The Role of the Androgen Receptor Cofactor p44/WDR77 in Astrocyte Activation

Astrogliosis is induced by neuronal damage and is also a pathological feature of the major aging-related neurodegenerative disorders. The mechanisms that control the cascade of astrogliosis have not been well established. In a previous study, we identified a novel androgen receptor (AR)-interacting protein (p44/WDR77) and found that it plays a critical role in the control of proliferation and differentiation of prostate epithelial cells. In the present study, we found that deletion of the p44 gene in the mouse brain caused accelerated aging with dramatic astrogliosis. The p44/WDR77 is expressed in astrocytes and loss of p44/WDR77 expression in astrocytes leads to astrogliosis. Our results reveal a novel role of p44/WDR77 in astrocytes, which may explain the well-documented role of androgens in suppression of astrogliosis. While many of detailed mechanisms of astrocyte activation remain to be elucidated, a number pathways have been implicated in astrocyte activation including p21Cip1 and the NF-kB pathway. Astrocytic activation induced by p44/WDR77 gene deletion was associated with a significant increase of p21Cip1 expression and NF-kB activation characterized by p65 nuclear localization. We found that down-regulation of p21Cip1 expression inhibited astrocyte activation induced by the p44/WDR77 deletion and was accompanied by a decreased p65 nuclear localization. While p21Cip1 role in astrocyte activation and NF-kB activation is not well understood, studies of other cell cycle regulators have implicated cell cycle control systems as modulators of astrocyte activation, thus p21Cip1 could induce secondary effect to induce p65 nuclear localization. However, p65 knockdown completely relieved the inhibition of astrocyte growth induced by the p44/WDR77 deletion, while p21Cip1 knockdown only partially recovered this inhibition. Thus, NF-kB activity performs additional regulatory actions not mediated by p21Cip1. These analyses imply that p4/WDR77 suppresses astrocyte activation through modulating p21Cip1 expression and NF-kB activation.

Optical imaging of postsynaptic odor representation in the glomerular layer of the mouse olfactory bulb.

Olfactory glomeruli are the loci where the first odor-representation map emerges. The glomerular layer comprises exquisite local synaptic circuits for the processing of olfactory coding patterns immediately after their emergence. To understand how an odor map is transferred from afferent terminals to postsynaptic dendrites, it is essential to directly monitor the odor-evoked glomerular postsynaptic activity patterns. Here we report the use of a transgenic mouse expressing a Ca(2+)-sensitive green fluorescence protein (GCaMP2) under a Kv3.1 potassium-channel promoter. Immunostaining revealed that GCaMP2 was specifically expressed in mitral and tufted cells and a subpopulation of juxtaglomerular cells but not in olfactory nerve terminals. Both in vitro and in vivo imaging combined with glutamate receptor pharmacology confirmed that odor maps reported by GCaMP2 were of a postsynaptic origin. These mice thus provided an unprecedented opportunity to analyze the spatial activity pattern reflecting purely postsynaptic olfactory codes. The odor-evoked GCaMP2 signal had both focal and diffuse spatial components. The focalized hot spots corresponded to individually activated glomeruli. In GCaMP2-reported postsynaptic odor maps, different odorants activated distinct but overlapping sets of glomeruli. Increasing odor concentration increased both individual glomerular response amplitude and the total number of activated glomeruli. Furthermore, the GCaMP2 response displayed a fast time course that enabled us to analyze the temporal dynamics of odor maps over consecutive sniff cycles. In summary, with cell-specific targeting of a genetically encoded Ca(2+) indicator, we have successfully isolated and characterized an intermediate level of odor representation between olfactory nerve input and principal mitral/tufted cell output.

The Effect of Proximity, Explicitness, and Representation of Basic Science Information on Student Clinical Problem-Solving

Problem: Medical and veterinary students memorize facts but then have difficulty applying those facts in clinical problem solving. Cognitive engineering research suggests that the inability of medical and veterinary students to infer concepts from facts may be due in part to specific features of how information is represented and organized in educational materials. First, physical separation of pieces of information may increase the cognitive load on the student. Second, information that is necessary but not explicitly stated may also contribute to the student’s cognitive load. Finally, the types of representations – textual or graphical – may also support or hinder the student’s learning process. This may explain why students have difficulty applying biomedical facts in clinical problem solving. Purpose: To test the hypothesis that three specific aspects of expository text – the patial distance between the facts needed to infer a rule, the explicitness of information, and the format of representation – affected the ability of students to solve clinical problems. Setting: The study was conducted in the parasitology laboratory of a college of veterinary medicine in Texas. Sample: The study subjects were a convenience sample consisting of 132 second-year veterinary students who matriculated in 2007. The age of this class upon admission ranged from 20-52, and the gender makeup of this class consisted of approximately 75% females and 25% males. Results: No statistically significant difference in student ability to solve clinical problems was found when relevant facts were placed in proximity, nor when an explicit rule was stated. Further, no statistically significant difference in student ability to solve clinical problems was found when students were given different representations of material, including tables and concept maps. Findings: The findings from this study indicate that the three properties investigated – proximity, explicitness, and representation – had no statistically significant effect on student learning as it relates to clinical problem-solving ability. However, ad hoc observations as well as findings from other researchers suggest that the subjects were probably using rote learning techniques such as memorization, and therefore were not attempting to infer relationships from the factual material in the interventions, unless they were specifically prompted to look for patterns. A serendipitous finding unrelated to the study hypothesis was that those subjects who correctly answered questions regarding functional (non-morphologic) properties, such as mode of transmission and intermediate host, at the family taxonomic level were significantly more likely to correctly answer clinical case scenarios than were subjects who did not correctly answer questions regarding functional properties. These findings suggest a strong relationship (p < .001) between well-organized knowledge of taxonomic functional properties and clinical problem solving ability. Recommendations: Further study should be undertaken investigating the relationship between knowledge of functional taxonomic properties and clinical problem solving ability. In addition, the effect of prompting students to look for patterns in instructional material, followed by the effect of factors that affect cognitive load such as proximity, explicitness, and representation, should be explored.