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Based on the intellicage paradigm, we have developed a novel cognitive, emotional and social phenotyping battery that permits comprehensive standardized behavioral characterization of mice in an experimenter-independent social setting . Evaluation of this battery in a large number of male and female C57BL/6 wildtype mice, tested in >20 independent cohorts, revealed high reproducibility of the behavioral readouts and may serve as future reference tool. We noticed robust sex-specific differences in general activity, cognitive and emotional behavior, but not regarding preference for social pheromones. Specifically, female mice revealed higher activity, decreased sucrose preference, impaired reversal and place-time-reward learning. Furthermore, female mice reacted more sensitively than males to reward-withdrawal showing a negative emotional contrast/Crespi-effect. In a series of validation experiments, we tested mice with different pathologies, including neuroligin-3 deficient mice (male Nlgn3 y/− and female Nlgn3 +/− ) for autistic behavior, oligodendrocyte-specific erythropoietin receptor knockout ( oEpoR −/− ) mice for cognitive impairment, as well as mouse models of renal failure (unilateral ureteral obstruction and 5/6 nephrectomy) and of type 2 diabetes ( ApoE −/− ) – for delineating potentially confounding effects of motivational factors (thirst, glucose-craving) on learning and memory assessments. As prominent features, we saw in Nlgn3 mutants reduced preference for social pheromones, whereas oEpoR −/− mice showed learning deficits in place or reversal learning tasks. Renal failure led to increased water intake, and diabetic metabolism to enhanced glucose preference, limiting interpretation of hereon based learning and memory performance in these mice. The phenotyping battery presented here may be well-suited as high-throughput multifaceted diagnostic instrument for translational neuropsychiatry and behavioral genetics. [ABSTRACT FROM AUTHOR]

Impairments in social skills are central to mental disease, and developing tools for their assessment in mouse models is essential. Here we present the SocioBox, a new behavioral paradigm to measure social recognition. Using this paradigm, we show that male wildtype mice of different strains can readily identify an unfamiliar mouse among 5 newly acquainted animals. In contrast, female mice exhibit lower locomotor activity during social exploration in the SocioBox compared to males and do not seem to discriminate between acquainted and unfamiliar mice, likely reflecting inherent differences in gender-specific territorial tasks. In addition to a simple quantification of social interaction time of mice grounded on predefined spatial zones (zone-based method), we developed a set of unbiased, data-driven analysis tools based on heat map representations and characterized by greater sensitivity. First proof-of-principle that the SocioBox allows diagnosis of social recognition deficits is provided using male PSD-95 heterozygous knockout mice, a mouse model related to psychiatric pathophysiology. [ABSTRACT FROM AUTHOR]

In this study, we have investigated the contribution of oligodendrocytic connexin47 (Cx47) and astrocytic Cx30 to panglial gap junctional networks as well as myelin maintenance and function by deletion of both connexin coding DNAs in mice. Biocytin injections revealed complete disruption of oligodendrocyte-to-astrocyte coupling in the white matter of 10- to 15-d-old Cx30/Cx47 double-deficient mice, while oligodendrocyte-to-oligodendrocyte coupling was maintained. There were no quantitative differences regarding cellular networks in acute brain slices obtained from Cx30/Cx47 double-null mice and control littermates, probably caused by the upregulation of oligodendrocytic Cx32 in Cx30/Cx47 double-deficient mice. We observed early onset myelin pathology, and ∼40% of Cx30/Cx47 doubledeficient animals died within 42 to 90 d after birth, accompanied by severe motor impairments. Histological and ultrastructural analyses revealed severe vacuolization and myelination defects in all white matter tracts of the CNS. Furthermore, Cx30/Cx47 double-deficient mice exhibited a decreased number of oligodendrocytes, severe astrogliosis, and microglial activation in white matter tracts. Although less affected concerning motor impairment, surviving double-knock-out (KO) mice showed behavioral alterations in the open field and in the rotarod task. Vacuole formation and thinner myelin sheaths were evident also with adult surviving double-KO mice. Since interastrocytic coupling due to Cx43 expression and interoligodendrocytic coupling because of Cx32 expression are still maintained, Cx30/Cx47 double-deficient mice demonstrate the functional role of both connexins for interastrocytic, interoligodendrocytic, and panglial coupling, and show that both connexins are required for maintenance of myelin. [ABSTRACT FROM AUTHOR]

Gap junction channels are intercellular conduits that allow diffusional exchange of ions, second messengers, and metabolites. Human oligodendrocytes express the gap junction protein connexin47 (Cx47), which is encoded by the GJC2 gene. The autosomal recessive mutation hCx47M283T causes Pelizaeus-Merzbacher-like disease 1 (PMLD1), a progressive leukodystrophy characterized by hypomyelination, retarded motor development, nystagmus, and spasticity. We introduced the human missense mutation into the orthologous position of the mouse Gjc2 gene and inserted the mCx47M282T coding sequence into the mouse genome via homologous recombination in embryonic stem cells. Three-week-old homozygous Cx47M282T mice displayed impaired rotarod performance but unchanged open-field behavior. 10-15-day-old homozygous Cx47M282T and Cx47 null mice revealed a more than 80% reduction in the number of cells participating in glial networks after biocytin injections into oligodendrocytes in sections of corpus callosum. Homozygous expression of mCx47M282T resulted in reduced MBP expression and astrogliosis in the cerebellum of ten-day-old mice which could also be detected in Cx47 null mice of the same age. Three-month-old homozygous Cx47M282T mice exhibited neither altered open-field behavior nor impaired rotarod performance anymore. Adult mCx47M282T expressing mice did not show substantial myelin alterations, but homozygous Cx47M282T mice, additionally deprived of connexin32, which is also expressed in oligodendrocytes, died within six weeks after birth and displayed severe myelin defects accompanied by astrogliosis and activated microglia. These results strongly suggest that PMLD1 is caused by the loss of Cx47 channel function that results in impaired panglial coupling in white matter tissue. [ABSTRACT FROM AUTHOR]

Abstract: The mammalian tachykinins are a family of closely related peptides including substance P, neurokinin A, neurokinin B and, recently, also hemokinin-1. They are present in the peripheral and central nervous systems, and bind to three known neurokinin (NK) receptors, the NK1-, NK2- and NK3 receptors. In both rodents and humans, NK3 receptors are expressed in brain structures which have been associated with learning and memory. Evidence for a role of NK3 receptors in learning and memory has been found in NK3 receptor knockout mice. Here, we investigated the influence of the NK3 receptor agonist, senktide (0.1, 0.2 and 0.4mg/kg), on the performance of C57BL/6 mice in a recently developed episodic-like memory task. Since a promnestic effect of senktide was expected, we employed an experimental protocol that provided sub-optimal learning conditions for episodic-like memory. The results indicate that senktide promotes episodic-like memory in mice in a dose-dependent manner, providing, for the first time, evidence for an involvement of NK3 receptors in episodic-like memory. [Copyright &y& Elsevier]

Abstract: Rats and mice are attracted by novel objects. They readily approach novel objects and explore them with their vibrissae, nose and forepaws. It is assumed that such a single explorative episode leaves a lasting and complex memory trace, which includes information about the features of the object explored, as well as where and even when the object was encountered. Indeed, it has been shown that rodents are able to discriminate a novel from a familiar object (one-trial object recognition), can detect a mismatch between the past and present location of a familiar object (one-trial object–place recognition), and can discriminate different objects in terms of their relative recency (temporal order memory), i.e., which one of two objects has been encountered earlier. Since the novelty-preference paradigm is very versatile and has some advantages compared to several other memory tasks, such as the water maze, it has become a powerful tool in current neurophamacological, neuroanatomical and neurogenetical memory research using both rats and mice. This review is intended to provide a comprehensive summary on key findings delineating the brain structures, neurotransmitters, molecular mechanisms and genes involved in encoding, consolidation, storage and retrieval of different forms of one-trial object memory in rats and mice. [Copyright &y& Elsevier]

Abstract: The histaminergic system in the central nervous system is involved in a variety of physiological, pathological and behavioral processes. There is now substantial evidence for an important role of histaminergic neurotransmission in learning and memory related processes. The histamine H1 receptor (H1R) is the most abundant histamine receptor in the mammalian brain. We have recently demonstrated that the genetic inactivation of the H1R in mice impairs episodic-like memory, defined as the ability to remember previous experiences with respect to their content and their temporal and spatial context. The ability to encode and retrieve the temporal order of unique events, that is its temporal context, is a core feature of episodic memory. Here we asked whether episodic-like memory deficits of H1R-KO mice are possibly due to changes in the processing, encoding or maintenance of temporal or sequence information which is critical for episodic-like memory formation. H1R-KO mice were tested in the temporal object memory (TOM) task with different inter-trial intervals (ITIs). H1R-KO mice showed impaired TOM when being tested under both, short and longer ITIs. Another aim of the study was to determine whether temporal order discrimination is based on either familiarity or recollection-based memory processes. The performance of wild type (WT) animals in the TOM task suggests that they used recollection-like discrimination strategies. [Copyright &y& Elsevier]

The histamine H1-receptor (H1R) is expressed in wide parts of the brain including the hippocampus, which is involved in spatial learning and memory. Previous studies in H1R knockout (H1R-KO) mice revealed deficits in a variety of learning and memory tasks. It was also proposed that H1R activation is crucial for neuronal differentiation of neural progenitors. Therefore, the aim of this study was to investigate negatively reinforced spatial learning in the water-maze and to assess survival and neuronal differentiation of newborn cells in the adult hippocampus of H1R-KO mice. H1R-KO and wild-type (WT) mice were subjected to the following sequence of tests: (a) cued version, (b) place learning, (c) spatial probe, (d) long-term retention and (e) reversal learning. Furthermore hippocampal neurogenesis in terms of survival and differentiation was assessed in H1R-KO and WT mice. H1R-KO mice showed normal cued learning, but impaired place and reversal learning as well as impaired long-term retention performance. In addition, a marked reduction of newborn neurons in the hippocampus but no changes in differentiation of neural progenitors into neuronal and glial lineage was found in H1R-KO mice. Our data suggest that H1R deficiency in mice is associated with pronounced deficits in hippocampus-dependent spatial learning and memory. Furthermore, we herein provide first evidence that H1R deficiency in the mouse leads to a reduced neurogenesis. However, the exact mechanisms for the reduced number of cells in H1R-KO mice remain elusive and might be due to a reduced survival of newborn hippocampal neurons and/or a reduction in cell proliferation. [ABSTRACT FROM AUTHOR]

The N-acyl chain length of ceramides is determined by the specificity of different ceramide synthases (CerS). The CerS family in mammals consists of six members with different substrate specificities and expression patterns. We have generated and characterized a mouse line harboring an enzymatically inactive ceramide synthase 6 (CerS6KO) gene and lacz reporter cDNA coding for β-galactosidase directed by the CerS6 promoter. These mice display a decrease in C16:0 containing sphingolipids. Relative to wild type tissues the amount of C16:0 containing sphingomyelin in kidney is∼35%, whereas we find a reduction of C16:0 ceramide content in the small intestine to about 25%. The CerS6KO mice show behavioral abnormalities including a clasping abnormality of their hind limbs and a habituation deficit. LacZ reporter expression in the brain reveals CerS6 expression in hippocampus, cortex, and the Purkinje cell layer of the cerebellum. Using newly developed antibodies that specifically recognize the CerS6 protein we show that the endogenous CerS6 protein is N-glycosylated and expressed in several tissues of mice, mainly kidney, small and large intestine, and brain. [ABSTRACT FROM AUTHOR]

Ceramide synthase 1 (CerS1) catalyzes the synthesis of C18 ceramide and is mainly expressed in the brain. Custom-made antibodies to a peptide from the C-terminal region of the mouse CerS1 protein yielded specific immunosignals in neurons but no other cell types of wild type brain, but the CerS1 protein was not detected in CerS1-deficient mouse brains. To elucidate the biological function of CerS1-derived sphingolipids in the brain, we generated CerS1-deficient mice by introducing a targeted mutation into the coding region of the cers1 gene. General deficiency of CerS1 in mice caused a foliation defect, progressive shrinkage, and neuronal apoptosis in the cerebellum. Mass spectrometric analyses revealed up to 60% decreased levels of gangliosides in cerebellum and forebrain. Expression of myelinassociated glycoprotein was also decreased by about 60% in cerebellum and forebrain, suggesting that interaction and stabilization of oligodendrocytic myelin-associated glycoprotein by neuronal gangliosides is due to the C18 acyl membrane anchor of CerS1-derived precursor ceramides. A behavioral analysis of CerS1-deficient mice yielded functional deficits including impaired exploration of novel objects, locomotion, and motor coordination. Our results reveal an essential function of CerS1- derived ceramide in the regulation of cerebellar development and neurodevelopmentally regulated behavior [ABSTRACT FROM AUTHOR]

N-methyl-d-aspartate receptor (NMDAR) composition in granule cells changes characteristically during cerebellar development. To analyze the importance of NR2B replacement by NR2C and NR2A subunits until the end of the first month of age, we generated mice with lasting NR2B expression but deficiency for NR2C (NR2C-2B mice). Mutant phenotype was different from NR2C knock-out mice as loss of granule cells and morphological changes in NR2C/2B cerebellar architecture were already evident from the second postnatal week. Increased NR2B subunit levels led also to a gradual down-regulation of cerebellar NR2A levels, preceding the development of motor impairment in adult animals. Therefore, cerebellar NR2A is important for proper motor coordination and cannot be replaced by long-term expression of NR2B. Consequently, the physiological exchange of NMDA receptor subunits during cerebellar granule cell maturation is important for accurate postnatal development and function. [Copyright &y& Elsevier]