Modulation Of Neuronal Responses Research Articles

Optimal synchronization in pulse-coupled oscillator networks using reinforcement learning.

Spontaneous synchronization is ubiquitous in natural and man-made systems. It underlies emergent behaviors such as neuronal response modulation and is fundamental to the coordination of robot swarms and autonomous vehicle fleets. Due to its simplicity and physical interpretability, pulse-coupled oscillators has emerged as one of the standard models for synchronization. However, existing analytical results for this model assume ideal conditions, including homogeneous oscillator frequencies and negligible coupling delays, as well as strict requirements on the initial phase distribution and the network topology. Using reinforcement learning, we obtain an optimal pulse-interaction mechanism (encoded in phase response function) that optimizes the probability of synchronization even in the presence of nonideal conditions. For small oscillator heterogeneities and propagation delays, we propose a heuristic formula for highly effective phase response functions that can be applied to general networks and unrestricted initial phase distributions. This allows us to bypass the need to relearn the phase response function for every new network.

Neural correlates of cognitively controlled vocalizations in a corvid songbird

The neuronal basis of the songbird's song system is well understood. However, little is known about the neuronal correlates of the executive control of songbird vocalizations. Here, we record single-unit activity from the pallial endbrain region "nidopallium caudolaterale" (NCL) of crows that vocalize to the presentation of a visual go-cue but refrain from vocalizing during trials without a go-cue. We find that the preparatory activity of single vocalization-correlated neurons, but also of the entire population of NCL neurons, before vocal onset predicts whether or not the crows will produce an instructed vocalization. Fluctuations in baseline neuronal activity prior to the go-cue influence the premotor activity of such vocalization-correlated neurons and seemingly bias the crows' decision to vocalize. Neuronal response modulation significantly differs between volitional and task-unrelated vocalizations. This suggests that the NCL can take control over the vocal motor network during the production of volitional vocalizations in a corvid songbird.

Visual Stimulation Induces Distinct Forms of Sensitization of On-Off Direction-Selective Ganglion Cell Responses in the Dorsal and Ventral Retina.

Experience-dependent modulation of neuronal responses is a key attribute in sensory processing. In the mammalian retina, the On-Off direction-selective ganglion cell (DSGC) is well known for its robust direction selectivity. However, how the On-Off DSGC light responsiveness dynamically adjusts to the changing visual environment is underexplored. Here, we report that On-Off DSGCs tuned to posterior motion direction [i.e. posterior DSGCs (pDSGCs)] in mice of both sexes can be transiently sensitized by prior stimuli. Notably, distinct sensitization patterns are found in dorsal and ventral pDSGCs. Although responses of both dorsal and ventral pDSGCs to dark stimuli (Off responses) are sensitized, only dorsal cells show the sensitization of responses to bright stimuli (On responses). Visual stimulation to the dorsal retina potentiates a sustained excitatory input from Off bipolar cells, leading to tonic depolarization of pDSGCs. Such tonic depolarization propagates from the Off to the On dendritic arbor of the pDSGC to sensitize its On response. We also identified a previously overlooked feature of DSGC dendritic architecture that can support dendritic integration between On and Off dendritic layers bypassing the soma. By contrast, ventral pDSGCs lack a sensitized tonic depolarization and thus do not exhibit sensitization of their On responses. Our results highlight a topographic difference in Off bipolar cell inputs underlying divergent sensitization patterns of dorsal and ventral pDSGCs. Moreover, substantial crossovers between dendritic layers of On-Off DSGCs suggest an interactive dendritic algorithm for processing On and Off signals before they reach the soma.SIGNIFICANCE STATEMENT Visual neuronal responses are dynamically influenced by the prior visual experience. This form of plasticity reflects the efficient coding of the naturalistic environment by the visual system. We found that a class of retinal output neurons, On-Off direction-selective ganglion cells, transiently increase their responsiveness after visual stimulation. Cells located in dorsal and ventral retinas exhibit distinct sensitization patterns because of different adaptive properties of Off bipolar cell signaling. A previously overlooked dendritic morphologic feature of the On-Off direction-selective ganglion cell is implicated in the cross talk between On and Off pathways during sensitization. Together, these findings uncover a topographic difference in the adaptive encoding of upper and lower visual fields and the underlying neural mechanism in the dorsal and ventral retinas.

Perceptual Texture Dimensions Modulate Neuronal Response Dynamics in Visual Cortical Area V4.

Texture is an important visual attribute for surface pattern discrimination and therefore object segmentation, but the neural bases of texture perception are largely unknown. Previously, we demonstrated that the responses of V4 neurons to naturalistic texture patches are sensitive to four key features of human texture perception: coarseness, directionality, regularity, and contrast. To begin to understand how distinct texture perception emerges from the dynamics of neuronal responses, in 2 macaque monkeys (1 male, 1 female), we investigated the relative contribution of the four texture attributes to V4 responses in terms of the strength and timing of response modulation. We found that the different feature dimensions are associated with different temporal dynamics. Specifically, the response modulation associated with directionality and regularity was significantly delayed relative to that associated with coarseness and contrast, suggesting that the latter are fundamentally simpler feature dimensions. The population of texture-selective neurons could be grouped into multiple clusters based on the combination of feature dimensions encoded, and those subpopulations displayed distinct temporal dynamics characterized by the weighted combinations of multiple features. Finally, we applied a population decoding approach to demonstrate that texture category information can be obtained from short temporal windows across time. These results demonstrate that the representation of different perceptually relevant texture features emerge over time in the responses of V4 neurons. The observed temporal organization provides a framework to interpret how the processing of surface features unfolds in early and midlevel cortical stages, and could ultimately inform the interpretation of perceptual texture dynamics.SIGNIFICANCE STATEMENT To delineate how neuronal responses underlie our ability to perceive visual textures, we related four key perceptual dimensions (coarseness, directionality, regularity, and contrast) of naturalistic textures to the strength and timing of modulation of neuronal responses in area V4, an intermediate stage in the form-processing, ventral visual pathway. Our results provide the first characterization of V4 temporal dynamics for texture encoding along perceptually defined axes.

High-order interactions explain the collective behavior of cortical populations in executive but not sensory areas

One influential view in neuroscience is that pairwise cell interactions explain the firing patterns of large populations. Despite its prevalence, this view originates from studies in the retina and visual cortex of anesthetized animals. Whether pairwise interactions predict the firing patterns of neurons across multiple brain areas in behaving animals remains unknown. Here, we performed multi-area electrical recordings to find that 2nd-order interactions explain a high fraction of entropy of the population response in macaque cortical areas V1 and V4. Surprisingly, despite the brain-state modulation of neuronal responses, the model based on pairwise interactions captured ∼90% of the spiking activity structure during wakefulness and sleep. However, regardless of brain state, pairwise interactions fail to explain experimentally observed entropy in neural populations from the prefrontal cortex. Thus, while simple pairwise interactions explain the collective behavior of visual cortical networks across brain states, explaining the population dynamics in downstream areas involves higher-order interactions.

Fast-Trk(B)ing the mechanism of antidepressants

The mechanism by which antidepressants elicit clinical improvements has proven elusive. In a recent publication in Cell, Casarotto etal. (2021) reveal a surprising direct interaction between antidepressants and TrkB. This link provides an important mechanistic insight into synaptic remodeling that may assist in the design of improved antidepressant therapeutics.

Primary culture of the rat spinal dorsal horn: a tool to investigate the effects of inflammatory stimulation on the afferent somatosensory system

One maladaptive consequence of inflammatory stimulation of the afferent somatosensory system is the manifestation of inflammatory pain. We established and characterized a neuroglial primary culture of the rat superficial dorsal horn (SDH) of the spinal cord to test responses of this structure to neurochemical, somatosensory, or inflammatory stimulation. Primary cultures of the rat SDH consist of neurons (43%), oligodendrocytes (35%), astrocytes (13%), and microglial cells (9%). Neurons of the SDH responded to cooling (7%), heating (18%), glutamate (80%), substance P (43%), prostaglandin E2 (8%), and KCl (100%) with transient increases in the intracellular calcium [Ca2+]i. Short-term stimulation of SDH primary cultures with LPS (10 μg/ml, 2 h) caused increased expression of pro-inflammatory cytokines, inflammatory transcription factors, and inducible enzymes responsible for inflammatory prostaglandin E2 synthesis. At the protein level, increased concentrations of tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6) were measured in the supernatants of LPS-stimulated SDH cultures and enhanced TNFα and IL-6 immunoreactivity was observed specifically in microglial cells. LPS-exposed microglial cells further showed increased nuclear immunoreactivity for the inflammatory transcription factors NFκB, NF-IL6, and pCREB, indicative of their activation. The short-term exposure to LPS further caused a reduction in the strength of substance P as opposed to glutamate-evoked Ca2+-signals in SDH neurons. However, long-term stimulation with a low dose of LPS (0.01 μg/ml, 24 h) resulted in a significant enhancement of glutamate-induced Ca2+ transients in SDH neurons, while substance P-evoked Ca2+ signals were not influenced. Our data suggest a critical role for microglial cells in the initiation of inflammatory processes within the SDH of the spinal cord, which are accompanied by a modulation of neuronal responses.

Transient neocortical gamma oscillations induced by neuronal response modulation.

In this paper a mean field model of spatio-temporal electroencephalographic activity in the neocortex is used to computationally study the emergence of neocortical gamma oscillations as a result of neuronal response modulation. It is shown using a numerical bifurcation analysis that gamma oscillations emerge robustly in the solutions of the model and transition to beta oscillations through coordinated modulation of the responsiveness of inhibitory and excitatory neuronal populations. The spatio-temporal pattern of the propagation of these oscillations across the neocortex is illustrated by solving the equations of the model using a finite element software package. Thereby, it is shown that the gamma oscillations remain localized to the regions of neuronal modulation. Moreover, it is discussed that the inherent spatial averaging effect of commonly used electrocortical measurement techniques can significantly alter the amplitude and pattern of fast oscillations in neocortical recordings, and hence can potentially affect physiological interpretations of these recordings.

Neural mechanisms of contextual modulation in the retinal direction selective circuit

Contextual modulation of neuronal responses by surrounding environments is a fundamental attribute of sensory processing. In the mammalian retina, responses of On–Off direction selective ganglion cells (DSGCs) are modulated by motion contexts. However, the underlying mechanisms are unknown. Here, we show that posterior-preferring DSGCs (pDSGCs) are sensitive to discontinuities of moving contours owing to contextually modulated cholinergic excitation from starburst amacrine cells (SACs). Using a combination of synapse-specific genetic manipulations, patch clamp electrophysiology and connectomic analysis, we identified distinct circuit motifs upstream of On and Off SACs that are required for the contextual modulation of pDSGC activity for bright and dark contrasts. Furthermore, our results reveal a class of wide-field amacrine cells (WACs) with straight, unbranching dendrites that function as “continuity detectors” of moving contours. Therefore, divergent circuit motifs in the On and Off pathways extend the information encoding of On-Off DSGCs beyond their direction selectivity during complex stimuli.

Optogenetically induced low-frequency correlations impair perception.

Deployment of covert attention to a spatial location can cause large decreases in low-frequency correlated variability among neurons in macaque area V4 whose receptive-fields lie at the attended location. It has been estimated that this reduction accounts for a substantial fraction of the attention-mediated improvement in sensory processing. These estimates depend on assumptions about how population signals are decoded and the conclusion that correlated variability impairs perception, is purely hypothetical. Here we test this proposal directly by optogenetically inducing low-frequency fluctuations, to see if this interferes with performance in an attention-demanding task. We find that low-frequency optical stimulation of neurons in V4 elevates correlations among pairs of neurons and impairs the animal's ability to make fine sensory discriminations. Stimulation at higher frequencies does not impair performance, despite comparable modulation of neuronal responses. These results support the hypothesis that attention-dependent reductions in correlated variability contribute to improved perception of attended stimuli.

Absence of Neuronal Response Modulation with Familiarity in Perirhinal Cortex

The perirhinal cortex (PRH) is considered a crucial cortical area for familiarity memory and electrophysiological studies have reported the presence of visual familiarity encoding neurons in PRH. However, recent evidence has questioned the existence of these neurons. Here, we used a visual task in which head-restrained mice were passively exposed to oriented gratings or natural images. Evoked potentials and single-unit recordings showed evoked responses to novelty in V1 under some conditions. However, the PRH showed no response modulation with respect to familiarity under a variety of different conditions or retention delays. These results indicate that the PRH does not contribute to familiarity/novelty encoding using passively exposed visual stimuli.

Neuronal differentiation induces SNORD115 expression and is accompanied by post-transcriptional changes of serotonin receptor 2c mRNA

The serotonin neurotransmitter system is widespread in the brain and implicated in modulation of neuronal responses to other neurotransmitters. Among 14 serotonin receptor subtypes, 5-HT2cR plays a pivotal role in controlling neuronal network excitability. Serotonergic activity conveyed through receptor 5-HT2cR is regulated post-transcriptionally via two mechanisms, alternative splicing and A-to-I RNA editing. Brain-specific small nucleolar RNA SNORD115 harbours a phylogenetically conserved 18-nucleotide antisense element with perfect complementarity to the region of 5ht2c primary transcript that undergoes post-transcriptional changes. Previous 5ht2c minigene studies have implicated SNORD115 in fine-tuning of both post-transcriptional events. We monitored post-transcriptional changes of endogenous 5ht2c transcripts during neuronal differentiation. Both SNORD115 and 5ht2c were upregulated upon neuronal commitment. We detected increased 5ht2c alternative exon Vb inclusion already at the stage of neuronal progenitors, and more extensive A-to-I editing of non-targeted sites A and B compared to adjacent adenosines at sites E, C and D throughout differentiation. As the extent of editing is known to positively correlate with exon Vb usage while it reduces receptor functionality, our data support the model where SNORD115 directly promotes alternative exon inclusion without the requirement for conversion of key adenosines to inosines, thereby favouring production of full-length receptor isoforms with higher potency.

Attention enhances stimulus representations in macaque visual cortex without affecting their signal-to-noise level.

The magnitude of the attentional modulation of neuronal responses in visual cortex varies with stimulus contrast. Whether the strength of these attentional influences is similarly dependent on other stimulus properties is unknown. Here we report the effect of spatial attention on responses in the medial-temporal area (MT) of macaque visual cortex to moving random dots pattern of various motion coherences, i.e. signal-to-noise ratios. Our data show that allocating spatial attention causes a gain change in MT neurons. The magnitude of this attentional modulation is independent of the attended stimulus’ motion coherence, creating a multiplicative scaling of the neuron’s coherence-response function. This is consistent with the characteristics of gain models of attentional modulation and suggests that attention strengthens the neuronal representation of behaviorally relevant visual stimuli relative to unattended stimuli, but without affecting their signal-to-noise ratios.

Modulation of Neuronal Responses by Exogenous Attention in Macaque Primary Visual Cortex.

Visual perception is influenced by attention deployed voluntarily or triggered involuntarily by salient stimuli. Modulation of visual cortical processing by voluntary or endogenous attention has been extensively studied, but much less is known about how involuntary or exogenous attention affects responses of visual cortical neurons. Using implanted microelectrode arrays, we examined the effects of exogenous attention on neuronal responses in the primary visual cortex (V1) of awake monkeys. A bright annular cue was flashed either around the receptive fields of recorded neurons or in the opposite visual field to capture attention. A subsequent grating stimulus probed the cue-induced effects. In a fixation task, when the cue-to-probe stimulus onset asynchrony (SOA) was <240 ms, the cue induced a transient increase of neuronal responses to the probe at the cued location during 40-100 ms after the onset of neuronal responses to the probe. This facilitation diminished and disappeared after repeated presentations of the same cue but recurred for a new cue of a different color. In another task to detect the probe, relative shortening of monkey's reaction times for the validly cued probe depended on the SOA in a way similar to the cue-induced V1 facilitation, and the behavioral and physiological cueing effects remained after repeated practice. Flashing two cues simultaneously in the two opposite visual fields weakened or diminished both the physiological and behavioral cueing effects. Our findings indicate that exogenous attention significantly modulates V1 responses and that the modulation strength depends on both novelty and task relevance of the stimulus. Significance statement: Visual attention can be involuntarily captured by a sudden appearance of a conspicuous object, allowing rapid reactions to unexpected events of significance. The current study discovered a correlate of this effect in monkey primary visual cortex. An abrupt, salient, flash enhanced neuronal responses, and shortened the animal's reaction time, to a subsequent visual probe stimulus at the same location. However, the enhancement of the neural responses diminished after repeated exposures to this flash if the animal was not required to react to the probe. Moreover, a second, simultaneous, flash at another location weakened the neuronal and behavioral effects of the first one. These findings revealed, beyond the observations reported so far, the effects of exogenous attention in the brain.

Noradrenergic modulation of glutamate-induced excitatory responses in single neurons of the red nucleus: An electrophysiological study

The effect induced by noradrenaline (NA) on the spiking activity evoked by glutamate (Glu) on single neurons of the mesencephalic red nucleus (RN) of the rat was studied extracellularly. Long-lasting microiontophoretic applications of the amine induced a significant and reversible depression of the responsiveness of RN neurons to Glu. This effect was mediated by noradrenergic alpha2 receptors since it was mimicked by application of clonidine, an alpha2 adrenoceptor agonist, and blocked or at least reduced by application of yohimbine, an antagonist of NA for the same receptors. The effect appears homogeneously throughout the nucleus and is independent of the effect of NA on baseline firing rate. Application of isoproterenol, a beta adrenoceptor agonist, either enhanced or depressed neuronal responses to Glu in a high percentage (86%) of the tested neurons. Moreover, application of timolol, a beta adrenoceptor antagonist, was able to strengthen the depressive effects induced by NA application on neuronal responsiveness to Glu.Although these data suggest some involvement of beta adrenergic receptors in the modulation of neuronal responsiveness to Glu, the overall results indicate a short-term depressive action of NA, mediated by alpha2 receptors, on the responsiveness of RN neurons and suggest that stress initially leads to an attenuation of the relay function of the RN.

Vocalization-whisking coordination and multisensory integration of social signals in rat auditory cortex.

Social interactions involve multi-modal signaling. Here, we study interacting rats to investigate audio-haptic coordination and multisensory integration in the auditory cortex. We find that facial touch is associated with an increased rate of ultrasonic vocalizations, which are emitted at the whisking rate (∼8 Hz) and preferentially initiated in the retraction phase of whisking. In a small subset of auditory cortex regular-spiking neurons, we observed excitatory and heterogeneous responses to ultrasonic vocalizations. Most fast-spiking neurons showed a stronger response to calls. Interestingly, facial touch-induced inhibition in the primary auditory cortex and off-responses after termination of touch were twofold stronger than responses to vocalizations. Further, touch modulated the responsiveness of auditory cortex neurons to ultrasonic vocalizations. In summary, facial touch during social interactions involves precisely orchestrated calling-whisking patterns. While ultrasonic vocalizations elicited a rather weak population response from the regular spikers, the modulation of neuronal responses by facial touch was remarkably strong.

Lesions of prefrontal cortex reduce attentional modulation of neuronal responses and synchrony in V4.

It is widely held that the frontal eye field (FEF) in prefrontal cortex (PFC) modulates processing in visual cortex with attention, although the evidence for a necessary role is equivocal. To help identify critical sources of attentional feedback to area V4, we surgically removed the entire lateral PFC, including the FEF, in one hemisphere and transected the corpus callosum and anterior commisure in two macaques. This deprived V4 of PFC input in one hemisphere while keeping the other hemisphere intact. In the absence of PFC, attentional effects on neuronal responses and synchrony in V4 were significantly reduced and the remaining effects of attention were delayed in time indicating a critical role of PFC. Conversely, distracters captured attention and influenced V4 responses. However, because the effects of attention in V4 were not eliminated by PFC lesions, other sources of top-down attentional control signals to visual cortex must exist outside of PFC.

Noradrenergic modulation of neuronal responses to n-methyl-d-aspartate in the vestibular nuclei: An electrophysiological and immunohistochemical study

Excitatory responses evoked by N-methyl-d-aspartate (NMDA) in the vestibular nuclei (VN) of the rat were studied in vivo during microiontophoretic application of noradrenaline (NA) and/or its agonists and antagonists. Ejection of NA-modified excitatory responses mediated by NMDA receptors (NMDAR) in all neurons tested; the effect was enhancement in 59% of cases and depression in the remaining 41%. Enhancements prevailed in all VN with the exception of the lateral vestibular nucleus, where both effects were recorded in an equal number of cases.The enhancing action of NA on NMDAR-mediated responses was mimicked by the noradrenergic beta-receptor agonist isoproterenol, the beta1 specific agonist denopamine and the alpha2 agonist clonidine. These effects were blocked respectively by the generic beta-receptor antagonist timolol, the beta1 antagonist atenolol and the alpha2 antagonist yohimbine. In contrast, application of the alpha1 receptor agonist cirazoline and the specific alpha1 antagonist prazosin respectively mimicked and partially antagonized the depression of NMDAR-mediated excitations induced by NA.Double-labeling immunohistochemical techniques demonstrated broad colocalization of NMDAR (specifically NR1 and NR2 subunits) with noradrenergic receptors (alpha1, alpha2 and beta1) in many VN neurons; only minor differences were found between nuclei.These results indicate that NA can produce generalized modulation of NMDAR-mediated excitatory neurotransmission in VN, which may in turn modify synaptic plasticity within the nuclei.

Division of Labor for Division: Inhibitory Interneurons with Different Spatial Landscapes in the Olfactory System

Normalizing neural responses by the sum of population activity allows the nervous system to adjust its sensitivity according to task demands, facilitating intensity-invariant information processing. In this issue of Neuron, two studies, Kato etal. (2013) and Miyamichi etal. (2013), suggest that parvalbumin-positive interneurons in the olfactory bulb play a role in this process.

Repetition suppression/enhancement effects as a result of attractor dynamics in local cortical networks

Electrophysiological studies on short-term memory tasks have consistently reported three neural effects in associative cortices (i.e. ITC, PFC and PPC; [1]): a modulation of neuronal responses following stimulus repetition (repetition suppression --RS-- and repetition enhancement --RE-- effects) as well as sustained neural activity after the first stimulus has disappeared (persistent activity --PA--). For instance, in a standard delayed match-to-sample task, two visual stimuli are presented one after the other, with a delay period separating the two presentations. The task consists in recognizing if the first stimulus (the sample) matches the second (match) or not (non-match). While a certain proportion of cells respond less to a match stimulus than when the same identical stimulus is presented as sample or non-match (RS), some others show the opposite behavior, with an enhanced response to the match rather than to the sample or to the non-match (RE). Sustained neural activity (PA) is commonly observed in the delay period separating the presentation of sample and match/non-match. Although consistently observed in the same cortical areas and, often, in the same cell (e.g. a cell which shows RE also shows PA), these effects have never been related in terms of cellular and/or network mechanisms. Here, we argue that repetition effects, as well as persistent activity, are a signature of attractor dynamics in local networks. We show, by using a model network of spiking neurons which implements attractor dynamics, that the current network state affects the response to incoming inputs: persistent activity i.e. the internal dynamic state of the network, interacts with the incoming stimulus suppressing the responses of those neurons which are not highly selective for that stimulus (RS). On the other hand, the responses of those neurons which respond optimally for the incoming stimulus tend to be enhanced (RE). In agreement with the experimental data, we find that the less selective neural population shows a response to the match which is suppressed with respect to both sample and non-match. To the opposite, the most selective neurons'response to the match is enhanced with respect to both sample and non-match [2]. Moreover, the proportion of cells showing RE is correlated with the proportion of cells showing PA, consistently with the experimental data [3]. Interestingly, the magnitude of RE and RS effects should increase, according to the model predictions, with increasing firing rate during PA. Existing models and theories of repetition effects (e.g. [4]) suggest that suppression and/or enhancement of the neural response might be due to a modulatory top-down signal. However, the short latency observed in repetition effects implies that the modulation of the response should rather occur within the same cortical area. Here, we can explain in a unique and parsimonious framework the three main correlates of short-term memory and, more importantly, we can do so by fully relying on the local recurrent circuitry.