A behavioral paradigm to evaluate hippocampal performance in aged rodents for pharmacological and genetic target validation.

Aged-related cognitive ability is highly variable, ranging from unimpaired to severe impairments. The Morris water maze (a reliable tool for assessing memory) has been used to distinguish aged rodents that are superior learners from those that are learning impaired. This task, however, is not practical for pre- and post-pharmacological treatment, as the memory of the task is long lasting. In contrast, the object location memory task, also a spatial learning paradigm, results in a less robust memory that decays quickly. We demonstrate for the first time how these two paradigms can be used together to assess hippocampal cognitive impairments before and after pharmacological or genetic manipulations in rodents. Rats were first segregated into superior learning and learning impaired groups using the object location memory task, and their performance was correlated with future outcome on this task and on the Morris water maze. This method provides a tool to evaluate the effect of treatments on cognitive impairment associated with aging and neurodegenerative disorders

Statistical analysis shows a significant correlation between individual performance on OLM1 and OLM2.

<p>Data shown as novelty index, or proportion of total investigation time spent attending to the object in the novel location. (A) First round of OLM (OLM1) [young, n = 15; SL, n = 17; AI, n = 8]. (B) Second round of OLM (OLM2) using the same animals [young, n = 15; SL, n = 17; AI, n = 14]. Aged performance groups on OLM2 are delineated without reference to previous performance on OLM1. (C) For animals ranked as SL or AI on OLM1, a dotted line connects that individual’s performance on OLM1 to their performance on OLM2 (see also <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0062360#pone-0062360-t001" target="_blank">Table 1</a>). Only animals classified as SL or AI on OLM1 are shown, and their classification on OLM2 are shown as SL = black triangles, AI = white squares, and intermediates = grey diamonds. (D) Correlation analysis between individual performance on OLM1 and OLM2. Young = grey circles, aged = black diamonds (n = 44, all young, SL, AI, and Intermediate animals included). (E): Correlation analysis for the aged rats. Grey diamonds indicate animals that were categorized differently in OLM1 and OLM2, or were classified as Intermediate in both tests. For details on this group of animals please refer to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0062360#pone-0062360-t001" target="_blank">Tables 1</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0062360#pone-0062360-t002" target="_blank">2</a>.</p

The OLM paradigm features novel and familiar object locations.

<p>Overhead view of OLM arena. (A) Object locations on Training Day. (B, C) Object locations on Testing Day.</p

Category assignments from OLM1 and OLM2 of the same group of aged rats shown as a cross tabulation.

<p>For example, 6 rats classified as AI by OLM1 were also classified as AI in OLM2.</p

Raw data from OLM2 (novelty index) and MWM probe trial (% of total swim distance in target quadrant) illustrates the criteria used to categorize superior and impaired learning ability (one cohort shown of three).

<p>Horizontal lines show cutoffs for superior, intermediate and impaired categories.</p><p><b>ID#</b> - Rat identification number.</p><p><b>Rank</b> - Animals have been ranked in order of performance from high to low.</p

The protective role of TLR6 in a mouse model of asthma is mediated by IL-23 and IL-17A

TLRs are a family of receptors that mediate immune system pathogen recognition. In the respiratory system, TLR activation has both beneficial and deleterious effects in asthma. For example, clinical data indicate that TLR6 activation exerts protective effects in asthma. Here, we explored the mechanism or mechanisms through which TLR6 mediates this effect using mouse models of Aspergillus fumigatus–induced and house dust mite antigen–induced (HDM antigen–induced) chronic asthma. Tlr6–/– mice with fungal- or HDM antigen–induced asthma exhibited substantially increased airway hyperresponsiveness, inflammation, and remodeling compared with WT asthmatic groups. Surprisingly, whole-lung levels of IL-23 and IL-17 were markedly lower in Tlr6–/– versus WT asthmatic mice. Tlr6–/– DCs generated less IL-23 upon activation with lipopolysaccharide, zymosan, or curdlan. Impaired IL-23 generation in Tlr6–/– mice also corresponded with lower levels of expression of the pathogen-recognition receptor dectin-1 and expansion of Th17 cells both in vivo and in vitro. Exogenous IL-23 treatment of asthmatic Tlr6–/– mice restored IL-17A production and substantially reduced airway hyperresponsiveness, inflammation, and lung fungal burden compared with that in untreated asthmatic Tlr6–/– mice. Together, our data demonstrate that TLR6 activation is critical for IL-23 production and Th17 responses, which both regulate the allergic inflammatory response in chronic fungal-induced asthma. Thus, therapeutics targeting TLR6 activity might prove efficacious in the treatment of clinical asthma