Processing in layer 4 of the neocortical circuit: new insights from visual and somatosensory cortex

Recent experimental and theoretical results in cat primary visual cortex and in the whisker-barrel fields of rodent primary somatosensory cortex suggest common organizing principles for layer 4, the primary recipient of sensory input from the thalamus. Response tuning of layer 4 cells is largely determined by a local interplay of feed-forward excitation (directly from the thalamus) and inhibition (from layer 4 inhibitory interneurons driven by the thalamus). Feed-forward inhibition dominates excitation, inherits its tuning from the thalamic input, and sharpens the tuning of excitatory cells. Recurrent excitation enhances responses to effective stimuli.     

Characterization of the synaptic actions of an interneuron in the central nervous system of Tritonia

The motor program that drives the swimming behavior of the marine mollusk Tritonia diomedea is generated by three interneuronal populations in the cerebral ganglia. One of these populations, the pair of C2 neurons, is shown to also exert powerful synaptic actions upon most cells in the contralateral pedal ganglion. Intracellular staining with Co²⁺ showed that the C2 neurons projected to the contralateral pedal ganglion as a single unbranched axon, and nearly all contralateral pedal neurons received monosynaptic input from C2. Orthodromic stimulation of most peripheral nerves caused monosynaptic excitation of C2 by afferent sensory cells and, in some cases, monosynaptic inhibition from an unidentified source. C2 neurons produced four types of postsynaptic potential (PSP) on pedal neurons: (1) a fast, Cl^?-mediated inhibition (FIPSP); (2) a fast, Na⁺-mediated excitation (FEPSP); (3) a slow, K⁺-mediated inhibition (SIPSP); and (4) a slow, conductance-decrease excitation (SEPSP). All four could be recorded simultaneously in some pedal neurons. The C2 neurons appear to be high-order, multiaction neurons involved in both the generation of a complex motor program and the coordination of ancillary neuronal activity.     

Endogenous 5-HT2B receptor activation regulates neonatal respiratory activity in vitro

An implication of 5-HT(2B) receptors in central nervous system has not yet been clearly elucidated. We studied the role of different 5-HT(2) receptor subtypes in the medullary breathing center, the pre-B?tzinger complex, and on hypoglossal motoneurons in rhythmically active transversal slice preparations of neonatal rats and mice. Local microinjection of 5-HT(2) receptor agonists revealed tonic excitation of hypoglossal motoneurons. Excitatory effects of the 5-HT(2B) receptor agonist BW723C86 could be blocked by bath application of LY272015, a highly selective 5-HT(2B) receptor antagonist. Excitatory effects of the 5-HT(2A/B/C) receptor agonist alpha-methyl 5-HT could be blocked by the preferential 5-HT(2A) receptor antagonist ketanserin. Therefore, 5-HT-induced excitation of hypoglossal motoneurons is mediated by convergent activation of 5-HT(2A) and 5-HT(2B) receptors. Local microinjection of BW723C86 in the pre-B?tzinger complex increased respiratory frequency. Bath application of LY272015 blocked respiratory activity, whereas ketanserin had no effect. Therefore, endogenous 5-HT appears to support tonic action on respiratory rhythm generation via 5-HT(2B) receptors. In preparations of 5-HT(2B) receptor-deficient mice, respiratory activity appeared unaltered. Whereas BW723C86 and LY272015 had no effects, bath application of ketanserin disturbed and blocked rhythmic activity. This demonstrates a stimulatory role of endogenous 5-HT(2B) receptor activation at the pre-B?tzinger complex and hypoglossal motoneurons that can be taken up by 5-HT(2A) receptors in the absence of 5-HT(2B) receptors. The presence of functional 5-HT(2B) receptors in the neonatal medullary breathing center indicates a potential convergent regulatory role of 5-HT(2B) and -(2A) receptors on the central respiratory network.     

Synaptic integration in motoneurons with hyper-excitable dendrites

Motoneurons have extensive dendritic trees that receive the numerous inputs required to produce movement. These dendrites are highly active, containing voltage-sensitive channels that generate persistent inward currents (PICs) that can enhance synaptic input 5-fold or more. However, this enhancement is proportional to the level of activity of monoaminergic inputs from the brainstem that release serotonin and noradrenalin. The higher this activity, the larger the dendritic PIC and the higher the firing rate evoked by a given amount of excitatory synaptic input. This brainstem control of motoneuron input-output gain translates directly into control of system gain of a motor pool and its muscle. Because large dendritic PICs are probably necessary for motoneurons to have sufficient gain to generate large forces, it is possible that descending monoaminergic inputs scale in proportion to voluntary force. Inhibition from sensory inputs has a strong suppressive effect on dendritic PICs: the stronger the inhibition, the smaller the PIC. Thus, local inhibitory inputs within the cord may oppose the descending monoaminergic control of PICs. Most motor behaviors evoke a mixture of excitation and inhibition (e.g., the reciprocal inhibition between antagonists). Therefore, normal joint movements may involve constant adjustment of PIC amplitude.     

Feedforward excitation and inhibition evoke dual modes of firing in the cat's visual thalamus during naturalistic viewing

Thalamic relay cells transmit information from retina to cortex by firing either rapid bursts or tonic trains of spikes. Bursts occur when the membrane voltage is low, as during sleep, because they depend on channels that cannot respond to excitatory input unless they are primed by strong hyperpolarization. Cells fire tonically when depolarized, as during waking. Thus, mode of firing is usually associated with behavioral state. Growing evidence, however, suggests that sensory processing involves both burst and tonic spikes. To ask if visually evoked synaptic responses induce each type of firing, we recorded intracellular responses to natural movies from relay cells and developed methods to map the receptive fields of the excitation and inhibition that the images evoked. In addition to tonic spikes, the movies routinely elicited lasting inhibition from the center of the receptive field that permitted bursts to fire. Therefore, naturally evoked patterns of synaptic input engage dual modes of firing.     

Study on mammal (rat) of the neuro-muscular synapse function under hyperbaric conditions (11 ata): effects of the curarization

Under hyperbaric conditions (11 ata) obtained with normoxic O2-N2 mixtures spontaneous EMG activity disappears, as do reactions to noise, but this phenomenon is reversible after the substitution of Helium for Nitrogen in the mixture. Analysis of EMG responses to sciatic nerve excitation has revealed no difference between the EMG tracings recorded under normobaric pressure and those obtained under hyperbaric conditions (O2-N2 or O2-He, 11 ata), and hyperbaric conditions do not seem to interfere with neuro-muscular synaptic transmission. Furthermore, the effect of Pavulon (an antidepolarising, acetyl-cholino-competitive curare-mimetic drug) is similar under normal and hyperbaric conditions: hyperbaria change neither the onset of neuro-muscular blockage nor its intensity or duration. The absence of a specific effect on synapse function of a change in the diluting gas from nitrogen to helium suggests that there was no change in post-synaptic receptor function. This result is not in accordance with the hypothesis that inert gas pressures of less than 10 ata modify molecular structures particularly at the neuro-muscular synapse level.     

The mandibular common inhibitor system

Summary The mandibular common inhibitor neurones ofHomarus gammarus receive sensory input from a wide receptive field (Table 1, Figs. 2, 3) and from their symmetrical homologue (Ferrero and Wales, 1976).The CI system receives excitatory input from mandibular proprioceptors, with the notable exception of the mandibular muscle receptor organ, and its activity increases, during mandible opening and closing, towards the extremes of movement (Fig. 1). The output of CI neurones is usually coupled except during some high frequency bursts. Unilateral sensory input usually produces a coupled output. Electrical stimulation of a wide range of mandibular nerves (Table 2) has a similar effect and entrains the CI output at lower frequencies (Figs. 4, 5).Antidromic stimulation of a CI neurone causes excitation of its homologue but to a lower level of activity and without enhanced coupling. Even when the excitatory state is raised, by concurrent stimulation of a sensory nerve, the pathway activated by antidromic stimuli does not produce coupled activity at frequencies above 20 Hz (Fig. 8).Stimulation with single pulses will frequently produce short trains of impulses from the CI neurones (Figs. 6, 7) suggesting reciprocal excitation between the neurones.A model of the system based on current knowledge is presented.     

On shunting inhibition

The interaction between excitation and inhibition is analyzed for nerve cylinders when reversal potentials for synaptic action are included. Both impulsive and sustained conductance changes are employed to model synaptic action.Exact results, in terms of Green's functions are obtained for the solutions of the cable equation with reversal potentials when there are impulsive conductance changes. The amplification factor for an inhibitory input due to a prior excitatory input is found exactly. In the case of an infinite cylinder, the dependence of this factor on the spatial separation of the excitatory and inhibitory synapses is one plus a Gaussian density function. Similar results aply when excitation follows inhibition. There is shunting inhibition even for impulsive conductance changes in the cable, but it is very different from that for sustained conductance changes. The interaction of excitation and inhibition is also studied in the full cable equation with reversal potentials and sustained conductance changes. An exact result is obtained for the potential in response to simultaneous excitation and inhibition at the same space point in an infinite cable. The effects of timing and spatial separation of inputs is analyzed in a finite nerve cylinder by numerically integrating the cable equation by the Crank-Nicolson method. Shunting inhibition is found to be most effective, for the chosen parameter values, when inhibition quickly foolows excitation. The EPSP amplitude at the soma is found to be roughly proportional to the distance from the soma to the site of inhibition when the excitation is at the center of the nerve cylinder.Dedicated to Jane Pauley     

Odorant representations are modulated by intra- but not interglomerular presynaptic inhibition of olfactory sensory neurons

Input to the central nervous system from olfactory sensory neurons (OSNs) is modulated presynaptically. We investigated the functional organization of this inhibition and its role in odor coding by imaging neurotransmitter release from OSNs in slices and in vivo in mice expressing synaptopHluorin, an optical indicator of vesicle exocytosis. Release from OSNs was strongly suppressed by heterosynaptic, intraglomerular inhibition. In contrast, inhibitory connections between glomeruli mediated only weak lateral inhibition of OSN inputs in slices and did not do so in response to odorant stimulation in vivo. Blocking presynaptic inhibition in vivo increased the amplitude of odorant-evoked input to glomeruli but had little effect on spatial patterns of glomerular input. Thus, intraglomerular inhibition limits the strength of olfactory input to the CNS, whereas interglomerular inhibition plays little or no role. This organization allows for control of input sensitivity while maintaining the spatial maps of glomerular activity thought to encode odorant identity.     

Similar but not the same: normobaric and hyperbaric pulmonary oxygen toxicity, the role of nitric oxide

Pulmonary manifestations of oxygen toxicity were studied and quantified in rats breathing >98% O(2) at 1, 1.5, 2, 2.5, and 3 ATA to test our hypothesis that different patterns of pulmonary injury would emerge, reflecting a role for central nervous system (CNS) excitation by hyperbaric oxygen. At 1.5 atmosphere absolute (ATA) and below, the well-recognized pattern of diffuse pulmonary damage developed slowly with an extensive inflammatory response and destruction of the alveolar-capillary barrier leading to edema, impaired gas exchange, respiratory failure, and death; the severity of these effects increased with time over the 56-h period of observation. At higher inspired O(2) pressures, 2-3 ATA, pulmonary injury was greatly accelerated but less inflammatory in character, and events in the brain were a prelude to a distinct lung pathology. The CNS-mediated component of this lung injury could be attenuated by selective inhibition of neuronal nitric oxide synthase (nNOS) or by unilateral transection of the vagus nerve. We propose that extrapulmonary, neurogenic events predominate in the pathogenesis of acute pulmonary oxygen toxicity in hyperbaric oxygenation, as nNOS activity drives lung injury by modulating the output of central autonomic pathways.     

Excitatory local interneurons enhance tuning of sensory information

Neurons in the insect antennal lobe represent odors as spatiotemporal patterns of activity that unfold over multiple time scales. As these patterns unspool they decrease the overlap between odor representations and thereby increase the ability of the olfactory system to discriminate odors. Using a realistic model of the insect antennal lobe we examined two competing components of this process -lateral excitation from local excitatory interneurons, and slow inhibition from local inhibitory interneurons. We found that lateral excitation amplified differences between representations of similar odors by recruiting projection neurons that did not receive direct input from olfactory receptors. However, this increased sensitivity also amplified noisy variations in input and compromised the ability of the system to respond reliably to multiple presentations of the same odor. Slow inhibition curtailed the spread of projection neuron activity and increased response reliability. These competing influences must be finely balanced in order to decorrelate odor representations.     

Modelling Feedback Excitation,Pacemaker Properties and Sensory Switching of Electrically Coupled Brainstem Neurons Controlling Rhythmic Activity

What cellular and network properties allow reliable neuronal rhythm generation or firing that can be started and stopped by brief synaptic inputs? We investigate rhythmic activity in an electrically-coupled population of brainstem neurons driving swimming locomotion in young frog tadpoles, and how activity is switched on and off by brief sensory stimulation. We build a computational model of 30 electrically-coupled conditional pacemaker neurons on one side of the tadpole hindbrain and spinal cord. Based on experimental estimates for neuron properties, population sizes, synapse strengths and connections, we show that: long-lasting, mutual, glutamatergic excitation between the neurons allows the network to sustain rhythmic pacemaker firing at swimming frequencies following brief synaptic excitation; activity persists but rhythm breaks down without electrical coupling; NMDA voltage-dependency doubles the range of synaptic feedback strengths generating sustained rhythm. The network can be switched on and off at short latency by brief synaptic excitation and inhibition. We demonstrate that a population of generic Hodgkin-Huxley type neurons coupled by glutamatergic excitatory feedback can generate sustained asynchronous firing switched on and off synaptically. We conclude that networks of neurons with NMDAR mediated feedback excitation can generate self-sustained activity following brief synaptic excitation. The frequency of activity is limited by the kinetics of the neuron membrane channels and can be stopped by brief inhibitory input. Network activity can be rhythmic at lower frequencies if the neurons are electrically coupled. Our key finding is that excitatory synaptic feedback within a population of neurons can produce switchable, stable, sustained firing without synaptic inhibition.     

The synaptic mechanism of direction selectivity in distal processes of starburst amacrine cells

Patch-clamp recordings revealed that distal processes of starburst amacrine cells (SACs) received largely excitatory synaptic input from the receptive field center and nearly purely inhibitory inputs from the surround during both stationary and moving light stimulations. The direct surround inhibition was mediated mainly by reciprocal GABA(A) synapses between opposing SACs, which provided leading and prolonged inhibition during centripetal stimulus motion. Simultaneous Ca(2+) imaging and current-clamp recording during apparent-motion stimulation further demonstrated the contributions of both centrifugal excitation and GABA(A/C)-receptor-mediated centripetal inhibition to the direction-selective Ca(2+) responses in SAC distal processes. Thus, by placing GABA release sites in electrotonically semi-isolated distal processes and endowing these sites with reciprocal GABA(A) synapses, SACs use a radial-symmetric center-surround receptive field structure to build a polar-asymmetric circuitry. This circuitry may integrate at least three levels of interactions--center excitation, surround inhibition, and reciprocal inhibitions that amplify the center--surround antagonism-to generate robust direction selectivity in the distal processes.     

Rapid and transient excitation of respiration mediated by central chemoreceptor

We evaluated rapid and transient changes in phrenic nerve (PN) and internal intercostal (IIC) activities when 0.2-0.5 ml of saline saturated with 100% CO2 was injected into the vertebral artery during various respiratory phases in decerebrated spontaneously breathing cats. The injections evoked an initial transient inhibition of ongoing PN or IIC activity with a mean onset latency of 0.17 s, followed by excitation of subsequent respiratory activities with an onset latency ranging from 0.4 to 2.7 s; the average onset latency of expiratory excitation (1.49 s) was significantly longer than that of inspiratory facilitation (0.89 s). The initial inhibitory responses were analogous to reflex effects of injections of phenyl biguanide, indicating that the initial inhibition was due to activation of vascular nociceptors and the subsequent excitation was due to stimulation of the central chemoreceptors. In addition, CO2-saline injections during hypocapnic apnea developed a quick reappearance of respiratory rhythm, and the first facilitatory effect appeared in tonic IIC activity, which became more active before rhythm started. In summary, the present study, by use of a technique of vertebral arterial injections of 100% CO2-saline, revealed dynamic properties of respiratory control system mediated by central chemoreceptors and vascular nociceptors.     

Intracellular and computational evidence for a dominant role of internal network activity in cortical computations

The mammalian cerebral cortex is characterized by intense spontaneous activity, depending on brain region, age, and behavioral state. Classically, the cortex is considered as being driven by the senses, a paradigm which corresponds well to experiments in quiescent or deeply anesthetized states. In awake animals, however, the spontaneous activity cannot be considered as 'background noise', but is of comparable-or even higher-amplitude than evoked sensory responses. Recent evidence suggests that this internal activity is not only dominant, but also it shares many properties with the responses to natural sensory inputs, suggesting that the spontaneous activity is not independent of the sensory input. Such evidence is reviewed here, with an emphasis on intracellular and computational aspects. Statistical measures, such as the spike-triggered average of synaptic conductances, show that the impact of internal network state on spiking activity is major in awake animals. Thus, cortical activity cannot be considered as being driven by the senses, but sensory inputs rather seem to modulate and modify the internal dynamics of cerebral cortex. This view offers an attractive interpretation not only of dreaming activity (absence of sensory input), but also of several mental disorders.     

Electrical activity of phrenic nerve and diaphragm in utero.

Phrenic nerve activity, diaphragmatic EMG, and tracheal or pleural pressure changes were recorded in a chronic fetal sheep preparation. Three patterns of fetal phrenic nerve activity were observed: 1) a single burst; 2) irregular nonrhythmic bursts; and 3) prolonged rhythmic activity, seen only prior to fetal death. The total recording time was 54.53 h and the total duration of phrenic nerve activity was 65.34 min (2.16%). When an inactive period was defined as the absence of phrenic nerve activity for 60 s or more, active periods occupied 44.7% of the total time. Phrenic nerve activity was present in all fetuses and 97.5% of the time was coupled with diaphragmatic EMG. Both diaphragmatic EMG and intrapulmonary pressure changes occurred in the absence of phrenic nerve activity. In three fetal animals both phrenic nerves were transected. Tracheal pressure changes were seen which were not coupled with corresponding intrauterine pressure changes. Thus, changes in fetal tracheal pressure or diaphragmatic EMG do not necessarily represent the output of the fetal respiratory center. This study suggests that the fetal respiratory center is active in utero, but this activity is minimal and has a different pattern that that present after birth.     

Sparse balance: Excitatory-inhibitory networks with small bias currents and broadly distributed synaptic weights

Cortical circuits generate excitatory currents that must be cancelled by strong inhibition to assure stability. The resulting excitatory-inhibitory (E-I) balance can generate spontaneous irregular activity but, in standard balanced E-I models, this requires that an extremely strong feedforward bias current be included along with the recurrent excitation and inhibition. The absence of experimental evidence for such large bias currents inspired us to examine an alternative regime that exhibits asynchronous activity without requiring unrealistically large feedforward input. In these networks, irregular spontaneous activity is supported by a continually changing sparse set of neurons. To support this activity, synaptic strengths must be drawn from high-variance distributions. Unlike standard balanced networks, these sparse balance networks exhibit robust nonlinear responses to uniform inputs and non-Gaussian input statistics. Interestingly, the speed, not the size, of synaptic fluctuations dictates the degree of sparsity in the model. In addition to simulations, we provide a mean-field analysis to illustrate the properties of these networks.     

The sensory consequences of speaking: parametric neural cancellation during speech in auditory cortex

When we speak, we provide ourselves with auditory speech input. Efficient monitoring of speech is often hypothesized to depend on matching the predicted sensory consequences from internal motor commands (forward model) with actual sensory feedback. In this paper we tested the forward model hypothesis using functional Magnetic Resonance Imaging. We administered an overt picture naming task in which we parametrically reduced the quality of verbal feedback by noise masking. Presentation of the same auditory input in the absence of overt speech served as listening control condition. Our results suggest that a match between predicted and actual sensory feedback results in inhibition of cancellation of auditory activity because speaking with normal unmasked feedback reduced activity in the auditory cortex compared to listening control conditions. Moreover, during self-generated speech, activation in auditory cortex increased as the feedback quality of the self-generated speech decreased. We conclude that during speaking early auditory cortex is involved in matching external signals with an internally generated model or prediction of sensory consequences, the locus of which may reside in auditory or higher order brain areas. Matching at early auditory cortex may provide a very sensitive monitoring mechanism that highlights speech production errors at very early levels of processing and may efficiently determine the self-agency of speech input.     

A self-regulating feed-forward circuit controlling C. elegans egg-laying behavior

BACKGROUND: Egg laying in Caenorhabditis elegans has been well studied at the genetic and behavioral levels. However, the neural basis of egg-laying behavior is still not well understood; in particular, the roles of specific neurons and the functional nature of the synaptic connections in the egg-laying circuit remain uncharacterized. RESULTS: We have used in vivo neuroimaging and laser surgery to address these questions in intact, behaving animals. We have found that the HSN neurons play a central role in driving egg-laying behavior through direct excitation of the vulval muscles and VC motor neurons. The VC neurons play a dual role in the egg-laying circuit, exciting the vulval muscles while feedback-inhibiting the HSNs. Interestingly, the HSNs are active in the absence of synaptic input, suggesting that egg laying may be controlled through modulation of autonomous HSN activity. Indeed, body touch appears to inhibit egg laying, in part by interfering with HSN calcium oscillations. CONCLUSIONS: The egg-laying motor circuit comprises a simple three-component system combining feed-forward excitation and feedback inhibition. This microcircuit motif is common in the C. elegans nervous system, as well as in the mammalian cortex; thus, understanding its functional properties in C. elegans may provide insight into its computational role in more complex brains.     

Proportional inhibition in the cricket medial giant interneuron

Inhibitory effects on the number of wind-evoked impulses were studied in the medial giant interneuron of the cricket, Gryllus bimaculatus. The interneuron receives an inhibitory input from wind receptors on cercus ipsilateral to its soma. Using a dual channel wind stimulator, the intensity of inhibitory input was changed over 1,000-fold and effects on the number of spikes were observed. The ipsilateral inhibition reduced the number of outgoing spikes from a level elicited by excitation alone and it did so in proportion to the level of wind responsiveness displayed by each cell. A proportional coefficient of inhibition was derived and its value depended on the level of total excitation of the medial giant interneuron. The medial giant interneurons with high excitation showed a smaller value of the coefficient than those with low excitation. The proportional inhibition of the medial giant interneuron by the ipsilateral cercus suppresses the number of its spikes to a reasonable level for a wide range of stimulus intensities under natural conditions.