Preventing antisocial robots: A pathway to artificial empathy.

Given the accelerating powers of artificial intelligence (AI), we must equip artificial agents and robots with empathy to prevent harmful and irreversible decisions. Current approaches to artificial empathy focus on its cognitive or performative processes, overlooking affect, and thus promote sociopathic behaviors. Artificially vulnerable, fully empathic AI is necessary to prevent sociopathic robots and protect human welfare.

Behavioral analysis through the lifespan of disc1 mutant zebrafish identifies defects in sensorimotor transformation.

DISC1 is a genetic risk factor for multiple psychiatric disorders. Compared to the dozens of murine Disc1 models, there is a paucity of zebrafish disc1 models-an organism amenable to high-throughput experimentation. We conducted the longitudinal neurobehavioral analysis of disc1 mutant zebrafish across key stages of life. During early developmental stages, disc1 mutants exhibited abrogated behavioral responses to sensory stimuli across multiple testing platforms. Moreover, during exposure to an acoustic sensory stimulus, loss of disc1 resulted in the abnormal activation of neurons in the pallium, cerebellum, and tectum-anatomical sites involved in the integration of sensory perception and motor control. In adulthood, disc1 mutants exhibited sexually dimorphic reduction in anxiogenic behavior in novel paradigms. Together, these findings implicate disc1 in sensorimotor processes and the genesis of anxiogenic behaviors, which could be exploited for the development of novel treatments in addition to investigating the biology of sensorimotor transformation in the context of disc1 deletion.

A zebrafish model of combined saposin deficiency identifies acid sphingomyelinase as a potential therapeutic target.

Sphingolipidoses are a subcategory of lysosomal storage diseases (LSDs) caused by mutations in enzymes of the sphingolipid catabolic pathway. Like many LSDs, neurological involvement in sphingolipidoses leads to early mortality with limited treatment options. Given the role of myelin loss as a major contributor toward LSD-associated neurodegeneration, we investigated the pathways contributing to demyelination in a CRISPR-Cas9-generated zebrafish model of combined saposin (psap) deficiency. psap knockout (KO) zebrafish recapitulated major LSD pathologies, including reduced lifespan, reduced lipid storage, impaired locomotion and severe myelin loss; loss of myelin basic protein a (mbpa) mRNA was progressive, with no changes in additional markers of oligodendrocyte differentiation. Brain transcriptomics revealed dysregulated mTORC1 signaling and elevated neuroinflammation, where increased proinflammatory cytokine expression preceded and mTORC1 signaling changes followed mbpa loss. We examined pharmacological and genetic rescue strategies via water tank administration of the multiple sclerosis drug monomethylfumarate (MMF), and crossing the psap KO line into an acid sphingomyelinase (smpd1) deficiency model. smpd1 mutagenesis, but not MMF treatment, prolonged lifespan in psap KO zebrafish, highlighting the modulation of acid sphingomyelinase activity as a potential path toward sphingolipidosis treatment.

Top2a promotes the development of social behavior via PRC2 and H3K27me3.

Little is understood about the embryonic development of sociality. We screened 1120 known drugs and found that embryonic inhibition of topoisomerase IIα (Top2a) resulted in lasting social deficits in zebrafish. In mice, prenatal Top2 inhibition caused defects in social interaction and communication, which are behaviors that relate to core symptoms of autism. Mutation of Top2a in zebrafish caused down-regulation of a set of genes highly enriched for genes associated with autism in humans. Both the Top2a-regulated and autism-associated gene sets have binding sites for polycomb repressive complex 2 (PRC2), a regulatory complex responsible for H3K27 trimethylation (H3K27me3). Moreover, both gene sets are highly enriched for H3K27me3. Inhibition of the PRC2 component Ezh2 rescued social deficits caused by Top2 inhibition. Therefore, Top2a is a key component of an evolutionarily conserved pathway that promotes the development of social behavior through PRC2 and H3K27me3.

Microglia and its Genetics in Alzheimer's Disease.

Alzheimer's Disease (AD) is the most prevalent form of dementia across the world. While its discovery and pathological manifestations are centered on protein aggregations of amyloid- beta (Aß) and hyperphosphorylated tau protein, neuroinflammation has emerged in the last decade as a main component of the disease in terms of both pathogenesis and progression. As the main innate immune cell type in the central nervous system (CNS), microglia play a very important role in regulating neuroinflammation, which occurs commonly in neurodegenerative conditions, including AD. Under inflammatory response, microglia undergo morphological changes and status transition from homeostatic to activated forms. Different microglia subtypes displaying distinct genetic profiles have been identified in AD, and these signatures often link to AD risk genes identified from the genome-wide association studies (GWAS), such as APOE and TREM2. Furthermore, many AD risk genes are highly enriched in microglia and specifically influence the functions of microglia in pathogenesis, e.g. releasing inflammatory cytokines and clearing Aß. Therefore, building up a landscape of these risk genes in microglia, based on current preclinical studies and in the context of their pathogenic or protective effects, would largely help us to understand the complex etiology of AD and provide new insight into the unmet need for effective treatment.

Mild traumatic brain injury induces microvascular injury and accelerates Alzheimer-like pathogenesis in mice.

INTRODUCTION: Traumatic brain injury (TBI) is considered as the most robust environmental risk factor for Alzheimer's disease (AD). Besides direct neuronal injury and neuroinflammation, vascular impairment is also a hallmark event of the pathological cascade after TBI. However, the vascular connection between TBI and subsequent AD pathogenesis remains underexplored. METHODS: In a closed-head mild TBI (mTBI) model in mice with controlled cortical impact, we examined the time courses of microvascular injury, blood-brain barrier (BBB) dysfunction, gliosis and motor function impairment in wild type C57BL/6 mice. We also evaluated the BBB integrity, amyloid pathology as well as cognitive functions after mTBI in the 5xFAD mouse model of AD. RESULTS: mTBI induced microvascular injury with BBB breakdown, pericyte loss, basement membrane alteration and cerebral blood flow reduction in mice, in which BBB breakdown preceded gliosis. More importantly, mTBI accelerated BBB leakage, amyloid pathology and cognitive impairment in the 5xFAD mice. DISCUSSION: Our data demonstrated that microvascular injury plays a key role in the pathogenesis of AD after mTBI. Therefore, restoring vascular functions might be beneficial for patients with mTBI, and potentially reduce the risk of developing AD.

G Protein-Coupled Receptors in the Mammalian Blood-Brain Barrier.

The mammalian neurovascular unit (NVU) is comprised of neurons, glia, and vascular cells. The NVU is the nexus between the cardiovascular and central nervous system (CNS). The central component of the NVU is the blood-brain barrier (BBB) which consists of a monolayer of tightly connected endothelial cells covered by pericytes and further surrounded by astrocytic endfeet. In addition to preventing the diffusion of toxic species into the CNS, the BBB endothelium serves as a dynamic regulatory system facilitating the transport of molecules from the bloodstream to the brain and vis versa. The structural integrity and transport functions of the BBB are maintained, in part, by an orchestra of membrane receptors and transporters including members of the superfamily of G protein-coupled receptors (GPCRs). Here, we provide an overview of GPCRs known to regulate mammalian BBB structure and function and discuss how dysregulation of these pathways plays a role in various neurodegenerative diseases.

Blood-Brain Barrier Dysfunction in Mild Traumatic Brain Injury: Evidence From Preclinical Murine Models.

Mild traumatic brain injury (mTBI) represents more than 80% of total TBI cases and is a robust environmental risk factor for neurodegenerative diseases including Alzheimer's disease (AD). Besides direct neuronal injury and neuroinflammation, blood-brain barrier (BBB) dysfunction is also a hallmark event of the pathological cascades after mTBI. However, the vascular link between BBB impairment caused by mTBI and subsequent neurodegeneration remains undefined. In this review, we focus on the preclinical evidence from murine models of BBB dysfunction in mTBI and provide potential mechanistic links between BBB disruption and the development of neurodegenerative diseases.

Parallel Reaction Monitoring reveals structure-specific ceramide alterations in the zebrafish.

Extensive characterisations of the zebrafish genome and proteome have established a foundation for the use of the zebrafish as a model organism; however, characterisation of the zebrafish lipidome has not been as comprehensive. In an effort to expand current knowledge of the zebrafish sphingolipidome, a Parallel Reaction Monitoring (PRM)-based liquid chromatography-mass spectrometry (LC-MS) method was developed to comprehensively quantify zebrafish ceramides. Comparison between zebrafish and a human cell line demonstrated remarkable overlap in ceramide composition, but also revealed a surprising lack of most sphingadiene-containing ceramides in the zebrafish. PRM analysis of zebrafish embryogenesis identified developmental stage-specific ceramide changes based on long chain base (LCB) length. A CRISPR-Cas9-generated zebrafish model of Farber disease exhibited reduced size, early mortality, and severe ceramide accumulation where the amplitude of ceramide change depended on both acyl chain and LCB lengths. Our method adds an additional level of detail to current understanding of the zebrafish lipidome, and could aid in the elucidation of structure-function associations in the context of lipid-related diseases.