Consolidation of long-term memories depends on de novo protein synthesis. Several translational regulators have been identified, and their contribution to the formation of memory has been assessed in ...the mouse hippocampus. None of them, however, has been implicated in the persistence of memory. Although persistence is a key feature of long-term memory, how this occurs, despite the rapid turnover of its molecular substrates, is poorly understood. Here we find that both memory storage and its underlying synaptic plasticity are mediated by the increase in level and in the aggregation of the prion-like translational regulator CPEB3 (cytoplasmic polyadenylation element-binding protein). Genetic ablation of CPEB3 impairs the maintenance of both hippocampal long-term potentiation and hippocampus-dependent spatial memory. We propose a model whereby persistence of long-term memory results from the assembly of CPEB3 into aggregates. These aggregates serve as functional prions and regulate local protein synthesis necessary for the maintenance of long-term memory.
•CPEB3 forms aggregates after synaptic activity in the hippocampus•After aggregation, CPEB3 promotes the translation of AMPA receptors•CPEB3 conditional knockout mice have impaired long-term memory and LTP•CPEB3 mediates the persistence of memory through a prion-like mechanism
Fioriti et al. found that the translational regulator CPEB3 is a prion-like molecule that aggregates to form an amyloid-like structure in the brain of mice. CPEB3 aggregates mediate the maintenance of hippocampal-based long-term memories.
In this study we use historical emission data from installations under the European Union Emissions Trading System (EU ETS) to evaluate the impact of this policy on greenhouse gas emissions during ...the first two trading phases (2005–2012). As such the analysis seeks to disentangle two causes of emission abatement: that attributable to the EU ETS and that attributable to the economic crisis that hit the EU in 2008/09. To do so, we use a dynamic panel data approach. Our results suggest that, by far, the biggest share of abatement was attributable to the effects of the economic crisis. This finding has serious implications for future policy adjustments affecting core elements of the EU ETS, including the distribution of EU emission allowances.
•We untangle the effects of the EU ETS from those of the economic crisis on industrial emission abatement.•The empirical analysis uses verified emission data instead of estimated emission data.•Abatement of emissions in EU in the last years has been mainly due to the impact of the economic crisis.•Low level of abatement attributable to the EU ETS suggests that important changes must be made in environmental policy.
Exercise promotes learning and memory formation. These effects depend on increases in hippocampal BDNF, a growth factor associated with cognitive improvement and the alleviation of depression ...symptoms. Identifying molecules that are produced during exercise and that mediate hippocampal
expression will allow us to harness the therapeutic potential of exercise. Here, we report that an endogenous molecule produced during exercise in male mice induces the
gene and promotes learning and memory formation. The metabolite lactate, which is released during exercise by the muscles, crosses the blood-brain barrier and induces
expression and TRKB signaling in the hippocampus. Indeed, we find that lactate-dependent increases in BDNF are associated with improved spatial learning and memory retention. The action of lactate is dependent on the activation of the Sirtuin1 deacetylase. SIRT1 increases the levels of the transcriptional coactivator PGC1a and the secreted molecule FNDC5, known to mediate
expression. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF, and identify lactate as a potential endogenous molecule that may have therapeutic value for CNS diseases in which BDNF signaling is disrupted.
It is established that exercise promotes learning and memory formation and alleviates the symptoms of depression. These effects are mediated through inducing
expression and signaling in the hippocampus. Understanding how exercise induces
and identifying the molecules that mediate this induction will allow us to design therapeutic strategies that can mimic the effects of exercise on the brain, especially for patients with CNS disorders characterized by a decrease in
expression and who cannot exercise because of their conditions. We identify lactate as an endogenous metabolite that is produced during exercise, crosses the blood-brain barrier and promotes hippocampal dependent learning and memory in a BDNF-dependent manner. Our work identifies lactate as a component of the "exercise pill."
In this study, we use patent count data for overall Climate Change Mitigation Technologies, and for those related to energy production and distribution to evaluate the relationship between the ...sizable oversupply of European Union emissions Allowances and a policy shift marked by the transition from Phase I to Phase II under the European Union Emission Trading System, on the one hand, and on “green” patenting, on the other. According to our results, the expected negative impact of this oversupply on technological change seems to be confirmed. Thus, stakeholders take the actual supply of certificates into account when determining their innovative activity. In the same vein, they do so with respect to policy changes related to greater stringency, which generated a sizeable increase in patenting activity when controlling for other economic factors. Our results suggest that a critical evaluation of emission caps and allowances distribution must be undertaken.
•We study the impact of policy stringency measures on “green” technological change.•Policy stringency is measured using the actual oversupply of certificates.•Our sample includes 28 countries subject to the policy.•Higher stringency positively influences overall patent counts.
The European Union launched a set of policies as part of its 2020 climate and energy package aimed at meeting its 20/20/20 headline targets for smart, sustainable and inclusive growth. This paper ...evaluates how successful new-to-the-market climate change mitigation technologies (CCMT) are in helping EU member states (MS) reach these goals and, furthermore, whether there are differences between sectors subject to EU-wide polices. To do so, we relate CCMT patent counts to two specific headline targets: (1) achieving 20% of gross final energy consumption from renewables, and (2) achieving a 20% increase in energy efficiency. Our results provide the first ex-post evaluation of the effectiveness of these technologies for combating climate change. Moreover, our sectoral impact assessment points to significant differences in the way in which these technologies contribute to policy goals across the sectors.
The mouse cytoplasmic polyadenylation element-binding protein 3 (CPEB3) is a translational regulator implicated in long-term memory maintenance. Invertebrate orthologs of CPEB3 in Aplysia and ...Drosophila are functional prions that are physiologically active in the aggregated state. To determine if this principle applies to the mammalian CPEB3, we expressed it in yeast and found that it forms heritable aggregates that are the hallmark of known prions. In addition, we confirm in the mouse the importance of CPEB3’s prion formation for CPEB3 function. Interestingly, deletion analysis of the CPEB3 prion domain uncovered a tripartite organization: two aggregation-promoting domains surround a regulatory module that affects interaction with the actin cytoskeleton. In all, our data provide direct evidence that CPEB3 is a functional prion in the mammalian brain and underline the potential importance of an actin/CPEB3 feedback loop for the synaptic plasticity underlying the persistence of long-term memory.
Display omitted
•CPEB3 is a functional prion with a tripartite prion domain architecture•CPEB3 interacts with the actin cytoskeleton in yeast and at mouse synapses•Actin filaments are essential for CPEB3 prionization and actin mRNA is a CPEB3 target•Actin and CPEB3 constitute a positive feedback loop important for CPEB3 function
Mouse CPEB3 is a translational regulator implicated in long-term memory maintenance. Stephan et al. show that CPEB3 is a functional prion and that CPEB3 interaction with actin is essential for prion formation. They also find that actin mRNA is a CPEB3 target, suggesting a positive regulatory loop underlies CPEB3 function.
The establishment and maintenance of heterochromatin, a specific chromatin structure essential for genomic stability and regulation, rely on intricate interactions between chromatin-modifying enzymes ...and nucleosomal histone proteins. However, the precise trigger for these modifications remains unclear, thus highlighting the need for a deeper understanding of how methyltransferases facilitate histone methylation among others. Here, we investigate the molecular mechanisms underlying heterochromatin assembly by studying the interaction between the H3K9 methyltransferase Clr4 and H3K9-methylated nucleosomes. Using a combination of liquid-state nuclear magnetic resonance spectroscopy and cryo-electron microscopy, we elucidate the structural basis of Clr4 binding to H3K9-methylated nucleosomes. Our results reveal that Clr4 engages with nucleosomes through its chromodomain and disordered regions to promote de novo methylation. This study provides crucial insights into the molecular mechanisms governing heterochromatin formation by highlighting the significance of chromatin-modifying enzymes in genome regulation and disease pathology.
Chronic stress promotes depression in some individuals, but has no effect in others. Susceptible individuals exhibit social avoidance and anxious behavior and ultimately develop depression, whereas ...resilient individuals live normally. Exercise counteracts the effects of stress. Our objective was to examine whether lactate, a metabolite produced during exercise and known to reproduce specific brain exercise-related changes, promotes resilience to stress and acts as an antidepressant. To determine whether lactate promotes resilience to stress, male C57BL/6 mice experienced daily defeat by a CD-1 aggressor, for 10 days. On the 11th day, mice were subjected to behavioral tests. Mice received lactate before each defeat session. When compared with control mice, mice exposed to stress displayed increased susceptibility, social avoidance and anxiety. Lactate promoted resilience to stress and rescued social avoidance and anxiety by restoring hippocampal class I histone deacetylase (HDAC) levels and activity, specifically HDAC2/3. To determine whether lactate is an antidepressant, mice only received lactate from days 12-25 and a second set of behavioral tests was conducted on day 26. In this paradigm, we examined whether lactate functions by regulating HDACs using co-treatment with CI-994, a brain-permeable class I HDAC inhibitor. When administered after the establishment of depression, lactate behaved as antidepressant. In this paradigm, lactate regulated HDAC5 and not HDAC2/3 levels. On the contrary, HDAC2/3 inhibition was antidepressant-like. This indicates that lactate mimics exercise's effects and rescues susceptibility to stress by modulating HDAC2/3 activity and suggests that HDAC2/3 play opposite roles before and after establishment of susceptibility to stress.
Macroautophagy (or autophagy) is a conserved degradative pathway that has been implicated in a number of biological processes, including organismal aging, innate immunity, and the progression of ...human cancers. This pathway was initially identified as a cellular response to nutrient deprivation and is essential for cell survival during these periods of starvation. Autophagy is highly regulated and is under the control of a number of signaling pathways, including the Tor pathway, that coordinate cell growth with nutrient availability. These pathways appear to target a complex of proteins that contains the Atg1 protein kinase. The data here show that autophagy in Saccharomyces cerevisiae is also controlled by the cAMP-dependent protein kinase (PKA) pathway. Elevated levels of PKA activity inhibited autophagy and inactivation of the PKA pathway was sufficient to induce a robust autophagy response. We show that in addition to Atg1, PKA directly phosphorylates Atg13, a conserved regulator of Atg1 kinase activity. This phosphorylation regulates Atg13 localization to the preautophagosomal structure, the nucleation site from which autophagy pathway transport intermediates are formed. Atg13 is also phosphorylated in a Tor-dependent manner, but these modifications appear to occur at positions distinct from the PKA phosphorylation sites identified here. In all, our data indicate that the PKA and Tor pathways function independently to control autophagy in S. cerevisiae, and that the Atg1/Atg13 kinase complex is a key site of signal integration within this degradative pathway.
Stroke is one of the leading causes of death and disability in the world. Stroke not only affects the patients, but also their families who serve as the primary caregivers. Discovering novel ...therapeutic targets for stroke is crucial both from a quality of life perspective as well as from a health economic perspective. Exercise is known to promote neuroprotection in the context of stroke. Indeed, exercise induces the release of blood-borne factors that promote positive effects on the brain. Identifying the factors that mediate the positive effects of exercise after ischemic stroke is crucial for the quest for novel therapies. This approach will yield endogenous molecules that normally cross the blood brain barrier (BBB) and that can mimic the effects of exercise. In this minireview, we will discuss the roles of exercise factors released by the liver such as beta-hydroxybutyrate (DBHB), by the muscle such as lactate and irisin and by the bones such as osteocalcin. We will also address their therapeutic potential in the context of ischemic stroke.
PDF
