Diabetes mellitus (DM) induces a large number of diseases of the nervous, cardiovascular, and some other systems of the organism. One of the main causes of the diseases is the changes in the functional activity of hormonal signaling systems which lead to the alterations and abnormalities of the cellular processes and contribute to triggering and developing many DM complications. The key role in the control of physiological and biochemical processes belongs to the adenylyl cyclase (AC) signaling system, sensitive to biogenic amines and polypeptide hormones. The review is devoted to the changes in the GPCR-G protein-AC system in the brain, heart, skeletal muscles, liver, and the adipose tissue in experimental and human DM of the types 1 and 2 and also to the role of the changes in AC signaling in the pathogenesis and etiology of DM and its complications. It is shown that the changes of the functional state of hormone-sensitive AC system are dependent to a large extent on the type and duration of DM and in experimental DM on the model of the disease. The degree of alterations and abnormalities of AC signaling pathways correlates very well with the severity of DM and its complications. Diabetes mellitus (DM) is a major global health problem affecting, according to the World Health Organization, more than 346 million people worldwide . It is oαβγ-heterotrimeric G protein of the stimulatory (Gs) and inhibitory (Gi) types, and (iii) the enzyme adenylyl cyclase (AC) catalyzing the formation of cAMP, a second messenger. The system specifically recognizes a hormonal signal, amplifies it, and transmits to the intracellular cAMP-dependent effector proteins. The GPCR acts as a molecular switch that provides the transduction of hormonal signals from extracellular ligand-binding site to the G proteins located at the cytoplasmic side of the plasma membrane. Ligand-activated GPCR induces the conformational changes in the GDP-bound Gα subunit, leading to GTP exchange for GDP. Gα-GTP then dissociates from Gβγ-dimer complex, and Gα-GTP and Gβγ both interact with the enzyme AC, stimulating or inhibiting its activity. It is a common knowledge that in the regulation of physiological and biochemical processes the most important role belongs to a hormone-sensitive adenylyl cyclase (AC) signaling system. Activating or, alternatively, inhibiting this system, many hormones, growth factors, and hormone-like substances control the activity of cAMP-dependent signaling cascades and transcription factors and thus regulate gene expression and the other cell processes. The AC system has three main components: (i) G protein-coupled receptor (GPCR) of the serpentine type that recognizes and specifically interacts with hormone, (ii) the The present review is devoted to the alterations and abnormalities in the GPCR-G protein-AC signaling system regulated by biogenic amines and polypeptide hormones in the brain, heart, skeletal muscles, liver, and the adipose tissue in experimental and human DM and to the role of the changes in AC signaling cascades in the pathogenesis and etiology of DM and its complications. Many neurodegenerative disorders, diabetic encephalopathy and Alzheimer's disease in particular, are associated with DM. In diabetic patients, they are manifested as alterations in neurotransmission, electrophysiological abnormalities, structural changes, and cognitive deficit . Since ts-coupled DA receptors of types 1 and 5 (DA1R and DA5R) and inhibits the enzyme via Gi-coupled DA2R, DA3R, and DA4R. It was found experimentally that in the brain of diabetic animals the dopaminergic signaling was altered, mainly due to the changes at the initial stages of DA-induced signal transduction which involves DARs, Gi, or Gs proteins and their effectors, AC in particular, and these alterations are brain region specific [1R and DA2R and the total DAR binding were increased; in the cerebellum, DA1R was downregulated and DA2R upregulated, a total number of DARs being however decreased, and in the hypothalamus and brainstem a significant decrease in the DA content and the number of DA2Rs and an increase in DA2R affinity were shown [1R and DA2R expression and DA2R receptor binding parameters in the diabetic brain to near control, thereby improving the cognitive and emotional functions impaired in T1DM [DA is the predominant catecholamine neurotransmitter in the brain, which controls a variety of CNS functions  and plays multiple roles in the periphery as a modulator of cardiovascular function, hormone secretion, and gastrointestinal motility. DA activates AC via Gspecific . In the re shown , 28. The in T1DM . The alt in T1DM . It was  in T1DM . s-coupled DA1/5Rs did not change significantly [2R agonist bromocriptine and its stimulating effect on 5′ guanylylimidodiphosphate (GppNHp) binding of Gi proteins in the synaptosomal membranes isolated from the brain of diabetic rats were decreased, predominantly in T1DM [i proteins [2R agonist-induced suppression of appetite in STZ rats might be the result of reduction of Gi protein activity in the diabetic brain [We showed that, in the brain of rats with one-month T1DM, induced by STZ at a dose 65 mg/kg of body weight, and with prolonged, 7-month, T1DM, induced by three consecutive injections of STZ on the first, 10th, and 80th days of experiments at dropped doses 40, 35, and 30 mg/kg, the AC stimulating effect of DA realized via Gficantly , 32, andficantly . The AC  in T1DM , 35. As proteins . A similic brain . i-coupled 5-hydroxytryptamine receptor of the type 1 (5-HT1R) were altered significantly. One-week STZ-induced DM markedly reduced the flat body posture induced by 5-HT1AR agonist 8-hydroxy-2-(dipropylamino) tetralin hydrobromide (8-OH-DPAT), which indicated that STZ-induced T1DM profoundly affected the sensitivity to drugs acting via 5-HT1AR [The brain serotonergic signaling is involved in the regulation of feeding, locomotion, reproduction, sleep, pain, aggression, and stress responses, as well as thermogenesis, cardiovascular control, circadian rhythm, and pancreatic function. The abnormalities of 5-HT-regulated signaling cascades in the diabetic brain provoke disturbances in neuronal processing and the alteration of plasticity of neurotransmission and play an important role in DM-induced CNS disorders , 39. Thi 5-HT1AR . s-coupled 5-HT6R were detected, while AC sensitivity to agonists of Gi-coupled 5-HT1AR and 5-HT1BR was decreased significantly [1BR-agonist 5-nonyloxytryptamine were reduced by 79 and 70%, respectively. The increase of GppNHp binding of G proteins induced by 5-nonyloxytryptamine and nonselective 5-HT1R agonist 5-methoxy-N,N-dimethyltryptamine in the case of the neonatal model of T2DM was reduced by 57 and 51%, respectively [1R-mediated signaling may be associated with a decrease of expression and activity of Gi proteins, because in the diabetic brain the impairment of other Gi-coupled cascades was also detected. In our experiments, no alterations of the sensitivity of AC system in the brain of STZ rats to selective agonists of Gficantly , 35, 41.β-ARs by NE leads to facilitation of the synaptic transmission through the mechanism involving the increase of the level of intracellular cAMP and protein synthesis de novo, thus contributing to the memory acquisition and maintenance [s-coupled β-ARs in the regional brain of db/db mice was depressed, which demonstrates a considerable modification of adrenergic signaling [i/o-coupled α2-ARs in the frontal cortex, septal area, amygdala, hypothalamus, and medulla of 4–16-week-old db/db mice with T2DM-like state were, on the contrary, elevated compared to those of control animals and this increase correlated with the changes in blood glucose level and body weight [db/db mice, the genetic model of T2DM, may be causally associated with the consequences of the changes in structural integrity and neuronal competence of the medial basal hypothalamus. The alterations in the brain adrenergic signaling were also shown in STZ-induced T1DM. In the brainstem of STZ-treated rats, the content of epinephrine and the NE/epinephrine turnover were increased, and the affinity of α2-ARs to selective agonists was significantly reduced [α2-ARs to normal values. In the hypothalamus, thalamus, and amygdala of STZ rats, the density of β1-, but not of β2-, ARs was increased, and the rate of metabolism of NE was decreased [Due to their ability to regulate the synaptic mechanisms, NE and other ligands of adrenergic receptors (ARs) are essential modulators of memory. The activation of ntenance . It was ignaling . The levy weight . The alt reduced . Insulinecreased . β-ARs in the cerebral microvessels of Zucker diabetic fatty (fa/fa) rats and STZ rats was significantly decreased despite the receptor affinity did not change [β-AR-mediated regulation of cAMP-dependent signaling in T1DM [The neurodegenerative processes in the diabetic brain are largely associated with the damage in the cerebral microvessels whose functions are controlled via different signaling systems, the adrenergic in particular. The number of t change . The iso in T1DM . We show in T1DM . These r in T1DM . It foll4R) coupled with AC via Gs proteins in the brain was restricted, and MC4R-mediated signaling pathways were significantly reduced [4R-agonists α-melanocyte-stimulating hormone (α-MSH) and melanotan II promote a negative energy balance by decreasing the food intake and increasing the brain activity and energy expenditure, whereas hypothalamic agouti-related peptide (AgRP), MC4R antagonist, on the contrary, increases food intake [4R pathways regulate glucose metabolism and insulin sensitivity [4R-agonists reduces insulin secretion, while administration of MC4R-antagonists increases plasma insulin level. Indeed, elevated insulin level and impaired insulin sensitivity were detected in the young lean MC4R knockout mice, even before the development of pronounced hyperphagia and obesity [4R had obesity strikingly reminiscent of the agouti syndrome, which indicates that the disturbances in MC4R signaling pathways were the primary cause of the agouti obesity. The hypothalamic melanocortin system controlling adiposity levels rapidly and more efficiently than the other central signaling systems is regulated by leptin [4R and inhibited the production of AgRP [4Rs are involved in neuroprotective action, regeneration and promotion of adaptive plasticity of neuronal and glial cells [α-MSH and selective MC4R-agonists on neuronal plasticity and survival could be mediated by their influence on neuronal signaling regulated by other neurotransmitters, GABA in particular [In DM, there are significant changes in the brain AC system regulated by peptide hormones and neurotransmitters, such as melanocortin, glucagon-like peptide-1 (GLP-1), somatostatin, relaxin, and pituitary AC-activating polypeptide (PACAP). In human and experimental T2DM, the gene expression of melanocortin receptor of type 4  that are widely expressed in the brain with a distinct distribution pattern [i proteins in the diabetic brain were markedly reduced, as compared to control, but the therapy with intranasal insulin partially restored both effects. In prolonged, 18-month neonatal T2DM, the AC inhibitory effect of somatostatin was decreased by 33% compared with the nondiabetic rats of the same age, while, in the case of three- and six-month DM, this effect decreased only by 11% and 21% [In the brain, neuropeptide somatostatin specifically binds to five types of G pattern . The cen pattern –80. We s pattern , 35, 41.i proteins as one of the main causes responsible for the reduction of AC regulatory effects of somatostatin. At the same time, the reduced number of SSTRs can also contribute to the decrease of somatostatin signaling. The expression of some types of SSTRs was found to be decreased in the hypothalamus and pituitary of rats with T1DM [1R, SST2R, SST3R, and SST5R, in the diabetic pituitary, was reduced by 50–80%, and the level of SST1R and SST5R, restored by insulin treatment. The level of SST5R was reduced by 30% in the hypothalamus of STZ rats and completely restored by insulin. Taking into account the importance and complexity of the physiological and biochemical effects of somatostatin and its signaling cascades plus their involvement in the pathogenesis of a variety of neurodegenerative diseases, it would be right to say that the disturbances in somatostatin-sensitive AC system are likely to be responsible for the development of DM-induced CNS complications. We regard the decrease of expression and functional activity of Gith T1DM . The mRNAccording to the literature data, there are types of AC whose expression and functional activity in T2DM undergo changes along with the receptor and transducing components of AC system. Using real-time RT-PCR, it was shown that the expression of the type 3 AC (AC3) in the striatum and hypothalamus of Goto-Kakizaki rats, a spontaneous animal model of T2DM, was higher compared with Wistar rats, and the 15-day treatment of Goto-Kakizaki rats with insulin led to a decrease of the enzyme expression . It was DM is well known for its cardiovascular complications including acute myocardial infarction, congestive heart failure, and other manifestations of atherosclerosis and often termed as diabetic cardiomyopathy , 82. Hypβ-adrenergic receptors (β-ARs). β1- and β2-ARs stimulate AC activity via Gs proteins, and as a result, the intracellular cAMP level increased, and the activity of protein kinase A (PKA) is enhanced. This leads to phosphorylation of L-type calcium channels, phospholamban, troponin, and ryanodine receptors, all being essential for cardiac function, the control of heart rate, and contractility in particular. β3-AR is involved in the regulation of cardiac contractility through activation of Gi proteins and NO synthase signaling pathway and the stimulation of β3-AR, unlike that of β1- and β2-ARs, which decreases the contractile force in human ventricular muscle [The adrenergic signaling, which has a key role in the regulation of the cardiovascular system, changes to the greatest extent in DM. In the cardiac tissue, there are three pharmacologically distinct subtypes of r muscle , 89. β-AR subtypes and their functional activity and role in the regulation of heart rate and contractility were changed, and these alterations strongly progressed with increasing duration of DM. In the hearts of rats with STZ-induced T1DM duration of 6 to 14 weeks the expression of β1-AR and the density of β-ARs were decreased significantly compared with control animals [β2-AR in the heart of rats with 14-week STZ T1DM was increased, but the density of β2-AR protein was, on the contrary, decreased which can be attributed to the increased rate of β2-AR degradation and posttranslational modifications preventing the translocation of this receptor from the endoplasmic reticulum to the plasma membrane [β-ARs and the level of β1-AR mRNA observed in 6-week STZ T1DM [β-ARs to near or above control level was detected in the case of treatment of diabetic rats both with insulin and thyroid hormones [In the heart of rats with experimental T1DM, the mRNA and protein levels of  animals , 90–93. membrane . Insulinhormones . β3-AR in rats with 14-week STZ DM were twice those in control [β1-, β2- and β3-ARs in the heart of control and diabetic rats was 62 : 30 : 8 and 40 : 36 : 23, respectively, and the two-week insulin treatment of diabetic animals increased β1- and β2-AR contents, decreased the number of β3-ARs and, as a result, restored the ratio to 57 : 33 : 10. Note that the left ventricular cardiomyocytes samples from 29 failing human hearts showed a 2- to 3-fold increase of β3-AR density and a similar increase in the expression of β3-AR-coupled Gαi2 subunit mediating β3-AR agonist-induced inhibition of AC activity, as compared to nonfailing human hearts [β3-AR lead to obesity, insulin resistance, and T2DM [β3-AR gene, resulting in the replacement of tryptophan by arginine at codon 64, was associated with early onset of T2DM [The mRNA and protein level of cardiac  control . The estn hearts . There aand T2DM . It was  of T2DM , 98 and  of T2DM , 100. β1-AR in the diabetic heart led to a blunting of chronotropic effects of NE and other β-AR agonists, induced the impaired β1-mediated cardiac stimulation, and led to a decrease of their stimulating effects on cardiac AC activity [β1-AR function in the diabetic heart, especially in the case of prolonged T1DM, led to the prevention of β1-AR-stimulated apoptosis, which contributes to progressive myocardial dysfunction. It is well known that selective β1-AR-antagonists block apoptosis in the rat ventricular myocytes, while the blockers of β2-AR, on the contrary, enhance this process [The decrease of content and functional activity of activity , 94, 101 process . β2-AR was preserved in diabetic rats with 14-week STZ T1DM, which was demonstrated by the absence of difference between the diabetic and the control atria in their chronotropic and inotropic responses to β2-AR-selective agonist fenoterol [β-AR agonist, was decreased with no change in pD2 value, while in the case of NE acting preferably via β1-AR both pD2 value and maximum chronotropic effect were decreased significantly. The obtained data showed that the preservation of the β2-AR signaling in the diabetic rats may be a compensatory mechanism triggered by reducing the functional activity of β1-AR-mediated pathways. Another evidence in favor of compensatory redistribution of β1-AR and β2-AR-mediated signaling pathways in the diabetic heart is the fact that in the heart of 14-week-STZ diabetic rats the contents of β1-AR protein and β1-AR mRNA were decreased to 35% and 45%, respectively, whereas the decrease of the maximum chronotropic response of the right atria to β1-AR agonists exceeded 70% of that in control, indicating an increase of the contribution of β2-AR-signaling to β-AR-mediated chronotropic effects in T1DM [β3-AR, resulting in the enhanced negative inotropic effect and the bradycardia. The activation of β3-AR signaling involving both cAMP- and NO-dependent pathways may be a mechanism of preventing the overstimulation of heart muscle by catecholamines, whose level is increased in diabetic cardiomyopathy [The chronotropic response mediated via enoterol . In this in T1DM , 103. Inmyopathy . β-adrenergic responsiveness of the heart to isoproterenol infusion [β-AR agonists on AC was decreased due to the disturbances of the upstream components of this system [β-AR agonists were detected either at the level of receptor and its coupling to Gs proteins or at the level of downstream cAMP-dependent effector proteins but not at the level of AC, whose functional activity in the diabetic heart remained unchanged. This is indicated by the fact that the basal AC activity and the enzyme stimulation by NaF and forskolin in rats with STZ T1DM did not change [It was shown that patients with T1DM had a decreased infusion . In vents system , 104. Ins system , 105. Tht change , 107. It should be noted at this point that in the mesenteric artery of rats with STZ T1DM the changes in the expression and functional activity were identified not only in the downstream components of cAMP-dependent cascades, such as PKA and cAMP-dependent phosphodiesterase, but also in some types of AC . The mRNβ1-AR signaling in the diabetic heart in T1DM is the selective downregulation of β1-AR due to a significant increase of the level of NE that has high affinity for β1-AR. The elevation of cardiac NE concentration and NE turnover and uptake may be due to the increased sympathetic nerve activity in T1DM-induced diabetic cardiomyopathy, as in the case of other cardiovascular diseases [β1-AR [β-AR expression but improved the sensitivity of cardiac AC to isoproterenol [β-AR responsiveness to hormonal stimulation due to a significant decrease of β2-AR expression without affecting the reduced level of β1-AR [One of the main causes of alterations and abnormalities of diseases . It was  [β1-AR . It shouoterenol . At the f β1-AR . β-AR agonists in T1DM as well as T2DM were associated with the left ventricle, which is the main causal factor of diabetic cardiomyopathy [β-AR was 14% lower, and the forskolin- and GppNHp-stimulated AC activities were reduced by 34 and 23%, respectively, whereas the basal and isoproterenol-stimulated AC activities as well as the content of Gs and Gi proteins did not change. Despite these alterations, the stimulation of heart rate with isoproterenol and β-AR-dependent signaling pathways remained intact in the right atrium of diabetic swine [A majority of investigators showed that, as a rule, the alterations and abnormalities in AC sensitivity to myopathy , 114. Homyopathy . It was ic swine . β-AR-mediated signaling in ventricular cardiomyocytes from the heart of STZ rats, depending on the gender of animals [β-AR regulation of cardiac function [A significant difference was found in the changes of  animals . In the function . β-AR signaling, there were changes in α-AR-regulated signaling pathways in the diabetic heart. In T1DM, the hormonal sensitivity of myocardial α-ARs was increased, but the overall number of α-AR binding sites was decreased without significant changes in the affinity constants [α-AR agonists to acute diabetic animals led to a more pronounced α-AR-mediated responses of the myocardium, such as maximal change in pressure over time and developed tension [α-AR-dependent cardiac functions were mainly associated with the alterations in the α1-AR-mediated pathways involving Gq proteins and phospholipase C, while the AC signaling cascades regulated by α2-AR agonists via Gi/o proteins were changed to a lesser extent [i protein GppNHp-binding capacity [Alongside with the altered onstants , 118–120 tension –123. Ther extent . At the capacity . i-coupled SSTRs [i proteins, as well as with the reduced number of SSTRs, like in the diabetic atria with markedly reduced levels of SST2R mRNA and protein [We detected a significant decrease of the AC inhibitory effect of somatostatin acting via Ged SSTRs . There a protein . In the i-coupled AC cascades regulated by different hormones indicate that the functions of Gi proteins in the heart of animals with T1DM, the same as in the brain, are highly attenuated. This assumption is supported by the findings of other authors who showed the decrease of Gi proteins functions in the diabetic heart and no significant changes of Gs proteins expression and activity [i2 and Go proteins was reduced by 58% and 27%, respectively, whereas the expression of Gs proteins did not change [i, but not Gs proteins, was identified in the heart of rats with 4–6-week STZ DM [αi subunit and functional activity of Gi proteins was identified in the aorta of rats with short-term T1DM and in the aorta exposed to high glucose, without any changes in the levels and functions of Gsα subunit [αi2 and Gαi3 subunits as determined by immunoblotting techniques was reduced by about 40% three days after STZ treatment and decreased by about 70% and 50%, respectively, 5 days after the treatment. In the diabetic aorta, the inhibitory effects of GTPγS and hormonal agents, such as angiotensin II, oxotremorine, and atrial natriuretic peptide analogs, on forskolin-stimulated AC activity were attenuated compared with control, which points to the decrease of receptor-independent and -dependent functions of Gi proteins [αi2 and Gαi3 subunits and Gi-mediated AC signaling in the case of hyperglycemia induced by short-term STZ DM or high concentration of glucose (above 20 mM) may be attributed to the increase of O2− and ONOO− levels, since the treatment with antioxidants reversed the hyperglycemia-induced abnormalities in AC system to control [q/11α subunits and strengthening of the phospholipase Cβ signaling [The data on the weakening of Gactivity , 92, 101 subunit , 127. Thproteins . The dec control . It shouignaling . β-AR stimulation and AC stimulating effects of β-AR agonists was, as a rule, decreased, and, unlike in T1DM, the number of β-ARs did not differ significantly from control [β-agonist isoproterenol was increased, but not very much, and in the same tissue of 18-month-old diabetic rats, it was, on the contrary, reduced significantly compared with the respective control. The AC stimulating effect of relaxin, an insulin-like peptide, in the heart of rats with long-term neonatal T2DM was reduced to a high extent, and in 18-month-old rats it did not exceed 46% of that in the respective control. The AC inhibitory effect of NE on forskolin-stimulated AC activity in the myocardial membranes of eight- and 18-month-old diabetic rats was, at most, 51% and 46% of that in control. These findings suggest a significant decrease of the sensitivity of cardiac AC to adrenergic agonists and relaxin in very prolonged neonatal T2DM [In experimental and human T2DM, the responsiveness of the myocardium to  control , 130–132tal T2DM . fa/fa rats. On the other hand, GppNHp-stimulated AC activity was reduced in the diabetic heart, especially in the case of the neonatal model [s protein function with no change in the catalytic activity of the enzyme. One of the causes of the decline of Gs proteins activity is the T2DM-induced hyperhomocysteinemia that leads to the attenuation of Gs proteins activity and the decrease of the number of β2-ARs, as shown in db/db mice [β2-AR-Gs protein-AC system in the diabetic heart. There were no significant differences between the basal and forskolin-stimulated AC activities in the heart of control rats, on the one hand, and diabetic animals with prolonged neonatal STZ T2DM and Zucker al model , 41, 132/db mice . A decreβ-ARs and AC stimulating effect of β-AR agonists, reduced in different types of the skeletal muscles, for example, the soleus muscles and the vastus lateralis muscles, of rats with STZ DM, were partially restored by physical training that was a progressive 10-week treadmill running program [β-adrenergic agonists and the inhibitory effects of NE and 5-HT on AC activity were reduced, as compared with control [i proteins. A special mention deserves the fact that the acute hyperglycemia caused by very short STZ T1DM also led to a decrease of functional activity of Gi-coupled AC signaling cascades, as it follows from a significant weakening of inhibition of forskolin-stimulated AC activity and stimulation of GppNHp binding capacity of Gi proteins induced by somatostatin in the skeletal muscles of rats with one-day T1DM [The first data on the functional state of AC system in the skeletal muscles was obtained by Garber in 1980 . It was  program , 136. We control , 137. Thi proteins in the skeletal muscles in T1DM not only induced the abnormalities in the cAMP signaling, but also it reduced the sensitivity of the muscles to insulin action. It was shown that the expression of constitutively activated mutant form of the Gαi2-subunit with the replacement of Asn205 by Leu in the skeletal muscles, liver, and the adipose tissue of mice with STZ-induced T1DM markedly ameliorated glucose tolerance and fasting glucose levels and, in addition, restored glycogen synthase activity in the tissues of transgenic mice [αi2-subunit is involved in the regulation of the translocation of insulin-sensitive glucose transporter GLUT4, and in the in vivo conditions the expression of Q205L Gαi2-subunit led to the increase of glucose transport and GLUT4 translocation in the skeletal muscles even in the absence of insulin stimulation [The deficiency of Gnic mice . The abomulation . db/db mice the epinephrine-induced lipolytic activation was reduced, but the stimulating effects of this hormone on AC and glycogen phosphorylase activities were unaltered [db/db mice at the level of components of cAMP-dependent signaling cascades, downstream of AC. The data on the functioning of the AC system in the skeletal muscles in T2DM are rare. There is a report that in the skeletal muscles of young naltered . This gi2+-, and glucagon-stimulated AC activities in the hepatic plasma membranes isolated from the diabetic liver were reduced by 50%, and the content of Gs-coupled glucagon receptors was decreased by 67%, all these changes being partially reversed by insulin treatment. As early as 1984, it was found that in the hepatocytes of rats with STZ T1DM glucagon-mediated regulation of cAMP formation was deranged owing to a combined decrease of glucagon receptors, impairment of their coupling with AC, and altered basal AC activity . The basi-coupled signaling cascades, cAMP dependent in particular, underwent significant changes, and these alterations were mainly associated with reduced activity of Gαi subunits, preferably Gαi2 [i proteins function was due to decreased expression of Gαi subunits and their increased phosphorylation, depriving Gi proteins of the ability to participate in signal transduction. The levels of Gαi2 and Gαi3 subunits in the hepatocyte plasma membranes were decreased significantly, but the level of Gαs subunits was increased. However, in the whole liver, there were no detectable changes in the levels of Gαi2 and Gαi3 subunits, but only the decrease of transcription level of Gαi2, but not of Gαi3, subunit was found [αi2 subunit phosphorylation in hepatocytes. Gαi2 subunit in hepatocytes from diabetic animals was phosphorylated exclusively at the protein kinase C site but not observed at the PKA phosphorylation site. This reflected an augmentation of the protein kinase C signalling cascades in hepatocytes from STZ-treated rats due to an increased protein kinase C activity and a reduction in protein phosphatases activity [i-mediated signaling was associated with the increase of the signaling cascades involving Gs proteins and the enhancement of catalytic function of AC. Later, it was shown that, in the diabetic liver, Gly Gαi2 –144. Theas found . These ds/Gi-coupled receptors in the hepatic membranes directly depended on the duration and severity of the diabetic state [2+-, glucagon-, and isoproterenol-stimulated AC activities and the binding affinity and capacity of β-AR were observed within 3 days after STZ treatment. Fifteen days after the treatment, AC stimulation by hormonal and nonhormonal agents and the binding capacity of β-AR were greatly decreased, as compared to control. The amount of α-ARs was also reduced in the hepatic membranes isolated from rats with 15-day STZ T1DM, while it did not change in 3-day diabetic animals [The influence of STZ T1DM on the basal and hormone-sensitive AC activity and the binding of Gic state . No chan animals . These rβ-ARs, and G protein pattern were detected in the liver in the genetic models of T2DM. In the liver membranes isolated from ob/ob mice with hyperglycemia, hyperinsulinemia, and obesity typical of T2DM, the number of β2-AR binding sites was increased threefold, and the response of AC to catecholamines was significantly enhanced as compared to both control animals and db/db mice, the other animal model of T2DM [i and Gs proteins, especially their Gαi2 subunits, was reduced in the liver of ob/ob and db/db mice [db/db mice, the levels of expression of Gαi2, Gαi3, and Gβ subunits were reduced by 75%, 63%, and 73%, respectively, and the maximal inhibitory effect of GppNHp on forskolin-stimulated AC activity was reduced to 60%, as compared to lean animals, which indicates the abolition of Gi proteins activity in the liver in T2DM [i protein functions. For instance, in the early studies, there were no significant differences in the functional activity of Gi proteins in the membranes isolated from hepatocytes and the whole liver of the diabetic animals, such as fat Zucker (fa/fa) rats and rats with short, one-week, STZ T1DM [The alterations of AC signaling, hormonal sensitivity of  of T2DM . The con/db mice –148. In  in T2DM . RegrettSTZ T1DM , 151. The adipose tissue plays a pivotal role in the whole body energy homeostasis. The functioning of adipocytes is regulated via cAMP-dependent signaling pathways, some of which are canonical PKA-dependent pathways, while the others are carried out through the novel exchange protein activated by cAMP (Epac) . The derβ-AR agonists stimulate AC activity via Gs-coupled β-ARs and enhance lipolysis in the adipose tissue. It was found that adipocytes from genetically obese ob/ob C57BL/6J mouse and +/+ C57BL/6J mouse fed on a high fat diet for 16 weeks and Zucker fa/fa rats displayed an impaired response of AC to stimulation by β-AR agonists due to a significant decrease of β1-AR and, especially, β3-AR expression [β3-AR and β1-AR expression was found in the white and brown adipose tissues from 12-week-old ob/ob mice, whereas β2-AR mRNA level did not change significantly [β3-AR agonist CL316.243 was decreased by 75% in the epididymal white adipose tissue and by 90% in the brown adipose tissue, and the corresponding AC effects of β1/β2-AR agonist epinephrine were also decreased considerably, though to a lesser extent compared with those of CL316.243 [50 values for isoproterenol to increase lipolysis in the adipocytes from normal and obese rats were 2 and 7 nM, respectively [β-AR-mediated lipolytic activity in the adipose tissue of animals with T2DM-like metabolic disorders. In this connection, the assumption was put forward concerning alterations of the sensitivity of AC in the adipose tissue in T2DM to other activators of lipolysis, such as GLP-1, glucagon, and glucose-dependent insulinotropic polypeptide-1 [Regulation of metabolism in the adipose tissue has been shown to be impaired in genetically obese animals with hallmarks of developing T2DM, and the important role in these pathological changes belongs to adrenergic signaling . As is wpression –159. Theficantly , 158. AsL316.243 . The maxeptide-1 . But thieptide-1 . i-coupled adenosine receptor of the type 1, highly expressed in the adipose tissue, reduces AC activity and cAMP content, and, the same as insulin, inhibits lipolysis. As a result, the plasma free fatty acid concentration elevated in metabolic syndrome, and T2DM decreases; this fact may be of use in the treatment of these disorders. It was found that in the adipose tissue of ZDF and normal rats the antilipolytic activity of CVT-3619, a partial agonist of the type 1 adenosine receptor, and IC50 values of CVT-3619-induced inhibition of free fatty acid release from adipocytes were similar [i-coupled purinergic system responsible for antilipolytic activity can partially compensate for a considerable attenuation of insulin antilipolytic effect in the adipose tissue of rats with insulin resistance [It was established some time ago that endogenous adenosine in the adipocytes tonically activates G similar . In addisistance . i proteins functions were decreased, but Gi-mediated signaling was, on the contrary, unaltered or even strengthened [i proteins was manifested as decreased inhibitory effects of low concentrations of GppNHp on forskolin-stimulated AC activity and high concentrations of GTP on isoproterenol-stimulated AC activity. The AC inhibitory effects of N6-(phenylisopropyl)adenosine, nonmetabolizable adenosine analogue, prostaglandin E2, and nicotinate were either unchanged or even apparently more effective in the adipocyte membranes from diabetic animals [In the adipose tissue of STZ diabetic rats, Gngthened . The sig animals . Since insulin-mediated glucose uptake is highly sensitive to the levels of the facilitative glucose transporter protein GLUT4, repression of GLUT4 expression correlated with insulin resistance in the adipose tissue . The difThis review presents the data concerning the changes in AC signaling system sensitive to biogenic amines, peptide hormones, and purines in DM and its complications, such as diabetic encephalopathy, diabetic peripheral neuropathy, diabetic cardiomyopathy, and others. The main causes of the changes are hyperglycemia, lipidemia, oxidative stress, and other metabolic abnormalities typical of DM, as well as alterations in the central and peripheral signaling cascades induced by the resistance of the cells and tissues to the regulatory action of insulin/IGF-1 and leptin as well as by relative or absolute insulin deficiency. These changes largely depend on the type and duration of DM and on the model of the disease in the case of experimental DM. The degree of alterations and abnormalities in the AC signaling system correlates very well with the severity of the DM and its complications. The changes in AC signaling at the early stages of DM are compensatory and, as a rule, reversible, while at the later stages of the disease, when it is accompanied by many complications, these changes occurring in some particular AC signaling cascades induce the alterations in many signaling pathways, both cAMP dependent and independent, which leads to the disruption and unbalance of global integrated signaling network and, as a result, these changes become irreversible. The most complex pattern and dynamics of the changes of the AC system are in the brain, where they involve a large number of neurotransmitters and signaling cascades regulated by them and are region and cell specific. To know the origin and reversibility of changes in hormonal signaling in DM is very important for the development of effective strategy in diagnostics and treatment of this disease and its complications. s and Gi proteins. The same applies to cAMP-independent pathways. Along with this, there are pieces evidence that at the initial stages of DM or in prediabetes the disturbances occur only in one or a small number of AC signaling cascades, while the others remain unchanged. Then the alterations in one signaling cascade can induce, according to the “domino” principle, changes in the others. The domino principle is well illustrated by the fact that the disturbances in some particular signaling cascades of the brain cause numerous abnormalities in the neuronal network, which may lead to insulin resistance or insulin deficiency and, as a result, to the development of DM and its central and peripheral complications [One of the most important questions here is whether the abnormalities in DM occur in the tissue or organ in the AC system sensitive to one or a limited number of the related hormones; if so, how they cover the other signaling cascades, or whether at the initial stage of the disease they occur independent of each other in multiple AC signaling pathways. The latter seems more likely since a few days after T1DM induction by STZ treatment the alterations are detected in multiple AC cascades regulated by various hormones and involving both Gications , 165–169β-cells in T1DM. The causal relation between DM and the altered hormone-sensitive AC system is not a one-way avenue, from DM-induced alterations of hormonal signaling in CNS and peripheral organs; the alterations in AC signaling pathways may be a causal factor of DM and its complications. This speaks in favor of the use on a wide scale—not only in the treatment but also in prevention of DM—of hormonal and nonhormonal agents that control functional activity of signal proteins, the components of the AC system, and have an influence on availability, transport, and secretion of hormonal molecules. Among them are serotonin, D2-agonist bromocriptine, MC3R and MC4R agonists, the regulators of AC activity, and drugs controlling their uptake and transport, selective serotonin reuptake inhibitors in particular [Summing up, to identify the initial hot spots in AC signaling, the abnormalities of which lead to an avalanche of hormonal disturbances, we must know the etiology and pathogenesis of DM and its prevention at the stage of prediabetic state, such as obesity and metabolic syndrome in T2DM and autoimmune damage of pancreatic rticular , 170–173rticular , 175.


Flexible bell margins are characteristic components of rowing medusan morphologies and are expected to contribute towards their high propulsive efficiency. However, the mechanistic basis of thrust augmentation by flexible propulsors remained unresolved, so the impact of bell margin flexibility on medusan swimming has also remained unresolved. We used biomimetic robotic jellyfish vehicles to elucidate that propulsive thrust enhancement by flexible medusan bell margins relies upon fluid dynamic interactions between entrained flows at the inflexion point of the exumbrella and flows expelled from under the bell. Coalescence of flows from these two regions resulted in enhanced fluid circulation and, therefore, thrust augmentation for flexible margins of both medusan vehicles and living medusae. Using particle image velocimetry (PIV) data we estimated pressure fields to demonstrate a mechanistic basis of enhanced flows associated with the flexible bell margin. Performance of vehicles with flexible margins was further enhanced by vortex interactions that occur during bell expansion. Hydrodynamic and performance similarities between robotic vehicles and live animals demonstrated that the propulsive advantages of flexible margins found in nature can be emulated by human-engineered propulsors. Although medusae are simple animal models for description of this process, these results may contribute towards understanding the performance of flexible margins among other animal lineages. Medusae are thought to be the first metazoans to evolve muscular swimming. The simplicity yet functionality of the biomechanics of their swimming make them an ideal organismal model for studying fundamental mechanisms of animal propulsion. Many medusan species swim using rowing propulsion Existing literature provides a conflicting picture of the potential interactions between propulsor flexibility and swimming thrust production. Empirical An important reason for the absence of design criteria guiding application of flexible propulsor tips or margins is that, despite an extensive body of work on flexible propulsors, the mechanistic basis for thrust augmentation by flexible propulsor margins remains unclear A recently developed robotic jellyfish vehicle  has provOur approach to determining the mechanistic basis of thrust augmentation by flexible propulsor margins was to compare propulsion by robotic jellyfish vehicles with and without flexible bell margins to each other and to live medusae . With thAurelia aurita. The other was modified to represent the Cyanea capillata morphology by excising portions of the bell to form gaps along the bell margin  to quantify vehicle kinematics as well as fluid motions x and y coordinates of the apex of the vehicle bell and the tips of the bell margin over time. Swimming speed was calculated from the change in the position of the apex over time ash/d where h represents bell height and d represents bell diameter.Swimming kinematics were quantified by using ImageJ software (NIH) to track the u is the Eulerian velocity field.Pressure field data was inferred from the measured velocity fields by numerically integrating the inviscid Navier-Stokes equation, or Euler equation:u. The pressure term was then determined to within a constant of integration by integrating The material acceleration term To reduce errors in the numerical integration of the measured velocity data, the procedure of Liu and Katz kt and subsequently advected to new positions kt+1. The initial velocity of each fluid particle is given by the measured DPIV velocity field at time kt . The velocity of each fluid particle at time kt+1 depends on the measured DPIV velocity field at time kt+1 and on the position of the fluid particle at the same instant in time. To determine the position of each fluid particle in the flow at time kt+1, we defined an advection velocity field in which the fluid particles are carried. The advection velocity field was taken to be the average of two successive DPIV velocity fields:ua was assigned to the first time instant kt by the present convention. The positions of the advected data grid points at time kt+1 are therefore estimated asi and j are unit vectors in the x- and y-directions, respectively. The material acceleration was then estimated asThe input to the version of the code used presently (kindly provided by X. Liu) took as input a time series of DPIV data on a 128×128 grid. Preprocessing of the DPIV data was completed in MATLAB to compute the material acceleration As a check of the dependence of the results on viscous stresses, which are neglected in The output of the code was a time series of pressure fields with scalar pressure computed at each of the 128×128 nodes of the corresponding DPIV fields.Live medusae originated from cultured collections of the New England Aquarium, Boston, MA. Video and DPIV methods were the same for both live animals and medusan vehicles except that the live medusae were video recorded in filtered seawater.Aurelia and Cyanea vehicles. While we did not treat the two vehicles as replicates, because of their different bell configurations, the flap and no-flap versions of each do provide repeatable validation of the effects of a flexible propulsor on the fluid interactions and swimming performance of the vehicles. Means and variability estimates on figures with error bars were calculated by averaging over three consecutive swimming cycles.Due to the intensive effort involved in manual manufacturing of robotic vehicles we were limited in terms of number of the Aurelia aurita and Cyanea capillata. The proficiency of swimming was quantified as the diameter-normalized swimming speed to account for differences in size between the live and robotic jellyfish, U/D where U is medusa velocity and D is relaxed bell diameter Cyanea flap version was less than that of both Aurelia versions (flap and no-flap).Biomimetic robotic jellyfish vehicles closely replicated the morphology  and apprAurelia robot during bell contraction demonstrates how the flexible margin contributed to the differences we observed in wake circulation and swimming performance. During bell contraction there were two sources of fluid momentum that contributed to the starting vortex circulation, the flow that was expelled, or pushed, from the subumbrellar volume and the flow that was entrained, or pulled, from outside the bell by the contracting bell margin  was strongly related to the distance between the tip of the bell margin and the inflexion point . Furthermore, the enhanced performance was due to both thrust augmentation during bell contraction and to more optimal spacing between consecutive starting and stopping vortex rings during bell expansion. The strong resemblance of vorticity patterns generated by the robotic vehicles with those of living medusae supports the notion that the flexible bell margins of medusae function to enhance thrust similarly to the flaps of the robotic vehicles. These observations enable us to suggest some mechanisms by which thrust augmentation by flexible propulsors may guide future studies on this topic.The utilization of robotic vehicles to examine biological propulsion has provided insight into just how important flexible propulsors are for some swimming animals. These vehicles, in combination with the simple body plan of medusae, have also enabled us to visualize the structural differences in the fluid interactions of flexible and rigid propulsors. Visualizations are necessary to begin to understand the mechanistic basis of the enhancement in propulsion provided by flexible propulsors and begin applying these principles more generally. To summarize what can be taken away from these more or less preliminary observations of propulsion by robotic jellyfish, we found that flexibility significantly enhances the swimming performance of both the robotic vehicles examined (Much of the performance differences between the flap and no-flap vehicles can be attributed to the higher vortex circulation generated by flexible bell margins during bell contraction. Higher circulation is expected to augment performance because thrust production of a propulsor is proportional to the circulation generated at the propulsor margin Rather than the previously reported explanations, we suggest that increased circulation characterizing flexible bell margins was more likely due to unique hydrodynamic forces generated by bending at the inflexion point connecting the flexible margin to the more rigid actuating structure of the vehicle's bell. During bell contraction, a low pressure region extended along the exumbrellar surface from the bell margin to the inflexion point of the flap vehicles. This low pressure region was larger and lower in magnitude in the flap vehicles than the pressure along the bell margin of the no-flap vehicles. Consequently, entrained flow in this low pressure region at the inflexion point initiated vortex formation and merged with flow expelled from the inside the bell at the margin edge. The larger volume and velocity of this flow is directly related to the low pressure field and resulted in larger starting vortex formation at the bell margins, and hence, greater overall thrust production by vehicles with flexible margins. Although we have focused on empirical visualization and quantification of fluid flows surrounding vehicle margins, these results are consistent with computational fluid dynamic models describing pressure gradients surrounding swimming bells of oblate medusae. Swimming by oblate medusae generates pressure differences at the bell margin due to formation of a high pressure region within the medusa bell and a lower pressure region outside the bell margin at the region of greatest bell displacement Aurelia aurita are consistent with the proposed mechanism by which flexible margins enhance swimming performance. Other mechanisms likely contribute to this simple pressure mechanism such as the angular motions associated with flexible flapping which may facilitate vortex formation These observations lead us to suggest that one way that flexible propulsors enhance performance of swimming jellyfish is by intensifying the low pressure region associated with the propulsor thereby increasing fluid flow and therefore overall thrust . The relIn addition to enhanced thrust generated during bell contraction, performance of the flap vehicles was also better during bell expansion. Vortex interactions during bell expansion appear to largely influence the overall swimming performance of the vehicles. The collision of the stopping vortex of the no-flap vehicle with the oppositely spinning starting vortex cancelled out the overall circulation in the wake and stopped the vehicle's forward progress. This observation suggests two things, first, that interactions between starting and stopping vortices play important roles in determining the medusan swimming performance. Consequently, adequate spacing of these vortices by propulsor kinematics appears to be essential for swimming. Second, the flexible propulsor spaced the vortices more optimally than the rigid propulsor. By increasing the spacing between the two vortices, the starting and stopping vortices did not cancel each other out and the circulation in the wake dissipated slowly due to viscous dissipation. Consequently, the flap vehicles continued their forward progression during bell expansion. Numerical simulations of other flexible propulsors support the notion that flexibility increases spacing between shed vortex rings by increasing the downstream advection of the vortices The absence of complicating fluid interactions, such as with additional fins or appendages, makes the simple morphologies of medusae useful for exploration of essential fluid interactions between a propulsor margin and surrounding fluids. Despite their simplicity, the fluid mechanical basis of enhanced vortex production by flexible medusan margins may have wider application to other biological propulsors. The suitability of the medusan bell margin model for comparison with other flexible propulsors is influenced by the extent to which a propulsor margin's bending creates an inflexion point near the margin. A variety of biological propulsors such as wings and fins fit these conditions and fundamental relationships between actuator force, margin dimensions, and flexural stiffness distributions may be important factors influencing the role that flexible margins play in propulsive force generation by propulsors of both natural and man-made design. A more full understanding of these interactions will allow us to appreciate the means by which animals convert the energetic liability that tip vortices present for fixed wing aircraft


Interpersonal conflicts are a common element of many social relationships. One possible process in rebuilding social relationships is the act of apologizing. Behavioral studies have shown that apologies promote forgiveness. However, the neural bases of receiving an apology and forgiveness are still unknown. Hence, the aim of the present fMRI study was to investigate brain processes involved in receiving an apology and active forgiveness of an ambiguous offense. We asked one group of participants (player A) to make decisions, which were either positive or negative for another group of participants (player B). The intention of player A was ambiguous to player B. In case of a negative impact, participants in the role of player A could send an apology message to participants in the role of player B. Subsequently players B were asked whether they wanted to forgive player A for making a decision with negative consequences. We found that receiving an apology yielded activation in the left inferior frontal gyrus, the left middle temporal gyrus, and left angular gyrus. In line with previous research we found that forgiving judgments activated the right angular gyrus. Interpersonal relationships are an essential element of our lives in providing support, security and other important social resources. A common challenge to relationships is interpersonal conflict, with the potential of ultimately causing its breakdown. One possible process in rebuilding social relationships is the act of apologizing, since apologies promote forgiveness Behavioral economic research indicates that forgiveness is strongly influenced by apologies Research in psychology has mainly used retrospective reports. Participants are asked to recall an experienced transgression and to indicate some transgression related information, such as the impact the transgression had on them or the level of empathy they had towards the offender. These studies found that empathy is a determinant for forgiveness Neuroscience research has studied brain activation patterns in the process of forgiving. Brain areas that were found to be associated with forgiveness are the left ventromedial prefrontal cortex, posterior cingulate gyrus and right temporo parietal junction No study so far has analysed the neural correlates of receiving apologies. Different approaches were used to explore the neural correlates of forgiveness, which makes it difficult to compare the results. As a consequence, the evidence regarding the neural basis of forgiveness is quite inconclusive. Moreover, and in contrast to the present study, only narrative scenarios were used, which do not involve a consequence for either party and are therefore not ecologically valid.We aim at improving research on the nature of forgiving by combining behavioral measures and neuroscientific methods. In particular, we study the interplay between apologies and forgiveness combining a behavioral choice paradigm and functional magnetic resonance imaging (fMRI). In a two person game, one person can commit a transgression that has real monetary consequences for another person. The intention of the transgressor is ambiguous to the other person. The transgressor then has the option to apologize. We are interested in the neural processes underlying the effects of receiving an apology and active forgiveness in an ecologically valid setting.The design of our experiment is similar to the one used by Fischbacher and Utikal Note that we introduced monetary payoffs to induce real consequences for all decisions: transgressions and forgiveness decisions were payoff relevant. Player A’s transgression had consequences for the payoff of both players. Player B’s forgiveness decision influenced player A’s payoff, having no impact on player B’s payoff. It is arguable whether forgiving has some costs in reality. However, by keeping the payoff of player B constant, money-maximizing motives did not confound player B’s forgiveness decision.The aim of this design was to make the underlying intention behind the offense ambiguous. It was not obvious whether player A answered the question intentionally wrong or whether he did not know the answer. A wrong answer to a very easy question is likely to be intentional. A wrong answer to a very difficult question in contrast might be due to lack of knowledge. Therefore, we chose easy but not trivial questions; herewith we introduced ambiguousness of player A’s intention. The successful implementation of ambiguous intentionality can be inferred from the fact that 46% of the answers in our experiment were correct. When paid for every correct answer, participants solved 87% of the questions correctly (as tested in a pilot experiment). This means that participants were able to solve more answers than they actually did, indicating that they gave some wrong answers intentionally.Since there are no previous imaging studies about neural correlates of receiving an apology, our hypothesis about brain areas involved in processing apologies is rather explorative. Psychological research suggest an association between apologies, empathy towards the offender and forgiveness The paradigm used by Young and Saxe In the behavioural experiment, 38  participants were tested in two sessions. The participants received money depending on the decisions they made during the sessions. Part of the money was paid out immediately after the experiment and the other part four weeks later. The behavioral experiment was conducted in June 2011 at the BonnEconLab (Labor für experimentelle Wirtschaftsforschung) at the University of Bonn using z-Tree Thirty-two participants  took part in the fMRI experiment. They were all native German speakers. Participants had no history of psychiatric or neurological disorders. Written consent was given by all participants according to the Declaration of Helsinki  and the study was approved by the ethics committee of the University of Bonn. Participants from the same subject pool (BonnEconLab) as used for the behavioral experiment were invited to the fMRI experiment. All participants received a ten Euro show-up fee at the end of the experiment. Participants were informed that in addition they and the players A would receive their payoff depending on one randomly chosen decision they made during the experiment. The additional payoff was paid some weeks later. The experiment was conducted in June and July of 2011 at the Life and Brain Center Bonn, Department of NeuroCognition and Clinic of Epileptology, Bonn, Germany.Participants had to accomplish two consecutive phases in the experiments. Phase 1 was a training. During five periods, half of the participants played the role of player A and the other half were player B. Player A received a multiple choice question. If he gave the correct answer, he received 100 points and player B received 100 points as well. If he answered the question incorrectly, player B received 50 points and player A’s payoff depended on the decision of player B. Before player B’s decision, player A had the option to send a message to player B. Player B was presented with the question player A received and learned about the result of player A. In case of a correct answer, player B received 100 points and the game ended. In case of a wrong answer, the following procedure applied: Player B further received the message from player A. Player B could decide whether to forgive player A. If player B forgave player A giving a wrong answer, player A received 140 points. In case player B did not forgive player A, player A received 110 points .Prior to the experiment, participants received an instruction manual including four comprehension questions to ensure that all participants had understood the task.We used a perfect stranger matching to allocate participants for each period. This means that in each period, player A played against a different player B. At the end of the first experiment one of the participants threw a dice to determine which of the five periods was paid. The exchange rate of this experiment was 1 points = 5 cent. Participants received the money earned during this experiment at the end of the session. Phase 1 was a training; participants had the chance to get used to the task and additionally to learn what kind of messages might be useful to send.In phase 2, the task was almost the same as in phase 1, but now all participants were players A and ten periods were played. Participants were further informed about the following modified rules: players B will take part in the experiment at a later date, players B will not receive the entire messages sent by players A but a categorized version, and not all periods played by player A are transferred to players B but only a sample selected by the experimenters. In addition, participants were told that after the decisions of players B, a payoff-relevant period will be randomly selected, the exchange rate is 1 point = 30 cent, and that the payoff is about four weeks after the session. A set of the answers given in this experiment was presented to the participants of the fMRI experiment.In a pilot experiment, participants had to answer ten multiple choice questions of the same question pool as in both previous experiments. However, this time, participants received 2 points for each question they answered correctly. The exchange rate was 1 point = 5 cent. Participants received their payoff at the end of the session. We implemented this pilot experiment to study how many questions the participants were actually able to solve on average.All participants received detailed information about fMRI in general, exclusion criteria, the experiment, and the data handling. In addition, all subjects received detailed written and verbal instructions, and completed the same comprehension questions as in the behavioral experiment. In order to get an impression of what kind of messages were categorized as an apology players B participating in the fMRI experiment received six randomly chosen example messages of the category ‘apology’ before the experiment started. Furthermore, participants were shown all ‘apology’ messages after the experiment. The participants of the fMRI experiment played the role of player B. They received a set of 120 multiple choice questions answered by players A. The question set contained 30 correct answered questions and 90 incorrect answered questions. Of the 90 incorrect answered questions, 45 were followed by a message categorized as an apology. The multiple choice questions were presented for four seconds. After a time interval of four seconds (jittered between three and five seconds), Player B was informed of whether the answer of player A was right or wrong. This information was displayed for two seconds. After a time interval of four seconds (jittered between three and five seconds), player B received either an apology or no apology information. In case player A sent an apology, player B received an ‘apology message’. In case player A did not send a message at all, or a message which was not categorized as an apology, player B received a no apology message. The apology and no apology information were presented for two seconds. Four seconds (jittered between three and five seconds) later, player B had to decide whether he wanted to forgive player A for giving a wrong answer. The next trial started after a response of player B. The response time window was four seconds and the inter trial interval was four seconds, jittered between three and five seconds .Scanning was performed on a 3 Tesla Trio Scanner  using an 8-channel head coil. Functional data was acquired using EPI-sequences with a repetition time (TR) of 2.5 s, an echo time (TE) of 30 ms, and a flip angle of 90 degrees. Each volume comprised 37 slices acquired in an axial orientation covering all of the brain, including the midbrain, but sparing parts of the cerebellum. The presentation of the task and recording of behavioral responses were performed with Presentation® software version 14.9 . Subjects saw the experiment via video goggles  and gave their responses by response grips  using the index fingers of both hands.fMRI data of 29 participants were analyzed using SPM8 . Data sets of two participants were excluded due to excessive head motion and one because of technical problems. The following pre-processing steps were applied: slice time correction, motion correction, linear trend removal, high pass temporal filtering with a filter size of 128 seconds, spatial smoothing using a Gaussian kernel with full-width at half-maximum (FWHM) of 8 mm and spatial normalization by corregistering the functional data with the individual structural data and then transforming the data into the Montreal Neurological Institute (MNI) template space.For each participant, brain activation was estimated using a general linear model. Seven onset regressors were defined to estimate activation caused by the task. These onset regressors were: 1) question presentation, 2) correct answer, 3) wrong answer, 4) apology, 5) no apology, 6) forgiveness and 7) no forgiveness. In addition, six motion regressors were defined: three translation regressors, x, y, and z, and three rotation regressors, pitch, roll, and yaw. The regressors were convolved with a hemodynamic response function (HRF) in order to consider for the hemodynamic response of the measured blood oxygenation level dependent (BOLD) signal. For each onset regressor parameter estimates were generated and the contrasts ‘apology versus no apology’ and ‘forgiveness versus no forgiveness’ were calculated in the first level analyses. The obtained contrast images were transferred to the second level random effects analyses. In the second level analyses, one sample t-tests for the apology and forgiveness contrasts were conducted.In phase 2 players A wrongly answered on average 54% of the multiple choice questions. 74% of these wrongly answered questions were followed by a message. 31% of the messages were categorized as ‘apology’ and 43% were categorized as ‘no apology’. An overview of the behavioral results of the experiment is given in Players B forgave more often after an apology message  compared to a no apology message . Since the ‘apology’ versus ‘no apology’ contrast is rather explorative we further used a more liberal threshold of p<0.005 with a 10 voxels threshold extent At the whole brain level pFWE <0.05; p<0.001 uncorrected). The contrast ‘no forgiveness’ versus ‘forgiveness’ revealed no significant activation.For the contrast ‘forgiveness’ versus ‘no forgiveness’ we created an anatomical mask based on the results of Young and Saxe This study is a first attempt to investigate the neural correlates of receiving an apology and active forgiveness in an ecologically valid setting. We introduced a new paradigm combining fMRI with incentivized behavioral measures. The design of our study allowed us not only to compare changes in neural activity associated with forgiveness versus no forgiveness, but also activity associated with receiving an apology within the same setting. Our data show that receiving an apology leads to increased activity in a left lateralized network containing frontal, temporal and parietal regions. Forgiveness revealed increased activation in the right angular gyrus. In line with previous research, participants were more willing to forgive after an apology Activation in a network of frontal, temporal and parietal regions is often found in empathy processes In our study most of the empathy related brain regions showed increased activation when receiving an apology, namely the left IFG, left MTG and left angular gyrus (subpart of the TPJ). However, we did not find any activation in the MPFC, STS and IPC. Thus, the results provide partial evidence for a link between receiving an apology and empathy. Psychological literature suggests a link between apologies, empathy and forgiveness If empathy processes are involved when receiving an apology one open question is why we did not find any activation in the MPFC, STS and IPC. Especially the MPFC is frequently reported to be associated with empathy, activity in this region was shown to correlate with self-reported empathy and trait empathy First, empathy has no generally accepted definition; its different phenomena remain controversial Second, in contrast to most fMRI empathy studies we did not use any pictures in our paradigm. The STS is frequently reported to respond to facial stimuli Third, we have no data about the phenomenological experience of our participants. Thus, our data does not conclusively show that participants actually experienced empathy. Other cognitive processes in response to receiving an apology cannot be fully excluded. By asking participants about their experience when receiving an apology it might be possible to investigate whether the phenomenological experience matches the neuronal data.In summary, our results point at a possible involvement of empathy processes when receiving an apology. However, since this is the first neuroimaging study investigating the neural correlates of receiving an apology more research is needed to confirm this result.Our results indicate a recruitment of the right angular gyrus in forgiving. The right angular gyrus is a sub region of the temporo-parietal junction (TPJ). TPJ activation has been found with several paradigms that measure attention The right angular gyrus was also found to be involved in forgivability judgments by Young & Saxe Other imaging studies investigating forgiveness found the posterior cingulate gyrus and the left ventromedial prefrontal cortex to be activated during forgiveness Farrow et al. Our paradigm allowed us to investigate active forgiveness under conditions in which the intention of the offender is ambiguous and in which forgiving has an actual impact on the incentive of the offender. The results indicate that receiving an apology leads to increased activity in a left lateralized network containing frontal, temporal and parietal regions. During forgiving the right angular gyrus was activated.Table S1‘Apology’ versus ‘no apology’ contrast. Whole brain activation for the contrast no ‘apology’ versus ‘no apology’ .(DOCX)Click here for additional data file.Table S2‘Apology’ versus ‘no apology’ contrast small volume analysis. A priori-created anatomical masks of established empathy regions for a region of interest analysis puncorrected<0.001, whole brain).(DOCX)Click here for additional data file.Table S3‘Forgiveness’ versus ‘no forgiveness’ contrast. Whole brain activation for the contrast no ‘apology’ versus ‘no apology’ .(DOCX)Click here for additional data file.