bioRxiv Subject Collection: Neuroscience's Journal

Canary Mating Season Songs Move Between Order and Disorder
Many complex behaviors involve sequences of basic motor or vocal elements governed by syntactic rules, which facilitate flexible and adaptive actions. Songbirds that crystallize their repertoire of vocal syllables and transitions allow researchers to build probabilistic models of syntax rules, providing insight into underlying neural mechanisms. However, in many complex behaviors, syntax rules change over time, such as during learning or in response to new environmental and social contexts. In this study, we investigated the songs of canaries, a seasonal songbird species. Canaries learn a repertoire of 30-50 syllable types, produce syllables in repeat phrases, and organize these phrases into sequences with long-range syntactic dependencies. Since canaries are known to adapt their repertoire annually, we recorded their songs during the spring mating season and examined the syntactic properties that determine syllable sequencing. Over days and weeks, we observed changes in syllable usage rates, syllable numbers within phrases, phrase positions in songs, and in the long-range dependencies of phrase transitions. Acoustic features of syllables were also found to shift alongside these syntactic changes. Quantifying the variability of these properties revealed that the observed changes were not random. Most birds exhibited a clear trend of moving between order and disorder in their song's syntactic and acoustic features. Interestingly, this trend varied across individuals; some birds increased their stereotypy and decreased variability across days, while others adopted more disordered and variable song structures. These findings establish canaries as a valuable animal model for studying the neural mechanisms underlying syntax rules in complex motor sequences, their plasticity in social and environmental adaptation, and in implementing individual-specific strategies.

Neuronal plasticity at puberty in hypothalamic neurons controlling fertility in female mice
Puberty is a critical transition period to achieve fertility and reproductive capacity in all mammalian species. At puberty, the hypothalamic-pituitary-gonadal (HPG) is activated by neuroendocrine changes in the brain. Central to this are Kiss1 neurons that produce kisspeptin, a neuropeptide which is a potent stimulator of gonadotropin releasing hormone (GnRH) secretion. Kiss1 neurons in the arcuate region of the hypothalamus (Kiss1ARC) increase pulsatile secretion of GnRH at puberty. Other developmental maturational changes in the brain are often accompanied by neuronal plasticity changes but this has not been studied in Kiss1 neurons. Electrophysiological characterisation of Kiss1ARC neurons from female mice shows that these neurons undergo profound intrinsic plasticity at puberty with a critical window between 3 and 4 weeks. Immature Kiss1ARC neurons cannot sustain depolarisation-evoked firing for even 500 ms and instead fire a brief burst of high frequency spikes before falling silent. This would make them unsuitable for the sustained activity that is needed to activate GnRH neurons and trigger LH secretion in the HPG axis. After puberty, sustained firing can be maintained, which endows post-puberty Kiss1ARC neurons with a mature physiological phenotype that is amenable to neuropeptide modulation for generation of burst firing and pulsatile release of kisspeptin. There is a corresponding decrease in the threshold for action potential initiation, a more hyperpolarised post-spike trough and a larger medium after-hyperpolarisation (mAHP). Gene expression analysis showed a significant decrease in Scn2a (Nav1.2 channel), Kcnq2 (Kv7.2 channel) and Lrrc55 (BK channel auxiliary {gamma}3-subunit) expression and an increase in Hcn1 (hyperpolarization activated cyclic nucleotide-gated potassium channel) expression which may contribute to the observed electrophysiological changes. Ovariectomy and {beta}-estradiol replacement defined a window of estrogen-dependent plasticity of action potential firing at puberty, such that post-puberty Kiss1ARC neurons achieve a mature physiological phenotype for activation of the HPG axis.

After-effects of Parieto-occipital Gamma Transcranial Alternating Current Stimulation on Behavioral Performance and Neural Activity in Visuo-spatial Attention Task
Visuo-spatial attention enables selective focus on spatial locations while ignoring irrelevant stimuli which involves both endogenous and exogenous attention. Recent advancements in transcranial alternating current stimulation (tACS) have shown promise in modulating these attentional processes by targeting electrical oscillations in specific brain areas. Despite evidence of the online effects of tACS on the task performance of visuo-spatial attention, whether tACS can produce lasting after-effects on behavioral performance and neural activity during the visuo-spatial attention task remains unknown. This study aims to explore these after-effects on visuo-spatial attention by implementing a single-blind, sham-controlled, between-group experiment design. Twenty young and healthy participants were equally divided into two groups receiving either sham or active gamma tACS at 40 Hz targeted at the right parieto-occipital region. Each participant engaged in a version of the Posner cueing task, conducted with EEG recording before and after the tACS intervention. The results revealed that the active tACS group exhibited significant reductions in reaction time compared to the sham group. These changes were not uniform across different attention types, suggesting specific enhancements in cognitive processing. Additionally, EEG analysis showed that gamma tACS influenced various aspects of neural activity, including event-related potentials to the target, as well as the oscillatory power and long-range temporal correlations of EEG signal during the cue-target interval. The amplitude and latency of N1 and P3 components were modulated by gamma tACS. Notably, there was a decrease in alpha power and an increase in gamma power during the cue-target interval, alongside a decrease in long-range temporal correlations. These findings revealed the after-effect of gamma tACS on modulating the behavioral performance and neural activity in the visuo-spatial attention task, paving the way for future applications in cognitive enhancement and therapeutic interventions.

Early alterations of motor learning and corticostriatal network activity in a Huntington's disease mouse model
Huntington's disease (HD) is a neurodegenerative disorder that presents motor, cognitive and psychiatric symptoms as it progresses. Prior to motor symptoms onset, alterations and dysfunctions in the corticostriatal projections have been described along with cognitive deficits, but the sequence of early defects of brain circuits is largely unknown. There is thus a crucial need to identify early alterations that precede symptoms and that could be used as potential early disease markers. Using an HD knock-In mouse model (HdhCAG140/+) that recapitulates the human genetic alterations and that show a late and progressive appearance of anatomical and behavior deficits, we identified early alterations in the motor learning abilities of young mice, long before any motor coordination defects. In parallel, ex vivo two-photon calcium recordings revealed that young HD mice have altered basal activity patterns in both dorsomedial and dorsolateral parts of the striatum. In addition, while wild-type mice display specific reorganization of the activity upon motor training, network alterations present in the basal state of non-trained mice are not affected by motor training of HD mice. Our results thus identify early behavioral deficits and network alterations that could serve as early markers of the disease.

Alzheimer's disease-associated genotypes differentially influence chronic evoked seizure outcomes and antiseizure medicine activity in aged mice
INTRODUCTION: Alzheimer's disease (AD) patients are at greater risk of focal seizures than similarly aged adults; these seizures, left untreated, may worsen functional decline. Older people with epilepsy generally respond well to antiseizure medications (ASMs). However, whether specific ASMs can differentially control seizures in AD is unknown. The corneal kindled mouse model of acquired chronic secondarily generalized focal seizures allows for precisely timed drug administration studies to quantify the efficacy and tolerability of ASMs in an AD-associated genetic model. We hypothesized that mechanistically distinct ASMs would exert differential anticonvulsant activity and tolerability in aged AD mice (8-15 months) to define whether rational ASM selection may benefit specific AD genotypes. METHODS: Aged male and female PSEN2-N141I versus age-matched non-transgenic control (PSEN2 control) C57Bl/6J mice, and APPswe/PS1dE9 versus transgene negative (APP control) littermates underwent corneal kindling to quantify latency to fully kindled criterion. Dose-related ASM efficacy was then compared in each AD model versus matched control over 1-2 months using ASMs commonly prescribed in older adults with epilepsy: valproic acid, levetiracetam, lamotrigine, phenobarbital, and gabapentin. RESULTS: Sex and AD genotype differentially impacted seizure susceptibility. Male PSEN2-N141I mice required more stimulations to attain kindling criterion (X2=5.521; p<0.05). Male APP/PS1 mice did not differ in kindling rate versus APP control mice, but they did have more severe seizures. There were significant ASM class-specific differences in acute seizure control and dose-related tolerability. APP/PS1 mice were more sensitive than APP controls to valproic acid, levetiracetam, and gabapentin. PSEN2-N141I mice were more sensitive than PSEN2 controls to valproic acid and lamotrigine. DISCUSSION: AD genotypes may differentially impact ASMs activity and tolerability in vivo with advanced biological age. These findings highlight the heterogeneity of seizure risk in AD and suggest that precisely selected ASMs may beneficially control seizures in AD, thus reducing functional decline.

Changes in brain connectivity and neurovascular dynamics during dexmedetomidine-induced loss of consciousness
Understanding the neurophysiological changes that occur during loss and recovery of consciousness is a fundamental aim in neuroscience and has marked clinical relevance. Here, we utilize multimodal magnetic resonance neuroimaging to investigate changes in regional network connectivity and neurovascular dynamics as the brain transitions from wakefulness to dexmedetomidine-induced unconsciousness, and finally into early-stage recovery of consciousness. We observed widespread decreases in functional connectivity strength across the whole brain, and targeted increases in structure-function coupling (SFC) across select networks -- especially the cerebellum -- as individuals transitioned from wakefulness to hypnosis. We also observed robust decreases in cerebral blood flow (CBF) across the whole brain -- especially within the brainstem, thalamus, and cerebellum. Moreover, hypnosis was characterized by significant increases in the amplitude of low-frequency fluctuations (ALFF) of the resting-state blood oxygen level-dependent signal, localized within visual and somatomotor regions. Critically, when transitioning from hypnosis to the early stages of recovery, functional connectivity strength and SFC -- but not CBF -- started reverting towards their awake levels, even before behavioral arousal. By further testing for a relationship between connectivity and neurovascular alterations, we observed that during wakefulness, brain regions with higher ALFF displayed lower functional connectivity with the rest of the brain. During hypnosis, brain regions with higher ALFF displayed weaker coupling between structural and functional connectivity. Correspondingly, brain regions with stronger functional connectivity strength during wakefulness showed greater reductions in CBF with the onset of hypnosis. Earlier recovery of consciousness was associated with higher baseline (awake) levels of functional connectivity strength, CBF, and ALFF, as well as female sex. Across our findings, we also highlight the role of the cerebellum as a recurrent marker of connectivity and neurovascular changes between states of consciousness. Collectively, these results demonstrate that induction of, and emergence from dexmedetomidine-induced unconsciousness are characterized by widespread changes in connectivity and neurovascular dynamics.

The brain's "dark energy" puzzle upgraded: FDG uptake, delivery and phosphorylation, and their coupling with resting-state brain activity
The brain's resting-state energy consumption is expected to be mainly driven by spontaneous activity. In our previous work, we extracted a wide range of features from resting-state fMRI (rs-fMRI), and used them to predict [18F]FDG PET SUVR as a proxy of glucose metabolism. Here, we expanded upon our previous effort by estimating [18F]FDG kinetic parameters according to Sokoloff's model, i.e., Ki (irreversible uptake rate), K1 (delivery), k3 (phosphorylation), in a large healthy control group. The parameters' spatial distribution was described at a high spatial resolution. We showed that while K1 is the least redundant, there are relevant differences between Ki and k3 (occipital cortices, cerebellum and thalamus). Using multilevel modeling, we investigated how much of the regional variability of [18F]FDG parameters could be explained by a combination of rs-fMRI variables only, or with the addition of cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO2), estimated from 15O PET data. We found that combining rs-fMRI and CMRO2 led to satisfactory prediction of individual Ki variance (45%). Although more difficult to describe, Ki and k3 were both most sensitive to local rs-fMRI variables, while K1 was sensitive to CMRO2. This work represents the most comprehensive assessment to date of the complex functional and metabolic underpinnings of brain glucose consumption.

Complex slow waves radically reorganise human brain dynamics under 5-MeO-DMT
5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a psychedelic drug known for its uniquely profound effects on subjective experience, reliably eradicating the perception of time, space, and the self. However, little is known about how this drug alters large-scale brain activity. We collected naturalistic electroencephalography (EEG) data of 29 healthy individuals before and after inhaling a high dose (12mg) of vaporised synthetic 5-MeO-DMT. We replicate work from rodents showing amplified low-frequency oscillations, but extend these findings with novel tools for characterising the organisation and dynamics of complex low-frequency spatiotemporal fields of neural activity. We find that 5-MeO-DMT radically reorganises low-frequency flows of neural activity, causing them to become incoherent, heterogeneous, viscous, fleeting, nonrecurring, and to cease their typical travelling forwards and backwards across the cortex compared to resting state. Further, we find a consequence of this reorganisation in broadband activity, which exhibits slower, more stable, low-dimensional behaviour, with increased energy barriers to rapid global shifts. These findings provide the first detailed empirical account of how 5-MeO-DMT sculpts human brain dynamics, revealing a novel set of cortical slow wave behaviours, with significant implications for extant neuroscientific models of serotonergic psychedelics.

Continuous lesion images drive more accurate predictions of outcomes after stroke than binary lesion images
Current medicine cannot confidently predict who will recover from post-stroke impairments. Researchers have sought to bridge this gap by treating the post-stroke prognostic problem as a machine learning problem. Consistent with the observation that these impairments are caused by the brain damage that stroke survivors suffer, information concerning where and how much lesion damage they have suffered conveys useful prognostic information for these models. Much recent research has considered how best to encode this lesion information, to maximise its prognostic value. Here, we consider an encoding that, while not novel, has never before been formally examined in this context: 'continuous lesion images', which encode continuous evidence for the presence of a lesion, both within and beyond what might otherwise be considered the boundary of a binary lesion image. Current state of the art models employ information derived from binary lesion images. Here, we show that those models are significantly improved (i.e., with smaller Mean Squared Error between predicted and empirical outcome scores) when using continuous lesion images to predict a wide range of cognitive and language outcomes from a very large sample of stroke patients. We use further model comparisons to locate the predictive advantage to the provision of continuous lesion evidence beyond the boundary of binary lesion images. The continuous lesion images thus provide a straightforward way to incorporate details of both lesioned and non-lesioned tissue when predicting outcomes after stroke.

Local cytokine changes in response to mesenchymal stem cell-derived extracellular vesicles-based therapy in rat spinal cord injury
Aim: To investigate the effects of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), encapsulated in a fibrin matrix (FM), on pro-inflammatory and anti-inflammatory cytokine levels in a rat model of spinal cord injury (SCI) 60 days post-injury. Methods: MSCs were isolated from rat adipose tissue and cultured to obtain MSC-EVs using cytochalasin B. MSC-EVs encapsulated in the FM were applied to the injury site at doses of 5 and 10 ug. Four experimental groups included SCI without treatment, SCI with FM application, and SCI with FM+EVs at 5 and 10 ug doses. A multiplex assay was conducted to measure 23 cytokines in spinal cord tissue homogenates. Results: FM application to the injury site exhibited both pro- and anti-inflammatory cytokine shifts, with the most pronounced effect for G-CSF (2.8-fold) potentially due to the hemostatic properties of the FM. MSC-EVs led to significant modulation of cytokine levels. In the SCI FM+EVs10 group, concentrations of IL-10, IL-1b, IL-5, and IL-17A were significantly lower compared to the SCI and SCI FM groups. Here the most pronounced change was observed for IL-10, which decreased by 2.4-fold. Conclusion: Combined treatment with MSC-EVs and FM significantly influenced pro- and anti-inflammatory cytokine levels, demonstrating a dose-dependent effect. These findings highlight the potential of EVs to modulate inflammatory responses and promote regeneration in the chronic phase of spinal cord injury.

Neuropeptide-dependent spike time precision and plasticity in circadian output neurons
Circadian rhythms influence various physiological and behavioral processes such as sleep-wake cycles, hormone secretion, and metabolism. Circadian output neurons are a group of neurons that receive input from the central circadian clock located in the suprachiasmatic nucleus of the mammalian brain and transmit timing information to different regions of the brain and body, coordinating the circadian rhythms of various physiological processes. In Drosophila, an important set of circadian output neurons are called pars intercerebralis (PI) neurons, which receive input from specific clock neurons called DN1. These neurons can further be subdivided into functionally and anatomically distinctive anterior (DN1a) and posterior (DN1p) clusters. The neuropeptide diuretic hormones 31 (Dh31) and 44 (Dh44) are the insect neuropeptides known to activate PI neurons to control activity rhythms. However, the neurophysiological basis of how Dh31 and Dh44 affect circadian clock neural coding mechanisms underlying sleep in Drosophila is not well understood. Here, we identify Dh31/Dh44-dependent spike time precision and plasticity in PI neurons. We find that the application of synthesized Dh31 and Dh44 affects membrane potential dynamics of PI neurons in the precise timing of the neuronal firing through their synergistic interaction, possibly mediated by calcium-activated potassium channel conductance. Further, we characterize that Dh31/Dh44 enhances postsynaptic potentials in PI neurons. Together, these results suggest multiplexed neuropeptide-dependent spike time precision and plasticity as circadian clock neural coding mechanisms underlying sleep in Drosophila.

Reconcile sensory attenuation and enhancement: The temporal dynamics of self-generated sensory feedback
Self-generated touches are often perceived as weaker than externally generated ones, a phenomenon known as sensory attenuation. However, recent studies have challenged this view by providing evidences that actions could also enhance predicted touch. To investigate this paradox, we examined the temporal dynamics of perceptual processing using steady-state somatosensory evoked potentials (SSSEP) and sliding time window analysis. Results showed that SSSEP in the very early window was smaller in the no-delay and active conditions compared to the delayed and passive condition, respectively, consistent with sensory attenuation. However, this attenuation soon disappeared and reversed in the later windows and onward, indicating an early attenuation followed by a later enhancement. This study resolves the paradox of sensory attenuation and enhancement in self-generated sensory signals by demonstrating that these processes occur at different phases of sensory processing. The findings reveal a sophisticated dynamic balance in sensory processing, facilitating optimal interaction with the environment.

Separate timescales for spatial and anatomical information processing during action observation
Abstract Introduction: Observing actions primes us to perform similar movements. Prior work indicates this effect is influenced by factors such as spatial congruence, perspective, and presenting biological/non-biological stimuli. We hypothesized that the influence of these factors would vary depending on the amount of time that participants had to process visual stimuli. Method: Experiment 1 was a reaction time task (n=29) with stimuli varying in spatial congruence (congruent, incongruent, neutral), perspective (first- or third-person) and stimulus type (biological or non-biological). Experiment 2 (n=50) used the same stimuli in a Forced Response paradigm, which controlled the time participants had to prepare a response. This allowed us to assess responses as a function of preparation time. Results: Experiment 1 showed effects of spatial congruence, with longer reaction times and more errors for spatially incongruent stimuli. This effect was greater for biological stimuli. Experiment 2 showed that spatial information was processed faster than anatomical information, inducing incorrect responses at short preparation times for spatially incongruent biological stimuli. There was little-to-no corresponding effect for non-biological stimuli. Both experiments also showed weak-to-no effects of perspective, which appear to have been driven by spatial congruence. Discussion: Our results indicate that spatial information is processed faster than anatomical information during action observation. These data are consistent with the dual visual streams hypothesis, whereby spatial information would be processed rapidly via the dorsal stream, while anatomical processing would occur later via the ventral stream. These data also indicate differences in processing between biological and non-biological stimuli.

Multiple context discrimination in adult rats: sex variability and dynamics of time-dependent generalization of an aversive memory
Memory generalization can be defined as the transference of a conditioned fear response to novel contexts. It can be attained rapidly, by manipulating distinct hormonal and neurotransmitter systems, but, more importantly, in a time-dependent manner the interval between training and test sessions affects the quality of retrieved memory, due to a rearrangement in the recruitment of brain regions, as is the case in Systems Consolidation. However, less is known about how female and male subjects retrieve contextual memories over time. In this work, we aimed to investigate how rats of both sexes discriminate among multiple contexts gradually differentiated in similarity to the conditioning one, two days after training. In the pilot study, despite not obtaining, at first, a stepwise series of freezing responses, we found that, strangely, males displayed their higher levels of freezing to the least similar context, while females systematically displayed lower freezing levels compared to males as if they were better discriminators when tested in exact same contexts. With a second set of contexts, sorted according to other criteria, only males, at the 2 days interval, attained a staircase-like response to the successive contexts, while females displayed a completely different freezing pattern; in remote tests, 28 and 45 days later, freezings grouped into two levels, suggesting a partial time-dependent generalization for some of the contexts. Females and males, in discriminating between multiple, dissimilar aversive contexts, seem to deal with threat signals in distinct ways, through different sensory modalities, a clear demonstration of behavioural dimorphism.

Investigating Mechanically Activated Currents from Trigeminal Neurons of Non-Human Primates
Introduction: Pain sensation has predominantly mechanical modalities in many pain conditions. Mechanically activated (MA) ion channels on sensory neurons underly responsiveness to mechanical stimuli. The study aimed to address gaps in knowledge regarding MA current properties in higher order species such as non-human primates (NHP; common marmosets), and characterization of MA currents in trigeminal (TG) neuronal subtypes. Methods: We employed patch clamp electrophysiology and immunohistochemistry (IHC) to associate MA current types to different marmoset TG neuronal groups. TG neurons were grouped according to presumed marker expression, action potential (AP) width, characteristic AP features, after-hyperpolarization parameters, presence/absence of AP trains and transient outward currents, and responses to mechanical stimuli. Results: Marmoset TG were clustered into 5 C-fiber and 5 A-fiber neuronal groups. The C1 group likely represent non-peptidergic C-nociceptors, the C2-C4 groups resembles peptidergic C-nociceptors, while the C5 group could be either cold-nociceptors or C-low-threshold-mechanoreceptors (C-LTMR). Among C-fiber neurons only C4 were mechanically responsive. The A1 and A2 groups are likely A-nociceptors, while the A3-A5 groups probably denote different subtypes of A-low-threshold-mechanoreceptors (A-LTMRs). Among A-fiber neurons only A1 was mechanically unresponsive. IHC data was correlated with electrophysiology results and estimates that NHP TG has ~25% peptidergic C-nociceptors, ~20% non-peptidergic C-nociceptors, ~30% A-nociceptors, ~5% C-LTMR, and ~20% A-LTMR. Conclusion: Overall, marmoset TG neuronal subtypes and their associated MA currents have common and unique properties compared to previously reported data. Findings from this study could be the basis for investigation on MA current sensitizations and mechanical hypersensitivity during head and neck pain conditions.

Regional deficits in endogenous regeneration of mouse olfactory sensory neuron axons
Postnatal neurogenesis occurs in only a few regions of the mammalian nervous system. Hence, neurons that are lost due to neurodegenerative disease, stroke, traumatic brain injury or peripheral neuropathy cannot be replaced. Transplantation of stem cell-derived neurons provides a potential replacement strategy, but how these neurons can be encouraged to functionally integrate into circuits remains a significant challenge. In the mammalian olfactory epithelium (OE), olfactory sensory neurons (OSNs) continue to be generated throughout life from basal stem cells and can be repopulated even after complete ablation. However, the specialized population of navigator OSNs that ensures accurate odorant receptor-specific targeting of OSN axons to glomeruli in the olfactory bulb (OB) is only present perinatally. Despite this, some studies have reported complete regeneration of specific glomeruli, while others have found various degrees of recovery, following OSN cell death. Variability in the extent of both initial OSN ablation and subsequent repopulation of the OE, and the focus on anatomical recovery, leave the extent to which newly generated OSNs can reinnervate the OB unclear. Here, we employed the olfactotoxic drug methimazole to selectively ablate OSNs without damaging the basal stem cells that generate them, enabling us to assess the extent of functional recovery of OSN input to the OB in the context of complete OSN repopulation. We found profound deficits in the recovery of odor-evoked responses in OSN axons in the glomerular layer of the dorsal OB five weeks after OSN ablation, a time point at which OSNs are known to have repopulated the OE. Histological analysis of mature OSN axons in the OB at 10 and 20 weeks post-methimazole showed a persistent region-specific deficit in OSN axon reinnervation of the dorsal OB, with the dorsomedial region being particularly adversely affected. In contrast, reinnervation of the ventral, lateral and medial regions of the OB was almost complete by 10 weeks post-MMZ. Hence, we have identified a region-specific deficit in OSN reinnervation of the mouse OB, which sets the stage to identify the mechanisms that mediate successful vs. unsuccessful axonal regeneration in an endogenous population of stem cell-derived neurons.

Presynaptic filopodia form kinapses and modulate membrane mechanics for synchronous neurotransmission and seizure generation.
The structural stability of synapses directly contrasts with their functional plasticity. This conceptual dichotomy is explained by the assumption that all synaptic plasticity is generated via either electrical and/or biochemical signaling. Here, we challenge this dogma by revealing an activity-dependent presynaptic response that is physical in nature. We show that dynamic filopodia emerge during action potential discharge and transiently deform synaptic boutons to enhance connectivity. Filopodia generation requires neuronal activity, calcium and actin, and occurs in intact brain circuits and human brain. Mechanistically, their extension preserves synchronous neurotransmitter release by increasing presynaptic membrane tension. However, filopodia generation becomes maladaptive during dysregulated brain activity, exacerbating seizures in vivo. Therefore, we provide direct evidence that presynaptic mechanical forces determine the extent and timing of synaptic signals.

Ketamine reverses chronic stress-induced behavioral changes via the expression of Ca2+-permeable AMPA receptors in mice
Chronic stress affects brain functions leading to the development of mental disorders like anxiety and depression, as well as cognitive decline and social dysfunction. Among many biological changes in chronically stressed brains, disruptions in AMPA Receptor (AMPAR)-mediated synaptic transmission in the hippocampus are associated with stress responses. We have revealed that low-dose ketamine rapidly induces the expression of GluA1-containing, GluA2-lacking Ca2+-Permeable AMPARs (CP-AMPARs), which enhances glutamatergic synaptic strength in hippocampal neurons. Additionally, subanesthetic low-dose ketamine decreases anxiety- and depression-like behaviors in naive animals. In addition to reducing depression, some research indicates that ketamine may have protective effects against chronic stress in both humans and animals. However, the role of CP-AMPARs in the actions of ketamines antistress effects is largely unknown. Here, we use whole-cell patch-clamp recordings from CA1 pyramidal neurons in female and male hippocampal slices to affirm that subanesthetic low-dose ketamine treatment induces CP-AMPAR expression in these cells. Using multiple behavioral assays including reciprocal social interaction, contextual fear conditioning, and tail suspension test, we demonstrate that low-dose ketamine treatment reverses chronic restraint stress (CRS)-induced social dysfunction, hippocampus-dependent fear memory loss, and depression-like behavior in both female and male mice. Furthermore, we show that the ketamine-induced antistress effects on these behaviors are dependent on CP-AMPAR expression. From this, our findings suggest that subanesthetic low-dose ketamine rapidly triggers the expression of CP-AMPARs in the hippocampus, which in turn enhances synaptic strength to induce antidepressant and antistress effects.

Significant StatementThe subanesthetic low-dose ketamine-induced increase of glutamatergic synaptic strength is presumed to underlie antidepressant effects in humans and animals. Importantly, we have revealed that low-dose ketamine rapidly induces the expression of GluA1-containing, GluA2-lacking Ca2+-Permeable AMPARs (CP-AMPARs), important for ketamine antidepressant effects in naive animals. However, the role of CP-AMPARs in the actions of ketamines effects is largely unknown. The current study shows that subanesthetic low-dose ketamine can reverse depression-like behavior, fear memory loss, and social dysfunction caused by chronic restraint stress (CRS) in mice via CP-AMPAR expression. The significance of the current research is predicated on identifying the CP-AMPAR-mediated mechanisms of ketamines effects, which may guide the development of safer fast-acting therapy.

Suppressive interactions between nearby stimuli in visual cortex reflect crowding
Crowding is a phenomenon in which visual object identification is impaired by the close proximity of other stimuli. The neural processes leading to object recognition and its breakdown as seen in crowding are still debated. To assess how crowding affects the processing of stimuli in the visual cortex, we recorded steady-state visual evoked potentials (SSVEPs) elicited by flickering target and flanker stimuli while manipulating the spacing of these stimuli (Experiment 1) as well as target similarity (Experiment 2). Participants performed an orientation discrimination task while accuracy and speed of behavioural responses, along with frequency-tagged SSVEPs elicited by target and flanker stimuli, were recorded. Decreasing target-flanker distance reduced both behavioural performance and target-elicited SSVEP amplitudes. Estimates of the critical spacing, a measure of the spatial extent of crowding, from both behavioural data and SSVEP amplitudes were similar. Additionally, manipulating target similarity affected both measures in the same way. These findings establish a clear connection between the suppression of stimulus processing by nearby flankers in the visual cortex and crowding, and demonstrate the usefulness of SSVEPs in studying the cortical mechanisms of visual crowding.

Neural correlates differ between crystallized and fluid intelligence in adolescents
Fluid and crystallized intelligence are acknowledged as distinct facets of cognitive ability during brain development, but the specific neural substrates and molecular mechanisms underlying them remain unclear. This study used a sample comprising 7471 young adolescents (mean age 9.87 {+/-} 0.62 years) from the ABCD cohort to elucidate the differential neural correlates of fluid and crystallized intelligence. Our findings indicated that micro-level brain MRI phenotypes such as water diffusivity were closely associated with fluid intelligence, whereas macro-level brain MRI phenotypes such as gray matter cortical thickness were indicative of crystallized intelligence. We further investigated the molecular mechanisms underlying fluid and crystallized intelligence by correlating the characteristic MRI markers with spatial transcriptome profiles and PET imaging. Results showed that fluid intelligence had significant associations with serotonin and glutamate system, while crystallized intelligence was related to serotonin, dopamine and acetylcholine system. Furthermore, we examined the impacts of lifestyle factors on these two forms of intelligence and how the molecular pathways mediated these impacts. Our investigation suggested that physical activities, screen use and sleep duration influenced fluid intelligence mainly through mGlu5 receptors and crystallized intelligence through 5HT1a and D2 receptors. In conclusion, these findings illustrated a distinct neural basis between fluid and crystallized intelligence from the perspectives of neuroimaging, neurotransmitters, and lifestyles in young adolescents.

Blunted anterior midcingulate response to reward in opioid users is normalized by prefrontal transcranial magnetic stimulation
IntroductionAbnormalities in goal-directed behavior, mediated by mesocorticolimbic reward function and structure, contribute to worse clinical outcomes including higher risk of treatment dropout and drug relapse in opioid users (OU).

Material and MethodIn a sham-controlled randomized study design, we measured whether robot-assisted 10Hz transcranial magnetic stimulation (TMS) applied to the prefrontal cortex was able to modulate anterior midcingulate cortex (MCC) electrophysiological response to rewards, in OU and matched healthy controls.

ResultsWe show that OU exhibit a blunted anterior MCC reward response, compared to healthy controls (t(39) = 2.62, p = 0.01, d = 0.84), and that this is normalized following 10-Hz excitatory TMS (t(36) = .82, p = 0.42, d = 0.17).

ConclusionsExcitatory TMS modulated the putative reward function of the MCC in OU. Further work with increased sample sizes and TMS sessions is required to determine whether restoring MCC reward function increases reward-directed behaviors, which may enhance treatment success through the maintenance of treatment goals.

Contrastive functional connectivity defines neurophysiology-informed symptom dimensions in major depression
BackgroundMajor depressive disorder (MDD) is a prevalent psychiatric disorder characterized by substantial clinical and neurobiological heterogeneity. Conventional studies that solely focus on clinical symptoms or neuroimaging metrics often fail to capture the intricate relationship between these modalities, limiting their ability to disentangle the complexity in MDD. Moreover, patient neuroimaging data typically contains normal sources of variance shared with healthy controls, which can obscure disorder-specific variance and complicate the delineation of disease heterogeneity.

MethodsWe employed contrastive principal component analysis to extract disorder-specific variations in fMRI-based resting-state functional connectivity (RSFC) by contrasting MDD patients (N=233) with age-matched healthy controls (N=285). We then applied sparse canonical correlation analysis to identify latent dimensions in the disorder variations by linking the extracted contrastive connectivity features to clinical symptoms in MDD patients.

ResultsTwo significant and generalizable dimensions linking distinct brain circuits and clinical profiles were discovered. The first dimension, associated with an apparent "internalizing-externalizing" symptom dimension, was characterized by self-connections within the visual network and also associated with choice reaction times of cognitive tasks. The second dimension, associated with personality facets such as extraversion and conscientiousness typically inversely associated with depression symptoms, is primarily driven by self-connections within the dorsal attention network. This "depression-protective personality" dimension is also associated with multiple cognitive task performances related to psychomotor slowing and cognitive control.

ConclusionsOur contrastive RSFC-based dimensional approach offers a new avenue to dissect clinical heterogeneity underlying MDD. By identifying two stable, neurophysiology-informed symptom dimensions in MDD patients, our findings may enhance disease mechanism insights and facilitate precision phenotyping, thus advancing the development of targeted therapeutics for precision mental health.

Trial RegistrationEstablishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC), NCT#01407094

Hippocampal ripples during offline periods predict human motor sequence learning
High-frequency bursts in the hippocampus, known as ripples (80-120 Hz in humans), have been shown to support episodic memory processes. However, converging recent evidence in rodent models as well as human neuroimaging suggests that the hippocampus may be involved in a wider range of memory domains, including motor sequence learning (MSL). Nevertheless, no direct link between hippocampal ripples and MSL has yet been established. Here, we recorded intracranial electroencephalography from the hippocampus in 20 epilepsy patients during a MSL task in which participants showed steady improvement across nine 30-second training blocks interspersed with 30-second rest ( offline) periods. We first demonstrate that ripple rates strongly increase during rest periods relative to training blocks. Importantly, ripple rates during rest periods tracked learning behaviour, both across blocks and across participants. These results suggest that hippocampal ripples during offline periods play a functional role in motor sequence learning and that the hippocampus may be involved in offline learning beyond episodic memory.