Differences In Activity Patterns Research Articles

Investigation of a potential protein biomarker signature that may predict clinical benefit of NT-I7 and pembrolizumab in patients with cold gastrointestinal tumors.

2563 Background: Microsatellite stable colorectal (MSS-CRC) and pancreatic cancer (PDAC) are immunologically cold tumors due to low immunogenicity and lack of genomic diversity. NT-I7, a long-acting IL-7, and pembrolizumab (pembro) show efficacy in these hard-to-treat indications. While a limited set of patients (pts) achieve objective response, frequency and duration of the disease control rate point to a larger subset obtaining clinical benefit. To identify novel predictive biomarkers, we analyzed baseline peripheral and biopsy samples from pts based on treatment duration. Methods: Open-label Phase 2a study in pts with relapsed/refractory checkpoint inhibitor-naïve MSS-CRC and PDAC; NT-I7 1200 µg/kg IM every 6 weeks (Q6W), pembro 200 mg IV Q3W. Subjects were grouped by treatment duration, measured in NT-I7 doses administered before treatment discontinuation for any cause: 1 dose was short (ST), 2-3 doses medium (MT) and ≥4 doses long (LT). Correlative studies included peripheral (proteomics, T cell receptor sequencing [TCRseq], single cell RNA sequencing [scRNAseq]), and biopsy (genomics, transcriptomics, TCRseq). Results: As of 02OCT2023, 53 evaluable pts completed or discontinued treatment; 5 are still on follow up. ST group included 21 pts, MT 22 and LT 10 (including all 5 partial responders). Tumor biopsies were confirmed MSS with low tumor mutational burden (TMB). LT pts had similar age (59.0 [53.0-71.5] vs 66.0 [47.3-73.5]; ST vs LT) and lower baseline tumor burden (81.0 mm vs 58.0 mm; ST vs LT, p = 0.022). Biopsy analysis showed LT pts had, at baseline, upregulated pathways related to immune activity despite confirmed cold tumor status. Baseline scRNAseq in peripheral blood showed that stem-like CD8 T cells (precursors of exhausted [TPEX] and stem-cell memory [TSCM]) had a differential activation pattern in LT pts; those pathways were enriched in memory effector subsets in ST pts. Preserved antigen-specific stemness may be needed for NT-I7 + pembro efficacy. Baseline concentrations of 3 proteins that can be produced by growing tumors were significantly increased in ST pts. Pts were classified based on elevated levels of these potential biomarkers: POSITIVE (≥2 biomarkers; 20 pts) and NEGATIVE (≤1 biomarker; 33 pts). Pts with NEGATIVE signature at baseline had significantly higher overall survival, regardless of ST, MT or LT status (13.2 vs 8.9 months, p = 0.030). Conclusions: Preserved tumor-specific TPEX activity may be required for NT-I7 + pembro activity based on its presence in LT pts, who remained on treatment the longest. According to this analysis, there are 3 potentially predictive protein biomarkers that may help identify a pt subset more likely to experience clinical benefits from the combination treatment of NT-I7 + pembro. Further verification of the predictive nature of this signature in independent cohorts is ongoing. Clinical trial information: NCT04332653 .

Acute ethanol disrupts conditioned inhibition in the male rat.

Alcohol can disrupt conditioned sexual inhibition (CSI) established by first-order conditioning in male rats. CSI can also be induced using second-order conditioning, during which male rats are trained to associate a neutral odor with a nonreceptive female. As a result, when given access to two receptive females (one scented and one unscented) during a copulatory preference test, they display CSI toward the scented female. The present study examined the effect of low-to-moderate doses of alcohol on CSI and brain activation following exposure to alcohol and the olfactory cue alone. Sexually-naïve Long-Evans rats received alternate conditioning sessions with unscented receptive or scented (almond extract) non-receptive females. Following the conditioning phase, males were injected with saline, alcohol 0.5g/kg or 1g/kg, 45min before a copulatory test with two receptive females, with one bearing the olfactory cue. Fos activation was later assessed, following exposure to alcohol and the olfactory cue alone, in several brain regions involved in the expression and regulation of male sexual behavior. While males in the saline group displayed sexual avoidance towards the scented female, those injected with alcohol before the copulatory test, regardless of the dose, copulated indiscriminately with both females. Subsequent exposure to alcohol and the olfactory cue alone induced different Fos expression between groups in several brain regions. Low to moderate doses of alcohol disrupt conditioned sexual inhibition in male rats and induce a differential pattern of neural activation, particularly in regions involved in the expression and regulation of sexual behavior.

C57BL/6J offspring mice reared by a single-mother exhibit, compared to mice reared in a biparental parenting structure, distinct neural activation patterns and heightened ethanol-induced anxiolysis.

Parenting experiences with caregivers play a key role in neurodevelopment. We recently reported that adolescents reared by a single-mother (SM) display an anxiety-prone phenotype and drink more alcohol, compared to peers derived from a biparental (BP) rearing condition. To investigate if SM and BP offspring infant mice exhibit differential sensitivity to ethanol-induced locomotor activity and differential activity patterns in brain areas related to anxiety response. We also analyzed anxiety response and ethanol-induced anxiolysis in SM and BP adolescents. Mice reared in SM or BP conditions were assessed for (a) ethanol-induced locomotor activity at infancy, (b) central expression of Fos-like proteins (likely represented mostly by FosB, a transcription factor that accumulates after chronic stimuli exposure and serves as a molecular marker of neural plasticity) and cathecolaminergic activity, and (c) anxiety-like behavior and ethanol-induced anxiolysis in adolescence. Infant mice were sensitive to the stimulating effects of 2.0g/kg alcohol, regardless parenting structure. SM mice exhibited, relative to BP mice, a significantly greater number of Fos-like positive cells in the central amygdala and basolateral amygdala nuclei. Ethanol treatment, but not parenting condition, induced greater activation of dopaminergic neurons in ventral tegmental area. SM, but not BP, adolescent mice were sensitive to ethanol-induced anxiolysis. These results highlight the complex relationship between parenting experiences and neurodevelopment. The SM parenting may result in greater neural activation patterns in brain areas associated with anxiety response, potentially contributing to increased basal anxiety and alcohol sensitivity.

Differential Cortical and Subcortical Activations during Different Stages of Muscle Control: A Functional Magnetic Resonance Imaging Study.

Movement and muscle control are crucial for the survival of all free-living organisms. This study aimed to explore differential patterns of cortical and subcortical activation across different stages of muscle control using functional magnetic resonance imaging (fMRI). An event-related design was employed. In each trial, participants (n = 10) were instructed to gently press a button with their right index finger, hold it naturally for several seconds, and then relax the finger. Neural activation in these temporally separated stages was analyzed using a General Linear Model. Our findings revealed that a widely distributed cortical network, including the supplementary motor area and insula, was implicated not only in the pressing stage, but also in the relaxation stage, while only parts of the network were involved in the steady holding stage. Moreover, supporting the direct/indirect pathway model of the subcortical basal ganglia, their substructures played distinct roles in different stages of muscle control. The caudate nucleus exhibited greater involvement in muscle contraction, whereas the putamen demonstrated a stronger association with muscle relaxation; both structures were implicated in the pressing stage. Furthermore, the subthalamic nucleus was exclusively engaged during the muscle relaxation stage. We conclude that even the control of simple muscle movements involves intricate automatic higher sensory-motor integration at a neural level, particularly when coordinating relative muscle movements, including both muscle contraction and muscle relaxation; the cortical and subcortical regions assume distinct yet coordinated roles across different stages of muscle control.

Brain morphological changes and functional neuroanatomy related to cognitive and emotional distractors during working memory maintenance in post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is associated with abnormalities in the processing and regulation of emotion as well as cognitive deficits. This study evaluated the differential brain activation patterns associated with cognitive and emotional distractors during working memory (WM) maintenance for human faces between patients with PTSD and healthy controls (HCs) and assessed the relationship between changes in the activation patterns by the opposing effects of distraction types and gray matter volume (GMV). Twenty-two patients with PTSD and twenty-two HCs underwent T1-weighted magnetic resonance imaging (MRI) and event-related functional MRI (fMRI), respectively. Event-related fMRI data were recorded while subjects performed a delayed-response WM task with human face and trauma-related distractors. Compared to the HCs, the patients with PTSD showed significantly reduced GMV of the inferior frontal gyrus (IFG) (p < 0.05, FWE-corrected). For the human face distractor trial, the patients showed significantly decreased activities in the superior frontal gyrus and IFG compared with HCs (p < 0.05, FWE-corrected). The patients showed lower accuracy scores and slower reaction times for the face recognition task with trauma-related distractors compared with HCs as well as significantly increased brain activity in the STG during the trauma-related distractor trial was observed (p < 0.05, FWE-corrected). Such differential brain activation patterns associated with the effects of distraction in PTSD patients may be linked to neural mechanisms associated with impairments in both cognitive control for confusable distractors and the ability to control emotional distraction.

Different Influence Pattern of Conventional and Alternative Sources of Smoking on Adhesion Molecules and Cytokine Secretion in THP-1 Monocytes.

Tobacco is a carcinogen that is closely associated with the occurrence of lung cancer and head and neck squamous cell carcinoma (HNSCC). The consumption of tobacco is also leading to alterations in different immune cell subtypes. However, the impact of different conventional and alternative smoking sources on human monocytes remains elusive. In this study, we investigated the influence of aqueous extracts of different sources of smoking (cigarettes; heated tobacco product IQOS; e-cigarettes with and without nicotine; nicotine pouches) on different monocytic adhesion molecules, chemokine receptors and checkpoint molecule PD-L1 by flow cytometry. Cytokine expression patterns were evaluated using human cytokine arrays and the human monocyte leukemia cell line THP-1 as a model. Data revealed differential effects of the analyzed conventional and alternative smoking devices on monocyte adhesion molecules and cytokine secretion. The examined smoking devices can be assigned to two differential monocyte activation patterns. Monocytes stimulated with aqueous extracts of cigarettes, e-cigarette without nicotine, and heat not burn product IQOS revealed distinct alterations of surface markers and cytokines compared to the monocyte activation pattern in response to aqueous extracts of nicotine, nicotine pouches, and e-cigarette with nicotine. Our data indicate differential immunological consequences of different conventional and alternative smoking sources with and without nicotine. Further comprehensive analysis as well as in vivo investigations on peripheral blood monocyte subsets from smoking individuals using different smoking sources are required to better understand the impact on monocyte characteristics, especially with regard to the development of cancer.

Brain atrophy, reduced cerebral perfusion, arterial stiffening, and wall thickening with aging coincide with stimulus-specific changes in fMRI-BOLD responses.

The aim of this study was to investigate how aging affects blood flow and structure of the brain. It was hypothesized older individuals would have lower gray matter volume (GMV), resting cerebral blood flow (CBF0), and depressed responses to isometabolic and neurometabolic stimuli. In addition, increased carotid-femoral pulse-wave velocity (PWV), carotid intima-media thickness (IMT), and decreased brachial flow-mediated dilation (FMD) would be associated with lower CBF0, cerebrovascular reactivity (CVR), and GMV. Brain scans (magnetic resonance imaging) and cardiovascular examinations were conducted in young (age = 24 ± 3 yr, range = 22-28 yr; n = 13) and old (age = 71 ± 4 yr; range = 67-82 yr, n = 14) participants, and CBF0, CVR [isometabolic % blood oxygen level-dependent (BOLD) in response to a breath hold (BH)], brain activation patterns during a working memory task (neurometabolic %BOLD response to N-back trial), GMV, PWV, IMT, and FMD were measured. CBF0 and to a lesser extent CVRBH were lower in the old group (P ≤ 0.050); however, the increase in the %BOLD response to the memory task was not blunted (P ≥ 0.2867). Age-related differential activation patterns during the working memory task were characterized by disinhibition of the default mode network in the old group (P < 0.0001). Linear regression analyses revealed PWV, and IMT were negatively correlated with CBF0, CVRBH, and GMV across age groups, but within the old group alone only the relationships between PWV-CVRBH and IMT-GMV remained significant (P ≤ 0.0183). These findings suggest the impacts of age on cerebral %BOLD responses are stimulus specific, brain aging involves alterations in cerebrovascular and possibly neurocognitive control, and arterial stiffening and wall thickening may serve a role in cerebrovascular aging.NEW & NOTEWORTHY Cerebral perfusion was lower in old versus young adults. %Blood oxygen level-dependent (BOLD) responses to an isometabolic stimulus and gray matter volume were decreased in old versus young adults and associated with arterial stiffening and wall thickening. The increased %BOLD response to a neurometabolic stimulus appeared unaffected by age; however, the old group displayed disinhibition of the default mode network during the stimulus. Thus, age-related alterations in cerebral %BOLD responses were stimulus specific and related to arterial remodeling.

Age-related similarities and differences in cognitive and neural processing revealed by task-related microstate analysis

We explored neural processing differences associated with aging across four cognitive functions. In addition to ERP analysis, we included task-related microstate analyses, which identified stable states of neural activity across the scalp over time, to explore whole-head neural activation differences. Younger and older adults (YA, OA) completed face perception (N170), word-pair judgment (N400), visual oddball (P3), and flanker (ERN) tasks. Age-related effects differed across tasks. Despite age-related delayed latencies, N170 ERP and microstate analyses indicated no age-related differences in amplitudes or microstates. However, age-related condition differences were found for P3 and N00 amplitudes and scalp topographies: smaller condition differences were found for in OAs as well as broader centroparietal scalp distributions. Age group comparisons for the ERN revealed similar focal frontocentral activation loci, but differential activation patterns. Our findings of differential age effects across tasks are most consistent with the STAC-r framework which proposes that age-related effects differ depending on the resources available and the kinds of processing and cognitive load required of various tasks.

Differential cortical activation patterns: pioneering sub-classification of tinnitus with and without hyperacusis by combining audiometry, gamma oscillations, and hemodynamics.

The ongoing controversies about the neural basis of tinnitus, whether linked with central neural gain or not, may hamper efforts to develop therapies. We asked to what extent measurable audiometric characteristics of tinnitus without (T) or with co-occurrence of hyperacusis (TH) are distinguishable on the level of cortical responses. To accomplish this, electroencephalography (EEG) and concurrent functional near-infrared spectroscopy (fNIRS) were measured while patients performed an attentionally demanding auditory discrimination task using stimuli within the individual tinnitus frequency (fTin) and a reference frequency (fRef). Resting-state-fMRI-based functional connectivity (rs-fMRI-bfc) in ascending auditory nuclei (AAN), the primary auditory cortex (AC-I), and four other regions relevant for directing attention or regulating distress in temporal, parietal, and prefrontal cortex was compiled and compared to EEG and concurrent fNIRS activity in the same brain areas. We observed no group differences in pure-tone audiometry (PTA) between 10 and 16 kHz. However, the PTA threshold around the tinnitus pitch was positively correlated with the self-rated tinnitus loudness and also correlated with distress in T-groups, while TH experienced their tinnitus loudness at minimal loudness levels already with maximal suffering scores. The T-group exhibited prolonged auditory brain stem (ABR) wave I latency and reduced ABR wave V amplitudes (indicating reduced neural synchrony in the brainstem), which were associated with lower rs-fMRI-bfc between AAN and the AC-I, as observed in previous studies. In T-subjects, these features were linked with elevated spontaneous and reduced evoked gamma oscillations and with reduced deoxygenated hemoglobin (deoxy-Hb) concentrations in response to stimulation with lower frequencies in temporal cortex (Brodmann area (BA) 41, 42, 22), implying less synchronous auditory responses during active auditory discrimination of reference frequencies. In contrast, in the TH-group gamma oscillations and hemodynamic responses in temporoparietal regions were reversed during active discrimination of tinnitus frequencies. Our findings suggest that T and TH differ in auditory discrimination and memory-dependent directed attention during active discrimination at either tinnitus or reference frequencies, offering a test paradigm that may allow for more precise sub-classification of tinnitus and future improved treatment approaches.

Integrating mind and body: Investigating differential activation of nodes of the default mode network.

The default mode network (DMN) is a large-scale brain network tightly correlated with self and self-referential processing, activated by intrinsic tasks and deactivated by externally-directed tasks. In this study, we aim to investigate the novel approach of default mode activation during progressive muscle relaxation and examine whether differential activation patterns result from the movement of different body parts. We employed neuroimaging to investigate DMN activity during simple body movements, while performing progressive muscle relaxation. We focused on differentiating the neural response between facial movements and movements of other body parts. Our results show that the movement of different body parts led to deactivation in several DMN nodes, namely the temporal poles, hippocampus, medial prefrontal cortex (mPFC), and posterior cingulate cortex. However, facial movement induced an inverted and selective positive BOLD pattern in some of these areas precisely. Moreover, areas in the temporal poles selective for face movement showed functional connectivity not only with the hippocampus and mPFC but also with the nucleus accumbens. Our findings suggest that both conceptual and embodied self-related processes, including body movements during progressive muscle relaxation, may be mapped onto shared brain networks. This could enhance our understanding of how practices like PMR influence DMN activity and potentially offer insights to inform therapeutic strategies that rely on mindful body movements.

Impacts of repeated social defeat on behavior and the brain in a cichlid fish.

Social defeat is a powerful experience leading to drastic changes in physiology and behavior, many of which are negative. For example, repeated social defeat in vertebrates results in reduced reproductive success, sickness and behavioral abnormalities that threaten individual survival and species persistence. However, little is known about what neural mechanisms are involved in determining whether an individual is resilient or susceptible to repeated social defeat stress. It also remains unknown whether exclusive use of reactive behaviors after repeated social defeat is maintained over time and impacts future behaviors during subsequent contests. We used a resident-intruder experiment in the African cichlid fish Astatotilapia burtoni to investigate the behavior and neural correlates of these two opposing groups. Behavior was quantified by watching fish during defeat trials and used to distinguish resilient and susceptible individuals. Both resilient and susceptible fish started with searching and freezing behaviors, with searching decreasing and freezing increasing after repeated social defeat. After a 4day break period, resilient fish used both searching and freezing behaviors during a social defeat encounter with a new resident, while susceptible fish almost exclusively used freezing behaviors. By quantifying neural activation using pS6 in socially relevant brain regions, we identified differential neural activation patterns associated with resilient and susceptible fish and found nuclei that co-varied and may represent functional networks. These data provide the first evidence of specific conserved brain networks underlying social stress resilience and susceptibility in fishes.

ANGI-05. CDKN2A/B HOMOZYGOUS DELETION IN IDH-MUTANT ASTROCYTOMA ALTERS TUMOR CELL INVASION AND VASCULAR FORMATION

Abstract High-grade gliomas represent the most common type of primary adult malignant brain tumor historically diagnosed and graded from histologic criteria alone. Gliomas harboring isocitrate dehydrogenase (IDH) 1 or 2 mutations are associated with lower grade tumors and portend a favorable prognosis relative to IDH-wildtype glioma. However, molecular profiling has identified additional alterations in lower grade gliomas that confer an aggressive high-grade phenotype and a worse clinical prognosis. Of these, the loss of CDKN2A/B in IDH-mutant astrocytoma is the strongest implicated alteration and is sufficient to define a grade 4 tumor regardless of histologic grade. However, there remain no effective therapies targeted at molecular subgroups in aggressive gliomas to date. Here, we sought to elucidate the biologic pathways and functional outcomes associated with the acquisition of high-grade behavior under loss of CDKN2A/B in IDH-mutant astrocytoma to inform future therapeutic strategies. We analyzed a cohort of patient IDH-mutant astrocytomas with whole exome and RNA sequencing data and found several candidate genes/pathways regulated concurrent with CDKN2A/B loss, including regulators of embryonic development, extracellular matrix organization and regulation of vascular processes. Moreover, we identified 1 tumor that displayed intratumoral heterogeneity of CDKN2A/B expression across biopsies. Using grade 4 IDH-mutant astrocytoma patient-derived (PDX) and established cell-lines harboring CDKN2A/B homozygous deletion, we then stably re-expressed cell cycle regulators p14, p15, and p16 using a Tet-inducible lentiviral system and confirmed their decreased proliferation as compared to parental lines. IDH-mutant cell lines with re-expression of p14, p15 or p16 were characterized by differential transcription factor activation and distinct vascular formation patterns as compared to parental lines. These lines also displayed an increased cell migration and invasive potential and were associated with enhanced integrin signaling through integrin beta-3. Together, our work supports a hypothesis of regional tumor evolution with distinct biologic phenotypes across IDH-mutant gliomas.

Neural correlates of temporal recalibration to delayed auditory feedback of active and passive movements.

When we perform an action, its sensory outcomes usually follow shortly after. This characteristic temporal relationship aids in distinguishing self- from externally generated sensory input. To preserve this ability under dynamically changing environmental conditions, our expectation of the timing between action and outcome must be able to recalibrate, for example, when the outcome is consistently delayed. Until now, it remains unclear whether this process, known as sensorimotor temporal recalibration, can be specifically attributed to recalibration of sensorimotor (action-outcome) predictions, or whether it may be partly due to the recalibration of expectations about the intersensory (e.g., audio-tactile) timing. Therefore, we investigated the behavioral and neural correlates of temporal recalibration and differences in sensorimotor and intersensory contexts. During fMRI, subjects were exposed to delayed or undelayed tones elicited by actively or passively generated button presses. While recalibration of the expected intersensory timing (i.e., between the tactile sensation during the button movement and the tones) can be expected to occur during both active and passive movements, recalibration of sensorimotor predictions should be limited to active movement conditions. Effects of this procedure on auditory temporal perception and the modality-transfer to visual perception were tested in a delay detection task. Across both contexts, we found recalibration to be associated with activations in hippocampus and cerebellum. Context-dependent differences emerged in terms of stronger behavioral recalibration effects in sensorimotor conditions and were captured by differential activation pattern in frontal cortices, cerebellum, and sensory processing regions. These findings highlight the role of the hippocampus in encoding and retrieving newly acquired temporal stimulus associations during temporal recalibration. Furthermore, recalibration-related activations in the cerebellum may reflect the retention of multiple representations of temporal stimulus associations across both contexts. Finally, we showed that sensorimotor predictions modulate recalibration-related processes in frontal, cerebellar, and sensory regions, which potentially account for the perceptual advantage of sensorimotor versus intersensory temporal recalibration.

Interferon-λ Activates a Differential Response in Peripheral Neurons That Is Effective against Alpha Herpesvirus Infections.

Alpha herpesviruses (α-HV) infect host mucosal epithelial cells prior to establishing a life-long latent infection in the peripheral nervous system. The initial spread of viral particles from mucosa to the nervous system and the role of intrinsic immune responses at this barrier is not well understood. Using primary neurons cultured in compartmentalized chambers, prior studies performed on Pseudorabies virus (PRV) have demonstrated that type I and type II interferons (IFNs) induce a local antiviral response in axons via distinct mechanisms leading to a reduction in viral particle transport to the neuronal nucleus. A new class of interferons known as type III IFNs has been shown to play an immediate role against viral infection in mucosal epithelial cells. However, the antiviral effects of type III IFNs within neurons during α-HV infection are largely unknown. In this study, we focused on elucidating the antiviral activity of type III IFN against PRV neuronal infection, and we compared the interferon-stimulated gene (ISGs) induction pattern in neurons to non-neuronal cells. We found that IFN pre-exposure of both primary neurons and fibroblast cells significantly reduces PRV virus yield, albeit by differential STAT activation and ISG induction patterns. Notably, we observed that type III IFNs trigger the expression of a subset of ISGs mainly through STAT1 activation to induce an antiviral state in primary peripheral neurons.

EEG-Correlates of Emotional Memory and Seasonal Symptoms

The aim of this study was to investigate a potential all-year vulnerability of people with seasonal mood fluctuations. We compared behavioral and neurophysiological responses to emotional stimuli in summer between people who report seasonal symptoms in winter and those who do not. EEG was recorded in summer from 119 participants while they memorized 60 emotional pictures, balanced for valence and arousal. The Seasonal Pattern Assessment Questionnaire was used to determine seasonal symptoms. EEG power was analyzed in the alpha and gamma frequency bands and in early (50–150 ms) and late (300–400 ms) time-windows over frontal, temporal, and occipital sites. Positive pictures were more frequently recalled than negative and neutral pictures, and negative pictures were more frequently recalled than neutral pictures (p &lt; 0.001), but memory performance did not interact with seasonality. EEG power was overall higher in participants without elevated levels of seasonal symptoms (p = 0.043). This group difference interacted with emotional valence (p = 0.037), region of interest (p = 0.003), hemispheric differences (p = 0.027), frequency band (0.032), and time-window (0.018). This differential pattern of activation while viewing emotional pictures suggests a difference in emotional processing between the groups. The absence of behavioral effects but presence of differences in EEG activity suggests an all-year-long difference in processing of emotional contents in people who experience seasonal symptoms in winter.

Membrane potential dynamics of excitatory and inhibitory neurons in mouse barrel cortex during active whisker sensing.

Neocortical neurons can increasingly be divided into well-defined classes, but their activity patterns during quantified behavior remain to be fully determined. Here, we obtained membrane potential recordings from various classes of excitatory and inhibitory neurons located across different cortical depths in the primary whisker somatosensory barrel cortex of awake head-restrained mice during quiet wakefulness, free whisking and active touch. Excitatory neurons, especially those located superficially, were hyperpolarized with low action potential firing rates relative to inhibitory neurons. Parvalbumin-expressing inhibitory neurons on average fired at the highest rates, responding strongly and rapidly to whisker touch. Vasoactive intestinal peptide-expressing inhibitory neurons were excited during whisking, but responded to active touch only after a delay. Somatostatin-expressing inhibitory neurons had the smallest membrane potential fluctuations and exhibited hyperpolarising responses at whisking onset for superficial, but not deep, neurons. Interestingly, rapid repetitive whisker touch evoked excitatory responses in somatostatin-expressing inhibitory neurons, but not when the intercontact interval was long. Our analyses suggest that distinct genetically-defined classes of neurons at different subpial depths have differential activity patterns depending upon behavioral state providing a basis for constraining future computational models of neocortical function.

Spatiotemporal evidence uncovers differential neural activity patterns in cognitive and affective conflict control

Studies have shown that there are overlapping neural bases for cognitive and affective conflict control, but whether the neural activity patterns caused by the two types of conflict are similar remains to be explored. The present study utilizes electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI) to temporally and spatially analyze the differences between cognitive and affective conflict control. We employ a semantic conflict task which includes blocks of cognitive and affective judgements primed by conflicting and non-conflicting contexts. The results showed a typical neural conflict effect in the cognitive judgment blocks as reflected by greater amplitudes of P2, N400, and the late positive potential (LPP), as well as greater activation of the left pre-supplementary motor area (pre-SMA) and the right inferior frontal gyrus (IFG) in the conflict condition relative to the non-conflict condition. These patterns did not emerge in the affective judgments, but instead, showed reversed effects of the LPP and in the left SMA. Taken together, these findings suggest that cognitive and affective conflict control result in different neural activity patterns.

Patterns matter: differential effects of stress‐inducing and novelty‐associated locus coeruleus firing on pretangle tau pathophysiology in a rat model

AbstractBackgroundThe brainstem locus coeruleus (LC), the main source of brain norepinephrine (NE), is critically involved in several functions including wakefulness, vigilance, attention, learning and memory. LC functioning is firing pattern‐dependent. Phasic pattern promotes novelty and learning, while high tonic activity associates with stress and anxiety. LC has been identified as a key structure in Alzheimer’s disease (AD) development. Braak and colleagues propose that soluble abnormally phosphorylated tau (pretangle tau) originates in the LC early in life. The spreading of pretangle tau to other neuromodulatory areas and transentorhinal cortex constitutes Braak’s pretangle AD stages. Pretangle stages appear to be universal in human, however, only a portion of us develop AD. The selective vulnerability of individuals for AD is not understood. We hypothesized that differential LC activity patterns, influence the pretangle tau pathophysiology and the development of AD.MethodIn this study, an AAV carrying pseudo‐phosphorylated human tau (AAV9‐DIO‐EGFP‐htauE14) was infused into the LC of 2‐3 month‐old TH‐CRE rats, mimicking the onset of tauopathy during puberty in humans. Another AAV containing ChR2 opsin (AAVdj‐DIO‐ChR2‐mCherry) was co‐infused with htauE14. Chronic light stimulation of the LC of either a 10 Hz phasic pattern or a 25 Hz tonic pattern was carried out for 6 weeks. The performance of ChR2 rats in a battery of behavioral assays was compared with control groups without ChR2 (AAVdj‐DIO‐mCherry), 10 months following the AAV infusion. This was followed by immunohistochemistry and Western blotting comparing different biomarkers.ResultPhasic LC activation improved spatial and olfactory discrimination of the htauE14 rats, while chronic tonic activation increased stress level of the rats and led to anhedonia. Phasic pattern rescued axonal degeneration observed in the control htauE14 rats, showing higher density of LC fibers in the piriform cortex and hippocampal dentate gyrus. Tonic LC activation did not rescue LC fiber degeneration, instead, worsened LC neuronal health indexed by elevated level of active caspase 3. The learning performance was positively correlated with the LC fiber density.ConclusionThese results argue that variations in environmental experiences associated with differing LC activity patterns may account for individual susceptibility to development of AD in humans.

Talking with hands and feet: Selective somatosensory attention and fMRI enable robust and convenient brain-based communication

In brain-based communication, voluntarily modulated brain signals (instead of motor output) are utilized to interact with the outside world. The possibility to circumvent the motor system constitutes an important alternative option for severely paralyzed. Most communication brain-computer interface (BCI) paradigms require intact visual capabilities and impose a high cognitive load, but for some patients, these requirements are not given. In these situations, a better-suited, less cognitively demanding information-encoding approach may exploit auditorily-cued selective somatosensory attention to vibrotactile stimulation. Here, we propose, validate and optimize a novel communication-BCI paradigm using differential fMRI activation patterns evoked by selective somatosensory attention to tactile stimulation of the right hand or left foot. Using cytoarchitectonic probability maps and multi-voxel pattern analysis (MVPA), we show that the locus of selective somatosensory attention can be decoded from fMRI-signal patterns in (especially primary) somatosensory cortex with high accuracy and reliability, with the highest classification accuracy (85.93%) achieved when using Brodmann area 2 (SI-BA2) at a probability level of 0.2. Based on this outcome, we developed and validated a novel somatosensory attention-based yes/no communication procedure and demonstrated its high effectiveness even when using only a limited amount of (MVPA) training data. For the BCI user, the paradigm is straightforward, eye-independent, and requires only limited cognitive functioning. In addition, it is BCI-operator friendly given its objective and expertise-independent procedure. For these reasons, our novel communication paradigm has high potential for clinical applications.

MicroRNA-dependent regulation of gene expression in GABAergic interneurons.

Information processing within neuronal circuits relies on their proper development and a balanced interplay between principal and local inhibitory interneurons within those circuits. Gamma-aminobutyric acid (GABA)ergic inhibitory interneurons are a remarkably heterogeneous population, comprising subclasses based on their morphological, electrophysiological, and molecular features, with differential connectivity and activity patterns. microRNA (miRNA)-dependent post-transcriptional control of gene expression represents an important regulatory mechanism for neuronal development and plasticity. miRNAs are a large group of small non-coding RNAs (21-24 nucleotides) acting as negative regulators of mRNA translation and stability. However, while miRNA-dependent gene regulation in principal neurons has been described heretofore in several studies, an understanding of the role of miRNAs in inhibitory interneurons is only beginning to emerge. Recent research demonstrated that miRNAs are differentially expressed in interneuron subclasses, are vitally important for migration, maturation, and survival of interneurons during embryonic development and are crucial for cognitive function and memory formation. In this review, we discuss recent progress in understanding miRNA-dependent regulation of gene expression in interneuron development and function. We aim to shed light onto mechanisms by which miRNAs in GABAergic interneurons contribute to sculpting neuronal circuits, and how their dysregulation may underlie the emergence of numerous neurodevelopmental and neuropsychiatric disorders.