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Sonntag, I.

Publications and source records attributed to Sonntag, I..

5 recordsLinked to original sources

A Dual-Ensemble Model of Infralimbic Cortex Function in Behavioural Flexibility

The infralimbic cortex (IL) has been described as both facilitator and terminator of reward-seeking, yet both functions appear mutually exclusive. We reconcile this discrepancy by proposing a dual-ensemble model: one for action-outcome prediction and another for prediction correction. Using longitudinal miniscope imaging in rats, we show that during training, the action-outcome predictor ensemble sharpens its activity by suppressing the majority of the IL neuronal population. As contingencies stabilize, entropy decreases, reflecting a refined predictive model. During extinction, the prediction correction ensemble activates in response to reward omission. A computational simulation based on these two ensembles successfully recapitulated our experimental results. This framework reconciles conflicting models, where IL manipulation can either accelerate or abolish extinction by demonstrating that IL activity dynamically encodes predictive accuracy. Our findings indicate that IL functions as an action-outcome predictor that elegantly guides behavioural flexibility.

neuroscience↗

The AMD-associated genetic polymorphism CFH Y402H confers vulnerability to Hydroquinone-induced stress in iPSC-RPE cells

Age-related macular degeneration (AMD), a degenerative disease of the macula, is caused by an interplay of diverse risk factors (genetic predisposition, age and lifestyle habits). One of the main genetic risks includes the Y402H polymorphism in complement Factor H (FH), an inhibitor of complement system activation. There has been, and continues to be, much discussion around the functional consequences of this Y402H polymorphism, whether the soluble FH protein confers its risk association, or if the cells expressing the protein themselves are affected by the genetic alteration. In our study, we examined the cell characteristics of the retinal pigment epithelium (RPE) cells, which play a major role in retinal homeostasis and stability and which are synonymously linked to AMD. Here, we employ RPE cells derived from induced pluripotent stem cells (iPSC) generated from donors, carrying either homozygous 402Y (low risk) or 402H (high risk) variants of the CFH gene. RPE cells were treated with Hydroquinone (HQ), a component of cigarette smoke, to induce oxidative damage. Intriguingly, RPE cells carrying high genetic risk proved more vulnerable to oxidative insult when exposed to HQ, as demonstrated by increased cytotoxicity, caspase activation, compared to the low-risk RPE cells. The exposure of RPE cells to RPE conditioned medium, normal human serum (NHS) and inactivated NHS (iNHS) had minimal impact on cell cytotoxicity and caspase activation, nor did the presence of purified soluble FH rescue the observed effects. This suggests that the degree of cellular susceptibility to oxidative stress is not conferred by soluble FH protein and other complement sources, but intercellularly because of the corresponding genetic risk predisposition. Considering the known connection of oxidative stress to proteotoxic stress and degrading processes, we investigated the unfolded protein response (UPR) and autophagy. When exposed to HQ, RPE cells showed an increase in autophagy markers, however iPSC-RPE cells carrying high genetic risk showed an overall reduced autophagic flux. Our data support the hypothesis that RPE cells carrying high genetic risk are less resilient to oxidative stress.

cell biology↗

CFH loss in human RPE cells leads to inflammation and complement system dysregulation via the NF-B pathway

Age-related macular degeneration (AMD), the leading cause of vision loss in the elderly, is a degenerative disease of the macula, where retinal pigment epithelium (RPE) cells are damaged in the early stages of the disease and chronic inflammatory processes may be involved. Besides ageing and lifestyle factors as drivers of AMD, a strong genetic association to AMD is found in genes of the complement system, with a single polymorphism in the complement factor H gene (CFH), accounting for the majority of AMD risk. However, the exact mechanism by which CFH dysregulation confers such a great risk for AMD and its role in RPE cells homeostasis is unclear. To explore the role of endogenous CFH locally in RPE cells, we silenced CFH in human hTERT-RPE1 cells. We demonstrate that endogenously expressed CFH in RPE cells modulates inflammatory cytokine production and complement regulation, independent of external complement sources or stressors. We show that loss of the factor H protein (FH) results in increased levels of inflammatory mediators (e.g. IL-6, IL-8, GM-CSF) and altered levels of complement proteins (e.g. C3, CFB upregulation and C5 downregulation) that are known to play a role in AMD. Moreover, we identified the NF-{kappa}B pathway as the major pathway involved in the regulation of these inflammatory and complement factors. Our findings suggest that in RPE cells, FH and the NF-{kappa}B pathway work in synergy to maintain inflammatory and complement balance and in case either one of them is dysregulated, the RPE microenvironment changes towards a pro-inflammatory AMD-like phenotype.

immunology↗

Loss of Complement Factor H impairs antioxidant capacity and energy metabolism of human RPE cells

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly population. About 50% of AMD patients present polymorphisms in the Complement Factor H (CFH) gene, coding for Factor H protein (FH). AMD-associated CFH risk variants, Y402H in particular, impair FH function leading to complement overactivation. In AMD, retinal homeostasis is compromised due to dysfunction of retinal pigment epithelium (RPE) cells. Whether FH contributes to AMD pathogenesis only via complement system dysregulation remains unclear. To investigate the potential role of FH on energy metabolism and oxidative stress in RPE cells, we silenced CFH in human hTERT-RPE1 cells. FH-deprived RPE cells exposed to oxidative insult, showed altered metabolic homeostasis, including reduction of glycolysis and mitochondrial respiration, paralleled by an increase in lipid peroxidation. Our data suggest that FH protects RPE cells from oxidative stress and metabolic reprogramming, highlighting a novel function for FH in AMD pathogenesis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=148 SRC="FIGDIR/small/898551v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@32644borg.highwire.dtl.DTLVardef@569cf4org.highwire.dtl.DTLVardef@5a8aa2org.highwire.dtl.DTLVardef@43cc55_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

retroLEAP: rAAV-based retrograde trans-synaptic labeling, expression and perturbation

Identifying and manipulating synaptically connected neurons across brain regions remains a core challenge in understanding complex nervous systems. RetroLEAP is a novel approach for retrograde trans-synaptic Labelling, Expression And Perturbation. GFP-dependent recombinase (Flp-DOG) detects trans-synaptic transfer of GFP-tetanus toxin heavy chain fusion protein (GFP-TTC) and activates expression of any gene of interest in synaptically connected cells. RetroLEAP overcomes existing limitations, is non-toxic, highly flexible, efficient, sensitive and easy to implement.

neuroscience↗