Biology subjects

Walum, H.

Publications and source records attributed to Walum, H..

7 recordsLinked to original sources

bioRxiv2025

Deciphering Multiway Multiscale Brain Network Connectivity:Insights from Birth to 6 Months

Converging evidence suggests that understanding the human brain requires more than just examining pairwise functional brain interactions. The human brain is a complex, nonlinear system, and focusing solely on linear pairwise functional connectivity often overlooks important nonlinear and higher-order relationships. Infancy is a critical period marked by significant brain development that could contribute to future learning, health, and life success. Exploring higher-order functional relationships in the brain can provide insight into brain function and development. To the best of our knowledge, there is no existing research on multiway, multiscale brain network interactions in infants. In this study, we comprehensively investigate the interactions among brain intrinsic connectivity networks (ICNs), including both pairwise (pair-FNC) and triple relationships (tri-FNC). We focused on an infant dataset collected between birth and six months, a critical period for brain maturation. Our results revealed significant hierarchical, multiway, multiscale brain functional network interactions in the infant brain. These findings suggest that tri-FNC provide additional insights beyond what pairwise interactions reveal during early brain development. The tri-FNC predominantly involve the default mode, sensorimotor, visual, limbic, language, salience, and central executive domains. Notably, these triplet networks align with the classical triple network model of the human brain, which includes the default mode network, the salience network, and the central executive network. This suggests that the brain network system might already be initially established during the first six months of infancy. Interestingly, tri-FNC in the default mode and salience domains showed significantly stronger nonlinear interactions with age compared to pair-FNC. We also found that pair-FNC were less effective at detecting these networks. The present study suggests that exploring tri-FNC can offer additional insights beyond pair-FNC by capturing higher-order nonlinear interactions, potentially yielding more reliable biomarkers to characterize developmental trajectories.

neuroscience↗

bioRxiv2023

Natural variation in oxytocin receptor signaling causes widespread changes in brain transcription: a link to the natural killer gene complex

Oxytocin (OXT) is a highly conserved neuropeptide that modulates social cognition, and genetic variation in its receptor gene (Oxtr) is linked to divergent social phenotypes. However, the molecular mechanisms connecting Oxtr genotype to behavioral outcomes remain obscure. Here, we leverage naturally occurring Oxtr polymorphisms in the prairie vole that associate with striatal-specific OXTR density to investigate how OXTR signaling influences brain function. Specifically, we identify OXTR-dependent transcriptomic changes in the natural killer gene complex (NKC) - a genomic region classically associated with peripheral immune function. Centrally, OXTR-regulated NKC genes are positioned to influence microglia-neuron interactions. Consistent with a role for these genes in shaping neuronal connectivity, we show that genetic reduction of OXTR levels leads to increased dendritic spine density on striatal Oxtr-expressing neurons. In addition, we provide support for a similar relation between variation in OXTR mRNA levels and NKC transcription in humans. Together, our findings suggest a role for OXTR signaling in the shaping of neural circuits through transcriptional control of the NKC, outlining a mechanism via which variation in OXTR signaling may influence circuit connectivity to generate diversity in social behaviors.

neuroscience↗

bioRxiv2023

RNA in extracellular vesicles during adolescence reveal immune, energetic and microbial imprints of early life adversity.

Exposure to early life adversity (ELA), including childhood maltreatment, is one of the most significant risk factors for the emergence of neuropsychiatric disorders in adolescence and adulthood. Despite this relationship being well established, the underlying mechanisms remain unclear. One way to achieve this understanding is to identify molecular pathways and processes that are perturbed as a consequence of childhood maltreatment. Ideally, these perturbations would be evident as changes in DNA, RNA or protein profiles in easily accessible biological samples collected in the shadow of childhood maltreatment. In this study, we isolated circulating extracellular vesicles (EVs) from plasma collected from adolescent rhesus macaques that had either experienced nurturing maternal care (CONT) or maternal maltreatment (MALT) in infancy. RNA sequencing of RNA in plasma EVs and gene enrichment analysis revealed that genes related to translation, ATP synthesis, mitochondrial function and immune response were downregulated in MALT samples, while genes involved in ion transport, metabolism and cell differentiation were upregulated. Interestingly, we found that a significant proportion of EV RNA aligned to the microbiome and that MALT altered the diversity of microbiome-associated RNA signatures found in EVs. Part of this altered diversity suggested differences in prevalence of bacterial species in CONT and MALT animals noted in the RNA signatures of the circulating EVs. Our findings provide evidence that immune function, cellular energetics and the microbiome may be important conduits via which infant maltreatment exerts effects on physiology and behavior in adolescence and adulthood. As a corollary, perturbations of RNA profiles related to immune function, cellular energetics and the microbiome may serve as biomarkers of responsiveness to ELA. Our results demonstrate that RNA profiles in EVs can serve as a powerful proxy to identify biological processes that might be perturbed by ELA and that may contribute to the etiology of neuropsychiatric disorders in the aftermath of ELA.

zoology↗

bioRxiv2022

The Vacc-SeqQC Project: Benchmarking RNA-Seq for Clinical Vaccine Studies

Over the last decade, the field of systems vaccinology has emerged, in which high throughput transcriptomics and other omics assays are used to probe changes of the innate and adaptive immune system in response to vaccination. RNA-Seq technology has matured in recent years and is now widely deployed for transcriptional analysis of clinical specimens. The goal of this study was to benchmark technical parameters of RNA-Seq in the context of a multi-site, double-blind randomized clinical trial using primary patient samples. We collected longitudinal peripheral blood mononuclear cell (PBMC) samples from 10 subjects after vaccination with a live attenuated Francisella tularensis vaccine and performed RNA-Seq at two different sites using aliquots from the same sample to generate two large-scale replicate datasets. We evaluated the impact of: (i) filtering lowly-expressed genes, (ii) using external RNA controls, (iii) fold change and false discovery rate (FDR) filtering, (iv) read length, and (v) sequencing depth on differential expressed genes (DEGs) concordance between replicate datasets. Using synthetic mRNA spike-ins, we developed a method for empirically establishing minimal read-count thresholds for maintaining fold change accuracy on a per-experiment basis. We defined a reference PBMC transcriptome by pooling sequence data, and established the impact of read depth and gene filtering on transcript representation. Lastly, we modeled statistical power to detect DE genes for a range of sample sizes, effect sizes, and coverage depths. The results from this study provide RNA sequencing benchmarks and guidelines for planning future similar vaccine studies.

systems biology↗

bioRxiv2019

Becoming a better parent: mice learn sounds that improve a stereotyped maternal behavior

While mothering is often instinctive and stereotyped in species-specific ways, evolution can favor genetically "open" behavior programs that allow experience to shape infant care. Among experience-dependent maternal behavioral mechanisms, sensory learning about infants has been hard to isolate from motivational changes arising from sensitization with infants. We developed a paradigm where sensory learning of an infant-associated cue improves a stereotypical maternal behavior in female mice. Mice instinctively employed a spatial memory-based strategy when engaged repetitively in a pup search and retrieval task. However, by playing a sound from a T-maze arm to signal where a pup will be delivered for retrieval, mice learned within 7 days and retained for at least 2 weeks the ability to use this specific cue to guide a more efficient search strategy. The motivation to retrieve pups also increased, but that alone did not sufficiently explain the shift in search strategy. Bilaterally silencing auditory cortical activity significantly impaired the new strategy without changing the motivation to retrieve pups. Finally, motherhood as compared to infant-care experience alone accelerated how quickly the new sensory-based strategy was acquired, suggesting a role for the maternal hormonal state. By rigorously establishing that newly formed sensory associations can improve the performance of a natural maternal behavior, this work facilitates future studies into the neurochemical and circuit mechanisms that mediate novel sensory learning in the maternal context, as well as more learning-based mechanisms of parental behavior in rodents.

neuroscience↗

bioRxiv2019

Heritability and relationship of oxytocin receptor gene variants with social behavior and central oxytocin in colony-reared adult female rhesus macaques

The genetic contributions to sociality are an important research focus for understanding individual variation in social function and risk of social deficits in neurodevelopmental disorders (e.g. autism). The neuropeptide oxytocin (OXT) and its receptor, OXTR, influence social behavior across species. In humans and animals, common variants within the OXTR gene (OXTR) have been associated with varying socio-behavioral traits. However, the reported magnitude of influence of individual variants on complex behavior has been inconsistent. Compared to human studies, non-human primate (NHP) studies in controlled environments have the potential to result in robust effects detectable in relatively small samples. Here we estimate heritability of social behavior and central OXT concentrations in 214 socially-housed adult female rhesus macaques, a species sharing high similarity with humans in genetics, physiology, brain and social complexity. We present a bioinformatically-informed approach for identifying single nucleotide polymorphisms (SNPs) with likely biological relevance. We tested 13 common SNPs in regulatory and coding regions of OXTR for associations with behavior (pro-social, anxiety-like, and aggressive) and OXT concentration in cerebrospinal fluid (CSF). We found moderate rates of heritability for both social behavior and CSF OXT concentrations. No tested SNPs showed significant associations with behaviors or CSF in this sample. Associations between OXT CSF and social behavior were not significant either. SNP effect sizes were generally comparable to those reported in human studies of complex traits. While environmental control and a socio-biological similarity with humans is an advantage of rhesus models for detecting smaller genetic effects, it is insufficient to obviate large sample sizes necessary for appropriate statistical power.

neuroscience↗

bioRxiv2019

Proximate causes and consequences of intergenerational influences of salient sensory experience.

Salient sensory environments experienced by a parental generation can exert intergenerational influences on offspring, including offspring not conceived at the time of the parental experience. While these data provide an exciting new perspective on biological inheritance, questions remain about causes and consequences of intergenerational influences of salient sensory experience. We have previously shown that exposing male mice to a salient olfactory experience like olfactory fear conditioning results in offspring demonstrating a sensitivity to the odor used to condition the paternal generation and possessing an enhanced neuroanatomical representation for that odor. In this study, we first injected RNA extracted from sperm of male mice that underwent olfactory fear conditioning into naive single cell zygotes and found that both male and female adults that develop from these embryos have increased sensitivity and enhanced neuroanatomical representation for the odor (Odor A) with which the paternal male had been conditioned. Next, we found that female, but not male offspring sired by males conditioned with Odor A show enhanced freezing when presented with Odor A after being exposed to a sub-threshold olfactory fear conditioning protocol that consisted of only a single Odor A + shock pairing. Our data provide evidence that RNA found in the paternal germline after exposure to salient sensory experiences can contribute to intergenerational influences of such experiences, and that such intergenerational influences confer an element of adaptation to the filial generation. In so doing, our work suggests that some causes (sperm RNA) and consequences (behavioral flexibility) of intergenerational influences of parental experiences are conserved across experiences as diverse as stressors, dietary manipulations, and sensory experiences.

zoology↗