Mesoscale simulations predict the role of synergistic cerebellar plasticity during classical eyeblink conditioning.

According to the motor learning theory by Albus and Ito, synaptic depression at the parallel fibre to Purkinje cells synapse (pf-PC) is the main substrate responsible for learning sensorimotor contingencies under climbing fibre control. However, recent experimental evidence challenges this relatively monopolistic view of cerebellar learning. Bidirectional plasticity appears crucial for learning, in which different microzones can undergo opposite changes of synaptic strength (e.g. downbound microzones-more likely depression, upbound microzones-more likely potentiation), and multiple forms of plasticity have been identified, distributed over different cerebellar circuit synapses. Here, we have simulated classical eyeblink conditioning (CEBC) using an advanced spiking cerebellar model embedding downbound and upbound modules that are subject to multiple plasticity rules. Simulations indicate that synaptic plasticity regulates the cascade of precise spiking patterns spreading throughout the cerebellar cortex and cerebellar nuclei. CEBC was supported by plasticity at the pf-PC synapses as well as at the synapses of the molecular layer interneurons (MLIs), but only the combined switch-off of both sites of plasticity compromised learning significantly. By differentially engaging climbing fibre information and related forms of synaptic plasticity, both microzones contributed to generate a well-timed conditioned response, but it was the downbound module that played the major role in this process. The outcomes of our simulations closely align with the behavioural and electrophysiological phenotypes of mutant mice suffering from cell-specific mutations that affect processing of their PC and/or MLI synapses. Our data highlight that a synergy of bidirectional plasticity rules distributed across the cerebellum can facilitate finetuning of adaptive associative behaviours at a high spatiotemporal resolution.

Cardiorespiratory rhythm-contingent trace eyeblink conditioning in elderly adults.

Learning outcome is modified by the degree to which the subject responds and pays attention to specific stimuli. Our recent research suggests that presenting stimuli in contingency with a specific phase of the cardiorespiratory rhythm might expedite learning. Specifically, expiration-diastole (EXP-DIA) is beneficial for learning trace eyeblink conditioning (TEBC) compared with inspiration-systole (INS-SYS) in healthy young adults. The aim of this study was to investigate whether the same holds true in healthy elderly adults (n = 50, aged >70 yr). Participants were instructed to watch a silent nature film while TEBC trials were presented at either INS-SYS or EXP-DIA (separate groups). Learned responses were determined as eyeblinks occurring after the tone conditioned stimulus (CS), immediately preceding the air puff unconditioned stimulus (US). Participants were classified as learners if they made at least five conditioned responses (CRs). Brain responses to the stimuli were measured by electroencephalogram (EEG). Memory for the film and awareness of the CS-US contingency were evaluated with a questionnaire. As a result, participants showed robust brain responses to the CS, acquired CRs, and reported awareness of the CS-US relationship to a variable degree. There was no difference between the INS-SYS and EXP-DIA groups in any of the above. However, when only participants who learned were considered, those trained at EXP-DIA (n = 11) made more CRs than those trained at INS-SYS (n = 13). Thus, learned performance could be facilitated in those elderly who learned. However, training at a specific phase of cardiorespiratory rhythm did not increase the proportion of participants who learned.NEW & NOTEWORTHY We trained healthy elderly individuals in trace eyeblink conditioning, either at inspiration-systole or at expiration-diastole. Those who learned exhibited more conditioned responses when trained at expiration-diastole rather than inspiration-systole. However, there was no difference between the experimental groups in the proportion of individuals who learned or did not learn.

Evaluation of mechanomyogram efficacy as a tool for assessing paired-pulse inhibition of blink reflex early R1 component.

INTRODUCTION/AIMS: Paired-pulse stimulation provides clinically useful information regarding sensory inhibition. When supraorbital nerve stimulation is repeated within a short interval, the response to the second stimulation is reduced to varying degrees. This magnitude of change in stimulation response can be monitored by electromyogram (EMG) or by mechanomyogram (MMG) as in this report. MMG has some advantages such as being less time consuming and lacking stimulus artifact. We compared the use of MMG and EMG to validate MMG as an effective method of assessing blink reflex paired-pulse inhibition. METHODS: Eight volunteers participated. Participants received electrical stimulation to the supraorbital nerve of each side. A paired-pulse paradigm was employed, varying the conditioning-test interval between 5 and 800 ms. The R1 component of the induced blink reflex was simultaneously recorded by EMG using a pair of electrodes placed on the lower eyelid and by MMG using an accelerometer placed between the electrodes. RESULTS: The correlation coefficient of the R1 amplitude between MMG and EMG of the grand-averaged waveforms was 0.99. The average participant r value was .91 (range .76-.99). Similar analyses were performed for the amplitude variation of the second response relative to the first response. Results correlated well, yielding r values of .97 and .86 for the grand-averaged waveform and the average for each subject. DISCUSSION: The present results demonstrate that MMG could be an alternative to EMG in assessing paired-pulse inhibition of the electrical blink reflex R1 component.

A measure of the blink reflex to parametric variation of mechanical stimulation of the trigeminal nerve.

The primary goal of this study was to develop a parametric model that relates variation in stimulation of the trigeminal nerve to properties of the blink response. We measured blink responses in 17 healthy, adult participants to air puffs directed at the lateral canthus of the eye at five different, log-spaced intensities (3.5-60 PSI). Lid position over time was decomposed into amplitude and velocity components. We found that blink amplitude was systematically related to log stimulus intensity, with the relationship well described by a sigmoidal function. The parameters of the model fit correspond to the slope of the function and the stimulus intensity required to produce half of a maximal blink response (the half-response threshold). There was a reliable increase in the half-response threshold for the contralateral as compared to the ipsilateral blink response. This increase was consistent across participants despite substantial individual differences in the half-response threshold and slope parameters of the overall sensitivity function, suggesting that the laterality effect arises in the neural circuit subsequent to individual differences in sensitivity. Overall, we find that graded mechanical stimulation of the somatosensory trigeminal afferents elicits a graded response that is well described by a simple parametric model. We discuss the application of parametric measurements of the blink response to the detection of group differences in trigeminal sensitivity.

Altered pupil light and darkness reflex and eye-blink responses in late-life depression.

BACKGROUND: Late-life depression (LLD) is a prevalent neuropsychiatric disorder in the older population. While LLD exhibits high mortality rates, depressive symptoms in older adults are often masked by physical health conditions. In younger adults, depression is associated with deficits in pupil light reflex and eye blink rate, suggesting the potential use of these responses as biomarkers for LLD. METHODS: We conducted a study using video-based eye-tracking to investigate pupil and blink responses in LLD patients (n = 25), older (OLD) healthy controls (n = 29), and younger (YOUNG) healthy controls (n = 25). The aim was to determine whether there were alterations in pupil and blink responses in LLD compared to both OLD and YOUNG groups. RESULTS: LLD patients displayed significantly higher blink rates and dampened pupil constriction responses compared to OLD and YOUNG controls. While tonic pupil size in YOUNG differed from that of OLD, LLD patients did not exhibit a significant difference compared to OLD and YOUNG controls. GDS-15 scores in older adults correlated with light and darkness reflex response variability and blink rates. PHQ-15 scores showed a correlation with blink rates, while MoCA scores correlated with tonic pupil sizes. CONCLUSIONS: The findings demonstrate that LLD patients display altered pupil and blink behavior compared to OLD and YOUNG controls. These altered responses correlated differently with the severity of depressive, somatic, and cognitive symptoms, indicating their potential as objective biomarkers for LLD.

Ocular effects of exposure to low-humidity environment with contact lens wear: A pilot study.

PURPOSE: To compare the ocular effects of exposure to a low-humidity environment with and without contact lens (CL) wear using various non-invasive tests. METHODS: Fourteen habitual soft CL wearers were exposed to controlled low humidity (5% relative humidity [RH]) in an environmental chamber for 90 min on two separate occasions. First, when wearing their habitual spectacles and then, on a separate visit, when wearing silicone hydrogel CLs that were fitted specifically for this purpose. All participants had adapted to the new CL prior to data collection. Three non-invasive objective measurements were taken at each visit: blinking rate, objective ocular scatter (measured using the objective scatter index) and ocular surface cooling rate (measured using a long-wave infrared thermal camera). At each visit, measurements were taken before the exposure in comfortable environmental conditions (RH: 45%), and after exposure to environmental stress (low humidity, RH: 5%). RESULTS: CL wearers showed increased blinking rate (p < 0.005) and ocular scatter (p = 0.03) but similar cooling rate of the ocular surface (p = 0.08) when compared with spectacle wear in comfortable environmental conditions. The exposure to low humidity increased the blinking rate significantly with both types of corrections (p = 0.01). Interestingly, ocular scatter (p = 0.96) and cooling rate (p = 0.73) were not significantly different before and after exposure to low humidity. There were no significant two-way interactions between correction and exposure in any of the measurements. CONCLUSIONS: CLs significantly increased the blinking rate, which prevented a quick degradation of the tear film integrity as it was refreshed more regularly. It is hypothesised that the increased blinking rate in CL wearers aids in maintaining ocular scatter quality and cooling rate when exposed to a low-humidity environment. These results highlight the importance of blinking in maintaining tear film stability.

End-of-day assessment of asymptomatic versus highly symptomatic soft contact lens wearers.

PURPOSE: To investigate differences in key clinical parameters between asymptomatic and highly symptomatic soft contact lens (CL) wearers after 14 h of wear. METHODS: In this pilot investigation, Phase 1 identified asymptomatic (CLDEQ-8 score ≤ 7) and highly symptomatic (CLDEQ-8 score ≥ 20) subjects after fitting with nelfilcon A CLs. Phase 2 investigated the following over a single nelfilcon A CL-wearing day (14 ± 2 h): blinking characteristics, tear meniscus height (TMH), non-invasive tear break-up time (NIBUT), tear film osmolarity and eyelid margin staining. Parameters for the two groups were compared using linear mixed models and post-hoc testing. The relationship between comfort scores and the clinical parameters was also investigated. RESULTS: Overall, 161 and 42 subjects were enrolled into Phase 1 and 2, respectively. Twenty-five asymptomatic and 17 symptomatic subjects completed Phase 2. Lower eyelid TMH was decreased after 14 h in symptomatic compared with asymptomatic subjects (least square mean [LSM] difference -0.04 mm, 95% CI: -0.07, -0.01). Osmolarity was lower in symptomatic than in asymptomatic subjects at fitting (LSM difference -9.89, 95% CI: -18.91, -0.86). Upper eyelid margin staining was greater after 14 h in symptomatic than in asymptomatic subjects (LSM difference 0.53, 95% CI: 0.01, 1.05) and greater after 14 h than baseline in the symptomatic group (LSM difference 0.61, 95% CI: 0.16, 1.07). There was a significant relationship between comfort and upper eyelid margin staining (r = -0.40, 95% CI: -0.63, -0.11) and blink rate (r = -0.31, 95% CI: -0.57, -0.003). CONCLUSION: The potential parameters most effective in differentiating asymptomatic from symptomatic wearers were upper eyelid margin staining and lower TMH. The parameter with the strongest relationship to comfort was upper eyelid margin staining, where higher comfort scores were associated with lower levels of staining.

Blink Lagophthalmos in Graves Orbitopathy.

PURPOSE: To investigate the relationship between the kinematics of spontaneous blinks and the anterior area of the levator palpebrae superioris muscle in patients with Graves orbitopathy (GO). METHODS: This is a case-control study. The authors measured the margin reflex distance of the upper eyelid (margin reflex distance 1), the kinematics of spontaneous blinks, and the anterior area of levator palpebrae superioris muscle in CT coronal scans of patients with Graves upper eyelid retraction (GO) and a control group. The eye with the greatest margin reflex distance 1 was selected for analysis in each group. RESULTS: A total of 68 participants were included, with 36 in the GO group and 32 in the control group. In the GO group, the mean margin reflex distance 1 measured 6.5 mm, while in the control group, it was 3.9 mm. Almost all parameters related to the closing phase of spontaneous blinking activity, including amplitude, velocity, blinking rate, and interblink time, did not differ between the two groups. However, the effectiveness of the blink's amplitude (ratio of blink amplitude to margin reflex distance 1) and the main sequence (relationship between amplitude and velocity) were significantly reduced in the GO group compared with the control group. The area of the levator palpebrae superioris muscle was significantly larger in GO than in controls, with 71.4% of patients' muscles outside of the maximum range of the controls. CONCLUSIONS: In patients with GO, there is a reduction in blinking effectiveness, also known as blink lagophthalmos, which is a factor in the common occurrence of ocular surface symptoms. The increase in velocity with amplitude is also reduced in GO.

What is a blink? Classifying and characterizing blinks in eye openness signals.

Blinks, the closing and opening of the eyelids, are used in a wide array of fields where human function and behavior are studied. In data from video-based eye trackers, blink rate and duration are often estimated from the pupil-size signal. However, blinks and their parameters can be estimated only indirectly from this signal, since it does not explicitly contain information about the eyelid position. We ask whether blinks detected from an eye openness signal that estimates the distance between the eyelids (EO blinks) are comparable to blinks detected with a traditional algorithm using the pupil-size signal (PS blinks) and how robust blink detection is when data quality is low. In terms of rate, there was an almost-perfect overlap between EO and PS blink (F1 score: 0.98) when the head was in the center of the eye tracker's tracking range where data quality was high and a high overlap (F1 score 0.94) when the head was at the edge of the tracking range where data quality was worse. When there was a difference in blink rate between EO and PS blinks, it was mainly due to data loss in the pupil-size signal. Blink durations were about 60 ms longer in EO blinks compared to PS blinks. Moreover, the dynamics of EO blinks was similar to results from previous literature. We conclude that the eye openness signal together with our proposed blink detection algorithm provides an advantageous method to detect and describe blinks in greater detail.

Maturation of Temporal Saccade Prediction from Childhood to Adulthood: Predictive Saccades, Reduced Pupil Size, and Blink Synchronization.

When presented with a periodic stimulus, humans spontaneously adjust their movements from reacting to predicting the timing of its arrival, but little is known about how this sensorimotor adaptation changes across development. To investigate this, we analyzed saccade behavior in 114 healthy humans (ages 6-24 years) performing the visual metronome task, who were instructed to move their eyes in time with a visual target that alternated between two known locations at a fixed rate, and we compared their behavior to performance in a random task, where target onsets were randomized across five interstimulus intervals (ISIs) and thus the timing of appearance was unknown. Saccades initiated before registration of the visual target, thus in anticipation of its appearance, were labeled predictive [saccade reaction time (SRT) < 90 ms] and saccades that were made in reaction to its appearance were labeled reactive (SRT > 90 ms). Eye-tracking behavior including saccadic metrics (e.g., peak velocity, amplitude), pupil size following saccade to target, and blink behavior all varied as a function of predicting or reacting to periodic targets. Compared with reactive saccades, predictive saccades had a lower peak velocity, a hypometric amplitude, smaller pupil size, and a reduced probability of blink occurrence before target appearance. The percentage of predictive and reactive saccades changed inversely from ages 8-16, at which they reached adult-levels of behavior. Differences in predictive saccades for fast and slow target rates are interpreted by differential maturation of cerebellar-thalamic-striatal pathways.SIGNIFICANCE STATEMENT From the first moments of life, humans are exposed to rhythm (i.e., mother's heartbeat in utero), but the timeline of brain development to promote the identification and anticipation of a rhythmic stimulus, known as temporal prediction, remains unknown. Here, we used saccade reaction time (SRT) in the visual metronome task to differentiate between temporally predictive and reactive responses to a target that alternated at a fixed rate in humans aged 6-24. Periods of age-related change varied little by target rate, with matured predictive performance evident by mid-adolescence for fast and slow rates. A strong correlation among saccade, pupil, and blink responses during target prediction provides evidence of oculomotor coordination and dampened noradrenergic neuronal activity when generating rhythmic motor responses.

Cerebellar plasticity and associative memories are controlled by perineuronal nets.

Perineuronal nets (PNNs) are assemblies of extracellular matrix molecules, which surround the cell body and dendrites of many types of neuron and regulate neural plasticity. PNNs are prominently expressed around neurons of the deep cerebellar nuclei (DCN), but their role in adult cerebellar plasticity and behavior is far from clear. Here we show that PNNs in the mouse DCN are diminished during eyeblink conditioning (EBC), a form of associative motor learning that depends on DCN plasticity. When memories are fully acquired, PNNs are restored. Enzymatic digestion of PNNs in the DCN improves EBC learning, but intact PNNs are necessary for memory retention. At the structural level, PNN removal induces significant synaptic rearrangements in vivo, resulting in increased inhibition of DCN baseline activity in awake behaving mice. Together, these results demonstrate that PNNs are critical players in the regulation of cerebellar circuitry and function.

The Claustrum is Involved in Cognitive Processes Related to the Classical Conditioning of Eyelid Responses in Behaving Rabbits.

It is assumed that the claustrum (CL) is involved in sensorimotor integration and cognitive processes. We recorded the firing activity of identified CL neurons during classical eyeblink conditioning in rabbits, using a delay paradigm in which a tone was presented as conditioned stimulus (CS), followed by a corneal air puff as unconditioned stimulus (US). Neurons were identified by their activation from motor (MC), cingulate (CC), and medial prefrontal (mPFC) cortices. CL neurons were rarely activated by single stimuli of any modality. In contrast, their firing was significantly modulated during the first sessions of paired CS/US presentations, but not in well-trained animals. Neuron firing rates did not correlate with the kinematics of conditioned responses (CRs). CL local field potentials (LFPs) changed their spectral power across learning and presented well-differentiated CL-mPFC/CL-MC network dynamics, as shown by crossfrequency spectral measurements. CL electrical stimulation did not evoke eyelid responses, even in trained animals. Silencing of synaptic transmission of CL neurons by the vINSIST method delayed the acquisition of CRs but did not affect their presentation rate. The CL plays an important role in the acquisition of associative learning, mostly in relation to the novelty of CS/US association, but not in the expression of CRs.

Blink- and saccade-related suppression effects in early visual areas of the human brain: Intracranial EEG investigations during natural viewing conditions.

Blinks and saccades, both ubiquitous in natural viewing conditions, cause rapid changes of visual inputs that are hardly consciously perceived. The neural dynamics in early visual areas of the human brain underlying this remarkable visual stability are still incompletely understood. We used electrocorticography (ECoG) from electrodes directly implanted on the human early visual areas V1, V2, V3d/v, V4d/v and the fusiform gyrus to investigate blink- and saccade-related neuronal suppression effects during non-experimental, free viewing conditions. We found a characteristic, biphasic, broadband gamma power decrease-increase pattern in all investigated visual areas. During saccades, a decrease in gamma power clearly preceded eye movement onset, at least in V1. This may indicate that cortical information processing is actively suppressed in human early visual areas before and during saccades, which then possibly mediates perceptual visual suppression. The following eye movement offset-related increase in gamma power may indicate the recovery of visual perception and the resumption of visual processing.

MEGnet: Automatic ICA-based artifact removal for MEG using spatiotemporal convolutional neural networks.

Magnetoencephalography (MEG) is a functional neuroimaging tool that records the magnetic fields induced by neuronal activity; however, signal from non-neuronal sources can corrupt the data. Eye-blinks, saccades, and cardiac activity are three of the most common sources of non-neuronal artifacts. They can be measured by affixing eye proximal electrodes, as in electrooculography (EOG), and chest electrodes, as in electrocardiography (ECG), however this complicates imaging setup, decreases patient comfort, and can induce further artifacts from movement. This work proposes an EOG- and ECG-free approach to identify eye-blinks, saccades, and cardiac activity signals for automated artifact suppression. The contribution of this work is three-fold. First, using a data driven, multivariate decomposition approach based on Independent Component Analysis (ICA), a highly accurate artifact classifier is constructed as an amalgam of deep 1-D and 2-D Convolutional Neural Networks (CNNs) to automate the identification and removal of ubiquitous whole brain artifacts including eye-blink, saccade, and cardiac artifacts. The specific architecture of this network is optimized through an unbiased, computer-based hyperparameter random search. Second, visualization methods are applied to the learned abstraction to reveal what features the model uses and to bolster user confidence in the model's training and potential for generalization. Finally, the model is trained and tested on both resting-state and task MEG data from 217 subjects, and achieves a new state-of-the-art in artifact detection accuracy of 98.95% including 96.74% sensitivity and 99.34% specificity on the held out test-set. This work automates MEG processing for both clinical and research use, adapts to the acquired acquisition time, and can obviate the need for EOG or ECG electrodes for artifact detection.

Disruption of rat deep cerebellar perineuronal net alters eyeblink conditioning and neuronal electrophysiology.

The perineuronal net (PNN) is a specialized type of extracellular matrix found in the central nervous system. The PNN forms on fast spiking neurons during postnatal development but the ontogeny of PNN development has yet to be elucidated. By studying the development and prevalence of the PNN in the juvenile and adult rat brain, we may be able to understand the PNN's role in development and learning and memory. We show that the PNN is fully developed in the deep cerebellar nuclei (DCN) of rats by P18. By using enzymatic digestion of the PNN with chondroitinase ABC (ChABC), we are able to study how digestion of the PNN affects cerebellar-dependent eyeblink conditioning in vivo and perform electrophysiological recordings from DCN neurons in vitro. In vivo degradation of the PNN resulted in significant differences in eyeblink conditioning amplitude and area. Female animals in the vehicle group demonstrated higher levels of conditioning as well as significantly higher post-probe conditioned responses compared to males in that group, differences not present in the ChABC group. In vitro, we found that DCN neurons with a disrupted PNN following exposure to ChABC had altered membrane properties, fewer rebound spikes, and decreased intrinsic excitability. Together, this study further elucidates the role of the PNN in cerebellar learning in the DCN and is the first to demonstrate PNN degradation may erase sex differences in delay conditioning.

Humans quickly learn to blink strategically in response to environmental task demands.

Eye blinking is one of the most frequent human actions. The control of blinking is thought to reflect complex interactions between maintaining clear and healthy vision and influences tied to central dopaminergic functions including cognitive states, psychological factors, and medical conditions. The most imminent consequence of blinking is a temporary loss of vision. Minimizing this loss of information is a prominent explanation for changes in blink rates and temporarily suppressed blinks, but quantifying this loss is difficult, as environmental regularities are usually complex and unknown. Here we used a controlled detection experiment with parametrically generated event statistics to investigate human blinking control. Subjects were able to learn environmental regularities and adapted their blinking behavior strategically to better detect future events. Crucially, our design enabled us to develop a computational model that allows quantifying the consequence of blinking in terms of task performance. The model formalizes ideas from active perception by describing blinking in terms of optimal control in trading off intrinsic costs for blink suppression with task-related costs for missing an event under perceptual uncertainty. Remarkably, this model not only is sufficient to reproduce key characteristics of the observed blinking behavior such as blink suppression and blink compensation but also predicts without further assumptions the well-known and diverse distributions of time intervals between blinks, for which an explanation has long been elusive.

The diagnostic value of pain evoked potential by electrical stimulation combined with noceciptive blink reflex in trigeminal neuralgia.

Microvascular decompression is the first choice for treating the primary trigeminal neuralgia to provide the most extended duration of pain freedom. However, in microvascular decompression, we found that this kind of operation is only suitable for some patients. It is of great value to objectively judge the function and abnormality of the trigeminal pain conduction pathway in guiding the operation process. This brief report investigates the value of pain evoked potential by electrical stimulation and noceciptive blink reflex in trigeminal neuralgia. We detected the pain evoked potential in 34 patients with trigeminal neuralgia and 48 healthy controls treated by electrical stimulation and blink reflex. We demonstrated no significant differences in the latencies of V1, V2, V3, and R2 of the affected side and the contralateral side in patients with trigeminal neuralgia. The latencies of those four indicators of the affected side in patients with trigeminal neuralgia were notably decreased compared to those on the same side in healthy controls. The receiver operating characteristic curve analysis showed that the area under curve, sensitivity and specificity of the combined diagnosis of latency and amplitude were significantly higher than the single diagnosis. The latency and amplitude of V1 were highly sensitive, while those of V2 was highly specific. Trigeminal neuralgia can be effectively diagnosed by combining pain evoked potential by electrical stimulation and noceciptive blink reflex. The pathogenesis of trigeminal neuralgia should be combined with peripheral pathogenicity and the theory of central pathogenicity.

Awareness and differential eyeblink conditioning: effects of manipulating auditory CS frequencies.

The role of awareness in differential delay eyeblink conditioning (EBC) has been a topic of much debate. We tested the idea that awareness is required for differential delay EBC when two cues are perceptually similar. The present study manipulated frequencies of auditory conditioned stimuli (CS) to vary CS similarity in three groups of participants. Our findings indicate that awareness was not necessary for differential delay EBC when two tones are easily discriminable, awareness was also not needed for relatively similar tones but may facilitate earlier conditioning, and awareness alone was not sufficient for differential delay EBC.

The Transcriptional Regulator SnoN Promotes the Proliferation of Cerebellar Granule Neuron Precursors in the Postnatal Mouse Brain.

Control of neuronal precursor cell proliferation is essential for normal brain development, and deregulation of this fundamental developmental event contributes to brain diseases. Typically, neuronal precursor cell proliferation extends over long periods of time during brain development. However, how neuronal precursor proliferation is regulated in a temporally specific manner remains to be elucidated. Here, we report that conditional KO of the transcriptional regulator SnoN in cerebellar granule neuron precursors robustly inhibits the proliferation of these cells and promotes their cell cycle exit at later stages of cerebellar development in the postnatal male and female mouse brain. In laser capture microdissection followed by RNA-Seq, designed to profile gene expression specifically in the external granule layer of the cerebellum, we find that SnoN promotes the expression of cell proliferation genes and concomitantly represses differentiation genes in granule neuron precursors in vivo Remarkably, bioinformatics analyses reveal that SnoN-regulated genes contain binding sites for the transcription factors N-myc and Pax6, which promote the proliferation and differentiation of granule neuron precursors, respectively. Accordingly, we uncover novel physical interactions of SnoN with N-myc and Pax6 in cells. In behavior analyses, conditional KO of SnoN impairs cerebellar-dependent learning in a delayed eye-blink conditioning paradigm, suggesting that SnoN-regulation of granule neuron precursor proliferation bears functional consequences at the organismal level. Our findings define a novel function and mechanism for the major transcriptional regulator SnoN in the control of granule neuron precursor proliferation in the mammalian brain.SIGNIFICANCE STATEMENT This study reports the discovery that the transcriptional regulator SnoN plays a crucial role in the proliferation of cerebellar granule neuron precursors in the postnatal mouse brain. Conditional KO of SnoN in granule neuron precursors robustly inhibits the proliferation of these cells and promotes their cycle exit specifically at later stages of cerebellar development, with biological consequences of impaired cerebellar-dependent learning. Genomics and bioinformatics analyses reveal that SnoN promotes the expression of cell proliferation genes and concomitantly represses cell differentiation genes in vivo Although SnoN has been implicated in distinct aspects of the development of postmitotic neurons, this study identifies a novel function for SnoN in neuronal precursors in the mammalian brain.

Differential neural processing of spontaneous blinking under visual and auditory sensory environments: An EEG investigation of blink-related oscillations.

Blink-related oscillations (BROs) are a recently discovered neurophysiological response associated with spontaneous blinking, distinct from the well-known oculomotor and visual suppression effects. BROs strongly activate the bilateral precuneus along with other cortical regions involved in visuospatial processing and associative episodic memory, and are believed to represent environmental monitoring processes that occur following blink-induced visual interruptions. Although these responses have been reported across multiple imaging modalities under both resting and cognitive loading conditions, it is yet unknown whether these responses also exist under external sensory stimulation conditions. To address this, we investigated BRO responses in healthy adults using 64-channel electroencephalography (EEG), while participants underwent passive external auditory and visual stimulation. Our results showed that BRO responses are present under both auditory and visual stimulation conditions (p â€‹< â€‹0.05), with similar temporal and spectral features compared to rest. However, visual stimulation did result in decreased BRO amplitude compared to auditory and resting conditions (p â€‹< â€‹0.05), suggesting decreased neuronal resources for processing blink-related information in the visual but not auditory environment. There were also additional pre-blink spectral changes in the visual condition compared to rest (p â€‹< â€‹0.05), which suggest that passive visual stimulation induces neural preparatory processes occurring in anticipation of the upcoming blink event. Together, these findings provide new and compelling evidence that blink-related neural processes are modulated not only by the internal cognitive loading due to simultaneous task demands, but also by competing external sensory requirements. This highlights the link between blinking and cognition, and further demonstrates the importance of BROs as a new window into brain function.