Synaptic up-scaling is governed by transcription-dependent autophagy, a process driven by TFEB-mediated cytonuclear signaling, which is in turn initiated by the dephosphorylation of ERK and mTOR as a consequence of chronic neuronal inactivity, thus regulating CaMKII and PSD95. MTOR-dependent autophagy, often induced by metabolic hardships such as fasting, is consistently recruited and sustained during neuronal quiescence to maintain synaptic equilibrium, ensuring optimal brain function. Disruptions to this process can precipitate neuropsychiatric disorders such as autism. Nevertheless, a lingering question surrounds the methodology of this occurrence during synaptic up-scaling, a procedure dependent on protein turnover yet spurred by neuronal deactivation. Our findings indicate that mTOR-dependent signaling, which is often prompted by metabolic stressors like starvation, is exploited by chronic neuronal inactivation. This exploitation becomes a rallying point for the transcription factor EB (TFEB) cytonuclear signaling, leading to an increase in transcription-dependent autophagy. These results, for the first time, demonstrate a physiological part of mTOR-dependent autophagy in enduring neuronal plasticity, creating a bridge between central concepts of cell biology and neuroscience by means of a servo-loop that facilitates self-regulation in the brain.

Research consistently demonstrates that self-organization of biological neuronal networks tends towards a critical state with stable recruitment patterns. During neuronal avalanches, cascades of activity would statistically cause precisely one additional neuron to activate. However, the question remains open as to how this principle interacts with the rapid recruitment of neurons in neocortical minicolumns in living brains and in neuronal clusters cultivated in labs, implying the development of supercritical local circuits within the nervous system. Modular network models, incorporating regions of both subcritical and supercritical dynamics, are hypothesized to produce apparent criticality, thus resolving the discrepancy. We provide experimental backing by intervening in the self-organizing structure of cultured networks formed by rat cortical neurons (either male or female). In agreement with the anticipated outcome, we demonstrate that a rise in clustering within in vitro-developing neuronal networks is strongly associated with avalanche size distributions shifting from supercritical to subcritical neuronal activity patterns. Overall critical recruitment was indicated by the power law approximation of avalanche size distributions in moderately clustered networks. We advocate that activity-driven self-organization can adapt inherently supercritical networks, leading them to a mesoscale critical state, achieving a modular arrangement in neuronal circuits. check details How neuronal networks achieve self-organized criticality via the detailed regulation of their connectivity, inhibition, and excitability remains an area of intense scholarly disagreement. Empirical findings support the theoretical proposal that modularity modulates essential recruitment processes at the mesoscale level of interacting neuronal ensembles. Findings on criticality at mesoscopic network scales corroborate the supercritical recruitment patterns in local neuron clusters. In the context of criticality, altered mesoscale organization is a salient characteristic of several currently investigated neuropathological diseases. Subsequently, our results are expected to hold significance for clinical scientists who aim to correlate the functional and structural characteristics of such cerebral conditions.

The charged components within the prestin motor protein, located in the outer hair cell (OHC) membrane, are energized by transmembrane voltage gradients, facilitating OHC electromotility (eM) and amplifying auditory signals in the cochlea, essential for mammalian hearing. In consequence, the swiftness of prestin's conformational transitions restricts its dynamic bearing on the micro-mechanics of both the cell and the organ of Corti. The frequency responsiveness of prestin, determined by the voltage-dependent, nonlinear membrane capacitance (NLC) associated with charge movements in its voltage sensors, has been reliably documented only within the range up to 30 kHz. Accordingly, a controversy surrounds the effectiveness of eM in assisting CA at ultrasonic frequencies, a range within the hearing capabilities of some mammals. Prestin charge fluctuations in guinea pigs (either sex) were sampled at megahertz rates, allowing us to extend the investigation of NLC mechanisms into the ultrasonic frequency domain (up to 120 kHz). An order of magnitude larger response was detected at 80 kHz than previously predicted, indicating a possible influence from eM at these ultrasonic frequencies, similar to recent in vivo findings (Levic et al., 2022). To validate kinetic model predictions for prestin, we employ interrogations with expanded bandwidth. The characteristic cut-off frequency is observed directly under voltage clamp, labeled as the intersection frequency (Fis) near 19 kHz, where the real and imaginary components of the complex NLC (cNLC) intersect. The frequency response of prestin displacement current noise, a value determined using either Nyquist relations or stationary measures, is consistent with this cutoff. We ascertain that voltage stimulation correctly identifies the spectral extent of prestin activity, and voltage-dependent conformational changes are essential for physiological function within the ultrasonic range. The voltage-driven conformational adjustments within prestin's membrane are essential for its operation at extremely high frequencies. With megahertz sampling, we reach into the ultrasonic range for prestin charge movement measurements, and find that the magnitude of the response at 80 kHz is ten times greater than our previous estimations, while still acknowledging the established low-pass characteristic cutoff frequencies. Admittance-based Nyquist relations and stationary noise measurements of prestin noise's frequency response reveal a characteristic cut-off frequency. Voltage fluctuations in our data suggest precise measurements of prestin's function, implying its potential to enhance cochlear amplification to a higher frequency range than previously understood.

Behavioral reports concerning sensory input are predisposed by prior stimuli. The nature and direction of serial-dependence bias depend on the experimental framework; instances of both an appeal to and an avoidance of previous stimuli have been observed. The origins, both temporal and causal, of these biases within the human brain remain largely unexplored. Sensory processing shifts, or alternative pathways within post-perceptual functions such as maintenance or judgment, could be the genesis of these. This issue was addressed by testing 20 participants (11 female) on a working-memory task. Behavioral and magnetoencephalographic (MEG) data were gathered. The task presented two randomly oriented gratings sequentially, with one grating marked for later recall. Two distinct biases were apparent in the behavioral reactions: one repelling the subject from the previously encoded orientation on the same trial, and another attracting the subject to the relevant orientation from the previous trial. check details Stimulus orientation, as assessed through multivariate classification, showed neural representations during encoding deviating from the preceding grating orientation, independent of whether the within-trial or between-trial prior orientation was taken into account, even though the effects on behavior were opposite. Repulsive biases are evident in sensory processing, yet can be overridden by subsequent perceptual mechanisms, influencing attractive behavioral outcomes. It is yet to be determined exactly when serial biases emerge within the stimulus processing pathway. This study employed behavior and neurophysiological data (magnetoencephalography, MEG) to investigate whether the biases present in participants' reports also manifested in neural activity patterns during early sensory processing. In a working memory undertaking that unveiled various behavioral biases, responses showed a proclivity for preceding targets while steering clear of more current stimuli. Neural activity patterns were consistently biased against all previously relevant items. Our findings are inconsistent with the hypothesis that all serial biases develop in the initial stages of sensory processing. check details Instead, the neural activity showcased predominantly an adaptation-like response to recently presented stimuli.

In all animals, general anesthetics elicit a profound and pervasive absence of behavioral responsiveness. General anesthesia in mammals is, at least partially, induced by the amplification of endogenous sleep-promoting pathways, while deep anesthesia is argued to resemble a coma, according to the work of Brown et al. (2011). Anesthetic agents such as isoflurane and propofol, at concentrations used during surgical procedures, have been shown to disrupt the intricate neural connections throughout the mammalian brain; this disruption could explain the observed lack of responsiveness in animals exposed to them (Mashour and Hudetz, 2017; Yang et al., 2021). The consistent impact of general anesthetics on brain dynamics in all animals, or the presence of a sufficiently complex neural network in simpler organisms, such as insects, that could be affected by these drugs, remains uncertain. Whole-brain calcium imaging was applied to behaving female Drosophila flies to determine if isoflurane anesthetic induction activates sleep-promoting neurons. The consequent behavioral patterns of all other neurons throughout the fly brain under sustained anesthetic conditions were also characterized. Our study tracked the activity of hundreds of neurons across waking and anesthetized states, examining both spontaneous activity and responses to visual and mechanical stimulation. Whole-brain dynamics and connectivity were assessed under the influence of isoflurane exposure, and juxtaposed with the state of optogenetically induced sleep. Drosophila neurons continue their activity during both general anesthesia and induced sleep, even though the fly's behavior becomes unresponsive.