bioRxiv Subject Collection: Neuroscience's Journal
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Saturday, March 1st, 2025
| Time |
Event |
| 8:17a |
In vivo tractography of human neonatal white-matter pathways underlying hypothalamic and reward functions to study predispositions to neurodevelopmental conditions and obesity
White matter (WM) tracts of the reward, limbic, and autonomic systems implicate the hypothalamus, nucleus accumbens, ventral tegmental area and the amygdala and are associated with autism, ADHD, addiction and obesity. However, since most of these structures remain uncharacterised in vivo in human neonates, re- search on the early-life predispositions to these long-term "mind and body" conditions and the impact of common fetal exposures such as maternal obesity remains limited. Through the developing human connectome project, we acquired 3T brain diffusion and structural magnetic resonance imaging from healthy neonates born at-term to 137 normal-weight women (controls) and to 28 obese women and scanned at mean 40 weeks+6 days (+/-9 days) postmenstrual age (PMA). We first developed novel tractography protocols to reconstruct anatomical WM pathways for the neonatal medial forebrain bundle, ventral amygdalofugal pathway, amygdalo-accumbens fasciculus, stria terminalis and autonomic dorsal longitudinal fasciculus (DLF). We then quantified WM structure from the mean tract fibre bundle density (FD) and fibre cross-section (FC) and using regression path models evaluated WM change across PMA and the effects of antenatal obesity exposure and neonatal covariates. Lastly, we explored if neonatal WM FD and obesity exposure predicted child psycho-cognitive outcomes and anthropometry at 18 months. We show successful in vivo tractography of tracts with high topographical correspondence to adult histology, including in subcompartments of the hypothalamus and amygdala. The obesity exposure*PMA interaction was significant for mean FD in the bilateral amygdalo-accumbens fasciculus and right uncinate fasciculus. Males had larger FC in these same tracts bilaterally. Antenatal obesity exposure predicted lower cognitive scores and higher WHO weight and height z-scores at 18 months. Toddler reward-seeking temperament was correlated with higher weight z-score and was predicted by higher neonatal FD of the amygdalo-accumbens and uncinate fasciculi. Denser neonatal DLF predicted higher language and cognitive scores and fewer autistic traits at 18 months. In conclusion, we inform on neuroanatomical growth in vivo of discrete multisystemic regulatory networks and present evidence for early-life predispositions to psychological outcomes and obesity. | | 8:17a |
Maternal low protein diet alters the development of reward circuits from childhood to adulthood by reshaping its function
Inadequate nutrition during pregnancy can lead to intrauterine growth retardation and low birth weight, which in turn increases the risk of developing metabolic disorders in adulthood, according to various epidemiological and clinical studies. The inclina-tion of individuals born with low birth weight towards palatable foods indicates a possible modification in the hedonic aspect of their eating behavior. However, our understanding of the ontogenesis of structural organization and function within the brain's reward circuits remains limited. Therefore, the objective of this research is to investigate the preferences for palatable food, molec-ular signatures of reward circuits, and functional properties of the nucleus accumbens (NAc) in a rat model of perinatal protein restriction (LP). Starting from weaning, continuing into adolescence and adulthood, a longitudinal analysis was conducted on rats born to mothers with protein-restricted diets during gestation and lactation (LP pups), comparing them to pups born from control dams (CD pups). The LP group exhibited an increased preference for palatable food at day 25 after birth (P25), followed by a decreased preference during adolescence (P50), and no significant difference in palatable food preference at P95 (young adult) compared to CD rats. Molecular and electrophysiological assessments of medium spiny neurons (MSN) in the NAc revealed a reorganization of reward circuits during crucial developmental periods, potentially influencing the attractiveness of palatable food for the LP group. This study represents the first exploration of how preferences for palatable food evolve throughout an indi-vidual's lifespan and how these observations correlate with the remodeling of reward circuits. By shedding light on the molecular and functional aspects of reward circuits, we contribute to a better understanding of the link between perinatal nutrition, behav-ioral preferences, and the underlying neural mechanisms. | | 12:31p |
Multi-omic analysis of the ciliogenic transcription factor RFX3 reveals a role in promoting activity-dependent responses via enhancing CREB binding in human neurons
Heterozygous loss-of-function (LoF) variants in RFX3, a transcription factor known to play key roles in ciliogenesis, result in autism spectrum disorder (ASD) and neurodevelopmental delay. RFX binding motifs are also enriched upstream of genes found to be commonly dysregulated in transcriptomic analyses of brain tissue from individuals with idiopathic ASD. Still, the precise functions of RFX3 in the human brain is unknown. Here, we studied the impact of RFX3 deficiency using human iPSC-derived neurons and forebrain organoids. Biallelic loss of RFX3 disrupted ciliary gene expression and delayed neuronal differentiation, while monoallelic loss of RFX3 did not. Instead, transcriptomic and DNA binding analyses demonstrated that monoallelic RFX3 loss disrupted synaptic target gene expression and diminished neuronal activity-dependent gene expression. RFX3 binding sites co-localized with CREB binding sites near activity-dependent genes, and RFX3 deficiency led to decreased CREB binding and impaired induction of CREB targets in response to neuronal depolarization. This study demonstrates a novel role of the ASD-associated gene RFX3 in shaping neuronal synaptic development and plasticity. | | 12:31p |
Predicting the Regenerative Potential of Retinal Ganglion Cells Based on Developmental Growth Trajectories
Retinal ganglion cells in the mammalian central nervous system fail to regenerate following injury, with the capacity to survive and regrow varying by cell type. This variability may be linked to differences in developmental programs that overlap with the genetic pathways that mediate regeneration. To explore this correlation, we compared the structural changes in mouse retinal ganglion cells during development with those occurring after axonal injury. The dendritic trees of over 1,000 ganglion cells were reconstructed at different developmental stages, revealing that each cell type follows a distinct timeline. ON-sustained (sONa) cells reach maturity by P14, whereas ON-transient (tONa) cells achieve their maximum dendritic size by P10. Modeling of the dendritic changes indicate that while sONa and tONa follow similar growth programs the onset of growth was later in sONa. After optic nerve crush, the remodeling of dendritic architecture differed between the two cell-types. sONa cells exhibited rapid dendritic shrinkage, while tONa cells shrank more gradually with changes in branching features. Following injury, sONa cells reverted to an earlier developmental state than tONa cells. In addition, after co-deletion of PTEN and SOC3, neurons appeared to regress further back in developmental time. Our results provide evidence that a ganglion cell's resilience to injury and regenerative potential is predicted by its maturation timeline. Understanding these intrinsic differences could inform targeted neuroprotective interventions. | | 12:31p |
Longitudinal tracking of neuronal activity from the same cells in the developing brain using Track2p
Understanding cortical circuit development requires tracking neuronal activity across days in the growing brain. While in vivo calcium imaging now enables such longitudinal studies, automated tools for reliably tracking large populations of neurons across sessions remain limited. Here, we present a novel cell-tracking method based on sequential image registration, validated on calcium imaging data from the barrel cortex of mouse pups over one postnatal week. Our approach enables robust long-term analysis of several hundreds of individual neurons, allowing quantification of neuronal dynamics and representational stability over time. Using this method, we identified a key developmental transition in neuronal activity statistics, marking the emergence of arousal state modulation. Beyond this key finding, our method provides an essential tool for tracking developmental trajectories of individual neurons, which could help identify potential deviations associated with neurodevelopmental disorders. | | 12:31p |
Simultaneous analysis of single-cell gene expression and morphology provides new insight into how microglia change with age
Cellular morphology is intimately connected with function. While the link between morphology and functional states has been studied extensively, the role of subcellular transcript localization in cellular function remains unclear. Here we use microglia, the brain's resident macrophages, as a model to dissect the interaction of morphology, transcript localization, and function. Using multiplexed error-robust fluorescence in situ hybridization combined with fluorescent immunohistochemistry, we analyzed transcript distribution and morphology simultaneously in young and aged mouse brains. Our approach revealed how mRNA spatial organization varies across microglial states. We identified distinct transcript localization patterns within microglial processes and uncovered morphological heterogeneity within transcriptomically defined populations. Notably, we found a subpopulation of disease-associated microglia with a ramified morphology (displaying numerous processes), challenging the conventional assumption between morphology and microglial states. Finally, we found that aging not only alters the distribution of compartmentalized mRNAs but also reshapes their colocalization networks, shifting microglial functions from synaptic maintenance and phagocytic processes in younger brains to migration and catabolic pathways in older brains. Our findings highlight the role of subcellular transcript organization in shaping microglial morphology and function, offering new avenues for studying and modulating microglial states in health, disease, and aging. | | 12:31p |
Rapid and efficient generation of human oligodendrocytes myelinating adult human cortical neurons
Intracerebral transplantation of stem cell-derived oligodendrocytes (OLs) holds promise as a new strategy for repairing demyelinated brain tissue. However, two challenges hinder clinical translation: the slow and inefficient generation of human OLs for transplantation using the protocols described to date, and the limited insight into their remyelination potential, which has only been evaluated in vitro or in xenotransplantation studies, failing to capture critical human-specific cellular interactions involved in myelination. Here, we present a highly reproducible method for the rapid generation of myelinating human OLs from human induced pluripotent stem cell-derived long-term neuroepithelial-like stem (lt-NES) cells. Induced expression of SOX10 and OLIG2 in human lt-NES cells is sufficient to produce O4-expressing OLs with an efficiency of 80% within 7 days, as confirmed by flow cytometry and immunocytochemistry. Importantly, these OLs survive, differentiate and become functional when grafted into adult human brain slices ex vivo, demonstrating their ability to maintain their phenotype after allotransplantation in a system mimicking the clinical setting. Our new protocol has potential to further advance personalized medicine in the field of myelin disorders. | | 12:31p |
Dendritic Architecture Enables de Novo Computation of Salient Motion in the Superior Colliculus
Dendritic architecture plays a crucial role in shaping how neurons extract behaviorally relevant information from sensory inputs. Wide-field neurons in the superior colliculus integrate visual information from the retina to encode cues critical for visually guided orienting behaviors. However, the principles governing how these neurons filter their inputs to generate appropriate responses remain unclear. Using viral tracing, two-photon calcium imaging, and computational modeling, we show that wide-field neurons receive functionally diverse inputs from twelve retinal ganglion cell types, forming a layered, type-specific organization along their dendrites. This structured arrangement allows wide-field neurons to multiplex salient motion cues, selectively amplifying movement and suppressing static features. Computational models reveal that the spatial organization of dendrites and inputs enables the selective extraction of behaviorally relevant stimuli, including de novo computations. Our findings underscore the critical role of dendritic architecture in shaping sensory processing and neural circuit function. | | 12:31p |
Persistent representation of a prior schema in the orbitofrontal cortex facilitates learning of a conflicting schema
Schemas allow efficient behavior in new situations, but reliance on them can impair flexibility when new demands conflict, culminating in psychopathology. Evidence implicates the orbitofrontal cortex (OFC) in deploying schemas in new situations congruent with previously acquired knowledge. But how does this role affect learning of a conflicting behavioral schema? Here we addressed this question by recording single-unit activity in the OFC of rats learning odor problems with identical external information but orthogonal rules governing reward. Consistent with schema formation, OFC representations adapted to track the underlying rules, and both performance and encoding was faster on subsequent than initial problems. Surprisingly however, when the rule governing reward changed, persistent representation of the prior schema was correlated with acquisition of the new. Thus, OFC was not a source of interference and instead supported new learning by accurately and independently representing the old schema as the new was acquired. | | 12:31p |
Broadband synergy versus oscillatory redundancy in the visual cortex
The cortex generates diverse neural dynamics, ranging from broadband fluctuations to narrowband oscillations in specific frequency bands. Here, we investigated whether broadband and oscillatory dynamics play different roles in the encoding and transmission of synergistic and redundant information. We used information-theoretical measures to dissociate neural signals sharing common information (i.e., redundancy) from signals encoding complementary information (i.e., synergy). We analyzed electrocorticography (ECoG) and local field potentials (LFP) in the visual cortex of human and non-human primates (macaque) to investigate to what extent broadband signals (BB) and narrowband gamma (NBG) oscillations conveyed synergistic or redundant information about images. In both species, the information conveyed by BB signals was highly synergistic within and between visual areas. By contrast, the information carried by NBG was primarily redundant within and between the same visual areas. Finally, the information conveyed by BB signals emerged early after stimulus onset, while NBG sustained information at later time points. These results suggest that broadband activity encodes information synergistically while gamma-band oscillatory activity encodes information redundantly in the visual cortex. |
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