Biology subjects

Kovacs, K. J.

Publications and source records attributed to Kovacs, K. J..

4 recordsLinked to original sources

bioRxiv2023

Novel Insights into the Aortic Mechanical Properties of Mice Modeling Hereditary Aortic Diseases

OBJECTIVEHereditary aortic diseases (hADs) increase the risk of aortic dissections and ruptures. Recently, we have established an objective approach to measure the rupture force of the murine aorta, thereby explaining the outcomes of clinical studies and assessing the added value of approved drugs in vascular Ehlers-Danlos syndrome (vEDS). Here, we applied our approach to six additional mouse hAD models. APPROACH AND RESULTWe used two mouse models of Marfan syndrome (MFS) as well as one smooth-muscle-cell-specific knockout (SMKO) of Efemp2 and three CRISPR/Cas9-engineered knock-in models (Ltbp1, Mfap4, and Timp1). One of the two MFS models was subjected to 4-week-long losartan treatment. Per mouse, three rings of the thoracic aorta were prepared, mounted on a tissue puller, and uniaxially stretched until rupture. The aortic rupture force of the SMKO and both MFS models was significantly lower compared with wild-type mice but in both MFS models higher than in mice modeling vEDS. In contrast, the Ltbp1, Mfap4, and Timp1 knock-in models presented no impaired aortic integrity. As expected, losartan treatment reduced aneurysm formation but surprisingly had no impact on the aortic rupture force of our MFS mice. CONCLUSIONSOur read-out system can characterize the aortic biomechanical integrity of mice modeling not only vEDS but also related hADs, allowing the aortic-rupture-force- focused comparison of mouse models. Furthermore, aneurysm progression alone may not be a sufficient read-out for aortic rupture, as antihypertensive drugs reducing aortic dilatation might not strengthen the weakened aortic wall. Our results may enable identification of improved medical therapies of hADs. HighlightsO_LIAssay to measure the aortic rupture force as read-out for the biomechanical integrity identified weakened murine thoracic aorta prior to micro- and macroscopic changes in Fbn1+/C1041G mice. C_LIO_LIDespite reducing aneurysm growth, losartan treatment did not have any impact on the aortic rupture force of Fbn1mgR/mgR mice modeling MFS. C_LIO_LISmooth-muscle-cell-knock-out of Efemp2 significantly impaired the rupture force of the murine ascending aorta. C_LIO_LIAortic rupture force measurements could clarify the causality of novel candidate gene(s)/variant(s) in mouse models of aortic diseases. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/553452v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@a29d79org.highwire.dtl.DTLVardef@10a272org.highwire.dtl.DTLVardef@19071forg.highwire.dtl.DTLVardef@122ab40_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2023

Persistently increased post-stress activity of paraventricular thalamic neurons is essential for the emergence of stress-induced maladaptive behavior

ABSTRACTTraumatic events can immediately lead to debilitating symptoms collectively called Acute Stress Disorder (ASD), however the mechanisms of ASD are poorly understood. Using a rodent model of ASD here we identify a crucial communication bottleneck between the brainstem and the forebrain, the calretinin-positive neurons in the paraventricular thalamus (PVT/CR+), that controls ASD. We show that following a single acute stress event, the pre-sleep behavior of the mice is altered for several days in parallel with a persistent increase in the firing rate of PVT/CR+ cells. Optogenetic inhibition of PVT/CR+ neuronal activity after the stress event for one hour was sufficient to rescue both the ASD symptoms and the prolonged increase in PVT/CR+ firing rate. Inhibition applied 5 days later was still able to ameliorate some of the symptoms. These data suggest that post-stress activity of PVT/CR+ neurons play a critical role in mediating the acute forms of stress-related affective dysfunctions. One-Sentence SummaryPost-stress inhibition of paraventricular thalamic neurons prevents the emergence of acute stressed phenotype.

neuroscience↗

bioRxiv2022

Recruitment of Corticotropin-releasing Hormone CRH Neurons in response ton Categorically Distinct Stress Challenges in the Mouse Brain

1.Corticotropin-releasing hormone (CRH) neurons in the paraventricular hypothalamic nucleus (Pa) are in the position to integrate stress-related information and initiate adaptive neuroendocrine-, autonomic-, metabolic- and behavioral responses. In addition to hypophyseotropic cells, CRH is widely expressed in the CNS, however their involvement in organization of the stress response is not fully understood. In these experiments, we took the advantage of recently available Crh-IRES-Cre; Ai9 mouse line to study the recruitment of hypothalamic and extrahypothalamic CRH neurons in categorically distinct, acute stress reactions. Reporter mice were exposed to restraint, ether, high salt and lipopolisacharide stress. The induced activation of CRH neurons was detected by colocalization of immediate early gene c-Fos in Td tomato expressing cells. We found differential activation of CRH neurons in central amygdaloid nucleus (Ce), bed nucleus stria terminalis lateral division, ventral posterior (BSTLVP), medial preoptic nucleus (MPO), ventromedial hypothalamic nucleus (VMH), premammillary nucleus (PM) and prepositus hypoglossal nucleus (Pr) in response to physiological (ether, high salt and LPS) and psychological (restraint) stressors. CRH positive cells in Pa became activated, however in the Barringtons nucleus and locus coeruleus no actiovation could be observed due to most tested stressors. Furthermore no CRH neuron activation occured in dorsal (BSTLD) and posterior (BSTLP) region of lateral division of bed nucleus stria terminalis after restraint stress. In the inferior olive only ether exposition resulted in CRH neuron activation. These results confirm activation of CRH neurons in the Pa, reveals new subset of stress-related CRH cells through the mouse brain and disprove the recruitment of CRH cells in the SOL and in the Barringtons nucleus to acute psychological stress in mice.

neuroscience↗

bioRxiv2018

Absence of SIV-specific CD8+ T cells in germinal centers may set the stage for persistent infection

CD8+ T cells play an important role in controlling of HIV and SIV infections. However, these cells are largely excluded from B cell follicles where HIV and SIV producing cells concentrate during chronic infection. It is not known, however, if antigen-specific CD8+ T cells are excluded gradually as pathogenesis progresses from early to chronic phase, or this phenomenon occurs from the beginning infection. In this study we determined that SIV-specific CD8+ T cells were largely excluded from follicles during early infection, we also found that within follicles, they were entirely absent in 60% of the germinal centers (GCs) examined. Furthermore, levels of SIV-specific CD8+ T cells in follicular but not extrafollicular areas significantly correlated inversely with levels of viral RNA+ cells. In addition, subsets of follicular SIV-specific CD8+ T cells were activated and proliferating and expressed the cytolytic protein perforin. These studies suggest that a paucity of SIV-specific CD8+ T cells in follicles and complete absence within GCs during early infection may set the stage for the establishment of persistent chronic infection.\n\nAuthor SummaryA paucity of SIV-specific CD8+ T cells in lymphoid follicles and complete absence within most follicular germinal centers during early infection may set the stage for the establishment of persistent chronic infection.

immunology↗