Responses Of Individual Neurons Research Articles

Adapting and facilitating responses in mouse somatosensory cortex are dynamic and shaped by experience

Sensory adaptation is the process whereby brain circuits adjust neuronal activity in response to redundant sensory stimuli. Although sensory adaptation has been extensively studied for individual neurons on timescales of tens of milliseconds to a few seconds, little is known about it over longer timescales or at the population level. We investigated population-level adaptation in the barrel field of the mouse somatosensory cortex (S1BF) using invivo two-photon calcium imaging and Neuropixels recordings in awake mice. Among stimulus-responsive neurons, we found both adapting and facilitating neurons, which decreased or increased their firing, respectively, with repetitive whisker stimulation. The former outnumbered the latter by 2:1 in layers 2/3 and 4; hence, the overall population response of mouse S1BF was slightly adapting. We also discovered that population adaptation to one stimulus frequency (5Hz) does not necessarily generalize to a different frequency (12.5Hz). Moreover, responses of individual neurons to repeated rounds of stimulation over tens of minutes were strikingly heterogeneous and stochastic, such that their adapting or facilitating response profiles were not stable across time. Such representational drift was particularly striking when recording longitudinally across 8-9days, as adaptation profiles of most whisker-responsive neurons changed drastically from one day to the next. Remarkably, repeated exposure to a familiar stimulus paradoxically shifted the population away from strong adaptation and toward facilitation. Thus, the adapting vs. facilitating response profile of S1BF neurons is not a fixed property of neurons but rather a highly dynamic feature that is shaped by sensory experience across days.

Dynamics of Leaky Integrate‐and‐Fire Neurons Based on Oxyvanite Memristors for Spiking Neural Networks

Neuromorphic computing implemented with spiking neural networks (SNNs) based on volatile threshold switching is an energy‐efficient computing paradigm that may overcome future limitations of the von Neumann architecture. Herein, threshold switching in oxyvanite (V3O5) memristors and their application as a leaky integrate‐and‐fire (LIF) neuron are explored. The spiking response of individual neurons is examined as a function of circuit parameters, input pulse train, and temperature and reveals a pulse height‐dependent spike rate in which devices exhibit excitatory spiking behavior under low input voltages and protective inhibition spiking under high voltages. Resistively coupled LIF neurons are shown to exhibit additional neural functionalities (i.e., phasic, regular and adaptation, etc.) depending on the input voltage and circuit parameters. The behavior of both individual and coupled neurons is shown to be described by a physics‐based lumped element circuit model, which therefore provides a solid foundation for exploring more complex systems. Finally, the performance of a perceptron SNN employing these LIF neurons is assessed by simulating the classification of image recognition algorithm. These results advance the development of robust solid‐state neurons with low power consumption for neuromorphic computing.

Excitation creates a distributed pattern of cortical suppression due to varied recurrent input

Dense local, recurrent connections are a major feature of cortical circuits, yet how they affect neurons' responses has been unclear, with some studies reporting weak recurrent effects, some reporting amplification, and others indicating local suppression. Here, we show that optogenetic input to mouse V1 excitatory neurons generates salt-and-pepper patterns of both excitation and suppression. Responses in individual neurons are not strongly predicted by that neuron's direct input. A balanced-state network model reconciles a set of diverse observations: the observed dynamics, suppressed responses, decoupling of input and output, and long tail of excited responses. The model shows recurrent excitatory-excitatory connections are strong and also variable across neurons. Together, these results demonstrate that excitatory recurrent connections can have major effects on cortical computations by shaping and changing neurons' responses to input.

Neuronal Population Activity in Macaque Visual Cortices Dynamically Changes through Repeated Fixations in Active Free Viewing.

During free viewing, we move our eyes and fixate on objects to recognize the visual scene of our surroundings. To investigate the neural representation of objects in this process, we studied individual and population neuronal activity in three different visual regions of the brains of macaque monkeys (Macaca fuscata): the primary and secondary visual cortices (V1, V2) and the inferotemporal cortex (IT). We designed a task where the animal freely selected objects in a stimulus image to fixate on while we examined the relationship between spiking activity, the order of fixations, and the fixated objects. We found that activity changed across repeated fixations on the same object in all three recorded areas, with observed reductions in firing rates. Furthermore, the responses of individual neurons became sparser and more selective with individual objects. The population activity for individual objects also became distinct. These results suggest that visual neurons respond dynamically to repeated input stimuli through a smaller number of spikes, thereby allowing for discrimination between individual objects with smaller energy.

Angiotensin AT1A receptor signal switching in Agouti-related peptide neurons mediates metabolic rate adaptation during obesity

Resting metabolic rate (RMR) adaptation occurs during obesity and is hypothesized to contribute to failed weight management. Angiotensin II (Ang-II) type 1 (AT1A) receptors in Agouti-related peptide (AgRP) neurons contribute to the integrative control of RMR, and deletion of AT1A from AgRP neurons causes RMR adaptation. Extracellular patch-clamp recordings identify distinct cellular responses of individual AgRP neurons from lean mice to Ang-II: no response, inhibition via AT1A and Gαi, or stimulation via Ang-II type 2 (AT2) receptors and Gαq. Following diet-induced obesity, a subset of Ang-II/AT1A-inhibited AgRP neurons undergo a spontaneous G-protein "signal switch," whereby AT1A stop inhibiting the cell via Gαi and instead begin stimulating the cell via Gαq. DREADD-mediated activation of Gαi, but not Gαq, in AT1A-expressing AgRP cells stimulates RMR in lean and obese mice. Thus, loss of AT1A-Gαi coupling within the AT1A-expressing AgRP neuron subtype represents a molecular mechanism contributing to RMR adaptation.

Neuronal Spiking Responses to Direct Electrical Microstimulation in the Human Cortex.

Microstimulation can modulate the activity of individual neurons to affect behavior, but the effects of stimulation on neuronal spiking are complex and remain poorly understood. This is especially challenging in the human brain where the response properties of individual neurons are sparse and heterogeneous. Here we use microelectrode arrays in the human anterior temporal lobe in 6 participants (3 female) to examine the spiking responses of individual neurons to microstimulation delivered through multiple distinct stimulation sites. We demonstrate that individual neurons can be driven with excitation or inhibition using different stimulation sites, which suggests an approach for providing direct control of spiking activity at the single-neuron level. Spiking responses are inhibitory in neurons that are close to the site of stimulation, while excitatory responses are more spatially distributed. Together, our data demonstrate that spiking responses of individual neurons can be reliably identified and manipulated in the human cortex.SIGNIFICANCE STATEMENT One of the major limitations in our ability to interface directly with the human brain is that the effects of stimulation on the activity of individual neurons remain poorly understood. This study examines the spiking responses of neurons in the human temporal cortex in response to pulses of microstimulation. This study finds that individual neurons can either be excited or inhibited depending on the site of stimulation. These data suggest an approach for modulating the spiking activity of individual neurons in the human brain.

Model-Based Approach Shows ON Pathway Afferents Elicit a Transient Decrease of V1 Responses.

Neurons in the primary visual cortex (V1) receive excitation and inhibition from distinct parallel pathways processing lightness (ON) and darkness (OFF). V1 neurons overall respond more strongly to dark than light stimuli, consistent with a preponderance of darker regions in natural images, as well as human psychophysics. However, it has been unclear whether this "dark-dominance" is because of more excitation from the OFF pathway or more inhibition from the ON pathway. To understand the mechanisms behind dark-dominance, we record electrophysiological responses of individual simple-type V1 neurons to natural image stimuli and then train biologically inspired convolutional neural networks to predict the neurons' responses. Analyzing a sample of 71 neurons (in anesthetized, paralyzed cats of either sex) has revealed their responses to be more driven by dark than light stimuli, consistent with previous investigations. We show that this asymmetry is predominantly because of slower inhibition to dark stimuli rather than to stronger excitation from the thalamocortical OFF pathway. Consistent with dark-dominant neurons having faster responses than light-dominant neurons, we find dark-dominance to solely occur in the early latencies of neurons' responses. Neurons that are strongly dark-dominated also tend to be less orientation-selective. This novel approach gives us new insight into the dark-dominance phenomenon and provides an avenue to address new questions about excitatory and inhibitory integration in cortical neurons.SIGNIFICANCE STATEMENT Neurons in the early visual cortex respond on average more strongly to dark than to light stimuli, but the mechanisms behind this bias have been unclear. Here we address this issue by combining single-unit electrophysiology with a novel machine learning model to analyze neurons' responses to natural image stimuli in primary visual cortex. Using these techniques, we find slower inhibition to light than to dark stimuli to be the leading mechanism behind stronger dark responses. This slower inhibition to light might help explain other empirical findings, such as why orientation selectivity is weaker at earlier response latencies. These results demonstrate how imbalances in excitation versus inhibition can give rise to response asymmetries in cortical neuron responses.

Changes in operation of postural networks in rabbits with postural functions recovered after lateral hemisection of the spinal cord.

Acute lateral hemisection of the spinal cord (LHS) severely impairs postural functions, which recover over time. Here, to reveal changes in the operation of postural networks underlying the recovery, male rabbits with recovered postural functions after LHS at T12 (R-rabbits) were used. After decerebration, we characterized the responses of individual spinal interneurons from L5 along with hindlimb EMG responses to stimulation causing postural limb reflexes (PLRs) that substantially contribute to postural corrections in intact animals. The data were compared with those obtained in our previous studies of rabbits with the intact spinal cord and rabbits after acute LHS. Although, in R-rabbits, the EMG responses to postural disturbances both ipsilateral and contralateral to the LHS (ipsi-LHS and co-LHS) were only slightly distorted, PLRs on the co-LHS side (unaffected by acute LHS) were distorted substantially and PLRs on the ipsi-LHS side (abolished by acute LHS) were close to control. Thus, in R-rabbits, plastic changes develop in postural networks both affected and unaffected by acute LHS. PLRs on the ipsi-LHS side recover mainly as a result of changes at brainstem-cerebellum-spinal levels, whereas the forebrain is substantially involved in the generation of PLRs on the co-LHS side. We found that, in areas of grey matter in which the activity of spinal neurons of the postural network was significantly decreased after acute LHS, it recovered to the control level, whereas, in areas unaffected by acute LHS, it was significantly changed. These changes underlie the recovery and distortion of PLRs on the ipsi-LHS and co-LHS sides, respectively. KEY POINTS: After lateral hemisection of the spinal cord (LHS), postural functions recover over time. The underlying changes in the operation of postural networks are unknown. We compared the responses of individual spinal neurons and hindlimb muscles to stimulation causing postural limb reflexes (PLRs) in recovered LHS-rabbits with those obtained in rabbits with the intact spinal cord and rabbits after acute LHS. We demonstrated that changes underlying the recovery of postural functions take place not only in postural networks that are severely impaired, but also in those that are almost unaffected by acute LHS. PLRs on the LHS side recover mainly as a result of changes at brainstem-cerebellum-spinal levels, whereas the forebrain is substantially involved in the generation of PLRs contralateral to the LHS.

Activity Patterns of Individual Neurons and Ensembles Correlated with Retrieval of a Contextual Memory in the Dorsal CA1 of Mouse Hippocampus.

The hippocampus is crucial for retrieval of contextual memories. The activation of a subpopulation of neurons in the dorsal CA1 (dCA1) of the hippocampus is required for memory retrieval. Given that hippocampal neurons exhibit distinct patterns of response during memory retrieval, the activity patterns of individual neurons or ensembles may be critically involved in memory retrieval. However, this relation has been unclear. To investigate this question, we used an in vivo microendoscope calcium imaging technique to optically record neuronal activity in the dCA1 of male and female mice. We observed that a portion of dCA1 neurons increased their responses to the learned context after contextual fear conditioning (FC), resulting in overall increase in response of neuronal population compared with simple context exposure. Such increased response was specific to the conditioned context as it disappeared in neutral context. The magnitude of increase in neuronal responses by FC was proportional to memory strength during retrieval. The increases in activity preferentially occurred during the putative sharp wave ripple events and were not simply because of animal's movement and immobility. At the ensemble level, synchronous cell activity patterns were associated with memory retrieval. Accordingly, when such patterns were more similar between conditioned and neutral context, animals displayed proportionally more similar level of freezing. Together, these results indicate that increase in responses of individual neurons and synchronous cell activity patterns in the dCA1 neuronal network are critically involved in representing a contextual memory recall.SIGNIFICANCE STATEMENT Neurons in the dorsal CA1 of the hippocampus are crucial for memory retrieval. By using in vivo calcium imaging methods for recording neuronal activity, we demonstrate that dCA1 neurons increased their responses to the learned context specifically by FC and such changes correlated with memory strength during retrieval. Moreover, distinct synchronous cell activity patterns were formed by FC and involved in representing contextual memory retrieval. These findings reveal dynamic activity features of dCA1 neurons that are involved in contextual memory retrieval.

A detailed behavioral, videographic, and neural dataset on object recognition in mice

Mice adeptly use their whiskers to touch, recognize, and learn about objects in their environment. This behavior is enabled by computations performed by populations of neurons in the somatosensory cortex. To understand these computations, we trained mice to use their whiskers to recognize different shapes while we recorded activity in the barrel cortex, which processes whisker input. Here, we present a large dataset of high-speed video of the whiskers, along with rigorous tracking of the entire extent of multiple whiskers and every contact they made on the shape. We used spike sorting to identify individual neurons, which responded with precise timing to whisker contacts and motion. These data will be useful for understanding the behavioral strategies mice use to explore objects, as well as the neuronal dynamics that mediate those strategies. In addition, our carefully curated labeled data could be used to develop new computer vision algorithms for tracking body posture, or for extracting responses of individual neurons from large-scale neural recordings.

Independent response modulation of visual cortical neurons by attentional and behavioral states

Sensory processing is influenced by cognitive and behavioral states, but how these states interact to modulate responses of individual neurons is unknown. We trained mice in a visual discrimination task wherein they attended to different locations within a hemifield while running or sitting still, enabling us to examine how visual responses are modulated by spatial attention and running behavior. We found that spatial attention improved discrimination performance and strengthened visual responses of excitatory neurons in the primary visual cortex whose receptive fields overlapped with the attended location. Although individual neurons were modulated by both spatial attention and running, the magnitudes of these influences were not correlated. While running-dependent modulation was stable across days, attentional modulation was dynamic, influencing individual neurons to different degrees after repeated changes in attentional states. Thus, despite similar effects on neural responses, spatial attention and running act independently with different dynamics, implying separable mechanisms for their implementation.

Response of a neuronal network computational model to infrared neural stimulation.

Infrared neural stimulation (INS), as a novel form of neuromodulation, allows modulating the activity of nerve cells through thermally induced capacitive currents and thermal sensitivity ion channels. However, fundamental questions remain about the exact mechanism of INS and how the photothermal effect influences the neural response. Computational neural modeling can provide a powerful methodology for understanding the law of action of INS. We developed a temperature-dependent model of ion channels and membrane capacitance based on the photothermal effect to quantify the effect of INS on the direct response of individual neurons and neuronal networks. The neurons were connected through excitatory and inhibitory synapses and constituted a complex neuronal network model. Our results showed that a slight increase in temperature promoted the neuronal spikes and enhanced network activity, whereas the ultra-temperature inhibited neuronal activity. This biophysically based simulation illustrated the optical dose-dependent biphasic cell response with capacitive current as the core change condition. The computational model provided a new sight to elucidate mechanisms and inform parameter selection of INS.

Alzheimer's Disease Connected Genes in the Post-Ischemic Hippocampus and Temporal Cortex.

It is considered that brain ischemia can be causative connected to Alzheimer’s disease. In the CA1 and CA3 regions of the hippocampus and temporal cortex, genes related to Alzheimer’s disease, such as the amyloid protein precursor (APP), β-secretase (BACE1), presenilin 1 (PSEN1) and 2 (PSEN2), are deregulated by ischemia. The pattern of change in the CA1 area of the hippocampus covers all genes tested, and the changes occur at all post-ischemic times. In contrast, the pattern of gene changes in the CA3 subfield is much less intense, does not occur at all post-ischemic times, and is delayed in time post-ischemia relative to the CA1 field. Conversely, the pattern of gene alterations in the temporal cortex appears immediately after ischemia, and does not occur at all post-ischemic times and does not affect all genes. Evidence therefore suggests that various forms of dysregulation of the APP, BACE1 and PSEN1 and PSEN2 genes are associated with individual neuronal cell responses in the CA1 and CA3 areas of the hippocampus and temporal cortex with reversible cerebral ischemia. Scientific data indicate that an ischemic episode of the brain is a trigger of amyloidogenic processes. From the information provided, it appears that post-ischemic brain injury additionally activates neuronal death in the hippocampus and temporal cortex in an amyloid-dependent manner.

Brain-wide perception of the emotional valence of light is regulated by distinct hypothalamic neurons

Salient sensory stimuli are perceived by the brain, which guides both the timing and outcome of behaviors in a context-dependent manner. Light is such a stimulus, which is used in treating mood disorders often associated with a dysregulated hypothalamic-pituitary-adrenal stress axis. Relationships between the emotional valence of light and the hypothalamus, and how they interact to exert brain-wide impacts remain unclear. Employing larval zebrafish with analogous hypothalamic systems to mammals, we show in free-swimming animals that hypothalamic corticotropin releasing factor (CRFHy) neurons promote dark avoidance, and such role is not shared by other hypothalamic peptidergic neurons. Single-neuron projection analyses uncover processes extended by individual CRFHy neurons to multiple targets including sensorimotor and decision-making areas. In vivo calcium imaging uncovers a complex and heterogeneous response of individual CRFHy neurons to the light or dark stimulus, with a reduced overall sum of CRF neuronal activity in the presence of light. Brain-wide calcium imaging under alternating light/dark stimuli further identifies distinct and distributed photic response neuronal types. CRFHy neuronal ablation increases an overall representation of light in the brain and broadly enhances the functional connectivity associated with an exploratory brain state. These findings delineate brain-wide photic perception, uncover a previously unknown role of CRFHy neurons in regulating the perception and emotional valence of light, and suggest that light therapy may alleviate mood disorders through reducing an overall sum of CRF neuronal activity.

Local inhibition in a model of the indirect pathway globus pallidus network slows and deregularizes background firing, but sharpens and synchronizes responses to striatal input.

The external segment of globus pallidus (GPe) is a network of oscillatory neurons connected by inhibitory synapses. We studied the intrinsic dynamic and the response to a shared brief inhibitory stimulus in a model GPe network. Individual neurons were simulated using a phase resetting model based on measurements from mouse GPe neurons studied in slices. The neurons showed a broad heterogeneity in their firing rates and in the shapes and sizes of their phase resetting curves. Connectivity in the network was set to match experimental measurements. We generated statistically equivalent neuron heterogeneity in a small-world model, in which 99% of connections were made with near neighbors and 1% at random, and in a model with entirely random connectivity. In both networks, the resting activity was slowed and made more irregular by the local inhibition, but it did not show any periodic pattern. Cross-correlations among neuron pairs were limited to directly connected neurons. When stimulated by a shared inhibitory input, the individual neuron responses separated into two groups: one with a short and stereotyped period of inhibition followed by a transient increase in firing probability, and the other responding with a sustained inhibition. Despite differences in firing rate, the responses of the first group of neurons were of fixed duration and were synchronized across cells.

Coding of chromatic spatial contrast by macaque V1 neurons.

Color perception relies on comparisons between adjacent lights, but how the brain performs these comparisons is poorly understood. To elucidate the underlying mechanisms, we recorded spiking responses of individual V1 neurons in macaque monkeys to pairs of stimuli within the classical receptive field (RF). We estimated the spatial-chromatic RF of each neuron and then presented customized colored edges using a closed-loop technique. We found that many double-opponent (DO) cells, which have spatially and chromatically opponent RFs, responded to chromatic contrast as a weighted sum, akin to how other V1 neurons responded to luminance contrast. Yet other neurons integrated chromatic signals nonlinearly, confirming that linear signal integration is not an obligate property of V1 neurons. The functional similarity of cone-opponent DO cells and cone non-opponent simple cells suggests that these two groups may share a common underlying circuitry, promotes the construction of image-computable models for full-color image representation, and sheds new light on V1 complex cells.

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.