Frontiers in Neural Circuits最新文献

Action selection is a capital feature of cognition that guides behavior in processes that range from motor patterns to executive functions. Here, the ongoing actions need to be monitored and adjusted in response to sensory stimuli to increase the chances of reaching the goal. As higher hierarchical processes, these functions rely on complex neural circuits, and connective loops found within the brain and the spinal cord. Successful execution of motor behaviors depends, first, on proper selection of actions, and second, on implementation of motor commands. Thus, pathological conditions crucially affecting the integrity and preservation of these circuits and their connectivity will heavily impact goal-oriented motor behaviors. Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two neurodegenerative disorders known to share disease etiology and pathophysiology. New evidence in the field of ALS-FTD has shown degeneration of specific neural circuits and alterations in synaptic connectivity, contributing to neuronal degeneration, which leads to the impairment of motor commands and executive functions. This evidence is based on studies performed on animal models of disease, post-mortem tissue, and patient derived stem cells. In the present work, we review the existing evidence supporting pathological loss of connectivity and selective impairment of neural circuits in ALS and FTD, two diseases which share strong genetic causes and impairment in motor and executive functions.

We present a deep network-based model of the associative memory functions of the hippocampus. The proposed network architecture has two key modules: (1) an autoencoder module which represents the forward and backward projections of the cortico-hippocampal projections and (2) a module that computes familiarity of the stimulus and implements hill-climbing over the familiarity which represents the dynamics of the loops within the hippocampus. The proposed network is used in two simulation studies. In the first part of the study, the network is used to simulate image pattern completion by autoassociation under normal conditions. In the second part of the study, the proposed network is extended to a heteroassociative memory and is used to simulate picture naming task in normal and Alzheimer's disease (AD) conditions. The network is trained on pictures and names of digits from 0 to 9. The encoder layer of the network is partly damaged to simulate AD conditions. As in case of AD patients, under moderate damage condition, the network recalls superordinate words ("odd" instead of "nine"). Under severe damage conditions, the network shows a null response ("I don't know"). Neurobiological plausibility of the model is extensively discussed.

Connectomics is fundamental in propelling our understanding of the nervous system's organization, unearthing cells and wiring diagrams reconstructed from volume electron microscopy (EM) datasets. Such reconstructions, on the one hand, have benefited from ever more precise automatic segmentation methods, which leverage sophisticated deep learning architectures and advanced machine learning algorithms. On the other hand, the field of neuroscience at large, and of image processing in particular, has manifested a need for user-friendly and open source tools which enable the community to carry out advanced analyses. In line with this second vein, here we propose mEMbrain, an interactive MATLAB-based software which wraps algorithms and functions that enable labeling and segmentation of electron microscopy datasets in a user-friendly user interface compatible with Linux and Windows. Through its integration as an API to the volume annotation and segmentation tool VAST, mEMbrain encompasses functions for ground truth generation, image preprocessing, training of deep neural networks, and on-the-fly predictions for proofreading and evaluation. The final goals of our tool are to expedite manual labeling efforts and to harness MATLAB users with an array of semi-automatic approaches for instance segmentation. We tested our tool on a variety of datasets that span different species at various scales, regions of the nervous system and developmental stages. To further expedite research in connectomics, we provide an EM resource of ground truth annotation from four different animals and five datasets, amounting to around 180 h of expert annotations, yielding more than 1.2 GB of annotated EM images. In addition, we provide a set of four pre-trained networks for said datasets. All tools are available from https://lichtman.rc.fas.harvard.edu/mEMbrain/. With our software, our hope is to provide a solution for lab-based neural reconstructions which does not require coding by the user, thus paving the way to affordable connectomics.

The anterior cingulate cortex (ACC) plays a crucial role in encoding, consolidating and retrieving memories related to emotionally salient experiences, such as aversive and rewarding events. Various studies have highlighted its importance for fear memory processing, but its circuit mechanisms are still poorly understood. Cortical layer 1 (L1) of the ACC might be a particularly important site of signal integration, since it is a major entry point for long-range inputs, which is tightly controlled by local inhibition. Many L1 interneurons express the ionotropic serotonin receptor 3a (5HT3aR), which has been implicated in post-traumatic stress disorder and in models of anxiety. Hence, unraveling the response dynamics of L1 interneurons and subtypes thereof during fear memory processing may provide important insights into the microcircuit organization regulating this process. Here, using 2-photon laser scanning microscopy of genetically encoded calcium indicators through microprisms in awake mice, we longitudinally monitored over days the activity of L1 interneurons in the ACC in a tone-cued fear conditioning paradigm. We observed that tones elicited responses in a substantial fraction of the imaged neurons, which were significantly modulated in a bidirectional manner after the tone was associated to an aversive stimulus. A subpopulation of these neurons, the neurogliaform cells (NGCs), displayed a net increase in tone-evoked responses following fear conditioning. Together, these results suggest that different subpopulations of L1 interneurons may exert distinct functions in the ACC circuitry regulating fear learning and memory.

This review presents a broad perspective of the Neuroscience of our days with special attention to how the brain generates our behaviors, emotions, and mental states. It describes in detail how unconscious and conscious processing of sensorimotor and mental information takes place in our brains. Likewise, classic and recent experiments illustrating the neuroscientific foundations regarding the behavioral and cognitive abilities of animals and, in particular, of human beings are described. Special attention is applied to the description of the different neural regulatory systems dealing with behavioral, cognitive, and emotional functions. Finally, the brain process for decision-making, and its relationship with individual free will and responsibility, are also described.

Cortical inhibitory interneurons form a broad spectrum of subtypes. This diversity suggests a division of labor, in which each cell type supports a distinct function. In the present era of optimisation-based algorithms, it is tempting to speculate that these functions were the evolutionary or developmental driving force for the spectrum of interneurons we see in the mature mammalian brain. In this study, we evaluated this hypothesis using the two most common interneuron types, parvalbumin (PV) and somatostatin (SST) expressing cells, as examples. PV and SST interneurons control the activity in the cell bodies and the apical dendrites of excitatory pyramidal cells, respectively, due to a combination of anatomical and synaptic properties. But was this compartment-specific inhibition indeed the function for which PV and SST cells originally evolved? Does the compartmental structure of pyramidal cells shape the diversification of PV and SST interneurons over development? To address these questions, we reviewed and reanalyzed publicly available data on the development and evolution of PV and SST interneurons on one hand, and pyramidal cell morphology on the other. These data speak against the idea that the compartment structure of pyramidal cells drove the diversification into PV and SST interneurons. In particular, pyramidal cells mature late, while interneurons are likely committed to a particular fate (PV vs. SST) during early development. Moreover, comparative anatomy and single cell RNA-sequencing data indicate that PV and SST cells, but not the compartment structure of pyramidal cells, existed in the last common ancestor of mammals and reptiles. Specifically, turtle and songbird SST cells also express the Elfn1 and Cbln4 genes that are thought to play a role in compartment-specific inhibition in mammals. PV and SST cells therefore evolved and developed the properties that allow them to provide compartment-specific inhibition before there was selective pressure for this function. This suggest that interneuron diversity originally resulted from a different evolutionary driving force and was only later co-opted for the compartment-specific inhibition it seems to serve in mammals today. Future experiments could further test this idea using our computational reconstruction of ancestral Elfn1 protein sequences.

Introduction: Previous studies have demonstrated the effectiveness of therapeutic repetitive transcranial magnetic stimulation (rTMS) to treat pharmacoresistant depression. Nevertheless, these trials have primarily focused on the therapeutic and neurophysiological effects of rTMS following a long-term treatment course. Identifying brain-based biomarkers of early rTMS therapeutic response remains an important unanswered question. In this pilot study, we examined the effects of rTMS on individuals with pharmacoresistant depression using a graph-based method, called Functional Cortical Networks (FCN), and serial electroencephalography (EEG). We hypothesized that changes in brain activity would occur early in treatment course.

Methods: A total of 15 patients with pharmacoresistant depression underwent five rTMS sessions (5Hz over the left dorsolateral prefrontal cortex, 120%MT, up to 4,000 pulses/session). Five participants received additional rTMS treatment, up to 40 sessions. Resting EEG activity was measured at baseline and following every five sessions, using 64-channel EEG, for 10 minutes with eyes closed. An FCN model was constructed using time-varying graphs and motif synchronization. The primary outcome was acute changes in weighted-node degree. Secondary outcomes included serial FFT-based power spectral analysis and changes in depressive symptoms measured by the 9-Item Patient Health Questionnaire (PHQ-9) and the 30-item Inventory of Depressive Symptoms-Self Report (IDS-SR).

Results: We found a significant acute effect over the left posterior area after five sessions, as evidenced by an increase in weighted-node degree of 37,824.59 (95% CI, 468.20 to 75,180.98) and a marginal enhancement in the left frontal region (t (14) = 2.0820, p = 0.056). One-way repeated measures ANOVA indicated a significant decrease in absolute beta power over the left prefrontal cortex (F (7, 28) = 2.37, p = 0.048) following ten rTMS sessions. Furthermore, a significant clinical improvement was observed following five rTMS sessions on both PHQ-9 (t (14) = 2.7093, p = 0.017) and IDS-SR (t (14) = 2.5278, p = 0.024) and progressed along the treatment course.

Discussion: Our findings suggest that FCN models and serial EEG may contribute to a deeper understanding of mechanisms underlying rTMS treatment. Additional research is required to investigate the acute and serial effects of rTMS in pharmacoresistant depression and assess whether early EEG changes could serve as predictors of therapeutic rTMS response.

Introduction: Threatening environmental cues often generate enduring fear memories, but how these are formed and stored remains actively investigated. Recall of a recent fear memory is thought to reflect reactivation of neurons, in multiple brain regions, activated during memory formation, indicating that anatomically distributed and interconnected neuronal ensembles comprise fear memory engrams. The extent to which anatomically specific activation-reactivation engrams persist during long-term fear memory recall, however, remains largely unexplored. We hypothesized that principal neurons in the anterior basolateral amygdala (aBLA), which encode negative valence, acutely reactivate during remote fear memory recall to drive fear behavior.

Methods: Using adult offspring of TRAP2 and Ai14 mice, persistent tdTomato expression was used to "TRAP" aBLA neurons that underwent Fos-activation during contextual fear conditioning (electric shocks) or context only conditioning (no shocks) (n = 5/group). Three weeks later, mice were re-exposed to the same context cues for remote memory recall, then sacrificed for Fos immunohistochemistry.

Results: TRAPed (tdTomato +), Fos +, and reactivated (double-labeled) neuronal ensembles were larger in fear- than context-conditioned mice, with the middle sub-region and middle/caudal dorsomedial quadrants of aBLA displaying the greatest densities of all three ensemble populations. Whereas tdTomato + ensembles were dominantly glutamatergic in context and fear groups, freezing behavior during remote memory recall was not correlated with ensemble sizes in either group.

Discussion: We conclude that although an aBLA-inclusive fear memory engram forms and persists at a remote time point, plasticity impacting electrophysiological responses of engram neurons, not their population size, encodes fear memory and drives behavioral manifestations of long-term fear memory recall.

Vertebrate movement is orchestrated by spinal inter- and motor neurons that, together with sensory and cognitive input, produce dynamic motor behaviors. These behaviors vary from the simple undulatory swimming of fish and larval aquatic species to the highly coordinated running, reaching and grasping of mice, humans and other mammals. This variation raises the fundamental question of how spinal circuits have changed in register with motor behavior. In simple, undulatory fish, exemplified by the lamprey, two broad classes of interneurons shape motor neuron output: ipsilateral-projecting excitatory neurons, and commissural-projecting inhibitory neurons. An additional class of ipsilateral inhibitory neurons is required to generate escape swim behavior in larval zebrafish and tadpoles. In limbed vertebrates, a more complex spinal neuron composition is observed. In this review, we provide evidence that movement elaboration correlates with an increase and specialization of these three basic interneuron types into molecularly, anatomically, and functionally distinct subpopulations. We summarize recent work linking neuron types to movement-pattern generation across fish, amphibians, reptiles, birds and mammals.