Behavioral and Neuroanatomical Abnormalities in Pleiotrophin Knockout Mice

Pleiotrophin (PTN) is an extracellular matrix-associated protein with neurotrophic and neuroprotective effects that is involved in a variety of neurodevelopmental processes. Data regarding the cognitive-behavioral and neuroanatomical phenotype of pleiotrophin knockout (KO) mice is limited. The purpose of this study was to more fully characterize this phenotype, with emphasis on the domains of learning and memory, cognitive-behavioral flexibility, exploratory behavior and anxiety, social behavior, and the neuronal and vascular microstructure of the lateral entorhinal cortex (EC). PTN KOs exhibited cognitive rigidity, heightened anxiety, behavioral reticence in novel contexts and novel social interactions suggestive of neophobia, and lamina-specific decreases in neuronal area and increases in neuronal density in the lateral EC. Initial learning of spatial and other associative tasks, as well as vascular density in the lateral EC, was normal in the KOs. These data suggest that the absence of PTN in vivo is associated with disruption of specific cognitive and affective processes, raising the possibility that further study of PTN KOs might have implications for the study of human disorders with similar features

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Behavioral and neuroanatomical abnormalities in pleiotrophin knockout mice.

Pleiotrophin (PTN) is an extracellular matrix-associated protein with neurotrophic and neuroprotective effects that is involved in a variety of neurodevelopmental processes. Data regarding the cognitive-behavioral and neuroanatomical phenotype of pleiotrophin knockout (KO) mice is limited. The purpose of this study was to more fully characterize this phenotype, with emphasis on the domains of learning and memory, cognitive-behavioral flexibility, exploratory behavior and anxiety, social behavior, and the neuronal and vascular microstructure of the lateral entorhinal cortex (EC). PTN KOs exhibited cognitive rigidity, heightened anxiety, behavioral reticence in novel contexts and novel social interactions suggestive of neophobia, and lamina-specific decreases in neuronal area and increases in neuronal density in the lateral EC. Initial learning of spatial and other associative tasks, as well as vascular density in the lateral EC, was normal in the KOs. These data suggest that the absence of PTN in vivo is associated with disruption of specific cognitive and affective processes, raising the possibility that further study of PTN KOs might have implications for the study of human disorders with similar features

Entorhinal cortical cellular characteristics in PTN KOs and WTs.

<p>(a) Neuronal area and (b) interneuronal distance in layer IV and layer V of the entorhinal cortex in KOs (n = 9) and WTs (n = 10). Nissl-stained sections of layer IV of entorhinal cortical tissue in a (c) WT and (d) KO; and whole sections of entorhinal cortex in a (e) WT and (f) KO. Scale bar = 250 mm. *p = <0.05.</p

Elevated plus maze behavior in PTN KOs and WTs.

<p>(a) Percentage of time spent in, and entries into, open arms, (b) total number of arm entries, and (c) latency to first arm entry for KOs (n = 8) and WTs (n = 6). *p = <0.05.</p

Entorhinal cortical vascular characteristics in PTN KOs and WTs.

<p>(a) Vascular density and (b) vascular diameter in entorhinal cortex for KOs (n = 9) and WTs (n = 10) with alpha collagen IV-stained sections of entorhinal cortical tissue from a (c) WT and (d) KO. Scale bar = 10 mm. *p = <0.05.</p

Latencies to escape the Morris water maze for PTN KOs (n = 13) and WTs (n = 13).

<p>(a) Spatial version, first maze; (b) cued version, first maze; (c) cued version, second maze; (d) spatial version, second maze. *p = <0.05.</p

Social approach behavior in PTN KOs and WTs.

<p>(a) Time spent in the stranger 1 chamber, empty chamber, and center chamber during the sociability test; (b) time spent in the stranger 1 chamber, stranger 2 chamber, and center chamber during social novelty test; (c) total number of chamber entries made during the sociability and social novelty tests for KOs (n = 11) and WTs (n = 9). *p = <0.05.</p

Open field behavior in PTN KOs and WTs.

<p>(a) Latency to exit the center grid, (b) latency to groom, (c) total grid crosses, and (d) number of grooms for KOs (n = 9) and WTs (n = 5). *p = <0.05.</p