Redundant, weakly connected prefrontal hemispheres balance precision and capacity in spatial working memory.

Joao Barbosa
Institut de Neuromodulation and Neurospin, Paris, France

How the prefrontal hemispheres coordinate to adapt to spatial working memory (WM) demands remains an open question. Recently, two models have been proposed: A specialized model, where each hemisphere governs contralateral behavior, and a redundant model, where both hemispheres equally guide behavior in the full visual space. To explore these alternatives, we analyzed simultaneous bilateral prefrontal cortex recordings from three macaque monkeys performing a visuo-spatial WM task. Each hemisphere represented targets across the full visual field and equally predicted behavioral imprecisions. Furthermore, memory errors were weakly correlated between hemispheres, suggesting that redundant, weakly coupled prefrontal hemispheres support spatial WM. Attractor model simulations showed that the hemispheric redundancy improved precision in simple tasks, whereas weak inter-hemispheric coupling allowed for specialized hemispheres in complex tasks. This interhemispheric architecture reconciles previous findings thought to support distinct models into a unified architecture, providing a versatile interhemispheric architecture that adapts to varying cognitive demands.

Experience-Driven Regulation of Neuronal Gene Programs.

Ángel Barco
Instituto de Neurociencias, Universidad Miguel Hernández, Alicante, Spain

Transcriptional and epigenetic mechanisms provide a molecular framework through which environmental influences and life experiences exert lasting effects on the brain. In this talk, we will examine two examples that illustrate the interplay between genomic regulation and neuronal plasticity. First, we will discuss how environmental enrichment and deprivation shape cognitive function through specific gene expression programs. Second, we will explore the transcriptional signatures associated with memory encoding and recall in the hippocampus.

Epigenetic and cellular regulation of cortex expansion and folding .

Víctor Borrell
Institute of Neuroscience, CSIC-UMH. San Juan de Alicante, Spain

One of the most prominent features of the human brain is the fabulous size of the cerebral cortex and its intricate folding, both of which emerge during development. Over the last few years we have shown that cortex folding depends on high rates of neurogenesis and abundance of a particular type of basal progenitor, basal Radial Glia Cells (bRGCs). bRGCs profusely populate the Outer Subventricular Zone (OSVZ), and modify the organization of the radial fiber scaffold used by migrating neurons, hence driving cortex folding. The formation of the OSVZ along development, and of the highly stereotyped patterns of cortex folding, are linked to spatial-temporal patterns of progenitor cell proliferation, which are defined by a spatial-temporal protomap of gene expression within germinal layers. I will present recent findings from my laboratory revealing novel cellular and genetic mechanisms that regulate cortex expansion and folding. We have uncovered the contribution of epigenetic regulation to the establishment of the cortex folding protomap, modulating the expression levels of key transcription factors that control progenitor cell proliferation and cortex folding. At the single cell level, we have identified an unprecedented diversity of cortical progenitor cell classes in the ferret and human embryonic cortex. These are differentially enriched in gyrus versus sulcus regions and establish parallel cell lineages, not observed in mouse. Neurons born in gyrus versus sulcus are also transcriptomically distinct, especially related to human cortical malformation genes. Our findings show that genetic and epigenetic mechanisms in gyrencephalic species diversify cortical progenitor cell types and implement parallel cell linages, driving the expansion of neurogenesis and patterning cerebral cortex folds.

Investigating the function of GABAB receptors in human cortex, in comparison to rodents.

Sam A. Booker
Simons Initiative for the Developing Brain ESAT; Centre for Discovery Brain Sciences University of Edinburgh, Edinburgh, UK

How circuits of neurons balance input to output transformations relies on precisely timed inhibitory signaling. Fast GABAA receptors regulate signal propagation on short timescales, meanwhile GABAB receptors operate over longer, behaviorally relevant timescales to control excitatory and inhibitory neurotransmission. Despite much being known of the role of GABAB receptors in rodent circuit motifs, little is known of how this crucial receptor regulates neuron and circuit function in the living human cortex. This talk will discuss our recent work to define the functional role of GABABRs in human neocortex and how this relates to neuropathology, such as seizure disorders.

Cell vibes: how collicular cell-types contribute to guiding mice innate behaviors.

Anna Chrzanowska(1,2,6) Bram Nuttin(1,2), Arnau Sans-Dublanc(1,2), Micheline Grillet(1,3,4,5), Gabriel Montaldo(1,4), Alan Urban(1,2,3,5), Karl Farrow(1,2,3)
1. Neuro-Electronics Research Flanders. Leuven, Belgium
2. Department of Biology, Leuven Brain Institute, KU Leuven. Leuven, Belgium
3. VIB. Leuven, Belgium
4. Imec. Leuven, Belgium
5. Department of Neurosciences, Leuven Brain Institute, KU Leuven. Leuven, Belgium
6. Paris Brain Institute (ICM). Paris, France

Neuronal cell types are organized into brain-wide circuits that guide behavior. Using the mouse superior colliculus as a model, we first demonstrated how optogenetic activation of a set of genetically targetable collicular cell types each leads to various defensive behaviors, engaging distinct but overlapping brain-wide dynamics captured with functional ultrasound imaging (fUSI). Each cell type was functionally connected to at least 82 brain areas, including some not previously considered part of these networks. Since optogenetic activation differs from natural stimulus-driven activity, we next examined how specific pathways enable behavioral responses to ecologically relevant stimuli. We focused on wide- and narrow-field neurons and their responses to predator-like visual stimuli (e.g., sweeping and looming discs). Behavioral tests with chemogenetic inhibition of these populations showed that disrupting their activity impaired appropriate reactions to potential threats. Our findings highlight the role of neuronal cell types as fundamental units of brain function and raise questions about how their coordinated activity shapes behavior.

Who and what: How neuroimaging and AI inform the treatment of Major Depression.

W. Edward Craighead
Emory University. Atlanta, USA

The presentation will begin with a brief description of Major Depressive Disorder (MDD) including its prevalence and consequences for individuals and society. This will be followed by a description of the largest (344 MDD patients), single-site treatment study (PReDICT) of clinical and neuroimaging based differential moderators and mechanisms of remission of MDD when randomly assigned to treatments including CBT or SSRI (escitalopram) or SNRI (duloxetine). Knowing which patient will remit to which treatment answers the most pressing question regarding a personalized medicine approach to treating MDD; unfortunately, the answer largely remains trial and error. A pattern of neural connectivity at baseline differentially predicted which patients remitted with CBT and the antidepressants (ADT) whose prediction did not differ from each other. CBT and ADT had shared and unique mechanisms of neural connectivity changes associated with remission; each will be discussed in terms of the hypothesized theories of decreased MDD. The clinical implications of each of the preceding findings will be presented, including the finding that not all MDD patients respond to very high-quality CBT nor to appropriately administered ADT. Finally, data will be presented to demonstrate how machine learning and AI can be employed to enhance the preceding moderators and mechanisms of change. The discussion will include information on how matching treatments via moderators enhances remission rates. It will be suggested that adolescent prevention programs may be working by adaptive development of neural functioning rendering the ”at risk” adolescent more resistant to developing MDD. The ultimate objective of this research program is the development and dentification of a psychometrically sound self-report instrument that is both related to neural connectivity moderators of change and can also be used in clinical practice in any location to identify which patients will respond to CBT and which will respond to ADT.

Capacity Beyond Limits and Sex-Specific Regulation.

Elvira De Leonibus
Institute of Biochemistry and Cellular Biology (IBBC), National Research Council of Italy, (CNR), Monterotondo (Rome), Italy

Memory capacity—the number of items we can retain over a short time interval—is constrained by both temporal and informational load, and its regulation depends on dynamic interactions between cortical and subcortical circuits. Using behavioral, molecular, and circuit-level approaches in mice, we dissect the neural substrates underlying incidental memory capacity. In this presentation, we will address how the brain encodes high versus low memory load during incidental encoding, whether and how memory capacity can be expanded beyond its physiological limit, and how many of the items encoded in short-term memory (STM) are ultimately consolidated into long-term memory (LTM). The latter is made possible by the discovery that male and female mice engage distinct cortico-subcortical circuits under high memory load, with dorsal hippocampus activation in males and ventral midline thalamus recruitment in females. As memory capacity underlies fluid intelligence and is often compromised in neuropsychiatric and neurodegenerative conditions, these findings provide a foundation for developing targeted cognitive-enhancing treatments.

My place vs. your place - what can we say about the hippocampus and territoriality?

Dori Derdikman
Israel Institute of Technology - Technion, Haifa, Israel

Territoriality involves an understanding of the cognitive map, as animals must distinguish between areas they consider their own and those they do not. Accordingly, we expect the hippocampus to play a role in representing territoriality. We recorded neural activity from the dentate gyrus of a mouse in a resident-intruder paradigm, introducing an intruder into a resident mouse's territory over several consecutive days. We found that, after repeated exposures, dentate activity increased by an order of magnitude, suggesting a strong plasticity event that may underlie the learning of aggressive behavior by the resident. This provides an example of how a significant life event—such as the first appearance of an intruder—can drive substantial plastic changes in the hippocampus.

Could symptoms of Compulsive Sexual Behavior Disorder be cured? Insights from neuroimaging studies applied to the clinical trial intervention.

Małgorzata Draps
Clinical Neuroscience Laboratory, Institute of Psychology, Polish Academy of Sciences. Warsaw, Poland

Introduction: In 2019 Compulsive Sexual Behavior Disorder (CSBD) has been included into the International Classification of Diseases 11th revision (WHO, 2019), however there is still ongoing discussion on theory that explains the mechanisms underlying this disorder. In the context of treatment an important research aim seems to be to identify key processes maintaining the symptoms and then to apply targeted therapies. Recent studies show beneficial effects of pharmacological interventions with SSRIs or naltrexone for individuals with CSBD.
Methods: Studies using comprehensive measurement methods, including neuroimaging tools shows similarity between CSBD and addictions, thus pointing to the importance of sensitization processes. In this context a functional magnetic resonance imaging (fMRI) study examined brain reactivity towards erotic and monetary stimuli among 73 heterosexual CSBD male patients who were admitted for a 20-week double-blind and placebo-controlled randomized clinical trial were carried out.
Results: Clinical trial results from patients using paroxetine (20 mg/day) or naltrexone (50 mg/day) or placebo shows a significant effect of time during treatment on: severity of CSBD symptoms measured by self-report questionnaires, frequency of pornography consumption and sexual craving measured using ecological momentary assessment tool across all conditions. On neuronal level we analyze responses to erotic and monetary stimuli in the brain regions identified in previous research as differentiating males with CSBD from healthy controls. Results showed that in paroxetine and naltrexone groups a decrease of BOLD response in the brain regions which were initially hyperactive for erotic stimuli, while in the placebo group the increase of BOLD response to the monetary stimuli was pronounced.
Conclusions: Based on analyses of neuronal data, the importance of hyperactivity to erotic stimuli, understood as sensitization, has been shown. Moreover, the presented data show that these processes can be reversible as an effective pharmacological strategy for treating symptoms of CSBD.

Structural and Functional Specialization in Thalamic Reticular Nucleus Subnetworks: Implications for Sensory Processing and Salience Detection.

Zhanyan Fu, Nolan D. Hartley, Alexandra Krol, Yinqing Li, Violeta G. Lopez-Huerta, Xian Adiconis, Soonwook Choi, Kirsten Levandowski, Sean K. Simmons, Jiawen Tian, Sihak Lee, Ryan Kast, Joshua Z. Levin, Guoping Feng
1. Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, USA
2. McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, USA

The thalamic reticular nucleus (TRN), the primary source of thalamic inhibition, plays a crucial role in regulating sensation, action, and cognition. Despite its well-established function in modulating thalamocortical interactions, the organizational principles underlying its diverse functions remain incompletely understood. Here, we present an integrative framework for understanding the structural and functional specialization of TRN subnetworks and their implications for sensory processing and salience detection. Using a combination of single-cell transcriptomics, electrophysiology, and whole-brain circuit mapping, we identify two molecularly distinct TRN subpopulations that exhibit core- or shell-like anatomical organization and possess distinct electrophysiological properties. The TRN subpopulations form functionally segregated subnetworks by making differential connections with first-order (FO) and higher-order (HO) thalamic nuclei. We thus develop Cre mouse lines that selectively label the two genetically segregated populations of TRN. Comprehensive mapping of whole-brain afferent circuit connectivity further reveals different biases in cortical and thalamic inputs to each subnetwork. Functional interrogation via inhibitory chemogenetic perturbation demonstrates that disruption of the TRN subnetworks leads to distinct EEG and sensory deficits reminiscent of phenotypes commonly observed in neuropsychiatric disorders, suggesting their potential involvement in disease pathophysiology. Together, our findings provide a multi-scale analysis of TRN subnetwork specialization, linking molecularly indentity to the functional organization of thalamocortical circuits while highlighting the relevance of TRN dysfunction in neurodevelopmental and neuropsychiatric disorders.

Investigating Evolutionary Expansion of the Human Cerebellum Using Cross-Species Cerebellar Organoids.

Luca Guglielmi, Daniel Lloyd-Davies-Sánchez, José González Martínez, Madeline A. Lancaster
MRC LAboratory of Molecular Biology (LMB), Cambridge, UK

The human cerebellum, which contains approximately 80–90% of the neurons in the adult brain, plays a central role in motor control and cognitive functions. During human evolution, cerebellar expansion significantly contributed to the unique size of the human brain and the emergence of complex behaviours, such as tool-making and language. Compared to other species, the human cerebellum is not only substantially larger but also occupies a greater proportion of total brain volume, underscoring its importance in shaping human-specific traits. To investigate the evolutionary mechanisms underlying differences in cerebellar size, we developed a cross-species cerebellar organoid model (CeOs). By employing minimal and conserved cerebellar determinants, we override the default telencephalic fate in unguided cerebral organoids and stabilize cerebellar identities, reproducing neuronal diversity alongside species-specific differences in cerebellar size. Furthermore, when cultured at the air-liquid interface, CeOs can be maintained for several months, allowing the development of mature cerebellar cell types and morphologies, including the formation of Purkinje cells with polarized dendritic arbors. Using this model, we interrogate cerebellar development in human and mouse CeOs and present preliminary data pointing towards species-specific differences in morphogen signalling as a contributing factor to cerebellar size variation across species.

Palmitoylation of the glucocerebrosidase receptor LIMP-2: therapeutic target for Parkinson disease?

Gary Ho
Harvard Medical School, Brigham and Women’s Hospital, Boston, USA

Disruption of vesicle and protein trafficking by the neuronal protein alpha-synuclein (αS) is a key pathophysiological mechanism in Parkinson disease (PD). In contrast, palmitoylation, lipid modification of proteins at cysteines, has an essential role in trafficking in diverse cellular contexts, including in transport of lysosomal enzymes. We reasoned that enhancing palmitoylation may be a therapeutic strategy. Accordingly, we previously reported that increasing palmitoylation by inhibiting the depalmitoylase APT1 improved αS homeostasis and motor phenotypes in PD/DLB model mice, presumably by correcting vesicle trafficking. However, since the substrate(s) of APT1 and its selectivity are unknown, the pathway(s) underlying this improvement remained to be determined. We conducted an unbiased screen of APT1 substrates to identify specific proteins that could mediate these actions. Interestingly, we found LIMP-2 (lysosomal integral membrane protein 2) as a top “hit”. This was a remarkable finding to us because LIMP-2 is the trafficking receptor for beta-glucocerebrosidase (GCase), encoded by the GBA1 gene, the commonest genetic risk factor for PD. GCase is a lysosomal enzyme which hydrolyzes glucosylceramides into free ceramides and glucose. While homozygous mutations in GBA1 cause Gaucher’s disease, heterozygous mutations significantly increase the risk of PD. This is likely due to GBA1 mutations causing misfolding and mis-targeting of GCase and subsequent lysosomal dysfunction. Since LIMP-2 binds and transports GCase to the lysosome, and because increased palmitoylation improves PD phenotypes, we investigated the role of LIMP-2 palmitoylation in regulating GCase function and αS homeostasis in the context of PD. LIMP-2 palmitoylation had not previously been reported. Thus we confirmed that LIMP-2 is palmitoylated and identified the modified sites at cysteines 4, 5, and 458. Expression of LIMP-2-wt, but not the palmitoylation deficient mutant, restored GCase activity and αS homeostasis as measured by the level of physiological tetramers in GBA1 mutant patient-derived neurons. This finding links for the first time the fundamental cell biological process of palmitoylation to the central role of lysosomal function in PD and presents a potential novel therapeutic strategy.

Jacob: a synapto-nuclear messenger protein linking NMDAR activation to CREB- dependent gene expression.

Anna Karpova
Leibniz Institute for Neurobiology, Magdeburg, Germany

Pyramidal neurons of the hippocampus possess a highly complex dendritic arbor, decorated with a vast array of spine synapses that receive excitatory input. These synaptic signals not only exert local effects but are also transmitted to the nucleus of the postsynaptic neuron. Nuclear Ca²⁺ waves, triggered by NMDAR and L-type voltage-gated Ca²⁺ channels, along with synapse-to-nucleus protein transport, play crucial roles in regulating plasticity-related gene expression. Jacob is a protein that translocates a signalosome from N-methyl-D-aspartate receptors (NMDAR) to the nucleus, where it docks the signalosome to the transcription factor CREB. Intriguingly, its residence time in the nucleoplasm closely correlates with the pattern of nuclear Ca²⁺ transients ([Ca²⁺]ₙ) induced by neuronal activity, resulting in plasticity-dependent gene expression. In my talk, I will summarise the key findings regarding the “Jakobsweg” to the nucleus and the role of the protein messenger in plasticity and neurodegeneration.

Cortical and Hippocampal Circuits for Discriminating Positive Emotions and Social Learning in Mice.

Ewelina Knapska
Laboratory of Neurobiology of Emotions, Nencki-EMBL Partnership for Neural Plasticity and Brain Disorders–BRAINCITY, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland

How do social networks shape learning about rewards, and what neural circuits support this process? Despite its critical role in survival, the neural basis of socially transmitted reward learning remains poorly understood.
To investigate this, we used Eco-HAB, an automated system for tracking group behavior in mice. We found that scent cues from rewarded individuals guide conspecifics’ search behavior, with social rank modulating this effect. Prelimbic cortex plasticity is crucial for both maintaining social network stability and utilizing socially acquired reward information, while acute inhibition of the prelimbic cortex selectively disrupts responses to social cues, revealing distinct cortical contributions to social learning.
Beyond reward-seeking, animals must also use socially transmitted information to navigate their environment. Can rodents learn food locations from their peers? To address this, we developed the Socially Transmitted Place Preference (STPP) paradigm, demonstrating that mice and rats acquire food location knowledge through brief social interactions. Single-photon imaging reveals that hippocampal cells encoding these locations are reactivated during social interactions, suggesting a neural mechanism for the storage and retrieval of socially acquired spatial information.
Together, our findings suggest that distinct cortical and hippocampal circuits support different aspects of social learning: prefrontal circuits regulate social influence on decision-making, while hippocampal activity encodes and replays socially transmitted spatial knowledge.

Spatiotemporal methods to chart the cell states of brain development.

Gioele La Manno
Laboratory of Brain Development and Biological Data Science, Swiss Federal Technology Institute of Lausanne, Lausanne, Switzerland

The developing brain is like a complex chess game with millions of pieces - each belonging to one of hundreds of distinct cell types. While the single-cell revolution has revealed the foundation of this “game,” becoming true “Masters” is still ahead. With spatial transcriptomics, we aim to interpret each snapshot of cells in the tissue, distinguish normal from pathological states, and predict “future moves”. Here, we present two complementary approaches toward this dream. On the temporal front, VeloCycle, an advanced RNA velocity framework, tracks cell cycle-driven expression dynamics in real time to predict cellular trajectories. On the spatial front, PointillHist, a GNN-based mapper, reveals the organization of hundreds of distinct cell states across the embryonic brain. Applied to study folate deficiency, these tools uncover the differential susceptibility of radial-glial populations and a “catastrophic flipping” of patterned territories.

All IEGs Are not Created Equal – Diverse Roles of Activity-dependent Transcription Factors in Neural Circuit Plasticity.

Yingxi Lin
Department of Psychiatry, Psychiatry Neuroscience Research Division, UT Southwestern Medical Center. Dallas, US & Department of Neuroscience, O’Donnell Brain Institute, Dallas, US

Our research investigates the molecular and circuit mechanisms underlying neurodevelopment, memory formation, and neuropsychiatric disorders. Using a multidisciplinary approach that integrates genomic, molecular, synaptic, circuit, and behavioral analyses, we seek to understand how sensory and behavioral experiences reshape neural circuits to enable learning and memory. We focus on the mechanisms by which immediate-early genes (IEGs) direct distinct activity-dependent transcription pathways to regulate circuit plasticity and learned behavioral adaptation. This talk will highlight the diverse roles of individual IEGs in orchestrating circuit-specific transcriptional programs, shedding light on how activity-dependent transcription programs contribute to experience-dependent circuit reconfiguration across behavioral contexts.

The role of concept neurons in the human medial temporal lobe for working and long-term memory.

Florian Mormann
University of Bonn, Bonn, Germany

The human medial temporal lobe contains neurons that respond selectively to the semantic contents of a presented stimulus. These "concept cells" may respond to very different pictures of a given person and even to their written and spoken name. Their response latency is far longer than necessary for object recognition, they follow subjective, conscious perception, and they are found in brain regions that are crucial for declarative memory formation. It has thus been hypothesized that they may represent the semantic " building blocks " of episodic memories. In this talk I will present data from single unit recordings in the hippocampus, entorhinal cortex, parahippocampal cortex, amygdala, and piriform cortex during paradigms involving working and long- term memory in order to characterize the role of concept cells in these cognitive functions.
Our research investigates the molecular and circuit mechanisms underlying neurodevelopment, memory formation, and neuropsychiatric disorders. Using a multidisciplinary approach that integrates genomic, molecular, synaptic, circuit, and behavioral analyses, we seek to understand how sensory and behavioral experiences reshape neural circuits to enable learning and memory. We focus on the mechanisms by which immediate-early genes (IEGs) direct distinct activity-dependent transcription pathways to regulate circuit plasticity and learned behavioral adaptation. This talk will highlight the diverse roles of individual IEGs in orchestrating circuit-specific transcriptional programs, shedding light on how activity-dependent transcription programs contribute to experience-dependent circuit reconfiguration across behavioral contexts.

Dopaminergic modulation of GABAergic synaptic plasticity in mouse hippocampus.

Jerzy W. Mozrzymas(1), Patrycja Brzdąk(1)* & Katarzyna Lebida(1), Patrycja Droździel(1), Emilia Stefańczyk(1,2), Aleksandra Leszczyńska(1)
1. Dept. Biophysics and Neuroscience, Wrocław Medical University, Poland
2. Dept. Mol. Physiology and Neuroscience, University of Wrocław, Poland

Dopamine is a major modulator of key brain functions such as memory and learning, and so far studies into underlying mechanisms have been largely focused on glutamatergic synapses and their plasticity. Little is known about the dopaminergic modulation of inhibitory plasticity at synapses formed by distinct GABAergic interneurons innervating different cells. Herein, we studied the role of D1-type dopamine receptors (D1Rs) in inhibitory plasticity at synaptic connections between interneurons (INs) and pyramidal cells (PCs), and also between INs in the CA1 region. Activation/blockade (with SKF/SCH) of D1Rs increased/reduced the mIPSCs amplitude (measured from PCs), while the decay kinetics was prolonged for SKF, indicating a postsynaptic mechanism. We also checked the D1Rs impact on heterosynaptic NMDA-induced inhibitory long-term potentiation (iLTP) measured at PCs. Blockade of D1Rs converted iLTP into inhibitory long-term depression (iLTD), while D1Rs activation slightly diminished the extent of iLTP. NMDA-induced iLTP in synapses formed by parvalbumin- (PV) positive INs on PCs was reduced to zero by SKF, while SCH converted iLTP to iLTD. Interestingly, both SKF and SCH reversed NMDA-evoked iLTP in the somatostatin- (SST) positive INs to iLTD, while these compounds were ineffective on baseline activity, and these effects were mirrored by changes in gephyrin clusters. Thus, the impact of D1Rs on inhibitory plasticity observed at the SST INs and PCs showed differences with respect to baseline activity, NMDA-induced plasticity, and the kinetics of synaptic currents. Altogether, we show that D1Rs modulate inhibitory long-term plasticity in a manner dependent on the presynaptic and target neurons.
Supported by the Polish National Science Center (Narodowe Centrum Nauki, NCN) grant 2021/43/B/NZ4/01675 and partially supported by NCN grant SONATINA 2023/48/C/NZ4/00072 and NCN grant MINIATURA 2023/07/X/NZ4/00687

Space, Time and Others in The Hippocampus & The Naming of Non-Human Primates.

David Omer
The Hebrew University Of Jerusalem, Jerusalem, Israel

I will first discuss our recent findings revealing the hippocampus’s critical role in social cognition. By examining dorsal CA1 activity in mammals, we identified explicit neuronal representations of others’ locations (“social place cells”) and integrated space-time codes (“social time cells”) for both self and others. These discoveries highlight how the hippocampus underpins the ability of social animals to synchronize behavior in space and time, essential for survival and reproduction
In the second part, I will present our recent work on non-human primates. Using machine learning to analyze spontaneous vocal interactions between marmoset monkeys (Callithrix jacchus), we discovered, for the first time, that these primates vocally label their conspecifics—a sophisticated cognitive function previously attributed only to humans and dolphins. These findings challenge long-held views of language evolution in humans and offer important perspectives on the evolutionary origins of language and underscore the need to elucidate the underlying neural basis of this ability.

Beyond dopamine: VTA to VP GABA signaling in reward valuation.

Marina Picciotto
Yale School of Medicine, New Haven, USA

Dopamine (DA) signaling from the ventral tegmental area (VTA) plays critical roles in reward-related behaviors, but less is known about the functions of VTA GABA projection neurons. We have used a genetically-encoded calcium sensor in vivo, to evaluate the firing pattern of VTA-to-ventral pallidum (VP) GABA neurons during performance of reward-relevant tasks along with chemogenetic and optogenetic stimulation to evaluate the effects of pathway stimulation on VP dynamics and tasks relevant to reward value. We found that activity of VTA-to-VP-projecting GABA neurons correlated consistently with size and palatability of reward and did not change following cue-learning, providing a direct and unvarying measure of reward value. Response of these neurons varied with satiety, suggesting that this pathway provides information about current reward value. Stimulation of this GABA projection increased activity of a subset of VP neurons that are active while mice seek reward, improved performance in cue-reward tasks and altered strategy in a probabilistic reward task. We conclude that this VTA GABA projection provides information about reward value directly to the VP that is distinct from the prediction error signal carried by VTA dopamine neurons. These data show that VTA GABA neurons maintain a stable representation of reward value that does not shift with habituation or learning and that activity of this pathway is critical for making appropriate choices for differentially rewarded outcomes.

The role of NEUROG2 T149 phosphorylation site in the developing human neocortex.

Julien Pigeon(1), Corentine Marie(1), Natasha Danda(1), Tamina Dietl(4), Ludovico Rizzuti(4), Clarisse Brunet Avalos(2), Miguel Silva(3), Diogo S. Castro(3), Alexandre D. Baffet(2), Carlos Parras(1), Boyan Bonev(4), Bassem A. Hassan(1)
1. Paris Brain Institute – Institut du Cerveau (ICM) / CNRS UMR 7225 / INSERM U 1127 / Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France
2. Institut Curie, PSL Research University, CNRS UMR144, Paris, France
3. Instituto de Investigação e Inovação em Saúde, IBMC Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
4. Helmholtz Pioneer Campus, Helmholtz Center Munich, Neuherberg, Germany

Neocortical expansion throughout evolution has been responsible for higher-order cognitive abilities and relies on the increased proliferative capacities of cortical progenitors to increase neuronal production. Therefore, in gyrencephalic species such as humans and primates, where the neurogenic period is protracted, the regulation of the balance between progenitor maintenance and differentiation is of key importance for the right neuronal production. The control of this balance in the neocortex is mediated by feedback regulation between Notch signaling and the proneural transcription factor Neurogenin2 (NEUROG2). As the expression of NEUROG2 alone is sufficient to induce neurogenesis in the neocortex, its regulation at the gene level has been extensively studied in mice. However, recent findings highlight that regulation at the protein level through post-translational modifications can profoundly influence protein activity and stability. Indeed, the modulation of the conserved NEUROG2 T149 phosphorylation site in the developing mouse neocortex results in an altered pool of progenitors and number of neurons in the deep and upper layers. Nevertheless, it is not known how such post-translation modification regulates NEUROG2 activity in the development of the human neocortex under endogenous levels and its contribution to the development of the neocortex. We hypothesize that phosphorylation of NEUROG2 at T149 modulates the timing of cortical progenitor differentiation in humans. To test this, we used 3D cortical organoids generated from CRISPR/Cas9-engineered iPSC lines. Using live imaging of radial glial cell (RGC) clones, immunohistochemistry, machine learning-based cell quantification, transcriptional activation assays, stem cell reprogramming, and multi-omics (snRNA-seq and snATAC-seq), we observed that preventing T149 phosphorylation shifts RGC division from proliferative to neurogenic modes. This results in increased neuron production during mid- and late-stages of organoid cortical development. Mechanistically, we identified an opening of JUN binding sites in RGCs, enhancing the transition to intermediate progenitors (IPs) and subsequently increasing neuron generation. Thus, the phosphorylation at T149 acts as a regulatory rheostat, modulating NEUROG2-driven neurogenesis in human cortical development.

The role of NEUROG2 T149 phosphorylation site in the developing human neocortex.

Rebecca Ann Piskorowski
Sorbonne University, Institut Biologie Paris Seine, Neurscience Paris Seine, France

How the hippocampus encodes social memories is not well understood. Only recently has it been demonstrated that hippocampal area CA2 plays an essential role in the encoding and recall of social information. In this talk, I will give a brief overview of what is known about the neurobiology, synaptic plasticity and circuitry of this under-studied region of the hippocampus and delve into recent finding in my lab linking oxytocin, endocannabinoid plasticity and social memory formation.

Contribution of thalamic projections to the hippocampus to memory processes.

Kasia Radwańska
Nencki Institute of Experimental Biology PAS, Warsaw, Poland

The ability to extinguish contextual fear in a changing environment is crucial for animal survival. Recent data support the role of the thalamic nucleus reuniens (RE) and its projections to the dorsal hippocampal CA1 area (RE→dCA1) in this process. However, it remains poorly understood how RE impacts dCA1 neurons during contextual fear extinction (CFE). During my talk I will discuss our recent data demonstrating that the RE→dCA1 pathway contributes to extinction of contextual fear by affecting CFE-induced molecular remodeling of excitatory synapses in dCA1 stratum lacunosum-moleculare.

Listening to light and seeing sound in the brain.

Daniel Razansky
University of Zurich and ETH Zurich, Switzerland

Development of more efficient and less intrusive ways to alter and observe brain activity is instrumental towards tackling neurological diseases in an aging population and for advancing basic neuroscience research. Light- and ultrasound-based technologies are growingly used for brain interrogation, modulation of neural activity, and treatment of brain diseases. The talk focuses on our latest additions to the arsenal of multi-scale neuroimaging techniques, including large-field multifocal illumination microscopy, super-resolution fluorescence localization imaging, whole-brain functional optoacoustic imaging, localization optoacoustic tomography, multi-modal combinations with functional ultrasound, magnetic resonance imaging and more. The new methods enable transcranial large-scale recordings of neural and hemodynamic activity and molecular agents at penetration depths and spatio-temporal resolution scales not covered with the existing micro- and macro-scopic functional neuroimaging techniques. Examples of applications include large-scale monitoring of neurovascular coupling and neural activity indicators, tracking circulating cells and microrobots, targeted molecular imaging of Alzheimer’s and Parkinson’s, studying microcirculation in stroke. Our current efforts are also geared toward employing optical and optoacoustic techniques for monitoring the effects of transcranial ultrasound stimulation of the living brain. The marriage between light and sound thus brings together the highly complementary advantages of both modalities toward high precision interrogation, stimulation, and therapy of the brain with strong impact in the fields of neuromodulation, gene and drug delivery, or noninvasive treatments of neurological and neurodegenerative disorders.

GABA transporter subtypes 1 and 3 as targets for novel memory-improving drug.

Kinga Sałat
Faculty of Pharmacy, Jagiellonian University Medical College, Cracow, Poland

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory decline and accompanying behavioral and psychological symptoms of dementia (depression, anxiety). Considering that the available anti-AD therapies based on the enhancement of cholinergic neurotransmission are weakly effective in advanced stages of the disease, novel molecular targets for memory-improving drugs are being explored.
GABAergic neurotransmission is found to be crucial for learning and memory both in humans and experimental animals. Several preclinical studies revealed that targeting GABAergic system holds potential in overcoming memory deficits in AD. Hence, GABAergic signaling presents a promising target for anti-AD drug development and recently GABA transporters (GAT) have become a subject of interest as a target for procognitive drugs.
Previously, we focused on GAT1 inhibition and we found that tiagabine, a selective GAT1 inhibitor, in contrast to many available antiepileptic drugs, not only effectively reduces seizures but it has also potential to attenuate memory deficits and reduce behavioral symptoms of dementia (anxiety and depression) in animal models. Our present research is therefore focused on investigating therapeutic potential of compounds acting at other less explored GAT, namely GAT-3 (human nomenclature).
Using a combination of crystallography and computational methods we developed a series of compounds among which the compound 6 demonstrated inhibition of GAT-1 (IC50=10.96 μM) and GAT-3 (IC50=7.76 μM), along with a favorable drug-likeness profile. Subsequent in vivo studies revealed the effectiveness of 6 in enhancing learning and memory retention and alleviating anxiety and depression symptoms in mouse models, while also proving safety and bioavailability for oral administration. The innovative ligand 6 offers a new approach to treat AD patients with symptoms of cognitive deficits and accompanying mood disorders.

Optical and computational tools to explore brain-wide behavior-specific circuits.

Ludovico Silvestri
Department of Physics and Astronomy, University of Florence; European Laboratory for Non-linear Spectroscopy, Florence

Complex behaviors are the result of the coordinated activity of large populations of interconnected neurons across the entire brain. A detailed charting of this orchestrated flow of information would be fundamental for understanding brain function in healthy and disease states. However, the detailed organization of brain-wide behavior-specific circuits remain elusive, mainly for technical reasons. Indeed, most imaging methods suffer from either poor resolution – insufficient to disentangle single cells – or limited field of view – offering only a partial view of wider brain networks. In this scenario, light-sheet fluorescence microscopy (LSFM), coupled with chemical clearing of tissue, surged as a potential game changer allowing full volumetric reconstruction of entire organs with sub-cellular resolution. However, despite the great promise hold by this method, its routine use is still often limited to the production of a couple of fancy 3D renderings without any real biological insight.
In this talk, I will analyze the optical and computational limitations of state-of-the-art LSFM, and discuss recent advances to achieve scalable, robust, and quantitative analysis of activation patterns in whole mouse brains. Finally, I will describe application of this “adaptive and smart” microscopy to the dissection of brain-wide circuits involved in fear memory, and discuss future directions of the field.

Navigating Astro-Neuro Dynamics: The Impact of Glial Wnt Signalling on Neuronal Development and Function.

Łukasz M. Szewczyk
University of Warsaw, Centre of New Technologies, Warsaw, Poland

The Wnt/β-catenin pathway contains multiple high-confidence risk genes that are linked to neurodevelopmental disorders, including autism spectrum disorder. However, its ubiquitous roles across brain cell types and developmental stages have made it challenging to define its impact on neural circuit development and behavior. Here, we show that TCF7L2, which is a key transcriptional effector of the Wnt/β-catenin pathway, plays a cell-autonomous role in postnatal astrocyte maturation and impacts adult social behavior. TCF7L2 was the dominant Wnt effector that was expressed in both mouse and human astrocytes, with a peak during astrocyte maturation. The conditional knockout of Tcf7l2 in postnatal astrocytes led to an enlargement of astrocytes with defective tiling and gap junction coupling. These mice also exhibited an increase in the number of cortical excitatory and inhibitory synapses and a marked increase in social interaction by adulthood. These data reveal an astrocytic role for developmental Wnt/β-catenin signaling in restricting excitatory synapse numbers and regulating adult social behavior.

Choosing to be different. Cell identity and fate choice in the developing brain.

Elena Taverna
Human Technopole. Milan, Italy

Neurons forming the neocortex are generated during embryonic development from two main classes of neural progenitor cells: apical and basal progenitors (APs and BPs, respectively). Our lab is interested in understanding the role of the Golgi apparatus and glycosylation in regulating neuronal stem cell behavior and fate choice during brain development. The Golgi apparatus is the main hub for glycosylation and defects in Golgi-associated glycosylation can lead to primary microcephaly, a neurodevelopmental defect associated with alterations in neural stem cell behavior and lineage progression. The cell biological mechanisms linking defective Golgi glycosylation and neurodevelopmental manifestations are currently unknown. We want to fill this gap by investigating the influence of the Golgi apparatus on stem cell identity and fate transition during brain development. We show that the Golgi apparatus is rearranged during APs to BPs fate transition, in particular in relation to its association with the centrosome. In addition, pharmacological and genetic perturbation of GA integrity in mouse embryos and human brain organoids favors the APs to BPs fate transition. Our data suggest that the Golgi apparatus structure and function are linked to cell fate switch during brain development.

Palmitoylation-dependent signaling in and from distal axons.

Gareth Thomas
Cellular and Molecular Neuroscience Lab Temple University School of Medicine in Philadelphia, Philadelphia, USA

Neuronal axons are thin, delicate projections whose integrity is critical for nervous system function. Many proteins that control the balance between axonal integrity and degeneration are covalently modified with the lipid palmitate. This process, palmitoylation, serves to target proteins to specific subcellular membranes. We and others have revealed critical roles for palmitoylated proteins that 'hitchhike' on axonal vesicles to convey responses from damaged or stressed axons back to neuronal cell bodies. These palmitoylated retrograde signaling proteins then drive pro-degenerative, or sometimes pro-regenerative, responses. Recently, we have investigated the potential of selectively preventing such axonal retrograde signaling as a novel neuroprotective strategy. We are also now revealing roles for palmitoylation in autonomously controlling the axo-degenerative process in distal axons themselves. These exciting findings provide new insights into axonal biology and may reveal new ways to lessen the impact of the many neuropathological conditions of which axon degeneration is a hallmark.

How parietal cortex and hippocampus contribute to space for action.

Sylvia Wirth
Centre national de la recherche scientifique, Paris, France

Non-human primates and rodents can find their way in virtual environments, avoiding obstacles and planning trajectories to reach goals. How can a sense of space arise from visual-only stimulation? Here we show how cells in the parietal cortex and the hippocampus of macaques navigating a virtual space are driven by visual explorations, titling the space as a function of the animal’s attention, expressed by saccades and fixations to paths and landmarks, salient elements of the virtual space. Further, we show how, both regions anticipated landmarks before they appeared in the field of view, suggesting a shared knowledge of the spatial layout. Yet, cells in the parietal cortex were sensitive to the side of appearance of the landmark while hippocampal ones weren’t, expressing egocentric versus allocentric complementarity. In light of these findings, I will discuss the neural processes that make up place in primates, stemming from visual exploration of objects in space combined with memory-driven actions.

Thalamic energy metabolism and autism-like deficits in a mouse model of the TCF7L2-related neurodevelopmental disorder.

Marta Wiśniewska
CeNT, Warsaw, Poland

The TCF7L2 gene, which encodes a transcription factor, is a recognised risk gene for psychiatric conditions. Its mutations lead to a recently identified rare neurodevelopmental disorder characterised, among other symptoms, by traits of autism spectrum disorder (ASD). TCF7L2 is an effector of Wnt signalling enriched in the brain, exhibiting particularly high expression in thalamic neurones. We investigated whether postnatal disruption of Tcf7l2 in the thalamus contributes to ASD-like symptoms in mice. Our findings indicate that thalamic TCF7L2 regulates energy metabolism within thalamocortical circuitry, with its deficiency resulting in the dysregulation of metabolism-related genes in the thalamus and a considerable reduction in pyruvate utilisation efficiency in both the thalamus and cortex. Furthermore, the ketogenic diet restored brain energy metabolism and normalised social behaviour, thereby linking metabolic deficits in thalamocortical circuitry to behavioural symptoms. These findings provide evidence that ASD may be directly associated with impaired brain energy metabolism and emphasise the role of thalamocortical circuit dysfunction in the pathogenesis of social deficits.

Protein palmitoylation in synaptic plasticity and spatial learning.

Tomasz Wójtowicz
Laboratory of Molecular Basis of Behaviour, Nencki Institute of Experimental Biology, Warsaw, Poland

Synaptic plasticity is a fundamental process underlying learning and memory. However, the molecular mechanisms governing this phenomenon remain incompletely understood. One emerging regulatory mechanism is S-palmitoylation - a reversible post-translational lipid modification that modulates the function of synaptic proteins by influencing their conformation, localization, trafficking, and molecular interactions. Over the past decade, S-palmitoylation (S-PALM) has been increasingly recognized as a key factor in the sorting and membrane localization of neuronal proteins. Despite numerous reports identifying S-PALM targets in vitro, the functional consequences of this modification on synaptic proteins and neural circuits remain largely unexplored. In this talk, I will present our most recent findings from several in vitro and in vivo models of neuronal plasticity in which S-PALM was manipulated pharmacologically. Our data support the view that both short- and long-term changes in synaptic strength, as well as increased neuronal spiking following network activation, require protein palmitoylation. We identified several pre-, post-, and intersynaptic proteins whose palmitoylation is dynamically regulated by synaptic activity. Furthermore, using mass spectrometry analysis of brain samples from rats exposed to a spatial learning paradigm, we identified a subset of synaptic proteins undergoing S-PALM in vivo. Notably, we found that S-PALM can occur locally at isolated excitatory synapses immediately after synaptic activity. Altogether, our findings highlight local and rapid protein-specific palmitoylation as a vital mechanism for synaptic plasticity, contributing to the dynamic regulation of neuronal network function and memory formation.

Memory in Sequence: Prefrontal and Medial Temporal Neurons Encode Order of Events in Humans.

Jie Zheng
University of California, Davis, USA

Remembering the temporal order of events is critical for episodic memory. Previous research suggest that linking individual events into temporally associated memories relies on the medial temporal lobe and prefrontal cortex. Damage to these regions can disrupt the ability to recall stories and real-life events in the correct order. However, little is known about how brain encodes and retrieves temporal order information at the neural level. To investigate this, we designed an order memory task using video clips that mimic real-life experiences. Each clip contained four sequential everyday events of varying length, with visual cuts inserted at event transitions (i.e., event boundaries). Participants watched the clip and were then asked to recall the order of event sequence within each clip and identify familiar scenes. This study involved 23 patients with refractory epilepsy who had depth electrodes implanted for seizure monitoring, allowing us to record single neuron activity while they performed the task. Among the 1014 recorded neurons, we identified "order selective neurons" (OSNs) in the hippocampus, amygdala, and orbitofrontal cortex that selectively responded to specific event orders (i.e., preferred order), regardless of event content and the absolute time. Most of these OSNs exhibit transient theta phase precession following their preferred order during memory encoding and also when retrieving order memory involving their preferred order. Furthermore, the strength of theta phase precession in OSNs predicted participants’ order memory performance (correct versus incorrect). These findings shed lights on how the brain weaves discrete episodic events into a coherent temporal narrative, advancing our understanding of human episodic memory.