Cross species review of the physiological role of D-serine in translationally relevant behaviors.

Bridging the gap between preclinical models of neurological and psychiatric disorders with their human manifestations is necessary to understand their underlying mechanisms, identify biomarkers, and develop novel therapeutics. Cognitive and social impairments underlie multiple neuropsychiatric and neurological disorders and are often comorbid with sleep disturbances, which can exacerbate poor outcomes. Importantly, many symptoms are conserved between vertebrates and invertebrates, although they may have subtle differences. Therefore, it is essential to determine the molecular mechanisms underlying these behaviors across different species and their translatability to humans. Genome-wide association studies have indicated an association between glutamatergic gene variants and both the risk and frequency of psychiatric disorders such as schizophrenia, bipolar disorder, and autism spectrum disorder. For example, changes in glutamatergic neurotransmission, such as glutamate receptor subtype N-methyl-D-aspartate receptor (NMDAR) hypofunction, have been shown to contribute to the pathophysiology of schizophrenia. Furthermore, in neurological disorders, such as traumatic brain injury and Alzheimer's disease, hyperactivation of NMDARs leads to synaptic damage. In addition to glutamate binding, NMDARs require the binding of a co-agonist D-serine or glycine to the GluN1 subunit to open. D-serine, which is racemized from L-serine by the neuronal enzyme serine racemase (SRR), and both SRR and D-serine are enriched in cortico-limbic brain regions. D-serine is critical for complex behaviors, such as cognition and social behavior, where dysregulation of its synthesis and release has been implicated in many pathological conditions. In this review, we explore the role of D-serine in behaviors that are translationally relevant to multiple psychiatric and neurological disorders in different models across species.

Dimensional clinical phenotyping using post-mortem brain donor medical records: post-mortem RDoC profiling is associated with Alzheimer's disease neuropathology.

Introduction: Transdiagnostic dimensional phenotypes are essential to investigate the relationship between continuous symptom dimensions and pathological changes. This is a fundamental challenge to post-mortem work, as assessments of phenotypic concepts need to rely on existing records. Methods: We adapted well-validated methodologies to compute National Institute of Mental Health Research Domain Criteria (RDoC) scores using natural language processing (NLP) from electronic health records (EHRs) obtained from post-mortem brain donors and tested whether cognitive domain scores were associated with Alzheimer's disease neuropathological measures. Results: Our results confirm an association of EHR-derived cognitive scores with neuropathological findings. Notably, higher neuropathological load, particularly neuritic plaques, was associated with higher cognitive burden scores in the frontal (ß = 0.38, P = 0.0004), parietal (ß = 0.35, P = 0.0008), temporal (ß = 0.37, P = 0.0004) and occipital (ß = 0.37, P = 0.0003) lobes. Discussion: This proof-of-concept study supports the validity of NLP-based methodologies to obtain quantitative measures of RDoC clinical domains from post-mortem EHR. The associations may accelerate post-mortem brain research beyond classical case-control designs.

Dimensional clinical phenotyping using post-mortem brain donor medical records: Association with neuropathology.

INTRODUCTION: Transdiagnostic dimensional phenotypes are essential to investigate the relationship between continuous symptom dimensions and pathological changes. This is a fundamental challenge to postmortem work, as assessment of newly developed phenotypic concepts needs to rely on existing records. METHODS: We adapted well-validated methodologies to compute NIMH research domain criteria (RDoC) scores using natural language processing (NLP) from electronic health records (EHRs) obtained from post-mortem brain donors and tested whether RDoC cognitive domain scores were associated with hallmark Alzheimer's disease (AD) neuropathological measures. RESULTS: Our results confirm an association of EHR-derived cognitive scores with hallmark neuropathological findings. Notably, higher neuropathological load, particularly neuritic plaques, was associated with higher cognitive burden scores in the frontal (ß=0.38, p=0.0004), parietal (ß=0.35, p=0.0008), temporal (ß=0.37, p=0. 0004) and occipital (ß=0.37, p=0.0003) lobes. DISCUSSION: This proof of concept study supports the validity of NLP-based methodologies to obtain quantitative measures of RDoC clinical domains from postmortem EHR.

Top-down, auditory pallial regulation of the social behavior network.

Social encounters rely on sensory cues that carry nuanced information to guide social decision-making. While high-level features of social signals are processed in the telencephalic pallium, nuclei controlling social behaviors, called the social behavior network (SBN), reside mainly in the diencephalon. Although it is well known how mammalian olfactory pallium interfaces with the SBN, there is little information for how pallial processing of other sensory modalities can modulate SBN circuits. This is surprising given the importance of complex vocalizations, for example, for social behavior in many vertebrate taxa such as humans and birds. Using gregarious and highly vocal songbirds, female Zebra finches, we asked to what extent auditory pallial circuits provide consequential input to the SBN as it processes social sensory cues. We transiently inactivated auditory pallium of female Zebra finches during song playback and examined song-induced activation in SBN nuclei. Auditory pallial inactivation impaired responses to song specifically within the lateral ventromedial nucleus of the hypothalamus (VMHl), providing the first evidence in vertebrates of a connection between auditory pallium and the SBN. This same treatment elevated feeding behavior, which also correlated with VMHl activation. This suggests that signals from auditory pallium to VMHl can tune the balance between social attention and feeding drive. A descending influence of sensory pallium on hypothalamic circuits could therefore provide a functional connection for the integration of social stimuli with internal state to influence social decision-making. Significance: Sensory cues such as vocalizations contain important social information. These social signals can be substantially nuanced, containing information about vocalizer identity, prior experience, valence, and emotional state. Processing these features of vocalizations necessitates processing the fast, complex sound streams in song or speech, which depends on circuits in pallial cortex. But whether and how this information is then transferred to social circuits in limbic and hypothalamic regions remains a mystery. Here, we identify a top-down influence of the songbird auditory pallium on one specific node of the social behavior network within the hypothalamus. Descending functional connections such as these may be critical for the wide range of vertebrate species that rely on intricate sensory communication signals to guide social decision-making.

Animal Transmission of SARS-CoV-2 and the Welfare of Animals during the COVID-19 Pandemic.

The accelerated pace of research into Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) necessitates periodic summaries of current research. The present paper reviews virus susceptibilities in species with frequent human contact, and factors that are best predictors of virus susceptibility. Species reviewed were those in contact with humans through entertainment, pet, or agricultural trades, and for whom reports (either anecdotal or published) exist regarding the SARS-CoV-2 virus and/or the resulting disease state COVID-19. Available literature was searched using an artificial intelligence (AI)-assisted engine, as well as via common databases, such as Web of Science and Medline. The present review focuses on susceptibility and transmissibility of SARS-CoV-2, and polymorphisms in transmembrane protease serine 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2) that contribute to species differences. Dogs and pigs appear to have low susceptibility, while ferrets, mink, some hamster species, cats, and nonhuman primates (particularly Old World species) have high susceptibility. Precautions may therefore be warranted in interactions with such species, and more selectivity practiced when choosing appropriate species to serve as models for research.