Corticostriatal Plasticity Established by Initial Learning Persists After Behavioral Reversal

Corticostriatal Plasticity Established by Initial Learning Persists After Behavioral Reversal, The neural mechanisms that allow animals to adapt their previously learned associations in response to changes in the environment remain poorly understood. To probe the synaptic mechanisms that mediate such adaptive behavior, we trained mice on an auditory-motor reversal task, and tracked changes in the strength of corticostriatal synapses associated with the formation of learned associations.,

The neural mechanisms that allow animals to adapt their previously learned associations in response to changes in the environment remain poorly understood. To probe the synaptic mechanisms that mediate such adaptive behavior, we trained mice on an auditory-motor reversal task, and tracked changes in the strength of corticostriatal synapses associated with the formation of learned associations. Using a ChR2-based electrophysiological assay in acute striatal slices, we measured the strength of these synapses after animals learned to pair auditory stimuli with specific actions. Here we report that the pattern of synaptic strength initially established by learning remains unchanged even when the task contingencies are reversed. Our findings reveal that synaptic changes associated with the initial acquisition of this task are not erased or over-written, and that behavioral reversal of learned associations may recruit a separate neural circuit. These results suggest a more complex role of the striatum in regulating flexible behaviors where activity of striatal neurons may vary given the behavioral contexts of specific stimulus-action associations.

Significance We have established that learning a specific auditory-motor association establishes a distinct pattern of plasticity in the tonotopic projection from auditory cortex to auditory striatum in mice. The sign of this association can be read out postmortem, with nearly perfect fidelity, using electrophysiological measurements from a single acute brain slice. We then trained another cohort of mice to reverse this association after the initial training period, and measured the plasticity pattern in this circuit. Surprisingly, even after learning the new association successfully, the corticostriatal plasticity pattern represented the initial association, acquired over 2 weeks ago. Our results have implications for the role of corticostriatal plasticity in forming stimulus-action associations and understanding the neural basis of learning in adaptive behaviors.

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Auditory brainstem deficits from early treatment with a CSF1R inhibitor largely recover with microglial...

Auditory brainstem deficits from early treatment with a CSF1R inhibitor largely recover with microglial..., Signaling between neurons and glia is necessary for the formation of functional neural circuits. A role for microglia in the maturation of connections in the medial nucleus of the trapezoid body (MNTB was previously demonstrated by postnatal microglial elimination using a colony stimulating factor 1 receptor (CSF1R).,

Signaling between neurons and glia is necessary for the formation of functional neural circuits. A role for microglia in the maturation of connections in the medial nucleus of the trapezoid body (MNTB was previously demonstrated by postnatal microglial elimination using a colony stimulating factor 1 receptor (CSF1R). Defective pruning of calyces of Held and significant reduction of the mature astrocyte marker glial fibrillary acidic protein (GFAP) were observed after hearing onset. Here, we investigated the time course required for microglia to populate the mouse MNTB after cessation of CSF1R inhibitor treatment. We then examined whether defects seen after microglial depletion were rectified by microglial repopulation. We found that microglia returned to control levels at 4 weeks (wk) of age (18 days post cessation of treatment). Calyceal innervation of MNTB neurons was comparable to control levels at 4 wk, and GFAP expression recovered by 7 wk. We further investigated the effects of microglia elimination and repopulation on auditory function using auditory brainstem recordings (ABR). Temporary microglial depletion significantly elevated auditory thresholds in response to 4. 8, and 12 kHz at 4 wk. Treatment significantly affected latencies, interpeak latencies, and amplitudes of all the ABR peaks in response to many of the frequencies tested. These effects largely recovered by 7 wk. These findings highlight the functions of microglia in the formation of auditory neural circuits early in development. Further, the results suggest that microglia retain their developmental functions beyond the period of circuit refinement.

Significance Statement Auditory brainstem pathways are optimized for their special functions that are shaped during development, which rely on the functions of non-neuronal cells, such as microglia and astrocytes. When microglia were pharmacologically eliminated during the early postnatal period with a CSF1R inhibitor, excess calyces were not pruned and astrocytes did not mature properly in the auditory brainstem. Here we show that once this drug is withdrawn, microglia gradually return to the auditory nuclei. After microglia re-emerge in the MNTB, synaptic pruning of calyces of Held resumes and maturation of astrocytes and auditory function recover. The findings suggest that the auditory brainstem pathways can be shaped by microglia even after their normal period of circuit development.

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Neural representations of covert attention across saccades: comparing pattern similarity to shifting and...

Neural representations of covert attention across saccades: comparing pattern similarity to shifting and..., We can focus visuospatial attention by covertly attending to relevant locations, moving our eyes, or both simultaneously. How does shifting versus holding covert attention during fixation compare with maintaining covert attention across saccades? We acquired human fMRI data during a combined saccade and covert attention task.,

We can focus visuospatial attention by covertly attending to relevant locations, moving our eyes, or both simultaneously. How does shifting versus holding covert attention during fixation compare with maintaining covert attention across saccades? We acquired human fMRI data during a combined saccade and covert attention task. On Eyes-fixed trials, participants either held attention at the same initial location ("hold attention") or shifted attention to another location midway through the trial ("shift attention"). On Eyes-move trials, participants made a saccade midway through the trial, while maintaining attention in one of two reference frames: The "retinotopic attention" condition involved holding attention at a fixation-relative location but shifting to a different screen-centered location, whereas the "spatiotopic attention" condition involved holding attention on the same screen-centered location but shifting relative to fixation. We localized the brain network sensitive to attention shifts (shift > hold attention), and used multivoxel pattern time-course analyses to investigate the patterns of brain activity for spatiotopic and retinotopic attention across saccades. In the attention shift network, we found transient information about both whether covert shifts were made and whether saccades were executed. Moreover, in this network, both retinotopic and spatiotopic conditions were represented more similarly to shifting than to holding covert attention. An exploratory searchlight analysis revealed additional regions where spatiotopic was relatively more similar to shifting and retinotopic more to holding. Thus, maintaining retinotopic and spatiotopic attention across saccades may involve different types of updating that vary in similarity to covert attention "hold" and "shift" signals across different regions.

Significance Statement To our knowledge, this study is the first attempt to directly compare human brain activity patterns of covert attention (to a peripheral spatial location) across saccades and during fixation. We applied fMRI multivoxel pattern time course analyses to capture the dynamic changes of activity patterns, with specific focus on the critical timepoints related to attention shifts and saccades. Our findings indicate that both retinotopic and spatiotopic attention across saccades produce patterns of activation similar to "shifting" attention in the brain, even though both tasks could be interpreted as "holding" attention by the participant. The results offer a novel perspective to understand how the brain processes and updates spatial information under different circumstances to fit the needs of various cognitive tasks.

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Perceptual learning with complex objects: A comparison between full-practice training and memory reactivation

Perceptual learning with complex objects: A comparison between full-practice training and memory reactivation, Perception improves with repeated exposure. Evidence has shown object recognition can be improved by training for multiple days in adults. In particular, a study of Amar-Halpert et al. (2017) has compared the learning effect of repetitive and brief, at-threshold training on a discrimination task and reported similar improvement in both groups.,

Perception improves with repeated exposure. Evidence has shown object recognition can be improved by training for multiple days in adults. In particular, a study of Amar-Halpert et al. (2017) has compared the learning effect of repetitive and brief, at-threshold training on a discrimination task and reported similar improvement in both groups. The finding is interpreted as evidence that memory reactivation benefits discrimination learning. This raises the question how this process might influence different perceptual tasks, including tasks with more complex visual stimuli. Here, this preregistered study investigates whether reactivation induces improvements in a visual object learning task that includes more complex visual stimuli. Participants were trained to recognize a set of objects during five days of training. After the initial training, a group was trained with repeated practice, the other with brief, near-threshold reactivation trials. In both groups we found improved object recognition at brief exposure durations. Traditional intense training shows a daily improvement; however, the group with reactivation does not reach the same level of improvement. Our findings show that reactivation has a smaller effect relative to large amounts of practice.

Significance Statement Perceptual learning helps to explore adult plasticity in visual processing. Gradual improvements in the perception of complex objects have been demonstrated across multiple daily training sessions of hundreds of trials. These improvements in the trained objects and the transfer to new objects, in that sense, support "practice makes perfect." Recent research challenges this idea, and suggests that a few critical reactivation trials can boost the learning processes. Here, we extend this idea to other learning tasks and investigate the extent to which short reactivation with a small number of trials can replace extensive training with complex visual objects. In our paradigm, we found larger training effects with extensive training.

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CaMKII Phosphorylation Regulates Synaptic Enrichment of Shank3

CaMKII Phosphorylation Regulates Synaptic Enrichment of Shank3, SHANK3 is a large scaffolding protein in the postsynaptic density (PSD) that organizes protein networks, which are critical for synaptic structure and function. The strong genetic association of SHANK3 with autism spectrum disorder (ASD) emphasizes the importance of SHANK3 in neuronal development.,

SHANK3 is a large scaffolding protein in the postsynaptic density (PSD) that organizes protein networks, which are critical for synaptic structure and function. The strong genetic association of SHANK3 with autism spectrum disorder (ASD) emphasizes the importance of SHANK3 in neuronal development. SHANK3 has a critical role in organizing excitatory synapses and is tightly regulated by alternative splicing and posttranslational modifications. In this study, we examined basal and activity-dependent phosphorylation of Shank3 using mass spectrometry (MS) analysis from in vitro phosphorylation assays, in situ experiments, and studies with cultured neurons. We found that Shank3 is highly phosphorylated, and we identified serine 782 (S782) as a potent CaMKII phosphorylation site. Using a phosphorylation state-specific antibody, we demonstrate that CaMKII can phosphorylate Shank3 S782 in vitro and in heterologous cells on cotransfection with CaMKII. We also observed an effect of a nearby ASD-associated variant (Shank3 S685I), which increased S782 phosphorylation. Notably, eliminating phosphorylation of Shank3 with a S782A mutation increased Shank3 and PSD-95 synaptic puncta size without affecting Shank3 colocalization with PSD-95 in cultured hippocampal neurons. Taken together, our study revealed that CaMKII phosphorylates Shank3 S782 and that the phosphorylation affects Shank3 synaptic properties.

Significance Statement The precise regulation of scaffolding proteins is important for both neuronal development and dysregulation underlies some neurodevelopmental disorders. As an excitatory synapse scaffolding protein, SHANK3 plays a critical role in synapse structure and function and has a strong genetic linkage to autism spectrum disorder (ASD). In this report, we examined the fine regulation of Shank3 by phosphorylation. Our study characterizes a CaMKII phosphorylation site on Shank3 (S782) in vitro, in situ, and in neurons. The Shank3 phosphorylation is modulated by a neighboring ASD-associated mutation. Furthermore, S782 phosphorylation is involved in Shank3 synaptic enrichment. These findings reveal molecular mechanisms of SHANK3 function at excitatory synapses and a potential role in ASD etiology.

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Suppress me if you can: Neurofeedback of the Readiness Potential

Suppress me if you can: Neurofeedback of the Readiness Potential, Voluntary movements are usually preceded by a slow, negative-going brain signal over motor areas, the so-called readiness potential (RP). To date, the exact nature and causal role of the RP in movement preparation have remained heavily debated.,

Voluntary movements are usually preceded by a slow, negative-going brain signal over motor areas, the so-called readiness potential (RP). To date, the exact nature and causal role of the RP in movement preparation have remained heavily debated. Although the RP is influenced by several motorical and cognitive factors, it has remained unclear whether people can learn to exert mental control over their RP, for example by deliberately suppressing it. If people were able to initiate spontaneous movements without eliciting an RP, this would challenge the idea that the RP is a necessary stage of the causal chain leading up to a voluntary movement. We tested the ability of participants to control the magnitude of their RP in a neurofeedback experiment. Participants performed self-initiated movements and after every movement they were provided with immediate feedback about the magnitude of their RP. They were asked to find a strategy to perform voluntary movements such that the RPs were as small as possible. We found no evidence that participants were able to to willfully modulate or suppress their RPs while still eliciting voluntary movements. This suggests that the RP might be an involuntary component of voluntary action over which people cannot exert conscious control.

Significance statement The readiness potential (RP), a brain signal that precedes spontaneous, voluntary movements, has been a matter of controversial research for several decades. There has been a long debate on the nature of this signal and the degree to which it undermines the control a person has over their behavior. Thus, assessing the degree to which people are able to exert control over this brain signal is of vital importance. We addressed this question in a neurofeedback experiment. Our results show that people are unable to willfully suppress their RPs, even when explicitly trying to do so. This suggests that the RP is an involuntary and irrevocable component of voluntary action over which people have no control.

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Short-term synaptic plasticity makes neurons sensitive to the distribution of presynaptic population firing...

Short-term synaptic plasticity makes neurons sensitive to the distribution of presynaptic population firing..., The ability to discriminate spikes that encode a particular stimulus from spikes produced by background activity is essential for reliable information processing in the brain.,

The ability to discriminate spikes that encode a particular stimulus from spikes produced by background activity is essential for reliable information processing in the brain. We describe how synaptic short-term plasticity (STP) modulates the output of presynaptic populations as a function of the distribution of the spiking activity and find a strong relationship between STP features and sparseness of the population code, which could solve this problem. Furthermore, we show that feedforward excitation followed by inhibition (FF-EI), combined with target-dependent STP, promote substantial increase in the signal gain even for considerable deviations from the optimal conditions, granting robustness to this mechanism. A simulated neuron driven by a spiking FF-EI network is reliably modulated as predicted by a rate analysis and inherits the ability to differentiate sparse signals from dense background activity changes of the same magnitude, even at very low signal-to-noise conditions. We propose that the STP-based distribution discrimination is likely a latent function in several regions such as the cerebellum and the hippocampus.

Significance statement What is the optimal way to distribute a fixed number of spikes over a set of neurons so the we get a maximal response in the downstream neuron? This question is at the core of neural coding. Here we show that when synapses show short-term facilitation, sparse code (when a few neurons increase their firing rate in a task-dependent manner) is more effective than dense code (when many neurons increase their firing rate in a task-dependent manner). By contrast, when synapses show short-term depression a dense code is more effective than a sparse code. Thus, for the first time, we show that the dynamics of synapses itself has an effect in deciding the most effective neural code.

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Passive motor learning: Oculomotor adaptation in the absence of behavioral errors

Passive motor learning: Oculomotor adaptation in the absence of behavioral errors, Motor adaptation is commonly thought to be a trial-and-error process in which the accuracy of movement improves with repetition of behavior. We challenged this view by testing whether erroneous movements are necessary for motor adaptation.,

Motor adaptation is commonly thought to be a trial-and-error process in which the accuracy of movement improves with repetition of behavior. We challenged this view by testing whether erroneous movements are necessary for motor adaptation. In the eye movement system, the association between movements and errors can be disentangled, since errors in the predicted stimulus trajectory can be perceived even without movements. We modified a smooth pursuit eye movement adaptation paradigm in which monkeys learn to make an eye movement that predicts an upcoming change in target direction. We trained the monkeys to fixate on a target while covertly, an additional target initially moved in one direction and then changed direction after 250 ms. The monkeys showed a learned response to infrequent probe trials in which they were instructed to follow the moving target. Further experiments confirmed that probing learning or residual eye movements during fixation did not drive learning. These results show that motor adaptation can be elicited in the absence of movement and provide an animal model for studying the implementation of passive motor learning. Current models assume that the interaction between movement and error signals underlies adaptive motor learning. Our results point to other mechanisms that may drive learning in the absence of movement.

Significance statement What are the signals that drive learning? Many experimental and theoretical studies have approached this question from the perspective of motor adaptation as it is both extremely relevant to everyday life and allows for tight experimental control. Motor adaptation is thought to be a gradual process in which errors in behavior are corrected. Here we challenged this view and developed a behavioral paradigm for studying whether movement is necessary for motor adaptation. We found that motor adaptive learning can be elicited in the absence of movement, thus suggesting that motor adaptation has a crucial passive component.

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Altered Activity of Lateral Orbitofrontal Cortex Neurons in Mice Following Chronic Intermittent Ethanol...

Altered Activity of Lateral Orbitofrontal Cortex Neurons in Mice Following Chronic Intermittent Ethanol..., The Lateral Orbito-Frontal Cortex (LOFC) is thought to encode information associated with consumption of rewarding substances and is essential for flexible decision making. Indeed, firing patterns of LOFC neurons are modulated following changes in reward value associated with an action outcome relationship.,

The Lateral Orbito-Frontal Cortex (LOFC) is thought to encode information associated with consumption of rewarding substances and is essential for flexible decision making. Indeed, firing patterns of LOFC neurons are modulated following changes in reward value associated with an action outcome relationship. Damage to the LOFC impairs behavioral flexibility in humans and is associated with sub-optimal performance in reward devaluation protocols in rodents. As chronic intermittent ethanol (CIE) exposure also impairs OFC-dependent behaviors, we hypothesized that CIE exposure would alter LOFC neuronal activity during alcohol drinking, especially under conditions when the reward value of ethanol was modulated by aversive or appetitive tastants. To test this hypothesis, we monitored LOFC activity using GCaMP6f fiber photometry in mice receiving acute injections of ethanol and in those trained in operant ethanol self-administration. In naïve mice, an acute injection of ethanol caused a dose-dependent decrease in the frequency but not amplitude of GCaMP6f transients. In operant studies, mice were trained on an fixed-ratio one schedule of reinforcement and were then separated into CIE or Air groups. Following four cycles of CIE exposure, GCaMP6f activity was recorded during self-administration of alcohol, alcohol + quinine (aversive), or alcohol + sucrose (appetitive) solutions. LOFC neurons showed discrete patterns of activity surrounding lever presses and surrounding drinking bouts. Responding for and consumption of ethanol was greatly enhanced by CIE exposure, was aversion resistant, and was associated with signs of LOFC hyperexcitability. CIE exposed mice also showed altered patterns of LOFC activity that varied with the ethanol solution consumed.

Significance Statement: These studies demonstrate that, in intact mice, LOFC neurons are acutely inhibited by alcohol and become hyperexcitable following CIE exposure. Furthermore, we report that unique patterns of LOFC neuronal activity occur during alcohol seeking and consumption. Interestingly, these patterns of activity are modulated following CIE exposure, particularly when the rewarding properties of the alcohol solution are modulated through adulterations with quinine (aversive) or sucrose (appetitive). Conversely, control animals have considerably more stable patterns of LOFC activity following exposure to air. These unique effects of CIE exposure on LOFC activity likely contribute to the development of excessive alcohol consumption and behavioral inflexibility that are associated with the onset of alcohol dependence.

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Combination of defined CatWalk gait parameters for predictive locomotion recovery in experimental spinal cord...

Combination of defined CatWalk gait parameters for predictive locomotion recovery in experimental spinal cord..., In many preclinical spinal cord injury (SCI) studies, assessment of locomotion recovery is key to understanding the effectiveness of the experimental intervention. In such rat SCI studies, the most basic locomotor recovery scoring system is a subjective observation of animals freely roaming in an open field, the Basso Beattie Bresnahan (BBB)-score.,

In many preclinical spinal cord injury (SCI) studies, assessment of locomotion recovery is key to understanding the effectiveness of the experimental intervention. In such rat SCI studies, the most basic locomotor recovery scoring system is a subjective observation of animals freely roaming in an open field, the Basso Beattie Bresnahan (BBB)-score. In comparison, CatWalk is an automated gait analysis system, providing further parameter specifications. Although together the CatWalk parameters encompass gait, studies consistently report single parameters, which differ in significance from other behavioral assessments. Therefore, we believe no single parameter produced by the CatWalk can represent the fully-coordinated motion of gait. Typically, other locomotor assessments, such as the BBB-score, combine several locomotor characteristics into a representative score. For this reason, we ranked the most distinctive CatWalk parameters between uninjured and SC injured rats. Subsequently, we combined nine of the topmost parameters into an SCI gait index score based upon linear discriminant analysis (LDA). The resulting combination was applied to assess gait recovery in SCI experiments comprising of three thoracic contusions, a thoracic dorsal hemisection, and a cervical dorsal column lesion model. For thoracic lesions, our unbiased machine learning model revealed gait differences in lesion type and severity. In some instances, our LDA was found to be more sensitive in differentiating recovery than the BBB-score alone. We believe the newly developed gait parameter combination presented here should be used in CatWalk gait recovery work with preclinical thoracic rat SCI models.

Significance Statement As a quantitative locomotion analysis system, CatWalk provides an objective assessment of gait for rodents by computing numerous parameters. This gives an alternative to the current popular subjective locomotor assessment for rat SCI models, i.e., BBB score. As SCI affects multiple gait parameters, analyzing gait is challenging. Here we developed a CatWalk gait parameter combination for sensitive and efficient gait recovery assessment in rat thoracic SCI models.

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MRI Compatible, Customizable, and 3D Printable Microdrive for Neuroscience Research

MRI Compatible, Customizable, and 3D Printable Microdrive for Neuroscience Research, The effective connectivity of brain networks can be assessed using functional magnetic resonance imaging (fMRI) to quantify the effects of local electrical microstimulation (EM) on distributed neuronal activity.,

The effective connectivity of brain networks can be assessed using functional magnetic resonance imaging (fMRI) to quantify the effects of local electrical microstimulation (EM) on distributed neuronal activity. The delivery of EM to specific brain regions, particularly with layer specificity, requires MRI compatible equipment that provides fine control of a stimulating electrode’s position within the brain while minimizing imaging artifacts. To this end, we developed a microdrive made entirely of MRI compatible materials. The microdrive uses an integrated penetration grid to guide electrodes and relies on a micro-drilling technique to eliminate the need for large craniotomies, further reducing implant maintenance and image distortions. The penetration grid additionally serves as a built-in MRI marker, providing a visible fiducial reference for estimating probe trajectories. Following the initial implant procedure, these features allow for multiple electrodes to be inserted, removed, and repositioned with minimal effort, using a screw-type actuator. To validate the design of the microdrive, we conducted an EM-coupled fMRI study with a male macaque monkey. The results verified that the microdrive can be used to deliver EM during MRI procedures with minimal imaging artifacts, even within a 7 Tesla (7T) environment. Future applications of the microdrive include neuronal recordings and targeted drug delivery. We provide computer aided design (CAD) templates and a parts list for modifying and fabricating the microdrive for specific research needs. These designs provide a convenient, cost-effective approach to fabricating MRI compatible microdrives for neuroscience research.

Significance Statement We provide designs for a customizable, MRI compatible microdrive capable of positioning various types of probes (e.g., stimulating electrodes, recording electrodes, drug cannulae, or optogenetic fibers) within the brain. The design integrates a cranial implant, penetration grid for guiding probes, and a microdrive body assembly with actuators. A micro-drilling technique, which helps reduce implant maintenance and potential imaging artifacts, is described for introducing probes into the brain. Our open-source designs allow for the customization and fabrication of microdrive components to meet the unique demands of specific research projects and various animal models. Microdrives based on these designs can fulfill a variety of research needs within the neuroscience community related to electrical microstimulation, neuronal recording, and local drug delivery.

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Effects of optogenetic stimulation of primary somatosensory cortex and its projections to striatum on...

Effects of optogenetic stimulation of primary somatosensory cortex and its projections to striatum on..., Tactile sensation is one of our primary means to collect information about the nearby environment and thus crucial for daily activities and survival. Therefore, it is of high importance to restore sensory feedback after sensory loss. Optogenetic manipulation allows local or pathway specific write-in of information.,

Tactile sensation is one of our primary means to collect information about the nearby environment and thus crucial for daily activities and survival. Therefore, it is of high importance to restore sensory feedback after sensory loss. Optogenetic manipulation allows local or pathway specific write-in of information. However, it remains elusive whether optogenetic stimulation can be interpreted as tactile sensation to guide operant behavior and how it is integrated with tactile stimuli. To address these questions we employed a vibrotactile detection task combined with optogenetic neuromodulation in freely moving rats. By bidirectionally manipulating the activity of neurons in primary somatosensory cortex (S1), we demonstrated that optical activation as well as inhibition of S1 reduced the detection rate for vibrotactile stimuli. Interestingly, activation of corticostriatal terminals improved the detection of tactile stimuli, while inhibition of corticostriatal terminals did not affect the performance. To manipulate the corticostriatal pathway more specifically, we employed a dual viral system. Activation of corticostriatal cell bodies disturbed the tactile perception while activation of corticostriatal terminals slightly facilitated the detection of vibrotactile stimuli. In the absence of tactile stimuli, both corticostriatal cell bodies as well as terminals caused a reaction. Taken together, our data confirmed the possibility to restore sensation using optogenetics and demonstrated that S1 and its descending projections to striatum play differential roles in the neural processing underlying vibrotactile detection.

Significance Statement The capability of writing-in information locally or pathway-specific makes optogenetic manipulation a promising approach to restore sensation. The extent to which the optogenetic stimulation can be interpreted as tactile sensation to guide operant behavior remains to be clarified. In this work we applied bidirectional manipulation of S1 and its striatal terminals as well as pathway-specific activations, and found that cortical manipulations disturbed the performance of vibrotactile stimuli. Corticostriatal terminal activation enhanced the performance in the presence of vibrotactile stimuli, while corticostriatal inhibition did not affect the performance. This study provides insights into the contributions of S1 and its descending projections to striatum to the neural processing underlying vibrotactile detection.

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Retrograde suppression of post-tetanic potentiation at the mossy fiber-CA3 pyramidal cell synapse

Retrograde suppression of post-tetanic potentiation at the mossy fiber-CA3 pyramidal cell synapse, In the hippocampus, the excitatory synapse between dentate granule cell axons – or mossy fibers (MF) – and CA3 pyramidal cells (MF-CA3) expresses robust forms of short-term plasticity, such as frequency facilitation and post-tetanic potentiation (PTP). These forms of plasticity are due to increases in neurotransmitter release, and can be engaged when dentate granule cells fire in bursts (e.g.,

In the hippocampus, the excitatory synapse between dentate granule cell axons – or mossy fibers (MF) – and CA3 pyramidal cells (MF-CA3) expresses robust forms of short-term plasticity, such as frequency facilitation and post-tetanic potentiation (PTP). These forms of plasticity are due to increases in neurotransmitter release, and can be engaged when dentate granule cells fire in bursts (e.g. during exploratory behaviors) and bring CA3 pyramidal neurons above threshold. While frequency facilitation at this synapse is limited by endogenous activation of presynaptic metabotropic glutamate receptors, whether MF-PTP can be regulated in an activity-dependent manner is unknown. Here, using physiologically relevant patterns of mossy fiber stimulation in acute mouse hippocampal slices, we found that disrupting postsynaptic Ca2+ dynamics increases MF-PTP, strongly suggesting a form of Ca2+-dependent retrograde suppression of this form of plasticity. PTP suppression requires a few seconds of MF bursting activity and Ca2+ release from internal stores. Our findings raise the possibility that the powerful MF-CA3 synapse can negatively regulate its own strength not only during PTP-inducing activity typical of normal exploratory behaviors, but also during epileptic activity.

SIGNIFICANCE STATEMENT The powerful mossy fiber-CA3 synapse exhibits strong forms of plasticity that are engaged during location-specific exploration, when dentate granule cells fire in bursts. While this synapse is well-known for its presynaptically-expressed LTP and LTD, much less is known about the robust changes that occur on a shorter time scale. How such short-term plasticity is regulated, in particular, remains poorly understood. Unexpectedly, an in vivo-like pattern of presynaptic activity induced robust post-tetanic potentiation (PTP) only when the postsynaptic cell was loaded with a high concentration of Ca2+ buffer, indicating a form of Ca2+–dependent retrograde suppression of PTP. Such suppression may have profound implications for how environmental cues are encoded into neural assemblies, and for limiting network hyperexcitability during seizures.

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Flexible and accurate substrate processing with distinct presenilin/{gamma}-secretases in human cortical...

Flexible and accurate substrate processing with distinct presenilin/{gamma}-secretases in human cortical..., Mutations in the presenilin genes (PS1, PS2) have been linked to the majority of familial Alzheimer’s disease (AD). Although great efforts have been made to investigate pathogenic PS mutations, which ultimately cause an increase in the toxic form of β-amyloid (Aβ), the intrinsic physiological functions of PS in human neurons remain to be determined.,

Mutations in the presenilin genes (PS1, PS2) have been linked to the majority of familial Alzheimer’s disease (AD). Although great efforts have been made to investigate pathogenic PS mutations, which ultimately cause an increase in the toxic form of β-amyloid (Aβ), the intrinsic physiological functions of PS in human neurons remain to be determined. In this study, to investigate the physiological roles of PS in human neurons, we generated PS1 conditional knockout induced pluripotent stem cells (iPSCs), in which PS1 can be selectively abrogated under Cre transduction with or without additional PS2 knockout. We showed that iPSC-derived neural progenitor cells do not confer a maintenance ability in the absence of both PS1 and PS2, showing the essential role of PS in Notch signaling. We then generated PS-null human cortical neurons, where PS1 was intact until full neuronal differentiation occurred. Aβ40 production was reduced exclusively in human PS1/PS2-null neurons along with a concomitant accumulation of APP-CTFs, whereas Aβ42 was decreased in neurons devoid of PS2. Unlike previous studies in mice, in which APP cleavage is largely attributable to PS1, -secretase activity seemed to be comparable between PS1 and PS2. In contrast, cleavage of another substrate, N-cadherin, was impaired only in neurons devoid of PS1. Moreover, PS2/-secretase exists largely in late endosomes/lysosomes, as measured by specific antibody against the -secretase complex, in which Aβ42 species are supposedly produced. Using this novel stem cell-based platform, we assessed important physiological PS1/PS2 functions in mature human neurons, the dysfunction of which could underlie AD pathogenesis.

Significance Statement Presenilins are crucial catalytic subunits of -secretase, an intramembranous protease complex, whose mutations underlie AD pathogenesis via the dysregulation of Aβ generation. The -secretase complex exhibits heterogeneity via the assembly of PS1 or PS2, but the correlation of -secretase heterogeneity with substrate processing remains to be established in human neurons. Here, using a novel iPSC-derived cellular model carrying PS1 and/or PS2 conditional knockout alleles, we uncovered the unique processing of three substrates, Notch, APP and N-cadherin, by PS1 or PS2 in human neural cell contexts. Furthermore, the intrinsic subcellular localization of -secretase depends on PS1 or PS2, leading to putative differences in the processing of substrates. This novel platform will help ensure the correlation of -secretase/substrates in human neurons.

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Unique effects of social defeat stress in adolescent male mice on the Netrin-1/DCC pathway, prefrontal cortex...

Unique effects of social defeat stress in adolescent male mice on the Netrin-1/DCC pathway, prefrontal cortex..., For some individuals, social stress is a risk factor for psychiatric disorders characterised by adolescent onset, prefrontal cortex (PFC) dysfunction and cognitive impairments. Social stress may be particularly harmful during adolescence when dopamine (DA) axons are still growing to the PFC, rendering them sensitive to environmental influences.,

For some individuals, social stress is a risk factor for psychiatric disorders characterised by adolescent onset, prefrontal cortex (PFC) dysfunction and cognitive impairments. Social stress may be particularly harmful during adolescence when dopamine (DA) axons are still growing to the PFC, rendering them sensitive to environmental influences. The guidance cue Netrin-1 and its receptor, DCC, coordinate to control mesocorticolimbic DA axon targeting and growth during this age. Here we adapted the accelerated social defeat (AcSD) paradigm to expose male mice to social stress in either adolescence or adulthood and categorised them as "resilient" or "susceptible" based on social avoidance behaviour. We examined whether stress would alter the expression of DCC and Netrin-1 in mesolimbic dopamine regions and would have enduring consequences on PFC dopamine connectivity and cognition. While in adolescence the majority of mice are resilient but exhibit risk-taking behaviour, AcSD in adulthood leads to a majority of susceptible mice without altering anxiety-like traits. In adolescent, but not adult mice, AcSD dysregulates DCC and Netrin-1 expression in mesolimbic DA regions. These molecular changes in adolescent mice are accompanied by changes in PFC DA connectivity. Following AcSD in adulthood, cognitive function remains unaffected, but all mice exposed to AcSD in adolescence show deficits in inhibitory control when they reach adulthood. These findings indicate that exposure to AcSD in adolescence vs. adulthood has substantially different effects on brain and behaviour and that stress-induced social avoidance in adolescence does not predict vulnerability to deficits in cognitive performance.

Significance statement During adolescence, dopamine circuitries undergo maturational changes which may render them particularly vulnerable to social stress. While social stress can be detrimental to adolescents and adults, it may engage different mechanisms and impact different domains, depending on age. The accelerated social defeat (AcSD) model implemented here allows exposing adolescent and adult male mice to comparable social stress levels. AcSD in adulthood leads to a majority of socially avoidant mice. However, the predominance of AcSD-exposed adolescent mice does not develop social avoidance, and these resilient mice show risk-taking behaviour. Nonetheless, in adolescence only, AcSD dysregulates Netrin-1/DCC expression in mesolimbic dopamine regions, possibly disrupting mesocortical dopamine and cognition. The unique adolescent responsiveness to stress may explain increased psychopathology risk at this age.

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