Ultraschallvokalisationen bei Maus und Ratte - Kommunikative Signale des motivational-affektiven Zustands?

Mäuse und Ratten verfügen über die Fähigkeit, Ultraschallvokalisationen auszusenden. Diese Ultraschallvokalisationen treten in motivational relevanten Kontexten auf. Sie sind für die biopsychologische Forschung von großer Bedeutung, da die Tiere in Abhängigkeit ihres motivational-affektiven Zustandes unterschiedliche Vokalisationen emittieren und somit Einblicke in die Grundlagen von Emotion und Motivation gewähren können. Über die funktionale Bedeutung dieser Ultraschallvokalisationen besteht jedoch Unklarheit. In den vorgelegten Arbeiten sollte daher geprüft werden, inwiefern es sich bei den Ultraschallvokalisationen um kommunikative Signale des motivational-affektiven Zustands handelt. Hierzu wurde zum einen geprüft, welche Bedeutung soziale Faktoren, wie maternale Fürsorge oder An- beziehungsweise Abwesenheit eines Artgenossen, für den Sender, das heißt für die Produktion von Rufen, haben. Zum anderen wurde geprüft, welchen Einfluss die Produktion von Rufen auf den Empfänger hat. Es konnte gezeigt werden, dass sich die erfahrene maternale Pflege auf die Produktion isolations-induzierter Vokalisationen im Jungtier als auch auf die im Erwachsenenalter auftretenden 22-kHz Vokalisationen auswirkt, wohingegen die aktuelle An- beziehungsweise Abwesenheit eines Artgenossen die Emission von 22-kHz Rufen nicht beeinflusst. Die Effekte maternaler Fürsorge sind möglicherweise über Beeinflussung des Aufteretensverhältnisses von aktiven und passiven Bewältigungsstrategien in aversiven Situationen vermittelt. Ferner konnte gezeigt werden, dass obwohl die An- beziehungsweise Abwesenheit eines Artgenossen keinen steigernden Einfluss auf die Produktion von 22-kHz Rufen hat, diese dennoch angst-ähnliches Verhalten beim Empfänger induzieren können. Im Gegensatz zu der durch 22-kHz Rufe induzierten lokomotorischen Inhibition, steigern 50-kHz Rufe die lokomotorische Aktivität und führen zu Annäherungsverhalten. In Übereinstimmung mit den entgegengesetzten Verhaltensreaktion aktivieren 22-kHz Rufe Hirnstrukturen, die an der Regulation von Angst und Furcht beteiligt sind, wohingegen 50-kHz Rufe Strukturen aktivieren, die mit Belohnungsprozessen in Zusammenhang stehen. Die vorgelegten Arbeiten stützen demnach die Hypothese, dass Ultraschallvokalisationen als kommunikative Signale des motivational-affektiven Zustands dienen. Die hier etablierten Verhaltensparadigmen werden es zukünftig ermöglichen die biopsychologischen Grundlagen verschiedener Aspekte von Sozialverhalten zu untersuchen. So kann beispielsweise die durch die Präsentation von 50-kHz Vokalisationen induzierte Verhaltensreaktion der Tiere genutzt werden, um die genetischen und neurochemischen Grundlagen sozialen Annäherungsverhaltens zu beschreiben und so möglicherweise Einblick in die Pathomechanismen von psychischen Störungen gewähren, die durch Defizite im Sozialverhalten gekennzeichnet sind

17-β estradiol increases parvalbumin levels in Pvalb heterozygous mice and attenuates behavioral phenotypes with relevance to autism core symptoms

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by two core symptoms: impaired social interaction and communication, and restricted, repetitive behaviors and interests. The pathophysiology of ASD is not yet fully understood, due to a plethora of genetic and environmental risk factors that might be associated with or causal for ASD. Recent findings suggest that one putative convergent pathway for some forms of ASD might be the downregulation of the calcium-binding protein parvalbumin (PV). PV-deficient mice (PV−/−, PV+/−), as well as Shank1−/−, Shank3−/−, and VPA mice, which show behavioral deficits relevant to all human ASD core symptoms, are all characterized by lower PV expression levels.Methods: Based on the hypothesis that PV expression might be increased by 17-β estradiol (E2), PV+/− mice were treated with E2 from postnatal days 5–15 and ASD-related behavior was tested between postnatal days 25 and 31.Results: PV expression levels were significantly increased after E2 treatment and, concomitantly, sociability deficits in PV+/− mice in the direct reciprocal social interaction and the 3- chamber social approach assay, as well as repetitive behaviors, were attenuated. E2 treatment of PV+/+ mice did not increase PV levels and had detrimental effects on sociability and repetitive behavior. In PV−/− mice, E2 obviously did not affect PV levels; tested behaviors were not different from the ones in vehicle-treated PV−/− mice.Conclusion: Our results suggest that the E2-linked amelioration of ASD-like behaviors is specifically occurring in PV+/− mice, indicating that PV upregulation is required for the E2-mediated rescue of ASD-relevant behavioral impairments

Reduction in parvalbumin expression not loss of the parvalbumin-expressing GABA interneuron subpopulation in genetic parvalbumin and shank mouse models of autism

Background A reduction of the number of parvalbumin (PV)-immunoreactive (PV⁺) GABAergic interneurons or a decrease in PV immunoreactivity was reported in several mouse models of autism spectrum disorders (ASD). This includes Shank mutant mice, with SHANK being one of the most important gene families mutated in human ASD. Similar findings were obtained in heterozygous (PV+/-) mice for the Pvalb gene, which display a robust ASD-like phenotype. Here, we addressed the question whether the observed reduction in PV immunoreactivity was the result of a decrease in PV expression levels and/or loss of the PV-expressing GABA interneuron subpopulation hereafter called “Pvalb neurons”. The two alternatives have important implications as they likely result in opposing effects on the excitation/inhibition balance, with decreased PV expression resulting in enhanced inhibition, but loss of the Pvalb neuron subpopulation in reduced inhibition.Methods Stereology was used to determine the number of Pvalb neurons in ASD-associated brain regions including the medial prefrontal cortex, somatosensory cortex and striatum of PV-/-, PV+/-, Shank1-/- and Shank3B-/- mice. As a second marker for the identification of Pvalb neurons, we used Vicia Villosa Agglutinin (VVA), a lectin recognizing the specific extracellular matrix enwrapping Pvalb neurons. PV protein and Pvalb mRNA levels were determined quantitatively by Western blot analyses and qRT-PCR, respectively.Results Our analyses of total cell numbers in different brain regions indicated that the observed “reduction of PV⁺ neurons” was in all cases, i.e., in PV+/-, Shank1-/- and Shank3B-/- mice, due to a reduction in Pvalb mRNA and PV protein, without any indication of neuronal cell decrease/loss of Pvalb neurons evidenced by the unaltered numbers of VVA⁺ neurons.ConclusionsOur findings suggest that the PV system might represent a convergent downstream endpoint for some forms of ASD, with the excitation/inhibition balance shifted towards enhanced inhibition due to the down-regulation of PV being a promising target for future pharmacological interventions. Testing whether approaches aimed at restoring normal PV protein expression levels and/or Pvalb neuron function might reverse ASD-relevant phenotypes in mice appears therefore warranted and may pave the way for novel therapeutic treatment strategies

Interaction of the Psychiatric Risk Gene Cacna1c With Post-weaning Social Isolation or Environmental Enrichment Does Not Affect Brain Mitochondrial Bioenergetics in Rats

The pathophysiology of neuropsychiatric disorders involves complex interactions between genetic and environmental risk factors. Confirmed by several genome-wide association studies, Cacna1c represents one of the most robustly replicated psychiatric risk genes. Besides genetic predispositions, environmental stress such as childhood maltreatment also contributes to enhanced disease vulnerability. Both, Cacna1c gene variants and stressful life events are associated with morphological alterations in the prefrontal cortex and the hippocampus. Emerging evidence suggests impaired mitochondrial bioenergetics as a possible underlying mechanism of these regional brain abnormalities. In the present study, we simulated the interaction of psychiatric disease-relevant genetic and environmental factors in rodents to investigate their potential effect on brain mitochondrial function using a constitutive heterozygous Cacna1c rat model in combination with a four-week exposure to either post-weaning social isolation, standard housing, or social and physical environmental enrichment. Mitochondria were isolated from the prefrontal cortex and the hippocampus to evaluate their bioenergetics, membrane potential, reactive oxygen species production, and respiratory chain complex protein levels. None of these parameters were considerably affected in this particular gene-environment setting. These negative results were very robust in all tested conditions demonstrating that Cacna1c depletion did not significantly translate into altered bioenergetic characteristics. Thus, further investigations are required to determine the disease-related effects on brain mitochondria

Communication Impairments in Mice Lacking Shank1: Reduced Levels of Ultrasonic Vocalizations and Scent Marking Behavior

Autism is a neurodevelopmental disorder with a strong genetic component. Core symptoms are abnormal reciprocal social interactions, qualitative impairments in communication, and repetitive and stereotyped patterns of behavior with restricted interests. Candidate genes for autism include the SHANK gene family, as mutations in SHANK2 and SHANK3 have been detected in several autistic individuals. SHANK genes code for a family of scaffolding proteins located in the postsynaptic density of excitatory synapses. To test the hypothesis that a mutation in SHANK1 contributes to the symptoms of autism, we evaluated Shank1−/− null mutant mice for behavioral phenotypes with relevance to autism, focusing on social communication. Ultrasonic vocalizations and the deposition of scent marks appear to be two major modes of mouse communication. Our findings revealed evidence for low levels of ultrasonic vocalizations and scent marks in Shank1−/− mice as compared to wildtype Shank1+/+ littermate controls. Shank1−/− pups emitted fewer vocalizations than Shank1+/+ pups when isolated from mother and littermates. In adulthood, genotype affected scent marking behavior in the presence of female urinary pheromones. Adult Shank1−/− males deposited fewer scent marks in proximity to female urine than Shank1+/+ males. Call emission in response to female urinary pheromones also differed between genotypes. Shank1+/+ mice changed their calling pattern dependent on previous female interactions, while Shank1−/− mice were unaffected, indicating a failure of Shank1−/− males to learn from a social experience. The reduced levels of ultrasonic vocalizations and scent marking behavior in Shank1−/− mice are consistent with a phenotype relevant to social communication deficits in autism.National Institute of Mental Health (U.S.) (Intramural Research Program)Simons Foundatio

Disentangling the Role of SHANK1 in a Mouse Model for Autism Spectrum Disorder: From Brain to Behavior

Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders characterized by persistent deficits in social communication and interaction across multiple contexts, and restricted, repetitive patterns of behavior; frequently comorbid with intellectual disability (ID). Several studies highlight immense contribution of genetic factors to disease etiology. Particularly, the SHANK family of postsynaptic proteins has emerged as promising candidates, considering that mutations in SHANK1, SHANK2, and SHANK3 genes have repeatedly been reported in individuals with ASD. Animal models provide excellent translational tools to discover disease pathogenesis underlying behavioral and neurobiological abnormalities. This dissertation aimed at understanding these mechanisms by using the Shank1 knockout mouse model for ASD, with an in-depth and longitudinal focus on each diagnostic symptom. Specifically, ASD-like phenotypes were investigated throughout development and across different social contexts. While social behavior was only moderately affected in mice lacking SHANK1 (Study I), evidence for communication deficits and repetitive behavior throughout development and/or across different social contexts were demonstrated in these animals (Study II&III). In conjunction with ASD – ID comorbidity, deletion of Shank1 resulted in severe cognitive impairments (Study I). Highlighting the pivotal role of the hippocampus in this mechanism, elevated levels of learning-associated brain-derived neurotrophic factor were found in the hippocampi of Shank1 mutants. This increase in protein expression was paralleled by alterations in epigenetic regulation (Study I). Overall, results of the studies presented here indicate that SHANK1 is involved in ASD-relevant deficits across species. These findings further extend the knowledge on social communication and interaction, repetitive behaviors, and cognitive phenotypes displayed by the Shank1 mouse model for ASD in an age- and sex-dependent manner, underscoring the importance of social context in ASD research