bioRxiv Subject Collection: Neuroscience's Journal

Attention Modulates Stimulus Representations in Neural Feature Dimension Maps
Computational theories posit that attention is guided by a combination of spatial maps for individual features that can be dynamically weighted according to task goals. Consistent with this framework, when a stimulus contains several features, attending to one or another feature results in stronger fMRI responses in regions preferring the attended feature. We hypothesized that multivariate activation patterns across feature-responsive cortical regions form spatial 'feature dimension maps', which combine to guide attentional priority. We tested this prediction by reconstructing neural feature dimension maps from fMRI activation patterns across retinotopic regions of visual cortex using a spatial inverted encoding model. Participants viewed a peripheral visual stimulus at a random location which always contained moving colored dots. On each trial, participants were precued to report the predominant direction of motion or color of the stimulus, or to attend fixation. Stimulus representations in reconstructed priority maps were selectively enhanced in color-selective regions when color was attended, and in motion-selective regions when motion was attended, and this effect was primarily observed at the stimulus location. While enhancement was localized to the stimulus in color-selective regions, motion-selective regions were globally enhanced when motion was task relevant. These results suggest different cortical regions support spatial maps of different visual features, and that each map is uniquely reweighted based on task demands to guide visual behavior towards the most relevant locations based on important features.

CHOLINERGIC MODULATION OF CELLULAR RESONANCE IN NON-HUMAN PRIMATE HIPPOCAMPUS
Acetylcholine modulates the network physiology of the hippocampus, a crucial brain structure that supports cognition and memory formation in mammals (1-3). In this and adjacent regions, synchronized neuronal activity within theta-band oscillations (4-10Hz) is correlated with attentive processing that leads to successful memory encoding (4-10). Acetylcholine facilitates the hippocampus entering a theta oscillatory regime and modulates the temporal organization of activity within theta oscillations (11,12). Unlike rodents that exhibit constant theta oscillations during movement and exploration, primates only manifest theta oscillations in transient bouts during periods of acute attention, despite conserved hippocampal anatomy (13-16). The phasic nature of primate theta oscillations and their susceptibility to muscarinic antagonists (17), suggest that acetylcholine afferents acutely modulate local circuitry, resulting in a temporary shift in hippocampal rhythmic dynamics. However, we lack a mechanistic understanding that links cellular physiology to emergent theta-rhythmic network dynamics. We explored the hypothesis that acetylcholine induces a distinct modulation of cellular properties to facilitate synchronization within the theta band in non-human primate neurons. Here we show that non-human primate neurons from the CA1 region of monkey hippocampus are not homogeneous in their voltage response to inputs of varying frequencies, a phenomenon known as cellular resonance (18-19). We classified these neurons as resonant or non-resonant. Under the influence of carbachol, these two classes of neurons become indistinguishable in their resonance, suggesting that acetylcholine transiently creates a homogeneous susceptibility to inputs within the theta range. This change is mediated by metabotropic acetylcholine receptors that enhance sag potentials, indicating that acetylcholine acts on principal neurons to modulate Hyperpolarization-activated Cyclic Nucleotide-gated channels. Our results reveal a mechanism through which acetylcholine can rapidly modulate intrinsic properties of primate hippocampal neurons to facilitate synchronization within theta-rhythmic circuits, providing insight into the unique features of primate hippocampal physiology.

Subthalamic Signature of Freezing of Gait in Parkinson Disease
Freezing of gait (FOG) is a significant disability in Parkinson disease (PD). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) only partially alleviates it, with approximately one-third of patients experiencing worsening FOG within a year after surgery. The precise role of STN dysfunction in gait disabilities and FOG remains not fully elucidated. To investigate this, we recorded gait and STN local field potential (LFP) activity in 38 PD patients, both Off and On dopamine medication. Our analysis focused on the relationship between gait performance and STN neuronal activity, particularly examining differences in LFP activity across the posterior-sensorimotor and central-associative regions of the STN. When Off dopamine medication, 12 patients experienced FOG during recordings, with a total of 263 FOG episodes documented. Even in trials without FOG episodes, these patients exhibited altered gait initiation strategies, prioritizing stepping rhythm to manage balance and initiate walking. In contrast, non-FOG patients maintained a higher walking pace. STN activity patterns revealed key differences. In FOG patients, weaker STN alpha/low beta band activity in the STN was associated with walking pace, while stronger decreased low beta band activity correlated with rhythm and balance control. This low beta band association extended from the posterior-sensorimotor to the central-associative STN. In contrast, non-FOG patients showed a more restricted relationship between low beta band activity and gait performance, confined to the posterior STN. As stepping rhythm deteriorated further in FOG patients, FOG episodes occurred. FOG episodes were preceeded by a significant positive relationship between high beta power and rhythm restricted to the posterior STN, with a reverse negative relationship with pace, and a disruption in low beta desynchronization across both posterior and central STN regions. Dopamine medication significantly improved gait patterns, and partially restored STN neuronal activity, reducing differences between FOG and non-FOG patients. These findings differentiate two FOG states, i.e. predisposition and occurrence, each associated with distinct gait initiation strategies and STN activity patterns. They suggest distinct pathophysiological roles of low and high beta band STN activity within specific STN regions in regulating gait and FOG. These findings provide key insights for refining targeted DBS therapies.

Intracellular tension relaxation engineered through D-enantiomeric hydrogel maneuvers neurogenesis and immunomodulation to facilitate spinal cord repair
Microenvironment mechanics plays a vital role in regulating morphogenesis and immune response after injury, but their exploration has been hindered by the fragile mechanical strength and oxidative physiological environment in spinal cord injury (SCI). Here, we engineered self-assembly hydrogels of enantiomeric peptides with neural tissue-matching mechanical properties to persistently manipulate cellular membrane tension and mechanotransduction through stereo conformational recognition and consequent protein affinity difference. The D-enantiomeric hydrogel-induced intracellular tension relaxation activates neurogenesis and ECM remolding in astrocytes, suppresses pro-inflammation and promotes pro-regeneration in microglia, which significantly facilitates neuroprotection and functional recovery in a rat severe SCI model. The intracellular tension relaxation-induced morphogenesis may be neural characteristics, contrary to non-neural cells, as the downstream mechanical signaling is activated by the resulted neurogenic morphology change. Overall, inducing intracellular tension relaxation is a potential effective strategy for promoting nerve regeneration.

The Neurocognitive efficiency score: Derivation, validation, and application of a novel combination of concurrent electrophysiological and behavioral data
Perceptual and cognitive work require the expenditure of brain energy, and the efficiency of that energy expenditure can vary as a function of a range of exogenous and endogenous factors. The same is true for physical work, and tools have been developed to quantify energetic efficiency in the performance of physical work. The same is not true for the study of perceptual and cognitive work. We here draw on two lines of research---the formal characterization of workload capacity in perception and cognition, and the study of physical work---to propose a novel measure of neurocognitive efficiency. This neurocognitive efficiency score (NES) combines reaction time data with measures on concurrently acquired electroencephalographic (EEG) data to form a ratio that can be interpreted in terms of work accomplished relative to energy. We consider three measures on the EEG and show that one of them---global field power (GFP)---evidences a strong relationship to measures of metabolic energy expended. We then show how the NES can provide insights into differences in perceptual performance as a function of biological state. We argue that the NES has the potential for a wide range of applications in the study of perception and cognition in the context of factors including (but not limited to) aging, disease, stress, and differences in levels of expertise.

Enhancer Dynamics and Spatial Organization Drive Anatomically Restricted Cellular States in the Human Spinal Cord
Here, we report the spatial organization of RNA transcription and associated enhancer dynamics in the human spinal cord at single-cell and single-molecule resolution. We expand traditional multiomic measurements to reveal epigenetically poised and bivalent active transcriptional enhancer states that define cell type specification. Simultaneous detection of chromatin accessibility and histone modifications in spinal cord nuclei reveals previously unobserved cell-type specific cryptic enhancer activity, in which transcriptional activation is uncoupled from chromatin accessibility. Such cryptic enhancers define both stable cell type identity and transitions between cells undergoing differentiation. We also define glial cell gene regulatory networks that reorganize along the rostrocaudal axis, revealing anatomical differences in gene regulation. Finally, we identify the spatial organization of cells into distinct cellular organizations and address the functional significance of this observation in the context of paracrine signaling. We conclude that cellular diversity is best captured through the lens of enhancer state and intercellular interactions that drive transitions in cellular state. This study provides fundamental insights into the cellular organization of the healthy human spinal cord.

Non-mutated human tau stimulates Alzheimer's disease-relevant neurodegeneration in a microglia-dependent manner
The accumulation of abnormal, non-mutated tau protein is a key pathological hallmark of Alzheimer's disease (AD). Despite its strong association with disease progression, the mechanisms by which tau drives neurodegeneration in the brain remain poorly understood. Here, we selectively expressed non-mutated or mutated human microtubule-associated protein tau (hMAPT) in neurons across the brain and observed neurodegeneration in the hippocampus, especially associated with non-mutated human tau. Single-nuclei RNA sequencing confirmed a selective loss of hippocampal excitatory neurons by the wild-type tau and revealed the upregulation of neurodegeneration-related pathways in the affected populations. The accumulation of phosphorylated tau was accompanied by cellular stress in neurons and reactive gliosis in multiple brain regions. Notably, the lifelong absence of microglia significantly and differentially influenced the extent of neurodegeneration in the hippocampus and thalamus. Therefore, our study established an AD-relevant tauopathy mouse model, elucidated both neuron-intrinsic and neuron-extrinsic responses, and highlighted critical and complex roles of microglia in modulating tau-driven neurodegeneration.

Respiration facilitates behaviour during multisensory integration
The brain processes information from the external environment alongside signals generated by the body. Among bodily rhythms, respiration emerges as a key modulator of sensory processing. Multisensory integration, the non-linear combination of information from multiple senses to reduce environmental uncertainty, may be influenced by respiratory dynamics. This study investigated how respiration modulates reaction times and multisensory integration in a simple detection task. Forty healthy participants were presented with unimodal (Auditory, Visual, Tactile) and bimodal (Audio-Tactile, Audio-Visual, Visuo-Tactile) stimuli while their respiratory activity was recorded. Results revealed that reaction times systematically varied with respiration, with faster responses during peak inspiration and early expiration but slower responses during the expiration-to-inspiration transition. Applying the race model inequality approach to quantify multisensory integration, we found that Audio-Tactile and Audio-Visual stimuli exhibited the highest integration during the expiration-to-inspiration phase. These findings conceivably reflect respiration phase-locked changes in cortical excitability which in turn, orchestrates multisensory integration. Interestingly, participants also tended to adapt their respiratory cycles, aligning response onsets preferentially with early expiration. This suggests that, rather than a mere bottom-up mechanism, respiration is actively adjusted to maximise the signal-to-noise balance between interoceptive and exteroceptive signals.

Seeking rhythmic patterns in microglial cells within the circadian pineal gland from male rats
Microglia, the innate immune cells of the brain, constitute a highly dynamic cell population that displays several functions influenced by the light:dark (L:D) cycle. Within the pineal gland (PG), a key organ of the circadian timing system, microglia actively participate in its development and homeostasis. However, little is known about their rhythmic features in this circadian organ. This study aimed to elucidate morphological and functional phenotypes of pineal microglial cells at two time points of the L:D cycle. We performed immunofluorescence staining and confocal microscopy on paraffin-embedded pineal sections from 3- and 18-month-old Wistar rats, analyzing samples collected at midday (ZT6) and midnight (ZT18). Our results showed that the density and spatial distribution of IBA1+ microglial cells did not vary between ZT6 and ZT18 in the 3-month-old PG. However, these cells exhibited reduced size and amoeboid-like shapes, along with a reduction in the expression of the phagocytosis inhibitor SIRP alpha, at ZT18 compared to ZT6. Moreover, IBA1+ cells were immunoreactive for the lysosomal marker CD68 and the autophagic marker LC3B at both ZTs. Additionally, contacts with PAX6+ cells were detected in the two ZTs analyzed. Interestingly, IBA1+ cells showed attenuated or abolished rhythmicity in morphological parameters and SIRP alpha expression levels in the 18-month-old PG. Our findings suggest that microglia undergo transitions into alerted states at night, characterized by small, rounded shapes and enhanced phagocytic capacity. This adaptation likely prepares them to respond to potential invading agents and other insults in the PG, which could impact the nocturnal melatonin production.

Dynamic Norm-Based Coding of Vocal Identity in the Primate Auditory Cortex
Voice identity recognition is vital for social communication, yet its neural encoding mechanisms remain unclear. We investigated whether neurons in the anterior temporal voice area (aTVA) of macaques use norm-based coding (NBC), similar to face encoding in vision. Using synthetic vocalizations morphed along identity trajectories, we found that early neuronal responses (100 to 150 ms) exhibited V-shaped tuning, with minimal activity for the average voice and increased responses for extreme identities. Later (200 ms), a distinct rebound in activity for the average voice emerged, driven by a unique subpopulation. These results highlight a dynamic, multi-stage encoding strategy, extending NBC principles to auditory processing.

Correlation between circadian and photoperiodic latitudinal clines in Drosophila littoralis
Insects can survive harsh conditions, including Arctic winters, by entering a hormonally induced state of dormancy, known as diapause. Diapause is triggered by environmental cues such as shortening of the photoperiod (lengthening of the night). The time of entry into diapause depends on the latitude of the insects' habitat, and this applies even within a species: populations living at higher latitudes enter diapause earlier in the year than populations living at lower latitudes. A long-standing question in biology is whether the internal circadian clock, which governs daily behaviour and serves as a reference clock to measure night length, shows similar latitudinal adaptations. To address this question, we examined the onset of diapause and various behavioural and molecular parameters of the circadian clock in the cosmopolitan fly, Drosophila littoralis, a species distributed throughout Europe from the Black Sea (41 degrees N) to arctic regions (69 degrees N). We found that all clock parameters examined showed the same correlation with latitude as the critical night length for diapause induction. We conclude that the circadian clock has adapted to the latitude and that this may result in the observed latitudinal differences in the onset of diapause.

How Intrinsic Neural Timescales Relate To Event-Related Activity - Key Role For Intracolumnar Connections
The relationship of the brains intrinsic neural timescales (INTs) during the resting state with event-related activity in response to external stimuli remains poorly understood. Here, we bridge this gap by combining computational modeling with magnetoencephalography (MEG) data to investigate the relation of intrinsic neuronal timescales (INT) with task-related activity, e.g., event-related fields (ERFs). Using the Jansen-Rit model, we first show that intracolumnar (and thus intra-regional) excitatory and inhibitory connections (rather than inter-regional feedback, feedforward and lateral connections between the columns of different regions) strongly influence both resting state INTs and task-related ERFs. Secondly, our results demonstrate a positive relationship between the magnitude of event-related fields (mERFs) and INTs, observed in both model simulations and empirical MEG data collected during an emotional face recognition task. Thirdly, modeling shows that the positive relationship of mERF and INT depends on intracolumnar connections through observing that the correlation between them disappears for fixed values of intracolumnar connections. Together, these findings highlight the importance of intracolumnar connections as a shared biological mechanism underlying both the resting-states INTs and the task-states event-related activity including their interplay.

Neural signatures of model-based and model-free reinforcement learning across prefrontal cortex and striatum
Animals integrate knowledge about how the state of the environment evolves to choose actions that maximise reward. Such goal-directed behaviour - or model-based (MB) reinforcement learning (RL) - can flexibly adapt choice to changes, being thus distinct from simpler habitual - or model-free (MF) RL - strategies. Previous inactivation and neuroimaging work implicates prefrontal cortex (PFC) and the caudate striatal region in MB-RL; however, details are scarce about its implementation at the single-neuron level. Here, we recorded from two PFC regions - the dorsal anterior cingulate cortex (ACC) and dorsolateral PFC (DLPFC), and two striatal regions, caudate and putamen - while two rhesus macaques performed a sequential decision-making (two-step) task in which MB-RL involves knowledge about the statistics of reward and state transitions. All four regions, but particularly the ACC, encoded the rewards received and tracked the probabilistic state transitions that occurred. However, ACC (and to a lesser extent caudate) encoded the key variables of the task - namely the interaction between reward, transition and choice - which underlies MB decision-making. ACC and caudate neurons also encoded MB-derived estimates of choice values. Moreover, caudate value estimates of the choice options flipped when a rare transition occurred, demonstrating value update based on structural knowledge of the task. The striatal regions were unique (relative to PFC) in encoding the current and previous rewards with opposing polarities, reminiscent of dopaminergic neurons, and indicative of a MF prediction error. Our findings provide a deeper understanding of selective and temporally dissociable neural mechanisms underlying goal-directed behaviour.

Neural correlates of approach and avoidance tendencies toward physical activity and sedentary stimuli: An fMRI study
Automatic tendencies toward physical activity and sedentary stimuli are involved in the regulation of physical activity behavior. However, the brain regions underlying these automatic tendencies remain largely unknown. Here, we used an approach-avoidance task and magnetic resonance imaging (MRI) in 42 healthy young adults to investigate whether cortical and subcortical brain regions underpinning reward processing and executive function are associated with these tendencies. At the behavioral level, results showed more errors in avoidance behavior following sedentary stimuli than physical activity stimuli. At the brain level, avoidance behavior following sedentary stimuli was associated with more activation of the motor control network (dorsolateral-prefrontal cortex, primary and secondary motor cortices, somatosensory cortex). In addition, increased activation of the bilateral parahippocampal gyrus -- and structural deformation of the right hippocampus - were associated with a tendency toward approaching sedentary stimuli. Together, these results suggest that avoiding sedentary stimuli requires higher levels of behavioral control than avoiding physical activity stimuli.

Monoamine-induced diacylglycerol signaling rapidly accumulates Unc13 in nanoclusters for fast presynaptic potentiation
Neuromodulators control mood, arousal, and behavior by inducing synaptic plasticity via G-protein coupled receptors. Long-term potentiation of presynaptic neurotransmitter release requires structural changes, but how fast potentiation is achieved within minutes remains enigmatic. Using the Drosophila melanogaster neuromuscular junction, we show that on the timescale of one minute, octopamine, the invertebrate analog of nor-epinephrine, rapidly potentiates evoked neurotransmitter release by a G protein coupled pathway involving presynaptic OAMB receptors and phospholipase C. No changes of presynaptic calcium influx were seen, but confocal signals of the release factor Unc13A and the scaffolding protein Bruchpilot increased within one minute of octopamine treatment. On the same timescale, live, single-molecule imaging of endogenously tagged Unc13 revealed its instantly reduced motility and its increased concentration in synaptic nanoclusters with potentiation. Presynaptic knockdown of Unc13A fully blocked fast potentiation and removal of its N-terminal localization sequence delocalized the protein fragment to the cytosol, but it was rapidly recruited to the plasma membrane by DAG analog phorbol esters and octopamine, pointing to a role in C-terminal domains. Point mutation of endogenous Unc13 disrupting diacylglycerol-binding to its C1 domain blocked plasticity-induced nanoscopic enrichment and synaptic potentiation. The mutation increased basal neurotransmission but reduced Unc13 levels, revealing a gain of function and potential homeostatic compensation. The mutation also blocked phorbol ester-induced potentiation, decreased the calcium-sensitivity of neurotransmission and caused short-term synaptic depression. At the organismal level, the mutation reduced locomotion and survival while enhancing reproduction. Thus, the Unc13 C1 domain mediates acute subsynaptic compaction of Unc13 under monoamine-induced potentiation and influences short-term plasticity, locomotion, reproduction, and survival.

OPTN protects retinal ganglion cells and ameliorates neuroinflammation in optic neuropathies
Optineurin (OPTN) is a crucial component of the homeostatic pathway, playing a pivotal role in regulating a number of essential signaling pathways including NF-kB, interferon, autophagy, and vesicular trafficking. The dysfunction of OPTN has been implicated in the pathogenesis of several diseases, such as primary open angle glaucoma (POAG), amyotrophic lateral sclerosis (ALS), and frontotemporal lobar dementia. Interestingly, mutations in OPTN are implicated as gain-of-function in glaucoma pathology and loss-of-function in ALS. However, the role of loss-of-function OPTN in glaucoma pathology remains unclear. Here, we demonstrate that OPTN dysfunction contributes to chronic neuroinflammation, leading to sustained RGC death, which may represent a shared pathological mechanism in both normal tension glaucoma (NTG) and high-tension glaucoma (HTG). Retinal conditioned OPTN knockout contributes to short-term astrogliosis and long-term microglia activation, with the propagation of microglia activation spreading to the optic nerve. Moreover, OPTN loss-of-function and ocular hypertension affect the overlapped group of vulnerable RGCs, combined with the downregulation of OPTN in glaucoma patients, indicating an IOP-independent mechanism of glaucoma pathogenesis. Furthermore, we found that OPTN-driven NPY upregulation may suppress the CHOP-associated neurodegeneration. Our findings reveal a neuroprotective role for the OPTN-NPY signaling pathway, and its dysfunction promotes RGC loss in glaucoma pathology. The OPTN-NPY-mediated neuroinflammatory pathway provides a potential therapy for IOP-resistant glaucoma and highlights a druggable target for CHOP-associated neurodegeneration.

Neural decoding of competitive decision-making in Rock-Paper-Scissors using EEG hyperscanning
Social interactions are fundamental to daily life, yet social neuroscience research has often studied individuals' brains in isolation. Hyperscanning, the simultaneous recording of neural data from multiple participants, enables real-time investigation of social processes by examining multiple brains while they interact. Previous hyperscanning research has mostly focused on cooperative tasks and remains limited in competitive contexts. Here, we obtained electroencephalography (EEG) hyperscanning data for 62 participants (31 pairs) who played a computerised version of the Rock-Paper-Scissors game, a classic paradigm for studying competitive decision-making. Although the optimal strategy is to be unpredictable and thus act randomly, participants exhibited behavioural biases, deviating from this ideal. Using multivariate decoding methods, we found that neural signals contained information about decisions made by participants during gameplay, revealing certain strategies. Notably, losers showed unique reliance on prior trials, suggesting memory-based strategies that may impair optimal performance. These results reveal how competitive decision-making is shaped by cognitive biases and memory of previous outcomes, highlighting the difficulty of achieving randomness in strategic contexts. This work advances our understanding of decision-making and cognitive dynamics in competitive interactions.

The dependency of TMS-evoked potentials on electric-field orientation in the cortex
Transcranial magnetic stimulation (TMS) stimulates the brain by electromagnetic induction. The outcome depends on multiple stimulation parameters such as the induced electric-field pattern (in particular, the location of the peak field and its orientation), intensity and timing. However, it is not clear how the TMS-evoked responses are affected by all the stimulation parameters. This study elucidates the dependency of the TMS-evoked electroencephalography (EEG) responses on the orientation of the stimulating electric field. To achieve this, we analysed a dataset from six subjects who were given pulses with 36 stimulus orientations to the pre-supplementary motor area (pre-SMA). The TMS-evoked potentials (TEPs) and induced oscillations were analysed with cluster-based statistics. Source estimation was performed to assess the effects of stimulus orientation on the TMS-evoked signal propagation. The amplitudes of the early peaks (20 and 40 ms after the TMS pulse) strongly depended on the electric field orientation. Our analysis suggested orientation dependency up to 100 ms post-stimulus in most subjects, indicating changes in stimulation efficacy and potential changes in signal propagation from the stimulated site. These results suggest that different orientations may perturb different networks. Thus, the orientation is a crucial parameter for the stimulation outcome and should be adjusted according to the cortical network under investigation.

Transgenic A53T mice have astrocytic α-synuclein aggregates in dopamine and striatal regions
Parkinsons disease is considered biologically a neuronal alpha synuclein disease, largely ignoring the more widespread alpha synuclein deposition that occurs in astrocytes. Recent single cell transcriptomics have identified early astrocytic differences in both Parkinsons disease and mouse models with an increase in reactive astrocytes associated with proteostasis. To identify whether astrocytes accumulate alpha synuclein before or after neurons, the present study histologically assessed astrocytes and alpha synuclein accumulation in the M83 A53T transgenic mouse model of Parkinsons disease prior to significant neuronal alpha synuclein accumulation. The brains of M83 A53T transgenic and wild-type mice were perfusion fixed and serial sections of the midbrain and striatum processed for multiplex labelling. Digital images were captured from standardised sampling regions and astrocyte quantitation performed using QuPath software. Multivariate linear region models with Turkey posthoc tests were used to evaluate the effects of genotype on regional astrocyte morphology and numbers. The density of astrocytes within the substantia nigra pars compacta was approximately thirty percent greater compared with other sampled regions. Small aggregates of alpha synuclein were observed in astrocytic processes, including in wild-type mice where a quarter of all astrocytes had an obvious alpha synuclein aggregate. Compared to wild-type, A53T transgenic astrocytes had significantly enlarged somas with more processes consistent with a reactive phenotype. The expression of vascular endothelial growth factor A was present in analysed astrocytes, but not the synthesising enzyme for vitamin D CYP27B1. The A53T transgenic mice had more than double the numbers of astrocytes and 2.5 times more astrocytes with alpha synuclein aggregates compared to wild-type mice. These data suggest that alpha synuclein is normally cleared by astrocytes and that the substantia nigra pars compacta requires more astrocytic support than other midbrain dopaminergic regions or the striatum. This adds another vulnerability factor to those already known for the substantia nigra. In the A53T transgenic mouse model, astrocytes have an early upregulation of their clearance of alpha synuclein aggregates. While speculative, a loss of this ability to take up alpha synuclein in these regions may precipitate the selective neuronal degeneration and pathologies observed in Parkinsons disease. As we move to a biological definition for this disease, understanding this early role astrocytes needs to be considered further.

Understanding the high-order network plasticity mechanisms of ultrasound neuromodulation
Transcranial ultrasound stimulation (TUS) is an emerging non-invasive neuromodulation technique, offering a potential alternative to pharmacological treatments for psychiatric and neurological disorders. While functional analysis has been instrumental in characterizing TUS effects, understanding the underlying mechanisms remains a challenge. Here, we developed a whole-brain model to represent functional changes as measured by fMRI, enabling us to investigate how TUS-induced effects propagate throughout the brain with increasing stimulus intensity. We implemented two mechanisms: one based on anatomical distance and another on broadcasting dynamics, to explore plasticity-driven changes in specific brain regions. Finally, we highlighted the role of higher-order functional interactions in localizing spatial effects of off-line TUS at two target areas-the right thalamus and inferior frontal cortex-revealing distinct patterns of functional reorganization. This work lays the foundation for mechanistic insights and predictive models of TUS, advancing its potential clinical applications.

Long-term multichannel recordings in Drosophila flies reveal distinct responses to deviant visual stimuli during sleep compared to wake
During sleep, behavioral responsiveness to external stimuli is decreased. This classical definition of sleep has been applied effectively across the animal kingdom to identify this common behavioral state in a growing list of creatures, from mammals to invertebrates. Yet it remains unclear whether decreased behavioral responsiveness during sleep is necessarily associated with decreased responsiveness in brain activity, especially in relative latecomers to the sleep field, such as insects. Here, we perform long-term multichannel electrophysiology in tethered Drosophila melanogaster flies exposed continuously to flashing visual stimuli. Flies were still able to sleep under these visual stimulation conditions, as determined by traditional immobility duration criteria for the field. Interestingly, local field potentials (LFPs) recorded in a transect through the fly brain failed to show any difference in amplitude during sleep compared to wake when the visual stimuli were invariant. In contrast, LFP responses were lower when visual stimuli were variable and of lower probability, especially in the central brain. Central brain responses to deviant stimuli were lowest during the deepest stage of sleep, characterized by more regular proboscis extensions. This shows that the sleeping fly brain processes low-probability visual stimuli in a different way than more repeated stimuli and presents Drosophila as a model system for studying the potential role of sleep in regulating predictive processing.

Enhanced Neural Speech Tracking in Aging and Hearing Loss: The Role of Stochastic Resonance
Tracking the envelope of speech in the brain is important for speech comprehension. Recent research suggests that acoustic background noise can enhance neural speech tracking, enabling the auditory system to robustly encode speech even under unfavorable conditions. Aging and hearing loss are associated with internal, neural noise in the auditory system, which raises the question whether additional acoustic background noise can enhance neural speech tracking in older adults. In the current electroencephalography study, younger (~25.5 years) and older adults (~68.5 years) listened to spoken stories either in quiet (clear) or in the presence of background noise at a wide range of different signal-to-noise ratios. In younger adults, neural speech tracking was enhanced by minimal background noise, indicating the presence of stochastic resonance, that is, the response facilitation through noise. In contrast, older adults, compared to younger adults, showed enhanced neural speech tracking for clear speech and speech masked by minimal background noise, but the acoustic noise led to little enhancement in neural tracking in older people. The data demonstrate different sensitivity of the auditory cortex to speech masked by noise between younger and older adults. The results are consistent with the idea that the auditory cortex of older people exhibits more internal, neural noise that enhances neural speech tracking - through stochastic resonance - but that additional acoustic noise does not further support speech encoding. The work points to a highly non-linear auditory system that differs between younger and older adults.