Circuit Function Research Articles

Neuronal Circuit Evolution: From Development to Structure and Adaptive Significance.

Neuronal circuits represent the functional units of the brain. Understanding how the circuits are generated to perform computations will help us understand how the brain functions. Nevertheless, neuronal circuits are not engineered, but have formed through millions of years of animal evolution. We posit that it is necessary to study neuronal circuit evolution to comprehensively understand circuit function. Here, we review our current knowledge regarding the mechanisms that underlie circuit evolution. First, we describe the possible genetic and developmental mechanisms that have contributed to circuit evolution. Then, we discuss the structural changes of circuits during evolution and how these changes affected circuit function. Finally, we try to put circuit evolution in an ecological context and assess the adaptive significance of specific examples. We argue that, thanks to the advent of new tools and technologies, evolutionary neurobiology now allows us to address questions regarding the evolution of circuitry and behavior that were unimaginable until very recently.

Three paradoxes related to the mode of action of pramipexole: The path from D2/D3 dopamine receptor stimulation to modification of dopamine-modulated functions.

Pramipexole, a D2/D3 dopamine receptor agonist, is used to treat the motor symptoms of Parkinson's disease, caused by degeneration of the dopaminergic nigrostriatal pathway. There are three paradoxes associated with its mode of action. Firstly, stimulation of D2/D3 receptors leads to neuronal inhibition, although pramipexole does not inhibit but promotes some dopamine-modulated functions, such as locomotion and reinforcement. Secondly, another dopamine-modulated function, arousal, is not promoted but inhibited by pramipexole, leading to sedation. Thirdly, pramipexole-evoked sedation is associated with an increase in pupil diameter, although sedation is expected to cause pupil constriction. To resolve these paradoxes, the path from stimulation of D2/D3 receptors to the modification of dopamine-modulated functions has been tracked. The functions considered are modulated by midbrain dopaminergic nuclei: locomotion - substantia nigra pars compacta (SNc), reinforcement/motivation - ventral tegmental area (VTA), sympathetic activity (as reflected in pupil function) - VTA; arousal - ventral periaqueductal grey (vPAG), with contributions from VTA and SNc. The application of genetics-based molecular techniques (optogenetics and chemogenetics) has enabled tracing the chains of neurones from the dopaminergic nuclei to their final targets executing the functions. The functional neuronal circuits linked to the D2/D3 receptors in the dorsal and ventral striata, stimulated by inputs from SNc and VTA, respectively, may explain how neuronal inhibition induced by pramipexole is translated into the promotion of locomotion, reinforcement/motivation and sympathetic activity. As the vPAG may increase arousal mainly by stimulating cortical D1 dopamine receptors, pramipexole would stimulate only presynaptic D2/D3 receptors on vPAG neurones, curtailing their activity and leading to sedation.

Impact of social reward on stress circuit function and regulation: Path differences between value affirmation and emotional support

BackgroundAs two typical types of social rewards, both value affirmation and emotional support could alleviate acute stress response, but it is not clear whether they can impact stress circuit function and regulation through different neural pathways. MethodSixty-two participants were randomly assigned to the value affirmation, emotional support, and non-reward conditions, then administered an adapted version of the ScanSTRESS paradigm. Participants’ subjective reports of uncontrollability and social evaluative threat were measured to explore the mitigation of stress by social rewards at the behavioral level. Meanwhile, their acute salivary cortisol response to stress was compared among different social reward conditions. Furthermore, we computed linear contrasts for performance (vs relaxation) and reward (vs non-reward) and used psychophysiological interaction (PPI) analysis to explore the impact of social reward on stress circuit function and regulation. ResultsBoth value affirmation and emotional support conditions reduced subjective reports of uncontrollability and social evaluation threat, but not cortisol response to stress. Furthermore, value affirmation reduced uncontrollability by enhancing putamen activation, whereas emotional support reduced social evaluation threat by enhancing putamen activation. More importantly, during stress, value affirmation enhanced the functional connectivity of the putamen-hippocampus and putamen-angular gyrus (AG), whereas emotional support enhanced the functional connectivity of the putamen-ventrolateral prefrontal cortex (vlPFC) and putamen-temporal pole mid, compared to the non-reward condition. ConclusionValue affirmation and emotional support alleviated acute stress response in different neural pathways. These findings suggested a precise categorization of social reward in intervention of a range of adverse psychological and physiological responses caused by stress.

Defensive behavior: Sensing threats from terrestrial and aerial predators

The dorsal periaqueductal gray (dPAG) contains a tonically GABAergic network controlling defensive responses. Determining how this intrinsic dPAG inhibitory circuit functions might provide critical insights into how anti-predatory responses are organized.

Clinicopathologic Dissociation: Robust Lafora Body Accumulation in Malin KO Mice Without Observable Changes in Home-Cage Behavior.

Lafora disease (LD) is a syndrome of progressive myoclonic epilepsy and cumulative neurocognitive deterioration caused by recessively inherited genetic lesions of EPM2A (laforin) or NHLRC1 (malin). Neuropsychiatric symptomatology in LD is thought to be directly downstream of neuronal and astrocytic polyglucosan aggregates, termed Lafora bodies (LBs), which faithfully accumulate in an age-dependent manner in all mouse models of LD. In this study, we applied home-cage monitoring to examine the extent of neurobehavioral deterioration in a model of malin-deficient LD as a means to identify robust preclinical endpoints that may guide the selection of novel genetic treatments. At 6 weeks, ∼6-7 months, and ∼12 months of age, malin-deficient mice ("KO") and wild-type (WT) littermates underwent a standardized home-cage behavioral assessment designed to non-obtrusively appraise features of rest/arousal, consumptive behaviors, risk aversion, and voluntary wheel-running. At all timepoints, and over a range of metrics that we report transparently, WT and KO mice were essentially indistinguishable. In contrast, within WT mice compared across the same timepoints, we identified age-related nocturnal hypoactivity, diminished sucrose preference, and reduced wheel-running. Neuropathological examinations in subsets of the same mice revealed expected age-dependent LB accumulation, gliosis, and microglial activation in cortical and subcortical brain regions. At 12 months of age, despite the burden of neocortical LBs, we did not identify spontaneous seizures during an electroencephalographic (EEG) survey, and KO and WT mice exhibited similar spectral EEG features. However, in an in vitro assay of neocortical function, paroxysmal bursts of network activity (UP states) in KO slices were more prolonged at 3 and 6 months of age, but similar to WT at 12 months. KO mice displayed a distinct response to pentylenetetrazole, with a greater incidence of clonic seizures and a more pronounced postictal suppression of movement, feeding, and drinking behavior. Together, these results highlight the clinicopathologic dissociation in a mouse model of LD, where the accrual of LBs may latently modify cortical circuit function and seizure threshold without clinically meaningful changes in home-cage behavior. Our findings allude to a delay between LB accumulation and neurobehavioral decline in LD: one that may provide a window for treatment, and whose precise duration may be difficult to ascertain within the typical lifespan of a laboratory mouse.

Neuromodulation modifies α-synuclein spreading dynamics in vivo and the pattern is predicted by changes in whole-brain function

BackgroundMany neurodegenerative disease treatments, such as deep brain stimulation for Parkinson's Disease, can alleviate symptoms by primarily compensating for circuit dysfunctions. However, the stimulation's effect on the underlying disease progression remains relatively unknown. Here, we report that neuromodulation can not only modulate circuit function but also modulate the in vivo spreading dynamics of α-synuclein pathology, the primary pathological hallmark observed in Parkinson's Disease. MethodsIn a mouse model, pre-formed fibrils were injected into the striatum to induce widespread α-synuclein pathology. Two days after fibril injection, mice were treated for two weeks with daily optogenetic stimulation of the Secondary Motor Area, Layer V. Whole brains were then extracted, immunolabeled, cleared, and imaged with light-sheet fluorescent microscopy. ResultsRepeated optogenetic stimulation led to a decrease in pathology at the site of stimulation and at various cortical and subcortical regions, while the contralateral cortex saw a consistent increase. Aligning the pathology changes with optogenetic-fMRI measured brain activity, we found that the changes in pathology and brain function had similar spatial locations but opposite polarity. ConclusionThese results demonstrate the ability to modulate and predict whole brain pathology changes using neuromodulation, opening a new horizon for investigating optimized neuromodulation therapies.

Flexible IGZO TFT Technology for Shift Register Drivers

AbstractActive sensing matrices play a pivotal role in various electronic devices, including optical and X‐ray imaging arrays, electronic skins, and artificial tactile arrays, among others. These matrices function through a thin‐film active switching mechanism, allowing for the scanning of rows and columns by external circuitry to read the sensory signals of individual pixels. Recently, indium–gallium‐zinc oxide thin‐film transistors (IGZO TFTs) have emerged as highly promising technology in the realm of flexible electronics. They enable the large‐scale integration of functional circuits on flexible substrates. Shift registers are commonly employed as peripheral scanning circuits to sequentially address active‐matrix arrays. To enhance system compactness and minimize external electrical connections, it is imperative to seamlessly integrate shift registers within the active matrices. However, contemporary flexible IGZO‐based shift registers suffer from high operating voltages and low frequencies, which constrain their applicability in high‐performance flexible sensors and displays. In response to this challenge, a breakthrough is presented in the form of low‐voltage, high‐frequency bootstrap shift registers implemented with flexible IGZO technology. The approach involves utilizing SU‐8 buffered polyimide (PI) polymer foils as substrates. These foils boast an exceptional level of surface smoothness, significantly increasing the yield and performance of electronic components, including vias, IGZO TFTs, and capacitors used in the shift register circuitry. Additionally, HfO2/Al2O3/HfO2 sandwich structures are employed as high‐k dielectric layers to reduce the operational voltage. Thanks to the innovative circuit design and optimized fabrication methods, the 16‐stage shift register can operate at just 1.8 V with a frequency of 15 kHz. This breakthrough promises to have a profound impact on a wide range of applications for driving flexible active‐matrix electronic systems.

Avionics Module Fault Diagnosis Algorithm Based on Hybrid Attention Adaptive Multi-Scale Temporal Convolution Network.

Since the reliability of the avionics module is crucial for aircraft safety, the fault diagnosis and health management of this module are particularly significant. While deep learning-based prognostics and health management (PHM) methods exhibit highly accurate fault diagnosis, they have disadvantages such as inefficient data feature extraction and insufficient generalization capability, as well as a lack of avionics module fault data. Consequently, this study first employs fault injection to simulate various fault types of the avionics module and performs data enhancement to construct the P2020 communications processor fault dataset. Subsequently, a multichannel fault diagnosis method, the Hybrid Attention Adaptive Multi-scale Temporal Convolution Network (HAAMTCN) for the integrated functional circuit module of the avionics module, is proposed, which adaptively constructs the optimal size of the convolutional kernel to efficiently extract features of avionics module fault signals with large information entropy. Further, the combined use of the Interaction Channel Attention (ICA) module and the Hierarchical Block Temporal Attention (HBTA) module results in the HAAMTCN to pay more attention to the critical information in the channel dimension and time step dimension. The experimental results show that the HAAMTCN achieves an accuracy of 99.64% in the avionics module fault classification task which proves our method achieves better performance in comparison with existing methods.

A ventral pallidal-thalamocortical circuit mediates the cognitive control of instrumental action

Predictive learning can engage a selective form of cognitive control that biases choice between actions based on information about future outcomes that the learning provides. This influence has been hypothesized to depend on a feedback circuit in the brain through which the basal ganglia modulate activity in the prefrontal cortex; however, direct evidence for this functional circuit has proven elusive. Here, using an animal model of cognitive control, we found that the influence of predictive learning on decision making is mediated by an inhibitory feedback circuit linking the medial ventral pallidum and the mediodorsal thalamus, the activation of which causes disinhibition of the orbitofrontal cortex via reduced activation of inhibitory parvalbumin interneurons during choice. Thus, we found that, for this function, the mediodorsal thalamus serves as a pallidal-cortical relay through which predictive learning controls action selection, which has important implications for understanding cognitive control and its vicissitudes in various psychiatric disorders and addiction.

Experimental verification of guided-wave lumped circuits using dielectric rod

Abstract This paper presents a method to realize equivalent lumped inductance/capacitance by adjusting the relative permittivity, diameter, and offset of the dielectric rod. The dielectric rod is used to replace the traditional reactance matching elements (metallic diaphragm, pin, and resonant window) in the substrate integrated waveguide, which avoids the problem of short circuit in the upper and lower metal plate of the substrate integrated waveguide, and has the advantage of high regulatory freedom, low radiation loss, and low crosstalk. Based on this method, three air rod filters are designed and verified by experiments. The three filters are designed based on the diameter and offset of a single dielectric hole and the offset of symmetrical dielectric rods. Compared with conventional filters, this method greatly adjusts the degree of freedom of media regulation in the substrate integrated waveguide. The experimental results are in good agreement with theoretical analysis and simulation results. It provides an effective platform for the design of substrate integrated waveguide functional lumped circuits.

Longitudinal tracking of hemocyte populations in vivo indicates lineage relationships and supports neural progenitor identity in adult neurogenesis

Adult neurogenesis, which takes place in both vertebrate and invertebrate species, is the process by which new neurons are born and integrated into existing functional neural circuits, long after embryonic development. Most studies in mammals suggest that self-renewing stem cells are the source of the new neurons, although the extent of self-renewal is a matter of debate. In contrast, research in the crayfish Procambarus clarkii has demonstrated that the neural progenitors producing adult-born neurons are capable of both self-renewing and consuming (non-self-renewing) divisions. However, self-renewing divisions are relatively rare, and therefore the production of adult-born neurons depends heavily on progenitors that are not replenishing themselves. Because the small pool of neural progenitors in the neurogenic niche is never exhausted throughout the long lives of these animals, we hypothesized that there must also be an extrinsic source of these cells. It was subsequently demonstrated that the neural progenitors originate in hemocytes (blood cells) produced by the immune system that travel in the circulation before ultimately integrating into niches where the neural lineage begins. The current study examines the developmental lineage of the three hemocyte types — hyaline (HC), semigranular (SGC) and granular (GC) cells — with the goal of understanding the origins of the progenitor cells that produce adult-born neurons. Longstanding qualitative metrics for hemocyte classification were validated quantitatively. Then, in a longitudinal study, proliferation markers were used to label the hemocytes in vivo, followed by sampling the circulating hemocyte population over the course of two months. Hemolymph samples were taken at intervals to track the frequencies of the different hemocyte types. These data reveal sequential peaks in the relative frequencies of HCs, SGCs and GCs, which were identified using qualitative and quantitative measures. These findings suggest that the three hemocyte types comprise a single cellular lineage that occurs in the circulation, with each type as a sequential progressive stage in hemocyte maturation beginning with HCs and ending with GCs. When combined with previously published data, this timeline provides additional evidence that HCs serve as the primary neural progenitor during adult neurogenesis in P. clarkii.

Minimally-invasive implantable device enhances brain cancer suppression

Current brain tumor treatments are limited by the skull and BBB, leading to poor prognosis and short survival for glioma patients. We introduce a novel minimally-invasive brain tumor suppression (MIBTS) device combining personalized intracranial electric field therapy with in-situ chemotherapeutic coating. The core of our MIBTS technique is a wireless-ultrasound-powered, chip-sized, lightweight device with all functional circuits encapsulated in a small but efficient “Swiss-roll” structure, guaranteeing enhanced energy conversion while requiring tiny implantation windows ( ~ 3 × 5 mm), which favors broad consumers acceptance and easy-to-use of the device. Compared with existing technologies, competitive advantages in terms of tumor suppressive efficacy and therapeutic resolution were noticed, with maximum ~80% higher suppression effect than first-line chemotherapy and 50–70% higher than the most advanced tumor treating field technology. In addition, patient-personalized therapy strategies could be tuned from the MIBTS without increasing size or adding circuits on the integrated chip, ensuring the optimal therapeutic effect and avoid tumor resistance. These groundbreaking achievements of MIBTS offer new hope for controlling tumor recurrence and extending patient survival.

Retrograde adenosine/A2A receptor signaling facilitates excitatory synaptic transmission and seizures

Retrograde signaling at the synapse is a fundamental way by which neurons communicate and neuronal circuit function is fine-tuned upon activity. While long-term changes in neurotransmitter release commonly rely on retrograde signaling, the mechanisms remain poorly understood. Here, we identified adenosine/A2A receptor (A2AR) as a retrograde signaling pathway underlying presynaptic long-term potentiation (LTP) at a hippocampal excitatory circuit critically involved in memory and epilepsy. Transient burst activity of a single dentate granule cell induced LTP of mossy cell synaptic inputs, a BDNF/TrkB-dependent form of plasticity that facilitates seizures. Postsynaptic TrkB activation released adenosine from granule cells, uncovering a non-conventional BDNF/TrkB signaling mechanism. Moreover, presynaptic A2ARs were necessary and sufficient for LTP. Lastly, seizure induction released adenosine in a TrkB-dependent manner, while removing A2ARs or TrkB from the dentate gyrus had anti-convulsant effects. By mediating presynaptic LTP, adenosine/A2AR retrograde signaling may modulate dentate gyrus-dependent learning and promote epileptic activity.

How omics is revealing new roles for glia in addiction.

Experiments to study the biology of addiction have historically focused on the mechanisms through which drugs of abuse drive changes in the functioning of neurons and neural circuits. Glia have often been ignored in these studies, however, and this has left many questions in the field unanswered, particularly, surrounding how glia contribute to changes in synaptic plasticity, regulation of neuroinflammation, and functioning of neural ensembles given massive changes in signaling across the CNS. Omics methods (transcriptomics, translatomics, epigenomics, proteomics, metabolomics, and others) have expanded researchers' abilities to generate hypotheses and carry out mechanistic studies of glial cells during acquisition of drug taking, intoxication, withdrawal, and relapse to drug seeking. Here, we present a survey of how omics technological advances are revising our understanding of astrocytes, microglia, oligodendrocytes, and ependymal cells in addiction biology.

Integration of Functional Human Auditory Neural Circuits Based on a 3D Carbon Nanotube System.

The physiological interactions between the peripheral and central auditory systems are crucial for auditory information transmission and perception, while reliable models for auditory neural circuits are currently lacking. To address this issue, mouse and human neural pathways are generated by utilizing a carbon nanotube nanofiber system. The super-aligned pattern of the scaffold renders the axons of the bipolar and multipolar neurons extending in a parallel direction. In addition, the electrical conductivity of the scaffold maintains the electrophysiological activity of the primary mouse auditory neurons. The mouse and human primary neurons from peripheral and central auditory units in the system are then co-cultured and showed that the two kinds of neurons form synaptic connections. Moreover, neural progenitor cells of the cochlea and auditory cortex are derived from human embryos to generate region-specific organoids and these organoids are assembled in the nanofiber-combined 3D system. Using optogenetic stimulation, calcium imaging, and electrophysiological recording, it is revealed that functional synaptic connections are formed between peripheral neurons and central neurons, as evidenced by calcium spiking and postsynaptic currents. The auditory circuit model will enable the study of the auditory neural pathway and advance the search for treatment strategies for disorders of neuronal connectivity in sensorineural hearing loss.

The transcriptomic and spatial organization of telencephalic GABAergic neuronal types.

The telencephalon of the mammalian brain comprises multiple regions and circuit pathways that play adaptive and integrative roles in a variety of brain functions. There is a wide array of GABAergic neurons in the telencephalon; they play a multitude of circuit functions, and dysfunction of these neurons has been implicated in diverse brain disorders. In this study, we conducted a systematic and in-depth analysis of the transcriptomic and spatial organization of GABAergic neuronal types in all regions of the mouse telencephalon and their developmental origins. This was accomplished by utilizing 611,423 single-cell transcriptomes from the comprehensive and high-resolution transcriptomic and spatial cell type atlas for the adult whole mouse brain we have generated, supplemented with an additional single-cell RNA-sequencing dataset containing 99,438 high-quality single-cell transcriptomes collected from the pre- and postnatal developing mouse brain. We present a hierarchically organized adult telencephalic GABAergic neuronal cell type taxonomy of 7 classes, 52 subclasses, 284 supertypes, and 1,051 clusters, as well as a corresponding developmental taxonomy of 450 clusters across different ages. Detailed charting efforts reveal extraordinary complexity where relationships among cell types reflect both spatial locations and developmental origins. Transcriptomically and developmentally related cell types can often be found in distant and diverse brain regions indicating that long-distance migration and dispersion is a common characteristic of nearly all classes of telencephalic GABAergic neurons. Additionally, we find various spatial dimensions of both discrete and continuous variations among related cell types that are correlated with gene expression gradients. Lastly, we find that cortical, striatal and some pallidal GABAergic neurons undergo extensive postnatal diversification, whereas septal and most pallidal GABAergic neuronal types emerge simultaneously during the embryonic stage with limited postnatal diversification. Overall, the telencephalic GABAergic cell type taxonomy can serve as a foundational reference for molecular, structural and functional studies of cell types and circuits by the entire community.

Adult expression of the cell adhesion protein Fasciclin 3 is required for the maintenance of adult olfactory interneurons.

The proper functioning of the nervous system is dependent on the establishment and maintenance of intricate networks of neurons that form functional neural circuits. Once neural circuits are assembled during development, a distinct set of molecular programs is likely required to maintain their connectivity throughout the lifetime of the organism. Here, we demonstrate that Fasciclin 3 (Fas3), an axon guidance cell adhesion protein, is necessary for the maintenance of the olfactory circuit in adult Drosophila. We utilized the TARGET system to spatiotemporally knockdown Fas3 in selected populations of adult neurons. Our findings show that Fas3 knockdown results in the death of olfactory circuit neurons and reduced survival of adults. We also demonstrated that Fas3 knockdown activates caspase-3-mediated cell death in olfactory local interneurons, which can be rescued by overexpressing baculovirus p35, an anti-apoptotic protein. This work adds to the growing set of evidence indicating a crucial role for axon guidance proteins in the maintenance of neuronal circuits in adults.

δ-containing GABA A receptors on parvalbumin interneurons modulate neuronal excitability and network dynamics in the mouse medial prefrontal cortex.

By selectively deleting δ-containing GABAA receptors in PV interneurons, we demonstrate the importance of these receptors on PV interneuron excitability, synaptic inhibition of pyramidal neurons, and circuit function.

Adherence and retention of elderly people in physical exercise

Background: The combination of aerobic exercise and transcutaneous microcurrent electrical stimulation (MES) application was shown to have a positive effect on localized abdominal adiposity (LAA) reduction. However, the effect of the combination of MES and high-intensity interval training (HIIT) is still unknown. Objective: This study aimed to evaluate the effect of combination of MES and HIIT on LAA reduction. Methods: 39 sedentary women with LAA, distributed in a control group (CG), an exercise group (EG), and a MES plus exercise group (MEG) participated in this randomized clinical trial. The CG was not submitted to intervention. The EG was submitted to a HIIT protocol (80% of heart rate max in a functional circuit) and MEG was submitted to abdominal transcutaneous application of MES prior to HIIT, 2x/week, during 5 weeks. The outcomes were collected by a blind evaluator and measured in three moments (before the 1st intervention, and after the 5th and 10th intervention), based on body composition parameters, anthropometric data, physical activity level (PAL), body satisfaction, quality of life (QOL), and lumbar functionality. Results: After 10 interventions, MEG showed significant improvement in skinfolds, QOL, and body satisfaction, but no significant difference compared to EG or CG. Regarding PAL, MEG differed significantly in relation to CG, but not in relation to EG. Conclusion: The combination of MES and HIIT in 10 interventions did not show satisfactory results for LAA reduction compared to HIIT, but the increase in PAL and the improvement in lumbar functionality may provide positive effects in the medium-term, although further studies are required.

Conductance-based dendrites perform Bayes-optimal cue integration.

A fundamental function of cortical circuits is the integration of information from different sources to form a reliable basis for behavior. While animals behave as if they optimally integrate information according to Bayesian probability theory, the implementation of the required computations in the biological substrate remains unclear. We propose a novel, Bayesian view on the dynamics of conductance-based neurons and synapses which suggests that they are naturally equipped to optimally perform information integration. In our approach apical dendrites represent prior expectations over somatic potentials, while basal dendrites represent likelihoods of somatic potentials. These are parametrized by local quantities, the effective reversal potentials and membrane conductances. We formally demonstrate that under these assumptions the somatic compartment naturally computes the corresponding posterior. We derive a gradient-based plasticity rule, allowing neurons to learn desired target distributions and weight synaptic inputs by their relative reliabilities. Our theory explains various experimental findings on the system and single-cell level related to multi-sensory integration, which we illustrate with simulations. Furthermore, we make experimentally testable predictions on Bayesian dendritic integration and synaptic plasticity.