Biology subjects

Grzyb, A. N.

Publications and source records attributed to Grzyb, A. N..

4 recordsLinked to original sources

bioRxiv2022

Pre-symptomatic reduction of individuality in the App NL-F knock-in model of Alzheimer's disease

While one third of the risk for Alzheimers disease (AD) is explained by environment and lifestyle, AD pathology also affects individual lifestyle, possibly long before clinical manifestation of dementia. To study this hidden disease effect with its potentially large impact on coping with AD, we examined in mice how the AppNL-F/NL-F (NL-F) knock-in mutation affects the pre-symptomatic response to environmental enrichment (ENR). We assessed the emergence of inter-individual phenotypic variation while both genetic background and the shared environment were held constant, thereby isolating the contribution of individual behavior ( non-shared environment). After 4 months of ENR, in NL-F both mean and variability of plasma ApoE were increased, suggesting a pre-symptomatic variation in pathogenic processes. Roaming entropy (RE) as a measure of behavioral activity was continuously assessed with radiofrequency identification (RFID) technology and revealed reduced habituation and variance in NL-F compared to controls. Intra-individual variation decreased but behavioral predictability and stability were reduced in NL-F. Seven months after discontinuation of ENR we found no difference in plaque size and number, but ENR increased variance in hippocampal plaque counts in NL-F. A reactive increase in adult hippocampal neurogenesis in NL-F, known from other models, was normalized by ENR. Our data suggest that, while NL-F has early effects on individual behavioral patterns in response to ENR, there are lasting effects at the level of cellular plasticity even after discontinuation of ENR. Hence, early behavior matters for maintaining individual behavioral trajectories and brain plasticity even under maximally constraint conditions.

neuroscience↗

bioRxiv2021

System genetics in the rat HXB/BXH family identifies Tti2 as a pleiotropic quantitative trait gene for adult hippocampal neurogenesis and serum glucose

Neurogenesis in the adult hippocampus contributes to learning and memory in the healthy brain but is dysregulated in metabolic and neurodegenerative diseases. The molecular relationships between neural stem cell activity, adult neurogenesis, and global metabolism are largely unknown. Here we applied unbiased systems genetic methods to quantify genetic covariation among adult neurogenesis and metabolic phenotypes in peripheral tissues of a genetically diverse family of rat strains, derived from a cross between the spontaneously hypertensive (SHR/OlaIpcv) strain and Brown Norway (BN-Lx/Cub). The HXB/BXH family is a very well established model to dissect genetic variants that modulate metabolic and cardiovascular disease and we have accumulated deep phenome and transcriptome data in a FAIR-compliant resource for systematic and integrative analyses. Here we measured rates of precursor cell proliferation, survival of new neurons, and gene expression in the hippocampus of the entire HXB/BXH family, including both parents. These data were combined with published metabolic phenotypes to detect a neurometabolic quantitative trait locus (QTL) for serum glucose and neuronal survival. We subsequently fine-mapped a key phenotype to a locus that includes the telo2-interacting protein 2 gene (Tti2)--a chaperone that modulates the activity and stability of PIKK kinases. To validate variants in or near Tti2 as a cause for differences in neurogenesis and glucose levels, we generated a targeted frameshift mutation on the SHR/OlaIpcv background. Heterozygous SHR-Tti2+/- mutants had lower rates of hippocampal neurogenesis and hallmarks of dysglycemia compared to wild-type littermates. Our findings highlight Tti2 as a causal genetic and molecular link between glucose metabolism and structural brain plasticity. In humans, more than 800 genomic variants are linked to TTI2 expression, seven of which have associations to protein and blood stem cell factor concentrations, blood pressure and frontotemporal dementia. Author summaryMetabolic and neurological disorders are often comorbid, suggesting that biological pathways which orchestrate peripheral homeostasis and the integrity of the nervous system intersect. The genetic architecture behind these relationships is still poorly described, in part because molecular processes in the human brain are very difficult to study. We thus used a rodent genetic reference population to investigate links between adult hippocampal neurogenesis-- a cellular plasticity mechanism important for learning flexibility--and metabolism. We measured adult neurogenesis in the family of 30 HXB/BXH rat recombinant inbred strains, who are characterised by stable differences in metabolism, behaviour, and gene expression levels. Because gene variants affecting distinct traits segregated into different members of the family, we discovered that previously published phenotypes correlated to adult neurogenesis due to shared genomic sequence. We found that expression levels of Tti2--a part of a specialised protein chaperone complex regulating stability of PIKK kinases--were concomitantly influencing adult neurogenesis and serum glucose levels. In human populations hundreds of genomic variants regulate TTI2 expression, potentially affecting brain function and glucose homeostasis.

neuroscience↗

bioRxiv2019

Early-life environmental enrichment generates persistent individualized behavior in mice

Individuals differ in their response to environmental stimuli, but the stability of individualized behaviors and their associated changes in brain plasticity are poorly understood. We developed a novel model of enriched environment to longitudinally monitor 40 inbred mice exploring 35 connected cages over periods of three to six months. We show that behavioral individuality that emerged during the first three months of environmental enrichment persisted when mice were withdrawn from the enriched environment for three additional months. Behavioral trajectories were associated with stable inter-individual differences in adult hippocampal neurogenesis and persistent epigenetic effects on neuronal plasticity genes in the hippocampus. Using genome-wide DNA methylation sequencing, we show that one third of the DNA methylation changes were maintained after withdrawal from the enriched environment. Our results suggest that, even under the most constraint conditions controlling genes and environment, early-life experiences result in lasting individualized changes in behavior and brain plasticity.

neuroscience↗

bioRxiv2018

Selective increases in inter-individual variability in response to environmental enrichment

One manifestation of individualization is a progressively differential response of individuals to the non-shared components of the same environment. Individualization has practical implications in clinical setting, where subtle differences between patients are often decisive for the success of an intervention, yet there has been no suitable animal model to study its underlying biological mechanisms. Here we show that enriched environment (ENR) can serve as a model of brain individualization. We kept 40 isogenic mice for 3 months in ENR and compared the effects on a wide range of phenotypes on both mean and variance to an equally sized group of standard-housed control animals. While ENR influenced multiple parameters and restructured correlation patterns between them, it only increased differences among individuals in traits related to brain and behavior (adult hippocampal neurogenesis, motor cortex thickness, open field and object exploration, rotarod performance), in agreement with the hypothesis of a specific activity-dependent development of brain individuality.

neuroscience↗