Phasic and tonic patterns of locus coeruleus output differentially modulate sensory network function in the awake rat

Neurons of the nucleus locus coeruleus (LC) discharge with phasic bursts of activity superimposed on highly regular tonic discharge rates. Phasic bursts are elicited by bottom-up input mechanisms involving novel/salient sensory stimuli and top-down decision making processes; whereas tonic rates largely fluctuate according to arousal levels and behavioral states. Although it is generally believed that these two modes of activity differentially modulate information processing in LC targets, the unique role of phasic versus tonic LC output on signal processing in cells, circuits, and neural networks of waking animals is not well understood. In the current study, simultaneous recordings of individual neurons within ventral posterior medial thalamus and barrel field cortex of conscious rats provided evidence that each mode of LC output produces a unique modulatory impact on single neuron responsiveness to sensory-driven synaptic input and representations of sensory information across ensembles of simultaneously recorded cells. Each mode of LC activation specifically modulated the relationship between sensory-stimulus intensity and the subsequent responses of individual neurons and neural ensembles. Overall these results indicate that phasic versus tonic modes of LC discharge exert fundamentally different modulatory effects on target neuronal circuits within the rodent trigeminal somatosensory system. As such, each mode of LC output may differentially influence signal processing as a means of optimizing behaviorally relevant neural computations within this sensory network. Likely the ability of the LC system to differentially regulate neural responses and local circuit operations according to behavioral demands extends to other brain regions including those involved in higher cognitive functions.     

Signals and noise in an inhibitory interneuron diverge to control activity in nearby retinal ganglion cells

Information about sensory stimuli is represented by spatiotemporal patterns of neural activity. The complexity of the central nervous system, however, frequently obscures the origin and properties of signals and noise that underlie these activity patterns. We minimized this constraint by examining mechanisms governing correlated activity in mouse retinal ganglion cells (RGCs) under conditions in which light-evoked responses traverse a specific circuit, the rod bipolar pathway. Signals and noise in this circuit produced correlated synaptic input to neighboring On and Off RGCs. Temporal modulation of light intensity did not alter the degree to which noise in the input to nearby RGCs was correlated, and action potential generation in individual RGCs was largely insensitive to differences in network noise generated by dynamic and static light stimuli. Together, these features enable noise in shared circuitry to diminish simultaneous action potential generation in neighboring On and Off RGCs under a variety of conditions.     

Cellular mechanisms of suppressive interactions between somatosensory responses in vivo

The neural integration of afferent inputs evoked by spatiotemporally distributed sensory stimuli is a critical step in the formation of coherent and continuous perceptual representations. Integration mechanisms in various systems include linear and nonlinear summation of sensory responses. One well-known example in the rat barrel system is the suppressive interaction between responses to the consecutive deflection of neighboring whiskers. The mechanism underlying cross-whisker suppression has long been postulated to rely on intracortical postsynaptic inhibition, although this hypothesis has been challenged by recent reports. Here we show, using intracellular and extracellular recordings in vivo, that cross-whisker suppression occurs in the absence of cortical activity. Instead, suppression arises from local circuit operations at multiple levels of the subcortical afferent pathway and is amplified by the nonlinear transformation of synaptic input into spike output in both the thalamus and cortex. Because these cellular processes are common to neural circuits subserving visual and auditory modalities, we propose that the suppressive mechanisms elucidated here are a general property of thalamocortical sensory systems.     

Synaptic interactions underlying song-selectivity in the avian nucleus HVC revealed by dual intracellular recordings

Stimulus-dependent synaptic interactions underlying selective sensory representations in neural circuits specialized for sensory processing and sensorimotor integration remain poorly understood. The songbird telencephalic nucleus HVC is a sensorimotor area essential to learned vocal control with one projection neuron (PN) type (HVC(RA)) innervating a song premotor pathway, another PN (HVC(X)) innervating a basal ganglia pathway essential to vocal plasticity, and interneurons (HVC(Int)). Playback of the bird's own song (BOS), but not other songs, evokes action potential bursts from both PNs, but HVC(RA) and HVC(X) display distinct BOS-evoked subthreshold responses. To characterize synaptic interactions underlying HVC's BOS-selective responses and assess stimulus-evoked changes in functional interactions between HVC neurons, we made simultaneous in vivo intracellular recordings from various HVC neuron pairs in urethan-anesthetized zebra finches. Spike-triggered averaging revealed that all HVC neuron types receive common excitation and that the onset of this excitation occurs during a narrower time window in projection neurons during BOS playback. To distinguish local from extrinsic contributions to HVC subthreshold response patterns, we inactivated the HVC local circuit with GABA or occluded inhibition in single HVC(X) cells. After either treatment, BOS-evoked responses in HVC(X) neurons became purely depolarizing and subthreshold responses of HVC(X) and HVC(RA) cells became remarkably similar to one another while retaining BOS selectivity. Therefore both PN types receive a common extrinsic source of BOS-selective excitation, and local inhibition specifically alters processing of auditory information in HVC(X) cells. In HVC, excitatory and inhibitory synaptic interactions are recruited in a stimulus-dependent fashion, affecting auditory representations of the BOS locally and in other song nuclei important to song learning and production.     

Integrative spike dynamics of rat CA1 neurons: a multineuronal imaging study

The brain operates through a coordinated interplay of numerous neurons, yet little is known about the collective behaviour of individual neurons embedded in a huge network. We used large-scale optical recordings to address synaptic integration in hundreds of neurons. In hippocampal slice cultures bolus-loaded with Ca²⁺ fluorophores, we stimulated the Schaffer collaterals and monitored the aggregate presynaptic activity from the stratum radiatum and individual postsynaptic spikes from the CA1 stratum pyramidale. Single neurons responded to varying synaptic inputs with unreliable spikes, but at the population level, the networks stably output a linear sum of synaptic inputs. Nonetheless, the network activity, even though given constant stimuli, varied from trial to trial. This variation emerged through time-varying recruitment of different neuron subsets, which were shaped by correlated background noise. We also mapped the input-frequency preference in spiking activity and found that the majority of CA1 neurons fired in response to a limited range of presynaptic firing rates (20–40 Hz), acting like a band-pass filter, although a few neurons had high pass-like or low pass-like characteristics. This frequency selectivity depended on phasic inhibitory transmission. Thus, our imaging approach enables the linking of single-cell behaviours to their communal dynamics, and we discovered that, even in a relatively simple CA1 circuit, neurons could be engaged in concordant information processing.     

Stochastic resonance improves signal detection in hippocampal CA1 neurons

Stochastic resonance (SR) is a phenomenon observed in nonlinear systems whereby the introduction of noise enhances the detection of a subthreshold signal for a certain range of noise intensity. The nonlinear threshold detection mechanism that neurons employ and the noisy environment in which they reside makes it likely that SR plays a role in neural signal detection. Although the role of SR in sensory neural systems has been studied extensively, its role in central neurons is unknown. In many central neurons, such as the hippocampal CA1 cell, very large dendritic trees are responsible for detecting neural input in a noisy environment. Attenuation due to the electrotonic length of these trees is significant, suggesting that a method other than passive summation is necessary if signals at the distal ends of the tree are to be detected. The hypothesis that SR plays an important role in the detection of distal synaptic inputs first was tested in a computer simulation of a CA1 cell and then verified with in vitro rat hippocampal slices. The results clearly showed that SR can enhance signal detection in CA1 hippocampal cells. Moreover, high levels of noise were found to equalize detection of synaptic signals received at varying positions on the dendritic tree. The amount of noise needed to evoke the effect is compared with physiological noise in slices and in vivo.     

Stimulus selection via differential response latencies in visual cortical area V4

Any given region of the cerebral cortex gets multiple inputs, and how these inputs are combined or selected is a key component of cortical function. Experiments in brain slices or other reduced preparations have shown that excitatory inputs to cortex produce a delayed feed-forward inhibition, which suggests that the relative timing of inputs at the scale of tens of milliseconds is crucial to cortical operation. Other mechanisms, such as synaptic depression and feedback inhibition, have also been shown to produce strong effects on this timescale. Thus, the relative timing of inputs should be fundamental in determining how a given region of cortex selects or combines its inputs. A rhesus monkey (Macaca mulatta) was trained to fixate on a spot of light for juice reward. Isolated single units in visual cortical area V4 were recorded using standard microelectrode techniques. Two visual stimuli were positioned such that each alone elicited a strong response. The stimuli were presented both separately and in combination, and their contrast and relative onset timing were varied. In general, the response of each neuron to two stimuli was locked to the response to that single stimulus that produced the shortest latency. A partial exception was that the responses to low-contrast stimuli were often less effective at suppressing later-arriving responses to high-contrast stimuli. The presentation of two stimuli in the receptive field of a visual cortical neuron is proposed as a model system for how changes in the relative timing of inputs affect cortical function in the intact system.     

An fMRI study of the functional distinction of neuronal circuits at the sites on ventral visual stream co-activated by visual stimuli of different objects

In functional studies of the human brain using functional magnetic resonance imaging (fMRI) we often observe some functional areas that are commonly activated by different stimulus inputs even when the inputs are of different categories. It is difficult to distinguish by fMRI whether the neuronal circuits activated for processing these inputs are separate and independent ones within the functional area or whether they are mutually interactive and possibly sharing a part of the circuits for processing some common features of the input information. In order to elucidate such property of the neuronal circuits, we used a novel paradigm in which paired input stimuli with varied inter stimulus interval (ISI) were presented during a stimulation period in fMRI experiments. The refractory suppression induced by an input pair depends on ISI as well as the differing characteristics of the input pair. The extent of suppression, an indicator for the interaction between the processing activities of the input pair, can be evaluated by the shape of the time-course of fMRI responses. We examined the functional characteristics of the neuronal circuits in areas that were activated by different inputs of inter-category types, namely face stimuli and building stimuli and also by intra-category input pairs such as different faces. In the ventral visual occipitotemporal region, we found functional areas where neuronal circuits were interacting to process these inputs rather than functioning as separate independent circuits. With this approach, one can probe functional system activity at the neuronal circuit level to learn the characteristics that determine the functional roles of certain brain areas.     

Activity-dependent modification of inhibitory synapses in models of rhythmic neural networks

The faithful production of rhythms by many neural circuits depends critically on the strengths of inhibitory synaptic connections. We propose a model in which the strengths of inhibitory synapses in a central pattern-generating circuit are subject to activity-dependent plasticity. The strength of each synapse is modified as a function of the global activity of the postsynaptic neuron and by correlated activity of the pre- and postsynaptic neurons. This allows the self-assembly, from random initial synaptic strengths, of two cells into reciprocal oscillation and three cells into a rhythmic triphasic motor pattern. This self-assembly illustrates that complex oscillatory circuits that depend on multiple inhibitory synaptic connections can be tuned via simple activity-dependent rules.     

Spike timing, synchronization and information processing on the sensory side of the central nervous system

To what extent is the variability of the neuronal responses compatible with the use of spike timing for sensory information processing by the central nervous system? In reviewing the state of the art of this question, I first analyze the characteristics of this variability with its three elements: synaptic noise, impact of ongoing activity and possible fluctuations in evoked responses. I then review the recent literature on the various sensory modalities: somato-sensory, olfactory, gustatory and visual and auditory processing. I emphasize that the conditions in which precise timing, at the millisecond level, is usually obtained, are conditions that usually require dynamic stimulation or sharp changes in the stimuli. By contrast, situations in which stimulation not belonging to the temporal domain is temporally encoded lead to much coarser temporal coding; although in both cases, neural networks transmit the signals with similarly high precision. Synchronization among neurons is an important tool in information processing in both cases but again seems to act either at millisecond or tens of millisecond levels. Information theory applied to both situations confirms that the average rate of information transmission is much higher in dynamic than in static situations. These facts suggest that channels of precise temporal encoding may exist in the brain but imply populations of neurons working in a yet to be discovered way.     

Stabilization of visual responses through cholinergic activation

Neuronal processing of sensory information requires that rapidly changing synaptic inputs are continuously transformed into action potentials. Variability of spike firing is generally considered as noise and might therefore interfere with the reliability of synaptic transmission in sensory systems. In a system in which the number of spikes is a variable that determines the quality of neuronal transmission, variability of spike counts is a paradoxical attribute. In contrast, in a system in which precisely correlated spike firing can influence synaptic integration, response variability might be used as an additional mechanism for coding information. As acetylcholine has been shown to reduce spike-frequency adaptation and enhance gamma frequency (21–70 Hz) oscillations, we set out to study the influence of cholinergic modulation on the variability of spike counts and gamma oscillations. Iontophoretic application of carbachol, a cholinergic agonist, in cat primary visual cortex or electrical stimulation of the mesencephalic reticular formation reduced the spike count variability and stabilized gamma frequency oscillations of visually induced responses. Response stabilization was correlated with enhancement of gamma-frequency oscillations but not with averaged firing rates. Lowering variability of sensory responses might be a mechanism to stabilize and improve reliability of neuronal transmission. Cholinergic activation may therefore influence the efficacy of neuronal transmission by modulating the precise timing of neuronal responses.     

Dopaminergic neuromodulation of synaptic transmission between mitral and granule cells in the teleost olfactory bulb

A growing body of evidence suggests that teleosts are important models for the study of neural processing of olfactory information, and the functional role of dopamine (DA), which is a potent neuromodulator endogenous to the mammalian olfactory bulb, has been one of the strongest focuses in this field. However, the cellular mechanisms of dopaminergic neuromodulation in olfactory bulbar neural circuits have not been fully understood. We investigated such mechanisms by using the goldfish, which offers several advantages for analyzing olfactory information processing by electrophysiological methods. First, we found in the olfactory bulb that numerous cell bodies of the dopaminergic neurons are mainly distributed in the mitral cell layer and extend fine processes to the glomerular layer. Next, we made in vitro field potential recordings and showed that synaptic transmissions from mitral to granule cells were suppressed by DA application. DA also increased the paired-pulse ratio, suggesting that the suppression of synaptic transmission is caused by a decrease in presynaptic glutamate release from the mitral cells. Furthermore, DA significantly suppressed the oscillatory activity of the olfactory bulb in response to olfactory stimuli. Although DA suppresses the synaptic inputs from the olfactory nerve to the olfactory bulbar neurons in mammals, this phenomenon was not observed in the goldfish. These findings indicate that suppression of the mitral to granule cell synaptic transmission in the reciprocal synapses plays an important role in the negative regulation of olfactory responsiveness in the goldfish olfactory bulb.     

Neural circuit-dependent odor adaptation in C. elegans is regulated by the Ras-MAPK pathway

The molecular machinery that mediates odor adaptation in the olfactory neurons is well documented in various animal species. However, types of adaptation that depend on neural circuits are mostly unexplored. We report here that the Ras-MAPK pathway is essential for such a type of odor adaptation, called early adaptation, in C. elegans. Early adaptation requires a pair of AIY interneurons, which receive synaptic inputs from olfactory neurons. Mutants of the Ras-MAPK pathway show defects in early adaptation. Continued exposure to an odorant causes activation of MAP kinase not only in the olfactory neurons, but also in the AIY interneurons. While activity of the Ras-MAPK pathway in the olfactory neurons is important for odor perception, its activity in the AIY interneurons is important for odor adaptation. Our results thus reveal a dual role of the Ras-MAPK pathway in sensory processing in the nervous system of C. elegans.     

Optical mapping of spatiotemporal emergence of functional synaptic connections in the embryonic chick olfactory pathway

In order to understand the functional maturation of the CNS, it is essential to first describe the functional maturation of sensory processing. We have approached this topic by following the ontogenetic patterning of neural circuit formation related to cranial and spinal sensory input using voltage-sensitive dye imaging. In previous studies, we have described the functional maturation of synapses in brainstem/midbrain neural circuits. Here, we elucidate the functional maturation of forebrain circuits by investigating neural networks related to the olfactory nerve (N. I) of chicken embryo. In the isolated N. I-olfactory bulb-forebrain preparation, application of electrical stimulation to N. I elicited excitatory postsynaptic potential (EPSP)-related slow optical signals in the olfactory bulb. The slow signal was mainly mediated by glutamate, and was easily fatigued with repetitive stimuli because of the immaturity of synapses in the embryonic CNS. Ontogenetically, the slow signal was detected from the 6-day embryonic stage, suggesting that functional synaptic connections between N. I and olfactory bulb emerge around this stage. In addition, from the 8-day embryonic stage, another response area was discriminated within the forebrain, which corresponded to the higher-ordered nucleus of the olfactory pathway. In comparison with our previous studies concerning the functional development of other cranial nerve-related sensory nuclei in the embryonic brainstem and midbrain, these results suggest that the olfactory pathway is functionally generated in the early stages of development when neural networks related to other visceral and somatic sensory inputs are also in the process of developing.     

Temporal integration by stochastic recurrent network dynamics with bimodal neurons

Temporal integration of externally or internally driven information is required for a variety of cognitive processes. This computation is generally linked with graded rate changes in cortical neurons, which typically appear during a delay period of cognitive task in the prefrontal and other cortical areas. Here, we present a neural network model to produce graded (climbing or descending) neuronal activity. Model neurons are interconnected randomly by AMPA-receptor-mediated fast excitatory synapses and are subject to noisy background excitatory and inhibitory synaptic inputs. In each neuron, a prolonged afterdepolarizing potential follows every spike generation. Then, driven by an external input, the individual neurons display bimodal rate changes between a baseline state and an elevated firing state, with the latter being sustained by regenerated afterdepolarizing potentials. When the variance of background input and the uniform weight of recurrent synapses are adequately tuned, we show that stochastic noise and reverberating synaptic input organize these bimodal changes into a sequence that exhibits graded population activity with a nearly constant slope. To test the validity of the proposed mechanism, we analyzed the graded activity of anterior cingulate cortex neurons in monkeys performing delayed conditional Go/No-go discrimination tasks. The delay-period activities of cingulate neurons exhibited bimodal activity patterns and trial-to-trial variability that are similar to those predicted by the proposed model.     

Coordinated excitatory effect of GABAergic interneurons on three feeding motor programs in the mollusk Clione limacina

Coordination between different motor centers is essential for the orderly production of all complex behaviors. Understanding the mechanisms of such coordination during feeding behavior in the carnivorous mollusk Clione limacina is the main goal of the current study. A bilaterally symmetrical interneuron identified in the cerebral ganglia and designated Cr-BM neuron produced coordinated activation of neural networks controlling three main feeding structures: prey capture appendages called buccal cones, chitinous hooks used for prey extraction from the shell, and the toothed radula. The Cr-BM neuron produced strong excitatory inputs to motoneurons controlling buccal cone protraction. It also induced a prominent activation of the neural networks controlling radula and hook rhythmic movements. In addition to the overall activation, Cr-BM neuron synaptic inputs to individual motoneurons coordinated their activity in a phase-dependent manner. The Cr-BM neuron produced depolarizing inputs to the radula protractor and hook retractor motoneurons, which are active in one phase, and hyperpolarizing inputs to the radula retractor and hook protractor motoneurons, which are active in the opposite phase. The Cr-BM neuron used GABA as its neurotransmitter. It was found to be GABA-immunoreactive in the double-labeling experiments. Exogenous GABA mimicked the effects produced by Cr-BM neuron on the postsynaptic neurons. The GABA antagonists bicuculline and picrotoxin blocked Cr-BM neuron-induced PSPs. The prominent coordinating effect produced by the Cr-BM neuron on the neural networks controlling three major elements of the feeding behavior in Clione suggests that this interneuron is an important part of the higher-order system for the feeding behavior.     

Dynamic afferent synapses to decision-making networks improve performance in tasks requiring stimulus associations and discriminations

Animals must often make opposing responses to similar complex stimuli. Multiple sensory inputs from such stimuli combine to produce stimulus-specific patterns of neural activity. It is the differences between these activity patterns, even when small, that provide the basis for any differences in behavioral response. In the present study, we investigate three tasks with differing degrees of overlap in the inputs, each with just two response possibilities. We simulate behavioral output via winner-takes-all activity in one of two pools of neurons forming a biologically based decision-making layer. The decision-making layer receives inputs either in a direct stimulus-dependent manner or via an intervening recurrent network of neurons that form the associative layer, whose activity helps distinguish the stimuli of each task. We show that synaptic facilitation of synapses to the decision-making layer improves performance in these tasks, robustly increasing accuracy and speed of responses across multiple configurations of network inputs. Conversely, we find that synaptic depression worsens performance. In a linearly nonseparable task with exclusive-or logic, the benefit of synaptic facilitation lies in its superlinear transmission: effective synaptic strength increases with presynaptic firing rate, which enhances the already present superlinearity of presynaptic firing rate as a function of stimulus-dependent input. In linearly separable single-stimulus discrimination tasks, we find that facilitating synapses are always beneficial because synaptic facilitation always enhances any differences between inputs. Thus we predict that for optimal decision-making accuracy and speed, synapses from sensory or associative areas to decision-making or premotor areas should be facilitating.     

Responses of a looming-sensitive neuron to compound and paired object approaches

The lobula giant movement detector (LGMD) and its target neuron, the descending contralateral movement detector (DCMD), constitute a motion-sensitive pathway in the locust visual system that responds preferentially to objects approaching on a collision course. LGMD receptive field properties, anisotropic distribution of local retinotopic inputs across the visual field, and localized habituation to repeated stimuli suggest that this pathway should be sensitive to approaches of individual objects within a complex visual scene. We presented locusts with compound looming objects while recording from the DCMD to test the effects of nonuniform edge expansion on looming responses. We also presented paired objects approaching from different regions of the visual field at nonoverlapping, closely timed and simultaneous approach intervals to study DCMD responses to multiple looming stimuli. We found that looming compound objects evoked characteristic responses in the DCMD and that the time of peak firing was consistent with predicted values based on a weighted ratio of the half size of each distinct object edge and the absolute approach velocity. We also found that the azimuthal position and interval of paired approaches affected DCMD firing properties and that DCMDs responded to individual objects approaching within 106 ms of each other. Moreover, comparisons between individual and paired approaches revealed that overlapping approaches are processed in a strongly sublinear manner. These findings are consistent with biophysical mechanisms that produce nonlinear integration of excitatory and feed-forward inhibitory inputs onto the LGMD that have been shown to underlie responses to looming stimuli.     

Local-distributed integration by a novel neuron ensures rapid initiation of animal locomotion

Animals are adapted to respond quickly to threats in their environment. In many invertebrate and some vertebrate species, the evolutionary pressures have resulted in rapidly conducting giant axons, which allow short response times. Although neural circuits mediating escape behavior are identified in several species, little attention has been paid to this behavior in the medicinal leech, a model organism whose neuronal circuits are well known. We present data that suggest an alternative to giant axons for the rapid initiation of locomotion. A novel individual neuron, cell E21, appears to be one mediator of this short-latency action in the leech. In isolated nerve cord and semi-intact preparations, cell E21 excitation initiates and extends swimming and reduces the cycle period. The soma of this cell is located caudally, but its axon extends nearly the entire length of the nerve cord. We found that cell E21 fires impulses following local sensory inputs anywhere along the body and makes excitatory synapses onto the gating cells that drive swimming behavior. These distributed input-output sites minimize the distance information travels to initiate swimming behavior, thus minimizing the latency between sensory input and motor output. We propose that this single cell E21 functions to rapidly initiate or modulate locomotion through its distributed synaptic connections.     

Distinct neural firing mechanisms to tonal stimuli offset in the inferior colliculus of mice in vivo

Offset neurons, which fire at the termination of sound, likely encode sound duration and serve to process temporal information. Offset neurons are found in most ascending auditory nuclei; however, the neural mechanisms that evoke offset responses are not well understood. In this study, we examined offset neural responses to tonal stimuli in the inferior colliculus (IC) in vivo with extracellular and intracellular recording techniques in mice. Based on peristimulus time histogram (PSTH) patterns, we classified extracellular offset responses into four types: Offset, Onset-Offset, Onset-Sustained-Offset and Inhibition-Offset types. Moreover, using in vivo whole-cell recording techniques, we found that offset responses were generated in most cells through the excitatory and inhibitory synaptic inputs. However, in a small number of cells, the offset responses were generated as a rebound to hyperpolarization during tonal stimulation. Many offset neurons fired robustly at a preferred duration of tonal stimulus, which corresponded with the timing of rich excitatory synaptic inputs. We concluded that most IC offset neurons encode the termination of the tone stimulus by responding to inherited ascending synaptic information, which is tuned to sound duration. The remainder generates offset spikes de novo through a post-inhibitory rebound mechanism.