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Many calcium-binding proteins are expressed in a region-and cell-type specific manner in the mammalian hippocampus. Neuronal calcium-binding proteins (NECABs) are also expressed in hippocampal neurons, but few species have been investigated, with partly controversial findings. We here describe NECAB1, NECAB2 and NECAB3 as well as parvalbumin, calbindin, and calretinin in the European mole, and compare staining patterns of these proteins with those in mouse and other species. While subtle differences are present, NECAB staining in the European mole was generally similar to those in mouse. Common to European moles, mice, and other species we investigated, large hilar polymorphic cells, likely to represent mossy cells, were positive for all three NECABs. NECAB1 and 2 are suitable as markers for these cells along the entire septotemporal axis of the hippocampus. In the European mole, parvalbumin, calbindin and calretinin showed traits that have been described in other species before, albeit in a unique combination. In summary, we provide the first description of distribution of these proteins in the hippocampus of the European mole. This subterranean, insectivorous, and solitary living species belongs to the Order of Eulipotyphla. Despite many similarities with other subterranean species from the rodent order in terms of lifestyle, its hippocampus is cytoarchitecturally much more elaborated than in, e.g., mole-rats. It remains an open question if the hippocampal structure of the European mole reflects evolutionary constraints or ecology. Our descriptive study highlights the diversity in hippocampal cytoarchitecture even in small mammalian species. [ABSTRACT FROM AUTHOR]

The IntelliCage (IC) permits the assessment of the behavior and learning abilities of mice in a social home cage context. To overcome water deprivation as an aversive driver of learning, we developed protocols in which spatial learning is motivated appetitively by the preference of mice for sweetened over plain water. While plain water is available at all times, only correct task responses give access to sweetened water rewards. Under these conditions, C57BL/6J mice successfully mastered a corner preference task with the reversal and also learned a more difficult time-place task with reversal. However, the rate of responding to sweetened water decreased strongly with increasing task difficulty, indicating that learning challenges and reduced success in obtaining rewards decreased the motivation of the animals to seek sweetened water. While C57BL/6J mice of both sexes showed similar initial taste preferences and learned similarly well in simple learning tasks, the rate of responding to sweetened water and performance dropped more rapidly in male than in female mice in response to increasing learning challenges. Taken together, our data indicate that male mice can have a disadvantage relative to females in mastering difficult, appetitively motivated learning tasks, likely due to sex differences in value-based decisionmaking. [ABSTRACT FROM AUTHOR]

The IntelliCage allows automated testing of cognitive abilities of mice in a social home cage environment without handling by human experimenters. Restricted water access in combination with protocols in which only correct responses give access to water is a reliable learning motivator for hippocampus-dependent tasks assessing spatial memory and executive function. However, water restriction may negatively impact on animal welfare, especially in poor learners. To better comply with the 3R principles, we previously tested protocols in which water was freely available but additional access to sweetened water could be obtained by learning a task rule. While this purely appetitive motivation worked for simple tasks, too many mice lost interest in the sweet reward during more difficult hippocampus-dependent tasks. In the present study, we tested a battery of increasingly difficult spatial tasks in which water was still available without learning the task rule, but rendered less attractive either by adding bitter tasting quinine or by increasing the amount of work to obtain it. As in previous protocols, learning of the task rule provided access to water sweetened with saccharin. The two approaches of dual motivation were tested in two cohorts of female C57BL/6 N mice. Compared to purely appetitive motivation, both novel protocols strongly improved task engagement and increased task performance. Importantly, neither of the added disincentives had an adverse impact on liquid consumption, health status or body weight of the animals. Our results show that it is possible to refine test protocols in the IntelliCage so that they challenge cognitive functions without restricting access to water. [ABSTRACT FROM AUTHOR]

The IntelliCage is an automated home-cage system that allows researchers to investigate the spontaneous behavior and learning abilities of group-housed mice. The IntelliCage enables us to increase the standardization and reproducibility of behavioral outcomes by the omission of experimenter-mouse interactions. Although the IntelliCage provides a less stressful environment for animals, standard IntelliCage protocols use controlled water access as the motivational driver for learning. To overcome possible water restrictions in slow learners, we developed a series of novel protocols based on appetitive learning, in which mice had permanent access to plain water but were additionally rewarded with sweetened water upon solving the task. C57BL/6NCrl female mice were used to assess the efficacy of these sweet reward-based protocols in a series of learning tasks. Compared to control mice tested with standard protocols, mice motivated with a sweet reward did equal to or better in operant performance and place learning tasks. Learning of temporal rules was slower than that in controls. When faced with a combined temporal x spatial working memory task, sweet-rewarded mice learned little and chose plain water. In a second set of experiments, the impact of environmental enrichment on appetitive learning was tested. Mice kept under enriched environment (EE) or standard housing (SH) conditions prior to the IntelliCage experiments performed similarly in the sweet-rewarded place learning task. EE mice performed better in the hippocampus-dependent spatial working memory task. The improved performance of EE mice in the hippocampus-dependent spatial working memory task might be explained by the observed larger volume of their mossy fibers. Our results confirm that environmental enrichment increases complex spatial learning abilities and leads to long-lasting morphological changes in the hippocampus. Furthermore, simple standard IntelliCage protocols could easily be adapted to sweet rewards, which improve animal welfare by removing the possibility of water restriction. However, complex behavioral tasks motivated by sweet reward-based learning need further adjustments to reach the same efficacy as standard protocols. [ABSTRACT FROM AUTHOR]

The hippocampus of many mammals contains a histoarchitectural region that is not present in laboratory mice and rats--the reflected blade of the CA3 pyramidal cell layer. Pyramidal cells of the reflected blade do not extend dendrites into the hippocampal molecular layer, and recent evidence indicates that they, like the proximal CA3 pyramids in laboratory rats and mice, partially integrate functionally with the dentate circuitry in pattern separation. Quantitative assessments of phylogenetic or disease-related changes in the hippocampal structure and function treat the reflected blade heterogeneously. Depending on the ease with which it can be differentiated, it is either assigned to the dentate hilus or to the remainder of CA3. Here, we investigate the impact that the differential assignment of reflected blade neurons may have on the outcomes of quantitative comparisons. We find it to be massive. If reflected blade neurons are treated as a separate entity or pooled with dentate hilar cells, the quantitative makeup of hippocampal cell populations can differentiate between species in a taxonomically sensible way. Assigning reflected blade neurons to CA3 greatly diminishes the differentiating power of all hippocampal principal cell populations, which may point towards a quantitative hippocampal archetype. A heterogeneous assignment results in a differentiation pattern with little taxonomic semblance. The outcomes point towards the reflected blade as either a major potential player in hippocampal functional and structural differentiation or a region that may have cloaked that hippocampi are more similarly organized across species than generally believed. [ABSTRACT FROM AUTHOR]

Translational research in behavioral neuroscience seeks causes and remedies for human mental health problems in animals, following leads imposed by clinical research in psychiatry. This endeavor faces several problems because scientists must read and interpret animal movements to represent human perceptions, mood, and memory processes. Yet, it is still not known how mammalian brains bundle all these processes into a highly compressed motor output in the brain stem and spinal cord, but without that knowledge, translational research remains aimless. Based on some four decades of experience in the field, the article identifies sources of interpretation problems and illustrates typical translational pitfalls. (1) The sensory world of mice is different. Smell, hearing, and tactile whisker sensations dominate in rodents, while visual input is comparatively small. In humans, the relations are reversed. (2) Mouse and human brains are equated inappropriately: the association cortex makes up a large portion of the human neocortex, while it is relatively small in rodents. The predominant associative cortex in rodents is the hippocampus itself, orchestrating chiefly inputs from secondary sensorimotor areas and generating species-typical motor patterns that are not easily reconciled with putative human hippocampal functions. (3) Translational interpretation of studies of memory or emotionality often neglects the ecology of mice, an extremely small species surviving by freezing or flight reactions that do not need much cognitive processing. (4) Further misinterpretations arise from confounding neuronal properties with system properties, and from rigid mechanistic thinking unaware that many experimentally induced changes in the brain do partially reflect unpredictable compensatory plasticity. (5) Based on observing hippocampal lesion effects in mice indoors and outdoors, the article offers a simplistic general model of hippocampal functions in relation to hypothalamic input and output, placing hypothalamus and the supraspinal motor system at the top of a cerebral hierarchy. (6) Many translational problems could be avoided by inclusion of simple species-typical behaviors as end-points comparable human cognitive or executive processing, and to rely more on artificial intelligence for recognizing patterns not classifiable by traditional psychological concepts. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is histopathologically characterized by Ab plaques and the accumulation of hyperphosphorylated Tau species, the latter also constituting key hallmarks of primary tauopathies. Whereas Ab is produced by amyloidogenic APP processing, APP processing along the competing nonamyloidogenic pathway results in the secretion of neurotrophic and synaptotrophic APPsa. Recently, we demonstrated that APPsa has therapeutic effects in transgenic AD model mice and rescues Ab-dependent impairments. Here, we examined the potential of APPsa to mitigate Tau-induced synaptic deficits in P301S mice (both sexes), a widely used mouse model of tauopathy. Analysis of synaptic plasticity revealed an aberrantly increased LTP in P301S mice that could be normalized by acute application of nanomolar amounts of APPsa to hippocampal slices, indicating a homeostatic function of APPsa on a rapid time scale. Further, AAV-mediated in vivo expression of APPsa restored normal spine density of CA1 neurons even at stages of advanced Tau pathology not only in P301S mice, but also in independent THY-Tau22 mice. Strikingly, when searching for the mechanism underlying aberrantly increased LTP in P301S mice, we identified an early and progressive loss of major GABAergic interneuron subtypes in the hippocampus of P301S mice, which may lead to reduced GABAergic inhibition of principal cells. Interneuron loss was paralleled by deficits in nest building, an innate behavior highly sensitive to hippocampal impairments. Together, our findings indicate that APPsa has therapeutic potential for Tau-mediated synaptic dysfunction and suggest that loss of interneurons leads to disturbed neuronal circuits that compromise synaptic plasticity as well as behavior. [ABSTRACT FROM AUTHOR]

We have recently identified point mutation V336Y in mitoribosomal protein Mrps5 (uS5m) as a mitoribosomal ram (ribosomal ambiguity) mutation conferring error-prone mitochondrial protein synthesis. In vivo in transgenic knock-in animals, homologous mutation V338Y was associated with a discrete phenotype including impaired mitochondrial function, anxiety-related behavioral alterations, enhanced susceptibility to noise-induced hearing damage, and accelerated metabolic aging in muscle. To challenge the postulated link between Mrps5 V338Y-mediated misreading and the in vivo phenotype, we introduced mutation G315R into the mouse Mrps5 gene as Mrps5 G315R is homologous to the established bacterial ram mutation RpsE (uS5) G104R. However, in contrast to bacterial translation, the homologous G → R mutation in mitoribosomal Mrps5 did not affect the accuracy of mitochondrial protein synthesis. Importantly, in the absence of mitochondrial misreading, homozygous mutant MrpS5G315R/G315R mice did not show a phenotype distinct from wild-type animals. [ABSTRACT FROM AUTHOR]

Behavioral phenotyping of mice has received a great deal of attention during the past three decades. However, there is still a pressing need to understand the variability caused by environmental and biological factors, human interference, and poorly standardized experimental protocols. The inconsistency of results is often attributed to the inter-individual difference between the experimenters and environmental conditions. The present work aims to dissect the combined influence of the experimenter and the environment on the detection of behavioral traits in two inbred strains most commonly used in behavioral genetics due to their contrasting phenotypes, the C57BL/6J and DBA/2J mice. To this purpose, the elevated O-maze, the open field with object, the accelerating rotarod and the Barnes maze tests were performed by two experimenters in two diverse laboratory environments. Our findings confirm the well-characterized behavioral differences between these strains in exploratory behavior, motor performance, learning and memory. Moreover, the results demonstrate how the experimenter and the environment influence the behavioral tests with a variable-dependent effect, often with mutually exclusive contributions. In this context, our study highlights how both the experimenter and the environment can have an impact on the strain effect size without altering the direction of the conclusions. Importantly, the general agreement on the results is reached by converging evidence from multiple measures addressing the same trait. In conclusion, the present work elucidates the contribution of both the experimenter and the laboratory environment in the intricate field of reproducibility in mouse behavioral phenotyping. [ABSTRACT FROM AUTHOR]