A Face Versus Non-Face Context Influences Amygdala Responses to Masked Fearful Eye Whites

The structure of the mask stimulus is crucial in backward masking studies and we recently demonstrated such an effect when masking faces. Specifically, we showed that activity of the amygdala is increased to fearful facial expressions masked with neutral faces and decreased to fearful expressions masked with a pattern mask—but critically both masked conditions discriminated fearful expressions from happy expressions. Given this finding, we sought to test whether masked fearful eye whites would produce a similar profile of amygdala response in a face vs non-face context. During functional magnetic resonance imaging scanning sessions, 30 participants viewed fearful or happy eye whites masked with either neutral faces or pattern images. Results indicated amygdala activity was increased to fearful vs happy eye whites in the face mask condition, but decreased to fearful vs happy eye whites in the pattern mask condition—effectively replicating and expanding our previous report. Our data support the idea that the amygdala is responsive to fearful eye whites, but that the nature of this activity observed in a backward masking design depends on the mask stimulus

Positional Cloning of a Type 2 Diabetes Quantitative Trait Locus; Tomosyn-2, a Negative Regulator of Insulin Secretion

We previously mapped a type 2 diabetes (T2D) locus on chromosome 16 (Chr 16) in an F2 intercross from the BTBR T (+) tf (BTBR) Lepob/ob and C57BL/6 (B6) Lepob/ob mouse strains. Introgression of BTBR Chr 16 into B6 mice resulted in a consomic mouse with reduced fasting plasma insulin and elevated glucose levels. We derived a panel of sub-congenic mice and narrowed the diabetes susceptibility locus to a 1.6 Mb region. Introgression of this 1.6 Mb fragment of the BTBR Chr 16 into lean B6 mice (B6.16BT36–38) replicated the phenotypes of the consomic mice. Pancreatic islets from the B6.16BT36–38 mice were defective in the second phase of the insulin secretion, suggesting that the 1.6 Mb region encodes a regulator of insulin secretion. Within this region, syntaxin-binding protein 5-like (Stxbp5l) or tomosyn-2 was the only gene with an expression difference and a non-synonymous coding single nucleotide polymorphism (SNP) between the B6 and BTBR alleles. Overexpression of the b-tomosyn-2 isoform in the pancreatic β-cell line, INS1 (832/13), resulted in an inhibition of insulin secretion in response to 3 mM 8-bromo cAMP at 7 mM glucose. In vitro binding experiments showed that tomosyn-2 binds recombinant syntaxin-1A and syntaxin-4, key proteins that are involved in insulin secretion via formation of the SNARE complex. The B6 form of tomosyn-2 is more susceptible to proteasomal degradation than the BTBR form, establishing a functional role for the coding SNP in tomosyn-2. We conclude that tomosyn-2 is the major gene responsible for the T2D Chr 16 quantitative trait locus (QTL) we mapped in our mouse cross. Our findings suggest that tomosyn-2 is a key negative regulator of insulin secretion

Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number

Elevated basal serum tryptase levels are present in 4-6% of the general population, but the cause and relevance of such increases are unknown. Previously, we described subjects with dominantly inherited elevated basal serum tryptase levels associated with multisystem complaints including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility. Here we report the identification of germline duplications and triplications in the TPSAB1 gene encoding α-tryptase that segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multisystem complaints. Individuals harboring alleles encoding three copies of α-tryptase had higher basal serum levels of tryptase and were more symptomatic than those with alleles encoding two copies, suggesting a gene-dose effect. Further, we found in two additional cohorts (172 individuals) that elevated basal serum tryptase levels were exclusively associated with duplication of α-tryptase-encoding sequence in TPSAB1, and affected individuals reported symptom complexes seen in our initial familial cohort. Thus, our findings link duplications in TPSAB1 with irritable bowel syndrome, cutaneous complaints, connective tissue abnormalities, and dysautonomia

The Stock Market Evaluation of IPO-Firm Takeovers

We conduct an event study to assess the stock market evaluation of public takeover announcements. Unlike the majority of previous research, we specifically focus on acquisitions targeted at newly public IPO-firms and show that the stock market positively evaluates these M&As as R&D. However, bidders' abnormal announcement returns are significantly lower for takeovers directed at targets with critical intangible assets and innovative capabilities inalienably bound to their initial owners than for those that have internally accumulated respective resources and capabilities. We explain these findings with the acquirer's post-acquisition dependence on continued access to the IPO-firm founders' target-specific human capital. Our results contribute to literature in that they show that the stock market perceives these potential impediments to successful exploitation of acquired strategic resources and thus identify a potential cause for heretofore mostly inconsistent evidence on bidder abnormal returns in corporate takeovers found in previous research

[Avian cytogenetics goes functional] Third report on chicken genes and chromosomes 2015

High-density gridded libraries of large-insert clones using bacterial artificial chromosome (BAC) and other vectors are essential tools for genetic and genomic research in chicken and other avian species... Taken together, these studies demonstrate that applications of large-insert clones and BAC libraries derived from birds are, and will continue to be, effective tools to aid high-throughput and state-of-the-art genomic efforts and the important biological insight that arises from them

Short-term inhibition of 11β-hydroxysteroid dehydrogenase type 1 reversibly improves spatial memory but persistently impairs contextual fear memory in aged mice

AbstractHigh glucocorticoid levels induced by stress enhance the memory of fearful events and may contribute to the development of anxiety and posttraumatic stress disorder. In contrast, elevated glucocorticoids associated with ageing impair spatial memory. We have previously shown that pharmacological inhibition of the intracellular glucocorticoid-amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) improves spatial memory in aged mice. However, it is not known whether inhibition of 11β-HSD1 will have any beneficial effects on contextual fear memories in aged mice. Here, we examined the effects of UE2316, a selective 11β-HSD1 inhibitor which accesses the brain, on both spatial and contextual fear memories in aged mice using a vehicle-controlled crossover study design.Short-term UE2316 treatment improved spatial memory in aged mice, an effect which was reversed when UE2316 was substituted with vehicle. In contrast, contextual fear memory induced by foot-shock conditioning was significantly reduced by UE2316 in a non-reversible manner. When the order of treatment was reversed following extinction of the original fear memory, and a second foot-shock conditioning was given in a novel context, UE2316 treated aged mice (previously on vehicle) now showed increased fear memory compared to vehicle-treated aged mice (previously on UE2316). Renewal of the original extinguished fear memory triggered by exposure to a new environmental context may explain these effects. Thus 11β-HSD1 inhibition reverses spatial memory impairments with ageing while reducing the strength and persistence of new contextual fear memories. Potentially this could help prevent anxiety-related disorders in vulnerable elderly individuals

Investigations of limbic structures on a novel conditioned discrimination task: Lesion studies, hippocampal place cells, and the effects of age

A task was developed to simultaneously examine place learning and fear motivated context discrimination. Rats were trained to alternate along a high-walled, diamond shaped runway between two chambers for food. On half the trials, a tone signaled the fact that a fixed section at the apex of the runway was electrified. The animals were required to cross over this shock region to enter the successive goal chamber and gain reinforcement. The behavioral performance of rats with small lesions of the amygdala or dorsal hippocampus was compared to that of sham lesioned controls. All groups displayed significant discrimination, hesitating more on tone trials while in areas of the runway adjacent to the shock region. Animals with lesions to the hippocampus were similar to controls in tone discrimination, yet were delayed in learning the location of the shock region. Conversely, amygdala lesions did not affect place learning, however these animals were impaired in their suppression of the fear response following repeated unpaired trials. ^ Hippocampal unit activity was recorded from animals performing the task, and was analyzed to investigate the effect of discriminative fear conditioning on place field remapping. Rats of varying ages were used as subjects in order to investigate whether the nature of place cell re-mapping was different across the life span. The majority of neurons recorded were unaffected by the discriminative behavior, and did not change spatial firing patterns across conditions. This finding is in contrast with previous studies in which substantial proportions of cells displayed task-specific activity. In those previous experiments, the pathways traversed by the animals were not constrained, and in fact, the pathways taken in order to receive reinforcement changed between tasks. Therefore, the results presented in this dissertation seem to demonstrate that place field re-mapping (in dorsal regions of hippocampus) is driven primarily by changes in routes traveled, rather than by altered emotional or motivational context. Still, a small percentage of neurons displayed condition-specific activity, indicating that the hippocampus is not an exclusively “spatial”, and can also encode changes in context. Finally, there was no effect of age on the extent of re-mapping observed.