bioRxiv Subject Collection: Neuroscience's Journal

Social Experience Shapes Fighting Strategies for Reproductive Success
Social isolation generally increases aggression but decreases mating competition, resulting in an intricate and ambiguous relationship between social experience, aggression, and reproductive success. In male Drosophila, aggression is often characterized by lunging, a frequent and comparatively gentle combat behavior. Here, we establish a behavioral paradigm for studying a less frequent but more vigorous fighting form known as tussling. We discover that while social enrichment decreases lunging, aligning with past observations, it heightens the more forceful tussling behavior. These two forms of aggression rely on different olfactory receptor neurons, specifically Or67d for lunging and Or47b for tussling. We further identify three pairs of central pC1 neurons that specifically promote tussling. Moreover, shifting from lunging to tussling in socially enriched males facilitates better territory control and mating success, mitigating the disadvantages associated with aging. These findings reveal how social experience shapes fighting strategies to optimize reproductive success.

Continuous integration of heading and goal directions guides steering
Navigating animals must integrate a diverse array of sensory cues into a single locomotor decision. Insects perform intricate navigational feats using a brain region termed the central complex in which an animal's heading direction is transformed through several layers of circuitry to elicit goal-directed locomotion. These transformations occur mostly in the fan-shaped body (FB), a major locus of multi-sensory integration in the central complex. Key aspects of these sensorimotor computations have been extensively characterized by functional studies, leveraging the genetic tools available in the fruit fly. However, our understanding of how neuronal activity in the FB dictates locomotor behaviors during navigation remains enigmatic. Here, we manipulate the activity of two key neuronal populations that input into the FB--the PFNa and PFNd neurons--used to encode the direction of two complex navigational cues: wind plumes and optic flow, respectively. We find that flies presented with unidirectional optic flow steer along curved walking trajectories, but silencing PFNd neurons abolishes this curvature. We next use optogenetic activation to introduce a fictive heading signal in the PFNs to establish the causal relationship between their activity and steering behavior. Our studies reveal that the central complex guides locomotion by summing the PFN-borne directional signals and shifting movement trajectories left or right accordingly. Based on these results, we propose a model of central complex-mediated locomotion wherein the fly achieves fine-grained control of sensory-guided steering by continuously integrating its heading and goal directions over time.

Saccade onset, not fixation onset, best explains early sensory responses across the human visual cortex during naturalistic vision
Visual processing has traditionally been investigated using static viewing paradigms, where participants are presented with streams of randomized stimuli. Observations from such experiments have been generalized to naturalistic vision, which is based on active sampling via eye movements. In studies of naturalistic vision, visual processing stages are thought to be initiated at the onset of fixations, equivalent to a stimulus onset. Here we test whether findings from static visual paradigms translate to active, naturalistic vision. Utilizing head-stabilized magnetoencephalography (MEG) and eye tracking data of 5 participants who freely explored thousands of natural images, we show that saccade onset, not fixation onset, explains most variance in latency and amplitude of the early sensory component M100. Source-projected MEG topographies of image and saccade onset were anticorrelated, demonstrating neural dynamics that share similar topographies but produce oppositely oriented fields. Our findings challenge the prevailing approach for studying natural vision and highlight the role of internally generated signals in the dynamics of sensory processing.

Body-wandering reveals an embodied dimension of thought with distinct affective and neural signatures
Humans often engage in self-generated thoughts when unoccupied by external events, a phenomenon commonly known as mind-wandering. Previous research has predominantly focused on the cognitive aspects of mind-wandering, overlooking the potential embodied or interoceptive components that contribute to our ongoing thought patterns. In this study, we addressed this gap by exploring "body-wandering"-thoughts related to internal bodily sensations such as breathing, heartbeat, and gastrointestinal functions. To assess body-wandering, we applied a retrospective multi-dimensional interoceptive experience sampling approach in 536 healthy participants concurrently with resting-state functional brain imaging. Our findings revealed that body-wandering is distinct from cognitively focused thoughts, underscoring the unique role of embodied processes in ongoing experience. Embodied thought patterns were associated with increased negative affect, heightened physiological arousal, and reduced ADHD symptoms. In contrast, cognitive-focused thoughts were linked to decreased negative affect, lower arousal, and higher depression symptoms. Notably, body-wandering corresponded with a unique neural signature involving increased connectivity between somatomotor, interoceptive, and thalamocortical brain networks. These results emphasise the importance of incorporating embodied processes into theoretical models of mind-wandering and suggest that individual differences in body-wandering significantly impact emotional states and mental health.

Reward invigorates isometric gripping actions
Individuals exhibit a propensity to move faster toward more rewarding stimuli. While this phenomenon has been observed in movements, the effect of reward on implicit control of isometric actions, like gripping or grasping, is relatively unknown. How reward-related invigoration generalizes to other effortful actions is an important question. Reward invigorates reaching movements and saccades, supporting the idea that reward pays the additional effort cost of moving faster. Effort in isometric force generation is less understood, so here we ask whether and how reward-related invigoration generalizes to isometric force gripping. And if so, what implicit characteristics of gripping change when there is a prospect of reward? Participants (N=19) gripped a force transducer and the force applied was mapped to radial position of an onscreen cursor. Each trial, a target appeared in one of four locations; increasing grip force moved the cursor toward the target. The gripping action was interchangeable for all target positions. In each block of 100 trials, one target was consistently rewarded, while the other targets were not. When gripping to acquire the rewarded target, participants reacted faster, generated force more rapidly and to a greater extent, while intriguingly maintaining the same accuracy and integral of force over time. These findings support the generalization of reward-related invigoration in isometric force tasks, and that the brain exquisitely trades-off reward and effort costs to obtain reward more rapidly without compromising accuracy or more effort costs than necessary.

Statistical method accounts for microscopic electric field distortions around neurons when simulating activation thresholds
Notwithstanding advances in computational models of neuromodulation, there are mismatches between simulated and experimental activation thresholds. Transcranial Magnetic Stimulation (TMS) of the primary motor cortex generates motor evoked potentials (MEPs). At the threshold of MEP generation, whole-head models predict macroscopic (at millimeter scale) electric fields (50-70 V/m) which are considerably below conventionally simulated cortical neuron thresholds (200-300 V/m). We hypothesize that this apparent contradiction is in part a consequence of electrical field warping by brain microstructure. Classical neuronal models ignore the physical presence of neighboring neurons and microstructure and assume that the macroscopic field directly acts on the neurons. In previous work, we performed advanced numerical calculations considering realistic microscopic compartments (e.g., cells, blood vessels), resulting in locally inhomogeneous (micrometer scale) electric field and altered neuronal activation thresholds. Here we combine detailed neural threshold simulations under homogeneous field assumptions with microscopic field calculations, leveraging a novel statistical approach. We show that, provided brain-region specific microstructure metrics, a single statistically derived scaling factor between microscopic and macroscopic electric fields can be applied in predicting neuronal thresholds. For the cortical sample considered, the statistical methods match TMS experimental thresholds. Our approach can be broadly applied to neuromodulation models, where fully coupled microstructure scale simulations may not be practical.

Loss of Calcitonin gene-related Related Receptor component protein (RCP) in nervous system can bias gepant antagonism
We examined calcitonin gene-related peptide (CGRP) effects on behavioral surrogates for motion-induced nausea and static imbalance in the nestinRCP null (-/-), a novel mouse model that loses expression of receptor component protein (RCP) in the nervous system after tamoxifen induction. The assays used were the motion-induced thermoregulation and center of pressure (CoP) assays. Findings suggest CGRP affects behavioral measures in the nestinRCP (-/-) similarly to littermate controls, since CGRP was observed to increase female sway and diminish tail vasodilations to provocative motion in both sexes. However, the CGRP-receptor antagonist olcegepant did not antagonize CGRPs effects in the nestinRCP (-/-) null mice, whereas it was effective in littermate controls. Findings suggest RCP loss may change the sensitivity of the CGRP receptor and affect the efficacy of receptor antagonists.

Brain-like learning with exponentiated gradients
Computational neuroscience relies on gradient descent (GD) for training artificial neural network (ANN) models of the brain. The advantage of GD is that it is effective at learning difficult tasks. However, it produces ANNs that are a poor phenomenological fit to biology, making them less relevant as models of the brain. Specifically, it violates Dale's law, by allowing synapses to change from excitatory to inhibitory and leads to synaptic weights that are not log-normally distributed, contradicting experimental data. Here, starting from first principles of optimisation theory, we present an alternative learning algorithm, exponentiated gradient (EG), that respects Dale's Law and produces log-normal weights, without losing the power of learning with gradients. We also show that in biologically relevant settings EG outperforms GD, including learning from sparsely relevant signals and dealing with synaptic pruning. Altogether, our results show that EG is a superior learning algorithm for modelling the brain with ANNs.

Meditation in the third-person perspective modulates minimal self and heartbeat-evoked potentials
Experienced meditation practitioners often report altered states of their sense of self, including decentering and distancing the self from the body and current concerns. Altered states of the sense of self, such as disembodiment and distancing of the self from the body, have also been induced experimentally using virtual reality (VR) and linked neurally to heartbeat evoked potentials (HEPs). Whereas many studies investigated the related neural correlates of such decentering during meditation, none experimentally modulated the sense of self during meditation practice using VR nor determined the potentially associated behavioral changes of the sense of self. Here we determined HEPs and behavioral measures in 23 participants who performed a guided meditation practice in VR, either from a third-person (3PP) or first-person perspective (1PP) to modulate the sense of self. In the 3PP versus 1PP meditation condition, we report stronger sensations of detachment and disconnection, reduced salience of the perceived body boundary, and reduced self-identification with the body. HEP analysis revealed differential neural responses between conditions, characterized by a more negative HEP amplitude in the 3PP condition, associated with activation of the posterior cingulate cortex and medial prefrontal cortex. Leveraging a new VR-supported meditation platform and methods, these data link the sense of self in meditation practice to the neuroscience of the bodily self, based on subjective, behavioral, and neural measures.

Chronic activation of corticospinal tract neurons after pyramidotomy injury enhances neither behavioral recovery nor axonal sprouting
Modulation of neural activity is a promising strategy to influence the growth of axons and improve behavioral recovery after damage to the central nervous system. The benefits of neuromodulation likely depend on optimization across multiple input parameters. Here we used a chemogenetic approach to achieve continuous, long-term elevation of neural activity in murine corticospinal tract (CST) neurons. To specifically target CST neurons, AAV2-retro-DIO-hM3Dq-mCherry or matched mCherry control was injected to the cervical spinal cord of adult Emx1-Cre transgenic mice. Pilot studies verified efficient transgene expression in CST neurons and effective elevation of neural activity as assessed by cFos immunohistochemistry. In subsequent experiments mice were administered either DIO-hM3Dq-mCherry or control DIO-mCherry, were pre-trained on a pellet retrieval task, and then received unilateral pyramidotomy injury to selectively ablate the right CST. Mice then received continual clozapine via drinking water and weekly testing on the pellet retrieval task, followed by cortical injection of a viral tracer to assess cross-midline sprouting by the spared CST. After sacrifice at eight weeks post-injury immunohistochemistry for cFos verified elevated CST activity in hM3Dq-treated animals and immunohistochemistry for PKC-gamma verified unilateral ablation of the CST in all animals. Despite the chronic elevation of CST activity, however, both groups showed similar levels of cross-midline CST sprouting and similar success in the pellet retrieval task. These data indicate that continuous, long-term elevation of activity that is targeted specifically to CST neurons does not affect compensatory sprouting or directed forelimb movements.

Encoding manifolds constructed from grating responses organize responses to natural scenes in cortical visual areas
We have created "encoding manifolds" to reveal the overall responses of a brain area to a variety of stimuli. Encoding manifolds organize response properties globally: each point on an encoding manifold is a neuron, and nearby neurons respond similarly to the stimulus ensemble in time. We previously found, using a large stimulus ensemble including optic flows, that encoding manifolds for the retina were highly clustered, with each cluster corresponding to a different ganglion cell type. In contrast, the topology of the V1 manifold was continuous. Now, using responses of individual neurons from the Allen Institute Visual Coding-Neuropixels dataset in the mouse, we infer encoding manifolds for V1 and for five higher cortical visual areas (VISam, VISal, VISpm, VISlm, and VISrl). We show here that the encoding manifold topology computed only from responses to various grating stimuli is also continuous, not only for V1 but also for the higher visual areas, with smooth coordinates spanning it that include, among others, orientation selectivity and firing-rate magnitude. Surprisingly, the encoding manifold for gratings also provides information about natural scene responses. To investigate whether neurons respond more strongly to gratings or natural scenes, we plot the log ratio of natural scene responses to grating responses (mean firing rates) on the encoding manifold. This reveals a global coordinate axis organizing neurons' preferences between these two stimuli. This coordinate is orthogonal (i.e., uncorrelated) to that organizing firing rate magnitudes in VISp. Analyzing layer responses, a preference for gratings is concentrated in layer 6, whereas preference for natural scenes tends to be higher in layers 2/3 and 4. We also find that preference for natural scenes dominates the responses of neurons that prefer low (0.02 cpd) and high (0.32 cpd) spatial frequencies, rather than intermediate ones (0.04 to 0.16 cpd). Conclusion: while gratings seem limited and natural scenes unconstrained, machine learning algorithms can reveal subtle relationships between them beyond linear techniques.

The impact of dwell time on the contextual effect of visual and passive lead-in movements
Contextual cues arising from distinct movements are crucial in shaping control strategies for human movement. Here, we examine the impact of visual and passive lead-in movement cues on unimanual motor learning, focusing on the influence of dwell time, in which two-part movements are separated by the interval between the end of the first movement and the start of the second. We used a robotic manipulandum to implement a point-to-point interference task with switching opposing viscous curl-fields in male and female human participants. Consistent with prior research, in both visual and passive lead-in conditions, participants showed significant adaptation to opposing dynamics with short dwell times. As dwell time increased for both visual and passive signals, past movement information had less contextual influence. However, the efficacy of visual movement cues declined faster as dwell times increased. At dwell times greater than 800ms, the contextual influence of prior visual movement was small, whereas the effectiveness of passive lead-in movement was found to be significantly greater. This indicates that the effectiveness of sensory movement cues in motor learning is modality-dependent. We hypothesize that such differences may arise because proprioceptive signals directly relate to arm movements, whereas visual inputs can relate to many aspects of movement in the environment and not just to our own arm movements. Therefore, the motor system may not always find them as relevant for predictive control of dynamics.

Resting-state functional connectivity changes following audio-tactile speech training
Understanding speech in background noise is a challenging task, especially if the signal is also distorted. In a series of previous studies we have shown that comprehension can improve if simultaneously to the auditory speech, the person receives speech-extracted low-frequency signals on fingertips. The effect increases after short audio-tactile speech training. Here we use resting-state functional magnetic resonance, measuring spontaneous low-frequency oscillations in the brain while at rest, to assess training-induced changes in functional connectivity. We show enhanced connectivity within a right-hemisphere cluster encompassing the middle temporal motion area (MT), and the extrastriate body area (EBA), and lateral occipital cortex (LOC), which before training is found to be more connected to bilateral dorsal anterior insula. Furthermore, early visual areas are found to switch from increased connectivity with the auditory cortex before, to increased connectivity with an association sensory/multisensory parietal hub, contralateral to the palm receiving vibrotactile inputs, after. Also the right sensorimotor cortex, including finger representations, is more connected internally after training. The results altogether can be interpreted within two main complementary frameworks. One, speech-specific, relates to the pre-existing brain connectivity for audio-visual speech processing, including early visual, motion and body regions for lip-reading and gesture analysis in difficult acoustic conditions, which the new audio-tactile speech network might be built upon. The other refers to spatial/body awareness and audio-tactile integration, including in the revealed parietal and insular regions. It is possible that an extended training period may be necessary to more effectively strengthen direct connections between the auditory and sensorimotor brain regions, for the utterly novel speech comprehension task. The outcomes of the study can be relevant for both basic neuroscience, as well as development of rehabilitation tools for the hearing impaired population.

Overt visual attention modulates decision-related signals in ventral and dorsal medial prefrontal cortex
When indicating a preference between two options, decision makers are thought to compare and accumulate evidence in an attention-guided process. Little is known about this process's neural substrates or how visual attention affects the representations of accumulated evidence. We conducted a simultaneous eye-tracking and fMRI experiment in which human subjects gradually learned about the value of two food-lotteries. With this design we were able to extend decisions over a prolonged time-course, manipulate the temporal onset of evidence, and therefore dissociate sampled and accumulated evidence. Consistent with past work, we found correlates of sampled evidence in ventromedial prefrontal cortex (vmPFC), and correlates of accumulated evidence in the prefrontal and parietal cortex. We also found that more gaze at an option increased its choice probability and that gaze amplified sampled-value signals in the vmPFC and ventral striatum. Most importantly, we found that gaze modulated accumulated-value signals in the pre-supplementary motor area (pre-SMA), providing novel evidence that visual attention has lasting effects on decision variables and suggesting that activity in the pre-SMA reflects accumulated evidence and not decision conflict. These results shed new light on the neural mechanisms underlying gaze-driven decision processes.

Spatially global effects of feature-based attention in functional subdivisions of human subcortical nuclei
Attention can prioritize the processing of non-spatial features throughout the visual field. While human subcortical nuclei are known to play important roles in spatial attention, the subcortical mechanisms of feature-based attention remain elusive.Using high-resolution 7T fMRI, we investigated the spatially global effects of color-based attention in functional subdivisions of human subcortical nuclei. Paying attention to a color matching the unattended stimulus across the visual field selectively modulated BOLD signals in the parvocellular (P) layers of the lateral geniculate nucleus (LGN) of the thalamus, enhancing the response to the unattended stimulus while reducing the response to the attended stimulus. The spatially global effects of color-based attention were also found in the deeper layers of the superior colliculus (SC), early visual cortices, and the intraparietal sulcus (IPS) of the parietal lobe. Effective connectivity analyses further revealed enhanced feedforward and feedback connectivity between LGN and V1, along with top down modulation from IPS through the SC and ventral pulvinar. Finally, attended color can be decoded from multi-voxel response patterns in frontoparietal regions. These findings demonstrate that color-based attention selectively modulates color processing in P subdivisions of the LGN of the thalamus throughout the visual field, controlled by top-down signals from the parietal cortex through the SC and pulvinar.

Apelin-13 in the paraventricular nucleus protects myocardium from ischemia via V1a receptor of the paraventricular nucleus and GABAA receptor γ2 of the nucleus tractus solitarii in rats
Background: Apelin system plays a significant role in central blood pressure regulation, but its role in neural control of myocardial injury protection is poorly understood. Thus, this study was undertaken to evaluate the effects of apelin-13 in the paraventricular nucleus (PVN) on myocardial infarction (MI) and ischemia/reperfusion (I/R). Methods: The cardiac functions were assessed after microinjecting or transferring the apelin-13 gene into the paraventricular nucleus (PVN) of rat models with myocardial infarction (MI) or ischemia/reperfusion (I/R). Results: In MI rats, we showed that apelin-13 expression decreased in PVN, V1a receptor expression increased in PVN and nucleus tractus solitarii (NTS), and GABAA receptor (GAR) {gamma}2 expression increased in NTS. In primary cultured hypothalamus and medulla oblongata neurons, V1a receptor expression was downregulated by APJ receptor antagonist or GAR agonist, indicating that there are interactions between these receptors in neurons. Apelin-13 overexpression in PVN significantly improved cardiac function of MI and I/R rats, including left-ventricular end-diastolic diameter, left-ventricular end-systolic diameter, left-ventricular ejection fraction, and left-ventricular fractions shortening, accompanied by decreased noradrenaline and increased vasopressin plasma levels. Myocardial ischemia-related apoptotic and inflammatory pathway markers (Bcl-1, Bax, TGF-{beta}1, CCR5, Smad2) were downregulated and four neuropeptides of the parasympathetic endocrine system (somatostatin, cholecystokinin, glucagon-like peptide 1, vasoactive intestinal peptide) were increased in serum correspondingly with cardiac function improving. V1a receptor antagonist in PVN or NTS and GAR agonist in NTS decreased the effects of apelin-13 overexpression on cardiac function of MI and I/R rats. Conclusions: Overexpression of apelin-13 in PVN leads to cardiac function improvement via V1a receptor in PVN and NTS, and GAR?{gamma}2 in NTS. Parasympathetic endocrine system and myocardial ischemia?related apoptotic and inflammation signaling pathways are involved in apelin-13 in PVN-mediated cardiac function regulation, which provides evidence for neural regulation of cardiovascular diseases.

Aberrant iron deposition in the multiple sclerosis spinal cord relates to neurodegeneration
Background: Iron accumulates in microglia-macrophages at the edge of multiple sclerosis (MS) lesions in the brain. Iron-rimmed brain lesions strongly predict disability accumulation, supporting iron metabolism is crucial in MS pathology. Little is known about iron distribution in the spinal cord. Methods: Autopsy cervical, thoracic and lumbar spinal cord samples from 9 controls and 46 MS donors of whom a subset (n=36) had mesiofrontal motor cortical tissue available for study, were labelled and systematically assessed for iron (DAB-enhanced Turnbull), myelin (PLP), axons (Palmgren silver), microglia-macrophages (TMEM119, Iba1, CD68), astroglia (GFAP), oligodendroglia (OLIG2), acute axonal injury (B-APP, SMI-32, NPY-1R) and oxidative stress (E06). MS lesional and non-lesional areas were considered. Total non-haem iron was quantified by inductively coupled plasma optical emission spectroscopy (ICP-OES). Results: In controls, iron predominantly localised to oligodendrocytes with total non-haem iron relating to total myelin fraction, which markedly differed in MS where iron accumulated in microglia-macrophages, subpial astrocytes, and axons in non-lesional areas. Iron laden microglia-macrophages were over-represented relative to total microglial-macrophages and displayed dysmorphic features. Iron-positive axons showed a disto-proximal gradient (highest at lumbar level) with a predilection for the corticospinal tracts. The extent of iron axon positivity related to smaller spinal cord area, lower total axonal counts, and greater oxidative stress. Iron positivity in each cellular compartment (i.e. subpial astrocytes, microglia-macrophage and axons) related to one-another and total non-haem iron correlated with axonal counts in MS. No iron-rimmed lesions were detected in the spinal cord unlike in cortical grey and subcortical white matter of the same cases where 22% and 80% of iron-rimmed lesions, respectively, were seen. Conclusions: Despite the conspicuous absence of iron-rimmed lesions in the MS spinal cord, we demonstrate widespread aberrant iron distribution in the MS spinal cord that relates to oxidative stress and neurodegeneration independent of demyelination. The distal cord predominant and corticospinal tract specific accumulation of iron in axons mirrors the pattern of length-dependent motoric disability commonly encountered in progressive MS. These findings implicate aberrant iron accumulation as a novel, clinically relevant, feature of MS spinal cord pathology.

Complex Properties of Training Stimuli Affect Brain Alignment in a Deep Network Model of Mouse Visual Cortex
Deep convolutional neural networks are important models of the visual cortex that account relatively well for brain activity and are able to perform ethologically relevant functions. However, it is unknown which combination of factors, such as network architecture, training objectives, and data best align this family of models with the brain. Here we investigate the statistics of training data. We hypothesized that stimuli that are naturalistic for mice would lead to higher similarity between deep network models and activity in mouse visual cortex. We used a video-game engine to create training datasets in which we varied the naturalism of the environment, the movement statistics, and the optics of the modelled eye. The naturalistic environment substantially and consistently led to greater brain similarity, while the other factors had more subtle and area-specific effects. We then hypothesized that differences in brain similarity between the two environments arose due to differences in spatial frequency spectra, distributions of color and orientation, and/or temporal autocorrelations. To test this, we created abstract environments, composed of cubes and spheres, that resembled the naturalistic and non-naturalistic environments in these respects. Contrary to our expectations, these factors accounted poorly for differences in brain similarity due to the naturalistic and non-naturalistic environments. This suggests that the higher brain similarities we observed after training with the naturalistic environment were due to more complex factors.

A novel male accessory gland peptide reduces female post-mating receptivity in the brown planthopper
Mating in insects commonly induces a profound change in the physiology and behavior of the female that serves to secure numerous and viable offspring and to ensure paternity for the male by reducing receptivity of the female to further mating attempts. Here, we set out to characterize the post-mating response (PMR) in a pest insect, the brown planthopper (BPH) Nilaparvata lugens and to identify a functional analog of sex peptide (SP) and/or other seminal fluid factors that contribute to the PMR in Drosophila. We find that BPHs display a distinct PMR that lasts for about 4 days and includes a change in female behavior with decreased receptivity to males and increased oviposition. Extract from male accessory glands (MAG) injected into virgin females triggers a similar PMR, lasting about 24h. Since SP does not exist in BPHs, we screened for candidate mediators by performing a transcriptional and proteomics analysis of MAG extract. We identified a novel 51 amino acid peptide present only in the MAG and not in female BPHs. This peptide, that we designate maccessin (macc), affects the female PMR. Females mated by males with macc knockdown display receptivity to wild type males in a second mating, which does not occur in controls. However, oviposition is not affected. Injection of recombinant macc reduces female receptivity, with no effect on oviposition. Thus, macc is so far the only candidate seminal fluid peptide that promotes a PMR in BPHs. Our analysis suggests that the gene encoding the macc precursor is restricted to species closely related to BPHs.

Effects of one-night partial sleep deprivation on perivascular space volume fraction: Findings from the Stockholm Sleepy Brain Study
Increased waste clearance in the brain is thought to occur most readily during late-stage sleep (stage N3). Sleep deprivation disrupts time spent in deeper sleep stages, fragmenting the clearance process. Here, we have utilized the publicly available Stockholm Sleepy Brain Study to investigate whether various sleep-related measures are associated with changes in perivascular space (PVS) volume fraction following a late-night short-sleep experiment. Our sample consisted of 60 participants divided into old (65-75 years) and young (20-30 years) age groups. We found that partial sleep deprivation was not significantly associated with major PVS changes. In the centrum semiovale, we observed an interaction between percentage of total sleep time spent in N3 and sleep deprivation status on PVS volume fraction. In the basal ganglia, we saw an interaction between N2 (both percentage of total sleep time and absolute time in minutes) and sleep deprivation status. However, the significance of these findings did not survive multiple comparisons corrections. This work highlights the need for future longitudinal studies of PVS and sleep, allowing for quantification of within-subject morphological changes occurring in PVS due to patterns of poor sleep. Our findings here provide insight on the impacts that a single night of late-night short-sleep has on the perivascular waste clearance system.

Cortical layer 6b mediates state-dependent changes in brain activity and effects of orexin on waking and sleep
One of the most distinctive features of the mammalian cerebral cortex is its laminar structure. Of all cortical layers, layer 6b (L6b) is by far the least-studied, despite exhibiting direct sensitivity to orexin and having widespread connectivity, suggesting an important role in regulating cortical oscillations and brain state. We performed chronic electroencephalogram (EEG) recordings in mice in which a subset of L6b neurons was conditionally silenced, during undisturbed conditions, after sleep deprivation (SD), and after intracerebroventricular (ICV) administration of orexin. While the total amount of waking and sleep or the response to SD were not altered, L6b-'silenced' mice showed a slowing of theta-frequency (6-9 Hz) during wake and REM sleep, and a marked reduction of total EEG power, especially in NREM sleep. The infusion of orexin A increased wakefulness in both genotypes, but the effect was more pronounced in L6b-silenced mice, while the increase in theta-activity by orexin B was attenuated in L6b silenced animals. In summary, we show the role of cortical L6b in state-dependent brain oscillations and global vigilance state control, which could be mediated by orexinergic neurotransmission. Our findings provide new insights in the understanding of abnormal regulation of arousal states in neurodevelopmental and anxiety disorders.

Low Intestinal Doses of Botulinum Neurotoxins types A and B favour infection by Salmonella and Shigella without the flaccid paralysis of botulism
Botulism is a life-threatening disease characterized by a descending flaccid paralysis caused by a protein neurotoxin (BoNT) released by different anaerobic bacterial species of the genus Clostridium. The paralysis results from blockade of neurotransmitter release from the terminals of peripheral cholinergic, skeletal and autonomic neurons exerted by BoNT through the cleavage of SNARE proteins, which are essential for neuroexocytosis. Here, we investigated the effect of different doses of BoNT serotypes A and B, the serotypes most commonly associated with human botulism, on enteric nervous system neurons which play an important role in gut health and physiology. We found that BoNT/A and BoNT/B enter cholinergic neurons where they cleave SNARE proteins even at doses that do not cause signs of flaccid neuroparalysis. However, these low BoNT doses favour the invasion and infection of the mouse body by Salmonella thyphimurium and Shigella flexneri. This may have significant animal health implications.