Journal of Neuroscience最新文献

Huntington's disease (HD) is a progressive neurodegenerative disorder with no cure, characterized by significant neurodegeneration of striatal GABAergic medium spiny neurons (MSNs). Early stages of the disease are characterized by the loss of dopamine 2 receptor-expressing MSNs (D2 MSNs) followed by degeneration of dopamine 1 receptor-expressing MSNs (D1 MSNs), leading to aberrant basal ganglia signaling. While the early degeneration of D2 MSNs and impaired GABAergic transmission are well-documented, potassium chloride cotransporter 2 (KCC2), a key regulator of intracellular chloride (Cl^-), and therefore GABAergic signaling, has not been characterized in D1 and D2 MSNs in HD. We aimed to investigate whether Cl^- regulation was differentially altered in D1 and D2 MSNs and may contribute to the early degeneration of D2 MSNs in male and female symptomatic R6/2 mice. We used electrophysiology to record the reversal potential for GABA_A receptors (E_GABA), a read-out for the efficacy of Cl^- regulation, in striatal D1 and D2 MSNs and their corresponding output structures. During the early symptomatic phase (P55-P65)_, Cl^- impairments were observed in D2 MSNs in R6/2 mice, with no change in D1 MSNs. Cl^- regulation was also dysfunctional in the globus pallidus externa, resulting in GABA-mediated excitation. When we overexpressed KCC2 in D2 MSNs using AAV-mediated delivery, we delayed the onset of motor impairments in R6/2 mice. We demonstrate that Cl^- homeostasis is differentially altered in D1 and D2 MSNs and may contribute to the enhanced susceptibility of D2 MSNs during HD progression.Significance Statement Huntington's Disease is an inherited neurodegenerative disease caused by a repeat expansion in the Huntingtin gene and characterized by the sequential loss of dopamine 2 and dopamine 1 receptor-expressing medium spiny neurons (D2 and D1 MSNs) of the striatum. MSNs release GABA, which depends on proper Cl^- regulation for inhibition. We asked whether Cl^- homeostasis is differentially altered in D1 and D2 MSNs and their output structures, and whether this altered expression contributes to the pattern of degeneration between these two principal striatal cell types. Using electrophysiology, biochemistry, and fluorescence imaging, we determined that Cl^- regulation was impaired in D2 MSNs in R6/2 mice, with no change in D1 MSNs. Cl^- was also dysregulated in the globus pallidus externa resulting in excitatory GABA.

The interplay between attention, alertness and motor planning is crucial for our manual interactions. To investigate the neural bases of this interaction, and challenging the views that attention cannot be disentangled from motor planning, we instructed human volunteers of both sexes to plan and execute reaching movements while attending to the target, while attending elsewhere, or without constraining attention. We recorded reaction times to reach initiation and pupil diameter and interfered with the functions of the medial posterior parietal cortex (mPPC) with online repetitive transcranial magnetic stimulation to test the causal role of this cortical region in the interplay between spatial attention and reaching. We found that mPPC plays a key role in the spatial association of reach planning and covert attention. Moreover, we have found that alertness, measured by pupil size, is a good predictor of the promptness of reach initiation only if we plan a reach to attended targets, and mPPC is causally involved in this coupling. Different from previous understanding, we suggest that mPPC is neither involved in reach planning per se, nor in sustained covert attention in absence of a reach plan, but it is specifically involved in attention functional to reaching.Significance Statement Attention is required to perform dexterous arm movements. In this work we show the neural bases of the interplay between attention and reaching preparation, with the aim to provide information useful to address effective rehabilitation strategies to treat functional deficits observed in attention-related diseases. We discuss how brain areas are involved in orchestrating attention and reaching by signaling the alignment of their spatial coordinates. Moreover, we found that pupil size changes during reach preparation are related to reach initiation, suggesting a coordination between vigilance and reach promptness when preparing a reach to attended targets.

Primate vision relies on retinotopically organized cortical parcels defined by representations of hemifield (upper versus lower visual field), eccentricity (fovea versus periphery), and area (V1, V2, V3, V4). Here we test for functional signatures of these organizing principles. We used fMRI to measure responses to gratings varying in spatial frequency, color, and saturation across retinotopically defined parcels in two macaque monkeys, and we developed a Sparse Supervised Embedding (SSE) analysis to identify stimulus features that best distinguish cortical parcels from each other. Constraining the SSE model to distinguish just eccentricity representations of the voxels revealed the expected variation of spatial frequency and S-cone modulation with eccentricity. Constraining the model according to the dorsal-ventral location and retinotopic area of each voxel provided unexpected functional signatures, which we investigated further with standard univariate analyses. Posterior parcels (V1) were distinguished from anterior parcels (V4) by differential responses to chromatic and luminance contrast, especially of low spatial frequency gratings. Meanwhile, ventral parcels were distinguished from dorsal parcels by differential responses to chromatic and luminance contrast, especially of colors that modulate all three cone types. The dorsal-ventral asymmetry not only resembled differences between candidate dorsal and ventral subdivisions of human V4, but also extended to include all retinotopic visual areas, starting in V1 and increasing from V1 to V4. The results provide insight into the functional roles of different retinotopic areas and demonstrate the utility of Sparse Supervised Embedding as a data-driven tool for generating hypotheses about cortical function and behavior.Significance Statement This study demonstrates a new analysis, Sparse Supervised Embedding (SSE), which promises to be useful for visualizing and understanding complex neuroimaging datasets. The paper uses SSE to explore the functional roles of retinotopic visual areas (V1, V2, V3, V4, V3a, MT). The results show that retinotopic areas parcellated by representations for eccentricity and upper/lower visual hemifield have functional signatures, which are defined by unique combinations of responses to color, spatial frequency, and contrast. The functional signatures provide hypotheses for the different roles that the parcels play in vision and help resolve apparent differences between human and macaque visual cortex organization.

Humans can recognize their whole-body movements even when displayed as dynamic dot patterns. The sparse depiction of whole-body movements, coupled with a lack of visual experience watching ourselves in the world, has long implicated non-visual mechanisms to self-action recognition. We aimed to identify the neural systems for this ability. Using general linear modeling and multivariate analyses on human brain imaging data from male and female participants, we first found that cortical areas linked to motor processes, including frontoparietal and primary somatomotor cortices, exhibit greater engagement and functional connectivity when recognizing self-generated versus other-generated actions. Next, we show that these regions encode self-identity based on motor familiarity, even after regressing out idiosyncratic visual cues using multiple regression representational similarity analysis. Last, we found the reverse pattern for unfamiliar individuals: encoding localized to occipito-temporal visual regions. These findings suggest that self-awareness from actions emerges from the interplay of motor and visual processes.Significance Statement: We report for the first time that self-recognition from visual observation of our whole-body actions implicates brain regions associated with motor processes. On functional neuroimaging data, we found greater activity and unique representational patterns in brain areas and networks linked to motor processes when viewing our own actions relative to viewing the actions of others. These findings introduce an important role of motor mechanisms in distinguishing the self from others.

The mammalian cochlea amplifies sounds selectively to improve frequency resolution. However, vibrations around the outer hair cells (OHCs) are amplified non-selectively. The mechanism of the selective or non-selective amplification is unknown. This study demonstrates that active force transmission through the extracellular fluid in the organ of Corti (Corti fluid) can explain how the cochlea achieves selective sound amplification despite the non-frequency-selective action of OHCs. Computational model simulations and experiments with excised cochleae from young gerbils of both sexes were exploited. OHC motility resulted in characteristic off-axis motion of the joint between the OHC and Deiters cell (ODJ). Incorporating the Corti fluid dynamics was critical to account for the ODJ motion due to OHC motility. The incorporation of pressure transmission through the Corti fluid resulted in three distinct frequency tuning patterns depending on sites in the organ of Corti. In the basilar membrane, the responses were amplified near the best-responding frequency (BF). In the ODJ region, the responses were amplified non-selectively. In the reticular lamina, the responses were amplified near the BF but suppressed in lower frequencies. The suppressive effect of OHCs was further examined by observing the changes in tuning curves due to local inhibition of OHC motility. The frequency response of the reticular lamina resembled neural tuning, such as the hypersensitivity of tuning-curve tails after hair cell damage. Our results demonstrate how active OHCs exploit the elastic frame and viscous fluid in the organ of Corti to amplify and suppress cochlear vibrations for better frequency selectivity.Significance Statement Active outer hair cells have been considered to selectively amplify the basilar membrane vibrations near the sound's tonotopic location. However, recent observations from different labs showed that outer hair cells' action is non-selective-it spreads over the broad span of traveling waves. These observations challenge the existing theory pegged to basilar-membrane mechanics. The motion at the joint between the outer hair cell and the Deiters (ODJ) cell holds the key to account for the non-selective action of outer hair cells. We show that the characteristic motions at the ODJ are explained coherently when Corti fluid acts as the medium for outer hair cell force transmission. Our results demonstrate how non-selective outer hair cell action produces selective neural responses.

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.

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.

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.

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.