Cannabinoid CB1 receptor in the regulation of sociability, stress coping, and its interaction with the serotonergic system

Cannabinerge Substanzen können das Verhalten in einer dosisabhängigen, aber biphasischen Weise beeinflussen. Eine Erklärung für diese Art der Effekte könnte die Verteilung des CB1 Rezeptors auf verschiedenen Neuronentypen sein. CB1 Rezeptoren in glutamatergen und GABAergen Neuronen sind hier besonders wichtig, da die entsprechenden Neurotransmitter als Gegenspieler die neuronale Erregung kontrollieren. Spezifische Deletion des CB1 Rezeptor-Gens von einer der beiden Populationen führte zu gegensätzlichen Phenotypen, genauer gesagt, einem erniedrigten, bzw. einem gesteigerten Interaktiondrang. Tiere, bei denen der CB1 Rezeptor ausschließlich in striatalen, GABAergen „Medium Spiny“ Neuronen deletiert wurde, zeigten keinen veränderten Phänotyp. Dies legt nahe, dass der CB1 Rezeptor in kortikalen glutamatergen und GABAergen Neuronen für einen ausgeglichenen Interaktionsdrang entscheidend ist (siehe Kapitel 3).rnDiese dosisabhängigen, biphasischen Effekte auf das Verhalten können auch im „Forced Swim Test“ (FST) beobachtet werden. Ein möglicher Mechanismus, durch den Cannabinoide das Stressverhalten beeinflussen können, wäre die Regulierung der Monoaminausschüttung. Um die Abhängigkeit der Cannabinoideffekte von der Serotonintransmission zu untersuchen, wurden Dosen von CB1 Rezeptoragonisten und –antagonisten mit antidepressiv-induzierenden Eigenschaften bei gleichzeitiger Inhibition der Serotonintransmission im FST getestet. Die Ergebnisse zeigten, dass lediglich der Agonisteffekt durch die Inhibition der Serotoninauschüttung beeinflusst wird. Zusätzlich konnte die Abhängigkeit des Antagonisteneffekts von funktionsfähigen GABAergen CB1 Rezeptoren nachweisen werden. Interessanter Weise konnte der durch die Deletion von glutamatergen CB1 Rezeptoren induzierte Phänotyp durch Inhibition der Serotoninausschüttung blockiert werden (siehe Kapitel 4). rnEin indirekter Einfluss auf Serotoninausschüttung scheint also wahrscheinlich zu sein. Bis jetzt blieb jedoch unklar, inwieweit cannabinerge Substanzen direkt auf serotonerge Neuronen wirken können. Im Jahr 2007 konnte unsere Gruppe die Expression des CB1 Rezeptors in serotonergen Neuronen auf mRNA- und Proteinebene nachweisen. Die Züchtung und Analyse einer mutanten Mauslinie, in welcher der CB1-Rezeptor spezifisch in serotonergen Neuronen ausgeschaltet wurde, zeigte bei männlichen Tieren eine schwache, aber signifikante Verhaltensänderungen, die durch soziale Stimuli und lebensbedrohlichen Situationen ausgelöst wurde. So ist es erstmals gelungen nachzuweisen, dass serotonerge CB1-Rezeptoren eine physiologische Relevanz besitzen (siehe Kapitel 5).rnCannabinergic drugs have been found to inversely influence the behavioral outcome depending on the dose applied. This so-called biphasic effect might be caused by the distribution of the cannabinoid type 1 (CB1) receptor on different neuronal populations. Two relevant populations in this respect are cortical glutamatergic and GABAergic neurons, as the two respective neurotransmitters opposingly influence excitability. Specific deletion of the CB1 receptor in either of these two neuronal populations displayed opposite phenotypes, namely a decrease and increase in exploratory drive, respectively. No changes were observed for mice lacking CB1 receptor specifically in dopamine receptor type 1 positive GABAergic medium spiny neurons, suggesting cortical glutamatergic and GABAergic CB1 receptor to be responsible for a balanced exploratory behavior (see Chapter 3). rnSuch a dose dependent cannabinoid-induced biphasic effect on the behavioral performance was also observed in the forced swim test (FST). One possible mechanism underlying cannabinoid effects on stress-related responses might be by modulating of monoaminergic signaling. In order to evaluate the dependence of cannabinoid function on serotonin transmission, doses of CB1 receptor agonist and antagonist mimicking anti-depressant effects were tested in the FST in combination with drugs which inhibit serotonin signalling. The results showed that only the cannabinoid agonist effect was reversed by blocking serotonin signaling. In addition, the dependence of the antagonist effect on functional CB1 receptor on GABAergic neurons was shown. Interestingly, the phenotype induced by deletion of the receptor from cortical glutamatergic neurons is attenuated by blocking serotonin signalling (see Chapter 4). rnThese findings suggest that cannabinoids modulate GABAergic and glutamatergic neurons, which themselves regulate serotonergic neurons. However, it has remained unclear whether a direct connection for the cannabinergic effects on serotonin release exists. In 2007, our group could identify the mRNA expression and protein localization of CB1 receptor in serotonergic neurons. The generation and analysis of a knock-out mouse line, lacking the CB1 receptor specifically in these neurons revealed that male mice showed low but significant changes in anxiety in response to social and object stimuli. Thus, I could show for the first time that the direct influence of the eCB system on serotonin signalling is of physiological importance (see Chapter 5).rn110 S

Cell type-specific genetic reconstitution of CB1 receptor subsets to assess their role in exploratory behaviour, sociability, and memory

Several studies support the notion that exploratory behaviour depends on the functionality of the cannabinoid type 1 (CB1) receptor in a cell type-specific manner. Mice lacking the CB1 receptor in forebrain GABAergic or dorsal telencephalic glutamatergic neurons have served as essential tools revealing the necessary CB1 receptor functions in these two neuronal populations. However, whether these specific CB1 receptor populations are also sufficient within the endocannabinoid system for wild-type-like exploratory behaviour has remained unknown. To evaluate cell-type-specific sufficiency of CB1 receptor signalling exclusively in dorsal telencephalic glutamatergic neurons (Glu-CB1-RS) or in forebrain GABAergic neurons (GABA-CB1-RS), we utilised a mouse model in which CB1 receptor expression can be reactivated conditionally at endogenous levels from a complete CB1-KO background. The two types of conditional CB1-rescue mice were compared with CB1 receptor-deficient [no reactivation (Stop-CB1)] and wild-type [ubiquitous reactivation of endogenous CB1 receptor (CB1-RS)] controls to investigate the behavioural consequences. We evaluated social and object exploratory behaviour in four different paradigms. Remarkably, the reduced exploration observed in Stop-CB1 animals was rescued in Glu-CB1-RS mice and sometimes even surpassed CB1-RS (wild-type) exploration. In contrast, GABA-CB1-RS animals showed the lowest exploratory drive in all paradigms, with an even stronger phenotype than Stop-CB1 mice. Interestingly, these effects weakened with increasing familiarity with the environment, suggesting a causal role for altered neophobia in the observed phenotypes. Taken together, using our genetic approach, we were able to substantiate the opposing role of the CB1 receptor in dorsal telencephalic glutamatergic versus forebrain GABAergic neurons regarding exploratory behaviour

Circuit Specific Functions of Cannabinoid CB1 Receptor in the Balance of Investigatory Drive and Exploration

Well balanced novelty seeking and exploration are fundamental behaviours for survival and are found to be dysfunctional in several psychiatric disorders. Recent studies suggest that the endocannabinoid (eCB) system is an important control system for investigatory drive. Pharmacological treatment of rodents with cannabinergic drugs results in altered social and object investigation. Interestingly, contradictory results have been obtained, depending on the treatment, drug concentration and experimental conditions. The cannabinoid type 1 (CB1) receptor, a central component of the eCB system, is predominantly found at the synapses of two opposing neuronal populations, i.e. on inhibitory GABAergic and excitatory glutamatergic neurons. In the present study, using different transgenic mouse lines, we aimed at investigating the impact of CB1 receptor inactivation in glutamatergic or GABAergic neurons on investigatory behaviour. We evaluated animate (interaction partner) and inanimate (object) exploratory behaviour in three different paradigms. We show that exploration was increased when CB1 receptor was deleted from cortical and striatal GABAergic neurons. No effect was observed when CB1 receptor was deleted specifically from dopamine receptor D1-expressing striatal GABAergic medium spiny neurons. In contrast, deletion of CB1 receptor from cortical glutamatergic neurons resulted in a decreased exploration. Thus, our results indicate that exploratory behaviour is accurately balanced in both, the social and non-social context, by the eCB system via CB1 receptor activation on cortical glutamatergic and GABAergic neurons. In addition, the results could explain the contradictory findings of previous pharmacological studies and could further suggest a possibility to readjust an imbalance in exploratory behaviour observed in psychiatric disorders

Cloud and Precipitation Observed with Radar

Meteorological radar is an essential tool for research, diagnosis, and nowcasting of clouds and precipitation. Cloud radars use short wavelengths to enable detection of small ice particles or cloud droplets. The cloud radar at UFS Schneefernerhaus is operated since end of 2011. It has been used for a number of studies related to clouds and precipitation. In a synergistic combination with additional remote sensing instruments, a large variety of cloud and precipitation properties can be retrieved. The measurements at UFS Schneefernerhaus can be used for the evaluation of numerical weather prediction models and satellite measurements. The long-term observations allow assessing the seasonal and long-term evolution of cloud properties above the UFS in a warming climate

The Myocyte Expression of Adiponectin Receptors and PPARδ Is Highly Coordinated and Reflects Lipid Metabolism of the Human Donors

Muscle lipid oxidation is stimulated by peroxisome proliferator-activated receptor (PPAR) δ or adiponectin receptor signalling. We studied human myocyte expression of the PPARδ and adiponectin receptor genes and their relationship to lipid parameters of the donors. The mRNA levels of the three adiponectin receptors, AdipoR1, AdipoR2, and T-cadherin, were highly interrelated (r ≥ 0.91). However, they were not associated with GPBAR1, an unrelated membrane receptor. In addition, the adiponectin receptors were positively associated with PPARδ expression (r ≥ 0.75). However, they were not associated with PPARα. Using stepwise multiple linear regression analysis, PPARδ was a significant determinant of T-cadherin (P = .0002). However, pharmacological PPARδ activation did not increase T-cadherin expression. The myocyte expression levels of AdipoR1 and T-cadherin were inversely associated with the donors' fasting plasma triglycerides (P < .03). In conclusion, myocyte expression of PPARδ and the adiponectin receptors are highly coordinated, and this might be of relevance for human lipid metabolism in vivo

Association of obesity risk SNPs in PCSK1 with insulin sensitivity and proinsulin conversion

<p>Abstract</p> <p>Background</p> <p>Prohormone convertase 1 is involved in maturation of peptides. Rare mutations in gene <it>PCSK1</it>, encoding this enzyme, cause childhood obesity and abnormal glucose homeostasis with elevated proinsulin concentrations. Common single nucleotide polymorphisms (SNPs) within this gene, rs6232 and rs6235, are associated with obesity. We studied whether these SNPs influence the prediabetic traits insulin resistance, β-cell dysfunction, or glucose intolerance.</p> <p>Methods</p> <p>We genotyped 1498 German subjects for SNPs rs6232 and rs6235 within <it>PCSK1</it>. The subjects were metabolically characterized by oral glucose tolerance test with glucose, insulin, proinsulin, and C-peptide measurements. A subgroup of 512 subjects underwent a hyperinsulinemic-euglycemic clamp.</p> <p>Results</p> <p>The minor allele frequencies were 25.8% for SNP rs6235 and 6.0% for rs6232. After adjustment for sex and age, we found no association of SNPs rs6235 and rs6232 with BMI or other weight-related traits (all p ≥ 0.07). Both minor alleles, adjusted for sex, age, BMI and insulin sensitivity were associated with elevated AUC_proinsulinand AUC_proinsulin/AUC_insulin(rs6235: p_{additive model}≤ 0.009, effect sizes 8/8%, rs6232: p_{dominant model}≤ 0.01, effect sizes 10/21%). Insulin secretion was not affected by the variants (different secretion parameters, all p ≥ 0.08). The minor allele of SNP rs6232 was additionally associated with 15% higher OGTT-derived and 19% higher clamp-derived insulin sensitivity (p_dom≤ 0.0047), 4.5% lower HOMA_IR(p_dom= 0.02) and 3.5% lower 120-min glucose (p_dom= 0.0003) independently of BMI and proinsulin conversion. SNP rs6235 was not associated with parameters of glucose metabolism.</p> <p>Conclusions</p> <p>Like rare mutations in <it>PCSK1</it>, the more common variants tested determine glucose-stimulated proinsulin conversion, but not insulin secretion. In addition, rs6232, encoding the amino acid exchange N221D, influences insulin sensitivity and glucose homeostasis.</p

Common Genetic Variation in the SERPINF1 Locus Determines Overall Adiposity, Obesity-Related Insulin Resistance, and Circulating Leptin Levels

OBJECTIVE: Pigment epithelium-derived factor (PEDF) belongs to the serpin family of peptidase inhibitors (serpin F1) and is among the most abundant glycoproteins secreted by adipocytes. In vitro and mouse in vivo data revealed PEDF as a candidate mediator of obesity-induced insulin resistance. Therefore, we assessed whether common genetic variation within the SERPINF1 locus contributes to adipose tissue-related prediabetic phenotypes in humans. SUBJECTS/METHODS: A population of 1,974 White European individuals at increased risk for type 2 diabetes was characterized by an oral glucose tolerance test with glucose and insulin measurements (1,409 leptin measurements) and genotyped for five tagging SNPs covering 100% of common genetic variation (minor allele frequency ≥ 0.05) in the SERPINF1 locus. In addition, a subgroup of 486 subjects underwent a hyperinsulinaemic-euglycaemic clamp and a subgroup of 340 magnetic resonance imaging (MRI) and spectroscopy (MRS). RESULTS: After adjustment for gender and age and Bonferroni correction for the number of SNPs tested, SNP rs12603825 revealed significant association with MRI-derived total adipose tissue mass (p = 0.0094) and fasting leptin concentrations (p = 0.0035) as well as nominal associations with bioelectrical impedance-derived percentage of body fat (p = 0.0182) and clamp-derived insulin sensitivity (p = 0.0251). The association with insulin sensitivity was completely abolished by additional adjustment for body fat (p = 0.8). Moreover, the fat mass-increasing allele of SNP rs12603825 was significantly associated with elevated fasting PEDF concentrations (p = 0.0436), and the PEDF levels were robustly and positively associated with all body fat parameters measured and with fasting leptin concentrations (p<0.0001, all). CONCLUSION: In humans at increased risk for type 2 diabetes, a functional common genetic variant in the gene locus encoding PEDF contributes to overall body adiposity, obesity-related insulin resistance, and circulating leptin levels

Decomposition numbers for the cyclotomic Brauer algebras in characteristic zero

We study the representation theory of the cyclotomic Brauer algebra via truncation to idempotent subalgebras which are isomorphic to a product of walled and classical Brauer algebras. In particular, we determine the block structure and decomposition numbers in characteristic zero.Comment: 20 pages, 12 figure