Responses Of Individual Neurons Research Articles

Effects of Light Isoflurane Anesthesia on Organization of Direction and Orientation Selectivity in the Superficial Layer of the Mouse Superior Colliculus.

The superior colliculus (SC) is the midbrain center for integrating visual and multimodal sensory information. Neurons in the SC exhibit direction and orientation selectivity. Recent studies reported that neurons with similar preferences formed clusters in the mouse SC (Ahmadlou and Heimel, 2015; Feinberg and Meister, 2015; de Malmazet et al., 2018; Li et al., 2020). However, it remains controversial as to how these clusters are organized within the SC (Inayat et al., 2015; Chen et al., 2021). Here, we found that different brain states (i.e., awake or anesthetized with isoflurane) changed the selectivity of individual SC neurons and organizations of the neuronal population in both male and female mice. Using two-photon Ca2+ imaging, we examined both individual neuronal responses and the spatial patterns of their population responses. Under isoflurane anesthesia, orientation selectivity increased and a larger number of orientation-selective cells were observed when compared with the awake condition, whereas the proportions of direction-selective cells were similar in both conditions. Furthermore, direction- and orientation-selective cells located at closer positions showed more similar preferences, and cluster-like spatial patterns were enhanced. Inhibitory responses of direction-selective neurons were also reduced under isoflurane anesthesia. Thus, the changes in the spatial organization of response patterns were considered to be because of changes in the balance of excitation and inhibition, with excitation dominance, in the local circuits. These results provide new insights into the possibility that the functional organization of feature selectivity in the brain is affected by brain state.SIGNIFICANCE STATEMENT Recent large-scale recording studies are changing our view of visual maps in the superior colliculus (SC), including findings of cluster-like localizations of direction- and orientation-selective neurons. However, results from several laboratories are conflicting regarding the presence of cluster-like organization. Here, we demonstrated that light isoflurane anesthesia affected the direction- and orientation-tuning properties in the mouse superficial SC and that their cluster-like localization pattern was enhanced by the anesthesia. Furthermore, the effect of anesthesia on direction selectivity appeared to be different in the excitatory and inhibitory populations in the SC. Our results suggest that the functional organization of direction and orientation selectivity might be regulated by the excitation-inhibition balance that depends on the brain state.

Host plant shift differentially alters olfactory sensitivity in female and male Drosophila mojavensis

Animals may vary in their utilization of plants depending on plant availability, and also on the sex of the animal. Evolutionary adaptations may arise, particularly in specialist animals to the chemistry of the host plants, and these adaptations may differ between the sexes due to differences in their interactions with the plants. Drosophila mojavensis uses different host cacti across its range, and volatile chemicals emitted by the host are the primary cue for host plant identification. In this study, we measured responses of individual olfactory sensory neurons to a large suite of odorants across males and females of the two southern D. mojavensis populations. We show that a switch in host plant is accompanied by changes in the olfactory system, but the effect of this switch is minor compared to that of sex. That is, we observe differences in olfactory receptor neuron specificity and sensitivity to odorants between sexes, and to a lesser extent between populations. The majority of sensory differences are restricted to only three of the 17 sensory neurons measured. Further, we found numerous differences between sexes that only occur within one population, i.e., sex-by-population interactions.

Mouse vision: Variability and stability across the visual processing hierarchy

The response of individual neurons to stable sensory input or behavioral output can change over time. A new study provides evidence from the mouse visual system that such drift does not follow the hierarchy of information flow across the brain.

Voxel-wise binocular energy models for binocular disparity decoding

Binocular disparity is a powerful cue for depth perception in three-dimensional (3D) space. Some neurophysiological studies proposed the binocular phase-shift and position-shift energy models to predict the responses of individual disparity-tuned neurons in cats and macaques. By far, it is unclear how to use binocular energy models to characterize the voxels’ responses in human visual cortex. In this study, we introduced the binocular energy models to the functional magnetic resonance imaging study and constructed the position-shift receptive-field model (Position-RFM) and the phase-shift receptive-field model (Phase-RFM) to predict voxel responses to disparity and to identify novel disparity levels from voxel responses. The results revealed that Phase-RFM outperformed Position-RFM in fitting the voxel responses for all the visual regions. Moreover, the novel disparity levels can be better identified from voxel’s responses in visual regions by Phase-RFM than Position-RFM. The findings may suggest that Phase-RFM can better encode the responses of disparity-tuned neuron populations than Position-RFM for human visual regions.

Stable representation of a naturalistic movie emerges from episodic activity with gain variability

Visual cortical responses are known to be highly variable across trials within an experimental session. However, the long-term stability of visual cortical responses is poorly understood. Here using chronic imaging of V1 in mice we show that neural responses to repeated natural movie clips are unstable across weeks. Individual neuronal responses consist of sparse episodic activity which are stable in time but unstable in gain across weeks. Further, we find that the individual episode, instead of neuron, serves as the basic unit of the week-to-week fluctuation. To investigate how population activity encodes the stimulus, we extract a stable one-dimensional representation of the time in the natural movie, using an unsupervised method. Most week-to-week fluctuation is perpendicular to the stimulus encoding direction, thus leaving the stimulus representation largely unaffected. We propose that precise episodic activity with coordinated gain changes are keys to maintain a stable stimulus representation in V1.

Predicting individual neuron responses with anatomically constrained task optimization

Artificial neural networks trained to solve sensory tasks can develop statistical representations that match those in biological circuits. However, it remains unclear whether they can reproduce properties of individual neurons. Here, we investigated how artificial networks predict individual neuron properties in the visual motion circuits of the fruit fly Drosophila. We trained anatomically constrained networks to predict movement in natural scenes, solving the same inference problem as fly motion detectors. Units in the artificial networks adopted many properties of analogous individual neurons, even though they were not explicitly trained to match these properties. Among these properties was the split into ON and OFF motion detectors, which is not predicted by classical motion detection models. The match between model and neurons was closest when models were trained to be robust to noise. These results demonstrate how anatomical, task, and noise constraints can explain properties of individual neurons in a small neural network.

Broad frequency sensitivity and complex neural coding in the larval zebrafish auditory system

Most animals have complex auditory systems that identify salient features of the acoustic landscape to direct appropriate responses. In fish, these features include the volume, frequency, complexity, and temporal structure of acoustic stimuli transmitted through water. Larval fish have simple brains compared to adults but swim freely and depend on sophisticated sensory processing for survival.1-5 Zebrafish larvae, an important model for studying brain-wide neural networks, have thus far been found to possess a rudimentary auditory system, sensitive to a narrow range of frequencies and without evident sensitivity to acoustic features that are salient and ethologically important to adult fish.6,7 Here, we have combined a novel method for delivering water-borne sounds, a diverse assembly of acoustic stimuli, and whole-brain calcium imaging to describe the responses of individual auditory-responsive neurons across the brains of zebrafish larvae. Our results reveal responses to frequencies ranging from 100Hz to 4 kHz, with evidence of frequency discrimination from 100Hz to 2.5 kHz. Frequency-selective neurons are located in numerous regions of the brain, and neurons responsive to the same frequency are spatially grouped in some regions. Using functional clustering, we identified categories of neurons that are selective for a single pure-tone frequency, white noise, the sharp onset of acoustic stimuli, and stimuli involving a gradual crescendo. These results suggest a more nuanced auditory system than has previously been described in larval fish and provide insights into how a young animal's auditory system can both function acutely and serve as the scaffold for a more complex adult system.

In vivo Calcium Imaging of Mouse Geniculate Ganglion Neuron Responses to Taste Stimuli.

Within the last ten years, advances in genetically encoded calcium indicators (GECIs) have promoted a revolution in in vivo functional imaging. Using calcium as a proxy for neuronal activity, these techniques provide a way to monitor the responses of individual cells within large neuronal ensembles to a variety of stimuli in real time. We, and others, have applied these techniques to image the responses of individual geniculate ganglion neurons to taste stimuli applied to the tongues of live anesthetized mice. The geniculate ganglion is comprised of the cell bodies of gustatory neurons innervating the anterior tongue and palate as well as some somatosensory neurons innervating the pinna of the ear. Imaging the taste-evoked responses of individual geniculate ganglion neurons with GCaMP has provided important information about the tuning profiles of these neurons in wild-type mice as well as a way to detect peripheral taste miswiring phenotypes in genetically manipulated mice. Here we demonstrate the surgical procedure to expose the geniculate ganglion, GCaMP fluorescence image acquisition, initial steps for data analysis, and troubleshooting. This technique can be used with transgenically encoded GCaMP, or with AAV-mediated GCaMP expression, and can be modified to image particular genetic subsets of interest (i.e., Cre-mediated GCaMP expression). Overall, in vivo calcium imaging of geniculate ganglion neurons is a powerful technique for monitoring the activity of peripheral gustatory neurons and provides complementary information to more traditional whole-nerve chorda tympani recordings or taste behavior assays.

Visual Cortex: Binocular Matchmaking

Most binocular neurons in the mammalian visual cortex show matched selectivity for light stimuli presented through either eye. A recent study tracked the responses of individual neurons in early visual cortex over time, revealing that matched binocular selectivity develops through major rearrangements of binocular visual circuits.

Covert Attention Increases the Gain of Stimulus-Evoked Population Codes.

Covert spatial attention has a variety of effects on the responses of individual neurons. However, relatively little is known about the net effect of these changes on sensory population codes, even though perception ultimately depends on population activity. Here, we measured the EEG in human observers (male and female), and isolated stimulus-evoked activity that was phase-locked to the onset of attended and ignored visual stimuli. Using an encoding model, we reconstructed spatially selective population tuning functions from the pattern of stimulus-evoked activity across the scalp. Our EEG-based approach allowed us to measure very early visually evoked responses occurring ∼100 ms after stimulus onset. In Experiment 1, we found that covert attention increased the amplitude of spatially tuned population responses at this early stage of sensory processing. In Experiment 2, we parametrically varied stimulus contrast to test how this effect scaled with stimulus contrast. We found that the effect of attention on the amplitude of spatially tuned responses increased with stimulus contrast, and was well described by an increase in response gain (i.e., a multiplicative scaling of the population response). Together, our results show that attention increases the gain of spatial population codes during the first wave of visual processing.SIGNIFICANCE STATEMENT We know relatively little about how attention improves population codes, even though perception is thought to critically depend on population activity. In this study, we used an encoding-model approach to test how attention modulates the spatial tuning of stimulus-evoked population responses measured with EEG. We found that attention multiplicatively scales the amplitude of spatially tuned population responses. Furthermore, this effect was present within 100 ms of stimulus onset. Thus, our results show that attention improves spatial population codes by increasing their gain at this early stage of processing.

Pancreatic β-Cells Communicate With Vagal Sensory Neurons

Destroying visceral sensory nerves impacts pancreatic islet function, glucose metabolism, and diabetes onset, but how islet endocrine cells interact with sensory neurons has not been studied. We characterized the anatomical pattern of pancreatic sensory innervation by combining viral tracing, immunohistochemistry, and reporter mouse models. To assess the functional interactions of β-cells with vagal sensory neurons, we recorded Ca2+ responses in individual nodose neurons invivo while selectively stimulating β-cells with chemogenetic and pharmacologic approaches. We found that pancreatic islets are innervated by vagal sensory axons expressing Phox2b, substance P, calcitonin-gene related peptide, and the serotonin receptor 5-HT3R. Centrally, vagal neurons projecting to the pancreas terminate in the commissural nucleus of the solitary tract. Nodose neurons responded invivo to chemogenetic stimulation of β-cells and to pancreas infusion with serotonin, but were not sensitive to insulin. Responses to chemogenetic and pharmacologic stimulation of β-cells were blocked by a 5-HT3R antagonist and were enhanced by increasing serotonin levels in β-cells. We further confirmed directly in living pancreas slices that sensory terminals in the islet were sensitive to serotonin. Our study establishes that pancreatic β-cells communicate with vagal sensory neurons, likely using serotonin signaling as a transduction mechanism. Serotonin is coreleased with insulin and may therefore convey information about the secretory state of β-cells via vagal afferent nerves.

Frequency-separated principal component analysis of cortical population activity.

A hallmark of neocortical activity is the presence of low-dimensional fluctuations in firing rate that are coordinated across neurons. However, the impact of these fluctuations on sensory processing remains unclear. Here, we examined fluctuations in populations of orientation-selective neurons from anesthetized macaque primary visual cortex (V1) during stimulus viewing as well as spontaneous activity. We introduce a novel approach termed frequency-separated principal component analysis (FS-PCA) to characterize these fluctuations. This method unveiled a distribution of components with a broad range of frequencies whose eigenvalues and variance followed an approximate power law. During stimulus viewing, subpopulations of V1 neurons correlated either positively or negatively with low-dimensional fluctuations. These two subpopulations displayed distinct activation properties and noise correlations in response to sensory input. Together, results suggest that slow, low-dimensional fluctuations in V1 population activity shape the response of individual neurons to oriented stimuli and may impact the transmission of sensory information to downstream regions of the primary visual system.NEW & NOTEWORTHY A method termed frequency-separated principal component analysis (FS-PCA) is introduced for analyzing populations of simultaneously recorded neurons. This framework extends standard principal component analysis by extracting components of activity delimited to specific frequency bands. FS-PCA revealed that circuits of the primary visual cortex generate a broad range of components dominated by low-frequency activity. Furthermore, low-dimensional fluctuations in population activity modulated the response of individual neurons to sensory input.

Timing of response onset and offset in macaque V4: stimulus and task dependence.

In the primate visual cortex, both the magnitude of the neuronal response and its timing can carry important information about the visual world, but studies typically focus only on response magnitude. Here, we examine the onset and offset latency of the responses of neurons in area V4 of awake, behaving macaques across several experiments in the context of a variety of stimuli and task paradigms. Our results highlight distinct contributions of stimuli and tasks to V4 response latency. We found that response onset latencies are shorter than typically cited (median = 75.5 ms), supporting a role for V4 neurons in rapid object and scene recognition functions. Moreover, onset latencies are longer for smaller stimuli and stimulus outlines, consistent with the hypothesis that longer latencies are associated with higher spatial frequency content. Strikingly, we found that onset latencies showed no significant dependence on stimulus occlusion, unlike in inferotemporal cortex, nor on task demands. Across the V4 population, onset latencies had a broad distribution, reflecting the diversity of feedforward, recurrent, and feedback connections that inform the responses of individual neurons. Response offset latencies, on the other hand, displayed the opposite tendency in their relationship to stimulus and task attributes: they are less influenced by stimulus appearance but are shorter in guided saccade tasks compared with fixation tasks. The observation that response latency is influenced by stimulus- and task-associated factors emphasizes a need to examine response timing alongside firing rate in determining the functional role of area V4.NEW & NOTEWORTHY Onset and offset timing of neuronal responses can provide information about visual environment and neuron's role in visual processing and its anatomical connectivity. In the first comprehensive examination of onset and offset latencies in the intermediate visual cortical area V4, we find neurons respond faster than previously reported, making them ideally suited to contribute to rapid object and scene recognition. While response onset reflects stimulus characteristics, timing of response offset is influenced more by behavioral task.

Widespread receptor-driven modulation in peripheral olfactory coding.

Olfactory responses to single odors have been well characterized but in reality we are continually presented with complex mixtures of odors. We performed high-throughput analysis of single-cell responses to odor blends using Swept Confocally Aligned Planar Excitation (SCAPE) microscopy of intact mouse olfactory epithelium, imaging ~10,000 olfactory sensory neurons in parallel. In large numbers of responding cells, mixtures of odors did not elicit a simple sum of the responses to individual components of the blend. Instead, many neurons exhibited either antagonism or enhancement of their response in the presence of another odor. All eight odors tested acted as both agonists and antagonists at different receptors. We propose that this peripheral modulation of responses increases the capacity of the olfactory system to distinguish complex odor mixtures.

The perception of complex scents

Neuroscience It is generally assumed that olfactory receptors faithfully report information to the brain in the form of a linear, additive code. However, under realistic conditions, the olfactory system handles a far more complex input, usually mixtures of odors. Xu et al. found that when we smell scents, the nasal olfactory sensory neurons relay a more complex pattern of signals to the brain than previously thought. The responses of individual neurons within the peripheral olfactory epithelium were either amplified or attenuated by the presence of other odors, which could explain the common perception of one odor in a mixture dominating over others. This effect occurs within the peripheral sensory organ's receptors and not within the brain. Science , this issue p. [eaaz5390][1] [1]: /lookup/doi/10.1126/science.aaz5390

Synaptic circuit restoration and functional recovery in the mouse visual cortex after ischemic injury and direct in vivo reprogramming of astrocytes into neurons

Ischemic injury caused by stroke is one of the leading causes of severe morbidity and mortality. Neuronal loss, proliferation of reactive astrocytes and the formation of a glial scar represent the three critical problems preventing the functional recovery. Direct reprogramming of astrocytes into neurons in vivo using NeuroD1‐containing AAV virus represents a new promising gene therapy capable of replenishing the neuronal population and reducing gliosis. We have used NeuroD1‐containing AAV virus to convert astrocytes into neurons in the mouse primary visual cortex (V1) following focal ischemic injury. We have demonstrated that this in vivo reprogramming can restore visual evoked potentials (VEPs) and individual neuronal responses impaired after ischemic injury in V1. We have used Channelrhodopsin Assisted Circuit Mapping (CRACM) to demonstrate that this functional restoration is accompanied by the integration of the newly reprogrammed neurons into the visual microcircuit and reestablishment of the specific interlaminar long‐range connections. Our work suggests that in vivo NeuroD1‐based viral therapy can convert reactive astrocytes into neurons and restore visual function lost after local ischemiaSupport or Funding InformationPurdue Research Foundation

A124 SYNERGISTIC INTERACTION OF CANNABINOIDS AND OPIOIDS REDUCES PAIN SIGNALING IN COLONIC NOCICEPTIVE NERVES

Abstract Background With the recent legalization of recreational marijuana in Canada, increasing numbers of patients with gastrointestinal (GI) disorders are using cannabis to treat their pain, either alone or together with opioids. However, little is known about potential benefits of cannabinoids for treating visceral pain originating within the GI tract and whether the combined use of cannabinoids and opioids could enable the reduction or even discontinuation of opioids. Aims To investigate the effects of cannabinoids alone or in combination with opioids on colonic nociceptive nerves. Methods Extracellular afferent nerve recordings were obtained from ex vivo flat sheet preparations of male C57BL/6 mouse distal colons. Single unit analysis discriminated individual afferent neuron responses to mechanical probing of the colon with a 1g von Frey hair before and after superfusion of HU-210, a selective CB1 receptor agonist, HU-308, a selective CB2 receptor agonist, DAMGO, a selective mu-opioid receptor (MOR) agonist, or a combination. In parallel studies, perforated patch clamp techniques were employed to assess the rheobase as a measure of neuronal excitability in acutely dissociated dorsal root ganglia (DRG) neurons in the presence of one or more of these agonists. Data were analyzed using a one-way ANOVA with Bonferroni multiple comparisons test. Results Superfusion of HU-210 (1 μM), caused significant inhibition in afferent nerve mechanosensitivity compared to control (6.2±1.1 vs. 13.7±2.5 Hz, p=0.005, n=10); lower concentrations (10 nM and 100 nM) had no effect (p>0.99, n=11; p=0.600, n=10 respectively). Conversely, the CB2 agonist HU-308 (1 μM and 10 μM), did not alter mechanosensitivity (p>0.9, n=8 for both concentrations). Superfusion of HU-210 alone (100 nM) or DAMGO (1 nM) alone in the same recording had no effect, but when both agonists were superfused together, there was a significant reduction in mechanosensitivity (8.1±1.7 vs. 14.8±2.3 Hz, p<0.01, n=10). In patch clamp recordings of DRG neurons, HU-210 (1 μM) decreased excitability (i.e. increased rheobase, 94.4±9.4 vs. 62.7±6.4 pA; p=0.031, n=9), whereas a lower concentration (100 nM) had no effect. Similar to afferent nerve recordings, when applied alone, DAMGO (1 nM) and HU-210 (100 nM) did not affect rheobase (DAMGO: p>0.99, n=9; HU-210: p>0.99, n=10), whereas the combination of both agonists significantly decreased excitability (123.0±13.4 vs. 62.7±6.4 pA, p<0.01, n=10). Conclusions Activation of CB1 receptors inhibits mechanosensitivity of colonic afferent nerves while a CB2 agonist had no effect. Interestingly, combination of sub-threshold concentrations of CB1 and MOR agonists inhibited colonic afferent nerves and thus, may suggest that cannabinoids could enable opioid dose reduction or discontinuation. Funding Agencies None

Nonlinear response characteristics of neural networks and single neurons undergoing optogenetic excitation

Optogenetic stimulation has become the method of choice for investigating neural computation in populations of neurons. Optogenetic experiments often aim to elicit a network response by stimulating specific groups of neurons. However, this is complicated by the fact that optogenetic stimulation is nonlinear, more light does not always equal to more spikes, and neurons that are not directly but indirectly stimulated could have a major impact on how networks respond to optogenetic stimulation. To clarify how optogenetic excitation of some neurons alters the network dynamics, we studied the temporal and spatial response of individual neurons and recurrent neural networks. In individual neurons, we find that neurons show a monotonic, saturating rate response to increasing light intensity and a nonmonotonic rate response to increasing pulse frequency. At the network level, we find that Gaussian light beams elicit spatial firing rate responses that are substantially broader than the stimulus profile. In summary, our analysis and our network simulation code allow us to predict the outcome of an optogenetic experiment and to assess whether the observed effects can be attributed to direct or indirect stimulation of neurons.

Cuneate spiking neural network learning to classify naturalistic texture stimuli under varying sensing conditions

We implemented a functional neuronal network that was able to learn and discriminate haptic features from biomimetic tactile sensor inputs using a two-layer spiking neuron model and homeostatic synaptic learning mechanism. The first order neuron model was used to emulate biological tactile afferents and the second order neuron model was used to emulate biological cuneate neurons. We have evaluated 10 naturalistic textures using a passive touch protocol, under varying sensing conditions. Tactile sensor data acquired with five textures under five sensing conditions were used for a synaptic learning process, to tune the synaptic weights between tactile afferents and cuneate neurons. Using post-learning synaptic weights, we evaluated the individual and population cuneate neuron responses by decoding across 10 stimuli, under varying sensing conditions. This resulted in a high decoding performance. We further validated the decoding performance across stimuli, irrespective of sensing velocities using a set of 25 cuneate neuron responses. This resulted in a median decoding performance of 96% across the set of cuneate neurons. Being able to learn and perform generalized discrimination across tactile stimuli, makes this functional spiking tactile system effective and suitable for further robotic applications.

Multiple Timescales Account for Adaptive Responses across Sensory Cortices.

Sensory systems encounter remarkably diverse stimuli in the external environment. Natural stimuli exhibit timescales and amplitudes of variation that span a wide range. Mechanisms of adaptation, a ubiquitous feature of sensory systems, allow for the accommodation of this range of scales. Are there common rules of adaptation across different sensory modalities? We measured the membrane potential responses of individual neurons in the visual, somatosensory, and auditory cortices of male and female mice to discrete, punctate stimuli delivered at a wide range of fixed and nonfixed frequencies. We find that the adaptive profile of the response is largely preserved across these three areas, exhibiting attenuation and responses to the cessation of stimulation, which are signatures of response to changes in stimulus statistics. We demonstrate that these adaptive responses can emerge from a simple model based on the integration of fixed filters operating over multiple time scales.SIGNIFICANCE STATEMENT Our recent sensations affect our current expectations and perceptions of the environment. Neural correlates of this process exist throughout the brain and are loosely termed adaptation. Adaptive processes have been described across sensory cortices, but direct comparisons of these processes have not been possible because paradigms have been tailored specifically for each modality. We developed a common stimulus set that was used to characterize adaptation in somatosensory, visual, and auditory cortex. We describe here the similarities and differences in adaptation across these cortical areas and demonstrate that adaptive responses may emerge from a set of static filters that operate over a broad range of timescales.