bioRxiv Subject Collection: Neuroscience's Journal
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Monday, May 26th, 2025
| Time |
Event |
| 9:30a |
Age and Alzheimer's disease affect functional connectivity along separate axes of functional brain organization
Aging and Alzheimer's disease (AD) are associated with alterations in functional connectivity (FC), yet their spatial and temporal characteristics remain debated. Whole-cortex functional gradients, which organize regions along axes of functional similarity, are positioned here as a framework for understanding such alterations. Across two independent cohorts (BioFINDER-2, N=973; ADNI, N=129), we demonstrate that hyper- and hypoconnectivity in both healthy aging and biomarker-confirmed AD progression coexist systematically, forming consistent spatial patterns that align with two distinct axes of brain organization. Using a combination of longitudinal and non-linear analyses, we show that the early (but not late) stages of AD pathology accumulation is associated with functional alteration along the sensory-association axis, a pattern that vanishes in later stages of AD. However, functional alteration along the sensory-association axis is associated with worse cognition throughout the AD spectrum, and even in older adults without AD pathology, suggesting that these FC patterns may reflect a general neural response to cognitive strain. Independently of AD, older age was associated with alterations instead along the executive-nonexecutive axis, a finding that was consistent throughout the adult lifespan. These findings highlight the fundamental role of intrinsic functional organization in shaping how the brain responds to aging and to AD, helping to resolve previously reported discrepancies. | | 9:30a |
Task-relevant cognitive maps in episodic memory
Cognitive maps support navigation by representing locations in internal spaces with Euclidean distances. Similar organizational principles may govern the representation of non-spatial sensory and conceptual features, enabling higher cognitive functions including decision making and model-based reinforcement learning. Previous studies have shown that medial temporal lobe (MTL) structures support the embedding of stimuli into cognitive maps. However, these studies investigated the generation of novel cognitive maps, while the recruitment of existing semantic knowledge into task-relevant representational spaces and their remapping according to changing goals has not been investigated. In addition, it is not clear how the MTL interacts with neocortical representations of task-relevant stimulus features and whether this influences the formation of novel episodic memory traces. Here we show that the neural representations of natural stimuli in both MTL and neocortex are organized in behaviorally relevant cognitive maps of conceptual features and influence the accessibility of novel memory traces. Cognitive maps organize information into internal spaces with Euclidean distances, adapt to ongoing task demands, and influence performance. Their representational structure matches neural similarities in the MTL, with a specific role of the hippocampus for task-dependent remapping. Further, we isolated task-relevant and stimulus-driven representations of natural stimuli and show how they contribute to the formation of memory traces. Together, our results suggest that conceptual representations are flexibly recruited in spatially organized cognitive maps of task-relevant features and that Euclidean distances in these cognitive maps affect subsequent memory. | | 9:30a |
Combinatorial mechanisms specify cellular location and neurotransmitter identity during regeneration of planarian neurons
During regenerative neurogenesis, neurons must be created in the right types and locations. Though regenerative neurogenesis is limited in humans, other animals use regenerative neurogenesis to faithfully restore form and function after brain injury. Planarians are flatworms with extraordinary capacity for brain regeneration. Planarians use pluripotent stem cells to create neurons after injury, rather than resident progenitors. In this context, genetic mechanisms that produce diverse neurons with correct local identity remain unknown. Here, we report the discovery of factors important for regenerative neurogenesis of dopaminergic neurons in the planarian central, peripheral, and pharyngeal nervous systems. Distinct genes promote dopaminergic neuronal identity and instruct neurons to inhabit regions of the nervous system. Our results demonstrate that planarian neuronal fate requires factors that simultaneously direct neurotransmitter choice and regional location. Our work suggests that combinatorial direction of cell type could inform and improve exogenous stem cell therapies aimed at precisely replacing neurons. | | 12:16p |
Mapping early patterning events in human neural development usingan in-vitro microfluidic stem cell model
Stem cell models can provide insights into human brain development at embryonic stages which are normally inaccessible. We previously developed the Microfluidic Stem Cell Regionalisation (MiSTR) model, which recapitulates the rostro-caudal patterning of human neural tube through a WNT activation (WNTa) gradient. Through temporal single cell transcriptomics of rostro-caudal and dorso-ventral gradient-patterned MiSTR, we found that rostro-caudal subtypes were regionally specified and fate determined already during the late epiblast stage, several days before onset of neuralisation at day 3-4. Rostral cells were characterised by expression of HESX1 and SHISA2 during pre-neuralisation and PAX6 during early neuralisation, whereas caudal cells expressed FST and HOXA1 during pre-neuralisation and SOX1 as the dominant neuralising factor. In contrast to the early rostro-caudal specification, response to ventralisation in telencephalic progenitors was developmentally delayed and occurred around day 9. We further uncovered temporal events in human midbrain-hindbrain boundary formation and ventral forebrain patterning, contributing new knowledge on early human neural region-specification. | | 4:34p |
Noninvasive focal gene transfer of chemogenetic proteins in the primate brain
The development of chemogenetic neuromodulators, including Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), have enabled focally specific, long-lasting, and reversible neuromodulation in the primate brain. Although systemically delivered synthetic ligands allow for noninvasive actuation of chemogenetic receptors, direct intraparenchymal injection remains atop the available methods to precisely deliver chemogenetic payloads to a specific target of the brain. The requirement of trephination, however, is accompanied by inherent risks of infection, long recovery times, and often tissue damage with concomitant behavioral complications. When considering therapeutic injections, the requirement of transcranial surgery does not translate well to the clinic, especially when repeated administrations are required. Here, we leverage our recent development of transcranial focused ultrasound (tFUS) for noninvasive and focal delivery of adeno-associated viruses (AAVs) carrying excitatory Gq-DREADDs to frontal cortical targets (areas 6DR and 8aD) in the marmoset brain. Using [18F]-fluorodeoxyglucose (FDG) positron emission tomography, we demonstrate significant increases in glucose metabolism at the site of viral delivery after administering the DREADD-specific agonist deschloroclozapine (DCZ), as compared to vehicle control. Focal neuronal DREADD expression was confirmed by immunohistochemistry at the site of opening. Through comparison of awake resting-state functional connectivity (whole brain connectivity with the sites of delivery) and structural connectivity (directly injected viral neuronal tracing at the sites of delivery) we demonstrate that the increase in glucose metabolism occurs at both mono- and polysynaptically connected brain regions. Taken together, these results demonstrate the ability to focally deliver excitatory chemogenetics without the need for surgery, allowing for activation of long-range frontal cortex circuits of the primate brain. | | 11:46p |
Epigenetic mechanisms governing cell type specific somatic expansion and toxicity in Huntington's disease
Huntington's disease (HD) is characterized by neuronal dysfunction and degeneration that varies markedly by brain region and cell type. We previously showed that CAG repeat expansion in exon 1 of the mHTT gene correlates with increased expression of the mismatch repair genes MSH2 and MSH3 in striatal medium spiny neurons1, and demonstrated that, in the striatum and cerebral cortex of individuals with HD, hundreds of genes are dysregulated in neuronal cell types carrying somatically expanded CAG repeat in mHTT1,2. Here we employ comprehensive epigenetic profiling in specific neuronal and glial cell types from the human striatum, cerebral cortex, hippocampus and cerebellum of control and HD donor samples to identify cell type- and species-specific transcriptional control mechanisms in the mismatch repair genes MSH2, MSH3 and FAN1 that can explain the specificity of somatic CAG expansion in the first stage of HD. In the second, toxic phase of HD we identify two distinct epigenetic mechanisms that disrupt regulation of hundreds of genes in the majority of HD MSNs, including several that cause haploinsufficient neurological disorders. Our data support a mechanistic model of HD pathogenesis in which regulation of mismatch repair gene transcription determines the selectivity of somatic expansion, and DNA methylation stabilizes the toxic effect of mutant huntingtin on HD-modifying proteins MED15 and TCERG1, which regulate enhancer function and transcription elongation. |
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