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The CACNA1C gene encodes the pore-forming ��1C-subunit of the L-type calcium channel (LTCC) isoform Cav1.2, which is expressed in the brain, smooth muscle and the heart. In the brain and in its development, the Cav1.2 isoform is involved in the regulation of synaptic plasticity, neuronal activity and thus also in learning processes and behaviour. In the heart, Cav1.2 is responsible for the sarcolemmal calcium (Ca) influx during the action potential and the Ca-induced Ca-release from the sarcoplasmic reticulum (SR) which leads to contraction of the cardiomyocyte. In genome-wide association studies, polymorphisms in the CACNA1C gene have been linked to the occurrence of psychiatric disorders (depression, bipolar disorder, schizophrenia, anxiety disorders & autism), but variants of the gene can also manifest in heart disease (Brugada syndrome, Timothy syndrome or long-QT syndrome). On the one hand, psyche and heart function are linked via the CACNA1C gene; on the other hand, psychiatric diseases also increase the risk of developing cardiac diseases and vice versa. The heterozygous Cacna1c+/- knockout in the rat/mouse model leads to the development of a behavioural phenotype associated with deficits in social communication, increased anxiety and autism-like behaviours - confirming the important role of the gene at the behavioural level. This study presents the first characterisation of the Cacna1c+/- rat model at the cardiac level. For this purpose, Ca-homeostasis of ventricular myocytes as well as expression and phosphorylation of Ca-handling proteins in the heart of these animals were investigated and compared to their wild-type (WT) littermates. In a basal characterisation, the Cacna1c+/- animals showed unchanged heart rates but decreased blood pressure values without evidence of the development of cardiac hyper- or hypotrophy. Electrically stimulated Ca-transients (CaT) were examined in isolated cardiomyocytes at the confocal microscope using the Ca dye Fluo-4. CaT, SR Ca content, fractional SR Ca release and sarcolemmal Ca influx in Cacna1c+/- myocytes under basal conditions were comparable to WT myocytes, despite a 30% reduction in Cav1.2 expression in Cacna1c+/- myocardium. However, remodelling of Ca-handling proteins accompanied by increased expression of SR-Ca-ATPase (SERCA) and Na-Ca exchanger (NCX) as well as basally increased protein kinase A (PKA) dependent phosphorylation at Cav1.2 (Ser1928) and ryanodine receptor type-2 (RyR2) (Ser2808) could be detected, which can be regarded as a kind of compensatory mechanism. Since the Cacna1c+/- rat model has a behavioural phenotype and psychological stress is also associated with increased sympathetic activity, the second part of the work simulated sympathetic stimulation in which ventricular myocytes were treated with the ��-adrenergic agonist isoprenaline (ISO). Under ISO (100 nM), the amplitude of CaT was increased and the decline in CaT accelerated. Both WT and Cacna1c+/- myocytes showed a corresponding response to ISO treatment, although the increase in CaT amplitude was significantly weaker in Cacna1c+/- myocytes. After ISO administration, fractional SR Ca release increased from 60% to 90% in WT myocytes, whereas the increase from 60% to 75% was also weaker in Cacna1c+/- myocytes. Accordingly, using an ISO concentration-response curve, a significantly higher EC50 of 13 nM was determined in Cacna1c+/--myocytes compared to WT (EC50: 4 nM). Furthermore, after blocking the SR, the sarcolemmal Ca-influx was decreased under ISO in Cacna1c+/- myocytes. In Langendorff-perfused hearts, the ISO-mediated increase in phosphorylation of key Ca-handling proteins was investigated. The increase in phosphorylation of RyR2 at Ser2808 was significantly weaker in Cacna1c+/- hearts than in WT. Since in the Cacna1c+/- myocardium this site was already more strongly phosphorylated basally, the ISO-mediated increase could not be as pronounced as in the WT. This reduced phosphorylation reserve in Cacna1c+/- myocytes is presumably responsible for the impaired ability to stimulate SR-Ca release and increase CaT to the same extent as the WT. Compensatory mechanisms take place in Cacna1c+/- myocytes that allow maintenance of normal CaT under basal conditions. However, under stressed conditions, these mechanisms reach their limits, revealing an impaired response of Cacna1c+/- myocytes to sympathetic stress. This study thus provides the first evidence that a heterozygous knockout of the Cacna1c+/- gene, in addition to the development of a behavioural phenotype, also results in a phenotype at the cardiac level., Das CACNA1C-Gen codiert f��r die porenbildende ��1C-Untereinheit der L-Typ-Calcium-Kanal (LTCC)-Isoform Cav1.2, welche im Gehirn, in Glattmuskelzellen und im Herzen exprimiert wird. Im Gehirn und in dessen Entwicklung ist die Cav1.2-Isoform beteiligt an der Regulation der synaptischen Plastizit��t, der Neuronenaktivit��t und damit auch an Lernprozessen und Verhalten. Im Herzen ist Cav1.2 verantwortlich f��r den sarkolemmalen Calcium (Ca)-Einstrom w��hrend des Aktionspotentials und die Ca-induzierte Ca-Freisetzung aus dem sarkoplasmatischen Retikulum (SR), die in der Kontraktion des Kardiomyozyten resultiert. In genomweiten Assoziationsstudien konnten Polymorphismen im CACNA1C-Gen mit dem Auftreten von psychiatrischen Erkrankungen (Depressionen, Bipolare St��rungen, Schizophrenie, Angstst��rungen & Autismus) in Verbindung gebracht werden, aber Varianten des Gens k��nnen sich auch in Herzerkrankungen (Brugada Syndrom, Timothy Syndrom oder dem long-QT Syndrom) ��u��ern. Psyche und Herzfunktion sind einerseits ��ber das CACNA1C-Gen miteinander verbunden, andererseits erh��hen psychiatrische Erkrankungen auch das Risiko f��r die Entwicklung kardialer Erkrankungen und vice versa. Der heterozygote Cacna1c+/--Knockout im Ratten/Mausmodell f��hrt zur Entwicklung eines Verhaltensph��notyps, einhergehend mit Defiziten in der sozialen Kommunikation, erh��hter ��ngstlichkeit und Autismus-��hnlichen Verhaltensweisen ��� und best��tigt so den wichtigen Einfluss des Gens auf Verhaltensebene. Die vorliegende Arbeit pr��sentiert die erste Charakterisierung des Cacna1c+/--Rattenmodells auf kardialer Ebene. Daf��r wurde die Ca-Hom��ostase ventrikul��rer Myozyten sowie die Expression und Phosphorylierung der Ca-regulierenden-Proteine im Herzen dieser Tiere untersucht und mit ihren Wildtyp (WT)-Wurfgeschwistern verglichen. In einer basalen Charakterisierung zeigten die Cacna1c+/--Tiere unver��nderte Herzfrequenzen aber verminderte Blutdruckwerte ohne Hinweise auf die Entwicklung einer Herzhyper- oder -hypotrophie. In isolierten Kardiomyozyten wurden am Konfokalmikroskop, mithilfe des Ca-Farbstoffs Fluo-4, elektrisch stimulierte Ca-Transienten (CaT) untersucht. Dabei waren in Cacna1c+/--Myozyten unter basalen Bedingungen die CaT, der SR-Ca-Gehalt, die fraktionelle SR-Ca-Freisetzung, als auch der sarkolemmale Ca-Einstrom vergleichbar mit den WT-Myozyten, trotz einer 30%igen Reduktion der Cav1.2-Expression im Cacna1c+/--Myokard. Jedoch konnten Umbauprozesse der Ca-regulierenden Proteine, einhergehend mit erh��hter Expression der SR-Ca-ATPase (SERCA) und des Na-Ca-Austauschers (NCX) sowie einer basal erh��hten Proteinkinase A (PKA)-abh��ngigen Phosphorylierung an Cav1.2 (Ser1928) und dem Ryanodinrezeptor-Typ-2 (RyR2) (Ser2808) festgestellt werden, die als eine Art Kompensationsmechanismus angesehen werden k��nnen. Da das Cacna1c+/--Rattenmodell einen Verhaltensph��notyp aufweist und psychischer Stress auch mit erh��hter Sympathikusaktivit��t einhergeht, wurde im zweiten Teil der Arbeit eine Sympathikusstimulierung simuliert, bei der Ventrikelmyozyten mit dem ��-adrenergen Agonisten Isoprenalin (ISO) behandelt wurden. Unter ISO (100 nM) war die Amplitude der CaT erh��ht und der Abfall der CaT beschleunigt. Sowohl WT- als auch Cacna1c+/--Myozyten zeigten eine entsprechende Antwort auf die Behandlung mit ISO, wobei die Erh��hung der CaT-Amplitude in Cacna1c+/--Myozyten signifikant schw��cher ausgepr��gt war. Nach ISO-Gabe erh��hte sich die fraktionelle Ca-Freisetzung in WT-Myozyten von 60% auf 90%, wohingegen die Erh��hung von 60% auf 75% in Cacna1c+/--Myozyten ebenfalls schw��cher ausfiel. Entsprechend wurde mittels einer ISO-Konzentrations-Wirkungskurve in Cacna1c+/--Myozyten ein signifikant h��herer EC50 von 13 nM im Vergleich zum WT (EC50: 4 nM) ermittelt. Dar��ber hinaus war nach Ausschalten des SR der sarkolemmale Ca-Einstrom unter ISO in Cacna1c+/--Myozyten vermindert. In Langendorff-perfundierten Herzen wurde die ISO-vermittelte Steigerung der Phosphorylierung der wichtigsten Ca-regulierenden Proteinen untersucht. Die Steigerung der Phosphorylierung des RyR2 an Ser2808 war dabei in Cacna1c+/--Herzen signifikant schw��cher ausgepr��gt als im WT. Da im Cacna1c+/--Myokard diese Stelle bereits basal st��rker phosphoryliert war, konnte die ISO-vermittelte Steigerung auch nicht mehr so ausgepr��gt stattfinden wie im WT. Diese reduzierte Phosphorylierungs-Reserve in Cacna1c+/--Myozyten ist mutma��lich verantwortlich f��r die beeintr��chtigte F��higkeit im selben Ma��e wie der WT eine SR-Ca-Freisetzung zu stimulieren und die CaT zu erh��hen. In Cacna1c+/--Myozyten finden Kompensationsmechanismen statt, die unter basalen Bedingungen eine Aufrechterhaltung normaler CaT erm��glichen. Unter gestressten Bedingungen gelangen diese Mechanismen jedoch an ihre Grenzen und offenbaren eine beeintr��chtigte Antwort der Cacna1c+/--Myozyten auf sympathischen Stress. Diese Studie liefert somit erste Evidenz, dass ein heterozygoter Knockout des Cacna1c+/--Gens neben der Entwicklung eines Verhaltens-Ph��notyp, ebenfalls in einem Ph��notyp auf kardialer Ebene resultiert.

Anxiety is characterized by low confidence in daily decisions, coupled with high levels of phenomenological stress. Ventromedial prefrontal cortex (vmPFC) plays an integral role in maladaptive anxious behaviors via decreased sensitivity to threatening vs. non-threatening stimuli (fear generalization). vmPFC is also a key node in approach-avoidance decision making requiring two-dimensional integration of rewards and costs. More recently, vmPFC has been implicated as a key cortical input to the sympathetic branch of the autonomic nervous system. However, little is known about the role of this brain region in mediating rapid stress responses elicited by changes in confidence during decision making. We used an approach-avoidance task to examine the relationship between sympathetically mediated cardiac stress responses, vmPFC activity and choice behavior over long and short time-scales. To do this, we collected concurrent fMRI, EKG and impedance cardiography recordings of sympathetic drive while participants made approach-avoidance decisions about monetary rewards paired with painful electric shock stimuli. We observe first that increased sympathetic drive (shorter pre-ejection period) in states lasting minutes are associated with choices involving reduced decision ambivalence. Thus, on this slow time scale, sympathetic drive serves as a proxy for “mobilization” whereby participants are more likely to show consistent value-action mapping. In parallel, imaging analyses reveal that on shorter time scales (estimated with a trial-to-trial GLM), increased vmPFC activity, particularly during low-ambivalence decisions, is associated with decreased sympathetic state. Our findings support a role of sympathetic drive in resolving decision ambivalence across long time horizons and suggest a potential role of vmPFC in modulating this response on a moment-to-moment basis.

Appraising sequential offers relative to an unknown future opportunity and a time cost requires an optimization policy that draws on a learned estimate of an environment’s richness. Converging evidence points to a learning asymmetry, whereby estimates of this richness update with a bias toward integrating positive information. We replicate this bias in a sequential foraging (prey selection) task and probe associated activation within the sympathetic branch of the autonomic system, using trial-by-trial measures of simultaneously recorded cardiac autonomic physiology. We reveal a unique adaptive role for the sympathetic branch in learning. It was specifically associated with adaptation to a deteriorating environment: it correlated with both the rate of negative information integration in belief estimates and downward changes in moment-to-moment environmental richness, and was predictive of optimal performance on the task. The findings are consistent with a framework whereby autonomic function supports the learning demands of prey selection. Electronic supplementary material The online version of this article (10.3758/s13415-020-00799-0) contains supplementary material, which is available to authorized users.

The exposure to sympathetic stress during the entire period of gestation (4 °C/3 h/day) strongly affects the postnatal reproductive performance of the first generation of female offspring and their fertility capacity. The aim of this work was to determine whether this exposure to sympathetic stress affects the reproductive capacity of the next three generations of female offspring as adults. Adult female Sprague–Dawley rats were mated with males of proven fertility. We studied the reproductive capacity of the second, third, and fourth generations of female offspring (the percentage of pregnancy and the number and weight of female offspring). The estrus cycle activity of the progenies was studied, and a morphological analysis of the ovaries was carried out to study the follicular population. The second generation had a lower number of pups per litter and a 20% decrease in fertile capacity. The estrus cycle activity of the third generation decreased even more, and they had a 50% decrease in their fertile capacity, and their ovaries presented polycystic morphology. The fourth generation however, recovered their reproductive capacity but not the amount of newborns pups. Most probably, the chronic intrauterine exposure to the sympathetic stress programs the female gonads to be stressed in a stressful environment; since the fourth generation was the first born with no direct exposure to stress during development, it opens studies on intrauterine factors affecting early follicular development.