bioRxiv Subject Collection: Neuroscience's Journal

An orexin-sensitive subpopulation of layer 6 neurons regulates cortical excitability and anxiety behaviour.
Cortical layer 6 (L6) neurons uniquely respond to orexin, a neuropeptide influencing arousal and emotion. We show that Drd1a-Cre+ neurons in the prefrontal cortex are selectively sensitive to orexin and regulate prefrontal network activation in vitro and in vivo. Chronically silencing these neurons impairs orexin-induced prefrontal activation and reduces anxiety-like behaviour, indicating that orexin-responsive L6 neurons modulate emotional states and may be a substrate for anxiety regulation.

Parvalbumin interneuron ErbB4 controls ongoing network oscillations and olfactory behaviors in mice
Parvalbumin (PV)-positive interneurons modulate the processing of odor information. However, less is known about how PV interneurons dynamically remodel neural circuit responses in the olfactory bulb (OB) and its physiological significance. This study showed that a reinforced odor discrimination task up-regulated the activity of ErbB4 kinase in mouse OB. ErbB4 knock-out in the OB impaired dishabituation of odor responses and discrimination of complex odors, whereas odor memory or adaptation had no alteration in mice. RNAscope analysis demonstrated that ErbB4-positive neurons are localized throughout the OB, whereas within the internal and external plexiform layers, ErbB4 mRNA are largely expressed in PV-positive interneurons. ErbB4 knock-out in PV interneurons disrupted odor-evoked responses of mitral/tufted cells, and led to increased power in the ongoing local field potential in awake mice. We also found a decrease in the frequency of miniature inhibitory postsynaptic currents and deficits in stimulus-evoked recurrent and lateral inhibition onto mitral cells, suggesting broad impairments in inhibitory circuit following PV-ErbB4 loss. Similarly, ErbB4 ablation in OB PV interneurons disrupted olfactory discrimination and dishabituation in mice. These findings provide novel insights into the role of PV-ErbB4 signaling in inhibitory circuit plasticity, ongoing oscillations, and OB output, which underlies normal olfactory behaviors.

Multivariate Neural Patterns of Reward and Anxiety in Adolescents with Anorexia Nervosa
People with anorexia nervosa (AN) commonly exhibit elevated anxiety and atypical reward responsiveness. To examine multivariate neural patterns associated with reward and the impact of anxiety on reward, we analyzed fMRI data from a monetary reward task using representational similarity analysis, a multivariate approach that measures trial by trial consistency of neural responses. Twenty-five adolescent girls with AN and 22 mildly anxious controls lacking any history of AN were presented personalized anxiety-provoking or neutral words before receiving a reward, and neural response patterns in reward regions were analyzed. Consistent with our preregistered hypothesis, AN participants showed lower representational similarity than controls during neutral-word rewarded trials. Within groups, controls showed significant representational similarity in reward circuit regions including the left nucleus accumbens, left basolateral amygdala, and left medial orbitofrontal cortex, which were not observed in AN. Further, reward-related prefrontal cognitive control areas - left ventrolateral prefrontal cortex and left dorsolateral prefrontal cortex - showed significant representational similarity in both groups, but a larger spatial extent in controls. Contrary to predictions, there were no significant between-group differences for the effects of anxiety-words on reward representational similarity, and representational similarity did not predict longitudinal symptom change over six months. Overall, the results demonstrate relatively inconsistent trial-by-trial responses to reward receipt in the neutral state in AN compared with controls in both reward circuit and cognitive control regions, but no significant differential effects of anxiety states on reward responses. These results add to dynamic understandings of reward processing in AN that have potential implications for planning and guiding reward-focused interventions.

Factors behind poor cognitive outcome following a thalamic stroke
Objective: Thalamic strokes produce a range of neurological, cognitive, and behavioral symptoms depending on the thalamic nuclei involved. While thalamic strokes are traditionally associated with severe cognitive deficits, recent studies suggest more modest impairments. This study aims to identify the factors that influence the severity of cognitive impairment following thalamic stroke. Methods: We recruited 40 patients (median age 51) with chronic isolated thalamic stroke and 45 healthy subjects. All subjects underwent neuroimaging and neuropsychological testing. Cluster and principal component analyses were used to discriminate patients from healthy subjects based on cognitive performance. Disconnectome maps and cortical thickness were analyzed to understand the distant impact of thalamic strokes. Results: Two cognitive profiles emerged. Cluster 1 included mostly healthy subjects (n = 43) and patients with no or minor deficits (n = 20); Cluster 2 included patients (n = 19) and 2 healthy subjects with severe deficits of verbal memory, executive functions, and attention. Cluster 1 included all patients with right thalamic stroke. Cluster 2 included all patients with bilateral stroke or mammillothalamic tract disruption. Patients with left-sided stroke were equally divided between Cluster 1 and 2. Other significant differences included age, education, interthalamic adhesion disruption, lesion volume, and location. Disconnectome maps showed larger disruptions of the anterior thalamic projection in patients with left-sided stroke of Cluster 2. Interpretation: Contrary to common expectations, our findings indicate that many patients with thalamic stroke have relatively good cognitive outcomes. In contrast, we identified some of the factors behind poor outcomes that may help clinicians.

Reduced monitoring of task performance is an effective biomarker of autism
People continuously track and adjust their behavior using external and internal signals. Autistic individuals manifest reduced sensorimotor error correction and slower updating of perceptual priors, yielding reduced behavioral flexibility. A potential reason for this reduced flexibility is a lessened sensitivity to both external and internal feedback. A key brain region involved in online monitoring of behavior and updating world models, known to be atypically activated in autism spectrum disorder (ASD), is the anterior cingulate cortex (ACC). During a two-tone pitch discrimination task, we used EEG to track ASD participants' ACC response dynamics, as manifested in their feedback-related negativity (FRN) component produced following "incorrect" feedback. We found that the FRN is missing in more than half of the ASD (17/30) participants, while clearly present in almost all non-autistics (33/35). Moreover, only in non-autistics, feedback affected performance in the following trial. Their responses were slower following an erred trial, their accuracy was improved following hard and correct trials, and they were more affected by the perceptual priors following easy and correct trials. Non-autistics' EEG response to feedback was also sensitive to trial difficulty, while the EEG response of ASD participants was not. Overall, we observed EEG and behavioral correlates of reduced sensitivity to both external and internal feedback in ASD. These observations suggest that increasing the salience of the external feedback could improve ASDs' error monitoring and perhaps increase their behavioral flexibility.

Phonological representations of auditory and visual speech in the occipito-temporal cortex and beyond
Speech is a multisensory signal that can be extracted from the voice and the lips. Previous studies suggested that occipital and temporal regions encode both auditory and visual speech features but their precise location and nature remain unclear. We characterized brain activity using fMRI (in male and female) to functionally and individually define bilateral Fusiform Face Areas (FFA), the left Visual Word Form Area (VWFA), an audio-visual speech region in the left Superior Temporal Sulcus (lSTS) and control regions in bilateral Para-hippocampal Place Areas (PPA). In these regions, we performed multivariate patterns classification of corresponding phonemes (speech sounds) and visemes (lip movements). We observed that the VWFA and lSTS represent phonological information from both vision and sounds. The multisensory nature of phonological representations appeared selective to the anterior portion of VWFA, as we found viseme but not phoneme representation in adjacent FFA or even posterior VWFA, while PPA did not encode phonology in any modality. Interestingly, cross-modal decoding revealed aligned phonological representations across the senses in lSTS, but not in VWFA. A whole-brain cross-modal searchlight analysis additionally revealed aligned audio-visual phonological representations in bilateral pSTS and left somato-motor cortex overlapping with oro-facial articulators. Altogether, our results demonstrate that auditory and visual phonology are represented in the anterior VWFA, extending its functional coding beyond orthography. The geometries of auditory and visual representations do not align in the VWFA as they do in the STS and left somato-motor cortex, suggesting distinct multisensory representations across a distributed phonological network.

The Genetic Architecture of the Human Corpus Callosum and its Subregions
The corpus callosum (CC) is the largest set of white matter fibers connecting the two hemispheres of the brain. In humans, it is essential for coordinating sensorimotor responses, performing associative/executive functions, and representing information in multiple dimensions. Understanding which genetic variants underpin corpus callosum morphometry, and their shared influence on cortical structure and susceptibility to neuropsychiatric disorders, can provide molecular insights into the CCs role in mediating cortical development and its contribution to neuropsychiatric disease. To characterize the morphometry of the midsagittal corpus callosum, we developed a publicly available artificial intelligence based tool to extract, parcellate, and calculate its total and regional area and thickness. Using the UK Biobank (UKB) and the Adolescent Brain Cognitive Development study (ABCD), we extracted measures of midsagittal corpus callosum morphometry and performed a genome-wide association study (GWAS) meta-analysis of European participants (combined N = 46,685). We then examined evidence for generalization to the non-European participants of the UKB and ABCD cohorts (combined N = 7,040). Post-GWAS analyses implicate prenatal intracellular organization and cell growth patterns, and high heritability in regions of open chromatin, suggesting transcriptional activity regulation in early development. Results suggest programmed cell death mediated by the immune system drives the thinning of the posterior body and isthmus. Global and local genetic overlap, along with causal genetic liability, between the corpus callosum, cerebral cortex, and neuropsychiatric disorders such as attention-deficit/hyperactivity and bipolar disorders were identified. These results provide insight into variability of corpus callosum development, its genetic influence on the cerebral cortex, and biological mechanisms related to neuropsychiatric dysfunction.

Combined effects of pharmacological interventions and intermittent theta-burst stimulation on motor sequence learning
Drugs that modulate N-methyl-D-aspartate (NMDA) or {gamma}-Aminobutyric acid type A (GABAA) receptors can shed light on their role in synaptic plasticity mechanisms underlying the effects of non-invasive brain stimulation. However, research on the combined effects of these drugs and exogenous stimulation on motor learning is limited. This study aimed to investigate the effects of pharmacological interventions combined with intermittent theta-burst stimulation (iTBS) on human motor learning. Nine right-handed healthy subjects (mean age {+/-} SD: 31.56 {+/-} 12.96 years; 6 females) participated in this double-blind crossover study. All participants were assigned to four drug conditions in a randomized order: (1) D-cycloserine (partial NMDA receptor agonist), (2) D-cycloserine + dextromethorphan (NMDA receptor agonist + antagonist), (3) lorazepam (GABAA receptor agonist), and (4) placebo (identical microcrystalline cellulose capsule). After drug intake, participants practiced the 12-item keyboard sequential task as a baseline measure. Two hours after drug intake, iTBS was administered at the primary motor cortex. Following iTBS, the retention test was performed in the same manner as the baseline measure. Our findings revealed that lorazepam combined with iTBS impaired motor learning during the retention test. Future studies are still needed for a better understanding of the mechanisms through which TMS may influence human motor learning.

History-dependent spiking facilitates efficient encoding of polarization angles in neurons of the central complex
Many insects use the polarization pattern of the sky for spatial orientation. Since flying insects perform rapid maneuvers, including saccadic yaw turns which alternate with translational flight, they perceive highly dynamic polarization input to their navigation system. The tuning of compass-neurons in the central complex of insects, however, has been mostly investigated with polarized-light stimuli that rotated at slow and constant velocities, and thus were lacking these natural dynamics. Here we investigated the dynamic response properties of compass-neurons, using intracellular recordings in the central complex of bumblebees. We generated naturalistic stimuli by rotating a polarizer either according to a sequence of head orientations that have been reported from freely flying bumblebees, or at constant velocities between 30{degrees}/s and 1920{degrees}/s, spanning almost the entire range of naturally occurring rotation velocities. We found that compass neurons responded reliably across the entire range of the presented stimuli. In their responses, we observed a dependency on spiking history. We further investigated this dependency using a rate code model taking spiking history into account. Extending the model to a neuronal population with different polarization tuning, which mirrored the neuronal architecture of the central complex, suggests that spiking history has a directly impact on the overall population activity, which has two effects: First, it facilitates faster responses to stimulus changes during highly dynamic flight maneuvers, and increases sensitivity for course deviations during straight flight. Second, population activity during phases of constant polarization input is reduced, which might conserve energy during straight flight.

EFMouse: a Matlab toolbox to model electric fields in the mouse brain
Compared to the rapidly growing literature on transcranial electrical stimulation (tES) in humans, research into the mechanisms underlying neuromodulation by tES using in-vivo animal models is growing but still relatively rare. Such research, however, is key to overcoming experimental limitations in humans and essential to build a detailed understanding of the in-vivo consequences of tES that can ultimately lead to development of targeted and effective therapeutic applications of noninvasive brain stimulation. The sheer difference in scale and geometry between animal models and the human brain contributes to the complexity of designing and interpreting animal studies. Here we extend previous approaches to model intracranial electric fields to generate predictions that can be tested with in-vivo intracranial recordings. Although the toolbox has general applicability and could be used to predict intracranial fields for any tES study using mice, we illustrate its usage by comparing fields in a high-density multi-electrode montage with a more traditional two electrode montage. Our simulations show that both montages can produce strong focal homogeneous electric fields in targeted areas. However, the high-density montage produces a field that is more perpendicular to the visual cortical surface, which is expected to result in larger changes in neuronal excitability.

Sensorimotor restriction affects sleep-related motor memory consolidation through altered slow oscillation-spindle coupling.
Sleep benefits memory consolidation through periodic sleep spindle activity and associated memory reactivations. The temporal organization of spindles in "trains" is considered a critical sleep mechanism for the timed and repeated reactivation of memories. Also, evidence suggests that a timely phase-locking between slow oscillations (SO) and spindles facilitates learning-related synaptic plasticity. Here, we investigated the contribution of the clustering and coupling of spindles with SO in motor memory consolidation by experimentally promoting local synaptic depression in sensorimotor cortical regions, through upper-limb immobilization, following motor sequence learning. Our results reveal that the cluster-based organization of sleep spindles is independent of daytime sensorimotor experience, while leading to distinct overnight behavioral outcomes. Interestingly, immobilization induced a phase shift in the SO-spindle coupling for spindles occurring in trains but not when isolated outside trains. We demonstrate that spindle trains may promote skill-specific strengthening of motor memories, while isolated spindles may instead create memory-instability conditions leading to enhanced skill transfer.

Role of somatic HCN in epileptiform activity in subicular neurons
The subiculum, owing to its bursting nature and recurrent connections, plays a critical role in Temporal Lobe Epilepsy (TLE). Studying neuronal subtypes in the subiculum can elucidate the mechanisms underlying the patterning of epileptiform firing. We observed that epileptogenic 4AP-0Mg induced different patterns of epileptiform discharges in burst firing neurons and interneurons. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate the intrinsic excitability of the neurons by governing the neuronal firing properties and membrane potential. To study the role of Ih (HCN currents) in epileptiform activity in subicular neurons, we modeled subicular HCN currents in the dynamic clamp that mimicked downregulation and overexpression observed in epilepsy-associated pathophysiology. Our results indicated that the burst firing neurons contribute to the epileptic firing characteristics due to HCN in the subiculum. We subsequently investigated the homeostatic modulation of HCN during the epileptiform activity in subicular burster cells. Our study is the first report showing Ih in rat subicular neurons during 4AP 0Mg-induced epileptogenic activity undergoes modulation on a time scale of a few minutes. Additionally, we observed that the changes in sag and chirp responses were persistent after the wash-out of 4AP-0Mg; thus, the changes appear irreversible. Our studies further showed that the neuronal excitability changes paralleled the changes in the HCN conductance during epileptogenesis. We conclude that a very rapid decline in somatic HCN function during epileptiform activity represents a previously unidentified mechanism of homeostatic dysfunction over a very short period, impeding the ability of a neuron to reestablish its regulatory processes in the subicular burster cells.

Spatial (Mis)match Between EEG and fMRI Signal Patterns Revealed by Spatio-Spectral Source-Space EEG Decomposition
In this work, we aimed to directly compare and integrate EEG whole-brain patterns of neural dynamics with concurrently measured fMRI BOLD data. For that purpose, we set out to derive EEG patterns based on a spatio-spectral decomposition of band-limited EEG power in the source-reconstructed space. On a large data set of 72 subjects resting-state hdEEG-fMRI we showed that the proposed approach is reliable both in terms of the extracted patterns as well as their spatial BOLD signatures. The five most robust EEG spatio-spectral patterns include, but go beyond, the well-known occipital alpha power dynamics. The EEG spatial-spectral patterns show relatively weak, yet statistically significant spatial similarity to their fMRI BOLD signatures, particularly the patterns that show stronger temporal synchronization with BOLD. However, we observed an insignificant relation between the temporal synchronization and spatial overlap of the EEG spatio-spectral patterns and the classical fMRI BOLD resting state networks (as obtained by independent component analysis). This provides evidence that both EEG (frequency-specific) power and BOLD signal capture reproducible spatiotemporal patterns of neural dynamics. Rather than being mutually redundant, these are only partially overlapping, carrying to a large extent complementary information concerning the underlying low-frequency dynamics. Finally, we report and interpret the most stable source space EEG-fMRI patterns, along with the corresponding EEG electrode space patterns better known from the literature.

Guided by touch: Tactile Cues in Hand Movement Control
Traditionally, touch is associated with exteroception and is rarely considered a relevant sensory cue for controlling movements in space, unlike vision. We developed a technique to isolate and evaluate tactile involvement in controlling sliding finger movements over a surface. Young adults traced a 2D shape with their index finger under direct or mirror-reversed visual feedback to create a conflict between visual and somatosensory inputs. In this context, increased reliance on somatosensory input compromises movement accuracy. Based on the hypothesis that tactile cues contribute to guiding hand movements, we predicted poorer performance when the participants traced with their bare finger compared to when their tactile sensation was dampened using a smooth finger splint. The results supported this prediction. EEG source analyses revealed smaller current in the presumed somatosensory cortex during sensory conflict, but only when the finger directly touched the surface. This finding suggests the gating of task-irrelevant somatosensory inputs. Together, our results emphasize touch's involvement in movement control, challenging the notion that vision predominantly governs goal-directed hand or finger movements.

Environmental context sculpts spatial and temporal visual processing in thalamus
Behavioral state modulates neural activity throughout the visual system; this is largely due to changes in arousal that alter internal brain state. However, behaviors are constrained by the external environmental context, so it remains unclear if this context itself dictates the regime of visual processing, apart from ongoing changes in arousal. Here, we addressed this question in awake head-fixed mice while they passively viewed visual stimuli in two different environmental contexts: either a cylindrical tube, or a circular running wheel. We targeted high-density silicon probe recordings to the dorsal lateral geniculate nucleus (dLGN) and simultaneously measured several electrophysiological and behavioral correlates of arousal changes, and thus controlled for them across contexts. We found surprising differences in spatial and temporal processing in dLGN across contexts, even in identical states of alertness and stillness. The wheel context (versus tube) showed elevated baseline activity, faster visual responses, and smaller but less selective spatial receptive fields. Further, arousal caused similar changes to visual responsiveness across all conditions, but the environmental context mainly changed the overall set-point for this relationship. Together, our results reveal an unexpected influence of the physical environmental context on fundamental aspects of visual processing in the early visual system.

Olfactory projection neuron rewiring in the brain of an ecological specialist
Animals' behaviours can vary greatly between even closely-related species. While changes in the sensory periphery have frequently been linked to species-specific behaviours, very little is known about if and how individual cell types in the central brain evolve. Here, we develop a set of advanced genetic tools to compare homologous neurons in Drosophila sechellia - which specialises on a single fruit - and Drosophila melanogaster. Through systematic morphological analysis of olfactory projection neurons (PNs), we reveal that global anatomy of these second-order neurons is conserved. However, high-resolution, quantitative comparisons identify a striking case of convergent rewiring of PNs in two distinct olfactory pathways critical for D. sechellia's host location. Calcium imaging and labelling of pre-synaptic sites in these evolved PNs demonstrate that novel functional connections with third-order partners are formed in D. sechellia. This work demonstrates that peripheral sensory evolution is accompanied by highly-selective wiring changes in the central brain to facilitate ecological specialisation, and paves the way for systematic comparison of other cell types throughout the nervous system.

Engineering anti-amyloid antibodies with transferrin receptor targeting improves safety and brain biodistribution
Although the first generation of immunotherapies for Alzheimer's disease (AD) are now clinically approved, further optimization could improve both efficacy and safety. Here, we report an antibody transport vehicle (ATV) targeting the transferrin receptor (TfR) for brain delivery of amyloid beta (A{beta}) antibodies. We show that introduction of asymmetrical Fc mutations (ATVcisLALA) allowed the molecule to selectively retain effector function only when bound to A{beta} while mitigating TfR-related hematology liabilities. ATVcisLALA:A{beta} maintained the ability to induce microglial phagocytosis of A{beta} both ex vivo and in vivo. Mice treated with ATVcisLALA:A{beta} exhibited broad brain parenchymal antibody distribution and enhanced plaque target engagement, whereas anti-A{beta} IgG was highly localized to arterial perivascular spaces where cerebral amyloid angiopathy (CAA) is commonly found and likely plays a role in induction of amyloid-related imaging abnormalities (ARIA). Importantly, ATVcisLALA:A{beta} mitigated ARIA-like lesions and vascular inflammation associated with anti-A{beta} treatment in a mouse model of amyloid deposition. Taken together, ATVcisLALA has the potential to significantly improve both safety and efficacy of A{beta} immunotherapy through enhanced biodistribution mediated by transport across the blood-brain barrier.

Structured flexibility in recurrent neural networks via neuromodulation
The goal of theoretical neuroscience is to develop models that help us better understand biological intelligence. Such models range broadly in complexity and biological detail. For example, task-optimized recurrent neural networks (RNNs) have generated hypotheses about how the brain may perform various computations, but these models typically assume a fixed weight matrix representing the synaptic connectivity between neurons. From decades of neuroscience research, we know that synaptic weights are constantly changing, controlled in part by chemicals such as neuromodulators. In this work we explore the computational implications of synaptic gain scaling, a form of neuromodulation, using task-optimized low-rank RNNs. In our neuromodulated RNN (NM-RNN) model, a neuromodulatory subnetwork outputs a low-dimensional neuromodulatory signal that dynamically scales the low-rank recurrent weights of an output-generating RNN. In empirical experiments, we find that the structured flexibility in the NM-RNN allows it to both train and generalize with a higher degree of accuracy than low-rank RNNs on a set of canonical tasks. Additionally, via theoretical analyses we show how neuromodulatory gain scaling endows networks with gating mechanisms commonly found in artificial RNNs. We end by analyzing the low-rank dynamics of trained NM-RNNs, to show how task computations are distributed.

A second X chromosome improves cognition in aging male and female mice
Women show resilience to cognitive aging, in the absence of dementia, in many populations. To dissect sex differences, we utilized the FCG and XY* mouse models. Female gonads and sex chromosomes improved cognition in aging mice of both sexes. Further, presence of a second X in male and female mice conferred cognitive resilience while its absence in females blocked it. In the hippocampal proteome of aging female mice, the second X increased proteins involved in synaptogenesis signaling - a potential pathway to improved cognition.

Contrast-dependent response modulation in convolutional neural networks captures behavioral and neural signatures of visual adaptation
Human perception remains robust under challenging viewing conditions. Robust perception is thought to be facilitated by nonlinear response properties, including temporal adaptation (reduced responses to repeated stimuli) and contrast gain (shift in the contrast response function with pre-exposure to a stimulus). Temporal adaptation and contrast gain have both been shown to aid object recognition, however, their joint effect on perceptual and neural responses remains unclear. Here, we collected behavioural measurements and electrocorticography (EEG) data while human participants (both sexes) classified objects embedded within temporally repeated noise patterns, whereby object contrast was varied. Our findings reveal an interaction effect, with increased categorization performance as a result of temporal adaptation for higher but not lower contrast stimuli. This increase in behavioral performance after adaptation is associated with more pronounced contrast-dependent modulation of evoked neural responses, as well as better decoding of object information from EEG activity. To elucidate the neural computations underlying these effects, we endowed deep convolutional neural networks (DCNN) with various temporal adaptation mechanisms, including intrinsic suppression and temporal divisive normalisation. We demonstrate that incorporating a biologically-inspired contrast response function to modify temporal adaptation helps DCNNs to accurately capture human behaviour and neural activation profiles. Moreover, we find that networks with multiplicative temporal adaptation mechanisms, such as divisive normalization, show higher robustness against spatial shifts in the inputs compared to DCNNs employing additive mechanisms. Overall, we reveal how interaction effects between nonlinear response properties influence human perception in challenging viewing contexts and investigate potential computations that mediate these effects.

An aging-sensitive compensatory secretory phospholipase that confers neuroprotection and cognitive resilience
Cognitive reserve theory posits a role for compensatory mechanisms in the aging brain in moderating cognitive decline and risk for Alzheimer's Disease (AD). However, the identities of such mechanisms have remained elusive. A screen for hippocampal dentate granule cell (DGC) synapse loss-induced factors identified a secreted phospholipase, Pla2g2f, whose expression increases in DGCs during aging. Pla2g2f deletion in DGCs exacerbates aging-associated pathophysiological changes including synapse loss, inflammatory microglia, reactive astrogliosis, impaired neurogenesis, lipid dysregulation and hippocampal-dependent memory loss. Conversely, boosting Pla2g2f in DGCs during aging is sufficient to preserve synapses, reduce inflammatory microglia and reactive gliosis, prevent hippocampal-dependent memory impairment and modify trajectory of cognitive decline. Ex vivo, neuronal-PLA2G2F mediates intercellular signaling to decrease lipid droplet burden in microglia. Boosting Pla2g2f expression in DGCs of an aging-sensitive AD model reduces amyloid load and improves memory. Our findings implicate PLA2G2F as a compensatory neuroprotective factor that counteracts aging-associated cognitive decline.

Successful retrieval is its own reward
The ability to successfully remember past events is critical to our daily lives, yet the neural mechanisms underlying the motivation to retrieve is unclear. Although reward-system activity and feedback-related signals have been observed during memory retrieval, whether this signal reflects intrinsic reward or goal-attainment is unknown. Adjudicating between these two alternatives is crucial for understanding how individuals are motivated to engage in retrieval and how retrieval supports later remembering. To test these two accounts, we conducted between-subjects recognition memory tasks on human participants undergoing scalp electroencephalography and varied test-phase goals (recognize old vs. detect new items). We used an independently validated feedback classifier to measure positive feedback evidence. We find positive feedback following successful retrieval regardless of task goals. Together, these results suggest that successful retrieval is intrinsically rewarding. Such a feedback signal may promote future retrieval attempts as well as bolster later memory for the successfully retrieved events.

Epileptiform activity and seizure risk follow long-term non-linear attractor dynamics
Many biological systems display circadian and slow multi-day rhythms, such as hormonal and cardiac cycles. In patients with epilepsy, these cycles also manifest as slow cyclical fluctuations in seizure propensity. However, such fluctuations in symptoms are consequences of the complex interactions between the underlying physiological, pathophysiological, and external causes. Therefore, identifying an accurate model of the underlying system that governs the multi-day rhythms allows for a more reliable seizure risk forecast and targeted interventions. To achieve this goal, we adopt the Hankel alternative view of Koopman (HAVOK) analysis to approximate a linear representation of nonlinear seizure propensity dynamics. The HAVOK framework leverages Koopman theory and delay-embedding to decompose chaotic dynamics into a linear system of leading delay-embedded coordinates driven by the low-energy coordinate (i.e., forcing). Our findings reveal the topology of attractors underlying multi-day seizure cycles, showing that seizures tend to occur in regions of the manifold with strongly nonlinear dynamics. Moreover, we demonstrate that the identified system driven by forcings with short periods up to a few days accurately predicts patients' slower multi-day rhythms, which improves seizure risk forecasting.

A finite set of content-free pointers in visual working memory: MEG evidence
Human visual working memory (VWM) is known to be capacity-limited, but the nature of this limit continues to be debated. Recent work has proposed that VWM is supported by a finite (~ 3) set of content-free pointers, acting as stand-ins for individual objects and binding features together. Here, based on two visual working memory experiments (N=20 each) examining memory for simple and complex objects, we report a sustained MEG response over right pos-terior cortex whose magnitude tracks the core hypothesized properties of this system: load-dependent, capacity-limited and content-free. These results provide novel evidence for a finite set of content-free pointers underlying VWM.

Activating Cognitive Processes in Human Cortex at Multiple Low-Frequency Bands
Neural oscillations are fundamental for brain function, governing various cognitive processes. While electrophysiological studies have characterized the frequency properties of these oscillations, their spatial resolution is limited. In contrast, functional magnetic resonance imaging (fMRI) provides high spatial resolution but was initially restricted to a narrow frequency range. This study aims to bridge the gap by investigating the role of blood-oxygen-level-dependent (BOLD) oscillations across multiple frequency bands in cognitive processes using high temporal resolution task-fMRI data. Our findings reveal that different frequency bands are associated with distinct functional processes. Specifically, the slow-1 to slow-3 bands primarily contribute to local sensory information processing, while the slow-4 band is crucial for various fundamental cognitive functions, including somatic motor function and social cognitive function. The slow-5 band is involved in cognitive processes requiring higher memory load, integrated cognitive processing, and attention maintenance. Through multiband activation analysis, this study underscores the importance of analyzing a broad frequency range to capture the full spectrum of brain function. These findings highlight the diverse roles of different frequency bands in brain activity, shedding light on the underlying mechanisms of cognitive processes. This research enhances our understanding of the neural mechanisms underlying cognitive processes and has significant implications for cognitive neuroscience and clinical applications.