bioRxiv Subject Collection: Neuroscience's Journal

Discrete photoentrainment of mammalian central clock is regulated by bi-stable dynamic network in the suprachiasmatic nucleus.
The circadian clock, an evolutionarily conserved mechanism regulating the majority of physiological functions in many organisms, is synchronized with the environmental light-dark cycle through circadian photoentrainment. This process is mediated by light exposure at specific times, leading to a discrete phase shift including phase delays during early subjective night, phase advances during late subjective night, and no shift at midday, known as the dead zone. In mammals, such as mice, the intrinsically photosensitive retinal ganglion cells (ipRGCs) are crucial for conveying light information to the suprachiasmatic nucleus (SCN), the central clock consisting of approximately 20,000 neurons. While the intracellular signaling pathways that modulate clock gene expression post-light exposure are well-studied, the functional neuronal circuits responsible for the three discrete light responses are not well understood. Utilizing in vivo two-photon microscopy with gradient-index (GRIN) endoscopes, we have identified seven distinct light responses from SCN neurons. Our findings indicate that light responses from individual SCN neurons are mostly stochastic from trial to trial. However, at the population level, light response composition remains similar across trials, with only minor variations between circadian times, suggesting a dynamic populational coding for light input. Additionally, only a small subset of SCN neurons shows consistent light responses. Furthermore, by utilizing the targeted recombination in active populations (TRAP) system to label neurons that respond to light during early subjective night, we demonstrate that their activation can induce phase delays at any circadian time, effectively breaking the gate that produce photoentrainment dead zone typically observed at midday. Our results suggest the existence of at least two separate time-dependent functional circuits within the SCN. We propose a dynamic bi-stable network model for circadian photoentrainment in the mammalian central clock, where a shifting clock is driven by a dynamic functional circuit utilizing population coding to integrate information flow similar to proposed cortical computational network, rather than a simplistic, consistent linear circuit.

Leg choice for volitional goal-directed stepping is primarily influenced by effort rather than success: A preliminary investigation in neurotypical adults
During reaching, arm choice depends on success and motor effort. Whether these factors influence leg choice for stepping behavior is unknown. Here, we conducted two experiments (1: proof-of-principle; 2: kinematic analysis) to explore whether limb selection for goal-directed stepping depends on success and/or effort under two Choice conditions: Free (choose either leg) and Constrained (no choice - only left leg). For both experiments, in which Free trials always preceded Constrained trials, we adapted the classic center-out target array in which right-leg dominant neurotypical adults stood in the middle of the array and stepped to pre-cued targets as accurately as possible. The Free condition reflected the preferred limb choice. We compared success, effort, and self-perceived difficulty between Free and Constrained trials, separately for three (Experiment 1) and two (Experiment 2) regions. Overall, in Free condition, participants uniformly selected the limb ipsilateral to lateral left and right targets and with slight leg dominance-based bias for central targets. Success (step accuracy and consistency/precision) did not depend on Choice condition, rather, performance improved over repeated trials. Effort (peak vertical foot lift and step path ratio) depended on Choice condition. Finally, independent of Choice condition, participants perceived posterior targets (particularly far targets) as the most difficult during non-dominant left steps. Present findings suggest that effort may influence leg choice to a greater degree than success for goal-directed stepping. Future work that probes these findings robustness in patients with unilateral paresis (intrinsic constraint) may advance our understanding of the motor decision processes for goal-directed mobility behaviors.

Pleasurable music activates cerebral μ-opioid receptors: A combined PET-fMRI study
The -opioid receptor (MOR) system mediates incentive motivation and the hedonic component of primary rewards such as food and sex. However, there is no direct in vivo evidence for the involvement of the MOR system in pleasure derived from aesthetic rewards such as music. We measured MOR activation with positron emission tomography (PET) and the agonist radioligand [11C] carfentanil with high affinity for MORs during the listening of pleasurable music and neutral baseline condition. Haemodynamic responses to pleasurable music were measured using functional magnetic resonance imaging (fMRI). The PET results revealed that pleasurable music increased [11C]carfentanil binding in several cortical and subcortical regions, including ventral striatum and orbitofrontal cortex, known to contain "hedonic hotspots". Individual variation in baseline MOR tone influenced pleasure-dependent haemodynamic responses during music listening in regions associated with interoceptive, sensorimotor, and reward processing. Our results provide the first-ever neuroimaging evidence that listening to pleasurable music modulates MOR system activation and indicate that the -opioid system governs complex aesthetic rewards in addition to biologically salient primary rewards.

The relationship between event boundary strength and pattern shifts across the cortical hierarchy during naturalistic movie-viewing
Our continuous experience is spontaneously segmented by the brain into discrete events. However, the beginning of a new event (an event boundary) is not always sharply identifiable: phenomenologically, event boundaries vary in salience. How are the response profiles of cortical areas at event boundaries modulated by boundary strength during complex, naturalistic movie-viewing? Do cortical responses scale in a graded manner with boundary strength, or do they merely detect boundaries in a binary fashion? We measured cortical boundary shifts as transient changes in multi-voxel patterns at event boundaries with different strengths (weak, moderate, and strong), determined by across-subject agreement. Cortical regions with different processing timescales were examined. In auditory areas, which have short timescales, cortical boundary shifts exhibited a clearly graded profile both in group-level and individual-level analyses. In cortical areas with long timescales, including the default mode network, boundary strength modulated pattern shift magnitude at the individual subject level. We also observed a positive relationship between boundary strength and the extent of temporal alignment of boundary shifts across different levels of the cortical hierarchy. A strictly nested bottom-up hierarchical structure was not necessary to observe this relationship. Additionally, hippocampal activity was highest at event boundaries for which cortical boundary shifts were most aligned across hierarchical levels. Overall, we found that event boundary strength modulated cortical pattern shifts strongly in sensory areas and more weakly in higher-level areas, and that stronger boundaries were associated with greater alignment of these shifts across the cortical hierarchy.

Microglia drive diurnal variation in susceptibility to inflammatory blood-brain barrier breakdown
The blood-brain barrier (BBB) is critical for maintaining brain homeostasis but is susceptible to inflammatory dysfunction. Permeability of the BBB to lipophilic molecules shows circadian variation due to rhythmic transporter expression, while basal permeability to polar molecules is non-rhythmic. Whether daily timing influences BBB permeability in response to inflammation is unknown. Here, we induced systemic inflammation through repeated lipopolysaccharide (LPS) injections either in the morning (ZT1) or evening (ZT13) under standard lighting conditions, then examined BBB permeability to a polar molecule, sodium fluorescein. We observed clear diurnal variation in inflammatory BBB permeability, with a striking increase in paracellular leak across the BBB specifically following evening LPS injection. Evening LPS led to persisting glia activation and inflammation in the brain that was not observed in the periphery. The exaggerated evening neuroinflammation and BBB disruption were suppressed by microglial depletion or through keeping mice in constant darkness. Our data show that diurnal rhythms in microglial inflammatory responses to LPS drive daily variability in BBB breakdown and reveals time-of-day as a key regulator of inflammatory BBB disruption.

Implicit Adaptation is Fast, Robust and Independent from Explicit Adaptation
During classical visuomotor adaptation, the implicit process is believed to emerge rather slowly; however, recent evidence has found this may not be true. Here, we further quantify the time-course of implicit learning in response to diverse feedback types, rotation magnitudes, feedback timing delays, and the role of continuous aiming on implicit learning. Contrary to conventional beliefs, we affirmed that implicit learning unfolds at a high rate in all feedback conditions. Increasing rotation size not only raises asymptotes, but also generally heightens explicit awareness, with no discernible difference in implicit rates. Cursor-jump and terminal feedback, with or without delays, predominantly enhance explicit adaptation while slightly diminishing the extent or the speed of implicit adaptation. In a continuous aiming reports condition, there is no discernible impact on implicit adaptation, and both the rate of implicit and explicit adaptation progress at indistinguishable speeds. Finally, investigating the assumed negative correlation as an indicator of additivity between implicit and explicit processes, we consistently observe a weak association across conditions. Our observation of implicit learning early in training in all tested conditions signifies how fast and robust our innate adaptation system is.

Neurovascular coupling and briefCO2 interrogate distinct vascular regulations
Neurovascular coupling (NVC), which mediates rapid increases in cerebral blood flow in response to neuronal activation, is commonly used to map brain activation or dysfunction. Here we tested the reemerging hypothesis that CO2 generated by neuronal metabolism contributes to NVC. We combined functional ultrasound and two-photon imaging in the mouse barrel cortex to examine specifically the onsets of local changes in vessel diameter, blood flow dynamics, vascular/perivascular/intracellular pH, and intracellular calcium signals along the vascular arbor in response to briefCO2, a short and strong hypercapnic challenge (10 s, 20%) and whisker stimulation. We report that briefCO2 reversibly acidifies all cells of the arteriole wall and the periarteriolar space 3-4 seconds prior to the arteriole dilation. During this prolonged lag period, NVC triggered by whisker stimulation is not affected by the acidification of the entire neurovascular unit. As it also persists under condition of continuous inflow of CO2, we conclude that CO2 is not involved in NVC.

Macro- and Micro-Structural Alterations in the Midbrain in Early Psychosis
Introduction. Early psychosis (EP) is a critical period in the course of psychotic disorders during which the brain is thought to undergo rapid and significant functional and structural changes 1. Growing evidence suggests that the advent of psychotic disorders is early alterations in the brain's functional connectivity and structure, leading to aberrant neural network organization. The Human Connectome Project (HCP) is a global effort to map the human brain's connectivity in healthy and disease populations; within HCP, there is a specific dataset that focuses on the EP subjects (i.e., those within five years of the initial psychotic episode) (HCP-EP), which is the focus of our study. Given the critically important role of the midbrain function and structure in psychotic disorders (cite), and EP in particular (cite), we specifically focused on the midbrain macro- and micro-structural alterations and their association with clinical outcomes in HCP-EP. Methods: We examined macro- and micro-structural brain alterations in the HCP-EP sample (n=179: EP, n=123, Controls, n=56) as well as their associations with behavioral measures (i.e., symptoms severity) using a stepwise approach, incorporating a multimodal MRI analysis procedure. First, Deformation Based Morphometry (DBM) was carried out on the whole brain 3 Tesla T1w images to examine gross brain anatomy (i.e., seed-based and voxel-based volumes). Second, we extracted Fractional Anisotropy (FA), Axial Diffusivity (AD), and Mean Diffusivity (MD) indices from the Diffusion Tensor Imaging (DTI) data; a midbrain mask was created based on FreeSurfer v.6.0 atlas. Third, we employed Tract-Based Spatial Statistics (TBSS) to determine microstructural alterations in white matter tracts within the midbrain and broader regions. Finally, we conducted correlation analyses to examine associations between the DBM-, DTI- and TBSS-based outcomes and the Positive and Negative Syndrome Scale (PANSS) scores. Results: DBM analysis showed alterations in the hippocampus, midbrain, and caudate/putamen. A DTI voxel-based analysis shows midbrain reductions in FA and AD and increases in MD; meanwhile, the hippocampus shows an increase in FA and a decrease in AD and MD. Several key brain regions also show alterations in DTI indices (e.g., insula, caudate, prefrontal cortex). A seed-based analysis centered around a midbrain region of interest obtained from freesurfer segmentation confirms the voxel-based analysis of DTI indices. TBSS successfully captured structural differences within the midbrain and complementary alterations in other main white matter tracts, such as the corticospinal tract and cingulum, suggesting early altered brain connectivity in EP. Correlations between these quantities in the EP group and behavioral scores (i.e., PANSS and CAINS tests) were explored. It was found that midbrain volume noticeably correlates with the Cognitive score of PA and all DTI metrics. FA correlates with the several dimensions of the PANSS, while AD and MD do not show many associations with PANSS or CAINS. Conclusions: Our findings contribute to understanding the midbrain-focused circuitry involvement in EP and complimentary alteration in EP. Our work provides a path for future investigations to inform specific brain-based biomarkers of EP and their relationships to clinical manifestations of the psychosis course.

Circadian rhythms tied to changes in brain morphology in a densely-sampled male
Circadian, infradian, and seasonal changes in steroid hormone secretion have been tied to changes in brain volume in several mammalian species. However, the relationship between circadian changes in steroid hormone production and rhythmic changes in brain morphology in humans is largely unknown. Here, we examined the relationship between diurnal fluctuations in steroid hormones and multiscale brain morphology in a precision imaging study of a male who completed forty MRI and serological assessments at 7 A.M. and 8 P.M. over the course of a month, targeting hormone concentrations at their peak and nadir. Diurnal fluctuations in steroid hormones were tied to pronounced changes in global and regional brain morphology. From morning to evening, total brain volume, gray matter volume, and cortical thickness decreased, coincident with decreases in steroid hormone concentrations (testosterone, estradiol, and cortisol). In parallel, cerebrospinal fluid and ventricle size increased from A.M. to P.M. Global changes were driven by decreases within the occipital and parietal cortices. These findings highlight natural rhythms in brain morphology that keep time with the diurnal ebb and flow of steroid hormones.

PAK6 rescues pathogenic LRRK2-mediated ciliogenesis and centrosomal cohesion defects in a mutation-specific manner
P21 activated kinase 6 (PAK6) is a serine-threonine kinase with physiological expression enriched in the brain and overexpressed in a number of human tumors. While the role of PAK6 in cancer cells has been extensively investigated, the physiological function of the kinase in the context of brain cells is poorly understood. Our previous work uncovered a link between PAK6 and the Parkinson's disease (PD)-associated kinase LRRK2, with PAK6 controlling LRRK2 activity and subcellular localization via phosphorylation of 14-3-3 proteins. Here, to gain more insights into PAK6 physiological function, we performed protein-protein interaction arrays and identified a subgroup of PAK6 binders related to ciliogenesis. We confirmed that endogenous PAK6 localizes at both the centrosome and the cilium, and positively regulates ciliogenesis not only in tumor cells but also in neurons and astrocytes. Strikingly, PAK6 rescues ciliogenesis and centrosomal cohesion defects associated with the G2019S but not the R1441C LRRK2 PD mutation. Since PAK6 binds LRRK2 via its GTPase/Roc-COR domain and the R1441C mutation is located in the Roc domain, we used microscale thermophoresis and AlphaFold2-based computational analysis to demonstrate that PD mutations in LRRK2 affecting the Roc-COR structure substantially decrease PAK6 affinity, providing a rationale for the differential protective effect of PAK6 toward the distinct forms of mutant LRRK2. Altogether, our study discloses a novel role of PAK6 in ciliogenesis and points to PAK6 as the first LRRK2 modifier with PD mutation-specificity.

Neuropathic pain in a chronic CNS injury model is mediated by CST-targeted spinal interneurons
Chronic neuropathic pain is a persistent and debilitating outcome of traumatic central nervous system injury, affecting up to 80% of individuals with chronic injury. Post-injury pain is refractory to clinical treatments due to the limited understanding of the brain-spinal cord circuits that underlie pain signal processing. The corticospinal tract (CST) plays critical roles in sensory modulation during skilled movements and tactile sensation; however, a direct role for the CST in injury-associated neuropathic pain is unclear. Here we show that complete, selective CST transection at the medullary pyramids leads to hyperexcitability within lumbar deep dorsal horn and hindlimb allodynia in chronically injured adult mice. Chemogenetic regulation of CST-targeted lumbar spinal interneurons demonstrates that dysregulation of activity in this circuit underlies the development of tactile allodynia in chronic injury. Our findings shed light on an unrecognized circuit mechanism implicated in CNS injury-induced neuropathic pain and provide a novel target for therapeutic intervention.

Modulation of biphasic pattern of cortical reorganization in spinal cord transected rats by external magnetic fields.
Magnetic field induces electric field in the brain and has potential to modulate cortical plasticity giving rise to sustained excitability as well as behavioral modifications. The present study demonstrates the effect of extremely low frequency magnetic field (ELF-MF) on cortical reorganization after SCI in complete transaction rat model. The spinal cord of male albino Wistar rats was completed transected at T-13 spinal level and ELF-MF (50 Hz, 17.96 microtesla) exposure given either for 5 or 12 or 32 days for temporal observations. A significant functional recovery was evident in locomotor, sensorimotor and motor behavioral tests after 32 days of magnetic field exposure. This was associated with an amelioration in cortical electrical activity, decrease in the lesion area and volume and modulation of plasticity associated proteins like Nogo-A and BDNF in biphasic pattern. The results suggest improvement of functional, electrical and morphological parameters along with upregulation of plasticity associated proteins in an in-vivo SCI rat model following ELF-MF exposure for 32 days but not after 5, 12 days exposure.

Serotonin acts through multiple cellular targets during an olfactory critical period.
Serotonin(5-HT) is known to modulate early development during critical periods when experience drives heightened levels of plasticity in neurons. Here, we take advantage of the genetically tractable olfactory system of Drosophila to investigate how serotonin modulates critical period plasticity in the CO2 sensing circuit of fruit flies. Our study reveals that 5-HT modulation of multiple neuronal targets is necessary for experience-dependent structural changes in an odor processing circuit. The olfactory CPP is known to involve local inhibitory networks and consistent with this we found that knocking down 5-HT7 receptors in a subset of GABAergic local interneurons was sufficient to block CPP, as was knocking down GABA receptors expressed by olfactory sensory neurons (OSNs). Additionally, direct modulation of OSNs via 5-HT2B expression in the cognate OSNs sensing CO2 is also essential for CPP. Furthermore, 5-HT1B expression by serotonergic neurons in the olfactory system is also required during the critical period. Our study reveals that 5-HT modulation of multiple neuronal targets is necessary for experience-dependent structural changes in an odor processing circuit.

Cholinergic interneurons in the nucleus accumbens are a site of cellular convergence for corticotropin release factor and estrogen regulation
Cholinergic interneurons (ChIs) act as master regulators of striatal output, finely tuning neurotransmission to control motivated behaviors. ChIs are a cellular target of many peptide and hormonal neuromodulators, including corticotropin releasing factor, opioids, insulin and leptin, which can influence animal behavior by signaling stress, pleasure, pain and nutritional status. However, little is known about how sex hormones via estrogen receptors influence the function of these other neuromodulators. Here, we performed in situ hybridization on mouse striatal tissue to characterize the effect of sex and sex hormones on choline acetyltransferase (Chat), estrogen receptor alpha (Esr1), and corticotropin releasing factor type 1 receptor (Crhr1) expression. Although we did not detect sex differences in ChAT protein levels in the striatum, we found that female mice have more Chat mRNA-expressing neurons than males. At the population level, we observed a sexually dimorphic distribution of Esr1- and Crhr1-expressing ChIs in the ventral striatum that demonstrates an antagonistic correlational relationship, which is abolished by ovariectomy. Only in the NAc did we find a significant population of ChIs that co-express Crhr1 and Esr1. At the cellular level, Crhr1 and Esr1 transcript levels were negatively correlated only during estrus, indicating that changes in sex hormones levels can modulate the interaction between Crhr1 and Esr1 mRNA levels. Together, these data provide evidence for the unique expression and interaction of Esr1 and Crhr1 in ventral striatal ChIs, warranting further investigation into how these transcriptomic patterns might underlie important functions for ChIs at the intersection of stress and reproductive behaviors.

Neural representation of nouns and verbs in congenitally blind and sighted individuals
Language processing involves similar brain regions across languages and cultures. Intriguingly, one population escapes this universal pattern: in blind individuals, linguistic stimuli activate not only canonical language networks, but also the "visual" cortex. Theoretical implications of this finding are debated, particularly because it is unclear what properties of linguistic stimuli are represented in the blind visual cortex. To address this issue, we enrolled congenitally blind and sighted participants in an fMRI experiment, in which they listened to concrete, abstract, and pseudo nouns and verbs. We used multi-voxel pattern classification to investigate whether differences between nouns and verbs are represented in the blind visual cortex, and whether this effect is modulated by the word's semantic category. The classification of activation patterns for nouns and verbs was above chance level in the motion-sensitive area V5/MT in the blind participants, but not in other visual areas in this group. The effect in area V5/MT was driven by successful classification of activations for concrete nouns and verbs, in the absence of significant results for abstract and pseudo nouns and verbs. These findings suggest that the blind visual cortex represents the physical properties of noun and verb referents, more salient in the concrete word category, rather than more abstract linguistic distinctions, present in all word categories. Thus, responses to language in the blind visual cortex may be explained by preserved ability of this region to compute physical and spatial representations of the world.

Axo-axonic synaptic input drives homeostatic plasticity by tuning the axon initial segment structurally and functionally
Homeostatic plasticity maintains the stability of functional brain networks. The axon initial segment (AIS), where action potentials start, undergoes dynamic adjustment to exert powerful control over neuronal firing properties in response to network activity changes. However, it is poorly understood whether this plasticity involves direct synaptic input to the AIS. Here we show that changes of GABAergic synaptic input from chandelier cells (ChCs) drive homeostatic tuning of the AIS of principal neurons (PNs) in the prelimbic (PL) region, while those from parvalbumin-positive basket cells do not. This tuning is evident in AIS morphology, voltage-gated sodium channel expression, and PN excitability. Moreover, the impact of this homeostatic plasticity can be reflected in animal behavior. Social behavior, inversely linked to PL PN activity, shows time-dependent alterations tightly coupled to changes in AIS plasticity and PN excitability. Thus, AIS-originated homeostatic plasticity in PNs may counteract deficits elicited by imbalanced ChC presynaptic input at cellular and behavioral levels.

Spinal microcircuits go through multiphasic homeostatic compensations in a mouse model of motoneuron degeneration
In neurological conditions affecting the brain, early-stage neural circuit adaption is key for long-term preservation of normal behaviour. We tested if motoneurons and respective microcircuits also adapt in the initial stages of disease progression in a mouse model of progressive motoneuron degeneration. Using a combination of in vitro and in vivo electrophysiology and super-resolution microscopy, we found that, preceding muscle denervation and motoneuron death, recurrent inhibition mediated by Renshaw cells is reduced in half due to impaired quantal size associated with decreased glycine receptor density. Additionally, higher probability of release from proprioceptive Ia terminals leads to increased monosynaptic excitation to motoneurons. Surprisingly, the initial impairment in recurrent inhibition is not a widespread feature of inhibitory spinal circuits, such as group I inhibitory afferents, and is compensated at later stages of disease progression. We reveal that in disease conditions, spinal microcircuits undergo specific multiphasic homeostatic compensations to preserve force output.

Audio-visual concert performances synchronize an audience's heart rates
Despite the increasing availability of recorded music, people continue to engage in live musical experiences such as multimodal live concerts. However, the dynamics of audience engagement in such contexts are largely understudied. In a classical concert experiment, we presented audiences with audio-only (AO) and audio-visual (AV) piano performances while cardiorespiratory measures were continuously recorded. To investigate engagement, cardiorespiratory synchrony was calculated using both correlation and phase coherence methods. Only correlation measures remained significant in comparison to control (circular-shifted) data. Significant synchrony measures were then assessed between modalities, both across and within music pieces. AV performances evoked higher inter-subject correlation of heart rate (ISC-HR). However, self-reported engagement did not correspond to synchrony when averaged across music pieces. On the other hand, synchronized deceleration-acceleration heart rate (HR) patterns, typical of an 'orienting response' (an index of directed attention), occurred within music pieces at salient events (i.e., at section boundaries). In other words, seeing musicians perform heightened audience engagement at structurally important moments in the music. These results highlight the multimodal effects of music in real-world contexts, calling for future studies to explore wider-ranging genres and contexts to better understand dynamics of audience synchrony and engagement.

The C. elegans uv1 neuroendocrine cells provide direct mechanosensory feedback of vulval opening
Neuroendocrine cells react to physical, chemical, and synaptic signals originating from tissues and the nervous system, releasing hormones that regulate various body functions beyond the synapse. Neuroendocrine cells are often embedded in complex tissues making direct tests of their activation mechanisms and signaling effects difficult to study. In the nematode worm C. elegans, four uterine-vulval (uv1) neuroendocrine cells sit above the vulval canal next to the egg-laying circuit, releasing tyramine and neuropeptides that feedback to inhibit egg laying. We have previously shown uv1 cells are mechanically deformed during egg laying, driving uv1 Ca2+ transients. However, whether egg-laying circuit activity, vulval opening, and/or egg release triggered uv1 Ca2+ activity was unclear. Here we show uv1 responds directly to mechanical activation. Optogenetic vulval muscle stimulation triggers uv1 Ca2+ activity following muscle contraction even in sterile animals. Direct mechanical prodding with a glass probe placed against the worm cuticle triggers robust uv1 Ca2+ activity similar to that seen during egg laying. Direct mechanical activation of uv1 cells does not require other cells in the egg-laying circuit, synaptic or peptidergic neurotransmission, or TRPV and Piezo channels. EGL-19 L-type Ca2+ channels, but not P/Q/N-type or Ryanodine Receptor Ca2+ channels, promote uv1 Ca2+ activity following mechanical activation. L-type channels also facilitate the coordinated activation of uv1 cells across the vulva, suggesting mechanical stimulation of one uv1 cells cross-activates the other. Our findings show how neuroendocrine cells like uv1 report on the mechanics of tissue deformation and muscle contraction, facilitating feedback to local circuits to coordinate behavior.

Glial state changes and neuroinflammatory RIPK1 signaling are a key feature of ALS pathogenesis
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes motor neuron loss in the brain and spinal cord. Neuroinflammation driven by activated microglia and astrocytes is prominent in ALS, but an understanding of cell state dynamics and which pathways contribute to the disease remains unclear. Single nucleus RNA sequencing of ALS spinal cords demonstrated striking changes in glial cell states, including increased expression of inflammatory and glial activation markers. Many of these signals converged on RIPK1 and the necroptotic cell death pathway. Activation of the necroptosis pathway in ALS spinal cords was confirmed in a large bulk RNA sequencing dataset and at the protein level. Blocking RIPK1 kinase activity delayed symptom onset and motor impairment and modulated glial responses in SOD1G93A mice. We used a human iPSC-derived motor neuron, astrocyte, and microglia tri-culture system to identify potential biomarkers secreted upon RIPK1 activation, inhibited pharmacologically in vitro, and modulated in the CSF of people with ALS treated with a RIPK1 inhibitor. These data reveal ALS-enriched glial populations associated with inflammation and suggest a deleterious role for neuroinflammatory signaling in ALS pathogenesis.

The longitudinal behavioral effects of acute exposure to galactic cosmic radiation in female C57BL/6J mice: implications for deep space missions, female crews, and potential antioxidant countermeasures
Galactic cosmic radiation (GCR) is an unavoidable risk to astronauts that may affect mission success. Male rodents exposed to 33-beam-GCR (33-GCR) show short-term cognitive deficits but reports on female rodents and long-term assessment is lacking. Here we asked: What are the longitudinal behavioral effects of 33-GCR on female mice? Also, can an antioxidant/anti-inflammatory compound mitigate the impact of 33-GCR? Mature (6-month-old) C57BL/6J female mice received the antioxidant CDDO-EA (400 g/g of food) or a control diet (vehicle, Veh) for 5 days and either Sham-irradiation (IRR) or whole-body 33-GCR (0.75Gy) on the 4th day. Three-months post-IRR, mice underwent two touchscreen-platform tests: 1) location discrimination reversal (which tests behavior pattern separation and cognitive flexibility, two abilities reliant on the dentate gyrus) and 2) stimulus-response learning/extinction. Mice then underwent arena-based behavior tests (e.g. open field, 3-chamber social interaction). At the experiment end (14.25-month post-IRR), neurogenesis was assessed (doublecortin-immunoreactive [DCX+] dentate gyrus neurons). Female mice exposed to Veh/Sham vs. Veh/33-GCR had similar pattern separation (% correct to 1st reversal). There were two effects of diet: CDDO-EA/Sham and CDDO-EA/33-GCR mice had better pattern separation vs. their respective control groups (Veh/Sham, Veh/33-GCR), and CDDO-EA/33-GCR mice had better cognitive flexibility (reversal number) vs. Veh/33-GCR mice. Notably, one radiation effect/CDDO-EA countereffect also emerged: Veh/33-GCR mice had worse stimulus-response learning (days to completion) vs. all other groups, including CDDO-EA/33-GCR mice. In general, all mice show normal anxiety-like behavior, exploration, and habituation to novel environments. There was also a change in neurogenesis: Veh/33-GCR mice had fewer DCX+ dentate gyrus immature neurons vs. Veh/Sham mice. Our study implies space radiation is a risk to a female crew 's longitudinal mission-relevant cognitive processes and CDDO-EA is a potential dietary countermeasure for space-radiation CNS risks.

Classifying native versus foreign speech perception from EEG using linguistic speech features
When a person listens to natural speech, the relation between features of the speech signal and the corresponding evoked electroencephalogram (EEG) is indicative of neural processing of the speech signal. Using linguistic representations of speech, we investigate the differences in neural processing between speech in a native and foreign language that is not understood. We conducted experiments using three stimuli: a comprehensible language, an incomprehensible language, and randomly shuffled words from a comprehensible language, while recording the EEG signal of native Dutch-speaking participants. We modeled the neural tracking of linguistic features of the speech signals using a deep-learning model in a match-mismatch task that relates EEG signals to speech, while accounting for lexical segmentation features reflecting acoustic processing. The deep learning model effectively classifies languages. We also observed significant differences in tracking patterns between comprehensible and incomprehensible speech stimuli within the same language. It demonstrates the potential of deep learning frameworks in measuring speech understanding objectively.

Neural correlates of individual facial recognition in a social wasp
Individual recognition is critical for social behavior across species. Whether recognition is mediated by circuits specialized for social information processing has been a matter of debate. Here we examine the neurobiological underpinning of individual visual facial recognition in Polistes fuscatus paper wasps. Front-facing images of conspecific wasps broadly increase activity across many brain regions relative to other stimuli. Notably, we identify a localized subpopulation of neurons in the protocerebrum which show specialized selectivity for front-facing wasp images, which we term wasp cells. These wasp cells encode information regarding the facial patterns, with ensemble activity correlating with facial identity. Wasp cells are strikingly analogous to face cells in primates, indicating that specialized circuits are likely an adaptive feature of neural architecture to support visual recognition.

Chronic alcohol consumption alters sex-dependent BNST neuron function in rhesus macaques
Repeated alcohol drinking contributes to a number of neuropsychiatric diseases, including alcohol use disorder and co-expressed anxiety and mood disorders. Women are more susceptible to the development and expression of these diseases with the same history of alcohol exposure as men, suggesting they may be more sensitive to alcohol-induced plasticity in limbic brain regions controlling alcohol drinking, stress responsivity, and reward processing, among other behaviors. Using a translational model of alcohol drinking in rhesus monkeys, we examined sex differences in the basal function and plasticity of neurons in the bed nucleus of the stria terminalis (BNST), a brain region in the extended amygdala shown to be a hub circuit node dysregulated in individuals with anxiety and alcohol use disorder. We performed slice electrophysiology recordings from BNST neurons in male and female monkeys following daily open access (22 hr/day) to 4% ethanol and water for more than one year or control conditions. We found that BNST neurons from control females had reduced overall current density, hyperpolarization-activated depolarizing current (Ih), and inward rectification, as well as higher membrane resistance and greater synaptic glutamatergic release and excitatory drive, than those from control males, suggesting that female BNST neurons are more basally excited than those from males. Chronic alcohol drinking produced a shift in these measures in both sexes, decreasing current density, Ih, and inward rectification and increasing synaptic excitation. In addition, network activity-dependent synaptic inhibition was basally higher in BNST neurons of males than females, and alcohol exposure increased this in both sexes, a putative homeostatic mechanism to counter hyperexcitability. Altogether, these results suggest that the rhesus BNST is more basally excited in females than males and chronic alcohol drinking produces an overall increase in excitability and synaptic excitation. These results shed light on the mechanisms contributing to the female-biased susceptibility to neuropsychiatric diseases including co-expressed anxiety and alcohol use disorder.

Feedback scales the spatial tuning of cortical responses during visual memory
Perception, working memory, and long-term memory each evoke neural responses in visual cortex, suggesting that memory uses encoding mechanisms shared with perception. While previous research has largely focused on how perception and memory are similar, we hypothesized that responses in visual cortex would differ depending on the origins of the inputs. Using fMRI, we quantified spatial tuning in visual cortex while participants (both sexes) viewed, maintained in working memory, or retrieved from long-term memory a peripheral target. In each of these conditions, BOLD responses were spatially tuned and were aligned with the target's polar angle in all measured visual field maps including V1. As expected given the increasing sizes of receptive fields, polar angle tuning during perception increased in width systematically up the visual hierarchy from V1 to V2, V3, hV4, and beyond. In stark contrast, the widths of tuned responses were broad across the visual hierarchy during working memory and long-term memory, matched to the widths in perception in later visual field maps but much broader in V1. This pattern is consistent with the idea that mnemonic responses in V1 stem from top-down sources. Moreover, these tuned responses when biased (clockwise or counterclockwise of target) predicted matched biases in memory, suggesting that the readout of maintained and reinstated mnemonic responses influences memory guided behavior. We conclude that feedback constrains spatial tuning during memory, where earlier visual maps inherit broader tuning from later maps thereby impacting the precision of memory.

Atypical Pupil-Linked Arousal Induced by Low-Risk Probabilistic Choices, and Intolerance of Uncertainty in Adults with ASD
Adults with autism spectrum disorder (ASD) report stress when acting in a familiar probabilistic environment, but the underlying mechanisms are unclear. Their decision-making may be affected by the uncertainty aversion implicated in ASD, and associated with increased autonomic arousal. Previous studies have shown that in neurotypical (NT) people, decisions with predictably better outcomes are less stressful and elicit smaller pupil-linked arousal than those involving random 'trial-and-error' searches or self-imposed risk of exploration. Here, in a sample of 46 high-functioning ASD and NT participants, we explored pupil-linked arousal and behavioral performance in a probabilistic reward learning task with a stable advantage of one choice option over the other. Using mixed-effects model analysis, we contrasted pupil dilation response (PDR) between a preferred frequently rewarded exploitative decision and its explorative alternatives. We observed that subjects with ASD learned the advantageous probabilistic choices at the same rate over time and preferred them to the same degree as NT participants both in terms of choice ratio and decision speed. Despite similar reward prediction abilities, outcome predictability modulated decision-related PDR in ASD in the opposite direction than in NT individuals. Moreover, relatively enhanced PDR elicited by exploitative low-risk decisions predicted a greater degree of self-reported intolerance of uncertainty in everyday life. Our results suggest that in a non-volatile probabilistic environment, objectively good predictive abilities in people with ASD are coupled with elevated physiological stress and subjective uncertainty regarding the decisions with the best possible but still uncertain outcome that contributes to their intolerance of uncertainty.

A Novel Simple ImmunoAssay for Quantification of Blood Anti-NMDAR1 Autoantibodies
High titers of anti-NMDAR1 autoantibodies in human brain cause anti-NMDAR1 encephalitis, a rare disease that displays a variety of psychiatric symptoms and neurological symptoms. Currently, immunohistochemical staining and cell-based assays are the standard methods for detection and semi-quantification of the anti-NMDAR1 autoantibodies. Low titers of blood circulating anti-NMDAR1 autoantibodies have been reported in a significant subset of the general human population. However, detection and quantification of these low titers of blood circulating anti-NMDAR1 autoantibodies are problematic because of high non-specific background from less diluted serum/plasma. Development of a new method to quantify these low titers of blood anti-NMDAR1 autoantibodies is necessary to understand their potential impacts on psychiatric symptoms and cognition. Based on our previous One-Step assay, we report the development of a novel simple immunoassay to quantify cross-species blood anti-NMDAR1 autoantibodies, and its validation with immunohistochemistry and cell-based assays in both humans and mice.

Distinguishing microgliosis and tau deposition in the mouse brain using paramagnetic and diamagnetic susceptibility source separation
Tauopathies, including Alzheimer's disease (AD), are neurodegenerative disorders characterized by hyperphosphorylated tau protein aggregates in the brain. In addition to protein aggregates, microglia-mediated inflammation and iron dyshomeostasis are other pathological features observed in AD and other tauopathies. It is known that these alterations at the subcellular level occur much before the onset of macroscopic tissue atrophy or cognitive deficits. The ability to detect these microstructural changes with MRI therefore has substantive importance for improved characterization of disease pathogenesis. In this study, we demonstrate that quantitative susceptibility mapping (QSM) with paramagnetic and diamagnetic susceptibility source separation has the potential to distinguish neuropathological alterations in a transgenic mouse model of tauopathy. 3D multi-echo gradient echo data were acquired from fixed brains of PS19 (Tau) transgenic mice and age-matched wild-type (WT) mice (n = 5 each) at 11.7 T. The multi-echo data were fit to a 3-pool complex signal model to derive maps of paramagnetic component susceptibility (PCS) and diamagnetic component susceptibility (DCS). Group-averaged signal fraction and composite susceptibility maps showed significant region-specific differences between the WT and Tau mouse brains. Significant bilateral increases in PCS and |DCS| were observed in specific hippocampal and cortical sub-regions of the Tau mice relative to WT controls. Comparison with immunohistological staining for microglia (Iba1) and phosphorylated-tau (AT8) further indicated that the PCS and DCS differences corresponded to regional microgliosis and tau deposition in the PS19 mouse brains, respectively. The results demonstrate that quantitative susceptibility source separation may provide sensitive imaging markers to detect distinct pathological alterations in tauopathies.

Simultaneous cortical, subcortical, and brainstem mapping of sensory activation
Non-painful tactile sensory stimuli are processed in the cortex, subcortex, and brainstem. Recent functional magnetic resonance imaging (fMRI) studies have highlighted the value of whole-brain, systems-level investigation for examining pain processing. However, whole-brain fMRI studies are uncommon, in part due to challenges with signal to noise when studying the brainstem. Furthermore, the differentiation of small sensory brainstem structures such as the cuneate and gracile nuclei necessitates high resolution imaging. To address this gap in systems-level sensory investigation, we employed a whole-brain, multi-echo fMRI acquisition at 3T with multi-echo independent component analysis (ME-ICA) denoising and brainstem-specific modeling to enable detection of activation across the entire sensory system. In healthy participants, we examined patterns of activity in response to non-painful brushing of the right hand, left hand, and right foot, and found the expected lateralization, with distinct cortical and subcortical responses for upper and lower limb stimulation. At the brainstem level, we were able to differentiate the small, adjacent cuneate and gracile nuclei, corresponding to hand and foot stimulation respectively. Our findings demonstrate that simultaneous cortical, subcortical, and brainstem mapping at 3T could be a key tool to understand the sensory system in both healthy individuals and clinical cohorts with sensory deficits.

Network Spreading and Local Biological Vulnerability in Amyotrophic Lateral Sclerosis
Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that predominantly targets the motor system. Spread of pathology is thought to be driven by both local vulnerability and network architecture. Namely, molecular and cellular features may confer vulnerability to specific neuronal populations, while synaptic contacts may also increase exposure to pathology in connected neuronal populations. However, these principles are typically studied in isolation and it remains unknown how local vulnerability and network spreading interact to shape cortical atrophy. Here we investigate how network structure and local biological features jointly shape the spatial patterning of atrophy in ALS. We analyze the Canadian ALS Neuroimaging Consortium (CALSNIC) dataset and estimate cortical atrophy using deformation-based morphometry (DBM). We find that structural connectivity closely aligns with the course of atrophy. Atrophy is also more likely to occur in regions that share similar transcriptomic, neurotransmitter receptor and metabolic profiles. We identify disease epicenters in motor cortex. Epicenter probability maps show transcriptomic enrichment for biological pathways involved in mitochondrial function as well as support cells, including endothelial cells and pericytes. Finally, individual differences in epicenter location correspond to individual differences in clinical and cognitive symptoms, and differentiate patient subtypes.

Control without cause: How covariate control biases our insights into brain architecture and pathology
Inferential analysis of normal or pathological brain imaging data - as in brain mapping or the identification of neurological imaging markers - is often controlled for secondary variables. However, a rationale for covariate control is rarely given and formal criteria to identify appropriate covariates in such complex data are lacking. We investigated the impact and adequacy of covariate control in large-scale imaging data using the example of stroke lesion-deficit mapping. In 183 stroke patients, we evaluated control for age, sex, hypertension, or lesion volume when mapping real or simulated deficits. We found that the impact of covariate control varies and can be strong, but it does not necessarily improve the precision of results. Instead, it systematically shifts results towards the inversed associations between imaging features and the covariate. This effect of covariate control can bias results and, as shown in another experiment, can even create effects out of nothing. The widespread use of covariate control in the statistical analysis of clinical brain imaging data - and, likely, other biological high-dimensional data as well - may not generally improve statistical results, but it may just change them. Therefore, covariate control constitutes a problematic degree of freedom in the analysis of brain imaging data and may often not be justified at all.

Distinct mechanisms of visual and sound adaptation in the cat visual cortex
Sensory areas exhibit modular selectivity to stimuli, but they can also respond to features outside of their basic modality. Several studies have shown cross-modal plastic modifications between visual and auditory cortices; however, the exact mechanisms of these modifications are yet not completely known. To this aim, we investigated the effect of 12 minutes of visual vs. sound adaptation [forceful application of a non-optimal stimulus to a neuron(s) under observation] on the infra- and supra-granular primary visual neurons (V1) of the cat (Felis catus). Previous reports showed that both protocols induced orientation tuning shifts, but sound increased the bandwidths. Here, we compared visual vs. sound adaptation effects, specifically analysing the raw tuning curves by computing the area under the curve (AUC) on a trial-by-trial basis. We report that sound adaptation elicited broader tuning curves accompanied with increased variance in the supra- and infra-granular layers, compared with visual adaptation. These findings suggest unique modulation of dendritic structure by distinct adaptation protocols, resulting in disparate tunings. We suggest that broader tuning curves after sound adaptation may keep the visual cortex prepared across a spectrum of abstract representations that match with visual stimuli.

Individual variability in sensorimotor learning reflects trait-like neurobehavioral subject factors
Models of Human motor behaviour often emphasize the computations performed by the motor system during learning. Yet, there is an emerging consensus that the learning of even simple motor actions can be augmented by sophisticated cognitive strategies, which rely upon executive functions implemented throughout the cortex. These executive functions, in turn, have been linked to stable subject differences in intrinsic brain organization function, observable even during rest. Here we show, using behavioural studies in humans, that individual differences in the rate of sensorimotor adaptation are linked to differences in executive function, as assessed using the classic trail-making task. Secondly, using separate train and test functional MRI datasets, we show that specific patterns of resting-state functional connectivity between higher-order cognitive brain networks, which have been previously linked to executive function, subsequently predict more rapid learning during sensorimotor adaptation. Importantly, this relationship was unique to cognitive brain networks, as the functional connectivity between sensorimotor brain networks did not predict subsequent motor learning performance. Together, these findings suggest that individual differences in motor learning reflect, to a substantial degree, trait-like subject differences in cognitive brain network structure. This perspective invites broader consideration as to the origins of motor learning ability, and links motor performance to an expansive literature implicating the coordinated functioning of the default mode, ventral attention, and frontoparietal networks in flexible behavioral control.

Utilising activity patterns of a complex biophysical network model to optimise intra-striatal deep brain stimulation
In this study, we develop a large-scale biophysical network model for the isolated striatal body to optimise potential intrastriatal deep brain stimulation applied in, e.g. obsessive-compulsive disorder by using spatiotemporal patterns produced by the network. The model uses modified Hodgkin-Huxley models on small-world connectivity, while the spatial information, i.e. the positions of neurons, is obtained from a detailed human atlas. The model produces neuronal activity patterns that segregate healthy from pathological conditions. Three indices were used for the optimisation of stimulation protocols regarding stimulation frequency, amplitude and localisation: the mean activity of the entire network, the mean activity of the ventral striatal area (emerging as a defined community using modularity detection algorithms), and the frequency spectrum of the entire network activity. By minimising the deviation of the aforementioned indices from the normal state, we guide the optimisation of deep brain stimulation parameters regarding position, amplitude and frequency.

What underlies exceptional memory function in older age? No evidence for aging-specific relationships to hippocampal atrophy and retrieval activity
Some older adults show superior memory performance compared to same-age peers, even performing on par with young participants. These are often referred to as SuperAgers. It is not known whether their superior memory function is caused by special features of their brains in aging, or whether superior memory has the same brain foundation throughout adult life. To address this, we measured hippocampal volume and atrophy, microstructural integrity by diffusion tensor imaging, and activity during an episodic memory encoding and retrieval task, in 277 cognitively healthy adults (age 20.1-81.5 years at baseline, mean 49.2 years). For quantification of hippocampal atrophy, all participants had repeated MRIs, from two to seven examinations, covering a mean of 9.3 years between first and last scan (2.5-17.3 years). 15.7% of the participants above 60 years had episodic memory scores above the mean of the young and middle-aged participants and were classified as SuperAgers. We found that superior memory in older adults was associated with higher retrieval activity in the anterior hippocampus and less hippocampal atrophy. However, there were no significant age-interactions, suggesting that the relationships reflected stable correlates of superior memory function. Although SuperAgers had superior memory compared to their same-age peers, they still performed worse than the best-performing young participants. Further, age-memory performance curves across the full age-range were similar for participants with superior memory performance compared to those with normal and low performance. These trajectories were based on cross-sectional data, but do not indicate preserved memory among the superior functioning older adults. In conclusion, the current results confirm that aspects of hippocampal structure and function are related to superior memory across age, without evidence to suggest that SuperAgers have special features compared to their younger counterparts.

Chemogenetic stimulation of phrenic motor output and diaphragm activity
Impaired diaphragm activation contributes to morbidity and mortality in many neurodegenerative diseases and neurologic injuries. We conducted experiments to determine if expression of an excitatory DREADD (designer receptors exclusively activation by designer drugs) in the mid-cervical spinal cord would enable respiratory-related activation of phrenic motoneurons to increase diaphragm activation. Wild type (C57/bl6) and ChAT-Cre mice received bilateral intraspinal (C4) injections of an adeno-associated virus (AAV) encoding the hM3D(Gq) excitatory DREADD. In wild type mice, this produced non-specific DREADD expression throughout the mid-cervical ventral horn. In ChAT-Cre mice, a Cre-dependent viral construct was used to drive DREADD expression in C4 ventral horn motoneurons, targeting the phrenic motoneuron pool. Diaphragm EMG was recorded during spontaneous breathing at 6-8 weeks post-AAV delivery. The selective DREADD ligand JHU37160 (J60) caused a bilateral, sustained (>1 hr) increase in inspiratory EMG bursting in both groups; the relative increase was greater in ChAT-Cre mice. Additional experiments in a ChAT-Cre rat model were conducted to determine if spinal DREADD activation could increase inspiratory tidal volume (VT) during spontaneous breathing without anesthesia. Three to four months after intraspinal (C4) injection of AAV driving Cre-dependent hM3D(Gq) expression, intravenous J60 resulted in a sustained (>30 min) increase in VT assessed using whole-body plethysmography. Subsequently, direct nerve recordings confirmed that J60 evoked a >50% increase in inspiratory phrenic output. The data show that mid-cervical spinal DREADD expression targeting the phrenic motoneuron pool enables ligand-induced, sustained increases in the neural drive to the diaphragm. Further development of this technology may enable application to clinical conditions associated with impaired diaphragm activation and hypoventilation.

Neural dynamics of visual working memory representation during sensory distraction
Recent studies have provided evidence for the concurrent encoding of sensory percepts and visual working memory contents (VWM) across visual areas; however, it has remained unclear how these two types of representations are concurrently present. Here, we reanalyzed an open-access fMRI dataset where participants memorized a sensory stimulus while simultaneously being presented with sensory distractors. First, we found that the VWM code in several visual regions did not generalize well between different time points, suggesting a dynamic code. A more detailed analysis revealed that this was due to shifts in coding spaces across time. Second, we collapsed neural signals across time to assess the degree of interference between VWM contents and sensory distractors, specifically by testing the alignment of their encoding spaces. We find that VWM and feature-matching sensory distractors are encoded in separable coding spaces. Together, these results indicate a role of dynamic coding and temporally stable coding spaces in helping multiplex perception and VWM within visual areas.

Orbitofrontal cortex to dorsal striatum circuit is critical for incubation of oxycodone craving after forced abstinence
Relapse is a major challenge in treating opioid addiction, including oxycodone. During abstinence, oxycodone seeking progressively increases, and we previously demonstrated a causal role of the orbitofrontal cortex (OFC) in this incubation of oxycodone craving after forced abstinence. Here, we explored critical downstream targets of OFC by focusing on dorsal striatum (DS). We first examined dorsal striatal Fos (a neuronal activity marker) expression associated with oxycodone seeking after abstinence. Using a dopamine D1 receptor (D1R) antagonist, we also tested the causal role of DS in incubated oxycodone seeking. Next, we combined fluorescence-conjugated cholera toxin subunit B (CTb-555, a retrograde tracer) with Fos to assess whether the activation of OFC to DS projections was associated with incubated oxycodone seeking. We then used a series of pharmacological procedures to examine the causal role of the interaction between glutamatergic projections from OFC and D1R signaling in DS in incubation of oxycodone craving. We found that dorsal striatal Fos expression in DS exhibited a time-dependent increase in parallel with incubation of oxycodone craving, and DS inactivation decreased incubated oxycodone seeking. Moreover, OFC to DS projections were activated during incubated oxycodone seeking, and anatomical disconnection of OFC to DS projections, but not unilateral inactivation of OFC or DS, decreased incubated oxycodone seeking. Lastly, contralateral disconnection of OFC to DS projections had no effect on oxycodone seeking on abstinence day 1. Together, these results demonstrated a causal role of OFC to DS projections in incubation of oxycodone craving.

Role and modulation of various spinal pathways for human upper limb control in different gravity conditions
Humans can perform movements in various physical environments and positions (corresponding to different experienced gravity), requiring the interaction of the musculoskeletal system, the neural system and the external environment. The neural system is itself comprised of several interactive components, from the brain mainly conducting motor planning, to the spinal cord (SC) implementing its own motor control centres through sensory reflexes. Nevertheless, it remains unclear whether similar movements in various environmental dynamics necessitate replanning modulation at the brain level, correcting modulation at the spinal level, or both. Here, we addressed this question by focusing on upper limb motor control in various gravity conditions (magnitudes and directions) and using neuromusculoskeletal simulation tools. We integrated supraspinal sinusoidal commands with a modular SC model controlling a musculoskeletal model to reproduce recorded elbow flexion-extension trajectories (kinematics and EMGs) in different contexts. We first studied the role of various spinal pathways (such as stretch reflexes) in movement smoothness and robustness against perturbation. Then, we optimised the supraspinal sinusoidal commands without and with a fixed SC model including stretch reflexes to reproduce a target trajectory in various gravity conditions. Inversely, we fixed the supraspinal commands and optimised the spinal synaptic strengths in the different environments. In the first optimisation context, the presence of SC resulted in easier optimisation of the supraspinal commands (faster convergence, better performance). The main supraspinal commands modulation was found in the flexor sinusoid's amplitude, resp. frequency, to adapt to different gravity magnitudes, resp. directions. In the second optimisation context, the modulation of the spinal synaptic strengths also remarkably reproduced the target trajectory for the mild gravity changes. We highlighted that both strategies of modulation of the supraspinal commands or spinal stretch pathways can be used to control movements in different gravity environments. Our results thus support that the SC can assist gravity compensation.

A single-nucleus RNA sequencing atlas of the postnatal retina of the shark Scyliorhinus canicula
The retina, whose basic cellular structure is highly conserved across vertebrates, constitutes an accessible system for studying the central nervous system. In recent years, single-cell RNA-sequencing studies have uncovered cellular diversity in the retina of a variety of species, providing new insights on retinal evolution and development. However, similar data in cartilaginous fishes, the sister group to all other extant jawed vertebrates, are still lacking. Here, we present a single-nucleus RNA-sequencing atlas of the postnatal retina of the catshark Scyliorhinus canicula, consisting of the expression profiles for 17,438 individual cells from three female, juvenile catshark specimens. Unsupervised clustering revealed 22 distinct cell types comprising all major retinal cell classes, as well as retinal progenitor cells (whose presence reflects the persistence of proliferative activity in postnatal stages in sharks) and oligodendrocytes. Thus, our dataset serves as a foundation for further studies on the development and function of the catshark retina. Moreover, integration of our atlas with data from other species will allow for a better understanding of vertebrate retinal evolution.

Frontotemporal dementia patient-derived iPSC neurons show cell pathological hallmarks and evidence for synaptic dysfunction and DNA damage
Frontotemporal dementia (FTD) is the second most common cause of dementia in patients under 65 years, characterized by diverse clinical symptoms, neuropathologies, and genetic background. Synaptic dysfunction is suggested to play a major role in FTD pathogenesis. Disturbances in the synaptic function can also be associated with the C9orf72 repeat expansion (C9-HRE), the most common genetic mutation causing FTD. C9-HRE leads to distinct pathological hallmarks, such as C9orf72 haploinsufficiency and development of toxic RNA foci and dipeptide repeat proteins (DPRs). FTD patient brains, including those carrying the C9-HRE, are also characterized by neuropathologies involving accumulation of TDP-43 and p62/SQSTM1 proteins. This study utilized induced pluripotent stem cell (iPSC)-derived cortical neurons from C9-HRE-carrying or sporadic FTD patients and healthy control individuals. We report that the iPSC neurons derived from C9-HRE carriers developed typical C9-HRE-associated hallmarks, including RNA foci and DPR accumulation. All FTD neurons demonstrated increased TDP-43 nucleus-to-cytosolic shuttling and p62/SQSTM1 accumulation, and changes in nuclear size and morphology. In addition, the FTD neurons displayed reduced number and altered morphologies of dendritic spines and significantly altered synaptic function indicated by a decreased response to stimulation with GABA. These structural and functional synaptic disturbances were accompanied by upregulated gene expression in the FTD neurons related to synaptic function, including synaptic signaling, glutamatergic transmission, and pre- and postsynaptic membrane, as compared to control neurons. Pathways involved in DNA repair were significantly downregulated in FTD neurons. Only one gene, NUPR2, potentially involved in DNA damage response, was differentially expressed between the sporadic and C9-HRE-carrying FTD neurons. Our results show that the iPSC neurons from FTD patients recapitulate pathological changes of the FTD brain and strongly support the hypothesis of synaptic dysfunction as a crucial contributor to disease pathogenesis in FTD.

Moving in pain - A preliminary study evaluating the immediate effects of experimental knee pain on locomotor biomechanics.
Pain changes how we move, but it is often confounded by other factors due to disease or injury. Experimental pain offers an opportunity to isolate the independent affect of pain on movement. We used cutaneous electrical stimulation to induce experimental knee pain during locomotion to study the short-term motor adaptions to pain. While other models of experimental pain have been used in locomotion, they lack the ability to modulate pain in real-time. Twelve healthy adults completed the single data collection session where they experienced six pain intensity conditions (0.5, 1, 2, 3, 4, 5 out of 10) and two pain delivery modes (tonic and phasic). Electrodes were placed over the lateral infrapatellar fat pad and medial tibial condyle to deliver the 10 Hz pure sinusoid via a constant current electrical stimulator. Pain intensity was calibrated prior to each walking bout based on the target intensity and was recorded using an 11-point numerical rating scale. Knee joint angles and moments were recorded over the walking bouts and summarized in waveform and discrete outcomes to be compared with baseline walking. Knee joint angles changed during the swing phase of gait, with higher pain intensities resulting in greater knee flexion angles. Minimal changes in joint moments were observed but there was a consistent pattern of decreasing joint stiffness with increasing pain intensity. Habituation was limited across the 30-90 second walking bouts and the electrical current needed to deliver the target pain intensities showed a positive linear relationship. Experimental knee pain shows subtle biomechanical changes and favourable habituation patterns over short walking bouts. Further exploration of this model is needed in real-world walking conditions and over longer timeframes to quantify motor adaptations.

Sex-Specific Regulation of Stress Susceptibility by the Astrocytic Gene Htra1
Major depressive disorder (MDD) is linked to impaired structural and synaptic plasticity in limbic brain regions. Astrocytes, which regulate synapses and are influenced by chronic stress, likely contribute to these changes. We analyzed astrocyte gene profiles in the nucleus accumbens (NAc) of humans with MDD and mice exposed to chronic stress. Htra1, which encodes an astrocyte-secreted protease targeting the extracellular matrix (ECM), was significantly downregulated in the NAc of males but upregulated in females in both species. Manipulating Htra1 in mouse NAc astrocytes bidirectionally controlled stress susceptibility in a sex-specific manner. Such Htra1manipulations also altered neuronal signaling and ECM structural integrity in NAc. These findings highlight astroglia and the brains ECM as key mediators of sex-specific stress vulnerability, offering new approaches for MDD therapies.