eNeuro最新文献

Mouse lines with tetracycline-controlled gene expression in specific neuronal populations provide valuable tools for studying their development, function, connectivity and pathology in vivo. Our initial goal was to generate a mouse model that could express amyotrophic lateral sclerosis (ALS)-associated genes specifically in spinal cord motor neurons under the control of the HB9 promoter. However, HB9-tTA mice unexpectedly direct target gene expression in a small subset of dorsal horn neurons. These mice represent a new tool for scientists who are interested in studying these spinal cord neurons.Significance Statement We have generated new mouse lines that can manipulate gene expression in a small subset of dorsal horn neurons in the spinal cord. These new tools will be useful for scientists who are interested in studying the development, function, and connectivity of this small subset of spinal neurons in vivo.

Early and accurate diagnosis of Alzheimer's Disease (AD) will be key for effective personalized treatment plans (Cummings, 2023). Significant difficulties in auditory processing have been frequently reported in many patients with mild cognitive impairment (MCI), the prodromal form of AD (Tarawneh et al., 2022), making it an outstanding candidate as AD diagnostic biomarker. However, the efficiency of diagnosis with this parameter has not been explored. Here we show that when male mice with amyloidosis begin to show memory decline, changes in the auditory brainstem response (ABR) to clicks enable the reliable diagnosis of disease using a machine learning algorithm. Interpretation of the machine learning diagnosis revealed that the upper levels of the auditory pathway, including the inferior colliculus, were the probable sources of the defects. Histological analyses show that in these locations, neuroinflammation and plaque deposition temporally correlate with behavioral changes consistent with memory loss. While these findings are tempered by the caveat that they derive from amyloidosis mice, we propose that ABR measurements be evaluated as an additional rapid, low-cost, non-invasive biomarker to assist the diagnostic testing of early-stage AD.Significance Statement New disease modifying treatments for AD only work for a subset of patients and require precise disease staging. AD is highly correlated with both central auditory dysfunction and hearing loss, but these are not diagnostic. We find that characteristics of the passive auditory brainstem response test reliably diagnose the onset of memory decline in a mouse model of AD, correlating with the initiation of amyloid deposits and neuroinflammation in the upper auditory nuclei. We further highlight the role that one region, the inferior colliculus, plays in multi-sensory integration, speculating that dementia becomes evident when the plaque-burdened cortex is unable to compensate for the degradation of pre-conscious sensory processing.

Substantia nigra pars compacta (SNc) dopaminergic (DA) neurons are characterized by specific morphological and electrophysiological properties. First, in ∼90% of the cases, their axon arises from an axon-bearing dendrite (ABD) at highly variable distances from the soma. Second, they display a highly regular pattern of spontaneous activity (aka pacemaking) and a broad action potential (AP) that faithfully back-propagate through the entire dendritic arbor. In previous studies (Moubarak et al., 2019; Moubarak et al., 2022), we demonstrated that the presence of a high density of sodium current in the ABD and the complexity of this dendrite played a critical role in the robustness of pacemaking and setting the half-width of the AP. In the current study, we investigated the postnatal development of both morphology and AP shape in SNc DA neurons in order to determine when and how the mature electrophysiological phenotype of these neurons was achieved. To do so, we performed electrophysiological recordings of SNc DA neurons at 4 postnatal ages (P3, P7, P14, P21) and fully reconstructed their dendritic and proximal axon morphology. Our results show that several morphological parameters, including the length of the ABD, display abrupt changes between P7 and P14, such that a mature morphology is reached by P14. We then showed that AP shape followed a similar timecourse. Using realistic multicompartment Hodgkin-Huxley modeling, we then demonstrated that the rapid morpho-electrical maturation of SNc DA neurons likely arises from synergistic increases in dendritic length and in somatodendritic sodium channel density.Significance statement Substantia nigra pars compacta (SNc) dopaminergic (DA) neurons display several morphological and electrophysiological peculiarities. For instance, their axon arises in most cases from an axon-bearing dendrite (ABD) and their action potential (AP) is broad and faithfully back-propagates through the entire dendritic tree. In the present study, we performed electrophysiological recordings, neuronal reconstruction and computational modeling to determine the postnatal development of dendritic morphology and AP shape in SNc DA neurons. We found that ABD length rapidly increases after post-natal day 7 (P7) to reach maturity by P14 and that AP shape follows a similar timecourse. Computational modeling then suggested that the achievement of a mature AP comes from synergistic increases in dendritic length and in somatodendritic sodium channel density.

One pending question in social neuroscience is whether interpersonal interactions are processed differently by the brain depending on the bodily characteristics of the interactor, i.e., their physical appearance. To address this issue, we engaged participants in a minimally interactive task with an avatar either showing bodily features or not while recording their brain activity using Electroencephalography (EEG) in order to investigate indices of action observation and action monitoring processing. Multivariate results showed that bodily compared to non-bodily appearance modulated parieto-occipital neural patterns throughout the entire duration of the observed movement and that, importantly, such patterns differ from the ones related to initial shape processing. Furthermore, among the electrocortical indices of action monitoring, only the early observational Positivity (oPe) was responsive to the bodily appearance of the observed agent under the specific task requirement to predict the partner movement. Taken together, these findings broaden the understanding of how bodily appearance shapes the spatiotemporal processing of an interactor's movements. This holds particular relevance in our modern society, where human-artificial (virtual or robotic) agent interactions are rapidly becoming ubiquitous.Significance statement During interpersonal motor interactions, the observation and monitoring of other's actions are essential mechanisms depending on two interconnected brain networks. Whether the neurophysiological signatures of action observation and monitoring are modulated by the appearance of an interacting partner remains an open question of particular relevance in order to tackle how the brain interfaces with artificial agents. In the present study we used highly ecological virtual stimuli in a minimally interacting scenario as well as univariate and multivariate EEG analyses to broaden our understanding of the influence of bodily appearance on the spatiotemporal processing of biological movements in the AON and in the action monitoring system.

A decline in cognitive abilities is associated with the aging process, affecting nearly 33% of U.S. adults over the age of 70, and is a risk factor for the development of dementia and Alzheimer's disease. Several studies have reported age-related alterations in the transcriptome in the hippocampus, a major site of memory storage that is among the first regions impacted with age, dementia and Alzheimer's disease. However, much remains unknown about why these transcriptional changes exist in the aged hippocampus and how this impacts memory late in life. Here, we show that monoubiquitination of histone H2B (H2Bubi), an epigenetic mechanism recently reported to be major regulator of the epigenome and transcriptome during memory formation in the young adult brain, decreases with age in the hippocampus of male rats. In vivo CRISPR-dCas9 mediated upregulation of Rnf20, the only ubiquitin E3 ligase for H2B, in the hippocampus significantly improved memory retention in aged rats. Remarkably, RNA-seq analysis revealed that in addition to the 18 genes typically upregulated in the aged rat hippocampus following contextual fear conditioning, Rnf20 upregulation caused learning-related increases and decreases in 40 and 11 unique genes, respectively, suggesting that these 51 genes may be among those most critical for improving memory in advanced age. Together, these data suggest that H2B monoubiquitination is a significant regulator of age-related dysregulation of the transcriptome and impairments in memory. Significance Statement Age-related memory decline impacts the lives of millions of Americans and is a risk factor for developing dementia. It is imperative that we understand why brain molecular mechanisms change with age in order to reverse memory loss late in life. Here we show that changes in levels of a major epigenetic modification, histone H2B monoubiquitination (H2Bubi), in the hippocampus impacts memory late in life. Importantly, memory and gene expression can be improved in the aged hippocampus through the upregulation of H2Bubi ligase, Rnf20, using CRISPR-dCas9. This research gives insight into how gene expression in the hippocampus changes with age and leads to memory decline.

T-Type calcium channels shape neuronal excitability driving burst firing, plasticity, and neuronal oscillations that influence circuit activity. The three biophysically distinct T-type channel subtypes (Cav3.1, Cav3.2, Cav3.3) are differentially expressed in the brain, contributing to divergent physiological processes. Cav3.2 channels are highly expressed in the dentate gyrus (DG) of the hippocampus, and mice lacking Cav3.2 [knock-out (KO)] exhibit impairments in hippocampal dependent learning and memory tasks, as well as attenuated development of pilocarpine induced epilepsy. Owing to neurogenesis, granule cells (GCs) are continuously added to the DG, generating a heterogeneous population of maturational stages with distinct excitability. While initial studies identified the role of Cav3.2 in mature GC burst firing, its functional relevance in the intrinsic excitability of different GC subpopulations has not yet been examined. In this study, we used juvenile Cav3.2 KO mice to examine the contributions of Cav3.2 channels to GC excitability at three different stages of maturation. We recorded from cells throughout the GC layer using their electrophysiological and morphological features to allocate GCs into immature, intermediate, and mature groups. In immature GCs, loss of Cav3.2 channels reduced the proportion of cells that fired low-threshold calcium spikes. Conversely, Cav3.2 KO increased excitability in regular spiking intermediate and mature GCs, enabling higher-frequency firing, with little impact on the frequency-dependent response. Overall, this study shows that Cav3.2 channels differentially regulate GC excitability throughout maturation and suggest that calcium influx via Cav3.2 may have maturation-dependent contributions to DG processes such as GC survival, integration, and memory encoding.

Auditory masking-the interference of the encoding and processing of an acoustic stimulus imposed by one or more competing stimuli-is nearly omnipresent in daily life and presents a critical barrier to many listeners, including people with hearing loss, users of hearing aids and cochlear implants, and people with auditory processing disorders. The perceptual aspects of masking have been actively studied for several decades, and particular emphasis has been placed on masking of speech by other speech sounds. The neural effects of such masking, especially at the subcortical level, have been much less studied, in large part due to the technical limitations of making such measurements. Recent work has allowed estimation of the auditory brainstem response (ABR), whose characteristic waves are linked to specific subcortical areas, to naturalistic speech. In this study, we used those techniques to measure the encoding of speech stimuli that were masked by one or more simultaneous other speech stimuli. We presented listeners with simultaneous speech from one, two, three, or five simultaneous talkers, corresponding to a range of signal-to-noise ratios (clean, 0, -3, and -6 dB), and derived the ABR to each talker in the mixture. Each talker in a mixture was treated in turn as a target sound masked by other talkers, making the response quicker to acquire. We found consistently across listeners that ABR Wave V amplitudes decreased and latencies increased as the number of competing talkers increased.

Synchronous activity of neuronal networks is found in many brain areas and correlates with cognition and behavior. Gamma synchrony is particularly strong in the dentate gyrus, which is thought to process contextual information in the hippocampus. Several network mechanisms for synchrony generation have been proposed and studied computationally. One such mechanism relies solely on recurrent inhibitory interneuron connectivity, but it requires a large enough number of synapses. Here, we incorporate previously published connectivity data of the dentate gyrus from mice of either sex into a biophysical computational model to test its ability to generate synchronous activity. We find that recurrent interneuron connectivity is insufficient to induce synchronous activity. This applies to an interneuron ring network and the broader dentate gyrus circuitry. Despite asynchronous input, recurrent interneuron connectivity can have small synchronizing effects but can also desynchronize the network for some types of synaptic input. Our results suggest that biologically plausible recurrent inhibitory connectivity alone is likely insufficient to synchronize the dentate gyrus.Significance statement Neurons in the brain do not activate randomly but show synchronous activity with other neurons during states of high activity. In the hippocampus, a brain area responsible for memory storage, synchronous activity is well known and the recurrent inhibitory connections have been proposed to synchronize neurons. Here, we simulated a detailed model of a hippocampal brain area called the dentate gyrus with modern connectivity estimates. We found that the number of connections is insufficient to synchronize the network. This means that other models are more likely to explain synchronous activity in the dentate gyrus. Furthermore, we predict that future experiments interfering with recurrent connectivity will not affect synchronous activity.

Response preparation is accomplished by gradual accumulation in neural activity until a threshold is reached. In humans, such a preparatory signal, referred to as the lateralized readiness potential (LRP), can be observed in the EEG over sensorimotor cortical areas before execution of a voluntary movement. Although well described for manual movements, less is known about preparatory EEG potentials for saccadic eye movements in humans and nonhuman primates. Hence, we describe a LRP over the frontolateral cortex in macaque monkeys. Homologous to humans, we observed lateralized electrical potentials ramping before the execution of both rewarded and nonrewarded contralateral saccades. This potential parallels the neural spiking of saccadic movement neurons in the frontal eye field (FEF), suggesting that it may offer a noninvasive correlate of intracortical spiking activity. However, unlike neural spiking in the FEF, polarization in frontolateral channels did not distinguish between saccade generation and inhibition. These findings provide new insights into noninvasive electrophysiological signatures of saccadic preparation in nonhuman primates, highlighting the potential of EEG measures to bridge invasive neural recordings and noninvasive studies of eye movement control in humans.

Attention-deficit/hyperactivity disorder (ADHD) adversely affects the learning, social interaction, and daily living of affected children. Atomoxetine (ATX) hydrochloride (HCI) has been widely used in clinical practice. Electroencephalogram (EEG) biofeedback, as a nonpharmacological treatment approach, has also demonstrated potential in improving symptoms in children with ADHD. We aimed to investigate the clinical efficacy of combining ATX HCI with EEG biofeedback in the treatment of ADHD in children. We hypothesized that this combined therapy would be more effective in alleviating symptoms in children with ADHD. Ninety children with ADHD were randomly separated into the control group (receiving ATX HCI treatment for 12 weeks) and study group (receiving ATX HCI treatment for 12 weeks combined with 60 sessions of EEG biofeedback treatment; n = 45). Swanson, Nolan, and Pelham-IV (SNAP-IV) rating scale scores, integrated visual and auditory continuous performance test results, Conners parent symptom questionnaire (PSQ) scores, and adverse reactions were counted. After 12 weeks of treatment, SNAP-IV scores were lower in both groups and were much lower in the study group; full-scale attention quotient and full-scale response control quotient scores were elevated in both groups and were much higher in the study group; PSQ scores were lower in both groups and were much lower in the study group (all p < 0.05). During the treatment period, there was no difference in the incidence of adverse reactions between both groups (p > 0.05). The treatment combination of ATX HCI and EEG biofeedback is effective for children with ADHD, improving their behavioral issues and psychological conditions.