Neural Circuits Research Articles

Autophagy induction by piplartine ameliorates axonal degeneration caused by mutant HSPB1 and HSPB8 in charcot-marie-tooth type 2 neuropathies.

HSPB1 [heat shock protein family B (small) member 1] and HSPB8 are essential molecular chaperones for neuronal proteostasis, as they prevent protein aggregation. Mutant HSPB1 and HSPB8 primarily harm peripheral neurons, resulting in axonal Charcot-Marie-Tooth neuropathies (CMT2). Macroautophagy/autophagy is a shared mechanism by which HSPB1 and HSPB8 mutations cause neuronal dysfunction. Autophagosome formation is reduced in mutant HSPB1-induced pluripotent stem-cell-derived motor neurons from CMT type 2F patients. Likewise, the HSPB8K141N knockin mouse model, mimicking CMT type 2 L, exhibits axonal degeneration and muscle atrophy, with SQSTM1/p62-positive deposits. We show here that mouse embryonic fibroblasts isolated from a HSPB8K141N/green fluorescent protein (GFP)-LC3 model have diminished autophagosome production under conditions of MTOR inhibition. To correct the autophagic deficits in the HSPB1 and HSPB8 models, we screened by high-throughput autophagosome quantification the repurposing Spectrum Collection library for molecules that could boost the autophagic activity above the canonical MTOR inhibition. Hit compounds were validated on motor neurons obtained by differentiation of HSPB1P182L and HSPB8K141N patient-derived induced pluripotent stem cells, focusing on autophagy induction as well as neurite network density, axonal degeneration, and mitochondrial morphology. We identified molecules that specifically stimulate autophagosome formation in the HSPB8K141N cells, without affecting autophagy flux. Two top lead compounds induced autophagy and reduced axonal degeneration, thus promoting neuronal network maturation in the CMT2 patient-derived motor neurons. Based on these findings, the phenotypical screen revealed that piplartine rescued autophagy deficiencies in both the HSPB1 and HSPB8 models, demonstrating autophagy induction as an effective therapeutic strategy for CMT neuropathies and other chaperonopathies.

Dynamic changes in the hippocampal neuronal circuits activity following acute stress revealed by miniature fluorescence microscopy imaging

Coordinated activity of neuronal ensembles is a basis for information processing in the brain. Recent development of miniscope imaging technology enabled recordings of neuronal circuits activity in vivo in freely behaving animals. Acute stress is believed to affect various hippocampal functions, especially memory. In the current study, we utilized miniscope imaging to investigate the hippocampal neuronal circuits properties in a mouse as function of time and immediately in response to an acute stress, induced by passive restraint, 3 h and 10 days after. Comprehensive quantitative analysis of network activity changes at the neuronal ensembles level revealed highly stable neuronal activity parameters, which exhibited a rapid and robust shift in response to acute stress stimulation. This shift was accompanied by the restructuring of the pairwise-correlated neuronal pairs. Remarkably, we discovered that ensembles activity characteristics returned to the initial state following recovery period, demonstrating hippocampal homeostatic stability at the neuronal circuits level. Obtained results provide an evidence about hippocampal neuronal ensembles activity in response to acute stress over time.

Endoplasmic Reticulum Calcium Signaling in Hippocampal Neurons

The endoplasmic reticulum (ER) is a key organelle in cellular homeostasis, regulating calcium levels and coordinating protein synthesis and folding. In neurons, the ER forms interconnected sheets and tubules that facilitate the propagation of calcium-based signals. Calcium plays a central role in the modulation and regulation of numerous functions in excitable cells. It is a versatile signaling molecule that influences neurotransmitter release, muscle contraction, gene expression, and cell survival. This review focuses on the intricate dynamics of calcium signaling in hippocampal neurons, with particular emphasis on the activation of voltage-gated and ionotropic glutamate receptors in the plasma membrane and ryanodine and inositol 1,4,5-trisphosphate receptors in the ER. These channels and receptors are involved in the generation and transmission of electrical signals and the modulation of calcium concentrations within the neuronal network. By analyzing calcium fluctuations in neurons and the associated calcium handling mechanisms at the ER, mitochondria, endo-lysosome and cytosol, we can gain a deeper understanding of the mechanistic pathways underlying neuronal interactions and information transfer.

Alterations of the IKZF1-IKZF2 tandem in immune cells of schizophrenia patients regulate associated phenotypes

Schizophrenia is a complex multifactorial disorder and increasing evidence suggests the involvement of immune dysregulations in its pathogenesis. We observed that IKZF1 and IKZF2, classic immune-related transcription factors (TFs), were both downregulated in patients’ peripheral blood mononuclear cells (PBMCs) but not in their brain. We generated a new mutant mouse model with a reduction in Ikzf1 and Ikzf2 to study the impact of those changes. Such mice developed deficits in the three dimensions (positive–negative-cognitive) of schizophrenia-like phenotypes associated with alterations in structural synaptic plasticity. We then studied the secretomes of cultured PBMCs obtained from patients and identified potentially secreted molecules, which depended on IKZF1 and IKZF2 mRNA levels, and that in turn have an impact on neural synchrony, structural synaptic plasticity and schizophrenia-like symptoms in in vivo and in vitro models. Our results point out that IKZF1-IKZF2-dependent immune signals negatively impact on essential neural circuits involved in schizophrenia.

The NExT trial: Protocol for a two-phase randomized controlled trial testing transcranial magnetic stimulation to augment exposure therapy for youth with OCD

BackgroundExposure with Response Prevention (ERP) is a first-line treatment for OCD, but even when combined with first-line medications it is insufficiently effective for approximately half of patients. Compulsivity in OCD is thought to arise from an imbalance of two distinct neural circuits associated with specific subregions of striatum. Targeted modulation of these circuits via key cortical nodes (dorsolateral prefrontal cortex [dlPFC] or presupplementary motor area [pSMA]) has the potential to improve ERP efficacy by decreasing compulsions during therapy.MethodsThe NExT (Neuromodulation + Exposure Therapy) trial is a two-phase, multisite early-stage randomized controlled trial designed to examine whether TMS augmentation of ERP alters activity in dlPFC and/or pSMA-associated circuitry and reduces compulsions during therapy in youth with OCD age 12–21 years. Phase 1 (N = 60) will compare two different active TMS regimens with sham: A. continuous theta burst stimulation (cTBS) to pSMA vs. B. intermittent theta burst stimulation (iTBS) to dlPFC. A priori “Go/No-Go” criteria will inform a decision to proceed to Phase 2 and the choice of TMS regimen. Phase 2 (N = 60) will compare the selected TMS regimen vs. sham in a new sample.DiscussionThis trial is the first to test TMS augmentation of ERP in youth with OCD. Results will inform the potential of TMS to enhance ERP efficacy and enhance knowledge about mechanisms of change.Trial registrationClinicalTrials.gov NCT05931913. Registered prospectively on July 5, 2023.

Longitudinal changes in electrophysiology and widefield calcium imaging following electrode implantation.

Intracortical microelectrode arrays often fail to deliver reliable signal quality over chronic recordings, and the effect of an implanted recording array on local neural circuits is not completely understood. 

Approach: In this work we examined the degree of correlation and the spatial dependence of that relationship between widefield calcium imaging and electrophysiology in awake mice from the 4 days to 44 days post-implantation. Both correlation maps and spike-triggered averaging are used to characterize the relationship. 

Main results: We find that calcium imaging and electrophysiological signal are highly correlated in all animals, however, spatial variability in the correlation is affected by inherent correlation in the calcium imaging signal. Some animals exhibit a high degree of apparent neuronal synchrony in the vicinity of the probe at 4 days, while more diversity of response is detected at later timepoints.

Significance: Degree of synchrony appears to be related to the acute injury response to the implanted electrode, with later timepoints displaying less synchrony. Spike-triggered averaging may be used to uncover the diverse cortical connections of spiking units. &#xD.

Synaptic Gα12/13 signaling establishes hippocampal PV inhibitory circuits

Combinatorial networks of cell adhesion molecules and cell surface receptors drive fundamental aspects of neural circuit establishment and function. However, the intracellular signals orchestrated by these cell surface complexes remain less understood. Here, we report that the Gα12/13 pathway lies downstream of several GPCRs with critical synaptic functions. Impairment of the Gα12/13 pathway in postnatal hippocampal neurons diminishes inhibitory inputs without altering neuronal morphology or excitatory transmission. Gα12/13 signaling in hippocampal CA1 neurons in vivo selectively regulates PV interneuron synaptic connectivity, supporting an inhibitory synapse subtype-specific function of this pathway. Our studies establish Gα12/13 as a signaling node that shapes inhibitory hippocampal circuitry.

Disorder-specific neurodynamic features in schizophrenia inferred by neurodynamic embedded contrastive variational autoencoder model

Neurodynamic models that simulate how micro-level alterations propagate upward to impact macroscopic neural circuits and overall brain function may offer valuable insights into the pathological mechanisms of schizophrenia (SCZ). In this study, we integrated a neurodynamic model with the classical Contrastive Variational Autoencoder (CVAE) to extract and evaluate macro-scale SCZ-specific features, including subject-level, region-level parameters, and time-varying states. Firstly, we demonstrated the robust fitting of the model within our multi-site dataset. Subsequently, by employing representational similarity analysis and a deep learning classifier, we confirmed the specificity and disorder-related information capturing ability of SCZ-specific features. Moreover, analysis of the attractor characteristics of the neurodynamic system revealed significant differences in attractor space patterns between SCZ-specific states and shared states. Finally, we utilized Partial Least Squares (PLS) regression to examine the multivariate mapping relationship between SCZ-specific features and symptoms, identifying two sets of correlated modes implicating unique molecular mechanisms: one mode corresponding to negative and general symptoms, and another mode corresponding to positive symptoms. Our results provide valuable insights into disorder-specific neurodynamic features and states associated with SCZ, laying the foundation for understanding the intricate pathophysiology of this disorder.

Peter W. Kalivas: To the tetrapartite synapse and beyond – A pathway for new drug targets to treat behavioral disorders

Peter Kalivas stands as a pioneering architect in our understanding of addiction neuroscience, having transformed our knowledge of how substances of abuse reshape brain circuits and cellular function. Over four decades, his groundbreaking research has illuminated the fundamental mechanisms underlying substance use disorders, mainly through his seminal discoveries of glutamate's critical role in addiction and his innovative work on the “tetrapartite synapse” – revealing how astroglia and the extracellular matrix regulate addictive behaviors. With over 400 publications and eight edited volumes, his research has revolutionized our conceptual framework for treating addiction by identifying novel therapeutic targets beyond traditional neurotransmitter systems. After receiving his PhD in Pharmacology from the University of Washington and completing postdoctoral training at the University of North Carolina, Dr. Kalivas built an extraordinary scientific legacy at Washington State University and then as the founding Chair of Neuroscience at the Medical University of South Carolina. There, he established a world-renowned research program that has trained generations of addiction scientists while developing innovative approaches to understanding stress, PTSD, and substance use disorders. Now serving as Distinguished University Professor, he continues to pioneer new frontiers in addiction neuroscience through his work on neural circuits and synaptic plasticity. In this Genomic Press Interview, Dr. Kalivas shares insights from his remarkable journey investigating the neurobiology of addiction and his vision for the field's future.

Munir Gunes Kutlu: Exploring the neural mechanisms of learning and social behaviors – A scientist's journey and perspective

Dr. Munir “Gunes” Kutlu, Assistant Professor at the Center for Substance Abuse Research (CSAR) and the Department of Neural Sciences at Temple University Lewis Katz School of Medicine, investigates the neural mechanisms underlying associative learning, mainly focusing on reward, fear, and social interaction. Drawing from his computational neuroscience training at Duke University and postdoctoral work at Temple and Vanderbilt Universities, Dr. Kutlu combines systems neuroscience, computational approaches, and behavioral analysis to understand how our brains process environmental associations and how these processes can become maladaptive in disease states. His laboratory, dedicated to “bridging the brain-behavior gap,” fosters a collaborative environment that nurtures the next generation of neuroscientists while pursuing innovative neural circuit analysis approaches in reward and aversive learning contexts. In this Genomic Press interview, Dr. Kutlu shares his insights on these fascinating aspects of behavioral neuroscience and his laboratory's mission to advance our understanding of neural circuit function in health and disease.

The Intersection of Emotional Neuroscience and Learning: A Comprehensive Review of Current Research

This paper provides a broad-based review of how emotional neuroscience intersects with learning, emphasizing the critical role that emotions play in cognitive processes and memory formation. It discusses research into the neurobiological underpinnings and neural circuits that demonstrate the deep-seated influence of emotional states on attention, memory retention, and cognitive activities. It covers theoretical frameworks and strategies for how to enhance educational outcomes through emotional regulation using cognitive reappraisal and the strategic use of emotional content in educational materials. This research brings together insights from interdisciplinary research in psychology, neuroscience, and technology for a more accurate understanding of how important emotional intelligence is to academic and social performance. This paper argues that emotional arousal can be exploited to benefit memory retention and encourages further research in the field of emotional neuroscience to improve educational praxis. The results bear important implications for educators and show the prospect of implementing emotional intelligence and recognition tools in learning settings for better student involvement and academic performance.

Change on the Brain? The Neuroscience of Organizational Transformation

True transformations aim to change the core identity of an organization, are often disruptive, and rarely result in their intended outcomes. The objective of this paper is to propose a theoretical approach for more effective transformations via the syntheses of emerging findings in managerial science, organizational psychology, and social cognitive neuroscience. The authored conducted a literature review of traditional methods and the application of neuroscience to organizational transformation, proposing that consideration to leader and employee neuroanatomy can significantly impact transformation success. The emergent five-phase approach - Exploration & Discovery, Surfacing & Co-Creation, Enablement & Prioritization, Implementation, and Empowerment - integrates practices informed by neuroscience to enhance leadership alignment, employee engagement, and change sustainability. By focusing on activities such as vision alignment, co-creation, and leadership development, the approach seeks to optimize brain functions related to trust, motivation, and adaptability. Neuroscientific concepts like neural synchrony, hormone and neurotransmitter release, and specific neural circuit activations are utilized to improve team dynamics, decision-making, and learning. This neuro-informed approach challenges conventional practices by emphasizing co-creative solutioning with employees, piloting programs, and empowering middle managers to lead transformation efforts. Data from case studies demonstrate significant improvements in employee experience and sustainable shifts in organizational behavior. The paper concludes with a call for further research to solidify the emerging intersection of neuroscience and organizational transformation.

Advanced Neural Probe Sensors toward Multi‐Modal Sensing and Modulation: Design, Integration, and Applications

AbstractNeural probe devices have undergone significant advancements in recent years, evolving from basic single‐functional devices to sophisticated integrated systems capable of sensing, stimulating, and regulating neural activity. The neural probes have been demonstrated as effective tools for diagnosing and treating numerous neurological disorders, as well as for understanding sophisticated connections and functions of neuron circuits. The multifunctional neural probe platforms, which combine electrical, optical, and chemical sensing capabilities, hold promising potential for revolutionizing personalized healthcare through closed‐loop neuromodulation, particularly in the treatment of conditions such as epilepsy, Parkinson's disease, and depression. Despite these advances, several challenges remain to be further investigated, including biocompatibility, long‐term signal quality and stability, and miniaturization, all of which hinder their broader clinical application. This paper provides an overview of the design principles of the neural probe structures and sensors, fabrication strategies, and integration techniques for the advanced multi‐functional neural probes. Key electrical, optical, and chemical sensing mechanisms are discussed, along with the selection of corresponding functional materials. Additionally, several representative applications are highlighted, followed by a discussion of the challenges and opportunities that lie ahead for this emerging field.

Neural circuits and therapeutic mechanisms of empathic pain.

Empathy is the capacity to understand and share the experiences of others. This ability fosters connections between individuals, enriching the fabric of our shared world. One notable example is empathy for the pain of others. Such experiences facilitate the identification of potential dangers, both for oneself and for others. Neuroimaging studies have helped to pinpoint brain regions that modulate empathic pain. Recently, there has also been a surge in studies exploring the neural mechanisms of empathic pain in rodent models. Neuropsychiatric disorders such as autism, psychosis, and schizophrenia often exhibit empathy deficits. Targeting the modulation of empathic pain holds potential for alleviating core symptoms in these patients. Interestingly, empathy research may also benefit pain management, leading to new approaches for understanding the negative emotions associated with pain. This review summarizes recent advances in neuroimaging for the study of empathic pain, outlines the underlying neurocircuit mechanisms, describes therapeutic strategies, and explores promising avenues for future research.

A novel anti-epileptogenesis strategy of temporal lobe epilepsy based on nitric oxide donor.

The molecular mechanism underlying the role of hippocampal hilar interneuron degeneration in temporal lobe epilepsy (TLE) remains unclear. Especially, very few studies have focused on the role of neuronal nitric oxide synthase (nNOS, encoded by Nos1) containing hilar interneurons in TLE. In the present study, Nos1 conditional knockout mice were constructed, and we found that selective deletion of Nos1 in hilar interneurons rather than dentate granular cells (DGCs) triggered epileptogenesis. The level of nNOS was downregulated in patients and mice with TLE. Nos1 deletion led to excessive epilepsy-like excitatory input circuit formation and hyperexcitation of DGCs. Replenishment of hilar nNOS protein blocked epileptogenic development and memory impairment in pilocarpine-induced TLE mice. Moreover, chronic treatment with DETA/NONOate, a slowly released exogenous nitric oxide (NO) donor, prevented aberrant neural circuits of DGCs and the consequent epileptogenesis without acute antiseizure effects. Therefore, we concluded that NO donor therapy may be a novel anti-epileptogenesis strategy, different from existing antiseizure medications (ASMs), for curing TLE.

Human–machine interfaces and the NEU-CHiP Project: an interview with Dr Eric Hill

After spending 8 years developing his laboratory at Aston University, Dr Eric Hill is now a Reader in Cellular and Molecular Neurobiology at Loughborough University. His main research interests include the development of tissue engineering strategies to model stem cell behaviour in the development of neuronal networks and also during neurodegeneration.

Metaplasticity-Enabled Graphene Quantum Dot Devices for Mitigating Catastrophic Forgetting in Artificial Neural Networks.

The limitations of deep neural networks in continuous learning stem from oversimplifying the complexities of biological neural circuits, often neglecting the dynamic balance between memory stability and learning plasticity. In this study, artificial synaptic devices enhanced with graphene quantum dots (GQDs) that exhibit metaplasticity is introduced, a higher-order form of synaptic plasticity that facilitates the dynamic regulation of memory and learning processes similar to those observed in biological systems. The GQDs-assisted devices utilize interface-mediated modifications in asymmetric conductive pathways, replicating classical synaptic plasticity mechanisms. This allows for repeatable and linearly programmable adjustments to future weight changes linked to historical weights. Incorporating metaplasticity is essential for achieving generalization within deep neural networks, which enables them to adapt more fluidly to new information while retaining previously acquired knowledge. The GQDs-device-based system achieved a 97% accuracy on the fourth MNIST dataset task, while consistently achieving performance levels above 94% on prior tasks. This performance substantiates the feasibility of directly transferring metaplasticity principles to deep neural networks, thereby addressing the challenges associated with catastrophic forgetting. These findings present a promising hardware solution for developing neuromorphic systems with robust and sustained learning capabilities that can effectively bridge the gap between artificial and biological neural networks.

Role of Neural Circuits in Cognitive Impairment.

Cognitive impairment refers to abnormalities in learning, memory and cognitive judgment, mainly manifested as symptoms such as decreased memory, impaired orientation and reduced computational ability. As the fundamental unit of information processing in the brain, neural circuits have recently attracted great attention due to their functions in regulating pain, emotion and behavior. Furthermore, a growing number of studies have suggested that neural circuits play an important role in cognitive impairment. Neural circuits can affect perception, attention and decision-making, they can also regulate language skill, thinking and memory. Pathological conditions crucially affecting the integrity and preservation of neural circuits and their connectivity will heavily impact cognitive abilities. Nowadays, technological developments have led to many novel methods for studying neural circuits, such as brain imaging, optogenetic techniques, and chemical genetics approaches. Therefore, neural circuits show great promise as a potential target in mitigating cognitive impairment. In this review we discuss the pathogenesis of cognitive impairment and the regulation and detection of neural circuits, thus highlighting the role of neural circuits in cognitive impairment. Hence, therapeutic agents against cognitive impairment may be developed that target neural circuits important in cognition.

AcidAGE: a biological age determination neural network based on urine organic acids.

Organic acids reflect the course of all important metabolic processes and the effects of diet, nutrient deficiency, lifestyle, and microbiota composition. In present work, we focused on identifying age-related changes in organic acids in urine, and creating a neural network model based on them to determine biological age. The investigation involves data on concentrations of 60 organic acids in urine of 863 samples. Due to data analysis we found these acids could be used to determine human biological age. Two models were created for calculating biological age: a comprehensive AcidAGE model and a concise AcidAGE model based on 10 indicators. Both models demonstrate high accuracy. The presented models are useful for dynamically assessing the impact of medical interventions, lifestyle and diet amendments, and taking nutraceuticals on overall health and the risk of disease occurrence or progression. Their advantage lies in their ability to quickly update estimates as the corresponding biological processes change.

Neuronal circuit mechanisms of competitive interaction between action-based and coincidence learning.

How information is integrated across different forms of learning is crucial to understanding higher cognitive functions. Animals form classic or operant associations between cues and their outcomes. It is believed that a prerequisite for operant conditioning is the formation of a classical association. Thus, both memories coexist and are additive. However, the two memories can result in opposing behavioral responses, which can be disadvantageous. We show that Drosophila classical and operant olfactory conditioning rely on distinct neuronal pathways leading to different behavioral responses. Plasticity in both pathways cannot be formed simultaneously. If plasticity occurs at both pathways, interference between them occurs and learning is disrupted. Activity of the navigation center is required to prevent plasticity in the classical pathway and enable it in the operant pathway. These findings fundamentally challenge hierarchical views of operant and classical learning and show that active processes prevent coexistence of the two memories.