bioRxiv Subject Collection: Neuroscience's Journal

Olfactory combinatorial coding supports risk-reward decision making in C. elegans
Vertebrate and insect olfactory systems generate diversity in odor perception using combinatorial coding, where individual odorant molecules activate unique but overlapping sets of olfactory receptor neurons. It is not well understood how these patterns are decoded and transformed into downstream physiological responses. Here, we demonstrate that Caenorhabditis elegans uses combinatorial coding to formulate locomotory responses to the odorant 1-octanol (1-oct). Whole-network Ca++ imaging showed that 1-oct is encoded combinatorially, activating multiple sensory neurons including ASH and AWC, associated with repulsion and attraction, respectively. The temporal dynamics of these neuronal activations indicate that 1-oct stimulates attractive and repulsive afferent pathways simultaneously; altering the relative strengths of these pathways is sufficient to convert 1-oct from a repellent to an attractant in microfluidics-based behavioral assays. These results identify the balance between attraction and repulsion as a key factor determining chemotactic behavior, achieved through modulation of locomotory reversals and speed. At the circuit level, the attractive and repulsive pathways can both entrain the activity of the reverse command interneuron AVA, a key regulator of reversals, with the stronger pathway predominating. This coding strategy facilitates context-dependent modulation of sensory responses. 1-oct is present in decaying plant material, signaling the possible presence of bacterial food. However, 1-oct is also toxic, and therefore represents a high risk food signal. Adding a different food signal (representing better food in a different location) suppresses the 1-oct attraction pathway by depressing AWC activity, tips the sensory balance toward the aversive pathway, and converts 1-oct attraction into 1-oct repulsion.

Central nucleus of the amygdala to medial prefrontal cortex 5-HTergic neural circuit modulates the recovery of consciousness during sevoflurane anesthesia
General anesthesia, widely employed for its capacity to induce unconsciousness during surgical and diagnostic procedures, frequently results in postoperative recovery delays, a common complication. The precise mechanisms underpinning this delayed emergence from anesthesia remain not /fully understood. Prior research has established a strong association between sleep-wake neural circuits and the anesthetic effects of general anesthetics, with serotonin (5-HT) playing a pivotal role in the regulation of anesthesia emergence. Extensive projections exist between the amygdala and the medial prefrontal cortex (mPFC). In this study, we utilized pharmacological, chemogenetic, and optogenetic techniques to explore the relationship between the 5-HT neural circuitry within the central amygdala (CeA)-mPFC pathway and the process of awakening from general anesthesia. Our findings reveal that modulating the 5-HT system in both the CeA and mPFC, via endogenous and exogenous means, can effectively reverse delayed emergence. This suggests that the 5-HT-ergic pathway within the CeA-mPFC circuit is instrumental in regulating the awakening process from sevoflurane anesthesia. These insights may inform future clinical interventions designed to prevent delayed emergence and reduce postoperative risks.

Cocaine-Induced Gene Regulation in D1 and D2 Neuronal Ensembles of the Nucleus Accumbens Revealed by Single-Cell RNA Sequencing
Cocaine use disorder is characterized by persistent drug-seeking behavior and a high risk of relapse, driven by lasting molecular and circuit adaptations in the nucleus accumbens. To explore the transcriptomic changes underlying these alterations, we employed fluorescence-activated nucleus sorting coupled with single-nucleus RNA sequencing to analyze D1 and D2 medium spiny neurons in this brain region of male mice subjected to acute cocaine exposure or to prolonged withdrawal from repeated cocaine exposure without or with an acute cocaine rechallenge. This approach allowed us to precisely delineate and contrast transcriptionally distinct neuronal subpopulations[boxh]or ensembles - across various treatment conditions. We identified significant heterogeneity within both D1 and D2 MSNs, revealing distinct clusters with unique transcriptional profiles. Notably, we identified a discrete D1 MSN population characterized by the upregulation of immediate early genes, as well as another group of D1 MSNs linked to prolonged withdrawal, uncovering novel regulators of withdrawal-related transcriptome dynamics. Our findings provide a high-resolution transcriptomic map of D1 and D2 MSNs, illustrating the dynamic changes induced by cocaine exposure and withdrawal. These insights into the molecular mechanisms underlying cocaine use disorder highlight potential targets for therapeutic intervention aimed at preventing relapse.

Genetic ablation of the DNA demethylation pathway in retinal progenitor cells impairs photoreceptor development and function, leading to retinal dystrophy
Rod and cone photoreceptors are critical for vision, and their loss leads to blindness. We explored the role of epigenetic mechanisms in photoreceptor development and function that is still poorly understood. To this end, we created mice in which the DNA demethylation pathway was inactivated in retinal progenitor cells (RPCs). We have shown that DNA demethylation caused by the activity of TET oxidases is necessary during the differentiation of RPCs into photoreceptors. Disruption of the TET-dependent DNA demethylation pathway prevents the proper expression of genes necessary for photoreceptor development and function (e.g., Rho, Nr2e3, Prph2, Pde6a, Pde6b, Pde6g, Cplx4, Grk1, Cnga1, Cngb1, Cplx4). The result of this is underdevelopment or complete absence of outer segments and synaptic termini in photoreceptors of TET-deficient retinas, resulting in loss of rod and cone function, as assayed by electroretinogram. The number of photoreceptors decreases in the TET-deficient retinas over time, leading to retinal dystrophy.

Cortical inhibitory parvalbumin interneurons exhibit metabolic specializations coordinated by PGC-1α that are lost in rodents and humans after traumatic brain injury
Parvalbumin-positive interneurons (PV-INs) regulate neuronal and circuit activity, and their dysfunction is observed across neurological conditions, including traumatic brain injury (TBI), epilepsy, Alzheimers disease, and schizophrenia. PV-INs are particularly vulnerable to cell loss, potentially due to their increased metabolic demands arising from their uniquely high level of electrical activity, which render them susceptible to metabolic pressure. Here, we use single-nucleus RNA-sequencing (snRNAseq) data from a rodent model of TBI, as well as human TBI data, and demonstrate PV-INs have unique metabolic specializations that are lost after injury and can be rescued by in vivo treatment with the glycolytic inhibitor, 2-deoxyglucose. We generated a novel PV-IN transcriptional identity module comprised primarily of genes encoding specialized ion channels, metabolic enzymes, and synaptic machinery, that identifies heterogenous subsets of injury-associated PV-INs with loss of PV-IN transcriptional identity. We show that changes in metabolic specialization are coupled to changes in transcriptional identity in PV-INs and implicate the PV-IN-enriched transcriptional co-activator, Ppargc1a, as a key driver of PV-IN transcriptional metabolic dysfunction. We also identify a family of long non-coding RNAs enriched in this subset of transcriptionally dysfunctional PV-INs that negatively correlates with PV-IN metabolic specialization. Lastly, we utilize these tools to interrogate a published human TBI snRNAseq data set and find nearly identical changes, underscoring the importance of PV-IN metabolic dysfunction in the pathology of TBI.

Recovery after human bone marrow mesenchymal stem cells (hBM-MSCs)-derived extracellular vesicles (EVs) treatment in post-MCAO rats requires handling associated with repeated behavioral testing.
Rehabilitation is the only current intervention that improves sensorimotor function in ischemic stroke patients, similar to task-specific intensive training in animal models of stroke. Bone marrow mesenchymal stem cells (BM-MSCs)-derived extracellular vesicles (EVs) are promising in restoring brain damage and function in stroke models. Additionally, the non-invasive intranasal route allows EVs to reach the brain and target specific ischemic regions. Yet unclear is how handling might enhance recovery or influence other therapies such as EVs after stroke. We used the transient middle cerebral artery occlusion (MCAO) model of stroke in rats to assess how intensive handling alone, in the form of sensorimotor behavioral tests, or in combination with an intranasal multidose or single dose of EVs restored neurological function and ischemic damage. Handled rats were exposed to a battery of sensorimotor tests, including the modified Neurological Severity Score (mNSS), beam balance, corner, grid walking, forelimb placement, and cylinder tests, together with Magnetic Resonance Imaging (MRI) at 2, 7, 14, 21, and 28 days post-stroke (dps). Handled MCAO rats were also exposed to an intranasal multidose of EVs (8 doses in total across four weeks, each dose containing 0.8 x 109 EVs in 120 {micro}l) or a single dose of EVs (2.4 x 109 EVs in 200 {micro}l) at 2 dps. Non-handled rats were evaluated only by mNSS and MRI at 2, 28, and 56 dps and were treated with a single intranasal dose of EVs. Our results showed that handling animals after MCAO is necessary for EVs to work and that a single cumulative dose of EVs further improves the neurological function recovered during handling without affecting ischemic damage. These results show the importance of rehabilitation in combination with other treatments and highlight how intensive behavioral testing might influence functional recovery after stroke, especially when other treatments are also given.

Threat-Related Corticocortical Connectivity Elicited by Rapid Auditory Looms
While sounds of approaching objects are generally more salient than those of receding ones, the traditional association of this auditory looming bias with threat perception is subject to debate. Differences between looming and receding sounds may also be learned through non-threatening multisensory information, or influenced by confounding stimulus characteristics. To investigate, we analyzed corticocortical connectivity patterns from electroencephalography, examining the preferential processing of looming sounds under different attentional states. To simulate rapid distance changes we used complementary distance cues, previously studied in the looming bias literature. Notably, despite the absence of conscious threat perception, we observed crucial involvement of frontal cortical regions typically associated with threat and fear responses. Our findings suggest an underlying bias towards the ventral what stream over the dorsal where stream in auditory information processing, even when the participants task was solely focused on the discrimination of movement direction. These results support the idea, that the perceptual bias towards looming sounds reflects an auditory threat detection mechanism, while offering insights into the neural function involved in processing ecologically relevant environmental cues.

Rab27b promotes lysosomal function and alpha-synuclein clearance in neurons
Alpha-synuclein (syn) is the key pathogenic protein implicated in synucleinopathies including Parkinsons Disease (PD) and Dementia with Lewy Bodies (DLB). In these diseases, syn is thought to spread between cells where it accumulates and induces pathology; however, mechanisms that drive its propagation or aggregation are poorly understood. We have previously reported that the small GTPase Rab27b is elevated in human PD and DLB and that it can mediate the autophagic clearance and toxicity of syn in a paracrine syn cell culture neuronal model. Here, we expanded our previous work and further characterized a role for Rab27b in neuronal lysosomal processing and syn clearance. We found that Rab27b KD in this syn inducible neuronal model resulted in lysosomal dysfunction and increased syn levels in lysosomes. Similar lysosomal proteolytic defects and enzymatic dysfunction were observed in both primary neuronal cultures and brain lysates from Rab27b knockout (KO) mice. Syn aggregation was exacerbated in Rab27b KO neurons upon treatment with syn preformed fibrils. We found no changes in lysosomal counts or lysosomal pH in either model, but we did identify defects in acidic vesicle trafficking in Rab27b KO primary neurons which may drive lysosomal dysfunction and promote syn aggregation. Rab27b OE enhanced lysosomal activity and reduced insoluble syn accumulation. Finally we found elevated Rab27b levels in human postmortem incidental Lewy Body Disease (iLBD) subjects relative to healthy controls. These data suggest a role for Rab27b in neuronal lysosomal activity and identify it as a potential therapeutic target in synucleinopathies.

Functional and Structural Cerebellar-Behavior Relationships in Aging
Healthy aging is associated with deficits in cognitive performance and brain changes, including in the cerebellum. Yet, the precise link between cerebellar function/structure and cognition in aging remains poorly understood. We explored this relationship in 138 healthy adults (aged 35-86, 53% female) using resting-state functional connectivity MRI (fcMRI), cerebellar volume, and cognitive and motor assessments in an aging sample. We expected to find negative relationships between lobular volume for with age, and positive relationships between specific lobular volumes with motor and cognition respectively. We predicted lower cerebellar fcMRI to cortical networks and circuits with increased age. Behaviorally, we expected higher cerebello-frontal fcMRI cerebellar connectivity with association areas to correlate with better behavioral performance. Behavioral tasks broadly assessed attention, processing speed, working memory, episodic memory, and motor abilities. Correlations were conducted between cerebellar lobules I-IV, V, Crus I, Crus II, vermis VI and behavioral measures. We found lower volumes with increased age as well as bidirectional cerebellar connectivity relationships with increased age, consistent with literature on functional connectivity and network segregation in aging. Further, we revealed unique associations for both cerebellar structure and connectivity with comprehensive behavioral measures in a healthy aging population. Our findings underscore cerebellar involvement in behavior during aging.

Minimal background noise enhances neural speech tracking: Evidence of stochastic resonance
Neural activity in auditory cortex tracks the amplitude envelope of continuous speech, but recent work counter-intuitively suggests that neural tracking increases when speech is masked by background noise, despite reduced speech intelligibility. Noise-related amplification could indicate that stochastic resonance - the response facilitation through noise - supports neural speech tracking. However, a comprehensive account of the sensitivity of neural tracking to background noise and of the role cognitive investment is lacking. In five electroencephalography (EEG) experiments (N=109; box sexes), the current study demonstrates a generalized enhancement of neural speech tracking due to minimal background noise. Results show that a) neural speech tracking is enhanced for speech masked by background noise at very high SNRs (~30 dB SNR) where speech is highly intelligible; b) this enhancement is independent of attention; c) it generalizes across different stationary background maskers, but is strongest for 12-talker babble; and d) it is present for headphone and free-field listening, suggesting that the neural-tracking enhancement generalizes to real-life listening. The work paints a clear picture that minimal background noise enhances the neural representation of the speech envelope, suggesting that stochastic resonance contributes to neural speech tracking. The work further highlights non-linearities of neural tracking induced by background noise that make its use as a biological marker for speech processing challenging.

Metabolite T2 relaxation times decrease across the adult lifespan in a large multi-site cohort
Purpose: Relaxation correction is crucial for accurately estimating metabolite concentrations measured using in vivo magnetic resonance spectroscopy (MRS). However, the majority of MRS quantification routines assume that relaxation values remain constant across the lifespan, despite prior evidence of T2 changes with aging for multiple of the major metabolites. Here, we comprehensively investigate correlations between T2 and age in a large, multi-site cohort. Methods: We recruited approximately 10 male and 10 female participants from each decade of life: 18-29, 30-39, 40-49, 50-59, and 60+ years old (n=101 total). We collected PRESS data at 8 TEs (30, 50, 74, 101, 135, 179, 241, and 350 ms) from voxels placed in white-matter-rich centrum semiovale (CSO) and gray-matter-rich posterior cingulate cortex (PCC). We quantified metabolite amplitudes using Osprey and fit exponential decay curves to estimate T2. Results: Older age was correlated with shorter T2 for tNAA, tCr3.0, tCr3.9, tCho, Glx, and tissue water in CSO and PCC; rs = -0.21 to -0.65, all p<0.05, FDR-corrected for multiple comparisons. These associations remained statistically significant when controlling for cortical atrophy. T2 values did not differ across the adult lifespan for mI. By region, T2 values were longer in the CSO for tNAA, tCr3.0, tCr3.9, Glx, and tissue water and longer in the PCC for tCho and mI. Conclusion: These findings underscore the importance of considering metabolite T2 changes with aging in MRS quantification. We suggest that future 3T work utilize the equations presented here to estimate age-specific T2 values instead of relying on uniform default values.

Effects of chronodisruption and alcohol consumption on gene expression in reward-related brain areas in female rats.
Circadian dysfunction caused by exposure to aberrant light-dark conditions is associated with abnormal alcohol consumption in humans and animal models. Changes in drinking behavior have been linked to alterations in clock gene expression in reward-related brain areas, which could be attributed to either the effect of chronodisruption or alcohol. To date, however, the combinatory effect of circadian disruption and alcohol on brain functions is less understood. Moreover, despite known sex differences in alcohol drinking behavior, most research has been carried out on male subjects only, and therefore implications for females remain unclear. To address this gap, adult female rats housed under an 11h/11h light-dark cycle (LD22) or standard light conditions (LD24, 12h/ 12h light-dark) were given access to an intermittent alcohol drinking protocol (IA20%) to assess the impact on gene expression in brain areas implicated in alcohol consumption and reward: the prefrontal cortex (PFC), nucleus accumbens (NAc), and dorsal striatum (DS). mRNA expression of core clock genes (Bmal1, Clock, Per2), sex hormone receptors (ER{beta}, PR), glutamate receptors (mGluR5, GluN2B), a calcium-activated channel (Kcnn2), and an inflammatory cytokine (TNF-) were measured at two-time points relative to the locomotor activity cycle. Housing under LD22 did not affect alcohol intake but significantly disrupted circadian activity rhythms and reduced locomotion. Significant changes in the expression of Bmal1, ER{beta}, and TNF- were primarily related to the aberrant light conditions, whereas changes in Per2 and PR expression were associated with the effect of alcohol. Collectively, these results indicate that disruption of circadian rhythms and/or intermittent alcohol exposure have distinct effects on gene expression in the female brain, which may have implications for the regulation of alcohol drinking, addiction, and, ultimately, brain health. Keywords: Clock genes, alcohol, females, gene expression, neuroinflammation.

Loss of TDP-43 induces synaptic dysfunction that is rescued by UNC13A splice-switching ASOs
TDP-43 loss of function induces multiple splicing changes, including a cryptic exon in the amyotrophic lateral sclerosis and fronto-temporal lobar degeneration risk gene UNC13A, leading to nonsense-mediated decay of UNC13A transcripts and loss of protein. UNC13A is an active zone protein with an integral role in coordinating pre-synaptic function. Here, we show TDP-43 depletion induces a severe reduction in synaptic transmission, leading to an asynchronous pattern of network activity. We demonstrate that these deficits are largely driven by a single cryptic exon in UNC13A. Antisense oligonucleotides targeting the UNC13A cryptic exon robustly rescue UNC13A protein levels and restore normal synaptic function, providing a potential new therapeutic approach for ALS and other TDP-43-related disorders.

Glia-enriched stem-cell 3D model of the human brain mimics the glial-immune neurodegenerative phenotypes of multiple sclerosis
The role of central nervous system (CNS) glia in sustaining self-autonomous inflammation and driving clinical progression in multiple sclerosis (MS) is gaining scientific interest. We applied a single transcription factor (SOX10)-based protocol to accelerate oligodendrocyte differentiation from hiPSC-derived neural precursor cells, generating self-organizing forebrain organoids. These organoids include neurons, astrocytes, oligodendroglia, and hiPSC-derived microglia to achieve immunocompetence. Over 8 weeks, organoids reproducibly generated mature CNS cell types, exhibiting single-cell transcriptional profiles similar to the adult human brain. Exposed to inflamed cerebrospinal fluid (CSF) from MS patients, organoids properly mimic macroglia-microglia neurodegenerative phenotypes and intercellular communication seen in chronic active MS. Oligodendrocyte vulnerability emerged by day 6 post-MS-CSF exposure, with nearly 50% reduction. Temporally-resolved organoid data support and expand on the role of soluble CSF mediators in sustaining downstream events leading to oligodendrocyte death and inflammatory neurodegeneration. Such findings support implementing this organoid model for drug screening to halt inflammatory neurodegeneration.

Oxytocin receptor function regulates neural signatures of pair bonding and fidelity in the nucleus accumbens
The formation of enduring relationships dramatically influences future behavior, promoting affiliation between familiar individuals. How such attachments are encoded to elicit and reinforce specific social behaviors in distinct ethological contexts remains unknown. Signaling via the oxytocin receptor (Oxtr) in the nucleus accumbens (NAc) facilitates social reward as well as pair bond formation between mates in socially monogamous prairie voles1-9. How Oxtr function influences activity in the NAc during pair bonding to promote affiliative behavior with partners and rejection of other potential mates has not been determined. Using longitudinal in vivo fiber photometry in wild-type prairie voles and those lacking Oxtr, we demonstrate that Oxtr function sex-specifically regulates pair bonding behaviors and associated activity in the NAc. Oxtr function influences prosocial behavior in females in a state-dependent manner. Females lacking Oxtr demonstrate reduced prosocial behaviors and lower activity in the NAc during initial chemosensory investigation of novel males. Upon pair bonding, affiliative behavior with partners and neural activity in the NAc during these interactions increase, but these changes do not require Oxtr function. Conversely, males lacking Oxtr display increased prosocial investigation of novel females. Using the altered patterns of behavior and activity in the NAc of males lacking Oxtr during their first interactions with a female, we can predict their future preference for a partner or stranger days later. These results demonstrate that Oxtr function sex-specifically influences the early development of pair bonds by modulating prosociality and the neural processing of sensory cues and social interactions with novel individuals, unmasking underlying sex differences in the neural pathways regulating the formation of long-term relationships.

Reward responses to vicarious feeding depend on BMI
Eating is inherently social for humans. Yet, most neuroimaging studies of appetite and food-induced reward have focused on studying brain responses to food intake or viewing pictures of food alone. Here we used functional magnetic resonance imaging (fMRI) to measure haemodynamic responses to "vicarious" feeding. The subjects (n=97) viewed series of short videos representing naturalistic episodes of social eating intermixed with videos without feeding / appetite related content. Viewing the vicarious feeding (versus control) videos activated motor and premotor cortices, thalamus, and dorsolateral prefrontal cortices, consistent with somatomotor and affective engagement. Responses to the feeding videos were also downregulated as a function of the participants BMI. Altogether these results suggest that seeing others eating engages the corresponding motor and affective programs in the viewers brain, potentially increasing appetite and promoting mutual feeding.

Increased recognition memory precision with decreased neural discrimination
Mnemonic discrimination (MD), the ability to distinguish between similar experiences in memory, is essential for memory precision. We hypothesized that training mnemonic discrimination should improve memory precision by increasing the neural activity differences between a new experience and a similar familiar experience (repeat). Participants performed a 2-week, web-based training program. For group 1, memory similarity was adapted to performance. Group 2 trained non-adaptively and group 3 served as active control. Adaptivity improved training gain and led to transfer to other memory tasks. Surprisingly, training reduced neural activity differences between new (lure) and similar familiar (repeat) experiences. Thus, instead of enhancing neural activity to lures and decreasing neural activity to repeats, training led to increased activity to repeats. In several brain regions this pattern was associated with improved MD. These findings highlight an unexpected neural mechanism underpinning improved memory precision in recognition memory.

Perturbing human V1 degrades the fidelity of visual working memory
The main function of working memory is to extend the duration with which information remains available for use by a host of high-level cognitive systems 1. Decades of electrophysiological studies provide compelling evidence that persistent neural activity in prefrontal cortex is a key mechanism for working memory 2. Surprisingly, sophisticated human neuroimaging studies have convincingly demonstrated that the contents of working memory can be decoded from primary visual cortex (V1) 3,4. The necessity of this mnemonic information remains unknown and contentious. Here, we provide causal evidence that transcranial magnetic stimulation to human V1 disrupted the fidelity of visual working memory. Magnetic stimulation during the retention interval of a visuospatial working memory task caused a systematic increase in memory errors. Errors increased only for targets that were remembered in the portion of the visual field disrupted by stimulation, and were invariant to when in the delay stimulation was applied. Moreover, concurrently measured electroencephalography confirmed that stimulation disrupted not only memory behavior, but a standard neurophysiological signature of working memory. These results change the question from whether V1 is necessary for working memory into what mechanisms does V1 use to support memory. Moreover, they point to models in which the mechanisms supporting working memory are distributed across brain regions, including sensory areas that here we show are critical for memory storage.

Postmortem tissue biomarkers of menopausal transition
The menopausal transition (MT) is associated with an increased risk for many disorders including neurological and mental disorders. Brain imaging studies in living humans show changes in brain metabolism and structure that may contribute to the MT-associated brain disease risk. Although deficits in ovarian hormones have been implicated, cellular and molecular studies of the brain undergoing MT are currently lacking, mostly due to a difficulty in studying MT in postmortem human brain. To enable this research, we explored 39 candidate biomarkers for menopausal status in 42 pre-, peri-, and post-menopausal subjects across three postmortem tissues: blood, the hypothalamus, and pituitary gland. We identified thirteen significant and seven strongest menopausal biomarkers across the three tissues. Using these biomarkers, we generated multi-tissue and tissue-specific composite measures that allow the postmortem identification of the menopausal status across different age ranges, including the "perimenopausal", 45-55-year-old group. Our findings enable the study of cellular and molecular mechanisms underlying increased neuropsychiatric risk during the MT, opening the path for hormone status-informed, precision medicine approach in women's mental health.

An Information Processing Pattern from Robotics Predicts Properties of the Human Visual System
We tested the hypothesis that an algorithmic information processing pattern from robotics, Active InterCONnect (AICON), could serve as a useful representation for exploring human vision. We created AICON-based computational models for two visual illusions: the shape-contingent color aftereffect and silencing by motion. The models reproduced the effects seen in humans and generated novel predictions that we validated through human psychophysical experiments. Inconsistencies between model predictions and experimental results were resolved through iterative model adjustments. For the shape-contingent color aftereffect, the model predicted and experiments confirmed weaker aftereffects for outline shape manipulations and individual differences in perceived aftereffects. For silencing by motion, the model predicted and experiments validated unexpected trends as well as individual differences. Our findings demonstrate AICON's ability to capture relevant aspects of human visual information processing including variability across individuals. It highlights the potential for novel collaborations between synthetic and biological disciplines.

Divisive attenuation based on noisy sensorimotor predictions accounts for excess variability in self-touch
When one part of the body exerts force on another, the resulting tactile sensation is perceived as weaker than when the same force is applied by an external agent. This phenomenon has been studied using a force matching task, in which observers are first exposed to an external force on a passive finger and then instructed to reproduce the sensation by directly pressing on the passive finger with a finger of the other hand: healthy participants consistently exceed the original force level. However, this exaggeration of the target force is not observed if the observer generates the matching force indirectly, by adjusting a joystick or slider that controls the force output of a motor. Here we present the first formal computational account of this task, in which sensory signals are attenuated based on motor predictions. The modelling elucidates previously unappreciated contributions of multiple sources of noise, including memory noise, in determining matching force output. We show that the predictive component can be isolated by quantifying attenuation as the discrepancy between direct and indirect self-generated forces, rather than direct versus externally generated forces. Our computational account makes the novel prediction that attenuated sensations will display greater trial-to-trial variability than unattenuated ones, because they incorporate additional noise from motor prediction. Quantitative model fitting of force matching data based on close to 500 participants confirmed the prediction of excess variability in self-generated forces and provided evidence for a divisive rather than subtractive mechanism of attenuation, while highlighting its predictive nature.

Suppression of astrocyte BMP signaling improves fragile X syndrome molecular signatures and functional deficits
Fragile X syndrome (FXS) is a monogenic neurodevelopmental disorder with manifestations spanning molecular, neuroanatomical, and behavioral changes. Astrocytes contribute to FXS pathogenesis and show hundreds of dysregulated genes and proteins; targeting upstream pathways mediating astrocyte changes in FXS could therefore be a point of intervention. To address this, we focused on the bone morphogenetic protein (BMP) pathway, which is upregulated in FXS astrocytes. We generated a conditional KO (cKO) of Smad4 in astrocytes to suppress BMP signaling, and found this lessens audiogenic seizure severity in FXS mice. To ask how this occurs on a molecular level, we performed in vivo transcriptomic and proteomic profiling of cortical astrocytes, finding upregulation of metabolic pathways, and downregulation of secretory machinery and secreted proteins in FXS astrocytes, with these alterations no longer present when BMP signaling is suppressed. Functionally, astrocyte Smad4 cKO restores deficits in inhibitory synapses present in FXS auditory cortex. Thus, astrocytes contribute to FXS molecular and functional phenotypes, and targeting astrocytes can mitigate FXS symptoms.

ER-associated biogenesis of PINK1 preprotein for neuronal mitophagy
A central role in mitochondrial quality control is played by the Parkinson-related mitochondrial kinase PINK1, whose mRNA is transported in neurons by mitochondrial hitch- hiking. Using a live-cell imaging assay for the translation of the PINK1 precursor, we show that local translation of PINK1 requires a concerted interplay between mitochondria and the ER in neurons. For efficient translation, the Pink1 mRNA needs to relocate to ribosomes located near endolysosomes and the ER. The ER membrane-tethered chaperone DNAJB6 then shields the PINK1 precursor on transit to mitochondria following the ER-SURF pathway. Loss of DNAJB6 hence leads to persistence of ER/endolysosome-associated PINK1 precursor stores and failure of mitophagy upon mitochondrial damage.

Altered connectome topology in newborns at risk for cognitive developmental delay: a cross-etiologic study
The human brain connectome is characterized by the duality of highly modular structure and efficient integration, supporting information processing. Newborns with congenital heart disease (CHD), prematurity, or spina bifida aperta (SBA) constitute a population at risk for altered brain development and developmental delay (DD). We hypothesize that, independent of etiology, alterations of connectomic organization reflect neural circuitry impairments in cognitive DD. Our study aim is to address this knowledge gap by using a multi-etiologic neonatal dataset to reveal potential commonalities and distinctions in the structural brain connectome and their associations with DD. We used diffusion tensor imaging (DTI) of 187 newborns (42 controls, 51 with CHD, 51 with prematurity, and 43 with SBA). Structural weighted connectomes were constructed using constrained spherical deconvolution based probabilistic tractography and the Edinburgh Neonatal Atlas. Assessment of brain network topology encompassed the analysis of global graph features, network-based statistics, and low-dimensional representation of global and local graph features. The Cognitive Composite Score of the Bayley Scales of Infant and Toddler Development 3rd edition was used as outcome measure at corrected 2 years for the preterm born individuals and SBA patients, and at 1 year for the healthy controls and CHD.

We revealed differences in the connectomic structure of newborns across the four groups after visualizing the connectomes in a two-dimensional space defined by network integration and segregation. Further, ANCOVA analyses revealed differences in global efficiency (p < 0.0001), modularity (p < 0.0001), mean rich club coefficient (p = 0.017) and small-worldness (p = 0.016) between groups after adjustment for postmenstrual age at scan and gestational age at birth. Moreover, small-worldness was significantly associated with poorer cognitive outcome, specifically in the CHD cohort (r = -0.41, p = 0.005).

Our cross-etiologic study identified divergent structural brain connectome profiles linked to deviations from optimal network integration and segregation in newborns at risk for DD. Small-worldness emerges as a key feature, associating with early cognitive outcomes, especially within the CHD cohort, emphasizing small-worldness crucial role in shaping neurodevelopmental trajectories. Neonatal connectomic alterations associated with DD may serve as a marker identifying newborns at-risk for DD and provide early therapeutic interventions.

Infralimbic projections to the basal forebrain mediate extinction learning
Fear extinction learning and retrieval are critical for decreasing fear responses to a stimulus that no longer poses a threat. While it is known that the infralimbic region (IL) of the medial prefrontal cortex mediates retrieval of an extinction memory through projections to the basolateral amygdala (BLA), the contribution of the IL to extinction learning is not well-understood. Given the strong projection from the IL to the basal forebrain (BF), a center of attentional processing, we investigated whether this pathway participates in extinction, and compared it to the IL-BLA pathway. Using retrograde tracing, we first demonstrate that projections from the IL to the BF originate from superficial (L2/3) and deep cortical layers (L5), and that they are denser than IL projections to the BLA. Next, combining retrograde tracing with labeling of the immediate early gene cFos, we show increased activity of the L5 IL-BF pathway during extinction learning and increased activity of the L2/3 IL-BLA pathway during extinction retrieval. Our in vitro recordings demonstrate that neurons in the IL-BF pathway become more excitable towards the end of extinction learning, but less excitable during extinction retrieval. Finally, using optogenetics we show that inactivation of the IL-BF pathway impairs extinction learning, leaving retrieval intact. We propose that the IL acts as a switchboard operator during extinction, with increased L5 IL-BF communication during learning and increased L2/3 IL-BLA communication during retrieval. Anxiety and stress-related changes in IL physiology could affect one or multiple lines of communication, impairing different aspects of extinction.