Dorsal raphe to basolateral amygdala corticotropin-releasing factor circuit regulates cocaine-memory reconsolidation.

Environmental stimuli elicit drug craving and relapse in cocaine users by triggering the retrieval of strong cocaine-related contextual memories. Retrieval can also destabilize drug memories, requiring reconsolidation, a protein synthesis-dependent storage process, to maintain memory strength. Corticotropin-releasing factor (CRF) signaling in the basolateral amygdala (BLA) is necessary for cocaine-memory reconsolidation. We have hypothesized that a critical source of CRF in the BLA is the dorsal raphe nucleus (DR) based on its neurochemistry, anatomical connectivity, and requisite involvement in cocaine-memory reconsolidation. To test this hypothesis, male and female Sprague-Dawley rats received adeno-associated viruses to express Gi-coupled designer receptors exclusively activated by designer drugs (DREADDs) selectively in CRF neurons of the DR and injection cannulae directed at the BLA. The rats were trained to self-administer cocaine in a distinct environmental context then received extinction training in a different context. Next, they were briefly re-exposed to the cocaine-predictive context to destabilize (reactivate) cocaine memories. Intra-BLA infusions of the DREADD agonist deschloroclozapine (DCZ; 0.1 mM, 0.5 µL/hemisphere) immediately after memory reactivation attenuated cocaine-memory strength, relative to vehicle infusion. This was indicated by a selective, DCZ-induced and memory reactivation-dependent decrease in drug-seeking behavior in the cocaine-predictive context in DREADD-expressing males and females at test compared to respective controls. Notably, BLA-projecting DR CRF neurons that exhibited increased c-Fos expression during memory reconsolidation co-expressed the glutamatergic neuronal marker, vesicular glutamate transporter 3. Together, these findings suggest that the DRCRF → BLA circuit is engaged to maintain cocaine-memory strength after memory destabilization, and this phenomenon may be mediated by DR CRF and/or glutamate release in the BLA.

Brain-wide representation of social knowledge.

Understanding how the human brain maps different dimensions of social conceptualizations remains a key unresolved issue. We performed a functional magnetic resonance imaging (MRI) study in which participants were exposed to audio definitions of personality traits and asked to simulate experiences associated with the concepts. Half of the concepts were affective (e.g. empathetic), and the other half were non-affective (e.g. intelligent). Orthogonally, half of the concepts were highly likable (e.g. sincere) and half were socially undesirable (e.g. liar). Behaviourally, we observed that the dimension of social desirability reflected the participant's subjective ratings better than affect. FMRI decoding results showed that both social desirability and affect could be decoded in local patterns of activity through distributed brain regions including the superior temporal, inferior frontal, precuneus and key nodes of the default mode network in posterior/anterior cingulate and ventromedial prefrontal cortex. Decoding accuracy was better for social desirability than affect. A representational similarity analysis further demonstrated that a deep language model significantly predicted brain activity associated with the concepts in bilateral regions of superior and anterior temporal lobes. The results demonstrate a brain-wide representation of social knowledge, involving default model network systems that support the multimodal simulation of social experience, with a further reliance on language-related preprocessing.

Characterising the role of awareness in ensemble perception.

Ensemble representations are efficient codes that the brain generates effortlessly even under noisy conditions. However, the role of visual awareness for computing ensemble representations remains unclear. We present two psychophysical experiments (N = 15 × 2) using a bias-free paradigm to investigate the contribution of conscious and unconscious processing to ensemble perception. Here, we show that ensemble perception can unfold without awareness of the relevant features that define the ensemble. Computational modeling of the type-1 and type-2 drift-rates further suggest that awareness lags well behind the categorization processes that support ensemble perception. Additional evidence indicates that the dissociation between type-1 from type-2 sensitivity, was not driven by the type-2 inefficiency or a systematic disadvantage in type-2 decision making. The present study demonstrates the utility of robust measures for studying the role of visual consciousness and metacognition in stimuli and tasks of increasing complexity, crucially, without underestimating the contribution of unconscious processing in an otherwise visible stimulus. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Climate change disrupts the seasonal coupling of plant and soil microbial nutrient cycling in an alpine ecosystem.

The seasonal coupling of plant and soil microbial nutrient demands is crucial for efficient ecosystem nutrient cycling and plant production, especially in strongly seasonal alpine ecosystems. Yet, how these seasonal nutrient cycling processes are modified by climate change and what the consequences are for nutrient loss and retention in alpine ecosystems remain unclear. Here, we explored how two pervasive climate change factors, reduced snow cover and shrub expansion, interactively modify the seasonal coupling of plant and soil microbial nitrogen (N) cycling in alpine grasslands, which are warming at double the rate of the global average. We found that the combination of reduced snow cover and shrub expansion disrupted the seasonal coupling of plant and soil N-cycling, with pronounced effects in spring (shortly after snow melt) and autumn (at the onset of plant senescence). In combination, both climate change factors decreased plant organic N-uptake by 70% and 82%, soil microbial biomass N by 19% and 38% and increased soil denitrifier abundances by 253% and 136% in spring and autumn, respectively. Shrub expansion also individually modified the seasonality of soil microbial community composition and stoichiometry towards more N-limited conditions and slower nutrient cycling in spring and autumn. In winter, snow removal markedly reduced the fungal:bacterial biomass ratio, soil N pools and shifted bacterial community composition. Taken together, our findings suggest that interactions between climate change factors can disrupt the temporal coupling of plant and soil microbial N-cycling processes in alpine grasslands. This could diminish the capacity of these globally widespread alpine ecosystems to retain N and support plant productivity under future climate change.

Dorsal Raphe to Basolateral Amygdala Corticotropin-Releasing Factor Circuit Regulates Cocaine-Memory Reconsolidation.

Environmental stimuli elicit drug craving and relapse in cocaine users by triggering the retrieval of strong cocainerelated contextual memories. Retrieval can also destabilize drug memories, requiring reconsolidation, a protein synthesis-dependent storage process, to maintain memory strength. Corticotropin-releasing factor (CRF) signaling in the basolateral amygdala (BLA) is necessary for cocainememory reconsolidation. We have hypothesized that a critical source of CRF in the BLA is the dorsal raphe nucleus (DR) based on its neurochemistry, anatomical connectivity, and requisite involvement in cocaine-memory reconsolidation. To test this hypothesis, male and female Sprague-Dawley rats received adeno-associated viruses to express Gi-coupled designer receptors exclusively activated by designer drugs (DREADDs) selectively in CRF neurons of the DR and injection cannulae directed at the BLA. The rats were trained to self-administer cocaine in a distinct environmental context then received extinction training in a different context. They were then briefly reexposed to the cocaine-predictive context to destabilize (reactivate) cocaine memories. Intra-BLA infusions of the DREADD agonist deschloroclozapine (DCZ; 0.1 mM, 0.5 µL/hemisphere) after memory reactivation attenuated cocaine-memory strength, relative to vehicle infusion. This was indicated by a selective, DCZ-induced and memory reactivation-dependent decrease in drug-seeking behavior in the cocaine-predictive context in DREADD-expressing males and females at test compared to respective controls. Notably, BLA-projecting DR CRF neurons that exhibited increased c-Fos expression during memory reconsolidation co-expressed glutamatergic and serotonergic neuronal markers. Together, these findings suggest that the DRCRF → BLA circuit is engaged to maintain cocaine-memory strength after memory destabilization, and this phenomenon may be mediated by DR CRF, glutamate, and/or serotonin release in the BLA.

A novel image database for social concepts reveals preference biases in autistic spectrum in adults and children.

Human beings display the extraordinary ability of grasping and communicating abstract concepts. Yet, no standardized instruments exist to assess this ability. Developing these tools is paramount for understanding abstract representations such as social concepts, with ramifications in educational and clinical settings. Here, we developed an image database depicting abstract social concepts varying in social desirability. We first validated the image database in a sample of neurotypical participants. Then, we applied the database to test different hypotheses regarding how social concepts are represented across samples of adults and children with autism spectrum condition (ASC). Relative to the neurotypicals, we did not observe differences related to ASC in identification performance of the social desirability of the concepts, nor differences in metacognitive ability. However, we observed a preference bias away from prosocial concepts that was linked to individual autistic traits in the neurotypicals, and higher in ASC relative to the neurotypicals both in adults and children. These results indicate that abstract representations such as social concepts are dependent on individual neurodevelopmental traits. The image database thus provides a standardized assessment tool for investigating the representation of abstract social concepts in the fields of psycholinguistics, neuropsychology, neuropsychiatry, and cognitive neuroscience, across different cultures and languages.

Radiocarbon integrity of dissolved inorganic carbon (DIC) samples stored in plastic and glass bottles: implications for reliable groundwater age dating.

Various approaches based on the natural variations of carbon isotopes (14C and 13C) in dissolved inorganic carbon (DIC) are routinely used to study groundwater dynamics and to estimate recharge rates by deriving groundwater ages. However, differences in 14C activities in groundwater samples collected repeatedly from the same wells and discordantly young 14C groundwater ages compared to noble gases led some authors to question the validity of radiocarbon dating. Poor sampling protocols and storage effects (14C contamination) for radiocarbon analysis are a critical factor in explaining age determination discrepancies. We evaluated the impact of storage protocols on carbon isotope exchange with atmospheric carbon dioxide by comparing glass versus standard plastic field sampling bottles for various storage times before radiocarbon and 13C analyses. The 14C bias after 12 months in pre-evacuated glass vials was minimal and within analytical precision. However, storage of DIC samples in plastic sampling bottles led to marked changes in 14C and 13C contents (up to ∼15 pmC and ∼ 5 ‰, respectively, after 12 months), meaning contamination led to younger groundwater age estimations than it should have been. Protocols for sampling and storing DIC samples for radiocarbon using pre-evacuated glass bottles help avoid atmospheric 14CO2 contamination and microbial activity.

Unconscious Manipulation of Conceptual Representations with Decoded Neurofeedback Impacts Search Behavior.

The necessity of conscious awareness in human learning has been a long-standing topic in psychology and neuroscience. Previous research on non-conscious associative learning is limited by the low signal-to-noise ratio of the subliminal stimulus, and the evidence remains controversial, including failures to replicate. Using functional MRI decoded neurofeedback, we guided participants from both sexes to generate neural patterns akin to those observed when visually perceiving real-world entities (e.g., dogs). Importantly, participants remained unaware of the actual content represented by these patterns. We utilized an associative DecNef approach to imbue perceptual meaning (e.g., dogs) into Japanese hiragana characters that held no inherent meaning for our participants, bypassing a conscious link between the characters and the dogs concept. Despite their lack of awareness regarding the neurofeedback objective, participants successfully learned to activate the target perceptual representations in the bilateral fusiform. The behavioral significance of our training was evaluated in a visual search task. DecNef and control participants searched for dogs or scissors targets that were pre-cued by the hiragana used during DecNef training or by a control hiragana. The DecNef hiragana did not prime search for its associated target but, strikingly, participants were impaired at searching for the targeted perceptual category. Hence, conscious awareness may function to support higher-order associative learning. Meanwhile, lower-level forms of re-learning, modification, or plasticity in existing neural representations can occur unconsciously, with behavioral consequences outside the original training context. The work also provides an account of DecNef effects in terms of neural representational drift.

Think twice: Re-assessing confidence improves visual metacognition.

Metacognition is a fundamental feature of human behavior that has adaptive functional value. Current understanding of the factors that influence metacognition remains incomplete, and we lack protocols to improve metacognition. Here, we introduce a two-step confidence choice paradigm to test whether metacognitive performance may improve by asking subjects to reassess their initial confidence. Previous work on perceptual and mnemonic decision-making has shown that (type 1) perceptual sensitivity benefits from reassessing the primary choice, however, it is not clear whether such an effect occurs for type 2 confidence choices. To test this hypothesis, we ran two separate online experiments, in which participants completed a type 1 task followed by two consecutive confidence choices. The results of the two experiments indicated that metacognitive sensitivity improved after re-evaluation. Since post-decisional evidence accumulation following the first confidence choice is likely to be minimal, this metacognitive improvement is better accounted for by an attenuation of metacognitive noise during the process of confidence generation. Thus, here we argue that metacognitive noise may be filtered out by additional post-decisional processing, thereby improving metacognitive sensitivity. We discuss the ramifications of these findings for models of metacognition and for developing protocols to train and manipulate metacognitive processes.

Assessing the energy trap of industrial agriculture in North America and Europe: 82 balances from 1830 to 2012.

Early energy analyses of agriculture revealed that behind higher labor and land productivity of industrial farming, there was a decrease in energy returns on energy (EROI) invested, in comparison to more traditional organic agricultural systems. Studies on recent trends show that efficiency gains in production and use of inputs have again somewhat improved energy returns. However, most of these agricultural energy studies have focused only on external inputs at the crop level, concealing the important role of internal biomass flows that livestock and forestry recirculate within agroecosystems. Here, we synthesize the results of 82 farm systems in North America and Europe from 1830 to 2012 that for the first time show the changing energy profiles of agroecosystems, including livestock and forestry, with a multi-EROI approach that accounts for the energy returns on external inputs, on internal biomass reuses, and on all inputs invested. With this historical circular bioeconomic approach, we found a general trend towards much lower external returns, little or no increases in internal returns, and almost no improvement in total returns. This "energy trap" was driven by shifts towards a growing dependence of crop production on fossil-fueled external inputs, much more intensive livestock production based on feed grains, less forestry, and a structural disintegration of agroecosystem components by increasingly linear industrial farm managements. We conclude that overcoming the energy trap requires nature-based solutions to reduce current dependence on fossil-fueled external industrial inputs and increase the circularity and complexity of agroecosystems to provide healthier diets with less animal products. Supplementary Information: The online version contains supplementary material available at 10.1007/s13593-023-00925-5.

Cyclin D1-Cdk4 regulates neuronal activity through phosphorylation of GABAA receptors.

Nuclear Cyclin D1 (Ccnd1) is a main regulator of cell cycle progression and cell proliferation. Interestingly, Ccnd1 moves to the cytoplasm at the onset of differentiation in neuronal precursors. However, cytoplasmic functions and targets of Ccnd1 in post-mitotic neurons are unknown. Here we identify the α4 subunit of gamma-aminobutyric acid (GABA) type A receptors (GABAARs) as an interactor and target of Ccnd1-Cdk4. Ccnd1 binds to an intracellular loop in α4 and, together with Cdk4, phosphorylates the α4 subunit at threonine 423 and serine 431. These modifications upregulate α4 surface levels, increasing the response of α4-containing GABAARs, measured in whole-cell patch-clamp recordings. In agreement with this role of Ccnd1-Cdk4 in neuronal signalling, inhibition of Cdk4 or expression of the non-phosphorylatable α4 decreases synaptic and extra-synaptic currents in the hippocampus of newborn rats. Moreover, according to α4 functions in synaptic pruning, CCND1 knockout mice display an altered pattern of dendritic spines that is rescued by the phosphomimetic α4. Overall, our findings molecularly link Ccnd1-Cdk4 to GABAARs activity in the central nervous system and highlight a novel role for this G1 cyclin in neuronal signalling.

Heat exposure following encoding can interfere with subsequent recognition memory.

Correlational studies suggest that high temperatures may impair online cognitive performance and learning processes. Here, we tested the hypothesis that heat exposure blocks offline memory consolidation. We report two studies, including a pre-registered replication. First, during a study phase, participants were familiarized with neutral and negatively valenced images. One day later, half of the participants were exposed to high temperatures in a sauna session at 50 °C. Recognition memory was tested 24 h later. We found that participants exposed to high temperature showed an impairment in recognition memory performance, relative to a control group of participants that were not exposed to heat or that had a sauna at 28 °C. This occurred for both emotional and neutral items. These results indicate that heat exposure impairs memory consolidation, thereby opening the possibility of using heat exposure as an agent for the treatment of clinical mental disorders.

Computational Prediction of Trypanosoma cruzi Epitopes Toward the Generation of an Epitope-Based Vaccine Against Chagas Disease.

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is considered a Neglected Tropical Disease. Limited investment is assigned to its study and control, even though it is one of the most prevalent parasitic infections worldwide. An innovative vaccination strategy involving an epitope-based vaccine that displays multiple immune determinants originating from different antigens could counteract the high biological complexity of the parasite and lead to a wide and protective immune response. In this chapter, we describe a computational reverse vaccinology pipeline applied to identify the most promising peptide sequences from T. cruzi proteins, prioritizing evolutionary conserved sequences, to finally select a list of T and B cell epitope candidates to be further tested in an experimental setting.

Using serial dependence to predict confidence across observers and cognitive domains.

Our perceptual system appears hardwired to exploit regularities of input features across space and time in seemingly stable environments. This can lead to serial dependence effects whereby recent perceptual representations bias current perception. Serial dependence has also been demonstrated for more abstract representations, such as perceptual confidence. Here, we ask whether temporal patterns in the generation of confidence judgments across trials generalize across observers and different cognitive domains. Data from the Confidence Database across perceptual, memory, and cognitive paradigms was reanalyzed. Machine learning classifiers were used to predict the confidence on the current trial based on the history of confidence judgments on the previous trials. Cross-observer and cross-domain decoding results showed that a model trained to predict confidence in the perceptual domain generalized across observers to predict confidence across the different cognitive domains. The recent history of confidence was the most critical factor. The history of accuracy or Type 1 reaction time alone, or in combination with confidence, did not improve the prediction of the current confidence. We also observed that confidence predictions generalized across correct and incorrect trials, indicating that serial dependence effects in confidence generation are uncoupled to metacognition (i.e., how we evaluate the precision of our own behavior). We discuss the ramifications of these findings for the ongoing debate on domain-generality versus domain-specificity of metacognition.

Ikzf1 as a novel regulator of microglial homeostasis in inflammation and neurodegeneration.

In the last two decades, microglia have emerged as key contributors to disease progression in many neurological disorders, not only by exerting their classical immunological functions but also as extremely dynamic cells with the ability to modulate synaptic and neural activity. This dynamic behavior, together with their heterogeneous roles and response to diverse perturbations in the brain parenchyma has raised the idea that microglia activation is more diverse than anticipated and that understanding the molecular mechanisms underlying microglial states is essential to unravel their role in health and disease from development to aging. The Ikzf1 (a.k.a. Ikaros) gene plays crucial roles in modulating the function and maturation of circulating monocytes and lymphocytes, but whether it regulates microglial functions and states is unknown. Using genetic tools, here we describe that Ikzf1 is specifically expressed in the adult microglia in brain regions such as cortex and hippocampus. By characterizing the Ikzf1 deficient mice, we observed that these mice displayed spatial learning deficits, impaired hippocampal CA3-CA1 long-term potentiation, and decreased spine density in pyramidal neurons of the CA1, which correlates with an increased expression of synaptic markers within microglia. Additionally, these Ikzf1 deficient microglia exhibited a severe abnormal morphology in the hippocampus, which is accompanied by astrogliosis, an aberrant composition of the inflammasome, and an altered expression of disease-associated microglia molecules. Interestingly, the lack of Ikzf1 induced changes on histone 3 acetylation and methylation levels in the hippocampus. Since the lack of Ikzf1 in mice appears to induce the internalization of synaptic markers within microglia, and severe gliosis we then analyzed hippocampal Ikzf1 levels in several models of neurological disorders. Ikzf1 levels were increased in the hippocampus of these neurological models, as well as in postmortem hippocampal samples from Alzheimer's disease patients. Finally, over-expressing Ikzf1 in cultured microglia made these cells hyporeactive upon treatment with lipopolysaccharide, and less phagocytic compared to control microglia. Altogether, these results suggest that altered Ikzf1 levels in the adult hippocampus are sufficient to induce synaptic plasticity and memory deficits via altering microglial state and function.

The Scientific Study of Consciousness Cannot and Should Not Be Morally Neutral.

A target question for the scientific study of consciousness is how dimensions of consciousness, such as the ability to feel pain and pleasure or reflect on one's own experience, vary in different states and animal species. Considering the tight link between consciousness and moral status, answers to these questions have implications for law and ethics. Here we point out that given this link, the scientific community studying consciousness may face implicit pressure to carry out certain research programs or interpret results in ways that justify current norms rather than challenge them. We show that because consciousness largely determines moral status, the use of nonhuman animals in the scientific study of consciousness introduces a direct conflict between scientific relevance and ethics-the more scientifically valuable an animal model is for studying consciousness, the more difficult it becomes to ethically justify compromises to its well-being for consciousness research. Finally, in light of these considerations, we call for a discussion of the immediate ethical corollaries of the body of knowledge that has accumulated and for a more explicit consideration of the role of ideology and ethics in the scientific study of consciousness.

Use of Cultivated Epidermal Allograft in Chronic Wounds: A Novel Therapeutic Alternative.

Introduction: Chronic wounds represent a frequent cause of consultation for plastic and reconstructive surgeons. The use of epidermal culture stands out because they provide complete epithelialization, adequate aesthetic-functional results, and no morbidity for the patient. Epifast® is a pre-manufactured cultured epidermal allograft derived from the amplification in vitro of human keratinocytes. Materials and Methods: A prospective longitudinal multicenter study was carried out in four chronic wound reference centers, which were in charge of plastic and reconstructive surgery services. For a standardized wound bed preparation, the protocol synthesized by the acronym "TIME" was used. At the end of the "TIME" protocol, the pre-fabricated allograft was applied and removed 7 days after its application. Results: A total of 133 patients with diagnosis of chronic wound were included in the study. The median age was 69.3 ± 13.6 years. The most common comorbidity found was diabetes mellitus type 2 in 71.4% of the patients (n = 95) and systemic arterial hypertension in 60.2% of the patients (n = 80). The most frequent location of chronic wounds was seen in the lower extremity with 45.1% (n = 60). The mean duration for it to close was 46 ± 14 days, in which they closed within the first 3 months in 93% (n = 125) of the cases. About 91.7% (n = 122) of the wounds achieved total closure. Conclusion: Cultured epidermal allograft, combined with a meticulous technique and an adequate selection of patients, represents a safe and effective tool for chronic wounds.

Engineered red blood cells (activating antigen carriers) drive potent T cell responses and tumor regression in mice.

Activation of T cell responses is essential for effective tumor clearance; however, inducing targeted, potent antigen presentation to stimulate T cell responses remains challenging. We generated Activating Antigen Carriers (AACs) by engineering red blood cells (RBCs) to encapsulate relevant tumor antigens and the adjuvant polyinosinic-polycytidylic acid (poly I:C), for use as a tumor-specific cancer vaccine. The processing method and conditions used to create the AACs promote phosphatidylserine exposure on RBCs and thus harness the natural process of aged RBC clearance to enable targeting of the AACs to endogenous professional antigen presenting cells (APCs) without the use of chemicals or viral vectors. AAC uptake, antigen processing, and presentation by APCs drive antigen-specific activation of T cells, both in mouse in vivo and human in vitro systems, promoting polyfunctionality of CD8+ T cells and, in a tumor model, driving high levels of antigen-specific CD8+ T cell infiltration and tumor killing. The efficacy of AAC therapy was further enhanced by combination with the chemotherapeutic agent Cisplatin. In summary, these findings support AACs as a potential vector-free immunotherapy strategy to enable potent antigen presentation and T cell stimulation by endogenous APCs with broad therapeutic potential.

Dissociable rhythmic mechanisms enhance memory for conscious and nonconscious perceptual contents.

Understanding the neural mechanisms of conscious and unconscious experience is a major goal of fundamental and translational neuroscience. Here, we target the early visual cortex with a protocol of noninvasive, high-resolution alternating current stimulation while participants performed a delayed target-probe discrimination task and reveal dissociable mechanisms of mnemonic processing for conscious and unconscious perceptual contents. Entraining ß-rhythms in bilateral visual areas preferentially enhanced short-term memory for seen information, whereas α-entrainment in the same region preferentially enhanced short-term memory for unseen information. The short-term memory improvements were frequency-specific and long-lasting. The results add a mechanistic foundation to existing theories of consciousness, call for revisions to these theories, and contribute to the development of nonpharmacological therapeutics for improving visual cortical processing.