bioRxiv Subject Collection: Neuroscience's Journal
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Wednesday, September 4th, 2024
| Time |
Event |
| 12:31a |
Decreased Astrocytic CCL5 by MiR-324-5p Ameliorates Ischemic Stroke Injury via CCR5/ERK/CREB Pathway
Following ischemic stroke, Ccl5 mRNA expression increased, while miR-324-5p expression decreased in the peri-infract cortex of middle cerebral artery occlusion (MCAO) mice. However, the roles of CCL5 and miR-324-5p in stroke remain unclear. Here, we show that inhibiting CCL5 using antibodies or miR-324-5p not only reduced infarct area and preserved neurological function in MCAO mice but also attenuated astrocyte and microglia activation, protected dendritic structures, and maintained spine density. In an astrocyte-neuron co-culture system after oxygen-glucose deprivation (OGD), knockdown astrocytic CCL5 expression by antibody or miR-324-5p decreased neuronal apoptosis and preserved dendritic architecture. Importantly, the suppression of CCL5 enhanced the activation of the ERK/CREB pathway both in vivo and in vitro. Consistent with these findings, the application of Maraviroc, a CCR5 antagonist, reduced infarct size, decreased neuronal apoptosis, and upregulated the ERK/CREB pathway in neurons treated with OGD. In conclusion, targeting the CCL5 pathway via miR-324-5p represents a promising therapeutic strategy for alleviating ischemic stroke damage through modulation of neuronal CCR5/ERK/CREB pathway. | | 1:48a |
The sodium leak channel NALCN is regulated by neuronal SNARE complex proteins
The sodium leak channel NALCN is vital for the regulation of electrical activity in neurons and other excitable cells, and mutations in the channel or its auxiliary proteins lead to severe neurodevelopmental disorders. Here we show that the neuronal SNARE complex proteins syntaxin and SNAP25, which enable synaptic transmission in the nervous system, inhibit the activity of the NALCN channel complex in both heterologous systems and primary neurons. The existence of this interaction suggests that the neurotransmitter release machinery can regulate electrical signalling directly, and therefore modulate the threshold for its own activity. We further find that reduction of NALCN currents is sufficient to promote cell survival in syntaxin-depleted cells. This suggests that disinhibited NALCN may cause the puzzling phenomenon of rapid neuronal cell death in the absence of syntaxin. This interaction may offer opportunities for future drug development against genetic diseases linked to both NALCN- and SNARE protein-containing complexes. | | 8:18a |
Revealing the co-existence of written and spoken language coding neural populations in the left-ventral occipitotemporal cortex
Reading relies on the ability to map written symbols with speech sounds. The left ventral occipitotemporal cortex (left-vOT) plays a crucial role in this process. Through the automatization of the mapping ability, this specific part of the ventral visual pathway (a.k.a., the Visual Word Form Area) progressively becomes specialized in written word recognition. Yet, despite its key role in reading, the area also responds to speech. This observation raises questions about the actual nature of neural representations encoded in the left-vOT and, therefore, the underlying mechanism of the cross-modal responses. Here, we addressed this issue by applying fine-grained analyses of within- and cross-modal repetition suppression effects (RSEs) and Multi-Voxel Pattern Analyses in fMRI and sEEG experiments. Convergent evidence across analysis methods and protocols showed significant RSEs and successful decoding in both within-modal visual and auditory conditions suggesting that subpopulations of neurons within the left-vOT distinctly encode written and spoken language inputs. This functional organization of neural populations enables the area to respond to speech input directly and indirectly, i.e., after speech sounds are converted to orthographic representations. The finding opens further discussions on how the human brain may be prepared and adapted for an acquisition of a complex ability such as reading. | | 8:18a |
Cholinergic signaling differentially regulates song premotor circuits to stabilize songs in songbirds
Cholinergic modulation plays an important role in motor skill learning, including vocal learning. In songbirds, song premotor nucleus RA simultaneously receives inputs from song nuclei HVC and LMAN, and then its projection neurons (RAPNs) generate song motor control output. Using electrophysiological and pharmacological methods, we found that cholinergic signaling can enhance song stability by reducing HVC-RAPN excitatory synaptic transmission in adult male zebra finches, mediated by mAChRs. Although nAChRs are not effective overall, cholinergic signaling can also decrease LMAN-RAPN excitatory synaptic transmission induced by electrical stimulation via nAChRs, suggesting the potential role of cholinergic regulation in song behavior through LMAN-RA pathway. On the contrary, in adult female zebra finches, only LMAN-RAPN synaptic transmission was reduced by cholinergic signaling via mAChRs. The role of differential cholinergic regulation of song premotor circuits in songbirds' singing provides insights into the neural processes of motor skill learning. | | 9:31a |
Attention defines the context for implicit sensorimotor adaptation
Movement errors are used to continuously recalibrate the sensorimotor map, a process known as sensorimotor adaptation. Here we examined how attention influences this automatic and obligatory learning process. Focusing first on spatial attention, we compared conditions in which the visual feedback that provided information about the movement outcome was either attended or unattended. Surprisingly, this manipulation had no effect on the rate of adaptation. We next used a dual-task methodology to examine the influence of attentional resources on adaptation. Here, again, we found no effect of attention, with the rate of adaptation similar under focused or divided attention conditions. Interestingly, we found that attention modulates adaptation in an indirect manner: Attended stimuli serve as cues that define the context for learning. The rate of adaptation was significantly attenuated when the attended stimulus changed from the end of one trial to the start of the next trial. In contrast, similar changes to unattended stimuli had no impact on adaptation. Together, these results suggest that visual attention defines the cues that establish the context for sensorimotor learning. | | 9:31a |
Predictive Coding of Reward in the Hippocampus
A fundamental objective of the brain is to anticipate future outcomes. This process requires learning the states of the world as well as the transitional relationships between those states. The hippocampal cognitive map is believed to be one such internal model. However, evidence for predictive coding and reward sensitivity in the hippocampal neuronal representation suggests that its role extends beyond purely spatial representation. In fact, it raises the question of what kind of spatial representation is most useful for learning and maximizing future rewards? Here, we track the evolution of reward representation over weeks as mice learn to solve a cognitively demanding reward-based task. Our findings reveal a highly organized restructuring of hippocampal reward representations during the learning process. Specifically, we found multiple lines of evidence, both at the population and single-cell levels, that hippocampal representation becomes predictive of reward over weeks. Namely, both population-level information about reward and the percentage of reward-tuned neurons decrease over time. At the same time, the representation of the animals' choice and reward approach period (the period between choice and reward) increased over time. By tracking individual reward cells across sessions, we found that neurons initially tuned for reward shifted their tuning towards choice and reward approach periods, indicating that reward cells backpropagate their tuning to anticipate reward with experience. These findings underscore the dynamic nature of hippocampal representations, highlighting their critical role in learning through the prediction of future outcomes. | | 9:31a |
Temporal proteomic and PTMomic atlas of cerebral organoid development
Cerebral organoids (CBOs) are generated from pluripotent stem cells that undergo neuroectoderm specification and neuronal differentiation in three dimensions. The developing neurons in CBOs migrate and self-organize into cerebral cortex-like layers, mimicking human brain development. CBOs develop according to intrinsic signaling mechanisms and offer unique insights into mechanisms of early human brain development. This process requires coordinated spatiotemporal regulation of protein expression and function, where the latter can be achieved by post-translational modifications (PTMs) on proteins. Despite the importance of proteins in brain development and function, profiling of protein abundance and the involvement of PTMs in CBO development remain underexplored. To gain insight into protein and PTM abundance in CBOs, we performed a high-resolution temporal analysis of CBOs up to day 200 using proteomics, PTMomics and metabolomics. We quantified more than 9,300 proteins and various neurodevelopmentally relevant PTMs (including phosphorylation, lysine acetylation, sialylated N-glycosylation, and cysteine modifications). We demonstrate that protein abundance and dynamic PTMs show significant temporal changes during CBO development related to neuronal differentiation and energy metabolism, whereas calcium signaling is mainly regulated by dynamic PTMs. We further show that synaptic protein content correlated with neurotransmitter levels, and we detected astroglia beyond day 100. Lastly, comparative analysis showed proteomic similarities between CBOs and human fetal brain tissue, supporting the physiological relevance of CBOs. Overall, our study presents a temporal atlas of protein and PTM abundance in CBOs and provides a valuable resource for studying neurodevelopment in neural organoids. | | 12:21p |
Phonetic underpinnings of sound symbolism across multiple domains of meaning
Sound symbolism occurs when the sound of a word alone can convey its meaning, e.g. balloon and spike sound rounded and pointed, respectively. Sound-symbolic correspondences are widespread in natural languages, but it is unclear how they are instantiated across different domains of meaning. Here, participants rated auditory pseudowords on opposing scales of seven different sound-symbolic domains: shape (rounded-pointed), texture (hard-soft), weight (light-heavy), size (small-big), brightness (bright-dark), arousal (calming-exciting), and valence (good-bad). Ratings showed cross-domain relationships, some mirroring those between corresponding physical domains, e.g. size and weight ratings were associated, reflecting a physical size-weight relationship, while others involved metaphorical mappings, e.g., bright/dark mapped onto good/bad, respectively. The phonetic features of the pseudowords formed unique sets with characteristic feature weightings for each domain and tended to follow the cross-domain ratings relationships. These results suggest that sound-symbolic correspondences rely on domain-specific patterns of phonetic features, with cross-domain correspondences reflecting physical or metaphorical relationships. | | 2:20p |
Cis-regulatory elements driving motor neuron-restricted viral payload expression within the mammalian spinal cord
Spinal motor neuron (MN) dysfunction is the cause of a number of clinically significant movement disorders. Despite the recent approval of gene therapeutics targeting these MN-related disorders, there are no viral delivery mechanisms that achieve MN-restricted transgene expression. In this study, chromatin accessibility profiling of genetically defined mouse MNs was used to identify candidate cis-regulatory elements (CREs) capable of driving MN-selective gene expression. Subsequent testing of these candidates identified two CREs that confer MN-selective gene expression in the spinal cord as well as reduced off-target expression in dorsal root ganglia. Within one of these candidate elements, we identified a compact core transcription factor (TF)-binding region that drives MN-selective gene expression. Finally, we demonstrate that selective spinal cord expression of this mouse CRE is preserved in non-human primates. These findings suggest that the generation of cell-type-selective viral reagents, in which cell-type-selective CREs drive restricted gene expression, will be valuable research tools in mice and other mammalian species, with potentially significant therapeutic value in humans. | | 4:17p |
Musical training does not enhance neural sound encoding at early stages of the auditory system: A large-scale multisite investigation
Musical training has been associated with enhanced neural processing of sounds, as measured via the frequency following response (FFR), implying the potential for human subcortical neural plasticity. We conducted a large-scale multi-site preregistered study (n > 260) to replicate and extend the findings underpinning this important relationship. We failed to replicate any of the major findings published previously in smaller studies. Musical training was related neither to enhanced spectral encoding strength of a speech stimulus (/da/) in babble nor to a stronger neural-stimulus correlation. Similarly, the strength of neural tracking of a speech sound with a time-varying pitch was not related to either years of musical training or age of onset of musical training. Our findings provide no evidence for plasticity of early auditory responses based on musical training and exposure. | | 4:17p |
Periventricular and Deep White Matter Hyperintensity Thresholds in Aging: Exponential Progression, Cognitive Decline, and Neuroanatomic Atrophy
White matter hyperintensities (WMH), which are brain lesions associated with cerebral small vessel disease and aging, signify fiber loss and pruning. Analysis of T2-FLAIR MRI data from the NACC cohort, including cognitively normal (CN), cognitively impaired (CI), and Alzheimer's disease (CI-AD) subjects, revealed that a significant subset of participants, even those classified as CN, harbor substantial periventricular (PVWMH) and deep white matter hyperintensity (DWMH) loads, while others displayed minimal or no PVWMH and DWMH, across ages 50-94 years. In this study, we quantified the thresholds and progression kinetics of PVWMH and DWMH and their impact on cognitive performance and neuroanatomic changes in the aging cohort (NCN = 521, NCI = 146, NCI-AD = 319). Our findings explore the impact of PVWMH and DWMH loads on global and specific cognitive domains to determine whether cognitive impairments are directly induced by PVWMH and DWMH loads, or mediated through distinct neuroanatomic structures. PV and DWMH loads are higher in CI and CI-AD subjects compared to CN but the PVWMH and DWMH loads are not discriminative of CI and CI-AD. The progression kinetics of PVWMH and DWMH volume with age indicate an exponential rate of increase, with PVWMH escalating approximately twice as fast as DWMH particularly around an inflection point at 61 years of age. PVWMH load presents with increased probability of occurrence in frontal horn compared to occipital horn while DWMH is diffused and accumulates significantly at later age than that observed for PVWMH. Multivariate global regression suggested significant effect (p<0.01) of PVWMH on Trail making tests (TMTs)-A and B (executive function), animal naming tests (semantic memory), with no significant effects observed for DWMH load. Indeed, beyond a threshold of PVWMH volume >2.3 mL, significant deficits in TMTs were observed compared to the subjects without PVWMH load. A PVWMH volume >2.3 mL and DWMH >2.75 mL is significantly associated with impairments in attention & working memory (Digit Span Tests), and semantic memory. Noticeably, significant neuroanatomic atrophy in the cerebral cortex, nucleus accumbens, RMFG, precentral, and paracentral gyrus is observed for PVWMH load >2.3 mL, while DWMH load was not significantly associated with neuroanatomic loss. Furthermore, a mediation model employing neuroanatomic volumes as mediator, PVWMH load as predictor and cognitive tests as outcome suggested that PVWMH volume contributes significantly to deficits in TMT-B mediated through atrophy in precentral gyrus (64%), accumbens (39%), paracentral gyrus (32%), rostral middle frontal gyrus (31%), and lingual gyrus (30%), each contributing distinct proportions, alongside the direct effect. DWMH load did not emerge as a significant predictor (direct or indirect) for the cognitive deficits. Further, no significant neuroanatomic mediations from PVWMH load were observed for other cognitive tests indicative of direct involvement of PVWMH load. Global cognition like MMSE was affected only at a higher PVWMH accumulation (>6 ml). | | 4:17p |
Sex-specific differences in brain activity dynamics of youth with a family history of substance use disorder
An individual's risk of substance use disorder (SUD) is shaped by a complex interplay of potent biosocial factors. Current neurodevelopmental models posit vulnerability to SUD in youth is due to an overreactive reward system and reduced inhibitory control. Having a family history of SUD is a particularly strong risk factor, yet few studies have explored its impact on brain function and structure prior to substance exposure. Herein, we utilized a network control theory approach to quantify sex-specific differences in brain activity dynamics in youth with and without a family history of SUD, drawn from a large cohort of substance-naive youth from the Adolescent Brain Cognitive Development Study. We summarize brain dynamics by calculating transition energy, which probes the ease with which a whole brain, region or network drives the brain towards a specific spatial pattern of activation (i.e., brain state). Our findings reveal that a family history of SUD is associated with alterations in the brain's dynamics wherein: i) independent of sex, certain regions' transition energies are higher in those with a family history of SUD and ii) there exist sex specific differences in SUD family history groups at multiple levels of transition energy (global, network, and regional). Family history-by-sex effects reveal that energetic demand is increased in females with a family history of SUD and decreased in males with a family history of SUD, compared to their same-sex counterparts with no SUD family history. Specifically, we localize these effects to higher energetic demands of the default mode network in females with a family history of SUD and lower energetic demands of attention networks in males with a family history of SUD. These results suggest a family history of SUD may increase reward saliency in males and decrease efficiency of top-down inhibitory control in females. This work could be used to inform personalized intervention strategies that may target differing cognitive mechanisms that predispose individuals to the development of SUD. | | 8:32p |
Distinct neural manifolds and critical roles of primate caudate nucleus in multimodal decision-making
Perceptual decision-making is an important cognitive function involving distributed networks spanning cortico-subcortical levels, yet most studies only include single modality stimulus and reveal largely similar signals related with animal choice across areas, making it puzzling about individual's unique roles. Using a multimodal paradigm, here we showed dorsal medial striatum, namely caudate nucleus (CN) in primate, dramatically differs from association cortex in a reduced low-dimensional subspace. Specifically, bimodal neural state evolved towards nonvisual (vestibular) in CN, rather than towards visual as in frontal/parietal cortices. The distinct CN trajectories pattern may readily explain behaviors including close-to-vestibular but not visual reaction time under bimodal condition, or vestibular-overweighting during cue-conflict context. Further causal-link experiments including applying GABA-A-receptor agonist, and D1-receptor antagonist confirmed CN's essential role of dopaminergic input. Electrical-microstimulation also verified CN's sufficient contributions. Our results indicate beyond relay-station in cortico-striatal circuitry, CN plays distinct and critical roles in complex tasks with multimodal inputs. | | 9:48p |
Neuronal autophagosomes are transported to astrocytes for degradation
Autophagy is a vital catabolic process responsible for the degradation of cytosolic components, playing a key role in cellular homeostasis and survival. At synapses, autophagy is crucial for regulating neuronal activity and utilizes a specialized machinery. While considerable progress has been made in understanding the initiation of autophagy and autophagosome formation, the mechanisms governing the clearance of autophagosomes from synaptic sites remain poorly understood. Here, we identify a novel pathway in which astrocytes actively participate in the clearance of pre-synaptic autophagosomes. Using neurons derived from human induced pluripotent stem cell (hiPSC) lines expressing fluorescent autophagy markers and chimeric mouse models, we demonstrate that neuronal autophagosomal vesicles are physically transferred to astrocytes, a process that is enhanced when synaptic activity is suppressed. Autophagosome transfer does not require direct physical cellular contact, but it does require Dynamin and cholesterol-dependent endocytosis for the internalized neuronal autophagosomes to ultimately fuse with astrocytic lysosomes. Our findings reveal a previously unrecognized mechanism of neuronal autophagosome clearance that does not require slow axonal retrograde transport but their transfer to nearby astrocytes. |
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