A guide to the BRAIN Initiative Cell Census Network data ecosystem.

Characterizing cellular diversity at different levels of biological organization and across data modalities is a prerequisite to understanding the function of cell types in the brain. Classification of neurons is also essential to manipulate cell types in controlled ways and to understand their variation and vulnerability in brain disorders. The BRAIN Initiative Cell Census Network (BICCN) is an integrated network of data-generating centers, data archives, and data standards developers, with the goal of systematic multimodal brain cell type profiling and characterization. Emphasis of the BICCN is on the whole mouse brain with demonstration of prototype feasibility for human and nonhuman primate (NHP) brains. Here, we provide a guide to the cellular and spatial approaches employed by the BICCN, and to accessing and using these data and extensive resources, including the BRAIN Cell Data Center (BCDC), which serves to manage and integrate data across the ecosystem. We illustrate the power of the BICCN data ecosystem through vignettes highlighting several BICCN analysis and visualization tools. Finally, we present emerging standards that have been developed or adopted toward Findable, Accessible, Interoperable, and Reusable (FAIR) neuroscience. The combined BICCN ecosystem provides a comprehensive resource for the exploration and analysis of cell types in the brain.

A practical approach to the ethical use of memory modulating technologies.

BACKGROUND: Recent advancements in neuroscientific techniques have allowed us to make huge progress in our understanding of memories, and in turn has paved the way for new memory modification technologies (MMTs) that can modulate memories with a degree of precision, which was not previously possible. With advancements in such techniques, new and critical ethical questions have emerged. Understanding and framing these ethical questions within the current philosophical theories is crucial in order to systematically examine them as we translate these techniques to the clinic. MAIN BODY: In this paper, we discuss the ethical implications of modern neuroscience techniques that aim to disrupt or enhance memories. We attempt to frame the MMTs in the context of existing ethical philosophical theories to provide a cohesive analysis of the myriad of ethical quagmires that might emerge from such technologies. We argue the application of Aristotle's Golden Mean and multiple accounts of authenticity are useful in approaching the ethical questions surrounding MMTs. We then propose a framework in which ethical considerations can be systematically examined. Lastly, we provide caveats and considerations for the use of this framework. Overall, we provide a practical approach for the ethical use of MMTs depending on the situation. CONCLUSION: While at face value, our model appears to put severe limitations on the application of MMTs, we are not completely opposed to their use, but rather our framework guides the agent to consider the implications before making any decisions. Most importantly, we argue that the use of MMTs does not reduce the responsibility of the initial decision, and the agent must accept the post-MMT self as the new "true self" regardless of the outcome. As the developmental trajectory of MMTs suggests we are getting closer to practical clinical applications, ethical concerns across a wide range of disciplines need to be addressed to develop best strategies and policies when dealing with MMTs. If this can be achieved, we believe the ethical use of MMTs is not only possible but would also be of tremendous benefit to many people suffering from memory-related mental disorders.

Saffold virus, an emerging human cardiovirus.

Saffold virus (SAFV) is an emerging human cardiovirus that has been shown to be ubiquitous. Initial studies of SAFV focused on respiratory and gastrointestinal infection; however, it has also recently been associated with diverse clinical symptoms including the endocrine, cardiovascular, and neurological systems. Given the systemic nature of SAFV, and its high prevalence, understanding its pathogenicity and clinical impact is of utmost importance. This comprehensive review highlights and discusses recent developments in epidemiology, human pathogenicity, animal, and molecular studies related to SAFV. It also provides detailed insights into the neuropathogenicity of SAFV. We argue that human studies have been confounded by coinfections and therefore require support from robust molecular and animal research. Thereby, we aim to provide foresight into further research to better understand this emerging virus.

Immunohistochemical insights into Saffold virus infection of the brain of juvenile AG129 mice.

BACKGROUND: Saffold Virus (SAFV) is a human cardiovirus that is suspected of causing infection of the central nervous system (CNS) in children. While recent animal studies have started to elucidate the pathogenesis of SAFV, very little is known about the mechanisms behind it. METHOD: In this study, we attempted to elucidate some of the mechanisms of the pathogenesis of SAFV in the brain of a juvenile mouse model by using immunohistochemical methods. RESULTS: We first showed that SAFV is able to infect both neuronal and glial cells in the brain of 2 week-old AG129 mice. We then showed that SAFV is able to induce apoptosis in both neuronal and glial cells in the brain. Lastly, we showed that SAFV infection does not show any signs of gross demyelination in the brain. CONCLUSION: Overall, our results provide important insights into the mechanisms of SAFV in the brain.

Spatial Learning Requires mGlu5 Signalling in the Dorsal Hippocampus.

We examined the role of hippocampal metabotropic glutamate receptor 5 (mGlu5) in spatial learning and memory. Although it has been shown that mGlu5 signalling is required for certain forms of learning and memory, its role in spatial learning is unclear since studies using pharmacological or knockout mice models provide inconsistent findings. Additionally, the location in the brain where mGlu5 signalling may modulate such learning is yet to be precisely delineated. We stereotaxically injected rAAV-Cre into the dorsal hippocampus of mGlu5(loxP/loxP) mice to knockdown mGlu5 in that region. We show for the first time that knockdown of mGlu5 in the dorsal hippocampus is sufficient to impair spatial learning in Morris Water Maze. Locomotor activity and memory retrieval were unaffected by the mGlu5 knockdown. Taken together, these findings support a key role for dorsal hippocampal mGlu5 signalling in spatial learning.

Brain Data Standards - A method for building data-driven cell-type ontologies.

Large-scale single-cell 'omics profiling is being used to define a complete catalogue of brain cell types, something that traditional methods struggle with due to the diversity and complexity of the brain. But this poses a problem: How do we organise such a catalogue - providing a standard way to refer to the cell types discovered, linking their classification and properties to supporting data? Cell ontologies provide a partial solution to these problems, but no existing ontology schemas support the definition of cell types by direct reference to supporting data, classification of cell types using classifications derived directly from data, or links from cell types to marker sets along with confidence scores. Here we describe a generally applicable schema that solves these problems and its application in a semi-automated pipeline to build a data-linked extension to the Cell Ontology representing cell types in the Primary Motor Cortex of humans, mice and marmosets. The methods and resulting ontology are designed to be scalable and applicable to similar whole-brain atlases currently in preparation.

Antidepressant-like effects of transcorneal electrical stimulation in rat models.

BACKGROUND: Given that visual impairment is bi-directionally associated with depression, we examined whether transcorneal electrical stimulation (TES), a non-invasive treatment for visual disorders, can ameliorate depressive symptoms. OBJECTIVE: The putative antidepressant-like effects of TES and the underlying mechanisms were investigated in an S334ter-line-3 rat model of retinal degeneration and a rat model of chronic unpredictable stress (CUS). METHODS: TES was administered daily for 1 week in S334ter-line-3 and CUS rats. The effects of TES on behavioral parameters, plasma corticosterone levels, and different aspects of neuroplasticity, including neurogenesis, synaptic plasticity, and apoptosis, were examined. RESULTS: In S334ter-line-3 rats, TES induced anxiolytic and antidepressant-like behaviors in the cylinder, open field, home cage emergence, and forced swim tests. In the CUS rat model, TES induced hedonic-like behavior and decreased behavioral despair, which were accompanied by reduced plasma corticosterone levels and upregulated expression of neurogenesis-related genes. Treatment with the neurogenesis blocker temozolomide only inhibited the hedonic-like effect of TES, suggesting the antidepressant-like effects of TES were mediated through both neurogenesis-dependent and -independent mechanisms. Furthermore, TES was found to normalize the protein expression of synaptic markers and apoptotic Bcl-2-associated X protein in the hippocampus and amygdala in the CUS rat model. The improvements in neuroplasticity may involve protein kinase B (AKT) and protein kinase A (PKA) signaling pathways in the hippocampus and amygdala, respectively, as demonstrated by the altered pAKT/AKT and pPKA/PKA ratios. CONCLUSION: The overall findings suggest a possible neuroplasticity mechanism of the antidepressant-like effects of TES.

Ontology Development Kit: a toolkit for building, maintaining and standardizing biomedical ontologies.

Similar to managing software packages, managing the ontology life cycle involves multiple complex workflows such as preparing releases, continuous quality control checking and dependency management. To manage these processes, a diverse set of tools is required, from command-line utilities to powerful ontology-engineering environmentsr. Particularly in the biomedical domain, which has developed a set of highly diverse yet inter-dependent ontologies, standardizing release practices and metadata and establishing shared quality standards are crucial to enable interoperability. The Ontology Development Kit (ODK) provides a set of standardized, customizable and automatically executable workflows, and packages all required tooling in a single Docker image. In this paper, we provide an overview of how the ODK works, show how it is used in practice and describe how we envision it driving standardization efforts in our community. Database URL: https://github.com/INCATools/ontology-development-kit.

An existentialist approach to authentic science.

The pressures of the ethos of "publish or perish" in academia has led to a multitude of issues for science and scientists. In this paper, we argue that the existentialist philosophy concept of authenticity would be useful for scientists to prevent issues of reproducibility, data manipulation, fraud, and mentorship. We highlight some major caveats and call for policies to prevent them. Overall, we propose a way for scientists to ensure they do not succumb to the pressures of a career in science.

Prelimbic cortical stimulation disrupts fear memory consolidation through ventral hippocampal dopamine D2 receptors.

BACKGROUND AND PURPOSE: Anxiety disorders pose one of the biggest threats to mental health worldwide, yet current therapeutics have been mostly ineffective due to issues with relapse, efficacy and toxicity of the medications. Deep brain stimulation (DBS) is a promising therapy for treatment-resistant psychiatric disorders including anxiety, but very little is known about the effects of deep brain stimulation on fear memories. EXPERIMENTAL APPROACH: In this study, we employed a standard tone-footshock fear conditioning paradigm and modified plus maze discriminative avoidance task to probe the effects of prelimbic cortex deep brain stimulation on various stages of memory. KEY RESULTS: We identified memory consolidation stage as a critical time point to disrupt fear memory via prelimbic cortex deep brain stimulation. The observed disruption was partially modulated by the inactivation of the ventral hippocampus and the transient changes in ventral hippocampus dopamine (D2 ) receptors expression upon prelimbic cortex deep brain stimulation. We also observed wide-scale changes of various neurotransmitters and their metabolites in ventral hippocampus, confirming its important role in response to prelimbic cortex deep brain stimulation. CONCLUSION AND IMPLICATIONS: These findings highlight the molecular mechanism in the ventral hippocampus in response to prelimbic cortex stimulation and may have translational value, indicating that targeting the prelimbic cortex in the memory consolidation stage via non-invasive neuromodulation techniques may be a feasible therapeutic strategy against anxiety disorders.

Interdisciplinary Research in Alzheimer's Disease and the Roles International Societies Can Play.

An ever-increasing ageing population has elevated Alzheimer's disease to be one of the biggest challenges in modern medicine. Alzheimer's disease is highly complex, and we are still no closer to understanding the causes, let alone an effective treatment. The lack of good experimental models and lack of critical understanding has led to high failure rates of clinical trials with high associated costs, as well as difficulties in implementing treatments. The multifaceted nature of this disease highlights the need for an interdisciplinary approach to address these concerns. In this essay, we suggest how collaborative work can be useful in addressing some of the above issues. We then propose that international organisations and publishers need to support interdisciplinary research by creating platforms, lobbying funders, and pushing for interdisciplinary publications. We further highlight some of the issues involved in implementing these suggestions and argue that willpower of the research community, together with a re-evaluation of evaluation metrics and incentive systems, are needed in order to foster interdisciplinary research. Overall, we emphasise the need for interdisciplinary research in Alzheimer's disease and suggest that international societies should play a huge role in this endeavour.

Sex-Specific ADHD-like Behaviour, Altered Metabolic Functions, and Altered EEG Activity in Sialyltransferase ST3GAL5-Deficient Mice.

A deficiency in GM3-derived gangliosides, resulting from a lack of lactosylceramide-alpha-2,3-sialyltransferase (ST3GAL5), leads to severe neuropathology, including epilepsy and metabolic abnormalities. Disruption of ganglioside production by this enzyme may also have a role in the development of neuropsychiatric disorders. ST3Gal5 knock-out (St3gal5-/-) mice lack a-, b-, and c-series gangliosides, but exhibit no overt neuropathology, possibly owing to the production of compensatory 0-series glycosphingolipids. Here, we sought to investigate the possibility that St3gal5-/- mice might exhibit attention-deficit/hyperactivity disorder (ADHD)-like behaviours. In addition, we evaluated potential metabolic and electroencephalogram (EEG) abnormalities. St3gal5-/- mice were subjected to behavioural testing, glucose tolerance tests, and the levels of expression of brain and peripheral A and B isoforms of the insulin receptor (IR) were measured. We found that St3gal5-/- mice exhibit locomotor hyperactivity, impulsivity, neophobia, and anxiety-like behavior. The genotype also altered blood glucose levels and glucose tolerance. A sex bias was consistently found in relation to body mass and peripheral IR expression. Analysis of the EEG revealed an increase in amplitude in St3gal5-/- mice. Together, St3gal5-/- mice exhibit ADHD-like behaviours, altered metabolic and EEG measures providing a useful platform for better understanding of the contribution of brain gangliosides to ADHD and associated comorbidities.

Prelimbic Cortical Stimulation Improves Spatial Memory Through Distinct Patterns of Hippocampal Gene Expression in Aged Rats.

Dementia poses major health challenges worldwide, yet current treatments are faced with issues of efficacy and toxicity. Deep brain stimulation (DBS) is a promising non-pharmacological treatment for dementia, but most DBS studies use young healthy animals, which may not be aetiologically relevant. In this study, we used an aged rat model in which cognitive decline occurs through a natural ageing process. We used a Morris water maze (MWM) to determine the effects of prelimbic cortex (PrL) DBS on memory in aged rats. To investigate the underlying mechanisms of the effects of DBS, we carried out microarray, quantitative PCR analysis, and mass spectrometry to detect gene expression and neurotransmitter changes in the hippocampus. We showed PrL DBS improved the performance in MWM, with related distinct patterns of gene expression involving G protein-coupled receptor pathways. We further found neurotransmitter changes in the dorsal hippocampus, which corroborated and extended the microarray findings. Our results suggest that non-neurogenesis pathways play roles in the effects of DBS. Further studies are needed to investigate the effects of DBS on memory beyond neurogenesis and to consider the highlighted pathways suggested by our data.

Dropout in Neural Networks Simulates the Paradoxical Effects of Deep Brain Stimulation on Memory.

Neuromodulation techniques such as deep brain stimulation (DBS) are a promising treatment for memory-related disorders including anxiety, addiction, and dementia. However, the outcomes of such treatments appear to be somewhat paradoxical, in that these techniques can both disrupt and enhance memory even when applied to the same brain target. In this article, we hypothesize that disruption and enhancement of memory through neuromodulation can be explained by the dropout of engram nodes. We used a convolutional neural network (CNN) to classify handwritten digits and letters and applied dropout at different stages to simulate DBS effects on engrams. We showed that dropout applied during training improved the accuracy of prediction, whereas dropout applied during testing dramatically decreased the accuracy of prediction, which mimics enhancement and disruption of memory, respectively. We further showed that transfer learning of neural networks with dropout had increased the accuracy and rate of learning. Dropout during training provided a more robust "skeleton" network and, together with transfer learning, mimicked the effects of chronic DBS on memory. Overall, we showed that the dropout of engram nodes is a possible mechanism by which neuromodulation techniques such as DBS can both disrupt and enhance memory, providing a unique perspective on this paradox.

The Paradoxical Effect of Deep Brain Stimulation on Memory.

Deep brain stimulation (DBS) is a promising treatment for many memory-related disorders including dementia, anxiety, and addiction. However, the use of DBS can be a paradoxical conundrum-dementia treatments aim to improve memory, whereas anxiety or addiction treatments aim to suppress maladaptive memory. In this review, the key hypotheses on how DBS affects memory are highlighted. We consolidate the findings and conclusions from the current research on the effects of DBS on memory in attempt to make sense of the bidirectional nature of DBS in disrupting and enhancing memory. Based on the current literature, we hypothesize that the timing of DBS plays a key role in its contradictory effects, and therefore, we propose a consolidated model of how DBS can both disrupt and enhance memory.

Serotonergic treatment normalizes midbrain dopaminergic neuron increase after periaqueductal gray stimulation.

Electrical stimulation of the dorsolateral periaqueductal gray (dlPAG) in rats has been shown to elicit panic-like behaviour and can be a useful as an unconditioned stimulus for modelling anticipatory fear and agoraphobia in a contextual fear conditioning paradigm. In this study, we further analysed our previous data on the effects of escitalopram (a selective serotonin reuptake inhibitor, SSRI) and buspirone (a 5-HT1A receptor partial agonist) on dlPAG-induced anticipatory fear behaviour in a rat model using freezing as a measure. We then attempted to unravel some of the interactions with dopamine signalling using tyrosine hydroxylase (TH) immunohistochemistry to probe the effects on dopaminergic neurons. We showed that acute treatment of escitalopram, but not buspirone, was effective in reducing anticipatory freezing behaviour, while chronic administrations of both drugs were effective. We found that the dlPAG stimulation induced increase number of dopaminergic neurons in the ventral tegmental area (VTA) which was reversed in both chronic buspirone and escitalopram groups. We further found a strong positive correlation between the number of dopaminergic neurons and freezing in the VTA and showed positive correlations between dopaminergic neurons in the VTA and substantia nigra pars compacta (SNpc) in escitalopram and buspirone groups, respectively. Overall, we showed that chronic treatment with an SSRI and a 5-HT1A agonist reduced anticipatory freezing behaviour which seems to be associated, through correlative studies, with a reversal of dlPAG stimulation induced increase in number of dopaminergic neurons in the VTA and/or SNpc.

Eternal sunshine of the neuromodulated mind: Altering fear memories through neuromodulation.

Anxiety disorders pose one of the greatest threats to mental health. Modern treatment methods exist but are hindered by relapse, toxicity, and low efficacy. The use of neuromodulation to treat anxiety disorders has shown promising results, yet its underpinning mechanisms remain poorly understood. In this review, we make the case for further development of neuromodulation techniques to alter fear memories, with particular regard to future clinical applications in treating anxiety disorders. We start by briefly summarizing the neural circuitry of fear while identifying the pros and cons of possible neuromodulation targets. We then highlight recent advances in neuromodulation techniques that have been used to alter fear memories. Next, we apply a novel network-based approach to elucidate possible mechanisms of neuromodulation which may disrupt the consolidation of fear memory. Finally, we emphasize the need for more systematic neuromodulation studies on animal models and the developing brain. Overall, we aim to provide an integrated framework for future action, identifying key research priorities that must be addressed before effective neuromodulation-based treatments can be developed for practical use.

The Pathogenesis of Saffold Virus in AG129 Mice and the Effects of Its Truncated L Protein in the Central Nervous System.

Saffold Virus (SAFV) is a human cardiovirus that has been suggested to cause severe infection of the central nervous system (CNS). Compared to a similar virus, Theiler's murine encephalomyelitis virus (TMEV), SAFV has a truncated Leader (L) protein, a protein essential in the establishment of persistent CNS infections. In this study, we generated a chimeric SAFV by replacing the L protein of SAFV with that of TMEV. We then compared the replication in cell cultures and pathogenesis in a mouse model. We showed that both SAFV and chimeric SAFV are able to infect Vero and Neuro2a cells well, but only chimeric SAFV was able to infect RAW264.7. We then showed that mice lacking IFN-α/ß and IFN-γ receptors provide a good animal model for SAFV infection, and further identified the locality of the infection to the ventral horn of the spine and several locations in the brain. Lastly, we showed that neither SAFV nor chimeric SAFV causes persistence in this model. Overall, our results provide a strong basis on which the mechanisms underlying Saffold virus induced neuropathogenesis can be further studied and, hence, facilitating new information about its pathogenesis.

Tetratricopeptide repeat domain 9A modulates anxiety-like behavior in female mice.

Tetratricopeptide repeat domain 9A (TTC9A) expression is abundantly expressed in the brain. Previous studies in TTC9A knockout (TTC9A-/-) mice have indicated that TTC9A negatively regulates the action of estrogen. In this study we investigated the role of TTC9A on anxiety-like behavior through its functional interaction with estrogen using the TTC9A-/- mice model. A battery of tests on anxiety-related behaviors was conducted. Our results demonstrated that TTC9A-/- mice exhibited an increase in anxiety-like behaviors compared to the wild type TTC9A+/+ mice. This difference was abolished after ovariectomy, and administration of 17-ß-estradiol benzoate (EB) restored this escalated anxiety-like behavior in TTC9A-/- mice. Since serotonin is well-known to be the key neuromodulator involved in anxiety behaviors, the mRNA levels of tryptophan hydroxylase (TPH) 1, TPH2 (both are involved in serotonin synthesis), and serotonin transporter (5-HTT) were measured in the ventromedial prefrontal cortex (vmPFC) and dorsal raphe nucleus (DRN). Interestingly, the heightened anxiety in TTC9A-/- mice under EB influence is consistent with a greater induction of TPH 2, and 5-HTT by EB in DRN that play key roles in emotion regulation. In conclusion, our data indicate that TTC9A modulates the anxiety-related behaviors through modulation of estrogen action on the serotonergic system in the DRN.