them, which could be mediated through distinct behavioral and neural mechanisms. These differences could impact how we approach potential treatment options in clinical disorders with dysregulated fear responses. The objective of this review is to give an overview of the conditional discrimination and inhibition findings reported in both animal models and human neuropsychiatric disorders. Both behavioral and neural findings are reviewed among human and rodent studies that include conditional fear discrimination via conditional stimuli with and without reinforcement (CS+ vs. CS-, respectively) and/or conditional inhibition of fear through assessment of the fear response to a compound CS-/CS+ cue versus CS+. There are several parallels across species in behavioral fear expression as well as neural circuits promoting fear reduction in response to a CS- and/or CS-/CS+ compound cue. Continued and increased efforts to compare similar behavioral fear inhibition paradigms across species are needed to make breakthrough advances in our understanding and treatment approaches to individuals with fear disorders. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Sex differences in neural projections of fear memory processing in mice and humans.

It remains unexplored in the field of fear memory whether functional neuronal connectivity between two brain areas is necessary for one sex but not the other. Here, we show that chemogenetic silencing of centromedial (CeM)-Tac2 fibers in the lateral posterior BNST (BNSTpl) decreased fear memory consolidation in male mice but not females. Optogenetic excitation of CeM-Tac2 fibers in the BNSTpl exhibited enhanced inhibitory postsynaptic currents in males compared to females. In vivo calcium imaging analysis revealed a sex-dimorphic fear memory engram in the BNSTpl. Furthermore, in humans, the single-nucleotide polymorphism (SNP) in the Tac2 receptor (rs2765) (TAC3R) decreased CeM-BNST connectivity in a fear task, impaired fear memory consolidation, and increased the expression of the TAC3R mRNA in AA-carrier men but not in women. These sex differences in critical neuronal circuits underlying fear memory formation may be relevant to human neuropsychiatric disorders with fear memory alterations such as posttraumatic stress disorder.

Sex differences in the distribution and density of regulatory interneurons in the striatum.

Dysfunction of the cortico-basal circuitry - including its primary input nucleus, the striatum - contributes to neuropsychiatric disorders, such as autism and Tourette Syndrome (TS). These conditions show marked sex differences, occurring more often in males than in females. Regulatory interneurons, such as cholinergic interneurons (CINs) and parvalbumin-expressing GABAergic fast spiking interneurons (FSIs), are implicated in human neuropsychiatric disorders such as TS, and ablation of these interneurons produces relevant behavioral pathology in male mice, but not in females. Here we investigate sex differences in the density and distribution of striatal interneurons. We use stereological quantification of CINs, FSIs, and somatostatin-expressing (SOM) GABAergic interneurons in the dorsal striatum (caudate-putamen) and the ventral striatum (nucleus accumbens) in male and female mice. Males have a higher density of CINs than females, especially in the dorsal striatum; females have equal distribution between dorsal and ventral striatum. FSIs showed similar distributions, with a greater dorsal-ventral density gradient in males than in females. SOM interneurons were denser in the ventral than in the dorsal striatum, with no sex differences. These sex differences in the density and distribution of FSIs and CINs may contribute to sex differences in basal ganglia function, particularly in the context of psychopathology.

Effects of age and sex on photoperiod modulation of nucleus accumbens monoamine content and release in adolescence and adulthood

Day length, or photoperiod, is a reliable environmental cue encoded by the brain's circadian clock that indicates changing seasons and induces seasonal biological processes. In humans, photoperiod, age, and sex have been linked to seasonality in neuropsychiatric disorders, as seen in Seasonal Affective Disorder, Major Depressive Disorder, and Bipolar Disorder. The nucleus accumbens is a key locus for the regulation of motivated behaviors and neuropsychiatric disorders. Using periadolescent and young adult male and female mice, here we assessed photoperiod's effect on serotonin and dopamine tissue content in the nucleus accumbens core, as well as on accumbal synaptic dopamine release and uptake. We found greater serotonin and dopamine tissue content in the nucleus accumbens from young adult mice raised in a Short winter-like photoperiod. In addition, dopamine release and clearance were greater in the nucleus accumbens from young adult mice raised in a Long summer-like photoperiod. Importantly, we found that photoperiod's effects on accumbal dopamine tissue content and release were sex-specific to young adult females. These findings support that in mice there are interactions across age, sex, and photoperiod that impact critical monoamine neuromodulators in the nucleus accumbens which may provide mechanistic insight into the age and sex dependencies in seasonality of neuropsychiatric disorders in humans.

The potential of baicalin to enhance neuroprotection and mitochondrial function in a human neuronal cell model

Baicalin is a flavone glycoside derived from flowering plants belonging to the Scutellaria genus. Previous studies have reported baicalin’s anti-inflammatory and neuroprotective properties in rodent models, indicating the potential of baicalin in neuropsychiatric disorders where alterations in numerous processes are observed. However, the extent of baicalin’s therapeutic effects remains undetermined in a human cell model, more specifically, neuronal cells to mimic the brain environment in vitro. As a proof of concept, we treated C8-B4 cells (murine cell model) with three different doses of baicalin (0.1, 1 and 5 μM) and vehicle control (DMSO) for 24 h after liposaccharide-induced inflammation and measured the levels of TNF-α in the medium by ELISA. NT2-N cells (human neuronal-like cell model) underwent identical baicalin treatment, followed by RNA extraction, genome-wide mRNA expression profiles and gene set enrichment analysis (GSEA). We also performed neurite outgrowth assays and mitochondrial flux bioanalysis (Seahorse) in NT2-N cells. We found that in C8-B4 cells, baicalin at ≥ 1 μM exhibited anti-inflammatory effects, lowering TNF-α levels in the cell culture media. In NT2-N cells, baicalin positively affected neurite outgrowth and transcriptionally up-regulated genes in the tricarboxylic acid cycle and the glycolysis pathway. Similarly, Seahorse analysis showed increased oxygen consumption rate in baicalin-treated NT2-N cells, an indicator of enhanced mitochondrial function. Together, our findings have confirmed the neuroprotective and mitochondria enhancing effects of baicalin in human-neuronal like cells. Given the increased prominence of mitochondrial mechanisms in diverse neuropsychiatric disorders and the paucity of mitochondrial therapeutics, this suggests the potential therapeutic application of baicalin in human neuropsychiatric disorders where these processes are altered.

In Humans, Insulo-striate Structural Connectivity is Largely Biased Toward Either Striosome-like or Matrix-like Striatal Compartments.

The insula is an integral component of sensory, motor, limbic, and executive functions, and insular dysfunction is associated with numerous human neuropsychiatric disorders. Insular efferents project widely, but insulo-striate projections are especially numerous. The targets of these insulo-striate projections are organized into tissue compartments, the striosome and matrix. These striatal compartments have distinct embryologic origins, afferent and efferent connectivity, dopamine pharmacology, and susceptibility to injury. Striosome and matrix appear to occupy separate sets of cortico-striato-thalamo-cortical loops, so a bias in insulo-striate projections toward one compartment may also embed an insular subregion in distinct regulatory and functional networks. Compartment-specific mapping of insulo-striate structural connectivity is sparse; the insular subregions are largely unmapped for compartment-specific projections. In 100 healthy adults, diffusion tractography was utilized to map and quantify structural connectivity between 19 structurally-defined insular subregions and each striatal compartment. Insulo-striate streamlines that reached striosome-like and matrix-like voxels were concentrated in distinct insular zones (striosome: rostro- and caudoventral; matrix: caudodorsal) and followed different paths to reach the striatum. Though tractography was generated independently in each hemisphere, the spatial distribution and relative bias of striosome-like and matrix-like streamlines were highly similar in the left and right insula. 16 insular subregions were significantly biased toward 1 compartment: 7 toward striosome-like voxels and 9 toward matrix-like voxels. Striosome-favoring bundles had significantly higher streamline density, especially from rostroventral insular subregions. The biases in insulo-striate structural connectivity that were identified mirrored the compartment-specific biases identified in prior studies that utilized injected tract tracers, cytoarchitecture, or functional MRI. Segregating insulo-striate structural connectivity through either striosome or matrix may be an anatomic substrate for functional specialization among the insular subregions.

Comparative neurogenetics of dog behavior complements efforts towards human neuropsychiatric genetics.

Domestic dogs display a wide array of heritable behaviors that have intermediate genetic complexity thanks to a long history of human-influenced selection. Comparative genetics in dogs could address the scarcity of non-human neurogenetic systems relevant to human neuropsychiatric disorders, which are characterized by mental, emotional, and behavioral symptoms and involve vastly complex genetic and non-genetic risk factors. Our review describes the diverse behavioral "phenome" of domestic dogs, past and ongoing sources of behavioral selection, and the state of canine behavioral genetics. We highlight two naturally disordered behavioral domains that illustrate how dogs may prove useful as a comparative, forward neurogenetic system: canine age-related cognitive dysfunction, which can be examined more rapidly given the attenuated lifespan of dogs, and compulsive disorders, which may have genetic roots in purpose-bred behaviors. Growing community science initiatives aimed at the companion dog population will be well suited to investigating such complex behavioral phenotypes and offer a comparative resource that parallels human genomic initiatives in scale and dimensionality.

Association of rs6323 with neuropsychiatric disorders: a mini-review

Abstract A data mining analysis was conducted on the National Center for Biotechnology Information database to identify the most extensively studied single-nucleotide variant within the MAO-A gene, which encodes monoamine oxidase A—an enzyme found in mitochondria involved in metabolizing neurotransmitters such as dopamine, norepinephrine, and serotonin. These neurochemicals play crucial roles in the development of various neuropsychiatric disorders. The analysis revealed that the single-nucleotide variant rs6323 has been the subject of significant research concerning its association with human neuropsychiatric disorders and behavioral problems. A thorough literature review was performed, examining original research articles linked to PubMed to evaluate the connection between rs6323 and different neuropsychiatric disorders and behavioral attributes. Multiple studies on diverse ethnic populations across various countries have reported a link between rs6323 and neuropsychiatric disorders and related behavioral characteristics. This review provides valuable insights into the association between rs6323 and neuropsychiatric disorders.

A Lightweight Drive Implant for Chronic Tetrode Recordings in Juvenile Mice.

In vivo electrophysiology provides unparalleled insight into the sub-second-level circuit dynamics of the intact brain and represents a method of particular importance for studying mouse models of human neuropsychiatric disorders. However, such methods often require large cranial implants, which cannot be used in mice at early developmental time points. As such, virtually no studies of in vivo physiology have been performed in freely behaving infant or juvenile mice, despite the fact that a better understanding of neurological development in this critical window would likely provide unique insights into age-dependent developmental disorders such as autism or schizophrenia. Here, a micro-drive design, surgical implantation procedure, and post-surgery recovery strategy are described that allow for chronic field and single-unit recordings from multiple brain regions simultaneously in mice as they age from postnatal day 20 (p20) to postnatal day 60 (p60) and beyond, a time window roughly corresponding to the human ages of 2 years old through to adulthood. The number of recording electrodes and final recording sites can be easily modified and expanded, thus allowing flexible experimental control of the in vivo monitoring of behavior- or disease-relevant brain regions across development.

Does the functional polymorphism-1562C/T of MMP-9 gene influence brain disorders?

Metalloproteinase-9 (MMP-9) is one of the most strongly expressed matrix metalloproteinases (MMPs) in the brain. The MMP-9 activity in the brain is strictly regulated, and any disruptions in this regulation contribute to a development of many disorders of the nervous system including multiple sclerosis, brain strokes, neurodegenerative disorders, brain tumors, schizophrenia, or Guillain-Barré syndrome. This article discusses a relationship between development of the nervous system diseases and the functional single nucleotide polymorphism (SNP) at position -1562C/T within the MMP-9 gene. A pathogenic influence of MMP-9-1562C/T SNP was observed both in neurological and psychiatric disorders. The presence of the allele T often increases the activity of the MMP-9 gene promoter and consequently the expression of MMP-9 when compared to the allele C. This leads to a change in the likelihood of an occurrence of diseases and modifies the course of certain brain diseases in humans, as discussed below. The presented data indicates that the MMP-9-1562C/T functional polymorphism influences the course of many neuropsychiatric disorders in humans suggesting a significant pathological role of the MMP-9 metalloproteinase in pathologies of the human central nervous system.

An Analysis of Genetic Predisposition to Hereditary Catalepsy in a Mouse Model of Neuropsychiatric Disorders Using Whole-Genome Sequencing Data.

Catalepsy is a behavioral condition that is associated with severe psychopathologies, including schizophrenia, depression, and Parkinson's disease. In some mouse strains, catalepsy can be induced by pinching the skin at the scruff of the neck. The main locus of hereditary catalepsy in mice has recently been linked to the 105-115 Mb fragment of mouse chromosome 13 by QTL analysis. We performed whole-genome sequencing of catalepsy-resistant and catalepsy-prone mouse strains in order to pinpoint the putative candidate genes related to hereditary catalepsy in mice. We remapped the previously described main locus for hereditary catalepsy in mice to the chromosome region 103.92-106.16 Mb. A homologous human region on chromosome 5 includes genetic and epigenetic variants associated with schizophrenia. Furthermore, we identified a missense variant in catalepsy-prone strains within the Nln gene. Nln encodes neurolysin, which degrades neurotensin, a peptide reported to induce catalepsy in mice. Our data suggest that Nln is the most probable candidate for the role of major gene of hereditary, pinch-induced catalepsy in mice and point to a shared molecular pathway between catalepsy in mice and human neuropsychiatric disorders.

The folate-centric concept of pathogenesis and GBINC personalized multidisciplinary approach to the clinical management of children with neuropsychiatric syndromes. Review

Solving the problem of children’s neuropsychiatric diseases is a priority task of modern medicine. The latest scientific achievements in the field of genetics, molecular biology and immunology, which demonstrate biochemical and immune‑dependent ways of formation of human neuropsychiatric disorders, shed light on the mechanisms of brain damage in children with ASD. These research give reason for optimism about overcoming this severe psychiatric pathology in the future thanks to the implementation of genetic, biochemical and immunodiagnostic approaches, as well as metabolic and immunotherapeutic interventions with neuroprotective effects. Currently, the folate‑centric concept of polygenic inheritance of predisposition to the development of neuropsychiatric syndromes in children with multisystem damage has been established. Biochemical and immune‑dependent (infectious, autoimmune, immunoinflammatory, and allergic) pathways of microbe‑induced autoimmune inflammatory encephalopathy with neuropsychiatric clinical manifestations are discussed in the context of the folate‑centric concept. Taking into account the new data, two personalized multidisciplinary approaches to the management of children with ASD and other neuropsychiatric syndromes are proposed. The first approach of J. J. Bradstreet et al. (2010) is based on the empirical analysis of a large group of laboratory biomarkers, the relevance of which has been demonstrated in clinical studies, and the targeted correction of abnormalities identified by biomarkers (so‑called biomarker‑guided interventions). In 2022, Frye R. developed a multidisciplinary personalized approach called BaS‑BiSTOR (collect Baseline data, search for Symptoms, measure Biomarkers, Select Treatment, Observe for Response), which systematizes and stratifies diagnostic and treatment interventions based on the assessment of biomarkers. In order to improve existing recommendations regarding specific subtypes of neuropsychiatric syndromes in children, this article proposes an improved personalized multidisciplinary approach to the clinical management of patients with autistic spectrum disorders and neuropsychiatric manifestations associated with genetic deficiency of the folate cycle, called GBINS (Genetic‑Biochemical‑Immunological‑Neurological‑Symptomatic evaluation). There are reasons to believe that the successful testing in clinical practice of evidence‑based personalized multidisciplinary diagnostic and treatment strategies will allow making a breakthrough in the clinical management of children with severe mental disorders in the near future, which will provide not only the possibility of recovery from a prognostically unfavorable and currently incurable neuropsychiatric disorder, but also and will contribute to stopping the large‑scale threatening epidemic of neuropsychiatric syndromes in the modern child population.

Threats to Benefits: Assessing Knowledge Production in Nonhuman Models of Human Neuropsychiatric Disorders.

Recent reports and papers on chimeric research highlight the promise of chimeric models of human neuropsychiatric disorders to ameliorate human suffering due to autism spectrum disorders, depression, and schizophrenia. These calls, however, typically do not acknowledge, much less address, criticisms of model creation and validation, or concerns about scientific conduct more generally. The ethical justification for the use of nonhuman animals in research depends on the production of benefits to humans based on such research. But the assessment and production of benefits are highly uncertain and rife with both practical and conceptual challenges. This essay provides a general framework for classifying the benefits of biomedical research and then focuses on two factors that directly impact-and threaten-the production of knowledge in research that models neuropsychiatric disorders.

Extended gene set analysis of human neuro-psychiatric traits shows enrichment in brain-expressed human accelerated regions across development

Human neuropsychiatric disorders are associated with genetic and environmental factors affecting the brain, which has been subjected to strong evolutionary pressures resulting in an enlarged cerebral cortex and improved cognitive performance. Thus, genes involved in human brain evolution may also play a role in neuropsychiatric disorders. We test whether genes associated with 7 neuropsychiatric phenotypes are enriched in genomic regions that have experienced rapid changes in human evolution (HARs) and importantly, whether HAR status interacts with developmental brain expression to predict associated genes. We used the most recent publicly available GWAS and gene expression data to test for enrichment of HARs, brain expression, and their interaction. These revealed significant interactions between HAR status and whole-brain expression across developmental stages, indicating that the relationship between brain expression and association with schizophrenia and intelligence is stronger among HAR than non-HAR genes. Follow-up regional analyses indicated that predicted HAR-expression interaction effects may vary substantially across regions and developmental stages. Although depression indicated significant enrichment of HAR genes, little support was found for HAR enrichment among bipolar, autism, ADHD, or Alzheimer's associated genes. Our results indicate that intelligence, schizophrenia, and depression-associated genes are enriched for those involved in the evolution of the human brain. These findings highlight promising candidates for follow-up study and considerations for novel drug development, but also caution careful assessment of the translational ability of animal models for studying neuropsychiatric traits in the context of HARs, and the importance of using humanized animal models or human-derived tissues when researching these traits.

An experimental study of the effects of SNPs in the TATA boxes of the GRIN1, ASCL3 and NOS1 genes on interactions with the TATA-binding protein.

The GRIN1, ASCL3, and NOS1 genes are associated with various phenotypes of neuropsychiatric disorders. For instance, these genes contribute to the development of schizophrenia, Alzheimer’s and Parkinson’s diseases, and epilepsy. These genes are also associated with various cancers. For example, ASCL3 is overexpressed in breast cancer, and NOS1, in ovarian cancer cell lines. Based on our findings and literature data, we had previously obtained results suggesting that the single-nucleotide polymorphisms (SNPs) that disrupt erythropoiesis are highly likely to be associated with cognitive and neuropsychiatric disorders in humans. In the present work, using SNP_TATA_Z-tester, we investigated the influence of unannotated SNPs in the TATA boxes of the promoters of the GRIN1, ASCL3, and NOS1 genes (which are involved in neuropsychiatric disorders and cancers) on the interaction of the TATA boxes with the TATA-binding protein (TBP). Double-stranded oligodeoxyribonucleotides identical to the TATA-containing promoter regions of the GRIN1, ASCL3, and NOS1 genes (reference and minor alleles) and recombinant human TBP were employed to study in vitro (by an electrophoretic mobility shift assay) kinetic characteristics of the formation of TBP–TATA complexes and their affinity. It was found, for example, that allele A of rs1402667001 in the GRIN1 promoter increases TBP–TATA affinity 1.4-fold, whereas allele C in the TATA box of the ASCL3 promoter decreases the affinity 1.4-fold. The lifetime of the complexes in both cases decreased by ~20 % due to changes in the rates of association and dissociation of the complexes (ka and kd, respectively). Our experimental results are consistent with the literature showing GRIN1 underexpression in schizophrenic disorders as well as an increased risk of cervical, bladder, and kidney cancers and lymphoma during ASCL3 underexpression. The effect of allele A of the –27G>A SNP (rs1195040887) in the NOS1 promoter is suggestive of an increased risk of ischemic damage to the brain in carriers. A comparison of experimental TBP–TATA affinity values (KD) of wild-type and minor alleles with predicted ones showed that the data correlate well (linear correlation coefficient r = 0.94, p <0.01).

Atypicality and controllability of autistic brain state dynamics in humans

Cognitive and behavioural activities are underpinned by dynamic neural activities on large-scale brain network architectures. Thus, atypical cognitions and behaviours seen in neuropsychiatric conditions should be accounted for by characteristic brain network dynamics and controlled by modifying such brain state dynamics. Here, I will present empirical, numerical and causal evidence for such a notion by taking autism spectrum disorder as an example. First, I will talk about energy landscape analysis that enables us to elucidate global neural dynamics behind seemingly unstable and fluctuating cognitive and behavioural tendencies. Next, I will show that the data-driven analysis method identified overly stable brain state dynamics as a key mechanism of both the symptoms and unique intelligence of high-functioning autistic individuals. Finally, I will introduce a brain-state-driven non-invasive neural stimulation method and recent results based on the device. The observations indicate the causal roles of the brain state dynamics on human behaviours and the possibility that modifying the large-scale neural dynamics can mitigate atypical cognition and behaviours in some neuropsychiatric disorders in humans.

Understanding them to understand ourselves: The importance of NHP research for translational neuroscience.

Studying higher brain function presents fundamental scientific challenges but has great potential for impactful translation to the clinic, supporting the needs of many patients suffering from conditions that relate to neuronal dysfunction. For many key questions relevant to human neurological conditions and clinical interventions, non-human primates (NHPs) remain the only suitable model organism and the only effective way to study the relationship between brain structure and function with the knowledge and tools currently available. Here we present three exemplary studies of current research yielding important findings that are directly translational to human clinical patients but which would be impossible without NHP studies. Our first example shows how studies of the NHP prefrontal cortex are leading to clinically relevant advances and potential new treatments for human neuropsychiatric disorders such as depression and anxiety. Our second example looks at the relevance of NHP research to our understanding of visual pathways and the visual cortex, leading to visual prostheses that offer treatments for otherwise blind patients. Finally, we consider recent advances in treatments leading to improved recovery of movement and motor control in stroke patients, resulting from our improved understanding of brain stem parallel pathways involved in movement in NHPs. The case for using NHPs in neuroscience research, and the direct benefits to human patients, is strong but has rarely been set out directly. This paper reviews three very different areas of neuroscience research, expressly highlighting the unique insights offered to each by NHP studies and their direct applicability to human clinical conditions.

Topoisomerase IIIβ Deficiency Induces Neuro-Behavioral Changes and Brain Connectivity Alterations in Mice.

Topoisomerase IIIβ (Top3β), the only dual-activity topoisomerase in mammals that can change topology of both DNA and RNA, is known to be associated with neurodevelopment and mental dysfunction in humans. However, there is no report showing clear associations of Top3β with neuropsychiatric phenotypes in mice. Here, we investigated the effect of Top3β on neuro-behavior using newly generated Top3β deficient (Top3β−/−) mice. We found that Top3β−/− mice showed decreased anxiety and depression-like behaviors. The lack of Top3β was also associated with changes in circadian rhythm. In addition, a clear expression of Top3β was demonstrated in the central nervous system of mice. Positron emission tomography/computed tomography (PET/CT) analysis revealed significantly altered connectivity between many brain regions in Top3β−/− mice, including the connectivity between the olfactory bulb and the cerebellum, the connectivity between the amygdala and the olfactory bulb, and the connectivity between the globus pallidus and the optic nerve. These connectivity alterations in brain regions are known to be linked to neurodevelopmental as well as psychiatric and behavioral disorders in humans. Therefore, we conclude that Top3β is essential for normal brain function and behavior in mice and that Top3β could be an interesting target to study neuropsychiatric disorders in humans.