Modulation of Tcf7l2 Expression Alters Behavior in Mice

The comorbidity of type 2 diabetes (T2D) with several psychiatric diseases is well established. While environmental factors may partially account for these co-occurrences, common genetic susceptibilities could also be implicated in the confluence of these diseases. In support of shared genetic burdens, TCF7L2, the strongest genetic determinant for T2D risk in the human population, has been recently implicated in schizophrenia (SCZ) risk, suggesting that this may be one of many loci that pleiotropically influence both diseases. To investigate whether Tcf7l2 is involved in behavioral phenotypes in addition to its roles in glucose metabolism, we conducted several behavioral tests in mice with null alleles of Tcf7l2 or overexpressing Tcf7l2. We identified a role for Tcf7l2 in anxiety-like behavior and a dose-dependent effect of Tcf7l2 alleles on fear learning. None of the mutant mice showed differences in prepulse inhibition (PPI), which is a well-established endophenotype for SCZ. These results show that Tcf7l2 alters behavior in mice. Importantly, these differences are observed prior to the onset of detectable glucose metabolism abnormalities. Whether these differences are related to human anxiety-disorders or schizophrenia remains to be determined. These animal models have the potential to elucidate the molecular basis of psychiatric comorbidities in diabetes and should therefore be studied further

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29

Modulation of <i>Tcf7l2</i> Expression Alters Behavior in Mice

The comorbidity of type 2 diabetes (T2D) with several psychiatric diseases is well established. While environmental factors may partially account for these co-occurrences, common genetic susceptibilities could also be implicated in the confluence of these diseases. In support of shared genetic burdens, TCF7L2, the strongest genetic determinant for T2D risk in the human population, has been recently implicated in schizophrenia (SCZ) risk, suggesting that this may be one of many loci that pleiotropically influence both diseases. To investigate whether Tcf7l2 is involved in behavioral phenotypes in addition to its roles in glucose metabolism, we conducted several behavioral tests in mice with null alleles of Tcf7l2 or overexpressing Tcf7l2. We identified a role for Tcf7l2 in anxiety-like behavior and a dose-dependent effect of Tcf7l2 alleles on fear learning. None of the mutant mice showed differences in prepulse inhibition (PPI), which is a well-established endophenotype for SCZ. These results show that Tcf7l2 alters behavior in mice. Importantly, these differences are observed prior to the onset of detectable glucose metabolism abnormalities. Whether these differences are related to human anxiety-disorders or schizophrenia remains to be determined. These animal models have the potential to elucidate the molecular basis of psychiatric comorbidities in diabetes and should therefore be studied further.</p

Behavioral analyses from Tcf7l2 ablation.

<p>(A)–(C) Open field testing. (A) Center time shown as a percent of total time (%) in wild-type (WT, n = 14) and heterozygous null (+/−, n = 12) mice. (B) Total distance shown in meters (m) in wild-type (WT, n = 14) and heterozygous null (+/−, n = 12) mice. (C) Latency to periphery shown in seconds (s) in wild-type (WT, n = 14) and heterozygous null (+/−, n = 12) mice. (D)–(F) Light dark box testing. (D) Time in light shown as percent of total time (%) in wild-type (WT, n = 14) and heterozygous null (+/–, n = 12) mice. (E) Number of transitions between the light and dark compartments in wild-type (WT, n = 14) and heterozygous null (+/–, n = 12) mice. (F) Latency to the dark compartment shown in seconds (s) in wild-type (WT, n = 14) and heterozygous null (+/–, n = 12) mice. (G)–(I) Fear conditioning. (G) Contextual fear shown as a percent time spent freezing (%) in wild-type (WT, n = 14) and heterozygous null (+/–, n = 12) mice. (H) Cue-based fear shown as a percent time spent freezing (%) in wild-type (WT, n = 14) and heterozygous null (+/–, n = 12) mice. (I) Pre-training freezing shown as a percent time spent freezing (%) in wild-type (WT, n = 14) and heterozygous null (+/–, n = 12) mice. (J) Prepulse inhibition in wild-type (WT, n = 14) and heterozygous null (+/–, n = 12) mice. Prepulse inhibition (%) using prepulses of 3, 6 and 12 decibels (dB) are shown. (K) Startle response in wild-type (WT, n = 14) and heterozygous null (+/–, n = 12) mice. Wild-type data are shown in gray while heterozygous null data are shown in blue.</p

Behavioral analyses from <i>Tcf7l2</i> overexpression.

<p>(A)–(C) Open field testing. (A) Center time shown as a percent of total time (%) in wild-type (WT, n = 9) and BAC transgenic (BAC, n = 9) mice. (B) Total distance shown in meters (m) in wild-type (WT, n = 9) and BAC transgenic (BAC, n = 9) mice. (C) Latency to periphery shown in seconds (s) in wild-type (WT, n = 9) and BAC transgenic (BAC, n = 9) mice. (D)–(F) Light dark box testing. (D) Time in light shown as a percent of total time (%) in wild-type (WT, n = 9) and BAC transgenic (BAC, n = 9) mice. (E) Number of transitions between the light and dark compartments in wild-type (WT, n = 9) and BAC transgenic (BAC, n = 9) mice. (F) Latency to the dark compartment shown in seconds (s) in wild-type (WT, n = 9) and BAC transgenic (BAC, n = 9) mice. (G) – (I) Fear conditioning. (G) Contextual fear shown as a percent time spent freezing (%) in wild-type (WT, n = 9) and BAC transgenic (BAC, n = 9) mice. (H) Cue-based fear shown as a percent time spent freezing (%) in wild-type (WT, n = 9) and BAC transgenic (BAC, n = 9) mice. (I) Pre-training freezing shown as a percent time spent freezing (%) in wild-type (WT, n = 9) and BAC transgenic (BAC, n = 9) mice. (J) Prepulse inhibition in wild-type (WT, n = 9) and BAC transgenic (BAC, n = 9) mice. Prepulse inhibition (%) using prepulses of 3, 6 and 12 decibels (dB) are shown. (K) Startle response in wild-type (WT, n = 9) and BAC transgenic (BAC, n = 9) mice. Wild-type data are shown in gray while BAC transgenic data are shown in orange.</p