Remembering and imagining alternative versions of the personal past

Although autobiographical memory and episodic simulations recruit similar core brain regions, episodic simulations engage additional neural recruitment in the frontoparietal control network due to greater demands on constructive processes. However, previous functional neuroimaging studies showing differences in remembering and episodic simulation have focused on veridical retrieval of past experiences, and thus have not fully considered how retrieving the past in different ways from how it was originally experienced may also place similar demands on constructive processes. Here we examined how alternative versions of the past are constructed when adopting different egocentric perspectives during autobiographical memory retrieval compared to simulating hypothetical events from the personal past that could have occurred, or episodic counterfactual thinking. Participants were asked to generate titles for specific autobiographical memories from the last five years, and then, during functional magnetic resonance (fMRI) scanning, were asked to repeatedly retrieve autobiographical memories or imagine counterfactual events cued by the titles. We used an fMRI adaptation paradigm in order to isolate neural regions that were sensitive to adopting alternative egocentric perspectives and counterfactual simulations of the personal past. The fMRI results revealed that voxels within left posterior inferior parietal and ventrolateral frontal cortices were sensitive to novel visual perspectives and counterfactual simulations. Our findings suggest that the neural regions supporting remembering become more similar to those underlying episodic simulation when we adopt alternative egocentric perspectives of the veridical past

Modifying memory for a museum tour in older adults: reactivation-related updating that enhances and distorts memory is reduced in ageing

Memory reactivation, the activation of a latent memory trace when we are reminded of a past experience, strengthens memory but can also contribute to distortions if new information present during reactivation is integrated with existing memory. In a previous study in young adults (St. Jacques & Schacter, 2013; Psychological Science) we found that the quality of memory reactivation, manipulated using the principle of encoding specificity and indexed by recollection ratings, modulated subsequent true and false memories for events experienced during a museum tour. Here, we examined age-related changes in the quality of memory reactivation on subsequent memory. Young and older adults reactivated memories for museum stops immediately followed by the presentation of a novel lure photo from an alternate tour version (i.e., reactivation plus new information). There was an increase in subsequent true memories for reactivated targets and for subsequent false memories for lures that followed reactivated targets, when compared to baseline target and lure photos. However, the influence of reactivation on subsequent memories was reduced in older adults. These data reveal that aging alters reactivation-related updating processes that allow memories to be strengthened and updated with new information- consequently reducing memory distortions in older compared to young adults

Shifting visual perspective during retrieval shapes autobiographical memories

The dynamic and flexible nature of memories is evident in our ability to adopt multiple visual perspectives. Although autobiographical memories are typically encoded from the visual perspective of our own eyes they can be retrieved from the perspective of an observer looking at our self. Here, we examined the neural mechanisms of shifting visual perspective during long-term memory retrieval and its influence on online and subsequent memories using functional magnetic resonance imaging (fMRI). Participants generated specific autobiographical memories from the last five years and rated their visual perspective. In a separate fMRI session, they were asked to retrieve the memories across three repetitions while maintaining the same visual perspective as their initial rating or by shifting to an alternative perspective. Visual perspective shifting during autobiographical memory retrieval was supported by a linear decrease in neural recruitment across repetitions in the posterior parietal cortices. Additional analyses revealed that the precuneus, in particular, contributed to both online and subsequent changes in the phenomenology of memories. Our findings show that flexibly shifting egocentric perspective during autobiographical memory retrieval is supported by the precuneus, and suggest that this manipulation of mental imagery during retrieval has consequences for how memories are retrieved and later remembered

Elemental spatial and temporal association formation in left temporal lobe epilepsy

The mesial temporal lobe (MTL) is typically understood as a memory structure in clinical settings, with the sine qua non of MTL damage in epilepsy being memory impairment. Recent models, however, understand memory as one of a number of higher cognitive functions that recruit the MTL through their reliance on more fundamental processes, such as “self-projection” or “association formation”. We examined how damage to the left MTL influences these fundamental processes through the encoding of elemental spatial and temporal associations. We used a novel fMRI task to image the encoding of simple visual stimuli, either rich or impoverished, in spatial or spatial plus temporal information. Participants included 14 typical adults (36.4 years, sd. 10.5 years) and 14 patients with left mesial temporal lobe damage as evidenced by a clinical diagnosis of left temporal lobe epilepsy (TLE) and left MTL impairment on imaging (34.3 years, sd. 6.6 years). In-scanner behavioral performance was equivalent across groups. In the typical group whole-brain analysis revealed highly significant bilateral parahippocampal activation (right > left) during spatial associative processing and left hippocampal/parahippocampal deactivation in joint spatial-temporal associative processing. In the left TLE group identical analyses indicated patients used MTL structures contralateral to the seizure focus differently and relied on extra-MTL regions to a greater extent. These results are consistent with the notion that epileptogenic MTL damage is followed by reorganization of networks underlying elemental associative processes. In addition, they provide further evidence that task-related fMRI deactivation can meaningfully index brain function. The implications of these findings for clinical and cognitive neuropsychological models of MTL function in TLE are discussed

The Insertion and Transport of Anandamide in Synthetic Lipid Membranes Are Both Cholesterol-Dependent

International audienceBackground: Anandamide is a lipid neurotransmitter which belongs to a class of molecules termed the endocannabinoids involved in multiple physiological functions. Anandamide is readily taken up into cells, but there is considerable controversy as to the nature of this transport process (passive diffusion through the lipid bilayer vs. involvement of putative proteic transporters). This issue is of major importance since anandamide transport through the plasma membrane is crucial for its biological activity and intracellular degradation. The aim of the present study was to evaluate the involvement of cholesterol in membrane uptake and transport of anandamide.Methodology/Principal Findings: Molecular modeling simulations suggested that anandamide can adopt a shape that is remarkably complementary to cholesterol. Physicochemical studies showed that in the nanomolar concentration range, anandamide strongly interacted with cholesterol monolayers at the air-water interface. The specificity of this interaction was assessed by: i) the lack of activity of structurally related unsaturated fatty acids (oleic acid and arachidonic acid at 50 nM) on cholesterol monolayers, and ii) the weak insertion of anandamide into phosphatidylcholine or sphingomyelin monolayers. In agreement with these data, the presence of cholesterol in reconstituted planar lipid bilayers triggered the stable insertion of anandamide detected as an increase in bilayer capacitance. Kinetics transport studies showed that pure phosphatidylcholine bilayers were weakly permeable to anandamide. The incorporation of cholesterol in phosphatidylcholine bilayers dose-dependently stimulated the translocation of anandamide.Conclusions/Significance: Our results demonstrate that cholesterol stimulates both the insertion of anandamide into synthetic lipid monolayers and bilayers, and its transport across bilayer membranes. In this respect, we suggest that besides putative anandamide protein-transporters, cholesterol could be an important component of the anandamide transport machinery. Finally, this study provides a mechanistic explanation for the key regulatory activity played by membrane cholesterol in the responsiveness of cells to anandamide

Transcriptional regulation of bone formation by the osteoblast-specific transcription factor Osx

Bone formation is a complex developmental process involving the differentiation of mesenchymal stem cells to osteoblasts. Osteoblast differentiation occurs through a multi-step molecular pathway regulated by different transcription factors and signaling proteins. Osx (also known as Sp7) is the only osteoblast-specific transcriptional factor identified so far which is required for osteoblast differentiation and bone formation. Osx knock-out mice lack bone completely and cartilage is normal. This opens a new window to the whole research field of bone formation. Osx inhibits Wnt pathway signaling, a possible mechanism for Osx to inhibit osteoblast proliferation. These reports demonstrate that Osx is the master gene that controls osteoblast lineage commitment and the subsequent osteoblast proliferation and differentiation. This review is to highlight recent progress in understanding the molecular mechanisms of transcriptional regulation of bone formation by Osx

Observation of Orbitally Excited B_s Mesons

We report the first observation of two narrow resonances consistent with states of orbitally excited (L=1) B_s mesons using 1 fb^{-1} of ppbar collisions at sqrt{s} = 1.96 TeV collected with the CDF II detector at the Fermilab Tevatron. We use two-body decays into K^- and B^+ mesons reconstructed as B^+ \to J/\psi K^+, J/\psi \to \mu^+ \mu^- or B^+ \to \bar{D}^0 \pi^+, \bar{D}^0 \to K^+ \pi^-. We deduce the masses of the two states to be m(B_{s1}) = 5829.4 +- 0.7 MeV/c^2 and m(B_{s2}^*) = 5839.7 +- 0.7 MeV/c^2.Comment: Version accepted and published by Phys. Rev. Let

Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer

Purpose: Zoledronic acid (ZA) or denosumab treatment reduces skeletal-related events; however, the safety of prolonged therapy has not been adequately studied. Here, we describe safety results of extended denosumab therapy in patients with bone metastases from the open-label extension phase of two phase 3 trials. Methods: Patients with metastatic breast or prostate cancer received subcutaneous denosumab 120 mg Q4W or intravenous ZA 4 mg Q4W in a double-blinded fashion. Denosumab demonstrated superior efficacy in the blinded treatment phase; thus, patients were offered open-label denosumab for up to an additional 2 years. Results: Cumulative median (Q1, Q3) denosumab exposure was 19.1 (9.2, 32.2) months in the breast cancer trial (n = 1019) and 12.0 (5.6, 21.3) months in the prostate cancer trial (n = 942); 295 patients received denosumab for >3 years. No new safety signals were identified during the open-label phase, or among patients who switched from ZA to denosumab. During the blinded treatment phase, exposure-adjusted subject incidences of osteonecrosis of the jaw (ONJ) were 49 (1.9 %) and 31 (1.2 %) in the denosumab and ZA groups, respectively. In total, 32 (6.9 %) and 25 (5.5 %) new cases of ONJ (not adjusted for exposure) were reported for patients continuing and switching to denosumab, respectively. The incidences of hypocalcemia were 4.3 and 3.1 %, in patients continuing and switching to denosumab, respectively. Conclusion: These results describe the safety profile of denosumab after long-term exposure, or after switching to denosumab from ZA. No new safety signals were identified. Hypocalcemia rates were similar in the blinded treatment and open-label phases. ONJ rates increased with increasing exposure to antiresorptives, consistent with previous reports

Dkk4 and Eda Regulate Distinctive Developmental Mechanisms for Subtypes of Mouse Hair

The mouse hair coat comprises protective “primary” and thermo-regulatory “secondary” hairs. Primary hair formation is ectodysplasin (Eda) dependent, but it has been puzzling that Tabby (Eda-/y) mice still make secondary hair. We report that Dickkopf 4 (Dkk4), a Wnt antagonist, affects an auxiliary pathway for Eda-independent development of secondary hair. A Dkk4 transgene in wild-type mice had no effect on primary hair, but secondary hairs were severely malformed. Dkk4 action on secondary hair was further demonstrated when the transgene was introduced into Tabby mice: the usual secondary follicle induction was completely blocked. The Dkk4-regulated secondary hair pathway, like the Eda-dependent primary hair pathway, is further mediated by selective activation of Shh. The results thus reveal two complex molecular pathways that distinctly regulate subtype-based morphogenesis of hair follicles, and provide a resolution for the longstanding puzzle of hair formation in Tabby mice lacking Eda