bioRxiv Subject Collection: Neuroscience's Journal
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Thursday, December 5th, 2024
| Time |
Event |
| 7:16a |
Oral supplementation with Nicotinamide Riboside treatment protects RGCs in DBA/2J mouse model
PurposeThe aim of this study was to test whether oral administration of nicotinamide riboside (NR), the nicotinamide adenine dinucleotide (NAD+) precursors, protect retina ganglion cells (RGCs) from neurodegeneration in DBA/2J (D2) mice, which is a widely used mouse model of age-related inherited glaucoma.
MethodOral NR or NAM administration (NR low dose: 1150mg/kg; NR high dose: 4200mg/kg; NAM low dose group: 500mg/kg; NAM high dose: 2000mg/kg of body weight per day) essentially started when D2 mice were 4 or 9 months old and continued up to 12 months old. Control cohort identically received food/water without NAM or NR. Intraocular pressure (IOP) was measured every month until experiment completion. Pattern electroretinography (PERG) was recorded. Retinas were harvested for whole mount immunofluorescence staining with RGCs marker Brn3a and imaged by fluorescent confocal microscopy. Optic nerves were harvested for axon staining and quantification. Retinal NAD+ levels were enzymatically assayed.
ResultsNR oral supplementary treatment started at 4 months old robustly increased retinal NAD+ levels in D2 mice (NRHigh vs. vehicle: 273.7{+/-}23.59% vs. 108.70{+/-}12.10%, p<0.001). In aged vehicle group (12 months old), there was significantly diminution of the P1 and N2 components of PERG response compare with naive group (naive vs. vehicle: P1: 7.82{+/-} 0.70uV vs 1.63{+/-} 0.17uV, p<0.0001; N2: -13.29{+/-} 0.83uV vs. -3.22{+/-} 0.27uV, p<0.0001; Kruskal-Wallis test with Dunn s multiple comparison test). NR treatment preserved aged D2 visual function when mice were 9 and 12 months old. In addition, long-term NR high dose treatment significantly protected against total RGCs loss and optic nerve atrophy (RGC: NRHigh vs. vehicle: 1412{+/-}62.00vs 475.2{+/-}94.68 cells/field, p<0.00001; axon numbers: NRHigh vs. vehicle: 23990{+/-}1159 vs 8573{+/-}1160, n=41-53, p<0.0001). Furthermore, long-term NR supplementation prevent iris depigmentation and delayed IOP elevation.
ConclusionNR oral supplementary treatment significantly preserved RGC and axon numbers, potentially preserves retinal function via elevated retinal NAD+ level in aged D2 mice. Interestingly, NR treatment also prevented iris atrophy, delayed IOP elevation associated with this glaucoma model. NR oral supplementation thus treated several aspects of murine pigment dispersion glaucoma. Given parallels between this model and glaucoma in human, out data indicate that NR is worth exploring as a therapeutic candidate in treatment of glaucoma. | | 8:30a |
Human stem cell-derived GABAergic interneuron development reveals early emergence of subtype diversity followed by gradual electrochemical maturation
Medial ganglionic eminence-derived inhibitory GABAergic pallial interneurons (MGE-pINs) are essential regulators of cortical circuits; their dysfunction is associated with numerous neurological disorders. We developed human (h) MGE-pINs from pluripotent stem cells for the treatment of drug-resistant epilepsy. Here, we analyzed xenografted hMGE-pINs over the lifespan of host mice using single nuclei RNA sequencing. Comparative transcriptomics against endogenous human brain datasets revealed that 97% of grafted cells developed into somatostatin (SST) and parvalbumin (PVALB) subtypes, including populations that exhibit selective vulnerability in Alzheimers disease. Transplanted hMGE-pINs demonstrated rapid emergence of subclass features, progressing through distinct transcriptional states sequentially involving neuronal migration, synapse organization, and membrane maturation. We present molecular, electrophysiological, and morphological data that collectively confirm the derivation of diverse bona-fide human SST and PVALB subtypes, providing a high-fidelity model to study human MGE-pIN development and functional maturation as well as a compositional atlas for regenerative cell therapy applications. | | 8:30a |
Revealing rhythm categorization in human brain activity
Humans across cultures show an outstanding capacity to perceive, learn, and produce musical rhythms. These skills rely on mapping the infinite space of possible rhythmic sensory inputs onto a finite set of internal rhythm categories. What are the brain processes underlying rhythm categorization? We used electroencephalography (EEG) to measure brain activity as human participants listened to a continuum of rhythmic sequences characterized by repeating patterns of two inter-onset intervals. Using frequency and representational similarity analyses, we show that brain activity does not merely track the temporal structure of rhythmic inputs, but, instead, automatically produces categorical representation of rhythms. Surprisingly, despite this automaticity, these rhythm categories do not arise in the earliest stages of the ascending auditory pathway, but show strong similarity between implicit neural and overt behavioral responses. Together, these results and methodological advances constitute a critical step towards understanding the biological roots and diversity of musical behaviors across cultures. | | 8:30a |
Narcissistic and Antisocial Personality Traits are both encoded in the Triple Network: Connectomics evidence
The neural bases of narcissistic and antisocial traits are still under debate. One intriguing question is whether these traits are encoded within the so-called triple network e.g. the default mode (DMN), salience (SN), and fronto-parietal (FPN) networks, and whether these traits affect the same networks in a similar manner. Connectome-based analyses were conducted on resting-state scans from 183 participants, examining regional and global graph-theoretic metrics in the DMN, SN, and FPN, with the visual and sensorimotor networks as controls. Our findings revealed a clear involvement of the triple network in narcissistic and antisocial traits, confirming a shared neural substrate for the two traits. Both traits were negatively predicted by the anterior cingulate cortex of the SN, possibly indicating less awareness of dangers and more proneness to engage in risky behaviors. Additionally, both traits were positively predicted by the lateral prefrontal cortex of the FPN, suggesting augmented strategic thinking to manipulate others and increased planning skills to achieve personal goals. Besides similarities, there were also some differences. Specific hubs of the DMN were positively associated with narcissism but negatively related with antisocials, possibly explaining their differences in self-reflection and thinking about the self, largely present in the former, but usually reduced in the latter. These results extend previous findings on the involvement of the triple network in personality disorders and suggest both common and different mechanisms underlying narcissistic and antisocial traits. As such, these findings could pave the way for developing potential biomarkers of personality pathology and identify neurostimulation intervention targets. | | 9:47a |
Cholinergic interneurons of the dorsomedial striatum mediate winner-loser effects on social hierarchy dynamics in male mice.
Cholinergic interneurons of the dorsomedial striatum may play a role in social hierarchy dynamics. A social hierarchy is an organization of individuals by rank that occurs in social animals. Establishing a new social hierarchy involves flexible behavior in deciding whether to be a winner or loser, experience of winning or losing, and stabilization of rank. The neural circuits underlying such flexible behavior have yet to be fully understood, but previous research indicates that cholinergic interneurons in the dorsomedial striatum play a role in behavioral flexibility. We used the dominance tube test to measure ranking within group housed mice, before and after between-cage competitions using the same test. We found that the experience of winning or losing against mice from different cages not only contributes to new social hierarchies among the competitors, but also causally influences the subsequent social hierarchy among their cage mates in the home cage - supporting the hypothesis of winner-loser effects on later social ranking. To test the hypothesis that cholinergic interneurons contribute to social hierarchy dynamics, we made a selective lesion of cholinergic interneurons in the dorsomedial striatum. The lesion did not prevent social hierarchy formation among pairs of similarly ranked individuals from different cages. However, it reduced the loser effect of external competition on the subsequent home-cage rankings in dominant mice. In light of these results we suggest that cholinergic interneurons in dorsomedial striatum increase the flexibility of social hierarchy dynamics.
Significance statementThe effect of winning or losing a competition on subsequent ranking in mouse home cage social hierarchies was examined using the dominance tube test. We found that losing, when dominant mice were defeated by equally ranked mice from another cage, led to decreased social rank in their home cage. Conversely, winning by initially subordinate mice led to increased rank in the home cage social hierarchy. The loser effect on subsequent behavior in dominant mice was reduced after selective lesions of the cholinergic interneurons of the dorsomedial striatum. We suggest that losing might produce these effects by altering the activity of cholinergic interneurons, and thus modulating synaptic plasticity in neural circuits involved in flexible decision making and positive reinforcement. | | 9:47a |
Microglial cathepsin B promotes neuronal efferocytosis during brain development
Half of all newborn neurons in the developing brain are removed via efferocytosis - the phagocytic clearance of apoptotic cells. Microglia are brain-resident professional phagocytes that play important roles in neural circuit development including as primary effectors of efferocytosis. While the mechanisms through which microglia recognize potential phagocytic cargo are widely studied, the lysosomal mechanisms that are necessary for efficient digestion are less well defined. Here we show that the lysosomal protease cathepsin B promotes microglial efferocytosis of neurons and restricts the accumulation of apoptotic cells during brain development. We show that cathepsin B is microglia-specific and enriched in brain regions where neuronal turnover is high in both zebrafish and mouse. Myeloid-specific cathepsin B knockdown in zebrafish led to dysmorphic microglia containing undigested dead cells, as well as an accumulation of dead cells in surrounding tissue. These effects where phenocopied in mice globally deficient for Ctsb using markers for apoptosis. We also observed behavioral impairments in both models. Live imaging studies in zebrafish revealed deficits in phagolysosomal fusion and acidification, and live imaging of cultured mouse microglia reveal delayed phagocytosis consistent with impairments in digestion and resolution of phagocytosis rather than initial uptake. These data reveal a novel role for microglial cathepsin B in mediating neuronal efferocytosis during typical brain development. | | 9:47a |
Early-life stress impairs development of functional interactions and neuronal activity within prefrontal-amygdala networks in vivo
Early-life stress (ELS), such as parental neglect or abuse, predisposes an individual to develop mental disorders. Disease hallmarks include heightened amygdala reactivity and impaired prefrontal cortex-amygdala functional interactions, already during childhood and adolescence. However, which cellular and circuit mechanisms underlie these hallmarks, as well as the altered developmental trajectory of prefrontal-amygdala networks, is poorly understood. Here we performed simultaneous in vivo local-field potential and multi-unit recordings under light urethane anaesthesia in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) of male and female juvenile or adolescent mice, exposed to a resource scarcity model of ELS. We find a developmentally transient low-theta (3-5 Hz) oscillatory hypercoupling within mPFC-BLA networks in juvenile ELS males which seems to result from a precocious development of coupling strength after ELS. In the mPFC, neuronal spiking activity was decreased in juvenile males and the local theta entrainment of spike firing disrupted. In BLA, both sexes showed an increase in firing activity in a subpopulation of neurons after ELS, also confirmed by an increase in {Delta}FosB-positive neurons in BLA, which we identified to be non-GABAergic. Directed interactions, i.e. the ability to entrain spike firing in mPFC to the theta rhythm in BLA and vice versa, were also impaired predominantly in juvenile males after ELS, while females showed a milder phenotype. These early sex-dependent impairments in the functional development of prefrontal-amygdala circuits may promote abnormal fear learning and anxiety after ELS and may predispose to a disease phenotype later on. | | 11:47p |
Temporal and Hemispheric Dynamics in Neural Processing of Auditory and Speech Stimuli Across Linguistic Complexity: A MEG Source Space Study
In this study we investigated the neural processing of auditory stimuli of varying complexity: a non-linguistic (pure tone), a simple linguistic (phoneme) and a complex linguistic (word) stimulus. We recorded brain activity of 30 healthy, righthanded participants using magnetoencephalography (MEG), and compared the resulting evoked fields (ERFs) in source space in three different time intervals, i.e. early (0-250ms), mid (250-500ms) and late (500-750ms) responses. Our results reveal a bilateral activation during early response and rightlateralized activation in the mid-phase for all stimuli. Hoewever, the late response exhibited lateralization variations. The pure tone predominantly activated the right hemisphere, consistent with pitch processing theories. The phoneme primarily engaged the left hemisphere, supporting its role in phonemic processing. Notably, the word elicited activation in both hemispheres, reflecting phonemic processing on the left and stress patterns on the right. These findings highlight the intricate interplay between temporal processing and hemispheric lateralization in speech perception, emphasizing the importance of stimulus complexity and temporal dynamics in understanding auditory and speech processing. | | 11:47p |
Analyzing Differences in Processing Nouns and Verbs in the Human Brain using Combined EEG and MEG Measurements
Language and consequently the ability to transmit and spread complex information is unique to the human species. The disruptive event of the introduction of large language models has shown that the ability to process language alone leads to incredible abilities and, to some extent, to intelligence. However, how language is processed in the human brain remains elusive. Many insights originate from fMRI studies, as the high spatial resolution of fMRI devices provides valid information about where things happen. Nevertheless, the limited temporal resolution prevents us from gaining a deep understanding on the underlying mechanisms. In this study, we performed combined EEG and MEG measurements in 29 healthy right-handed human subjects during the presentation of continuous speech. We compared the evoked potentials (ERPs and ERFs) for different word types in source space and sensor space across the whole brain. We found characteristic spatio-temporal patterns for different word types (nouns, verbs) especially at latencies of 300ms to 1 s. This is further emphasized by the fact that we observe these effects in two pre-defined sub-samples of the data set (exploration and validation sample). We expect this study to be the starting point for further evaluations of semantic and syntactic processing in the brain. |
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