bioRxiv Subject Collection: Neuroscience's Journal

Diverse Calcium Signaling in Astrocytes: Insights from a Computational Model
Astrocytes are complex cells that influence a variety of brain functions and behaviors. They are active cells that show a sharp increase in intracellular Ca2+ concentration in response to neurotransmitters (events called Ca2+ signals). The main source of intracellular Ca2+ is the stores in endoplasmic reticulum (ER), released by the activation of IP3 receptor channels on the ER membrane. As neurons, astrocytes from different brain regions show distinct Ca2+ signals. In addition, astrocytes can also show different patterns of Ca2+ responses. It is not yet clear how the diversity of astrocyte response emerge from the same mechanisms. Here we present a two variable astrocyte compartmental model for the Ca2+ and IP3 dynamics. We show that Ca2+ signals with different characteristics can emerge from changing the parameters associated with the Ca2+ and IP3 dynamics and the transmembrane current. We also show that global Ca2+ signals are required for the model to trigger different patterns of Ca2+ responses. The model present here can be used to simulate astrocytes from different brain regions and with distinct types of response.

The Role of Glucocorticoid and Nicotinic Acetylcholine Receptors in the Reward-Enhancing Effects of Nicotine in the ICSS Procedure in Male and Female Rats
Tobacco use disorder is a chronic disorder that affects more than one billion people worldwide and causes the death of millions each year. The rewarding properties of nicotine are critical for the initiation of smoking. Previous research has shown that the activation of glucocorticoid receptors (GRs) plays a role in nicotine self-administration in rats. However, the role of GRs in the acute rewarding effects of nicotine are unknown. In this study, we investigated the effects of the GR antagonist mifepristone and the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine on the reward-enhancing effects of nicotine using the intracranial self-stimulation (ICSS) procedure in adult male and female rats. The rats were prepared with ICSS electrodes in the medial forebrain bundle and then trained on the ICSS procedure. Nicotine lowered the brain reward thresholds and decreased response latencies similarly in male and female rats. These findings suggest that nicotine enhances the rewarding effects of ICSS and has stimulant properties. Treatment with the GR antagonist mifepristone did not affect the reward-enhancing effects of nicotine but increased response latencies, suggesting a sedative effect. Mecamylamine did not affect the brain reward thresholds or response latencies of the control rats, but prevented the nicotine-induced decrease in brain reward thresholds and reward latencies. These findings indicate that the rewarding effects of nicotine are mediated via the activation of nAChRs, and that the activation of GRs does not contribute to the acute rewarding effects of nicotine. These studies enhance our understanding of the neurobiological mechanisms underlying tobacco use disorder.

Genetic liability underlying reward-related comorbidity in psychiatric disorders involves the coincident functions of autism-linked ADGRL1 and hevin
Comorbidity between psychiatric traits is thought to involve overlapping pleiotropic effects from sets of genes. Notably, substance abuse is a shared comorbid condition among various neurodevelopmental disorders with externalizing symptoms such as autism spectrum disorder and attention-deficit hyperactivity disorder, thus hinting at the nucleus accumbens (NAc) as a site for predisposition underlying convergence of genetic influences in reward-related comorbidity. Here, we identify the autism-related gene encoding the adhesion G protein-coupled receptor (aGPCR) Latrophilin-1/ADGRL1 as an essential transducer of reward mechanisms in the NAc. We found that ADGRL1 mRNA is ubiquitously expressed throughout major NAc neuronal populations in mice. A mouse model of pan-neuronal Adgrl1 deficiency in the NAc displayed cocaine-seeking impairments in adult individuals denoting its role in drug-induced reinforcement and reward. Connecting molecular pathways of cocaine-induced learning, we uncover that ADGRL1 constitutes a functional receptor for autism-related cocaine effector molecule hevin/SPARCL1. Indeed, hevin interacts with membrane-expressed ADGRL1 and induces its internalization while stabilizing its uncleaved fraction. Moreover, hevin alters the formation of intercellular adhesion contacts mediated by ADGRL1 and Neurexin-1. Importantly, the functional constitutive coupling between ADGRL1 and various G protein pathways is selectively modulated by hevin stimulation with a bias toward Gi3, Gs, and G13 proteins. These findings unveil the dual role of ADGRL1 and hevin as genetic risk factors for both psychiatric disorders and substance abuse to define the molecular etiology of comorbidity.

Simulating a medical expertise: a robust novel stress induction paradigm in chronic pain patients
Maladaptive stress responses may exacerbate chronic widespread pain (CWP) and deserve further investigations. Yet, existing paradigms lack relevance for individuals with this condition. Hence, we developed the Social Benefits Stress Test (SBST), adapted from the Trier Social Stress Test. Instead of a job interview, the patients task is to justify their inability to work in front of a simulated medical expert in social insurances. Forty women with a type of CWP: hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders were included. After a 30-min baseline, they had 5 minutes to justify their inability to work, followed by an arithmetic task. After a recovery period, patients were fully debriefed. The psychophysiological stress response was captured using self-reported stress ratings, salivary cortisol and -amylase, and continuous physiological monitoring including heart rate variability (HRV). Compared to baseline, the analysis revealed a significant and transient increase in stress ratings during the stress task associated with a peak in salivary biomarkers concentrations. Physiological stress response was reported through HRV during the task with significant increase in heart rate, decrease in high frequency power (HF), increase in low frequency power (LF) and in LF/HF ratio. Stress ratings positively correlated with changes in salivary biomarkers and LF/HF ratio. The results validate the SBST as a relevant experimental model of social stress in CWP patients as it induced a reproducible moderate stress response across subjective and physiological measures. The SBST opens up for important new studies on the relationship between stress and maintenance of chronic pain.

Postprandial sleep in short-sleeping Mexican cavefish
Interaction between sleep and feeding behaviors are critical for adaptive fitness. Diverse species suppress sleep when food is scarce to increase the time spent foraging. Post-prandial sleep, an increase in sleep time following a feeding event, has been documented in vertebrate and invertebrate animals. While interactions between sleep and feeding appear to be highly conserved, the evolution of postprandial sleep in response to changes in food availability remains poorly understood. Multiple populations of the Mexican cavefish, Astyanax mexicanus, have independently evolved sleep loss and increased food consumption compared to surface-dwelling fish of the same species, providing the opportunity to investigate the evolution of interactions between sleep and feeding. Here, we investigate effects of feeding on sleep in larval and adult surface fish, and two parallelly evolved cave populations of A. mexicanus. Larval surface and cave populations of A. mexicanus increase sleep immediately following a meal, providing the first evidence of postprandial sleep in a fish model. The amount of sleep was not correlated to meal size and occurred independently of feeding time. In contrast to larvae, postprandial sleep was not detected in adult surface or cavefish, that can survive for months without food. Together, these findings reveal that postprandial sleep is present in multiple short-sleeping populations of cavefish, suggesting sleep-feeding interactions are retained despite the evolution of sleep loss. These findings raise the possibility that postprandial sleep is critical for energy conservation and survival in larvae that are highly sensitive to food deprivation.

Ultra-high temporal resolution 4D angiography using arterial spin labeling with subspace reconstruction
Purpose: To achieve ultra-high temporal resolution non-contrast 4D angiography with improved spatiotemporal fidelity. Methods: Continuous data acquisition using 3D golden-angle sampling following an arterial spin labeling preparation allows for flexibly reconstructing 4D dynamic angiograms at arbitrary temporal resolutions. However, k-space data is often temporally "binned" before image reconstruction, negatively affecting spatiotemporal fidelity and limiting temporal resolution. In this work, a subspace was extracted by linearly compressing a dictionary constructed from simulated curves of an angiographic kinetic model. The subspace was used to represent and reconstruct the voxelwise signal timecourse at the same temporal resolution as the data acquisition without temporal binning. Physiological parameters were estimated from the resulting images using a Bayesian fitting approach. A group of 8 healthy subjects were scanned and the in-vivo results reconstructed by different methods were compared. Due to difficulty of obtaining ground truth 4D angiograms with ultra-high temporal resolution, the in-vivo results were cross-validated with numerical simulations. Results: The proposed method enables 4D time-resolved angiography with much higher temporal resolution (14.7 ms) than previously reported (~50 ms) whilst maintaining high spatial resolution (1.1 mm isotropic). Blood flow dynamics were depicted in greater detail, thin vessel visibility was improved, and the estimated physiological parameters also exhibited more realistic spatial patterns with the proposed method. Conclusion: Incorporating a subspace compressed kinetic model into the reconstruction of 4D ASL angiograms notably improved the temporal resolution and spatiotemporal fidelity, which was subsequently beneficial for accurate physiological modeling.

Functional assessment of a kcnb1 knock-out zebrafish to model KCNB1-related neurodevelopmental and epileptic disorders
KCNB1 encodes the Kv2.1 potassium channel alpha subunit. De novo pathogenic variants of KCNB1 with loss-of-function (LOF) properties have been associated with neurodevelopmental and epileptic disorders (DEE) diagnosed in early childhood. The study aims to characterize a knock-out (KO) zebrafish line targeting kcnb1 (kcnb1+/- and kcnb1-/-). We examined the spatial expression of kcnb1, as well as phenotypic behavior, cellular, and electrophysiological activity of fish during early development stages. In wild-type larval zebrafish, kcnb1 was found in various regions of the central nervous system but was undetected in the KO model. Both kcnb1+/- and kcnb1-/- zebrafish displayed impaired swimming behavior and epilepsy-like features that persisted through embryonic and larval development, with variable severity. When exposed to the chemoconvulsant pentylenetetrazol (PTZ), mutant fish showed elevated locomotor activity and epileptiform-like electrographic activity. In addition, PTZ-exposed kcnb1-/- larvae exhibited higher bdnf mRNA expression and activated c-Fos positive neurons in the telencephalon. In this KO model, neuronal circuits, muscle fibers and neuromuscular junction organization remained unaffected, including normal AchR cluster distribution, although a decreased AchE mRNA expression was observed. kcnb1 KO zebrafish develops early DEE-like phenotypes that affects neuronal functions. This study highlights the relevance of the model for investigating developmental neuronal signaling pathways in KCNB1-related DEEs.

Atypical chemokine receptor 3 regulates synaptic removal in disease astrocytes
Astrocytes participate in the clearance of obsolete or unwanted neuronal synapses. However, the molecular machinery recruited for the recognition of synapses is not fully clarified, especially in pathological conditions. Here, we investigated the phagocytic process through individual gene silencing using a druggable gene library. Our study demonstrates that astrocyte-mediated synapse engulfment is regulated by the Atypical chemokine receptor 3 (Ackr3). Mechanistically, we have shown that Ackr3 recognizes phosphatidylethanolamine (PE)-bound Cxcl12 at synaptic terminals both in vitro and in cell culture thus serving as a novel marker of synaptic dysfunction. Notably, both the receptor and its ligand are overexpressed in post-mortem AD human brains, and downregulation of the receptor in AD mouse models (5xFAD) significantly diminishes astrocyte-mediated synaptic elimination. Overall, this work unveils a novel, possibly targetable mechanism of astrocyte-mediated synaptic engulfment implicated in the most common neurodegenerative disease.

Hippocampal-entorhinal cognitive maps and cortical motor system represent action plans and their outcomes
Efficiently interacting with the environment requires weighing and selecting among multiple alternative actions based on their associated outcomes. However, the neural mechanisms underlying these processes are still debated. We showed that forming relations between arbitrary action-outcome associations involved building a cognitive map. Using a novel immersive virtual reality paradigm, participants learned 2D abstract motor action-outcome associations and later compared action combinations while their brain activity was monitored with fMRI. We observed a hexadirectional modulation of the activity in entorhinal cortex while participants compared different action plans. Furthermore, hippocampal activity scaled with the 2D similarity between outcomes of these action plans. Conversely, the supplementary motor area (SMA) represented individual actions, showing a stronger response to overlapping action plans. Crucially, the connectivity between hippocampus and SMA was modulated by the similarity between the action plans, suggesting their complementary roles in action evaluation. These findings provide evidence for the role of cognitive maps in action selection, challenging classical models of memory taxonomy and its neural bases.

Hierarchical cortical plasticity in congenital sight impairment
A robust learning system balances adaptability to new experiences with stability of its foundational architecture. To investigate how the human brain implements this we used a new approach to study plasticity and stability across hierarchical processing stages in visual cortex. We compare the rod system of individuals born with rod-only photoreceptor inputs (achromatopsia) to the typically developed rod system, allowing us to dissociate impacts of life-long versus transient responses to altered input. Cortical input stages (V1) exhibited high stability, with structural hallmarks of deprivation and no retinotopic reorganisation. However, plasticity manifested as reorganised read-out of these inputs by higher-order cortex, in a pattern that could compensate for the lower resolution of a rod-only system and its lack of high-density foveal input. We propose that these hierarchical dynamics robustly optimize processing of available input and could reflect a broader principle of brain organisation with important implications for emerging sight-recue therapies.

Retinal bipolar cells borrow excitability from electrically coupled inhibitory interneurons to amplify excitatory synaptic transmission
Bipolar cells of the retina carry visual information from photoreceptors in the outer retina to retinal ganglion cells (RGCs) in the inner retina. Bipolar cells express L-type voltage-gated Ca2+ channels at the synaptic terminal, but generally lack other types of channels capable of regenerative activity. As a result, the flow of information from outer to inner retina along bipolar cell processes is generally passive in nature, with no opportunity for signal boost or amplification along the way. Here we report the surprising discovery that blocking voltage-gated Na+ channels profoundly reduces the synaptic output of one class of bipolar cell, the type 6 ON bipolar cell (CBC6), despite the fact that the CBC6 itself does not express voltage-gated Na+ channels. Instead, CBC6 borrows voltage-gated Na+ channels from its neighbor, the inhibitory AII amacrine cell, with whom it is connected via an electrical synapse. Thus, an inhibitory neuron aids in amplification of an excitatory signal as it moves through the retina, ensuring that small changes in the membrane potential of bipolar cells are reliably passed onto downstream RGCs.

New Atg9 phosphorylation sites regulate autophagic trafficking in glia
We previously identified a role for dAuxilin (dAux), the fly homolog of Cyclin G-associated kinase (GAK), in glial autophagy contributing to Parkinson's disease (PD). To further dissect the mechanism, we present evidence here that lack of glial dAux enhanced the phosphorylation of the autophagy-related protein Atg9 at two newly identified threonine residues, T62 and T69. Enhanced Atg9 phosphorylation in the absence of glial dAux is potentially regulated through the master autophagy regulator Atg1, as the presence of which is required for Atg9 to interact with dAux in an otherwise separate condition. The enhanced Atg9 phosphorylation promotes autophagosome formation and Atg9 trafficking to the autophagosomes in glia. Whereas the expression of the non-phosphorylatable Atg9 variants suppresses the lack of dAux-induced increase in both autophagosome formation and Atg9 trafficking to autophagosome, the expression of the phophomimetic Atg9 variants restores the lack of Atg1-induced decrease in both events. Notably, Atg9 phosphorylation at T62 and T69 contributes to DA neurodegeneration and locomotor dysfunction implicated in PD. Thus, we have identified a dAux-Atg1-Atg9 axis relaying signals through the Atg9 phosphorylation at T62 and T69; these findings further elaborate the mechanism of dAux regulating glial autophagy and highlight the significance of protein degradation pathway in glia contributing to PD.

Simultaneous dual-color calcium imaging in freely-behaving mice
Miniaturized fluorescence microscopes (miniscopes) enable imaging of calcium events from a large population of neurons with single-cell resolution in freely behaving animals. Traditionally, miniscopes have only been able to record from a single fluorescence wavelength. Here, we present a new open-source dual-channel Miniscope that simultaneously records two wavelengths in freely behaving animals, providing more flexibility and function. To enable simultaneous acquisition of two fluorescent wavelengths, we incorporated two CMOS sensors with two independent sets of emission filters into a single Miniscope. This enables us to acquire images at the full frame rate that the CMOS sensor supports while simultaneously eliminating crosstalk between channels, which allows imaging fluorophores that heavily overlap in their emission spectrums (for example, GFP and tdTomato). We adopted a design that enables adjusting the position of one imaging sensor along the light path to match the focal plane of the other sensor, providing additional flexibility for calibration. To validate our dual-channel Miniscope in vivo, we imaged hippocampal CA1 region that co-expressed a dynamic calcium indicator (GCaMP) and a static nuclear signal (constitutively active tdTomato) while mice ran on a linear track. We used GCaMP signals to investigate spatial coding in the hippocampus and tdTomato signals as a landmark for registration of neurons across recording sessions. Our results suggest that, even when neurons were registered across recording sessions using tdTomato signals, hippocampal spatial coding changes over time as previously reported. In conclusion, our novel dual-channel Miniscope enables imaging of two fluorescence wavelengths in the same focal plane with minimal crosstalk between the two channels, opening the doors to a multitude of new experimental possibilities.

A scene with an invisible wall - navigational experience shapes visual scene representation
Human navigation heavily relies on visual information. Although many previous studies have investigated how navigational information is inferred from visual features of scenes, little is understood about the impact of navigational experience on visual scene representation. In this study, we examined how navigational experience influences both the behavioral and neural responses to a visual scene. During training, participants navigated in the virtual reality (VR) environments which we manipulated navigational experience while holding the visual properties of scenes constant. Half of the environments allowed free navigation (navigable), while the other half featured an invisible wall preventing the participants to continue forward even though the scene was visually navigable (non-navigable). During testing, participants viewed scene images from the VR environment while completing either a behavioral perceptual identification task (Experiment1) or an fMRI scan (Experiment2). Behaviorally, we found that participants judged a scene pair to be significantly more visually different if their prior navigational experience varied, even after accounting for visual similarities between the scene pairs. Neurally, multi-voxel pattern of the parahippocampal place area (PPA) distinguished visual scenes based on prior navigational experience alone. These results suggest that the human visual scene cortex represents information about navigability obtained through prior experience, beyond those computable from the visual properties of the scene. Taken together, these results suggest that scene representation is modulated by prior navigational experience to help us construct a functionally meaningful visual environment.

An orbitocortical-thalamic circuit suppresses binge alcohol-drinking.
Alcohol consumption remains a significant global health challenge, causing millions of direct and indirect deaths annually. Intriguingly, recent work has highlighted the prefrontal cortex, a major brain area that regulates inhibitory control of behaviors, whose activity becomes dysregulated upon alcohol abuse. However, whether an endogenous mechanism exists within this brain area that limits alcohol consumption is unknown. Here we identify a discrete GABAergic neuronal ensemble in the medial orbitofrontal cortex (mOFC) that is selectively recruited during binge alcohol-drinking and intoxication. Upon alcohol intoxication, this neuronal ensemble suppresses binge drinking behavior. Optogenetically silencing of this population, or its ablation, results in uncontrolled binge alcohol consumption. We find that this neuronal ensemble is specific to alcohol and is not recruited by other rewarding substances. We further show, using brain-wide analysis, that this neuronal ensemble projects widely, and that its projections specifically to the mediodorsal thalamus are responsible for regulating binge alcohol drinking. Together, these results identify a brain circuit in the mOFC that serves to protect against binge drinking by halting alcohol intake. These results provide valuable insights into the complex nature of alcohol abuse and offers potential avenues for the development of mOFC neuronal ensemble-targeted interventions.

Apparent Diffusion Coefficient fMRI shines a new light on white matter resting-state connectivity, as compared to BOLD
Resting-state functional MRI (rs-fMRI) detects spontaneous low-frequency oscillations in the MRI signal at rest. When they occur simultaneously in distant brain regions, they define functional connectivity (FC) between these regions. While blood oxygen level-dependent (BOLD) fMRI serves as the most widely used contrast for rs-fMRI, its reliance on neurovascular coupling poses challenges in accurately reflecting neuronal activity, resulting in limited spatial and temporal specificity and reduced sensitivity in white matter regions. To overcome these limitations, apparent diffusion coefficient fMRI (ADC-fMRI) is emerging as a promising alternative. This approach captures neuronal activity by monitoring changes in ADC resulting from activity-driven neuromorphological alterations such as transient cell swelling. Using graph theory analysis of resting-state FC networks, this study confirms that ADC-fMRI mirrors the positive correlations observed in BOLD-fMRI in the gray-to-gray matter edges (GM-GM), while diverging significantly from BOLD-fMRI for white-to-white matter (WM-WM) connections. While comparable average clustering and average node strength were found for GM-GM connections, higher average clustering (p < 10-3) and average node strength (p < 10-3) for ADC-fMRI in WM-WM edges suggests that it captures different information to BOLD in the WM. In addition, a significantly higher FC similarity between subjects for ADC-fMRI (mean 0.70, 95% CI [0.68, 0.72]) than BOLD-fMRI (0.38 [0.31, 0.44]) in WM-WM connections suggests a higher reliability of ADC-fMRI in this brain tissue type, demonstrating its broader applicability across the entire brain and reduced sensitivity to physiological noise. Taken together, these results indicate a higher sensitivity and robustness of ADC-fMRI in the WM, and encourage its use, together with careful mitigation of vascular contributions, to further investigate WM functional connectivity.

Poor Self-Reported Sleep is Associated with Prolonged White Matter T2 Relaxation in Psychotic Disorders
BackgroundSchizophrenia (SZ) and bipolar disorder (BD) are characterized by white matter (WM) abnormalities, however, their relationship with illness presentation is not clear. Sleep disturbances are common in both disorders, and recent evidence suggests that sleep plays a critical role in WM physiology. Therefore, it is plausible that sleep disturbances are associated with impaired WM integrity in these disorders. To test this hypothesis, we examined the association of self-reported sleep disturbances with WM transverse (T2) relaxation times in patients with SZ spectrum disorders and BD with psychotic features.

Methods28 patients with psychosis (17 BD-I, with psychotic features and 11 SZ spectrum disorders) were included. Metabolite and water T2 relaxation times were measured in the anterior corona radiata at 4T. Sleep was evaluated using the Pittsburgh Sleep Quality Index.

ResultsPSQI total score showed a moderate to strong positive correlation with water T2 (r = 0.64, p<0.001). Linear regressions showed that this association was specific to sleep disturbance but was not a byproduct of exacerbation in depressive, manic, or psychotic symptoms. In our exploratory analysis, sleep disturbance was correlated with free water percentage, suggesting that increased extracellular water may be a mechanism underlying the association of disturbed sleep and prolonged water T2 relaxation.

ConclusionOur results highlight the connection between poor sleep and WM abnormalities in psychotic disorders. Future research using objective sleep measures and neuroimaging techniques suitable to probe free water is needed to further our insight into this relationship.

Bayesian inference in arm posture perception
To configure our limbs in space the brain must compute their position based on sensory information provided by mechanoreceptors in the skin, muscles, and joints. Because this information is corrupted by noise, the brain is thought to process it probabilistically, and integrate it with prior belief about arm posture, following Bayes rule. Here, we combined computational modeling with behavioral experimentation to test this hypothesis. The model conceives the perception of arm posture as the combination of a probabilistic kinematic chain composed by the shoulder, elbow, and wrist angles, compromised with additive Gaussian noise, with a Gaussian prior about these joint angles. We tested whether the model explains errors in a VR-based posture-matching task better than a model that assumes a uniform prior. Human participants (N=20) were required to align their unseen right arm to a target posture, presented as a visual configuration of the arm in the horizontal plane. Results show idiosyncratic biases in how participants matched their unseen arm to the target posture. We used maximum likelihood estimation to fit the Bayesian model to these observations and retrieve key parameters including the prior means and its variance-covariance structure. The Bayesian model including a Gaussian prior explained the response biases and variance much better than a model with a uniform prior. The prior varied across participants, consistent with the idiosyncrasies in arm posture perception, and in alignment with previous behavioral research. Our work clarifies the biases in arm posture perception within a new perspective on the nature of proprioceptive computations.

Molecular and cellular rhythms in excitatory and inhibitory neurons in the mouse prefrontal cortex
Previous studies have shown that there are rhythms in gene expression in the mouse prefrontal cortex (PFC); however, the contribution of different cell types and potential variation by sex has not yet been determined. Of particular interest are excitatory pyramidal cells and inhibitory parvalbumin (PV) interneurons, as interactions between these cell types are essential for regulating the excitation/inhibition balance and controlling many of the cognitive functions regulated by the PFC. In this study, we identify cell-type specific rhythms in the translatome of PV and pyramidal cells in the mouse PFC and assess diurnal rhythms in PV cell electrophysiological properties. We find that while core molecular clock genes are conserved and synchronized between cell types, pyramidal cells have nearly twice as many rhythmic transcripts as PV cells (35% vs. 18%). Rhythmic transcripts in pyramidal cells also show a high degree of overlap between sexes, both in terms of which transcripts are rhythmic and in the biological processes associated with them. Conversely, in PV cells, rhythmic transcripts from males and females are largely distinct. Moreover, we find sex-specific effects of phase on action potential properties in PV cells that are eliminated by environmental circadian disruption. Together, this study demonstrates that rhythms in gene expression and electrophysiological properties in the mouse PFC vary by both cell type and sex. Moreover, the biological processes associated with these rhythmic transcripts may provide insight into the unique functions of rhythms in these cells, as well as their selective vulnerabilities to circadian disruption.

Glia control experience-dependent plasticity in an olfactory critical period
Sensory experience during developmental critical periods has lifelong consequences for circuit function and behavior, but the molecular and cellular mechanisms through which experience causes these changes are not well understood. The Drosophila antennal lobe houses synapses between olfactory sensory neurons (OSNs) and downstream projection neurons (PNs) in stereotyped glomeruli. Many glomeruli exhibit structural plasticity in response to early-life odor exposure, indicating a general sensitivity of the fly olfactory circuitry to early sensory experience. We recently found that glia regulate the development of the antennal lobe in young adult flies, leading us to ask if glia also drive experience-dependent plasticity. Here we define a critical period for structural and functional plasticity of OSN-PN synapses in the ethyl butyrate (EB)-sensitive glomerulus VM7. EB exposure for the first two days post-eclosion drives large-scale reductions in glomerular volume, presynapse number, and post-synaptic activity. The highly conserved engulfment receptor Draper is required for this critical period plasticity. Specifically, ensheathing glia upregulate Draper expression, invade the VM7 glomerulus, and phagocytose OSN presynaptic terminals in response to critical-period EB exposure. Crucially, synapse pruning during the critical period has long-term consequences for circuit function since both OSN-PN synapse number and spontaneous activity of PNs remain persistently decreased. These data demonstrate experience-dependent pruning of synapses in olfactory circuitry and argue that the Drosophila antennal lobe will be a powerful model for defining the function of glia in critical period plasticity.

A lasting impact of serotonergic psychedelics on visual processing and behavior
Serotonergic psychedelics (e.g., psilocybin) have shown potential for treating psychiatric disorders, with therapeutic effects lasting weeks after a single dose. Predictive processing theories posit that psychedelics work by loosening priors or high-level beliefs, including ingrained biases that have become pathological, leading to shifts in bottom-up vs top-down information processing that reconfigure perception, cognition, and mood. Because 5-HT2A receptors, the primary target of psychedelics, are enriched in visual cortices, we investigated whether psychedelics alter visual processing in a manner consistent with predictive processing theories. People who recently (<3 weeks) used 5-HT2A-agonist psychedelics (psilocybin, LSD) exhibited slowed response latencies and increased cortical involvement in generating saccades to targets in predictable locations, along with a generalization of sensory prediction errors (i.e., deviance detection) during passive visual processing. Individuals who recently used a 5-HT1A-selective psychedelic (5-MeO-DMT) displayed similar changes in saccade production, but unaltered deviance detection, suggesting circuit-specific effects. Mice administered DOI (5-HT2A-agonist) exhibited altered deviance detection within primary visual cortex (V1), along with weakened top-down feedback to V1 from higher cortical area ACa. These results concord with the hypothesis that psychedelics shift the balance from top-down to bottom-up in sensory cortical circuits -- an effect that persists beyond the acute exposure period.

Co-Transplantation-Based Human-Mouse Chimeric Brain Models to Study Human Glial-Glial and Glial-Neuronal Interactions
Human-mouse chimeric brain models, generated by transplanting human induced pluripotent stem cell (hiPSC)-derived neural cells, are valuable for studying the development and function of human neural cells in vivo. Understanding glial-glial and glial-neuronal interactions is essential for unraveling the complexities of brain function and developing treatments for neurological disorders. To explore these interactions between human neural cells within an intact brain environment, we employe a co-transplantation strategy involving the engraftment of hiPSC-derived neural progenitor cells along with primitive macrophage progenitors into the neonatal mouse brain. This approach creates human-mouse chimeric brains containing human microglia, macroglia (astroglia and oligodendroglia), and neurons. Using super-resolution imaging and 3D reconstruction techniques, we examine the dynamics between human neurons and glia, unveiling human microglia engulfing immature human neurons, microglia pruning synapses of human neurons, and significant interactions between human oligodendrocytes and neurons. Single-cell RNA sequencing analysis of the chimeric brain uncovers a close recapitulation of the human glial progenitor cell population, along with a dynamic stage in astroglial development that mirrors the processes found in the human brain. Furthermore, cell-cell communication analysis highlights significant neuronal-glial and glial-glial interactions, especially the interaction between adhesion molecules neurexins and neuroligins. This innovative co-transplantation model opens up new avenues for exploring the complex pathophysiological mechanisms underlying human neurological diseases. It holds particular promise for studying disorders where glial-neuronal interactions and non-cell-autonomous effects play crucial roles.

Evaluating theories of neural information integration during visual search
The brain routes and integrates information from many sources during behavior. A number of models explain this phenomenon within the framework of mixed selectivity theory, yet it is difficult to compare their predictions to understand how neurons and circuits integrate information. In this work, we apply time-series partial information decomposition [PID] to compare models of integration on a dataset of superior colliculus [SC] recordings collected during a multi-target visual search task. On this task, SC must integrate target guidance, bottom-up salience, and previous fixation signals to drive attention. We find evidence that SC neurons integrate these factors in diverse ways, including decision-variable selectivity to expected value, functional specialization to previous fixation, and code-switching (to incorporate new visual input).

"Magnetic Sand" : Illusions of Interactivity
We found a series of new illusions, in which actions performed near a random white-noise display lead to the perception that the display is altered interactively with the observers actions. The perceptions resemble interactions with a box of magnetic sand, where the hand can leave traces, or attract and repulse grains in its vicinity. 1) the observer puts a finger very close to a dynamic noise display, slowly moving as though drawing a letter or a shape. A trace appears left in the fingers path, decaying within 500 ms or so. 2) When the observer moves their palm toward and away from the display, opening and closing their fingers as if grabbing and releasing grains of sand, the random dots appear as though they were magnetically attracted to or repelled by the fingers. 3) When an open hand close to the display is slowly moved back and forth laterally, the nearby dots appear to get attracted to or captured by the fingers and thus appear to move with them. 4) The same kind of action capture occurs even when the hand is not visible, moving behind the display. These illusions are robust across a wide range of parameters, including frame rate, luminance contrast, dot size (spatial frequency), and finger movement factors. Inter-subject variability is not correlated across illusion types, and the illusions also diverge in behavior across dynamic and static noise conditions. This indicates that multiple mechanisms are involved to different extents across illusions. Several known visual motion detectors and other low-level mechanisms may be involved in seeding the perceptual phenomena. However, a complete explanation would require mechanisms of action capture, whereby the internal model of the persons actions and their predicted consequences organizes visual attention and processing of the random stimulus components.

Walking entrains unique oscillations for central and peripheral visual detection
It is important to investigate perception in the context of natural behaviour in order to reach a holistic account of how sensory processes are coordinated with actions. In particular, the effect of walking upon perceptual and cognitive functions has recently been investigated in the context of how common voluntary actions may dynamically impact upon visual detection. This work has revealed that walking can enhance peripheral visual processing, and that during walking, performance on a visual detection task oscillates through good and bad periods within the phases of the stride-cycle. Here, we extend this work by examining whether oscillations in visual detection performance are uniform across the visual field while walking. Participants monitored parafoveal (~3.7 d.v.a) and peripheral (~7 d.v.a) locations left/right of fixation for the onset of targets while walking at a natural pace in wireless virtual reality. For targets at all locations accuracy, reaction times and response likelihood oscillated within each individual's stride-cycle, at primarily 2 or 4 cycles per stride. Importantly, oscillations in accuracy and reaction time shared the same frequency at both locations but were decreased in amplitude and phase-lagged in the periphery, revealing an interaction between visual field locations and oscillations in performance. Together, these results demonstrate that oscillations in visual performance entrained by the stride-cycle occur with unique amplitudes and phases across the visual field.

Generative deep learning models for cognitive performance trajectories in real-world scenarios
The increasing prevalence of cognitive disorders, such as Alzheimer's disease, imposes significant challenges on healthcare systems and society. The ability to predict the future cognitive performance (CP) is crucial for professionals in neuropsychology, and real-world data emerges as an important source of complete and reliable information. However, its inherent complexities requires the use of advanced models to make predictions. To do so, we have implemented and compared three deep learning predictive strategies from CP trajectories: multilayer perceptron (MLP), convolutional neural networks (CNN) and long short-term memory (LSTM). The three models showed robustness on their predictions in different patient datasets. The CNN was the most suitable architecture due to its local pattern recognition capabilities and its robustness to overfitting. Therefore, professionals can have a complementary support for targeting treatment approaches to patients needs and anticipate undesired outcomes (e.g. cognitive impairment). Nonetheless, further studies are needed to validate whether neuropsychological interventions based on score predictions lead to improved intervention efficacy compared to traditional approaches for controlled patient groups.

Pan-cortical cellular imaging in freely behaving mice using a miniaturized micro-camera array microscope (mini-MCAM)
Understanding how circuits in the brain simultaneously coordinate their activity to mediate complex ethnologically relevant behaviors requires recording neural activities from distributed populations of neurons in freely behaving animals. Current miniaturized imaging microscopes are typically limited to imaging a relatively small field of view, precluding the measurement of neural activities across multiple brain regions. Here we present a miniaturized micro-camera array microscope (mini-MCAM) that consists of four fluorescence imaging micro-cameras, each capable of capturing neural activity across a 4.5 mm x 2.55 mm field of view (FOV). Cumulatively, the mini-MCAM images over 30 mm2 area of sparsely expressed GCaMP6s neurons distributed throughout the dorsal cortex, in regions including the primary and secondary motor, somatosensory, visual, retrosplenial, and association cortices across both hemispheres. We demonstrate cortex-wide cellular resolution in vivo Calcium (Ca2+) imaging using the mini-MCAM in both head-fixed and freely behaving mice.

Food texture preference reveals multisensory contributions of gustatory organs in behaviour and physiology
Summary Food presents a multisensory experience, with visual, taste, and olfactory cues being important in allowing an animal to determine the safety and nutritional value of a given substance. Texture, however, remains a surprisingly unexplored aspect, despite providing key information about the state of the food through properties such as hardness, liquidity, and granularity. Food perception is achieved by specialised sensory neurons, which themselves are defined by the receptor genes they express. While it was assumed that sensory neurons respond to one or few closely-related stimuli, more recent findings challenge this notion and support evidence that certain sensory neurons are more broadly tuned. In the Drosophila taste system, gustatory neurons respond to cues of opposing hedonic valence or to olfactory cues. Here, we identified that larvae ingest and navigate towards specific food substrate hardnesses, and probed the role of gustatory organs in this behaviour. By developing a genetic tool targeting specifically gustatory organs, we show that these organs are major contributors for evaluation of food texture and ingestion decision-making. We find that ablation of gustatory organs not only results in loss of chemosensation, but also navigation and ingestion preference to varied substrate textures. Furthermore, we show that certain neurons in the primary taste organ exhibit varied and concurrent physiological responses to mechanical and multimodal stimulation. We show that individual neurons house independent mechanisms for multiple sensory modalities, challenging assumptions about capabilities of sensory neurons. We propose that further investigations, across the animal kingdom, may reveal higher sensory complexity than currently anticipated.