Social housing enhances acquisition of task set independently of environmental enrichment: A longitudinal study in the Barnes maze.

Human studies suggest that healthy social relationships benefit cognition, yet little is known about the underlying neural mechanisms of this protective effect. In rodents, studies on acute isolation and environmental enrichment (EE) confirm the importance of social exposure. Despite the widely recognized importance of sociality, however, rodent models have yet to explore the independent contributions of social housing divorced of other forms of enrichment. This study dissociates the effects of social and physical enrichment on spatial learning and memory from adulthood to old age. Rats were placed in either single or group housing, provided with ample enrichment, and tested at three time points on several phases/versions of the Barnes maze (BM) (standard, retention probes, variable location, and reversal). We found that sustained social housing enhanced cognitive flexibility, as evidenced by superior acquisition of task set (standard BM), adaptability to a new task set (variable BM), and improved reversal learning (reversal BM). Long-term retention (BM retention probes) of spatial memory was unaffected by housing conditions. Recent studies from our lab, including this report, are the first to show that social housing confers cognitive benefits beyond those of physical enrichment. Importantly, our experimental design is ideal for exploring the neural underpinnings of this socially induced cognitive protection. Understanding how sociality influences cognition will be invaluable to translational models of aging, neuropsychiatric disease, and neurological injury.

Disconnection of the Perirhinal and Postrhinal Cortices Impairs Recognition of Objects in Context But Not Contextual Fear Conditioning.

The perirhinal cortex (PER) is known to process object information, whereas the rodent postrhinal cortex (POR), homolog to the parahippocampal cortex in primates, is thought to process spatial information. A number of studies, however, provide evidence that both areas are involved in processing contextual information. In this study, we tested the hypothesis that the rat POR relies on object information received from the PER to form complex representations of context. Using three fear-conditioning (FC) paradigms (signaled, unsignaled, and renewal) and two context-guided object recognition tasks (with 3D and 2D objects), we examined the effects of crossed excitotoxic lesions to the POR and the contralateral PER. Performance of rats with crossed lesions was compared with that of rats with ipsilateral POR plus PER lesions and sham-operated rats. We found that rats with contralateral PER-POR lesions were impaired in object-context recognition but not in contextual FC. Therefore, interaction between the POR and PER is necessary for context-guided exploratory behavior but not for associating fear with context. Our results provide evidence for the hypothesis that the POR relies on object and pattern information from the PER to encode representations of context. The association of fear with a context, however, may be supported by alternate cortical and/or subcortical pathways when PER-POR interaction is not available. Our results suggest that contextual FC may represent a special case of context-guided behavior.SIGNIFICANCE STATEMENT Representations of context are important for perception, memory, decision making, and other cognitive processes. Moreover, there is extensive evidence that the use of contextual representations to guide appropriate behavior is disrupted in neuropsychiatric and neurological disorders including developmental disorders, schizophrenia, affective disorders, and Alzheimer's disease. Many of these disorders are accompanied by changes in parahippocampal and hippocampal structures. Understanding how context is represented in the brain and how parahippocampal structures are involved will enhance our understanding and treatment of the cognitive and behavioral symptoms associated with neurological disorders and neuropsychiatric disease.

Objects and landmarks: hippocampal place cells respond differently to manipulations of visual cues depending on size, perspective, and experience.

Human navigation studies show that landmarks are used for orientation, whereas objects contribute to the contextual representation of an environment. What constitutes a landmark? Classic rodent studies show that hippocampal place fields are controlled by distal, polarizing cues. Place fields, however, are also influenced by local cues. One difficulty in examining mechanisms by which distal and local cues influence the activity of hippocampal cells is that distant cues are necessarily processed visually, whereas local cues are generally multimodal. Here, we compared the effects of 90° rotations under different cue conditions in which cues were restricted to the visual modality. Three two-dimensional visual cue conditions were presented in a square open field: a large vertical cue on one wall, a large floor cue in a corner abutting two walls, and a smaller complex floor cue in a corner adjacent to two walls. We show that rotations of large distal cues, whether on the wall or floor, were equally effective in controlling place fields. Rotations of the smaller floor cues were significantly more likely to result in remapping, whether or not animals were also exposed to the distal polarizing cues. Responses of distal and local cues were affected differently by extended experience. Our data provide evidence that hippocampal place cell responses to visual cues are influenced by perspective, salience of the cue, and prior experience. The hippocampus processes visual cues either as stable landmarks useful for orientation and navigation or as nonstationary objects or features of the local environment available for associative learning or binding items in context.

Identifying localized biases in large datasets: a case study using the avian tree of life.

Large-scale multi-locus studies have become common in molecular phylogenetics, with new studies continually adding to previous datasets in an effort to fully resolve the tree of life. Total evidence analyses that combine existing data with newly collected data are expected to increase the power of phylogenetic analyses to resolve difficult relationships. However, they might be subject to localized biases, with one or a few loci having a strong and potentially misleading influence upon the results. To examine this possibility we combined a newly collected 31-locus dataset that includes representatives of all major avian lineages with a published dataset of 19 loci that has a comparable number of sites (Hackett et al., 2008. Science 320, 1763-1768). This allowed us to explore the advantages of conducting total evidence analyses, and to determine whether it was also important to analyze new datasets independent of published ones. The total evidence analysis yielded results very similar to the published results, with only slightly increased support at a few nodes. However, analyzing the 31- and 19-locus datasets separately highlighted several differences. Two clades received strong support in the published dataset and total evidence analysis, but the support appeared to reflect bias at a single locus (ß-fibrinogen [FGB]). The signal in FGB that supported these relationships was sufficient to result in their recovery with bootstrap support, even when combined with 49 loci lacking that signal. FGB did not appear to have a substantial impact upon the results of species tree methods, but another locus (brain-derived neurotrophic factor [BDNF]) did have an impact upon those analyses. These results demonstrated that localized biases can influence large-scale phylogenetic analyses but they also indicated that considering independent evidence and exploring multiple analytical approaches could reveal them.

Efficient inducible Pan-neuronal cre-mediated recombination in SLICK-H transgenic mice.

Large-scale functional genomics in mice is becoming feasible through projects to develop conditional knockout alleles for every gene. Inducible neuron-specific gene knockout in such mice will permit the analysis of neuronal phenotypes while circumventing developmental defects or embryonic lethality. Here we describe a transgenic line, termed SLICK-H, that facilitates widespread inducible conditional genetic manipulation within most populations of projection neurons. In SLICK-H mice, the Thy1 promoter drives robust and relatively uniform expression of a drug-inducible form of cre recombinase throughout the peripheral and central nervous system. This permits efficient induction of cre-mediated genetic manipulation upon tamoxifen administration in adult mice. Importantly, cre activity in the absence of tamoxifen is minimal, permitting tight control of recombination. In the present study, we catalog in detail the transgene expression patterns and recombination efficiencies in SLICK-H mice. Our results highlight the utility of SLICK-H mice for functional genomics in the nervous system.

Social housing protects against age-related working memory decline independently of physical enrichment in rats.

Longitudinal human studies suggest that as we age, sociality provides protective benefits against cognitive decline. However, little is known about the underlying neural mechanisms. Rodent studies, which are ideal for studying cognition, fail to examine the independent effects of social housing while controlling for physical enrichment in all groups. In this study, rats were socially housed or nonsocially housed throughout their lifespan and tested in the radial arm maze to measure working memory (WM) and reference memory longitudinally at 3 ages. In old age, exclusively, socially housed rats made significantly less WM errors than nonsocially housed rats, while reference memory errors did not differ between groups at any age. Anxiety, as assessed behaviorally and physiologically, could not account for the observed differences in WM. These data provide the first evidence that social enrichment alone can prevent age-related WM deficits in spite of the effects of practice seen in longitudinal designs. Importantly, our model will facilitate future investigations into the mechanisms underlying the neuroprotective benefits of sociability in old age.

Decreased Anxiety-Related Behaviour but Apparently Unperturbed NUMB Function in Ligand of NUMB Protein-X (LNX) 1/2 Double Knockout Mice.

NUMB is a key regulator of neurogenesis and neuronal differentiation that can be ubiquitinated and targeted for proteasomal degradation by ligand of numb protein-X (LNX) family E3 ubiquitin ligases. However, our understanding of LNX protein function in vivo is very limited. To examine the role of LNX proteins in regulating NUMB function in vivo, we generated mice lacking both LNX1 and LNX2 expression in the brain. Surprisingly, these mice are healthy, exhibit unaltered levels of NUMB protein and do not display any neuroanatomical defects indicative of aberrant NUMB function. Behavioural analysis of LNX1/LNX2 double knockout mice revealed decreased anxiety-related behaviour, as assessed in the open field and elevated plus maze paradigms. By contrast, no major defects in learning, motor or sensory function were observed. Given the apparent absence of major NUMB dysfunction in LNX null animals, we performed a proteomic analysis to identify neuronal LNX-interacting proteins other than NUMB that might contribute to the anxiolytic phenotype observed. We identified and/or confirmed interactions of LNX1 and LNX2 with proteins known to have presynaptic and neuronal signalling functions, including the presynaptic active zone constituents ERC1, ERC2 and LIPRIN-αs (PPFIA1, PPFIA3), as well as the F-BAR domain proteins FCHSD2 (nervous wreck homologue) and SRGAP2. These and other novel LNX-interacting proteins identified are promising candidates to mediate LNX functions in the central nervous system, including their role in modulating anxiety-related behaviour.

Decreased dendritic spine density as a consequence of tetanus toxin light chain expression in single neurons in vivo.

Tetanus toxin light chain has been used for some time as a genetically-encoded tool to inhibit neurotransmission and thereby dissect mechanisms underlying neural circuit formation and function. In addition to cleaving v-SNARE proteins involved in axonal neurotransmitter release, tetanus toxin light chain can also block activity-dependent dendritic exocytosis. The application of tetanus toxin light chain as a research tool in mammalian models, however, has been limited to a small number of cell types. Here we have induced expression of tetanus toxin light chain in a very small number of fluorescently labeled neurons in many regions of the adult mouse brain. This was achieved by crossing SLICK (single-neuron labeling with inducible cre-mediated knockout) transgenic lines with RC::Ptox mice that have Cre recombinase-controlled expression of the tetanus toxin light chain. Using this system we have examined the cell-autonomous effects of tetanus toxin light chain expression on dendritic spines in vivo. We find that dendritic spine density is reduced by 15% in tetanus toxin expressing hippocampal CA1 pyramidal cells, while spine morphology is unaltered. This effect is likely to be a consequence of inhibition of activity-dependent dendritic exocytosis and suggests that on-going plasticity-associated exocytosis is required for long-term dendritic spine maintenance in vivo.