Journal of Neuroscience最新文献

Mesenchymal stromal cell (MSC) therapy has regenerative potentials to treat various pathological conditions including neurological diseases. MSCs isolated from various organs can differentiate into specific cell types to repair organ damages. However, their paracrine mechanisms are predicted to predominantly mediate their immunomodulatory, pro-angiogenic, and regenerative properties. While preclinical studies highlight the significant potential of MSC therapy in mitigating neurological damage from stroke and traumatic brain injury, the variability in clinical trial outcomes may stem from the inherent heterogeneity of somatic MSCs. Accumulating evidence has demonstrated that induced pluripotent stem cells (iPSCs) are an ideal alternative resource for the unlimited expansion and biomanufacturing of MSCs. Thus, we investigated how iPSC-derived MSCs (iMSCs) influence properties of iPSC-derived neurons. Our findings demonstrate that the secretome from iMSCs possesses neurotrophic effects, improving neuronal survival and promoting neuronal outgrowth and synaptic activity in vitro Additionally, the iMSCs enhance metabolic activity via mitochondrial respiration in neurons, both in vitro and in mouse models. Glycolytic pathways also increased following the administration of iMSC secretome to iPSC-derived neurons. Consistently, in vivo experiments showed that intravenous administration of iMSCs compensated for the elevated energetic demand in male mice with irradiation-induced brain injury by restoring synaptic metabolic activity during acute brain damage. ¹⁸F-FDG PET imaging also detected an increase in brain glucose uptake following iMSC administration. Together, our results highlight the potential of iMSC-based therapy in treating neuronal damage in various neurological disorders, while paving the way for future research and potential clinical applications of iMSCs in regenerative medicine.Significance Statement Regenerative biotherapeutics using MSCs have emerged as a promising intervention for treating various neurological diseases. Our study explored the potential beneficial effects of human iPSC-derived MSCs (iMSCs) on neurons. We demonstrated that molecules secreted into the culture medium by iMSCs enhance regenerative capabilities by improving neuronal survival, growth, and metabolic activity, as well as synaptic functions, in human iPSC-derived neurons. Mouse experiments also suggested the potential of iMSC therapy to mitigate synaptic mitochondrial dysfunction and enhance brain glucose uptake during acute radiation-induced brain injury, steps that contribute to restoring normal neuronal function. Our results highlight that iMSCs may be a promising alternative cell product for treating neuronal damage, overcoming the inconsistent efficacy of somatic MSCs due to cell variability.

A previous epidemiological study in Northern Europe showed that the A673T mutation (Icelandic mutation) in the amyloid precursor protein gene (APP) can protect against Alzheimer's disease (AD). While the effect of the A673T mutation on APP processing has been investigated primarily in vitro, its in vivo impact has not been evaluated. This is mainly because most existing AD mouse models carry the Swedish mutation. The Swedish and Icelandic mutations are both located near the β-cleavage site, and each mutation is presumed to have the opposite effect on β-cleavage. Therefore, in the AD mouse models with the Swedish mutation, its effects could compete with the effects of the Icelandic mutation. Here, we introduced the A673T mutation into App knock-in mice devoid of the Swedish mutation (App^G-F mice) to avoid potential deleterious effects of the Swedish mutation and generated App^G-F-A673T mice. APP-A673T significantly downregulated β-cleavage and attenuated the production of Aβ and amyloid pathology in the brains of these animals. The Icelandic mutation also reduced neuroinflammation and neuritic alterations. Both sexes were studied. This is the first successful demonstration of the protective effect of the Icelandic mutation on amyloid pathology in vivo. Our findings indicate that specific inhibition of the APP-BACE1 interaction could be a promising therapeutic approach. Alternatively, introduction of the disease-protective mutation such as APP-A673T using in vivo genome editing technology could be a novel treatment for individuals at high risk for AD, such as familial AD gene mutation carriers and APOE ε4 carriers.Significance statement The A673T mutation (Icelandic mutation) in the APP gene can protect against AD. The effect of the A673T mutation on amyloid pathology has not been evaluated in vivo. Utilizing a new AD mouse model that we have recently developed, we show that the APP-A673T attenuates amyloid pathology in vivo. We demonstrate that its protective effects are exerted by inhibiting β-cleavage and reducing the production of Aβ in the brain. Furthermore, we reveal that the Icelandic mutation also reduced neuroinflammation and neuritic alterations. Our findings indicate that specific inhibition of the APP-BACE1 interaction or introduction of protective variants via in vivo genome editing could be a promising therapeutic approach.

Behaving as desired requires selecting the appropriate behavior and inhibiting the selection of inappropriate behavior. This inhibitory function involves multiple processes, such as reactive and proactive inhibition, instead of a single process. In this study, two male macaque monkeys were required to perform a task in which they had to sequentially select (accept) or refuse (reject) a choice. Neural activity was recorded from the anterior striatum, which is considered to be involved in behavioral inhibition, focusing on the distinction between proactive and reactive inhibitions. We identified neurons with significant activity changes during the rejection of bad objects. Cluster analysis revealed three distinct groups, of which only one showed increased activity during object rejection, suggesting its involvement in proactive inhibition. This activity pattern was consistent irrespective of the rejection method, indicating a role beyond saccadic suppression. Furthermore, minimal activity changes during the fixation task indicated that these neurons were not primarily involved in reactive inhibition. In conclusion, these findings suggest that the anterior striatum plays a crucial role in cognitive control and orchestrates goal-directed behavior through proactive inhibition, which may be critical in understanding the mechanisms of behavioral inhibition dysfunction that occur in patients with basal ganglia disease.Significance statement This study revealed a group of neurons in the anterior striatum that plays a crucial role in cognitive control by actively participating in the rejection of unfavorable choices. Contrary to previous belief, these neurons were involved in proactive inhibition (i.e., the process of discarding unnecessary options), instead of suppressing automatic responses, to achieve a goal. This distinction is vital for understanding the mechanisms by which the brain makes decisions and may have implications for addressing neurological disorders associated with impaired decision-making and inhibitory control. Our findings provide new insights into the neural mechanisms underlying goal-directed behavior and highlight the importance of the anterior striatum in orchestrating complex cognitive functions.

Intracranial potentials are used as functional biomarkers of neural networks. As potentials spread away from the source populations, they become mixed in the recordings. In humans, interindividual differences in the gyral architecture of the cortex pose an additional challenge, as functional areas vary in location and extent. We used source separation techniques to disentangle mixing potentials obtained by exploratory deep arrays implanted in epileptic patients of either sex to gain access to the number, location, relative contribution and dynamics of co-active sources. The unique spatial profiles of separated generators made it possible to discern dozens of independent cortical areas for each patient, whose stability maintained even during seizure, enabling the follow up of activity for days and across states. Through matching these profiles to MRI, we associated each with limited portions of sulci and gyri, and determined the local or remote origin of the corresponding sources. We also plotted source-specific 3D coverage across arrays. In average, individual recording sites are contributed to by 3-5 local and distant generators from areas up to several centimeters apart. During seizure, 13-85 % of generators were involved, and a few appeared anew. Significant bias in location assignment using raw potentials is revealed, including numerous false positives when determining the site of origin of a seizure. This is not amended by bipolar montage, which introduce additional errors of its own. In this way, source disentangling reveals the multisource nature and far intracranial spread of potentials in humans, while efficiently addressing patient-specific anatomofunctional cortical divergence.Significance Statement Field potentials are used to better localize zones showing normal and pathological activity. However, as potentials spread throughout the brain volume, they mix with others and make their place of origin uncertain, even when recorded intracranially. We used advanced algorithms to disentangle the activity of each these zones by their unique spatial profiles, which allowed us to determine the 3D outline of normal and epileptic areas and follow their activity for days. Dozens of independent sources per patient can be explored and precisely located. The findings show that standard stereoEEG recordings are contributed by 3-5 populations, which after separation will help to plan clinical intervention to break epileptic networks by more accurately marking epileptic foci and avoiding false positives.

The capabilities of the human ear are remarkable. We can normally detect acoustic stimuli down to a threshold sound-pressure level of 0 dB (decibels) at the entrance to the external ear, which elicits eardrum vibrations in the picometer range. From this threshold up to the onset of pain, 120 dB, our ears can encompass sounds that differ in power by a trillionfold. The comprehension of speech and enjoyment of music result from our ability to distinguish between tones that differ in frequency by only 0.2%. All these capabilities vanish upon damage to the ear's receptors, the mechanoreceptive sensory hair cells. Each cochlea, the auditory organ of the inner ear, contains some 16,000 such cells that are frequency-tuned between ∼20 Hz (cycles per second) and 20,000 Hz. Remarkably enough, hair cells do not simply capture sound energy: they can also exhibit an active process whereby sound signals are amplified, tuned, and scaled. This article describes the active process in detail and offers evidence that its striking features emerge from the operation of hair cells on the brink of an oscillatory instability-one example of the critical phenomena that are widespread in physics.

GABAergic inhibitory interneurons comprise many subtypes that differ in their molecular, anatomical, and functional properties. In mouse visual cortex, they also differ in their modulation with an animal's behavioral state, and this state modulation can be predicted from the first principal component (PC) of the gene expression matrix. Here, we ask whether this link between transcriptome and state-dependent processing generalizes across species. To this end, we analysed seven single-cell and single-nucleus RNA sequencing datasets from mouse, human, songbird, and turtle forebrains. Despite homology at the level of cell types, we found clear differences between transcriptomic PCs, with greater dissimilarities between evolutionarily distant species. These dissimilarities arise from two factors: divergence in gene expression within homologous cell types and divergence in cell-type abundance. We also compare the expression of cholinergic receptors, which are thought to causally link transcriptome and state modulation. Several cholinergic receptors predictive of state modulation in mouse interneurons are differentially expressed between species. Circuit modelling and mathematical analyses suggest conditions under which these expression differences could translate into functional differences.

Dopamine (DA) and norepinephrine (NE) have been repeatedly implicated in neuropsychiatric vulnerability, in part via their roles in mediating the decision-making processes. Although two neuromodulators share a synthesis pathway and are coactivated under states of arousal, they engage in distinct circuits and modulatory roles. However, the specific role of each neuromodulator in decision-making, in particular the exploration-exploitation tradeoff, remains unclear. Revealing how each neuromodulator contributes to exploration-exploitation tradeoff is important in guiding mechanistic hypotheses emerging from computational psychiatric approaches. To understand the differences and overlaps of the roles of these two catecholamine systems in regulating exploration, a direct comparison using the same dynamic decision-making task is needed. Here, we ran male and female mice in a restless two-armed bandit task, which encourages both exploration and exploitation. We systemically administered a nonselective DA antagonist (flupenthixol), a nonselective DA agonist (apomorphine), a NE beta-receptor antagonist (propranolol), and a NE beta-receptor agonist (isoproterenol) and examined changes in exploration within subjects across sessions. We found a bidirectional modulatory effect of dopamine on exploration. Increasing dopamine activity decreased exploration and decreasing dopamine activity increased exploration. The modulatory effect of beta-noradrenergic receptor activity on exploration was mediated by sex. Reinforcement learning model parameters suggested that dopamine modulation affected exploration via decision noise and norepinephrine modulation affected exploration via sensitivity to outcome. Together, these findings suggested that the mechanisms that govern the exploration-exploitation transition are sensitive to changes in both catecholamine functions and revealed differential roles for NE and DA in mediating exploration.

Aggression involves both sexually monomorphic and dimorphic actions. How the brain implements these two types of actions is poorly understood. We found that in Drosophila melanogaster, a set of neurons, which we call CL062, previously shown to mediate male aggression also mediate female aggression. These neurons elicit aggression acutely and without the presence of a target. Although the same set of actions is elicited in males and females, the overall behavior is sexually dimorphic. The CL062 neurons do not express fruitless, a gene required for sexual dimorphism in flies, and expressed by most other neurons important for controlling fly aggression. Connectomic analysis in a female electron microscopy dataset suggests that these neurons have limited connections with fruitless expressing neurons that have been shown to be important for aggression and signal to different descending neurons. Thus, CL062 is part of a monomorphic circuit for aggression that functions parallel to the known dimorphic circuits.

In demanding listening situations, a listener's motivational state may affect their cognitive investment. Here, we aim to delineate how domain-specific sensory processing, domain-general neural alpha power, and pupil size as a proxy for cognitive investment encode influences of motivational state under demanding listening. Participants (male and female) performed an auditory gap-detection task while the pupil size and the magnetoencephalogram were simultaneously recorded. Task demand and a listener's motivational state were orthogonally manipulated through changes in gap duration and monetary-reward prospect, respectively. Whereas task difficulty impaired performance, reward prospect enhanced it. The pupil size reliably indicated the modulatory impact of an individual's motivational state. At the neural level, the motivational state did not affect auditory sensory processing directly but impacted attentional postprocessing of an auditory event as reflected in the late evoked-response field and alpha-power change. Both pregap pupil dilation and higher parietal alpha power predicted better performance at the single-trial level. The current data support a framework wherein the motivational state acts as an attentional top-down neural means of postprocessing the auditory input in challenging listening situations.