Friday, May 23rd, 2025

Time	Event
9:21a	Meta-analytic evidence for distinct neural correlates of conditioned vs. verbally induced placebo analgesia Placebo analgesia demonstrates that belief and expectation can significantly alter pain, even without active treatment. Placebo analgesia can be induced through verbal suggestion, classical conditioning, or their combination, though the role of conditioned neural responses above and beyond effects of verbal instructions remains unclear. We conducted a systematic meta-analysis of individual participant data from 16 within-participant placebo neuroimaging studies (n = 409), employing univariate and multivariate analyses to identify shared and distinct mechanisms of placebo analgesia induced by suggestions alone versus suggestions combined with conditioning. Both techniques increased activity during pain in the dorsolateral prefrontal and inferior parietal cortices and decreased activation in the insula, putamen, and primary sensory areas. Adding conditioning enhanced engagement of regions associated with context representation and pain modulation (e.g., dorsolateral/dorsomedial prefrontal cortices) and decreases in nociceptive regions (e.g., primary sensory and insular areas). Conditioning also strengthened the association between analgesia and nociceptive activity, as reflected in the Neurologic Pain Signature. Combining conditioning with instructions yielded greater analgesia, mediated by increased ventromedial prefrontal and dorsal caudate activity, alongside decreased sensory-nociceptive and cerebellar activity. These findings suggest the two strategies rely on partially distinct mechanisms, which could be combined to optimize placebo analgesias clinical application. (Comment on this)
12:46p	Diencephalic and white matter knock-on effects in hippocampal amnesia - why they matter Studies of brain-behaviour relationships in hippocampal amnesia largely ignore the presence and explanatory potential of knock-on effects beyond the medial temporal lobes. In a large cohort of patients (n=38) with hippocampal damage due to autoimmune limbic encephalitis, we had reported evidence that extra-hippocampal structural and functional abnormalities in the broader "hippocampal-diencephalic-cingulate network" fully mediated the effects of hippocampal damage on several aspects of episodic memory. However, we had not examined the specific diencephalic nuclei affected or the white matter pathways that would help explain these remote effects. In this study, we used recently developed methods of automated segmentation of diencephalic nuclei, as well as a range of analyses of white matter integrity. As expected, we found atrophy in the anterior thalamic nuclei and in the mammillary bodies, but also in the laterodorsal, pulvinar, and dorsomedial nuclei. The extent of atrophy in some of these nuclei was comparable to, if not larger than that observed for the hippocampal formation, even though none of our patients acute clinical scans disclosed thalamic damage. We also present evidence linking these volumes to patients episodic memory impairment over and above any correlation with hippocampal/subicular subfield volumes. White matter integrity was strongly compromised in the hippocampal-diencephalic-cingulate network, and the volumetric relationship between the hippocampal formation and the mammillary bodies was at least partly mediated by the integrity of the fornix across patients, consistent with the assumption of Wallerian degeneration following focal medial temporal lobe damage. However, evidence for the specialisation of the "hippocampal-diencephalic-cingulate network" in recollection/recall was mixed, and white matter abnormalities extended to regions well beyond this network. Our findings highlight the need to longitudinally examine diencephalic and white matter integrity in cohorts of hippocampal damage with different aetiologies and update neuroanatomical models of this network. (Comment on this)
12:46p	The shape of attention: How cognitive goals sculpt cortical representation of speech. Perception requires more than passive sensing--it involves prioritizing the features most relevant to ongoing cognitive goals, a process guided by selective attention. A central question is whether attention operates by enhancing all features of a selected target, or by optimizing neural encoding around the specific demands of the task--i.e., is selective attention fundamentally anchored around task targets or around task goals? Here, we recorded electroencephalography (EEG) while participants performed two speech tasks--comprehension and detection--on identical auditory stimuli. Task difficulty was manipulated by introducing controlled background noise that increased cognitive demands without reducing speech intelligibility. We developed a novel EEG-based method, the Modulation Response Function (MRF), which captures cortical sensitivity to spectro-temporal features via spectrogram reconstruction. Behaviorally, comprehension performance declined with increased difficulty, with greater reliance on semantic cues, while detection performance remained near ceiling. Neurally, both envelope tracking and MRF magnitude were higher during comprehension, reflecting greater cognitive engagement. Critically, spectro-temporal tuning differed across tasks: formant-related modulations were selectively enhanced during comprehension, whereas pitch-related modulations were emphasized during detection. These findings support a discriminative model of attention, where cortical encoding is flexibly reshaped according to cognitive goals, selectively amplifying the features most relevant for successful task performance. (Comment on this)
12:46p	A two-dimensional space of linguistic representations shared across individuals Our ability to extract meaning from linguistic inputs and package ideas into word sequences is supported by a network of left-hemisphere frontal and temporal brain areas. Despite extensive research, previous attempts to discover differences among these language areas have not revealed clear dissociations or spatial organization. All areas respond similarly during controlled linguistic experiments as well as during naturalistic language comprehension. To search for finer-grained organizational principles of language processing, we applied data-driven decomposition methods to ultra-high-field (7T) fMRI responses from eight participants listening to 200 linguistically diverse sentences. Using a cross-validation procedure that identifies shared structure across individuals, we find that two components successfully generalize across participants, together accounting for about 32% of the explainable variance in brain responses to sentences. The first component corresponds to processing difficulty, and the second--to meaning abstractness; we formally support this interpretation through targeted behavioral experiments and information-theoretic measures. Furthermore, we find that the two components are systematically organized within frontal and temporal language areas, with the meaning-abstractness component more prominent in the temporal regions. These findings reveal an interpretable, low-dimensional, spatially structured representational basis for language processing, and advance our understanding of linguistic representations at a detailed, fine-scale organizational level. (Comment on this)
12:46p	Early Indirect Neurogenesis transitions to late Direct Neurogenesis in mouse cerebral cortex development The cerebral cortex must contain the appropriate numbers of neurons in each layer to acquire its proper functional organization. Accordingly, neurogenesis requires precise regulation along development. Cortical neurons are made either directly by Radial Glia Cells (RGCs) that self- consume, or indirectly from RGCs via Intermediate Progenitor Cells (IPCs) and largely preserving the RGC pool. According to the standing model of cortical development, Direct Neurogenesis predominates at early stages of development, and progressively shifts to Indirect Neurogenesis, which predominates at late stages. However, neurogenesis at early stages should be compatible with RGC amplification, and neurogenesis at late stages needs to involve RGC consumption, which seems in conflict with the standing model. Here we studied the modes of neurogenesis along cortical development using multiple approaches, including birthdating, live imaging and MADM clone labeling. Contrary to the established dogma, our data show that Indirect Neurogenesis clearly predominates at early developmental stages, gradually shifting to Direct Neurogenesis at late stages. These findings challenge the current model of cortical neurogenesis, and prompt a re-evaluation of previous and ongoing work about the genetic and molecular mechanisms regulating this process. (Comment on this)
12:46p	A complex acoustical environment is necessary for maintenance and development in the zebra finch auditory pallium Postnatal experience is critical to auditory development in vertebrates. The zebra finch (Taeniopygia castanotis) provides a valuable model for understanding how complex social-acoustical environments influence development of the neural circuits that support perception of vocal communication signals. We previously showed that zebra finches raised in the rich acoustical environment of a breeding colony (colony-reared, CR) perform twice as well in an operant discrimination task as birds raised with only their families (pair-reared, PR), and we identified deficits in functional properties within the auditory pallium of PR birds that could explain this behavioral difference. Here, using single-unit extracellular recordings from the L3 subdivision of field L and caudomedial nidopallium (NCM) at three developmental timepoints (18-20, 30-35, and 90-110 days post hatch), we tracked how experience affects the emergence of these functional properties. Whereas CR birds showed stable single-unit response properties from fledging to adulthood alongside improvements in population-level encoding, PR birds exhibited progressive deterioration in neural function. Deficits in PR birds began emerging at 18 days for population metrics and by 30 days for single-unit properties, worsening into adulthood. These included altered spike waveforms, firing rates, selectivity, discriminability, coding efficiency, and noise invariance. Notably, these deficits occurred despite PR birds receiving normal exposure to the song of a male tutor, suggesting that learning to sing is robust enough to compensate for impaired auditory processing. Our findings demonstrate that a complex acoustical environment is necessary for both maintenance and development of the cortical-level auditory circuits that decode conspecific vocalizations. (Comment on this)
12:46p	GABAergic signaling by VIP interneurons gates running-dependent visual recovery in the adult brain Experience-dependent plasticity in the adult visual cortex is enhanced by locomotion, a process mediated by vasoactive intestinal peptide (VIP)-expressing interneurons. While VIP interneurons are known to signal through both Gamma-aminobutyric acid (GABA) and VIP peptide, the specific contributions of these pathways during different forms of plasticity remain unclear. Monocular deprivation (MD) in adult mice alters cortical responses, though more slowly and differently than during a critical period in early life. Here, we used two-photon calcium imaging in awake adult mice to dissect the roles of VIP and GABA release from VIP interneurons during adult MD and subsequent binocular recovery. We found comparable level of ocular dominance shifts after MD in mice deficient in either peptidergic or GABA signaling, but disrupting GABA signaling impaired recovery of binocular responses. We also showed that running preferentially enhances contralateral eye responses in binocular primary visual cortex. However, this eye-specific modulation of visual responses by running was altered during recovery from MD and was dependent on VIP signaling pathways. These findings highlight the GABA-mediated inhibition by VIP interneurons as a critical pathway for promoting visual restoration in the adult brain. Significance StatementUsing longitudinal two-photon imaging in awake adult mice with genetically altered signaling path-ways in VIP interneurons, we demonstrate that GABAergic, but not peptidergic, signaling from VIP interneurons is essential for the recovery of binocular vision following monocular deprivation. We further reveal that locomotion modulates cortical responses in an eye-specific manner, a property dynamically reshaped by plasticity and dependent on VIP interneuron function. These findings identify a discrete inhibitory circuit element that links behavioral state to sensory recovery and highlight GABA release from VIP cells as a potential therapeutic target for restoring visual function in adulthood. (Comment on this)
6:34p	Prelimbic cortical excitatory overdrive and inhibitory underdrive accompany environmental suppression of food seeking Cues associated with food, such as fast-food advertising, can provoke food cravings and may lead to unhealthy overeating. Environmental enrichment (EE) that enhances cognitive and physical stimulation can reduce cue-evoked sucrose seeking in mice and recruitment of sucrose cue-reactive neurons or neuronal ensembles in the prelimbic cortex (PL), which regulates appetitive behaviors. Hence, EE provides us with a behavioral model and neuronal targets to identify anti-craving relevant mechanisms. Here, we investigated in the PL how EE modulated neuronal excitability and activity patterns in cue-reactive neuronal populations. Chemogenetic inhibition of cue-reactive neurons in PL blocked cue-evoked sucrose seeking, thereby confirming the function of these neurons in sucrose cue memory. EE boosted the baseline excitability of originally, or before EE exposure, cue-reactive, excitatory pyramidal cells in PL. Furthermore, their sucrose cue-specificity was lost - resulting in their persistent activation and non-cue selective activation or excitatory overdrive. Furthermore, EE reduced recruitment of cue-reactive, inhibitory interneurons reflecting inhibitory underdrive. Taken together, impaired neuronal food cue processing due to simultaneous prefrontal cortical excitatory overdrive and inhibitory underdrive likely underlies EEs anti-craving action, thereby serving as potential neurophysiological targets to develop novel medications that help control food cravings. (Comment on this)
6:34p	Tau Oligomerization Drives Neurodegeneration via Nuclear Membrane Invagination and Lamin B Receptor Binding in Alzheimer's disease The microtubule-associated protein tau aggregates into oligomeric complexes that highly correlate with Alzheimers disease (AD) progression. Increasing evidence suggests that nuclear membrane disruption occurs in AD and related tauopathies, but whether this is a cause or consequence of neurodegeneration remains unclear. Using the optogenetically inducible 4R1N Tau::mCherry::Cry2Olig (optoTau) system in iPSC-derived neurons, we demonstrate that tau oligomerization triggers nuclear rupture and nuclear membrane invagination. Pathological tau accumulates at sites of invagination, inducing structural abnormalities in the nuclear envelope and piercing into the nuclear space. These findings were confirmed in the humanized P301S tau (PS19) transgenic mouse model, where nuclear envelope disruption appeared as an early-onset event preceding neurodegeneration. Further validation in post-mortem AD brain tissues revealed nuclear lamina disruption correlating with pathological tau emergence in early-stage patients. Notably, electron microscopy shows that tau-induced nuclear invagination triggers global chromatin reorganization, potentially driving aberrant gene expression and protein translation associated with AD. These findings suggest that nuclear membrane disruption is an early and possibly causative event in tau-mediated neurodegeneration, establishing a mechanistic link between tau oligomerization and nuclear stress. Further investigation into nuclear destabilization could inform clinical strategies for mitigating AD pathogenesis. (Comment on this)
6:34p	The Drosophila wing is a high-throughput and versatile screening tool for Tau-mediated disease mechanisms and drug discovery. Tau protein contributes to microtubule stability, which is disrupted in Alzheimers disease and other Tauopathies. In these diseases, Tau molecules become hyperphosphorylated, misfolded and aggregated, propagating pathology across the brain. Studies dissecting disease mechanisms or screening disease-modifying therapies rely on animal models that unveil pathogenic events in vivo but also take several weeks or months to complete. Here we describe a versatile experimental paradigm that yields results in days and yet offers all the advantages of a genetically tractable in vivo system: the Drosophila wing disc. Mimicking neurotoxicity, human Tau expression causes cell death in the wing disc leading to quantifiable phenotypes in the adult wing. The neuroprotective peptide NAP ameliorates Tau toxicity in this system, validating it as a cost-effective drug screening tool. Phenocopying adult neurons, Tau toxicity in the wing disc is exacerbated by simulating hyper-phosphorylation and prevented by suppressing aggregation. Additionally, we show that the wing disc can dissect disease mechanisms that underpin clinically relevant Tau variants. Thus, the wing disc offers an in vivo experimental paradigm for fast and efficient exploration of disease mechanism and screening. (Comment on this)
9:19p	Common pitfalls during model specification in psychophysiological interaction analysis Psychophysiological interaction (PPI) analysis is a widely used regression method in functional neuroimaging for capturing task-dependent changes in connectivity from a seed region. The present work identifies, and provides corrections for, common methodological pitfalls in PPI analysis that compromise model validity. Firstly, if the seed time series is extracted with prewhitening, the temporal structure of the signal is altered and subsequent deconvolution of prewhitened data becomes suboptimal. Furthermore, prewhitening again during model fitting results in double prewhitening of the seed regressor. Secondly, a failure to mean-centre the task regressor when calculating the interaction term can also lead to model misspecification and potentially spurious inferences. By using simulations and empirical language fMRI data from the Australian Epilepsy Project, we demonstrate the adverse effects of these issues, and how they are resolved when corrected. A systematic review of current practices revealed widespread model misspecification, and underreporting of methods, in published PPI studies. We provide clearer reporting guidelines, and advocate for appropriate methods for handling of prewhitening and mean-centring to ensure the validity of PPI analyses. (Comment on this)
9:19p	Identification and optimization of trans-species reactive TfR1-binding VHH as tools for drug delivery across the blood brain barrier The treatment of brain diseases is hindered by the blood-brain barrier (BBB), a major obstacle for efficient brain exposure of therapeutic agents, in particular biotherapeutics. Different strategies are currently evaluated to enhance drug delivery across the BBB, among which the development of vector molecules that target specific receptors expressed by BBB endothelial cells and involved in receptor-mediated transcytosis (RMT). In this process, therapeutic cargos conjugated to optimized molecular vectors can undergo trans-endothelial transport and delivery in the brain parenchyma. The transferrin receptor 1 (TfR1) is enriched in brain endothelial cells and is one of the most studied receptors for drug delivery to the central nervous system (CNS). Several antibodies and molecules derived thereof that target TfR1 have been developed, but few display trans-species reactivity, hindering the transition from preclinical to clinical development. In the present study, we selected and characterized cross-species reactive Variable domain of Heavy chain only antibody from camelids (VHH), and in particular C5 and B8, that bind rodent, rhesus monkey and human TfR1. When fused to a human Immunoglobulin 1 (IgG1) Fc region, C5 or B8 monomers or homodimers were taken up by engineered CHO cells expressing the rodent, human and rhesus monkey TfR1, and by rodent or human brain endothelial cells. Key human TfR1 amino-acid residues of the C5 and B8 epitopes were identified based on the generation of human TfR1 mutants. Assessment of their functional binding revealed an original binding region at the interface of the TfR1 dimer. Following systemic injection in mice of VHH-Fc fusions displaying different properties in terms of affinity and avidity toward TfR1, we demonstrated improved brain uptake compared to control molecules encompassing an irrelevant VHH. Brain delivery efficiency of the parental and optimized VHHTfR1 was further demonstrated using Neurotensin (NT)-induced hypothermia (HT) as a read-out in wild-type mice and in B-hTfR transgenic mice expressing the human TfR1 ectodomain. We established in vitro-in vivo correlations between the human TfR1 binding properties determined by surface plasmon resonance (SPR) of VHH-NT affinity variants, and their potential to induce HT in B-hTfR mice. We identified key human TfR1 binding parameters leading to efficient BBB transcytosis i.e.: a rapid dissociation rate and intermediate affinity. Some of the engineered C5 and B8 variants presented promising cross-species reactivity towards the murine, but also rhesus monkey TfR1. We also generated variants with very similar human-rhesus monkey TfR1 binding properties and optimal affinities for TfR1-dependant transcytosis. These VHHs could be further developed as molecular shuttles for the transport of imaging or therapeutic agents, including biomolecules, across the rodent, non-human primate and human BBB, allowing straightforward preclinical to clinical translation. (Comment on this)

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