Plenary Lectures Plenary Lectures
PL-04 Was macht eigentlich das Human Brain Project? *K. Amunts
PL-01 The physiology and clinical potential of the incretin hormones
Forschungszentrum Jülich GmbH, Institut für Neurowissenschaften und
*B. Göke
Jülich, Germany
Medizin, Strukturelle und funktionelle Organisation des Gehirns (INM-1),
University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Oral glucose stimulates insulin secretion much stronger than intravenous glucose making up for the incretin effect mediated by the gut peptides glucose-dependent insulin secreting polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). GIP (from the intestinal k-cells) and GLP-1 (L-cells) are released in response to oral nutrients. While GIP has much less activity in type 2 diabetics, GLP-1 is still effective. GLP-1 receptors were detected in endocrine pancreas, brain, lung, heart, blood vessels, stomach, and intestine suggesting a broad array of biological functions of GLP-1. Transgenic studies in rodents and pigs proved the importance of the incretins for glucose homeostasis. At the endocrine pancreas GLP-1 restores the first-phase insulin response to glucose, stimulates insulin secretion and suppresses glucagon release. GLP-1 does not induce hypogylcemia since the stimulation of insulin secretion is strictly glucose-dependent. GLP-1 regulates gastric emptying thereby reducing postprandial glucose levels. Furthermore, GLP-1 increases satiety, reduces food intake and decreases body weight. Based upon these properties GLP-1 appears as an ideal tool for the treatment of type 2 diabetes. However, upon release GLP-1 is rapidly degraded mainly by the dipeptidyl-peptidase 4 (DPP 4). Thus, native human GLP-1 cannot be orally or subcutaneously supplied and, therefore, can not be utilized for the treatment of diabetics. However, several stabile GLP-1 receptor agonists (GLP-1RA) are now available, either exendin-derived peptides or analoges of natural GLP-1. GLP-1 receptor agonists are able to restore a normal glucose tolerance in a significant proportion of type 2 diabetes complementing conventional antidiabetic drugs. After bariatric surgery there is evidence that incretins support the normalization of glucose homeostasis in adipositas. GLP-1 RAs exert multiple extrapancreatic actions, among them cardio- and neuroprotective protective effects. Conclusion: Restoring physiological conditions, incretins such as GLP-1 are interesting drug candidates, so far mainly established in the therapy of diabetes mellitus.
Studying the human brain remains one of the greatest scientific challenges. A comprehensive understanding of the structural and functional organization of the brain is not only of great importance for basic science, but also for the development of new approaches that improve diagnosis and the treatment of neurological and psychiatric diseases. With this mindset, the Human Brain Project (HBP) started its work in October 2013 with the aim of creating a European ICT infrastructure for neuroscience. The immense complexity of the brain, with its approximately 86 billion nerve cells, makes it essential to include modeling and simulation approaches, combined with methods of high performance computing (HPC), in order to analyze the organizational principles of the brain. Conversely, the understanding of neural mechanisms might inspire new advancements for HPC. Those insights into the brain provide simulation, and give computer scientists the opportunity to develop a new generation of computers and software that are inspired by the functional principles of the brain. HPC opens up new avenues for neuroscientists to develop virtual brain models, such as the BigBRAIN model, which connects the macroscopic with the microscopic organization level for the first time in a reference system. In such models, data from the genetic, molecular, and cellular levels up to cognitive systems could be combined together for a subsequent analysis at different scales. This is done in the HBP research area Data. To analyze these different levels of brain organization, particularly in the ramp-up phase, studies in mouse brains will be performed in addition to studies in human brains. In the ramp-up phase, six ITC platforms will be established in another research area, which includes the subprojects neuroinformatics, medical informatics, brain simulation, HPC, neurorobotics, and neuromorphic computing. These platforms are the basis for a new ICT infrastructure for neurosciences, which will be open to all scientists for their research. These subprojects will be accompanied by the research fields Theory, Ethics and Society, and Applications. The project will be funded with approximately € 1.19 billion, with 75% of funding from the EU, and the rest provided by partner countries and their institutions. The Human Brain Project now has unprecedented dimensions that significantly exceed previous EU projects both in the number of partners (currently about 80 institutions from 22 countries) as well as in the duration of its funding period (10 years). The HBP is coordinated by Henry Markram (EPFL, Switzerland). References: Amunts K, Lindner A, Zilles K (2014) The human brain project: Neuroscience perspectives and German contributions. e-Neuroforum 5:43-50. 10.1007/s13295-014-0058-4 Amunts K, Lepage C, Borgeat L et al (2013) BigBrain: an ultrahigh-resolution 3D human brain model. Science 340(6139):1472–1475
underline ( 4
) = Main Author
sign (*) = Presenting Author
Plenary Lectures PL-05 Genetics of human cardiomyopathy
PL-06 Dynamics of the auditory cortex and the perception of sounds
*C. Seidman
*S. Rumpel
Harvard Medical School, Department of Genetics, Boston, United States
University Medical Center of the Johannes Gutenberg University Mainz, Institute of Physiology, Working Group Systemic Neurophysiology,
Application of genomic technologies has enriched the discovery of inherited gene mutations that cause primary disorders of heart muscle. The two most common primary heart muscle diseases are hypertrophic (HCM) and dilated (DCM) cardiomyopathy. HCM is characterized by left ventricular hypertrophy, diastolic dysfunction with normal or enhanced systolic performance and a unique histopathology: myocyte hypertrophy, disarray and fibrosis. Dilated cardiomyopathy (DCM) exhibits enlarged ventricular volumes with depressed systolic performance and nonspecific histopathology. Both HCM and DCM increased risk for arrhythmias, sudden death, and heart failure. Human molecular genetic studies have demonstrated that these unique pathologies can both result from dominant mutations in genes that encode protein components of the sarcomere, the contractile unit in striated muscles. This presentation will review the prevalence and spectrum of sarcomere protein gene mutations in HCM and DCM patients and the prevalence and clinical impact of rare sarcomere gene variants that are found in the general population. The cell and molecular mechanisms by which gene mutations cause HCM and DCM will be explored by biophysical and biochemical analyses of mutant proteins and assessments of cell and animal models that carry human HCM or DCM mutations. The application of transcriptional analyses to define key molecules that drive the histopathologic features of cardiomyopathy will be discussed, with a focus on potential therapeutic targets that may be appropriate for translation into the clinical setting. Finally, emerging strategies to silence the expression of mutant alleles will be considered, to address their relevance as therapeutic options and to explore the mechanisms of disease.
Mainz, Germany
Circuits of the neocortex are believed to mediate conscious perception of the world. Strong evidence arises from the seminal observations by the neurosurgeon Wilder Penfield that microstimulation of sensory cortices can evoke hallucinations in awake patients. Given the fine and complex anatomy of neocortical circuits it still remains unclear how such relatively crude stimulation can lead to meaningful neuronal activity. We have applied in vivo two-photon calcium imaging to analyze sound-evoked activity patterns in local neuronal ensembles of the mouse auditory cortex. We found that activity patterns are highly constrained into few discrete response modes, which is surprising given how many patterns could theoretically generated by the combination of already a few neurons. Using on-line synthesis of sounds to tailor stimuli that allow precise probing of a given neuronal population, we observe highly non-linear dynamics indicating an antagonistic ‘winner-takes-all’-like competition between response patterns. Our observations suggest that local nonlinear dynamics shape the cortical representation of sounds into a basis set of spontaneous categories that are available for behavioral decisions. Furthermore, such dynamics may serve as a potential explanation how non-specific activity elicited by artificial stimulation may converge on activity patterns that are typically observed by natural sensory stimuli. In a next step, we have established procedures for optogenetic stimulation of the mouse auditory cortex in awake mice trained to discriminate two ‘target’ sounds in a go/no-go paradigm. The behavioral responses to a third stimulus presented in interspersed catch trials allows meas uring the perceived similarity to either one of the two ‘target sounds’. In this paradigm we assessed the generalization behavior across sound cues and optogenetically evoked activity. This strategy offers an entry point to a detailed analysis how artificially evoked patterns of neuronal are perceived in an experimentally accessible model organism.
5
Copyright of Acta Physiologica is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
PL-04 Was macht eigentlich das Human Brain Project? *K. Amunts
PL-01 The physiology and clinical potential of the incretin hormones
Forschungszentrum Jülich GmbH, Institut für Neurowissenschaften und
*B. Göke
Jülich, Germany
Medizin, Strukturelle und funktionelle Organisation des Gehirns (INM-1),
University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Oral glucose stimulates insulin secretion much stronger than intravenous glucose making up for the incretin effect mediated by the gut peptides glucose-dependent insulin secreting polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). GIP (from the intestinal k-cells) and GLP-1 (L-cells) are released in response to oral nutrients. While GIP has much less activity in type 2 diabetics, GLP-1 is still effective. GLP-1 receptors were detected in endocrine pancreas, brain, lung, heart, blood vessels, stomach, and intestine suggesting a broad array of biological functions of GLP-1. Transgenic studies in rodents and pigs proved the importance of the incretins for glucose homeostasis. At the endocrine pancreas GLP-1 restores the first-phase insulin response to glucose, stimulates insulin secretion and suppresses glucagon release. GLP-1 does not induce hypogylcemia since the stimulation of insulin secretion is strictly glucose-dependent. GLP-1 regulates gastric emptying thereby reducing postprandial glucose levels. Furthermore, GLP-1 increases satiety, reduces food intake and decreases body weight. Based upon these properties GLP-1 appears as an ideal tool for the treatment of type 2 diabetes. However, upon release GLP-1 is rapidly degraded mainly by the dipeptidyl-peptidase 4 (DPP 4). Thus, native human GLP-1 cannot be orally or subcutaneously supplied and, therefore, can not be utilized for the treatment of diabetics. However, several stabile GLP-1 receptor agonists (GLP-1RA) are now available, either exendin-derived peptides or analoges of natural GLP-1. GLP-1 receptor agonists are able to restore a normal glucose tolerance in a significant proportion of type 2 diabetes complementing conventional antidiabetic drugs. After bariatric surgery there is evidence that incretins support the normalization of glucose homeostasis in adipositas. GLP-1 RAs exert multiple extrapancreatic actions, among them cardio- and neuroprotective protective effects. Conclusion: Restoring physiological conditions, incretins such as GLP-1 are interesting drug candidates, so far mainly established in the therapy of diabetes mellitus.
Studying the human brain remains one of the greatest scientific challenges. A comprehensive understanding of the structural and functional organization of the brain is not only of great importance for basic science, but also for the development of new approaches that improve diagnosis and the treatment of neurological and psychiatric diseases. With this mindset, the Human Brain Project (HBP) started its work in October 2013 with the aim of creating a European ICT infrastructure for neuroscience. The immense complexity of the brain, with its approximately 86 billion nerve cells, makes it essential to include modeling and simulation approaches, combined with methods of high performance computing (HPC), in order to analyze the organizational principles of the brain. Conversely, the understanding of neural mechanisms might inspire new advancements for HPC. Those insights into the brain provide simulation, and give computer scientists the opportunity to develop a new generation of computers and software that are inspired by the functional principles of the brain. HPC opens up new avenues for neuroscientists to develop virtual brain models, such as the BigBRAIN model, which connects the macroscopic with the microscopic organization level for the first time in a reference system. In such models, data from the genetic, molecular, and cellular levels up to cognitive systems could be combined together for a subsequent analysis at different scales. This is done in the HBP research area Data. To analyze these different levels of brain organization, particularly in the ramp-up phase, studies in mouse brains will be performed in addition to studies in human brains. In the ramp-up phase, six ITC platforms will be established in another research area, which includes the subprojects neuroinformatics, medical informatics, brain simulation, HPC, neurorobotics, and neuromorphic computing. These platforms are the basis for a new ICT infrastructure for neurosciences, which will be open to all scientists for their research. These subprojects will be accompanied by the research fields Theory, Ethics and Society, and Applications. The project will be funded with approximately € 1.19 billion, with 75% of funding from the EU, and the rest provided by partner countries and their institutions. The Human Brain Project now has unprecedented dimensions that significantly exceed previous EU projects both in the number of partners (currently about 80 institutions from 22 countries) as well as in the duration of its funding period (10 years). The HBP is coordinated by Henry Markram (EPFL, Switzerland). References: Amunts K, Lindner A, Zilles K (2014) The human brain project: Neuroscience perspectives and German contributions. e-Neuroforum 5:43-50. 10.1007/s13295-014-0058-4 Amunts K, Lepage C, Borgeat L et al (2013) BigBrain: an ultrahigh-resolution 3D human brain model. Science 340(6139):1472–1475
underline ( 4
) = Main Author
sign (*) = Presenting Author
Plenary Lectures PL-05 Genetics of human cardiomyopathy
PL-06 Dynamics of the auditory cortex and the perception of sounds
*C. Seidman
*S. Rumpel
Harvard Medical School, Department of Genetics, Boston, United States
University Medical Center of the Johannes Gutenberg University Mainz, Institute of Physiology, Working Group Systemic Neurophysiology,
Application of genomic technologies has enriched the discovery of inherited gene mutations that cause primary disorders of heart muscle. The two most common primary heart muscle diseases are hypertrophic (HCM) and dilated (DCM) cardiomyopathy. HCM is characterized by left ventricular hypertrophy, diastolic dysfunction with normal or enhanced systolic performance and a unique histopathology: myocyte hypertrophy, disarray and fibrosis. Dilated cardiomyopathy (DCM) exhibits enlarged ventricular volumes with depressed systolic performance and nonspecific histopathology. Both HCM and DCM increased risk for arrhythmias, sudden death, and heart failure. Human molecular genetic studies have demonstrated that these unique pathologies can both result from dominant mutations in genes that encode protein components of the sarcomere, the contractile unit in striated muscles. This presentation will review the prevalence and spectrum of sarcomere protein gene mutations in HCM and DCM patients and the prevalence and clinical impact of rare sarcomere gene variants that are found in the general population. The cell and molecular mechanisms by which gene mutations cause HCM and DCM will be explored by biophysical and biochemical analyses of mutant proteins and assessments of cell and animal models that carry human HCM or DCM mutations. The application of transcriptional analyses to define key molecules that drive the histopathologic features of cardiomyopathy will be discussed, with a focus on potential therapeutic targets that may be appropriate for translation into the clinical setting. Finally, emerging strategies to silence the expression of mutant alleles will be considered, to address their relevance as therapeutic options and to explore the mechanisms of disease.
Mainz, Germany
Circuits of the neocortex are believed to mediate conscious perception of the world. Strong evidence arises from the seminal observations by the neurosurgeon Wilder Penfield that microstimulation of sensory cortices can evoke hallucinations in awake patients. Given the fine and complex anatomy of neocortical circuits it still remains unclear how such relatively crude stimulation can lead to meaningful neuronal activity. We have applied in vivo two-photon calcium imaging to analyze sound-evoked activity patterns in local neuronal ensembles of the mouse auditory cortex. We found that activity patterns are highly constrained into few discrete response modes, which is surprising given how many patterns could theoretically generated by the combination of already a few neurons. Using on-line synthesis of sounds to tailor stimuli that allow precise probing of a given neuronal population, we observe highly non-linear dynamics indicating an antagonistic ‘winner-takes-all’-like competition between response patterns. Our observations suggest that local nonlinear dynamics shape the cortical representation of sounds into a basis set of spontaneous categories that are available for behavioral decisions. Furthermore, such dynamics may serve as a potential explanation how non-specific activity elicited by artificial stimulation may converge on activity patterns that are typically observed by natural sensory stimuli. In a next step, we have established procedures for optogenetic stimulation of the mouse auditory cortex in awake mice trained to discriminate two ‘target’ sounds in a go/no-go paradigm. The behavioral responses to a third stimulus presented in interspersed catch trials allows meas uring the perceived similarity to either one of the two ‘target sounds’. In this paradigm we assessed the generalization behavior across sound cues and optogenetically evoked activity. This strategy offers an entry point to a detailed analysis how artificially evoked patterns of neuronal are perceived in an experimentally accessible model organism.
5
Copyright of Acta Physiologica is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
