Tilly, J. | Search bioRxiv

bioRxiv2024

Sphingosine-1-phosphate receptor 3 activation promotes sociability and regulates the expression of genes associated with anxiolytic-like behavior

We previously demonstrated that sphingosine-1-phosphate receptor 3 (S1PR3) in the medial prefrontal cortex (mPFC) prevents stress-mediated reductions in sociability. S1PR3 is a ubiquitously expressed G-protein coupled receptor that regulates immune system function, although its regulation of other biological processes is not well understood. Pharmacological activators of S1PR3 might provide important insights for understanding the neural substrates underlying sociability and/or serve as novel, preclinical treatments for social anxiety. Here we show that in mice, systemic injections of an S1PR3-specific agonist, CYM5541, promotes sociability in males and females whereas an S1PR3-specific antagonist, CAY10444, increases amygdala activation and promotes social anxiety-like behavior in females. S1PR3 expression is increased in the mPFC and dentate gyrus of females compared to males. RNA sequencing in the mPFC reveals that S1PR3 activation alters the expression of transcripts related to immune function, neurotransmission, transmembrane ion transport, and intracellular signaling. This work provides evidence that S1PR3 agonists, which have classically been used as immune modulators, might also be used as novel anxiolytics. S1PR3 might be an important hub gene for anxiolytic effects as it reduces inflammatory processes caused by stress and increases transcripts linked to anxiolytic neurotransmission. HighlightsO_LIThe Sphingosine-1-phosphate receptor 3 (S1PR3) agonist CYM5541 promotes sociability C_LIO_LIThe S1PR3 antagonist CAY10444 reduces sociability and promotes anxiety-like behavior in females C_LIO_LICAY10444 increases neuronal activity markers in the amygdala C_LIO_LIPharmacological activation of S1PR3 regulates the expression of genes in the prefrontal cortex that control a wide range of biological processes, including increasing GABAergic neurotransmission and reducing inflammatory processes C_LI

neuroscience↗

bioRxiv2023

A novel, wave-shaped profile of germline selection of pathogenic mtDNA mutations is discovered by bypassing a classical statistical bias.

The shift of the level of disease-causing mtDNA mutations (heteroplasmy) from mother to child is typically negatively correlated with the mothers heteroplasmy (Hm). In other words, mothers with low Hm tend to have children with a higher mutation level (Hch) than their own. In contrast, mothers with high Hm typically see a decrease in heteroplasmy in their children. This trend has been commonly interpreted as a result of a descending germline selection profile, i.e., positive selection at low Hm, gradually turning negative at high Hm. Here we demonstrate, however, that the negative correlation is mostly driven by RTM, or Regression To the Mean, a classical statistical bias. We further show that RTM can be nullified by using the average between the mothers and childs heteroplasmy, as a new variable, instead of the commonly used mothers heteroplasmy in blood. Additionally, we demonstrate that mother/child average is a better approximation of the actual germline heteroplasmy. Moreover, the elimination of RTM revealed a previously hidden wave-shaped HS-profile (positive mother-to-child shift at intermediate average mother-child heteroplasmy, decreasing towards high and low average heteroplasmy). In confirmation of this finding, we show that simulations that involve both wave-shaped HS-profile and RTM, reproduce the observed patterns of inheritance of mtDNA mutations in unprecedented detail. From the health care perspective, the uncovering of the wave-shaped HS-profile (and the removal of the RTM bias) are crucial for families affected by mtDNA disease. From the fundamental perspective, the wave- shaped profile offers a novel understanding of the dynamics of mtDNA in the germline and a novel potential mechanism that prevents the spread of detrimental mtDNA mutations in the population. SignificanceFrom the clinical perspective, the existence of wave-shaped selection may improve predictions and decisions for families affected by mtDNA diseases. From the fundamental perspective, it provides insight into the dynamics of general mtDNA mutations in the germline and in the population, as long as they follow wave-shaped selection profile. In Fig. 1, blue and red arrows represent the direction of expected changes of the heteroplasmy in a lineage with time/generations. With wave- shaped selection (Fig. 1B), a great majority of nascent low- fraction mutations are expected to converge back to zero and vanish. However, due to random intracellular genetic drift, some mutations will, occasionally, expand and enter the range of positive selection. Then they will be expanded by the selection to higher, detrimental levels, and become prone to downstream removal via death of highly mutated germ cells or inability of highly sick individuals to continue their lineage. In this way, the wave-shaped selection may help to prevent the spread of detrimental mutations in the population and in the species. In contrast, if the descending selection profile (Fig. 1A) was in effect, the nascent low heteroplasmy detrimental mutations would have been pushed to intermediate heteroplasmy levels where they will stay longer in hidden disease carriers enabling effective spread of mutation in the population. O_FIG O_LINKSMALLFIG WIDTH=192 HEIGHT=200 SRC="FIGDIR/small/568140v2_fig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1142cc0org.highwire.dtl.DTLVardef@186002aorg.highwire.dtl.DTLVardef@74d176org.highwire.dtl.DTLVardef@163ca6c_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1.C_FLOATNO (Graphic Summary) Pathogenic mtDNA mutations that cause a host of devastating inherited diseases are usually thought to follow an intriguing inheritance trend: Mothers with low levels of mutation (called mother heteroplasmy, Hm) tend to bear children with higher child heteroplasmy (Hch) then their own which constitutes positive Heteroplasmy Shift (HS=Hch-Hm). In contrast, mothers with high heteroplasmy Hm bear children with lower heteroplasmy Hc (negative HS). C_FIG

genomics↗

bioRxiv2023

The 'Stem' and the 'Workers' of the mtDNA population of the cell. Evidence from mutational analysis.

Every cell in our body contains a vibrant population of mitochondria, or, more precisely, of mitochondrial DNA molecules (mtDNAs). Just like members of any population mtDNAs multiply (by replication) and die (i.e., are removed, either by degradation or by distribution into the sister cell in mitosis). An intriguing question is whether all mitochondria in this population are equal, especially whether some are responsible primarily for reproduction and some - for empowering the various jobs of the mitochondrion, oxidative phosphorylation in the first place. Importantly, because mtDNA is highly damaged such a separation of responsibilities could help greatly reduce the conversion of DNA damage into real inheritable mutations. An unexpected twist in the resolution of this problem has been brought about by a recent high-precision analysis of mtDNA mutations (Sanchez-Contreras et al. 2023). They discovered that certain transversion mutations, unlike more common transitions, are not accumulating with age in mice. We argue that this observation requires the existence of a permanent replicating subpopulation/lineage of mtDNA molecules, which are protected from DNA damage, a.k.a. the stem mtDNA. This also implies the existence of its antipode i.e., the worker mtDNA, which empowers OSPHOS, sustains damage and rarely replicates. The analysis of long HiFi reads of mtDNA performed by PacBio closed circular sequencing confirms this assertion.

genomics↗