Biology subjects

Dalen, K. T.

Publications and source records attributed to Dalen, K. T..

3 recordsLinked to original sources

bioRxiv2026

Disruption of glutamine carrier Slc38a1 causes cognitive impairment, anxiety and depressive-like behavior

GABAergic deficit is associated with key neuropsychiatric disorders, such as major depressive disorder (MDD), anxiety, schizophrenia, and autism spectrum disorder (ASD). However, it is not known whether these disorders are causal to or a result of GABAergic dysfunction. We previously showed that the Solute carrier 38 member 1 (Slc38a1) accumulates glutamine in subpopulations of GABAergic neurons and sustains neurotransmitter GABA synthesis. Genetic inactivation of Slc38a1 in mice caused lowered GABA levels, altered synaptic vesicle morphology, slowed {gamma}-oscillations, and reduced cortical processing and plasticity, selectively at GABAergic synapses. We now demonstrate a significant reduction in learning and memory performance in the Morris water maze and increased signs of despair in the forced swim test in Slc38a1-/- mice compared to Slc38a1+/+ mice, implicating cognitive impairments and depressive-like behavior. Examination in the open field maze also indicates anxiety and/or reduced interest in exploration. There are no signs of impaired sociability or recognition of social novelty in the three-chambered test, speaking against involvement in schizophrenia- or ASD-like disorders. Metabolic phenotyping and measurement of the locomotion do not segregate the Slc38a1 genotypes, suggesting that the cognitive impairments, depressive-like behavior and anxiety are brain-dependent. Our data is further supported by a pathologic variant of Slc38a1 in a family with depression and suicidal behavior. Altogether, we demonstrate that dysfunction of Slc38a1-dependent GABA synthesis and the ensuing impaired {gamma}-oscillations underpin the pathogenesis of neurocognitive deficits, anxiety and depression.

animal behavior and cognition↗

bioRxiv2025

Mechanisms of sexually dimorphic adipose tissue remodelling upon prolonged breastfeeding

Early developmental cues exert lasting influence on the adipose tissue function and the metabolic health throughout adulthood. In mice, adipose tissue remodelling during the weaning transition programs long-term tissue plasticity, setting its capacity for expansion and thermogenesis in response to environmental stimuli. However, the mechanisms driving this remodelling, and the role of weaning-associated dietary changes in this process, are unknown. Here, we characterise the emergence of sexually dimorphic patterns of adipose tissue distribution and function during the post-weaning period. As subcutaneous adipocytes acquire a white phenotype, the tissue microenvironment undergoes a coordinated remodelling, including reduced innervation and an increase in immune cell content. Using a model of prolonged breastfeeding, we show that it promotes adipose tissue expansion through sex-dependent mechanisms, stimulating progenitor proliferation in males and adipocyte hypertrophy in females. In males, this is accompanied by accelerated tissue whitening, which we link to enhanced clearance of extracellular noradrenaline by mature adipocytes. Our findings reveal sex- and diet-dependent mechanisms governing adipose tissue maturation and highlight how early life nutritional cues shape the microenvironment and function of mature adipocytes. Highlights- The peri-weaning period associates with sexually dimorphic remodelling of the adipose tissue - Whitening of the adipose tissue associates with immune infiltration and decrease innervation in both sexes - Prolonged breastfeeding prevents drop in proliferation in males - Whitening is accelerated in males during prolonged breastfeeding

physiology↗

bioRxiv2025

Major waves of H2A.Z incorporation during mouse oogenesis

Mammalian oocytes and embryos have distinct epigenomes that undergo major transitions essential for transmitting life to the next generation. Here, we provide the first genome-wide maps of the histone variant H2A.Z during six different stages of mouse oogenesis. Utilizing picogram- scale chromatin immunoprecipitation and sequencing (picoChIP-seq), we reveal major waves of H2A.Z incorporation occurring early in growing oocytes. We identify distinct patterns of H2A.Z signal at oocyte-specific, embryo-specific, and constant H2A.Z loci. Late oocyte-specific loci precede reduced formation of lamina associated domains and early replication timing in the maternal compared to the paternal genome of 2-cell embryos. While constant H2A.Z is strongly associated with CpG islands (CGIs) and H3K4me3 near transcription start sites (TSS) of active genes, tens of thousands of oocyte- and embryo-specific H2A.Z incorporation sites exist independently of CGIs and TSSs. These TSS-distal H2A.Z sites are frequently enriched at transposable elements (TEs), and an intriguing inverse relationship exists between H2A.Z and H3K4me3 in low CpG environments, such as MTA and MTB retrotransposons (RTs). The existence of changes in H2A.Z distribution that persist across related developmental stages enable preservation of epigenetic information despite major concurrent changes in H3K4me3, H3K27me3, and DNA methylation. Altogether, this reveals new layers of regulation advancing our understanding of how histone variants contribute to the epigenetic landscape during mammalian oogenesis and preimplantation embryo development.

developmental biology↗