bioRxiv Subject Collection: Neuroscience's Journal
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Sunday, December 3rd, 2023
| Time |
Event |
| 12:30a |
Diagnostic images for mild cognitive impairment reveal biomarker status and abnormal scene processing
Research on the impairment of episodic memory in Alzheimer's disease often focuses on the processes of memory rather than the content of the specific images being remembered. We recently showed that patients with mild cognitive impairment (MCI), Stage 3 of Alzheimer's disease, can memorize certain images quite well, suggesting that episodic memory is not uniformly impaired. Certain images, on the other hand, could not be memorized by MCI patients and were instead diagnostic for distinguishing MCI from healthy older adults. In this study, we investigate whether poor memory for diagnostic images is related to impaired neural processing in specific brain regions due to Alzheimer's biomarker pathology. 64 healthy controls and 48 MCI participants in the DELCODE dataset performed a visual scene memory task during fMRI, with CSF Alzheimer's disease biomarker data collected (i.e., amyloid and tau biomarkers). We found that diagnostic images have larger behavior-biomarker correlations for total tau, phospho-tau, A{beta}42/A{beta}40, A{beta}42/phospho-tau compared to non-diagnostic images, suggesting that memory for these specific images are more affected by Alzheimer's disease pathology. The fMRI data revealed an interaction effect between group membership (healthy control / MCI) and image diagnosticity (diagnostic / non-diagnostic scene images), with MCI participants having higher activation in scene processing regions (parahippocampal place area, retrosplenial cortex and occipital place area) for diagnostic images than non-diagnostic images. In contrast, healthy controls showed no differences in processing between diagnostic and non-diagnostic images. These results suggest that MCI individuals may engage in inefficiently heightened encoding activation for these diagnostic images. Our results show that special "diagnostic" images exist that can reveal amyloid and tau pathology and differences in neural activity in scene regions. | | 12:30a |
The ALS-associated TDP-43M337V mutation dysregulates microglia-derived extracellular microRNAs in a sex-specific manner
Evidence suggests the presence of microglial activation and microRNA (miRNA) dysregulation in amyotrophic lateral sclerosis (ALS), the most common form of adult motor neuron disease. However, few studies have investigated whether the miRNA dysregulation may originate from microglia. Furthermore, TDP-43, involved in miRNA biogenesis, aggregates in tissues of ~98% of ALS cases. Thus, this study aimed to determine whether expression of the ALS-linked TDP-43M337V mutation in a transgenic mouse model dysregulates microglia-derived miRNAs. RNA sequencing identified several dysregulated miRNAs released by transgenic microglia, and a differential miRNA release by lipopolysaccharide-stimulated microglia, which was more pronounced in cells from female mice. We validated the downregulation of two candidate miRNAs, miR-16-5p and miR-99a-5p by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR), and identified their predicted targets, which include primarily genes involved in neuronal development and function. These results suggest that altered TDP-43 function leads to changes in the miRNA population released by microglia in a sex dependent manner, which may in turn influence disease progression in ALS. This has important implications for the role of neuroinflammation in ALS pathology and could provide potential therapeutic targets. | | 6:17a |
Transcription factor activity profiling reveals the role of REST and LEF1 in the recovery from depression
Psychophysiological disorders chronically impair brain functions, often accompanied by dysregulation of multiple genes, suggesting a multifaceted etiology behind the symptoms. To explore transcription factors (TFs) involved in such transcriptomic changes, we analyzed TF-activity profiles (TFAPs) from the brains of mice experienced chronic stress, and revealed alteration in TF-activity correlating with their pathophysiological phenotypes. We identified REST/NRSF and TCF/LEF associated with depressive phenotypes and discovered that neuropsychiatric drugs sertraline and lithium influence REST- and TCF/LEF-activity, both in vitro and in vivo, thereby affecting gene expression profiles. Pharmacological or genetic manipulation of REST- or TCF/LEF-activity in defeated mice impacts post-stress recovery from depressive phenotypes, with combined treatment further augmenting the outcomes. Our TFAP analysis enhances understanding of molecular mechanisms underpinning chronic diseases, aiding future therapeutic strategy development. | | 11:19a |
Selective Vulnerability of Parvocellular Oxytocin Neurons in Social Dysfunction
Selective vulnerability offers a conceptual framework for understanding neurodegenerative disorders, such as Parkinson's disease, where specific neuronal types are selectively affected while adjacent ones are spared. The applicability of this framework to neurodevelopmental disorders remains uncertain, particularly those characterized by atypical social behaviors such as autism spectrum disorder. Here, employing a single-cell transcriptome analysis in mice, we show that an embryonic disturbance known to induce social dysfunction preferentially impairs gene expressions crucial for neural functions in parvocellular oxytocin (OT) neurons, a subtype linked to social rewards, while neighboring cell types experience a lesser impact. Chemogenetic stimulation of OT neurons at the neonatal stage ameliorated social deficits in early adulthood, concurrent with a cell-type-specific sustained recovery of the pivotal gene expressions within parvocellular OT neurons. Collectively, our data shed light on the transcriptomic selective vulnerability within the hypothalamic social behavioral center and provide a potential therapeutic target through specific neonatal neurostimulation. | | 11:19a |
Adaptive stretching of representations across brain regions and deep learning model layers
Prefrontal cortex (PFC) is known to modulate the visual system to favor goal-relevant information by accentuating task-relevant stimulus dimensions. Does the brain broadly re-configures itself to optimize performance by stretching visual representations along task-relevant dimensions? We considered a task that required monkeys to selectively attend on a trial-by-trial basis to one of two dimensions (color or motion direction) to make a decision. Except for V4 (color bound) and MT (motion bound), the brain radically reconfigured itself to stretch representations along task-relevant dimensions in lateral PFC, frontal eye fields (FEF), lateral intraparietal cortex (LIP), and inferotemporal cortex (IT). Spike timing was crucial to this code. A deep learning model was trained on the same visual input and rewards as the monkeys. Despite lacking an explicit selective attention or other control mechanism, the model displayed task-relevant stretching as a consequence of error minimization, indicating that stretching is an adaptive strategy. | | 11:46a |
Visual working memories are abstractions of percepts
Pioneering studies demonstrating that the contents of visual working memory (WM) can be decoded from the patterns of multivoxel activity in early visual cortex transformed not only how we study WM, but theories of how memories are stored. For instance, the ability to decode the orientation of memorized gratings is hypothesized to depend on the recruitment of the same neural encoding machinery used for perceiving orientations. However, decoding evidence cannot be used to test the so-called sensory recruitment hypothesis without understanding the underlying nature of what is being decoded. Although unknown during WM, during perception decoding the orientation of gratings does not simply depend on activities of orientation tuned neurons. Rather, it depends on complex interactions between the orientation of the grating, the aperture edges, and the topographic structure of the visual map. Here, our goals are to 1) test how these aperture biases described during perception may affect WM decoding, and 2) leverage carefully manipulated visual stimulus properties of gratings to test how sensory-like are WM codes. For memoranda, we used gratings multiplied by radial and angular modulators to generate orthogonal aperture biases despite having identical orientations. Therefore, if WM representations are simply maintained sensory representations, they would have similar aperture biases. If they are abstractions of sensory features, they would be unbiased and the modulator would have no effect on orientation decoding. Results indicated that fMRI patterns of delay period activity while maintaining the orientation of a grating with one modulator (eg, radial) were interchangeable with patterns while maintaining a grating with the other modulator (eg, angular). We found significant cross-classification in visual and parietal cortex, suggesting that WM representations are insensitive to aperture biases during perception. Then, we visualized memory abstractions of stimuli using a population receptive field model of the visual field maps. Regardless of aperture biases, WM representations of both modulated gratings were recoded into a single oriented line. These results provide strong evidence that visual WM representations are abstractions of percepts, immune to perceptual aperture biases, and compel revisions of WM theory. | | 11:46a |
The Wingless Planar Cell Polarity pathway is essential for optimal activity-dependent synaptic plasticity.
From fly to man, the Wingless (Wg) / Wnt signaling molecule is essential for both the stability and plasticity of the nervous system. The Drosophila neuromuscular junction (NMJ) has proven to be a useful system for deciphering the role of Wg in directing activity-dependent synaptic plasticity, which, in the motoneuron, has been shown to be dependent on both the canonical and the noncanonical calcium Wg pathways. Here we show that the noncanonical planar cell polarity (PCP) pathway is an essential component of the Wg signaling system controlling plasticity at the motoneuron synapse. We present evidence that disturbing the PCP pathway leads to a perturbation in activity-dependent synaptic plasticity (ADSP). We first show that a PCP-specific allele of dishevelled (dsh) affects the de novo synaptic structures produced during ADSP. We then show that the Rho GTPases downstream of Dsh in the PCP pathway are also involved in regulating the morphological changes that take place after repeated stimulation. Finally, we show that Jun kinase is essential for this phenomenon, whereas we found no indication of the involvement of the transcription factor complex AP1 (Jun/Fos). This work shows the involvement of the neuronal PCP signaling pathway in supporting ADSP. Because we find that AP1 mutants can perform ADSP adequately, we hypothesize that, upon Wg activation, the Rho GTPases and Jun kinase are involved locally at the synapse, in instructing cytoskeletal dynamics responsible for the appearance of the morphological changes occurring during ADSP. | | 11:46a |
Role of Immature Choroid Plexus in the Pathology of Autism Spectrum Disorder
During gestation, the choroid plexus (ChP) produces protein-rich cerebrospinal fluid and matures prior to brain development. It is assumed that ChP dysfunction has a profound effect on developmental neuropsychiatric disorders, such as Autism Spectrum Disorder (ASD). However, the mechanisms linking immature ChP to the onset of ASD remain unclear. In this study, we found that ChP-specific CAMDI-knockout mice developed an immature ChP, alongside decreased multiciliogenesis and expression of differentiation marker genes following disruption of the cerebrospinal fluid barrier. These mice exhibited ASD-like behaviors, including impaired socialization with delayed critical period. Additionally, administration of Metformin, an FDA-approved drug, before the critical period achieved ChP maturation and restored social behaviors. Furthermore, ASD model mice and ASD patient-derived organoids developed immature ChP. These results indicate towards involvement of immature ChP in the pathogenesis of ASD and suggest the targeting of functional maturation of ChP as a therapeutic strategy for ASD. |
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