Journal of Neuroscience最新文献

Single-photon optogenetics enables precise, cell-type-specific modulation of neuronal circuits, making it a crucial tool in neuroscience. Its miniaturization in the form of fully implantable wide-field stimulator arrays enables long-term interrogation of cortical circuits and bares promise for Brain-Machine Interfaces for sensory and motor function restoration. However, achieving selective activation of functional cortical representations poses a challenge, as studies show that targeted optogenetic stimulation results in activity spread beyond one functional domain. While recurrent network mechanisms contribute to activity spread, here we demonstrate with detailed simulations of isolated pyramidal neurons from cat of unknown sex that already neuron morphology causes a complex spread of optogenetic activity at the scale of one cortical column. Since the shape of a neuron impacts its optogenetic response, we find that a single stimulator at the cortical surface recruits a complex spatial distribution of neurons that can be inhomogeneous and vary with stimulation intensity and neuronal morphology across layers. We explore strategies to enhance stimulation precision, finding that optimizing stimulator optics may offer more significant improvements than preferentially somatic expression of the opsin through genetic targeting. Our results indicate that, with the right optical setup, single-photon optogenetics can precisely activate isolated neurons at the scale of functional cortical domains spanning several hundred micrometers.Significance Statement Sensory features, such as the position or orientation of a visual stimulus, are mapped onto the surface of cortex as functional domains. Their selective activation, that may enable eliciting complex percepts, is intensively pursued for basic science and clinical applications. However, delivery of light into one functional domain in optogenetically transfected cortex results in complex, widespread neuronal activity, spreading beyond the targeted domain. Our computational study reveals that neuron morphology contributes to this diffuse response in a cortical-layer and intensity-dependent manner. We show that enhancing the stimulator optics is more effective than soma-targeting of the opsin in increasing spatial precision of stimulation. Our simulations provide insights for designing optogenetic stimulation protocols and hardware to achieve selective activation of functional domains.

Area TE is required for normal learning of visual categories based on perceptual similarity. To evaluate whether category learning changes neural activity in area TE, we trained two monkeys (both male) implanted with multi-electrode arrays to categorize natural images of cats and dogs. Neural activity during a passive viewing task was compared pre- and post-training. After the category training, the accuracy of abstract category decoding improved. Single units became more category-selective, the proportion of single units with category-selectivity increased, and units sustained their category-specific responses for longer. Visual category learning thus appears to enhance category separability in area TE by driving changes in the stimulus selectivity of individual neurons and by recruiting more units to the active network.Significance statement Neurons in Area TE are known to respond selectively to a small number of visual stimuli. Here we demonstrate that the neural activity in area TE is modulated by category learning of natural images (cats and dogs), thus demonstrating that this region is capable of undergoing rapid plastic changes in adult primates.

Reelin, a secreted glycoprotein, plays a crucial role in guiding neocortical neuronal migration, dendritic outgrowth and arborization, and synaptic plasticity in the adult brain. Reelin primarily operates through the canonical lipoprotein receptors apolipoprotein E receptor 2 (Apoer2) and very low-density lipoprotein receptor (Vldlr). Reelin also engages with noncanonical receptors and unidentified coreceptors; however, the effects of which are less understood. Using high-throughput tandem mass tag (TMT) liquid chromatography tandem mass spectrometry (LC-MS/MS)-based proteomics and gene set enrichment analysis (GSEA), we identified both shared and unique intracellular pathways activated by Reelin through its canonical and noncanonical signaling in primary murine neurons of either sex during dendritic growth and arborization. We observed pathway cross talk related to regulation of cytoskeleton, neuron projection development, protein transport, and actin filament-based process. We also found enriched gene sets exclusively by the noncanonical Reelin pathway including protein translation, mRNA metabolic process, and ribonucleoprotein complex biogenesis suggesting Reelin fine-tunes neuronal structure through distinct signaling pathways. A key discovery is the identification of aldolase A, a glycolytic enzyme and actin-binding protein, as a novel effector of Reelin signaling. Reelin induced de novo translation and mobilization of aldolase A from the actin cytoskeleton. We demonstrated that aldolase A is necessary for Reelin-mediated dendrite growth and arborization in primary murine neurons and mouse brain cortical neurons. Interestingly, the function of aldolase A in dendrite development is independent of its known role in glycolysis. Altogether, our findings provide new insights into the Reelin-dependent signaling pathways and effector proteins that are crucial for dendritic development.

Human sleep exhibits multiple, recurrent temporal regularities, ranging from circadian rhythms to sleep stage cycles and neuronal oscillations during nonrapid eye movement sleep. Moreover, recent evidence revealed a functional role of aperiodic activity, which reliably discriminates different sleep stages. Aperiodic activity is commonly defined as the spectral slope χ of the 1/frequency (1/f^χ) decay function of the electrophysiological power spectrum. However, several lines of inquiry now indicate that the aperiodic component of the power spectrum might be better characterized by a superposition of several decay processes with associated timescales. Here, we determined multiple timescales, which jointly shape aperiodic activity using human intracranial electroencephalography. Across three independent studies (47 participants, 23 female), our results reveal that aperiodic activity reliably dissociated sleep stage-dependent dynamics in a regionally specific manner. A principled approach to parametrize aperiodic activity delineated several, spatially and state-specific timescales. Lastly, we employed pharmacological modulation by means of propofol anesthesia to disentangle state-invariant timescales that may reflect physical properties of the underlying neural population from state-specific timescales that likely constitute functional interactions. Collectively, these results establish the presence of multiple intrinsic timescales that define the electrophysiological power spectrum during distinct brain states.

The visual world is richly adorned with texture, which can serve to delineate important elements of natural scenes. In anesthetized macaque monkeys, selectivity for the statistical features of natural texture is weak in V1, but substantial in V2, suggesting that neuronal activity in V2 might directly support texture perception. To test this, we investigated the relation between single cell activity in macaque V1 and V2 and simultaneously measured behavioral judgments of texture. We generated stimuli along a continuum between naturalistic texture and phase-randomized noise and trained two macaque monkeys to judge whether a sample texture more closely resembled one or the other extreme. Analysis of responses revealed that individual V1 and V2 neurons carried much less information about texture naturalness than behavioral reports. However, the sensitivity of V2 neurons, especially those preferring naturalistic textures, was significantly closer to that of behavior compared with V1. The firing of both V1 and V2 neurons predicted perceptual choices in response to repeated presentations of the same ambiguous stimulus in one monkey, despite low individual neural sensitivity. However, neither population predicted choice in the second monkey. We conclude that neural responses supporting texture perception likely continue to develop downstream of V2. Further, combined with neural data recorded while the same two monkeys performed an orientation discrimination task, our results demonstrate that choice-correlated neural activity in early sensory cortex is unstable across observers and tasks, untethered from neuronal sensitivity, and therefore unlikely to directly reflect the formation of perceptual decisions.

Cochlear hair cells (HCs) sense sound waves and allow us to hear. Loss of HCs will cause irreversible sensorineural hearing loss. It is well known that DNA damage repair plays a critical role in protecting cells in many organs. However, how HCs respond to DNA damage and how defective DNA damage repair contributes to hearing loss remain elusive. In this study, we showed that cisplatin induced DNA damage in outer hair cells (OHCs) and promoted OHC loss, leading to hearing loss in mice of either sex. Cisplatin induced the expression of Brca1, a DNA damage repair factor, in OHCs. Deficiency of Brca1 induced OHC and hearing loss, and further promoted cisplatin-induced DNA damage in OHCs, accelerating OHC loss. This study provides the first in vivo evidence demonstrating that cisplatin mainly induces DNA damage in OHCs and that BRCA1 promotes repair of DNA damage in OHCs and prevents hearing loss. Our findings not only demonstrate that DNA damage-inducing agent generates DNA damage in postmitotic HCs but also suggest that DNA repair factors, like BRCA1, protect postmitotic HCs from DNA damage-induced cell death and hearing loss.