Sensory Circuits Research Articles

Imaging whole-brain activity to understand behavior.

The brain evolved to produce behaviors that help an animal inhabit the natural world. During natural behaviors, the brain is engaged in many levels of activity from the detection of sensory inputs to decision-making to motor planning and execution. To date, most brain studies have focused on small numbers of neurons that interact in limited circuits. This allows analyzing individual computations or steps of neural processing. During behavior, however, brain activity must integrate multiple circuits in different brain regions. The activities of different brain regions are not isolated, but may be contingent on one another. Coordinated and concurrent activity within and across brain areas is organized by (1) sensory information from the environment, (2) the animal's internal behavioral state, and (3) recurrent networks of synaptic and non-synaptic connectivity. Whole-brain recording with cellular resolution provides a new opportunity to dissect the neural basis of behavior, but whole-brain activity is also mutually contingent on behavior itself. This is especially true for natural behaviors like navigation, mating, or hunting, which require dynamic interaction between the animal, its environment, and other animals. In such behaviors, the sensory experience of an unrestrained animal is actively shaped by its movements and decisions. Many of the signaling and feedback pathways that an animal uses to guide behavior only occur in freely moving animals. Recent technological advances have enabled whole-brain recording in small behaving animals including nematodes, flies, and zebrafish. These whole-brain experiments capture neural activity with cellular resolution spanning sensory, decision-making, and motor circuits, and thereby demand new theoretical approaches that integrate brain dynamics with behavioral dynamics. Here, we review the experimental and theoretical methods that are being employed to understand animal behavior and whole-brain activity, and the opportunities for physics to contribute to this emerging field of systems neuroscience.

Hierarchical timescales in the neocortex: Mathematical mechanism and biological insights

A cardinal feature of the neocortex is the progressive increase of the spatial receptive fields along the cortical hierarchy. Recently, theoretical and experimental findings have shown that the temporal response windows also gradually enlarge, so that early sensory neural circuits operate on short timescales whereas higher-association areas are capable of integrating information over a long period of time. While an increased receptive field is accounted for by spatial summation of inputs from neurons in an upstream area, the emergence of timescale hierarchy cannot be readily explained, especially given the dense interareal cortical connectivity known in the modern connectome. To uncover the required neurobiological properties, we carried out a rigorous analysis of an anatomically based large-scale cortex model of macaque monkeys. Using a perturbation method, we show that the segregation of disparate timescales is defined in terms of the localization of eigenvectors of the connectivity matrix, which depends on three circuit properties: 1) a macroscopic gradient of synaptic excitation, 2) distinct electrophysiological properties between excitatory and inhibitory neuronal populations, and 3) a detailed balance between long-range excitatory inputs and local inhibitory inputs for each area-to-area pathway. Our work thus provides a quantitative understanding of the mechanism underlying the emergence of timescale hierarchy in large-scale primate cortical networks.

Reciprocally inhibitory circuits operating with distinct mechanisms are differently robust to perturbation and modulation.

Reciprocal inhibition is a building block in many sensory and motor circuits. We studied the features that underly robustness in reciprocally inhibitory two neuron circuits. We used the dynamic clamp to create reciprocally inhibitory circuits from pharmacologically isolated neurons of the crab stomatogastric ganglion by injecting artificial graded synaptic (ISyn) and hyperpolarization-activated inward (IH) currents. There is a continuum of mechanisms in circuits that generate antiphase oscillations, with 'release' and 'escape' mechanisms at the extremes, and mixed mode oscillations between these extremes. In release, the active neuron primarily controls the off/on transitions. In escape, the inhibited neuron controls the transitions. We characterized the robustness of escape and release circuits to alterations in circuit parameters, temperature, and neuromodulation. We found that escape circuits rely on tight correlations between synaptic and H conductances to generate bursting but are resilient to temperature increase. Release circuits are robust to variations in synaptic and H conductances but fragile to temperature increase. The modulatory current (IMI) restores oscillations in release circuits but has little effect in escape circuits. Perturbations can alter the balance of escape and release mechanisms and can create mixed mode oscillations. We conclude that the same perturbation can have dramatically different effects depending on the circuits' mechanism of operation that may not be observable from basal circuit activity.

Lack of correlation between odor composition and neuron response in the olfactory cortex of mice

In the mammalian brain, sensory circuits are usually organized in a topographical way, meaning that, for a given brain region, neighboring neurons respond to stimuli close to each other in their sensory space. Olfaction is a notable exception to this rule; projections to the olfactory system are sparse and dispersed, leading to no apparent topography. Here, we assessed the presence of a topographical map in the mouse olfactory cortex, using a previously generated online dataset of neuronal recordings. The dataset consisted of about 1,800 olfactory cortical neurons collected from 10 mice, stimulated with a panel of 15 odorants. If there is no odor topography in the olfactory cortex, there should be no correlation between the chemical composition of odorants and their evoked neuronal response. To test this hypothesis, we first calculated odor similarity between each pair of odorants, using their chemical traits. Then, for each odor pair, we computed the similarity between their evoked neuronal responses. Finally, we assessed the relationship between odor similarity and neuronal response similarity. We found little to no correlation between the two variables (R2 averaged across all mice tested: 0.015), which suggests the lack of topography in the murine olfactory cortex and opens new questions into what other variables might play a role in odorant distinction.

The Role of Even-Skipped in Drosophila Larval Somatosensory Circuit Assembly.

Proper somatosensory circuit assembly is critical for processing somatosensory stimuli and for responding accordingly. In comparison to other sensory circuits (e.g., olfactory and visual), somatosensory circuits have unique anatomy and function. However, understanding of somatosensory circuit development lags far behind that of other sensory systems. For example, there are few identified transcription factors required for integration of interneurons into functional somatosensory circuits. Here, as a model, we examine one type of somatosensory interneuron, Even-skipped (Eve) expressing laterally placed interneurons (ELs) of the Drosophila larval nerve cord. Eve is a highly conserved, homeodomain transcription factor known to play a role in cell fate specification and neuronal axon guidance. Because marker genes are often functionally important in the cell types they define, we deleted eve expression specifically from EL interneurons. On the cell biological level, using single neuron labeling, we find eve plays several previously undescribed roles in refinement of neuron morphogenesis. Eve suppresses aberrant neurite branching, promotes axon elongation, and regulates dorsal-ventral dendrite position. On the circuit level, using optogenetics, calcium imaging, and behavioral analysis, we find eve expression is required in EL interneurons for the normal encoding of somatosensory stimuli and for normal mapping of outputs to behavior. We conclude that the eve gene product coordinately regulates multiple aspects of EL interneuron morphogenesis and is critically required to properly integrate EL interneurons into somatosensory circuits. Our data shed light on the genetic regulation of somatosensory circuit assembly.

Transient, developmental functional and structural connectivity abnormalities in the thalamocortical motor network in Rolandic epilepsy

Rolandic epilepsy (RE) is the most common focal, idiopathic, developmental epilepsy, characterized by a transient period of sleep-potentiated seizures and epileptiform discharges in the inferior Rolandic cortex during childhood. The cause of RE remains unknown but converging evidence has identified abnormalities in the Rolandic thalamocortical circuit. To better localize this transient disease, we evaluated Rolandic thalamocortical functional and structural connectivity in the sensory and motor circuits separately during the symptomatic and asymptomatic phases of this disease. We collected high resolution structural, diffusion, and resting state functional MRI data in a prospective cohort of children with active RE (n = 17), resolved RE (n = 21), and controls (n = 33). We then computed the functional and structural connectivity between the inferior Rolandic cortex and the ventrolateral (VL) nucleus of the thalamus (efferent pathway) and the ventroposterolateral (VPL) nucleus of the thalamus (afferent pathway) across development in children with active, resolved RE and controls. We compared connectivity with age in each group using linear mixed-effects models. We found that children with active RE have increasing thalamocortical functional connectivity between the VL thalamus and inferior motor cortex with age (p = 0.022) that is not observed in controls or resolved RE. In contrast, children with resolved RE have increasing thalamocortical structural connectivity between the VL nucleus and the inferior motor cortex with age (p = 0.025) that is not observed in controls or active RE. No relationships were identified between VPL nuclei and the inferior sensory cortex with age in any group. These findings localize the functional and structural thalamocortical circuit disruption in RE to the efferent thalamocortical motor pathway. Further work is required to determine how these circuit abnormalities contribute to the emergence and resolution of symptoms in this developmental disease.

Members of the vertebrate contactin and amyloid precursor protein families interact through a conserved interface

Contactins (CNTNs) are neural cell adhesion molecules that encode axon-target specificity during the patterning of the vertebrate visual and olfactory systems. Because CNTNs are tethered to the plasma membrane by a glycosylphosphatidylinositol anchor, they lack an intracellular region to communicate across the membrane. Instead, they form coreceptor complexes with distinct transmembrane proteins to transmit signals inside the cell. In particular, a complex of CNTN4 and amyloid precursor protein (APP) is known to guide the assembly of specific circuits in the visual system. Here, using in situ hybridization in zebrafish embryos, we show that CNTN4, CNTN5, and the APP homologs, amyloid beta precursor like protein 1 and amyloid beta precursor like protein 2, are expressed in olfactory pits, suggesting that these receptors may also function together in the organization of olfactory tissues. Furthermore, we use biochemical and structural approaches to characterize interactions between members of these two receptor families. In particular, APP and amyloid beta precursor like protein 1 interact with CNTN3–5, whereas amyloid beta precursor like protein 2 only binds to CNTN4 and CNTN5. Finally, structural analyses of five CNTN–amyloid pairs indicate that these proteins interact through a conserved interface involving the second fibronectin type III repeat of CNTNs and the copper-binding domain of amyloid proteins. Overall, this work sets the stage for analyzing CNTN–amyloid-mediated connectivity in vertebrate sensory circuits.

Transcranial Random Noise Stimulation Modulates Neural Processing of Sensory and Motor Circuits, from Potential Cellular Mechanisms to Behavior: A Scoping Review.

Noise introduced in the human nervous system from cellular to systems levels can have a major impact on signal processing. Using transcranial stimulation, electrical noise can be added to cortical circuits to modulate neuronal activity and enhance function in the healthy brain and in neurologic patients. Transcranial random noise stimulation (tRNS) is a promising technique that is less well understood than other non-invasive neuromodulatory methods. The aim of the present scoping review is to collate published evidence on the effects of electrical noise at the cellular, systems, and behavioral levels, and discuss how this emerging method might be harnessed to augment perceptual and motor functioning of the human nervous system. Online databases were used to identify papers published in 2008–2021 using tRNS in humans, from which we identified 70 publications focusing on sensory and motor function. Additionally, we interpret the existing evidence by referring to articles investigating the effects of noise stimulation in animal and subcellular models. We review physiological and behavioral findings of tRNS-induced offline after-effects and acute online benefits which manifest immediately when tRNS is applied to sensory or motor cortices. We link these results to evidence showing that activity of voltage-gated sodium ion channels might be an important cellular substrate for mediating these tRNS effects. We argue that tRNS might make neural signal transmission and processing within neuronal populations more efficient, which could contribute to both (1) offline after-effects in the form of a prolonged increase in cortical excitability and (2) acute online noise benefits when computations rely on weak inputs.

Sensory Circuit Remodeling and Movement Recovery After Spinal Cord Injury.

Restoring sensory circuit function after spinal cord injury (SCI) is essential for recovery of movement, yet current interventions predominantly target motor pathways. Integrated cortical sensorimotor networks, disrupted by SCI, are critical for perceiving, shaping, and executing movement. Corticocortical connections between primary sensory (S1) and motor (M1) cortices are critical loci of functional plasticity in response to learning and injury. Following SCI, in the motor cortex, corticocortical circuits undergo dynamic remodeling; however, it remains unknown how rehabilitation shapes the plasticity of S1-M1 networks or how these changes may impact recovery of movement.

Avian pallial circuits and cognition: A comparison to mammals.

Cognitive functions are similar in birds and mammals. So, are therefore pallial cellular circuits and neuronal computations also alike? In search of answers, we move in from bird's pallial connectomes, to cortex-like sensory canonical circuits and connections, to forebrain micro-circuitries and finally to the avian "prefrontal" area. This voyage from macro- to micro-scale networks and areas reveals that both birds and mammals evolved similar neural and computational properties in either convergent or parallel manner, based upon circuitries inherited from common ancestry. Thus, these two vertebrate classes evolved separately within 315 million years with highly similar pallial architectures that produce comparable cognitive functions.

High Dynamic Range Photocurrent Sensory Circuit with a Multi-Transistor Background Light Cancellation Loop for Photoplethysmography Sensing

In this article, we present a new photocurrent sensory circuit with a three-transistor background light cancellation. We describe our innovative photocurrent sensor-based blood pressure measuring device using a resistor-based current-to-voltage converter with a background light cancellation (BLC) loop. The photocurrent sensor is implemented using 0.35 μm standard CMOS technology and has zero average power consumption. The post-layout simulation for the photocurrent sensor shows a 1.3 MΩ transimpedance gain, a referred input noise current of 11 pA, and can reject a DC photocurrent up to 200 μA. This high DC rejection has been achieved due to the newly proposed multi-transistor BLC loop integrated with the sensor.

Opponent vesicular transporters regulate the strength of glutamatergic neurotransmission in a C. elegans sensory circuit

At chemical synapses, neurotransmitters are packaged into synaptic vesicles that release their contents in response to depolarization. Despite its central role in synaptic function, regulation of the machinery that loads vesicles with neurotransmitters remains poorly understood. We find that synaptic glutamate signaling in a C. elegans chemosensory circuit is regulated by antagonistic interactions between the canonical vesicular glutamate transporter EAT-4/VGLUT and another vesicular transporter, VST-1. Loss of VST-1 strongly potentiates glutamate release from chemosensory BAG neurons and disrupts chemotaxis behavior. Analysis of the circuitry downstream of BAG neurons shows that excess glutamate release disrupts behavior by inappropriately recruiting RIA interneurons to the BAG-associated chemotaxis circuit. Our data indicate that in vivo the strength of glutamatergic synapses is controlled by regulation of neurotransmitter packaging into synaptic vesicles via functional coupling of VGLUT and VST-1.

Development of astrocyte morphology and function in mouse visual thalamus.

The rodent visual thalamus has served as a powerful model to elucidate the cellular and molecular mechanisms that underlie sensory circuit formation and function. Despite significant advances in our understanding of the role of axon-target interactions and neural activity in orchestrating circuit formation in visual thalamus, the role of non-neuronal cells, such as astrocytes, is less clear. In fact, we know little about the transcriptional identity and development of astrocytes in mouse visual thalamus. To address this gap in knowledge, we studied the expression of canonical astrocyte molecules in visual thalamus using immunostaining, in situ hybridization, and reporter lines. While our data suggests some level of heterogeneity of astrocytes in different nuclei of the visual thalamus, the majority of thalamic astrocytes appeared to be labeled in Aldh1l1-EGFP mice. This led us to use this transgenic line to characterize the neonatal and postnatal development of these cells in visual thalamus. Our data show that not only have the entire cohort of astrocytes migrated into visual thalamus by eye-opening but they also have acquired their adult-like morphology, even while retinogeniculate synapses are still maturing. Furthermore, ultrastructural, immunohistochemical, and functional approaches revealed that by eye-opening, thalamic astrocytes ensheathe retinogeniculate synapses and are capable of efficient uptake of glutamate. Taken together, our results reveal that the morphological, anatomical, and functional development of astrocytes in visual thalamus occurs prior to eye-opening and the emergence of experience-dependent visual activity.

Activity-dependent alteration of early myelin ensheathment in a developing sensory circuit.

Myelination allows for the regulation of conduction velocity, affecting the precise timing of neuronal inputs important for the development and function of brain circuits. In turn, myelination may be altered by changes in experience, neuronal activity, and vesicular release, but the links between sensory experience, corresponding neuronal activity, and resulting alterations in myelination require further investigation. We thus studied the development of myelination in the Xenopus laevis tadpole, a classic model for studies of visual system development and function because it is translucent and visually responsive throughout the formation of its retinotectal system. We begin with a systematic characterization of the timecourse of early myelin ensheathment in the Xenopus retinotectal system using immunohistochemistry of myelin basic protein (MBP) along with third harmonic generation (THG) microscopy, a label-free structural imaging technique. Based on the mid-larval developmental progression of MBP expression in Xenopus, we identified an appropriate developmental window in which to assess the effects of early temporally patterned visual experience on myelin ensheathment. We used calcium imaging of axon terminals in vivo to characterize the responses of retinal ganglion cells over a range of stroboscopic stimulation frequencies. Strobe frequencies that reliably elicited robust versus dampened calcium responses were then presented to animals for 7 d, and differences in the amount of early myelin ensheathment at the optic chiasm were subsequently quantified. This study provides evidence that it is not just the presence but also to the specific temporal properties of sensory stimuli that are important for myelin plasticity.

Does non-motor phenotype of ‘freezers’ differ from ‘non-freezers’ in Parkinson's Disease? – A cross-sectional comparative study

Parkinsons disease (PD) is a multi-system disorder having motor and often disabling non-motor manifestations. Pathophysiology of freezing of gait (FOG) seems to be extending beyond motor circuits, into sensory, cognitive and affective neuronal circuits; and, involvement of both dopaminergic and non-dopaminergic mechanisms underlying nonmotor symptoms seem to be involved in FOG also. Aim: To compare the difference in non-motor symptoms between PD patients with freezing of gait (freezers) & those without freezing of gait (non-freezers) matched for age, disease duration, levodopa equivalent doses (LEDD).

W75. INVESTIGATING GENETIC ALLELES SHARED BETWEEN SCHIZOPHRENIA AND BLOOD METABOLITE CONCENTRATIONS

Ketamine is a noncompetitive antagonist of glutamatergic N-methyl-d-aspartate receptors. Its acute effects on healthy volunteers and schizophrenia patients mimic some acute psychotic, but also cognitive and negative symptoms of schizophrenia, and subchronic treatment with ketamine has been used as an animal model of psychotic disorders. Glutamatergic neurotransmission is tightly coupled to oxidative metabolism in the brain. Quantitative histochemical mapping of cytochrome c oxidase (COX) activity, which reflect long-term energy metabolism, was carried out in rats that received a daily subanaesthetic dose (30 mg/kg) of ketamine for 10 days. In total, COX activity was measured in 190 brain regions to map out metabolic adaptations to the subchronic administration of ketamine. Ketamine treatment was associated with elevated COX activity in nine brain sub-regions in sensory thalamus, basal ganglia, cortical areas, hippocampus and superior colliculi. Changes in pairwise correlations between brain regions were studied with differential correlation analysis. Ketamine treatment was associated with the reduction of positive association between brain regions in 66 % of the significant comparisons. Different layers of the superior colliculi showed the strongest effects. Changes in other visual and auditory brain centres were also of note. The locus coeruleus showed opposite pattern of increased coupling to mainly limbic brain regions in ketamine-treated rats. Our study replicated commonly observed activating effects of ketamine in the hippocampus, cingulate cortex, and basal ganglia. The current study is the first to extensively map the oxidative metabolism in the CNS in the ketamine model of schizophrenia. It shows that ketamine treatment leads to the re-organization of activity in sensory and memory-related brain circuits.

Olfactory bulb astrocytes mediate sensory circuit processing through Sox9 in the mouse brain

The role of transcription factors during astrocyte development and their subsequent effects on neuronal development has been well studied. Less is known about astrocytes contributions towards circuits and behavior in the adult brain. Astrocytes play important roles in synaptic development and modulation, however their contributions towards neuronal sensory function and maintenance of neuronal circuit architecture remain unclear. Here, we show that loss of the transcription factor Sox9 results in both anatomical and functional changes in adult mouse olfactory bulb (OB) astrocytes, affecting sensory processing. Indeed, astrocyte-specific deletion of Sox9 in the OB results in decreased odor detection thresholds and discrimination and it is associated with aberrant neuronal sensory response maps. At functional level, loss of astrocytic Sox9 impairs the electrophysiological properties of mitral and tufted neurons. RNA-sequencing analysis reveals widespread changes in the gene expression profiles of OB astrocytes. In particular, we observe reduced GLT-1 expression and consequential alterations in glutamate transport. Our findings reveal that astrocytes are required for physiological sensory processing and we identify astrocytic Sox9 as an essential transcriptional regulator of mature astrocyte function in the mouse OB.

A Comparative Study of Appearance Anxiety and Self-Esteem Among Indian Classical Dancers and Non-Dancers

India has a rich cultural heritage and more than thousand years of tradition of arts, classical and folk music and dance. Dance is considered as the medium of expression. It is the symbol of different cultural aspects of a civilization. Classical dance, in particular, is not just seen as an entertainment medium but it is considered as a form of meditation or yoga through which a dancer can reach the supreme Lord. It has a more spiritual rather a mere entertainment base. Dance is a good form of exercise that burns calories and builds muscles along with the release of endorphins. Hence there is instant happiness that is experienced by the dancers. Dance also influences the mind by contributing to the experience of satisfaction. Everyday a dancer may not achieve a specific goal in the process but through dancing they feel they have worked towards their goal by practicing which gives them satisfaction. An article in Scientific American Magazine 2008, a Columbia University neuroscientist put forth the fact that brain’s reward centers are stimulated by music, sensory and motor circuits are activated by dance. Dancers benefit from the physical exercise, increased heart and lung capacities and the overall feeling of wellbeing which increases their self-esteem. Many studies have indicated that dance can increase confidence and self-esteem level of the dancer. On the other hand, dancers are believed to be concerned about body image and they constantly worry about becoming thin or putting on weight to look presentable on the stage. Concerns with body image will lead to low self-esteem of the dancers as they negatively evaluate their body shape. So, there are conflicting results regarding self-esteem. On one hand, dance increases self-esteem but on the other hand, the presence of appearance concerns decreases dancers’ self-esteem. Hence, the objective of this study was to understand the appearance anxiety and self-esteem among dancers specifically among Indian Classical dancers and also to understand the interaction between appearance anxiety and self-esteem. The study adopted a quasi-experimental between-groups research design where in training in Indian classical dance form was the quasi-independent variable and the group of dancers were compared to non-dancers on appearance anxiety and self-esteem. A sample of 65 participants was chosen. The sample consisted of 35 Indian classical dancers and 30 non-dancers between the age group 16-30 years. Sample was selected through the method of purposive sampling. Participants were then given the Appearance Anxiety Inventory (AAI) (Veale, D., Eshkevari, E., Kanakam, N., Ellison, N., Costa, A., & Werner, T., 2014) and Rosenberg Self-esteem Scale (Rosenberg, 1965). It was found that that there was a negative correlation between appearance anxiety and self-esteem which means higher the appearance anxiety lower is the self-esteem. Indian classical dancers and non-dancers did not differ significantly with respect to appearance anxiety and Self-esteem.

Passive Clearing and 3D Lightsheet Imaging of the Intact and Injured Spinal Cord in Mice.

The spinal cord contains a diverse array of sensory and motor circuits that are essential for normal function. Spinal cord injury (SCI) permanently disrupts neural circuits through initial mechanical damage, as well as a cascade of secondary injury events that further expand the spinal cord lesion, resulting in permanent paralysis. Tissue clearing and 3D imaging have recently emerged as promising techniques to improve our understanding of the complex neural circuitry of the spinal cord and the changes that result from damage due to SCI. However, the application of this technology for studying the intact and injured spinal cord remains limited. Here, we optimized the passive CLARITY technique (PACT) to obtain gentle and efficient clearing of the murine spinal cord without the need for specialized equipment. We demonstrate that PACT clearing enables 3D imaging of multiple fluorescent labels in the spinal cord to assess molecularly defined neuronal populations, acute inflammation, long-term tissue damage, and cell transplantation. Collectively, these procedures provide a framework for expanding the utility of tissue clearing to enhance the study of spinal cord neural circuits, as well as cellular- and tissue-level changes that occur following SCI.

Tuning in to inflammation: A path forward for precise and efficacious microbiome medicines?

Gut microbes sense various external cues, including those found in inflammatory conditions, yielding possibilities for connecting sensory circuits to effector pathways to engineer precise and scaled interventions to target pathway activity. Scott et al. combined directed evolution and a synthetic gene circuit in yeast to fine-tune sensing of extracellular ATP, showing promise as a live therapeutic in two murine models of chemical colitis and a murine model of antibody-mediated enteritis.1.