bioRxiv Subject Collection: Neuroscience's Journal

The bispectral EEG (BSEEG) method quantifies post-operative delirium-like states in young and aged mice after head mount implantation surgery
Delirium, a syndrome characterized by an acute change in attention, awareness, and cognition, is commonly observed in older adults and has multiple potential triggers, including illness, drug, trauma, and surgery. There are few quantitative monitoring methods in clinical settings. We developed the bispectral electroencephalography (BSEEG) method in clinical research that can detect the presence of and quantify the severity of delirium using a novel algorithm. In the pre-clinical model, we reported that the BSEEG method can capture a delirium-like state in mice following LPS administration. However, its application to post-operative delirium (POD) has not yet been validated in animal experiments. Therefore, this study aimed to create a POD model mouse with the BSEEG method by monitoring BSEEG scores after EEG head-mount implantation surgery throughout the recovery phase. We compared the BSEEG scores of C57BL/6J young (2-3 months old) with aged (18-19 months old) mice for quantitative evaluation of the delirium-like state after the surgery. Postoperatively, both groups showed increased BSEEG scores and a loss of regular diurnal changes in BSEEG scores every daytime and night. In young mice, BSEEG scores and regular diurnal changes recovered relatively quickly to baseline by around postoperative day 3. On the other hand, aged mice had prolonged increases in postoperative BSEEG scores and it reached steady state only after around postoperative day 8. This study suggests the BSEEG method can be utilized to quantitatively evaluate POD and also assess the effect of aging on recovery from POD in pre-clinical model.

POMC neurons control fertility through differential signaling of MC4R in Kisspeptin neurons in the female mouse
Inactivating mutations in the melanocortin 4 receptor (MC4R) gene cause monogenic obesity. Interestingly, female patients also display various degrees of reproductive disorders, in line with the subfertile phenotype of MC4RKO female mice. However, the cellular mechanisms by which MC4R regulates reproduction are unknown. Kiss1 neurons directly stimulate gonadotropin-releasing hormone (GnRH) release through two distinct populations; the Kiss1 ARH neurons, controlling GnRH pulses, and the sexually dimorphic Kiss1 AVPV/PeN neurons controlling the preovulatory LH surge driving ovulation. In the present study, we show that Mc4r is expressed within Kiss1 ARH and Kiss1 AVPV/PeN neurons. In vivo, deletion of MC4R from Kiss1 neurons in female mice replicates the reproductive impairments of MC4RKO mice without inducing obesity. Conversely, reinsertion of MC4R in Kiss1 neurons of MC4R null mice restores estrous cyclicity and LH pulsatility without reducing their obese phenotype. In vitro, we show that MC4R activation excites Kiss1 ARH neurons through direct synaptic actions. In contrast, Kiss1 AVPV/PeN neurons are normally inhibited by MC4R activation except under elevated estradiol levels, thus facilitating the activation of Kiss1 AVPV/PeN neurons to induce the preovulatory LH surge driving ovulation in females. Our findings demonstrate that POMC ARH neurons acting through MC4R, directly regulate reproductive function in females by stimulating the pulse generator activity of Kiss1 ARH neurons and restricting the activation of Kiss1 AVPV/PeN neurons to the time of the estradiol-dependent LH surge, and thus unveil a novel pathway of metabolic regulation of fertility.

Differential weighting of information during aloud and silent reading: Evidence from representational similarity analysis of fMRI data
Single word reading depends on multiple types of information processing: readers must process low-level visual properties of the stimulus, form orthographic and phonological representations of the word, and retrieve semantic content from memory. Reading aloud introduces an additional type of processing wherein readers must execute an appropriate sequence of articulatory movements necessary to produce the word. To date, cognitive and neural differences between aloud and silent reading have mainly been ascribed to articulatory processes. However, it remains unclear whether articulatory information is used to discriminate unique words, at the neural level, during aloud reading. Moreover, very little work has investigated how other types of information processing might differ between the two tasks. The current work used representational similarity analysis (RSA) to interrogate fMRI data collected while participants read single words aloud or silently. RSA was implemented using a whole-brain searchlight procedure to characterize correspondence between neural data and each of five models representing a discrete type of information. Compared with reading silently, reading aloud elicited greater decodability of visual, phonological, semantic, and articulatory information. This occurred mainly in prefrontal and parietal areas implicated in speech production and cognitive control. By contrast, silent reading elicited greater decodability of orthographic information in right anterior temporal lobe. These results support an adaptive view of reading whereby information is weighted according to its task relevance, in a manner that best suits the readers goals.

Real-time activity of dynorphin-expressing neurons in mouse central amygdala during alcohol drinking
Alcohol use disorder (AUD) is a prevalent chronic relapsing disease, affecting 30 million people (10.5%) in the United States alone that poses significant economic burden and health risks. Evidence from human and animal studies has identified crucial brain regions that are important for driving binge alcohol (ethanol) drinking and excessive drinking produced by the development of AUD. In preclinical models, the central amygdala (CeA) has emerged as a key mediator of binge alcohol consumption. A dynorphin-expressing subpopulation within the CeA (CeADyn) has been implicated in excessive alcohol drinking across both acute and chronic alcohol exposure models. Yet, how cellular activity of CeADyn neurons is impacted by active alcohol drinking is not well-understood. Thus, it is pivotal to better understand specific brain mechanisms underlying the behavioral and physiological responses to alcohol that promote alcohol misuse. The goal of the current study was to probe the engagement of CeADyn neurons in male and female mice during voluntary alcohol consumption using fiber photometry and to compare alcohol phenotypes with that of water and sucrose. Activity of the Cre-dependent calcium sensor, GCaMP7f, in the CeA of prodynorphin-Cre (Pdyn-Cre) mice was recorded and time-locked to bouts of licking during 2-hr, 20% alcohol drinking. To rigorously analyze this photometry data, multilevel modeling protocols were applied to better understand sex and temporal effects in these complex time series data. Analysis revealed a large increase in CeADyn neuron calcium transients after bouts of licking for alcohol, and only modest increases during licking for water or 0.5% sucrose, indicating these neurons are uniquely engaged during alcohol consumption. Further testing revealed that differences in drinking behavior unique to alcohol (i.e. longer bout durations) do not fully explain signal differences between alcohol and other solutions nor is the alcohol response diminished across the 2-hr drinking session. These findings identified a unique functional signature for alcohol in a cell population that is known to control binge alcohol drinking.

Nerve injury downregulates δ-opioid and cannabinoid CB1 receptor genes through REST in primary sensory neurons
The transcription repressor REST in the dorsal root ganglion (DRG) is upregulated by peripheral nerve injury and promotes the development of chronic pain. However, the genes targeted by REST in neuropathic pain development remain unclear. The expression levels of 4 opioid receptor (Oprm1, Oprd1, Oprl1, Oprk1) and the cannabinoid CB1 receptor (Cnr1) genes in the DRG regulate nociception. In this study, we determined the role of REST in the control of their expression in the DRG induced by spared nerve injury (SNI) in both male and female mice. Transcriptomic analyses of male mouse DRGs showed that SNI upregulated expression of Rest and downregulated mRNA levels of all 4 opioid receptor and Cnr1 genes, but Oprm1 was upregulated in female mice. Analysis of publicly available bioinformatic data suggested that REST binds to the promoter regions of Oprm1 and Cnr1. Chromatin immunoprecipitation analyses indicated differing levels of REST at these promoters in male and female mice. Full-length Rest conditional knockout in primary sensory neurons reduced SNI-induced pain hypersensitivity and rescued the SNI-induced reduction in the expression of Oprd1 and Cnr1 in the DRG in both male and female mice. Our results suggest that nerve injury represses the transcription of Oprd1 and Cnr1 via REST in primary sensory neurons and that REST is a potential therapeutic target for neuropathic pain.

Episodic recruitment of attractor dynamics in frontal cortex reveals distinct mechanisms for forgetting and lack of cognitive control in short-term memory
Short-term memory (STM) is prone to failure, especially during prolonged memory maintenance or under limited cognitive control. Despite predictive mechanistic frameworks based on persistent neural activity and attractor states, a direct assessment of network dynamics during multifactorial STM failure is still missing. We addressed this in a delayed-response task where mice maintained a prospective response during a long variable delay. Mice behavior episodically switched between a task-engaged state described by an attractor model, and a task-disengaged state purely determined by previous choices. During task engagement, the anterolateral motor cortex (ALM) showed delay persistent activity stably encoding correct choices, whereas the encoding reversed during the delay in error trials. In contrast, in task-disengaged phases ALM showed no clear traces of attractor dynamics and instead exhibited enhanced synchrony at ~ 4-5 Hz. Thus, ALM switches between distinct error-generating dynamics: in control-capable trials, transitions between memory attractors cause forgetting errors, whereas non-memory errors are caused by the dissociation of ALM during the mnemonic period reflecting the lack of cognitive control.

Communication with Surprise - Computational and Neural Mechanisms for Non-Verbal Human Interactions
Communication, often grounded in shared expectations, faces challenges without common linguistic backgrounds. Our study explores how people instinctively turn to the fundamental principles of the physical world to overcome communication barriers. Specifically, through the Tacit Communication Game, we investigate how participants develop novel strategies for conveying messages without relying on common linguistic signals. We developed a new computational model built from the principle of expectancy violations of a set of common universal priors derived from movement kinetics. The model closely resembles the Sender's messages, with its core variable - the information-theoretic surprise - explaining the Receiver's physiological and neural responses. This is evidenced by a significant correlation with the pupil diameter, indicating cognitive effort, and neural activity in brain areas related to expectancy violations. This research highlights the adaptability of human communication, showing how surprise can be a powerful tool in forming new communicative strategies without relying on common language.

Polygenic Risk for Alcohol Use Disorder Affects Cellular Responses to Ethanol Exposure in a Human Microglial Cell Model
Polygenic risk scores (PRS) assess genetic susceptibility to Alcohol Use Disorder (AUD), yet their molecular implications remain underexplored. Neuroimmune interactions, particularly in microglia, are recognized as significant contributors to AUD pathophysiology. We investigated the interplay between AUD PRS and ethanol in human microglia derived from iPSCs from individuals with high- or low-PRS (HPRS or LPRS) of AUD. Ethanol exposure induced elevated CD68 expression and morphological changes in microglia, with differential responses between HPRS and LPRS microglial cells. Transcriptomic analysis revealed expression differences in MHCII complex and phagocytosis-related genes following ethanol exposure; HPRS microglial cells displayed enhanced phagocytosis and increased CLEC7A expression, unlike LPRS microglial cells. Synapse numbers in co-cultures of induced neurons with microglia after alcohol exposure were lower in HRPS co-cultures, suggesting possible excess synapse pruning. This study provides insights into the intricate relationship between AUD PRS, ethanol, and microglial function, potentially influencing neuronal functions in developing AUD.

Pathogenic tau induces an adaptive elevation in mRNA translation rate at early stages of disease
Alterations in the rate and accuracy of messenger RNA (mRNA) translation are associated with aging and several neurodegenerative disorders, including Alzheimer disease and related tauopathies. We previously reported that error-containing RNA that are normally cleared via nonsense-mediated mRNA decay (NMD), a key RNA surveillance mechanism, are translated in the adult brain of a Drosophila model of tauopathy. In the current study, we find that newly-synthesized peptides and translation machinery accumulate within nuclear envelope invaginations that occur as a consequence of tau pathology, and that the rate of mRNA translation is globally elevated in early stages of disease in adult brains of Drosophila models of tauopathy. Polysome profiling from adult heads of tau transgenic Drosophila reveals the preferential translation of specific mRNA that have been previously linked to neurodegeneration. Unexpectedly, we find that panneuronal elevation of NMD further elevates the global translation rate in tau transgenic Drosophila, as does treatment with rapamycin. As NMD activation and rapamycin both suppress tau-induced neurodegeneration, their shared effect on translation suggests that elevated rates of mRNA translation are an early adaptive mechanism to limit neurodegeneration. Our work provides compelling evidence that tau-induced deficits in NMD reshape the tau translatome by increasing translation of RNA that are normally repressed in healthy cells.

Prior cocaine use diminishes encoding of latent information by orbitofrontal, but not medial, prefrontal ensembles
Maladaptive decision-making is a hallmark of substance use disorders, though how drugs of abuse alter neural representations supporting adaptive behavior remains poorly understood. Past studies show the orbitofrontal (OFC) and prelimbic (PL) cortices are important for decision making, tracking both task-relevant and latent information. However, previous studies have focused on how drugs of abuse impact the firing rates of individual units. More work at the ensemble level is necessary to accurately characterize potential drug-induced changes. Using single-unit recordings in rats during a multidimensional decision-making task and then applying population and ensemble level analyses, we show that prior use of cocaine altered the strength and structure of task-relevant and latent representations in the OFC, changes relatable to suboptimal decision making in this and perhaps other settings. These data expand our understanding of the neuropathological underpinnings of maladaptive decision-making in SUDs, potentially enabling enhanced future treatment strategies.

Cas9 nickase-mediated contraction of CAG/CTG repeatsat multiple disease loci
Expanded CAG/CTG repeats cause at least 15 different neurodegenerative and neuromuscular diseases that all remain without an effective disease modifying treatment. Because the size of the repeat tract accounts for the majority of the variation in disease severity, contracting them presents an attractive therapeutic avenue. Here, we show that the CRISPR-Cas9 nickase targeting the CAG/CTG repeat itself leads to efficient contractions in Huntington's disease patient-derived neurons and astrocytes, as well as in myotonic dystrophy type 1 patient-derived neurons. Using single-cell DNA sequencing, PCR-free whole genome sequencing, and targeted long-read sequencing of the HTT locus, we found no off-target mutations above background in neurons and astrocytes. Furthermore, we delivered the Cas9 nickase and sgRNA stereotactically to a mouse model of Huntington's disease using adeno-associated viruses, and found contractions accumulating in over half of the infected cells over a period of 5 months. We also found that the Cas9 nickase was prone to silencing, further improving the safety of the approach. Our results provide the proof of concept for using the Cas9 nickase to contract the repeat tract safely in multiple cell types and diseases.

Habit learning shapes activity dynamics in the central nucleus of the amygdala
As animals perform instrumental tasks, they may develop a habit response with extended experience. Habits are automatic, inflexible, outcome value insensitive behaviors that are regulated by a network of brain regions including the central nucleus of the amygdala (CeA). Prior work has demonstrated that the CeA governs motivational pursuit and is necessary for habit formation. However, the behavioral features that CeA neurons encode in habit formation remain relatively unknown. To address this, we first used male and female Long-Evans rats to quantify CeA cFos expression after performance of a maze task. There, we found that animals with extended training show elevated cFos expression. Then, we implanted animals with drivable silicon probes to record in-vivo single unit electrophysiological activity from the CeA as animals developed habit responding on the maze. We observed significant activity during outcome consumption late in training while also observing elevated unit activity when animals consumed outcomes of larger magnitudes. Outcome related activity did not persist during probe tests following outcome devaluation, despite animals continuing to perform the task. Together, these data add to growing evidence that suggests that the CeA is involved in motivational processes that contribute to the development of habit formation.

Incomplete remyelination via endogenous or therapeutically enhanced oligodendrogenesis is sufficient to recover visual cortical function
Myelin loss induces deficits in action potential propagation that result in neural dysfunction and contribute to the pathophysiology of neurodegenerative diseases, injury conditions, and aging. Because remyelination is often incomplete, better understanding endogenous remyelination and developing remyelination therapies that seek to restore neural function are clinical imperatives. Here, we used in vivo two-photon microscopy and electrophysiology to study the dynamics of endogenous and therapeutic-induced cortical remyelination and functional recovery after cuprizone-mediated demyelination in mice. We focused on the visual pathway, which is uniquely positioned to provide insights into structure-function relationships during de/remyelination. We show that endogenous remyelination is driven by recent oligodendrocyte loss and is highly efficacious following mild demyelination, but fails to restore the oligodendrocyte population when high rates of oligodendrocyte loss occur too quickly. Testing a novel thyromimetic compared to clemastine fumarate, we find it better enhances oligodendrocyte gain during remyelination and hastens recovery of neuronal function. Surprisingly, its therapeutic benefit was temporally restricted, and it acted exclusively following moderate to severe demyelination to eliminate endogenous remyelination deficits. However, complete remyelination is unnecessary as partial oligodendrocyte restoration was sufficient to recover visual neuronal function. These findings advance our understanding of remyelination and its impact on functional recovery to inform future therapeutic strategies.

Behavioral fingerprinting of the naked mole-rat uncovers signatures of eusociality and social touch
The East African naked mole-rat (Heterocephalus glaber) lives in large and extremely cooperative subterranean colonies. However, both the biology that drives their social interactions and the behaviors that define their social hierarchy are poorly understood. Here, we study the spontaneous solitary and social behaviors of naked mole-rats using automated animal tracking coupled with unbiased behavior discovery and experimenter-determined behavior quantification. With this approach, we find that reproductive and non-reproductive castes engage in distinct spontaneous behaviors. Further, the relative usage frequencies of a specific animal's spontaneous behavior can be used to estimate its rank in the colony's dominance hierarchy. Strikingly, we discovered that face touch is a prominent form of social interaction-naked mole-rats actively engage in face-to-face contact hundreds of times in a single 10-minute social pairing. We speculate that face-to-face contact might be related to social recognition, as we observe it performed during interactions in which naked mole-rats need to identify each other. Lastly, to demonstrate the specific importance of face-to-face contact, we show that social housing conditions lead to widespread activation of the mechanosensory ion channel Piezo2 in neurons that innervate the face, but not the rest of the body. Together, these findings support the importance of both caste and rank for the organization of spontaneous behavior in naked mole-rats, and they show that face-to-face contact is a prominent social behavior in these animals.

Female mice lacking GluA3 show early onset of hearing loss, synaptopathy, and afferent swellings in ambient sound levels
AMPA-type glutamate receptors (AMPAR) mediate excitatory cochlear transmission. However, the unique roles of AMPAR subunits are unresolved. Lack of subunit GluA3 (Gria3KO) in male mice reduced cochlear output by 8-weeks of age. Since Gria3 is X-linked and considering sex differences in hearing vulnerability, we hypothesized accelerated presbycusis in Gria3KO females. Here, auditory brainstem responses (ABR) were similar in 3-week-old female Gria3WT and Gria3KO mice. However, when raised in ambient sound, ABR thresholds were elevated and wave-1 amplitudes were diminished at 5-weeks and older in Gria3KO. In contrast, these metrics were similar between genotypes when raised in quiet. Paired synapses were similar in number, but lone ribbons and ribbonless synapses were increased in female Gria3KO mice in ambient sound compared to Gria3WT or to either genotype raised in quiet. Synaptic GluA4:GluA2 ratios increased relative to Gria3WT, particularly in ambient sound, suggesting an activity-dependent increase in calcium-permeable AMPARs in Gria3KO. Swollen afferent terminals were observed by 5-weeks only in Gria3KO females reared in ambient sound. We propose that lack of GluA3 induces sex-dependent vulnerability to AMPAR-mediated excitotoxicity.

Fetal brain response to maternal inflammation requires microglia
In utero infection and maternal inflammation can adversely impact fetal brain development. Maternal systemic illness, even in the absence of direct fetal central nervous system infection, is associated with an increased risk of autism and schizophrenia in affected offspring. The cell types mediating the response of the fetal brain to maternal inflammation are largely unknown, hindering the development of therapies to prevent and treat adverse neuropsychiatric outcomes. Here, we show that microglia, the resident phagocytes of the brain, are enriched for expression of receptors for relevant pathogens and cytokines, throughout embryonic development. Using a rodent maternal immune activation (MIA) model in which polyinosinic:polycytidylic acid is injected into pregnant dams, we demonstrate long-lasting transcriptional changes in fetal microglia that persist into postnatal life. We find that MIA induces widespread gene expression changes in neuronal and non-neuronal cells; importantly, these responses are abolished by selective genetic deletion of microglia, indicating that microglia are required for the transcriptional response of other cortical cell types to MIA. These findings demonstrate that microglia play a critical, durable role in fetal response to maternal inflammation, pointing at microglia as a potential therapeutic cell target.

Exposure to bilingual or monolingual maternal speech during pregnancy affects the neurophysiological encoding of speech sounds in neonates differently
Exposure to maternal speech during the prenatal period shapes speech perception and linguistic preferences, allowing neonates to recognize stories heard frequently in utero and demonstrating an enhanced preference for their mother's voice and native language. Yet, with a high prevalence of bilingualism worldwide, it remains an open question whether monolingual or bilingual maternal speech during pregnancy influence differently the fetus' neural mechanisms underlying speech sound encoding. In the present study, the frequency-following response (FFR), an auditory evoked potential that reflects the complex spectrotemporal dynamics of speech sounds, was recorded to a two-vowel /oa/ stimulus in a sample of 131 healthy term neonates within the 1-3 days after birth. Newborns were divided into two groups according to maternal language usage during the last trimester of gestation (monolingual; bilingual). Spectral amplitudes and spectral signal-to-noise ratios (SNR) at the stimulus fundamental (F0) and first formant (F1) frequencies of each vowel were respectively taken as measures of pitch and formant structure neural encoding. Our results reveal that while spectral amplitudes at F0 did not differ between groups, neonates from bilingual mothers exhibited a lower spectral SNR. Additionally, monolingually exposed neonates exhibited a higher spectral amplitude and SNR at F1 frequencies. We interpret our results under the consideration that bilingual maternal speech, as compared to monolingual, is characterized by a greater complexity in the speech sound signal, rendering newborns from bilingual mothers more sensitive to a wider range of speech frequencies without generating a particularly strong response at any of them. Our results contribute to an expanding body of research indicating the influence of prenatal experiences on language acquisition and underscore the necessity of including prenatal language exposure in developmental studies on language acquisition, a variable often overlooked yet capable of influencing research outcomes.

Manipulating syntax without taxing working memory: MEG correlates of syntactic dependencies in a Verb-Second language
The neural basis of syntax is notoriously difficult to study without working memory and lexico-semantic confounds. To tackle these challenges, we presented dependencies in minimal Danish two-word sentences using Rapid Parallel Visual Presentation (RPVP), which eliminated the tem-poral delay between a filler and gap. Our stimuli involved dependencies high and low in the tree as a function of manipulating syntactic frame (declarative, yes/no question) and verb argument struc-ture (unergative, unaccusative, alternating unaccusative). Neural magnetoencephalography signals were increased and behaviour facilitated for sentences compared to list controls, replicating the Sentence Superiority Effect (SSE) of prior RPVP studies. Our left-lateral neural SSE at 231-407ms co-occurred with a right-lateral fronto-medial argument structure effect, while syntactic frame affected neural signals at 500-723ms. Thus hierarchically lower dependencies elicited faster neurophysiological correlates, raising the possibility that RPVP may offer a unique window into the brain's detection of syntax when removing temporally extended parsing decisions.

De Novo Sensorimotor Skill Learning Through Reuse of Movement Components
Recent theories of sensorimotor control propose that complex movements are constructed by combining simpler output-generating neural processes. Composing together reusable elements allows a rich variety of movements to be generated using a limited set of neural representations, but it may also impose limits on how new sensorimotor skills can be learned. If skill learning requires modification of existing compositional units, then other skills using the same components may be harmed when the new one is learned. Alternatively, if new skills simply reuse existing units, the repertoire of available units may impose limits on what skills can be learned. In this study, we used a myoelectric interface to explore whether learning a novel coordinated control task requires modification of the existing repertoire of output-generating components. Over five sessions on five consecutive days, participants learned to trace a series of trajectories using a computer cursor controlled by coordinated activation of two muscles. The timing of the generated cursor trajectory and its shape relative to the target improved for conditions trained with post-trial visual feedback. Improvements in timing transferred to all untrained conditions, but improvements in shape transferred only to untrained conditions requiring the trained order of muscle activation. Notably, all muscle outputs in the final session could already be generated during the first session. These results suggest that participants learned the new task by independently improving the selection and timing of existing output-generating components. This tendency toward reuse may help to protect existing skills from interference during learning of new skills.

Monosynaptically-interconnected Network Module (MNM) Approach for High-Resolution Brain Sub-Network Analysis
We introduce the Monosynaptically-interconnected Network Module (MNM) approach, an innovative method designed for efficiently analyzing the anatomical structure and functional dynamics of specific brain network modules in vivo. Utilizing an Intein-mediated split-Cre system combined with bidirectional adeno-associated viruses, this technique precisely targets and manipulates monosynaptically interconnected modular subnetworks in freely moving animals. We demonstrate its utility through anatomical and functional mapping of a specific MNM encompassing the prefrontal cortex (PFC), basolateral amygdala (BLA), and intermediary hub regions. Specifically, the MNM approach with Cre-reporter mice visualizes detailed network architecture and traces axonal connections among the nodes of the network. Additionally, combining the MNM approach with Cre-dependent Ca2+ indicator and multi-fiber photometry reveals enhanced correlative network activities in social contexts. This versatile technique offers significant potential for advancing our understanding of network functions that underlie complex behaviors, providing a modular network perspective.

Inhibition of Indirect Pathway Activity Causes Abnormal Decision-Making In a Mouse Model of Impulse Control Disorder in Parkinson's Disease
Healthy action selection relies on the coordinated activity of striatal direct and indirect pathway neurons. In Parkinson's disease (PD), in which loss of midbrain dopamine neurons is associated with progressive motor and cognitive deficits, this coordination is disrupted. Dopamine replacement therapy can remediate motor symptoms, but can also cause impulse control disorder (ICD), which is characterized by pathological gambling, hypersexuality, and/or compulsive shopping. The cellular and circuit mechanisms of ICD remain unknown. Here we developed a mouse model of PD/ICD, in which ICD-like behavior was assayed with a delay discounting task. We found that in parkinsonian mice, the dopamine agonist pramipexole drove more pronounced delay discounting, as well as disrupted firing in both direct and indirect pathway neurons. We found that chemogenetic inhibition of indirect pathway neurons in parkinsonian mice drove similar phenotypes. Together, these findings provide a new mouse model and insights into ICD pathophysiology.

Bayesian Workflow for Generative Modeling in Computational Psychiatry
Computational (generative) modelling of behaviour has considerable potential for clinical applications. In order to unlock the potential of generative models, reliable statistical inference is crucial. For this, Bayesian workflow has been suggested which, however, has rarely been applied in Translational Neuromodeling and Computational Psychiatry (TN/CP) so far. Here, we present a worked example of Bayesian workflow in the context of a typical application scenario for TN/CP. This application example uses Hierarchical Gaussian Filter (HGF) models, a family of computational models for hierarchical Bayesian belief updating. When equipped with a suitable response model, HGF models can be fit to behavioural data from cognitive tasks; these data frequently consist of binary responses and are typically univariate. This poses challenges for statistical inference due to the limited information contained in such data. We present a novel set of response models that allow for simultaneous inference from multivariate (here: two) behavioural data types. Using both simulations and empirical data from a speed-incentivised associative reward learning (SPIRL) task, we show that harnessing information from two different data streams (binary responses and continuous response times) improves the accuracy of inference (specifically, identifiability of parameters and models). Moreover, we find a linear relationship between log-transformed response times in the SPIRL task and participants' uncertainty about the outcome. Our analysis illustrates the benefits of Bayesian workflow for a typical use case in TN/CP. We argue that adopting Bayesian workflow for generative modelling helps increase the transparency and robustness of results, which in turn is of fundamental importance for the long-term success of TN/CP.

Breathwork-Induced Psychedelic Experiences Modulate Neural Dynamics
Breathwork is a term for an understudied school of practices that involve the intentional modulation of respiration to induce an altered state of consciousness (ASC). We map here the neural dynamics of mental content during breathwork, using a neurophenomenological approach by combining Temporal Experience Tracing, a quantitative phenomenological methodology that preserves the temporal dynamics of subjective experience, with low-density portable EEG devices for every session. Fourteen novice participants completed a series of up to 28 breathwork sessions - of 20, 40 or 60 minutes - in 28 days, yielding a neurophenomenological dataset of 301 breathwork sessions. Using hypothesis-driven and data-driven approaches, we found that positive psychedelic-like subjective experiences that occurred within the breathwork sessions were associated with increased neural Lempel-Ziv complexity. Further, exploratory analyses showed that the aperiodic exponent of the power spectral density (PSD) - but not oscillatory alpha power - was also associated with these psychedelic-like phenomenological substates. We demonstrate the strength of this neurophenomenological framework, maximising the concurrent data acquisition of brain activity and phenomenological dynamics in multiple experiential dimensions. Non-linear aspects of brain dynamics, like complexity and the aperiodic exponent of the PSD, neurally map both a data-driven complex composite of positive experiences, and hypothesis-driven aspects of psychedelic-like experience states such as high bliss.

What Causes Persistent Neural Activity?
The persistent neural activity at a global scale, either stationary or oscillatory, can be explained by the use of the excitatory inhibitory neural network models. This state of the network is, as can be inferred, crucial for the information processing and the memorizing ability of the brain. Though the goal for persistence to exists is visible; but from where the network achieves its ability to show rich variety of the persistent dynamical states is not clear. The following study investigates the possible reasons for the persistence in neuronal networks and shows that the action of the inhibitory components, among other favorable factors in the network, plays a key role in stabilizing neural activity, once it starts. The results strongly support previous research conducted with simpler or more specialized neural network models, as well as neurophysiological experiments.

Sniffing is initiated by the actions of dopamine on ventral striatum neurons
Sniffing is a motivated behavior displayed by all terrestrial vertebrates on the planet. While sniffing is associated with acquiring and processing odors, sniffing is also intertwined with affective and motivated states. The neuromodulatory systems which influence the display of sniffing are unclear. Here, we report that dopamine release into the ventral striatum, with exception of the nucleus accumbens core, is coupled with bouts of sniffing and that stimulation of dopaminergic terminals in those regions initiates sniffing. The activity of post-synaptic D1 and D2 receptor-expressing neurons in the ventral striatum is also coupled with sniffing and antagonism of ventral striatum D1 and D2 receptors squelches sniffing behavior. Together, these results support a model whereby sniffing is initiated by dopamines actions upon ventral striatum neurons. The nature of sniffing being integral to both olfaction and motivated behaviors implicates this circuit in a wide array of functions.

Enhanced stimulus-induced and stimulus-free gamma in open-eye meditators
Visual stimuli induce "narrowband" gamma oscillations (30-70 Hz) that are linked to attention/binding and attenuate with aging and neurodegeneration. In contrast, meditation increases power in a broad frequency range (>25 Hz). However, the effect of meditation on stimulus-induced gamma is unknown. We recorded EEG from meditators and controls performing open-eye meditation while gamma-inducing stimuli were presented before, during and after meditation. We found that stimulus-induced gamma, like stimulus-free gamma, was stronger in meditators. Interestingly, both gamma signatures co-existed during meditation but were unrelated and prominent in occipital and fronto-temporal regions, respectively. Further, power spectral density (PSD) slope, which becomes shallower with aging, was steeper for meditators. Meditation could boost inhibitory mechanisms leading to stronger gamma and steeper PSDs, potentially providing protection against aging and neurodegeneration.