Inhibitory postsynaptic potentials carry synchronized frequency information in active cortical networks

Temporal precision in spike timing is important in cortical function, interactions, and plasticity. We found that, during periods of recurrent network activity (UP states), cortical pyramidal cells in vivo and in vitro receive strong barrages of both excitatory and inhibitory postsynaptic potentials, with the inhibitory potentials showing much higher power at all frequencies above approximately 10 Hz and more synchrony between nearby neurons. Fast-spiking inhibitory interneurons discharged strongly in relation to higher-frequency oscillations in the field potential in vivo and possess membrane, synaptic, and action potential properties that are advantageous for transmission of higher-frequency activity. Intracellular injection of synaptic conductances having the characteristics of the recorded EPSPs and IPSPs reveal that IPSPs are important in controlling the timing and probability of action potential generation in pyramidal cells. Our results support the hypothesis that inhibitory networks are largely responsible for the dissemination of higher-frequency activity in cortex.     

Multiple neural oscillators and muscle feedback are required for the intestinal fed state motor program

After a meal, the gastrointestinal tract exhibits a set of behaviours known as the fed state. A major feature of the fed state is a little understood motor pattern known as segmentation, which is essential for digestion and nutrient absorption. Segmentation manifests as rhythmic local constrictions that do not propagate along the intestine. In guinea-pig jejunum in vitro segmentation constrictions occur in short bursts together with other motor patterns in episodes of activity lasting 40-60 s and separated by quiescent episodes lasting 40-200 s. This activity is induced by luminal nutrients and abolished by blocking activity in the enteric nervous system (ENS). We investigated the enteric circuits that regulate segmentation focusing on a central feature of the ENS: a recurrent excitatory network of intrinsic sensory neurons (ISNs) which are characterized by prolonged after-hyperpolarizing potentials (AHPs) following their action potentials. We first examined the effects of depressing AHPs with blockers of the underlying channels (TRAM-34 and clotrimazole) on motor patterns induced in guinea-pig jejunum, in vitro, by luminal decanoic acid. Contractile episode durations increased markedly, but the frequency and number of constrictions within segmenting bursts and quiescent period durations were unaffected. We used these observations to develop a computational model of activity in ISNs, excitatory and inhibitory motor neurons and the muscle. The model predicted that: i) feedback to ISNs from contractions in the circular muscle is required to produce alternating activity and quiescence with the right durations; ii) transmission from ISNs to excitatory motor neurons is via fast excitatory synaptic potentials (EPSPs) and to inhibitory motor neurons via slow EPSPs. We conclude that two rhythm generators regulate segmentation: one drives contractions within segmentation bursts, the other the occurrence of bursts. The latter depends on AHPs in ISNs and feedback to these neurons from contraction of the circular muscle.     

Physiological and pathological oscillatory networks in the human motor system.

Human brain functions are heavily contingent on neural interactions both at the single neuron and the neural population or system level. Accumulating evidence from neurophysiological studies strongly suggests that coupling of oscillatory neural activity provides an important mechanism to establish neural interactions. With the availability of whole-head magnetoencephalography (MEG) macroscopic oscillatory activity can be measured non-invasively from the human brain with high temporal and spatial resolution. To localise, quantify and map oscillatory activity and interactions onto individual brain anatomy we have developed the 'dynamic imaging of coherent sources' (DICS) method which allows to identify and analyse cerebral oscillatory networks from MEG recordings. Using this approach we have characterized physiological and pathological oscillatory networks in the human sensorimotor system. Coherent 8 Hz oscillations emerge from a cerebello-thalamo-premotor-motor cortical network and exert an 8 Hz oscillatory drive on the spinal motor neurons which can be observed as a physiological tremulousness of the movement termed movement discontinuities. This network represents the neurophysiological substrate of a discrete mode of motor control. In parkinsonian resting tremor we have identified an extensive cerebral network consisting of primary motor and lateral premotor cortex, supplementary motor cortex, thalamus/basal ganglia, posterior parietal cortex and secondary somatosensory cortex, which are entrained in the tremor or twice the tremor rhythm. This low frequency entrapment of motor areas likely plays an important role in the pathophysiology of parkinsonian motor symptoms. Finally, studies on patients with postural tremor in hepatic encephalopathy revealed that this type of tremor results from a pathologically slow thalamocortical and cortico-muscular coupling during isometric hold tasks. In conclusion, the analysis of oscillatory cerebral networks provides new insights into physiological mechanisms of motor control and pathophysiological mechanisms of tremor disorders.     

Feed-forward synchronization: propagation of temporal patterns along the retinothalamocortical pathway

Visual responses in the cortex and lateral geniculate nucleus (LGN) are often associated with synchronous oscillatory patterning. In this short review, we examine the possible relationships between subcortical and cortical synchronization mechanisms. Our results obtained from simultaneous multi-unit recordings show strong synchronization of oscillatory responses between retina, LGN and cortex, indicating that cortical neurons can be synchronized by oscillatory activity relayed through the LGN. This feed-forward synchronization mechanism operating in the 60 to 120 Hz frequency range was observed mostly for static stimuli. In response to moving stimuli, by contrast, cortical synchronization was independent of oscillatory inputs from the LGN, with oscillation frequency in the range of 30 to 60 Hz. The functional implications of synchronization of activity from parallel channels are discussed, in particular its significance for signal transmission and cortical integration processes.     

Synchronization without oscillatory neurons

Experimental results suggest that neurons in the cortex synchronize their action potentials on the millisecond time scale. More importantly this binding expresses functional relationships between the neurons. A model of neuronal interactions is proposed in which simultaneous discharges of neurons develop through specialized synaptic circuits. As an important prerequisite for this synchronization it is demonstrated that SynFire chains, generating different levels of excitation, propagate their activity waves at distinct velocities. Two chains were coupled by excitatory synapses and their activity was initiated at different times. Due to synaptic interactions, activity in the earlier-initiated chain accelerates propagation in the other chain until the two activity waves are synchronized. Compared with several neural network models with oscillatory units, physiologically more plausible neurons are simulated. It is still under debate whether neurons in the cortex show oscillatory dischargesper se. In particular, a high rate of noise relative to very weak synaptic gains cannot impair our results in the neural network simulations.     

Emergence of oscillations and spatio-temporal coherence states in a continuum-model of excitatory and inhibitory neurons

A neural field model of the reaction-diffusion type for the emergence of oscillatory phenomena in visual cortices is proposed. To investigate the joint spatio-temporal oscillatory dynamics in a continuous distribution of excitatory and inhibitory neurons, the coupling among oscillators is modelled as a diffusion process, combined with non-linear point interactions. The model exhibits cooperative activation properties in both time and space, by reacting to volleys of activations at multiple cortical sites with ordered spatio-temporal oscillatory states, similar to those found in the physiological experiments on slow-wave field potentials. The possible use of the resulting spatial distributions of coherent states, as a flexible medium to establish feature association, is discussed.     

Dendritic GABA release depresses excitatory transmission between layer 2/3 pyramidal and bitufted neurons in rat neocortex

GABAergic, somatostatin-containing bitufted interneurons in layer 2/3 of rat neocortex are excited via glutamatergic excitatory postsynaptic potentials (EPSPs) by pyramidal neurons located in the same cortical layer. Pair recordings showed that short bursts of backpropagating dendritic action potentials (APs) reduced the amplitude of unitary EPSPs. EPSP depression was dependent on a rise in dendritic [Ca2+]. The effect was blocked by the GABA(B) receptor (GABA(B)-R) antagonist CGP55845A and was mimicked by the GABA(B)-R agonist baclofen. As presynaptic GABA(B)-Rs were activated neither by somatostatin nor by GABA released from axon collaterals of the bitufted cell, we conclude that GABA(B)-Rs were activated by a retrograde messenger, most likely GABA, released from the dendrite. Because synaptic depression was prevented by loading bitufted neurons with GDP-beta-S, it is likely to be caused by exocytotic GABA release from dendrites.     

Synchronization and sensitivity enhancement of the Hodgkin-Huxley neurons due to inhibitory inputs

Recent experimental results imply that inhibitory postsynaptic potentials can play a functional role in realizing synchronization of neuronal firing in the brain. In order to examine the relation between inhibition and synchronous firing of neurons theoretically, we analyze possible effects of synchronization and sensitivity enhancement caused by inhibitory inputs to neurons with a biologically realistic model of the Hodgkin-Huxley equations. The result shows that, after an inhibitory spike, the firing probability of a single postsynaptic neuron exposed to random excitatory background activity oscillates with time. The oscillation of the firing probability can be related to synchronous firing of neurons receiving an inhibitory spike simultaneously. Further, we show that when an inhibitory spike input precedes an excitatory spike input, the presence of such preceding inhibition raises the firing probability peak of the neuron after the excitatory input. The result indicates that an inhibitory spike input can enhance the sensitivity of the postsynaptic neuron to the following excitatory spike input. Two neural network models based on these effects on postsynaptic neurons caused by inhibitory inputs are proposed to demonstrate possible mechanisms of detecting particular spatiotemporal spike patterns. Received: 15 April 1999 /Accepted in revised form: 25 November 1999     

Possible mechanisms of the anterior limbic cortex influence on the neuron activity of the vago-solitary complex

In ananesthetized cats, neurons of the nucleus of the tractus solitarius (NTS) and the dorsal motor nucleus of the vagus nerve (DMNV) revealed phasic excitatory responses to separate single vagal and cortical stimuli. Stimulation of the anterior limbic cortex combined with vagal stimulation resulted in inhibitory or excitatory modification of the vagal induced responses of the NTS and DMNV neurons. The data obtained suggest that complete inhibitory effects are related to general cortical mechanisms of control of the functional state of the brain stem visceral neurons. Selective inhibition of the vagal induced responses by limbic cortex stimulation is due to particular cortical mechanisms of the visceral sensory transmission control via the NTS neurons.     

Thalamic activation modulates the responses of neurons in rat primary auditory cortex: an in vivo intracellular recording study

Auditory cortical plasticity can be induced through various approaches. The medial geniculate body (MGB) of the auditory thalamus gates the ascending auditory inputs to the cortex. The thalamocortical system has been proposed to play a critical role in the responses of the auditory cortex (AC). In the present study, we investigated the cellular mechanism of the cortical activity, adopting an in vivo intracellular recording technique, recording from the primary auditory cortex (AI) while presenting an acoustic stimulus to the rat and electrically stimulating its MGB. We found that low-frequency stimuli enhanced the amplitudes of sound-evoked excitatory postsynaptic potentials (EPSPs) in AI neurons, whereas high-frequency stimuli depressed these auditory responses. The degree of this modulation depended on the intensities of the train stimuli as well as the intervals between the electrical stimulations and their paired sound stimulations. These findings may have implications regarding the basic mechanisms of MGB activation of auditory cortical plasticity and cortical signal processing.     

Cortical Resonance Frequencies Emerge from Network Size and Connectivity

Neural oscillations occur within a wide frequency range with different brain regions exhibiting resonance-like characteristics at specific points in the spectrum. At the microscopic scale, single neurons possess intrinsic oscillatory properties, such that is not yet known whether cortical resonance is consequential to neural oscillations or an emergent property of the networks that interconnect them. Using a network model of loosely-coupled Wilson-Cowan oscillators to simulate a patch of cortical sheet, we demonstrate that the size of the activated network is inversely related to its resonance frequency. Further analysis of the parameter space indicated that the number of excitatory and inhibitory connections, as well as the average transmission delay between units, determined the resonance frequency. The model predicted that if an activated network within the visual cortex increased in size, the resonance frequency of the network would decrease. We tested this prediction experimentally using the steady-state visual evoked potential where we stimulated the visual cortex with different size stimuli at a range of driving frequencies. We demonstrate that the frequency corresponding to peak steady-state response inversely correlated with the size of the network. We conclude that although individual neurons possess resonance properties, oscillatory activity at the macroscopic level is strongly influenced by network interactions, and that the steady-state response can be used to investigate functional networks.     

Organization of the spatial-temporal relationships of cerebral electrical processes in children during exposure to verbel commands]

An EEG cross-correlation analysis has shown that in children aged four to five years higher sensory analysis of verbal commands and their meaning was reflected in the nature of synchronous interactions between oscillatory processes and their spatial-temporal patterns. At the moment of perception of the command "listen" highly synchronous synphasic relations were recorded between biopotentials in the associative infero-parietal cortex and projection temporal centres of the left hemisphere. Oscillations of the parietal areas preceded the rhythms of the occipital, motor and frontal lobes in the left hemisphere; slow oscillations with a 3 osc/sec frequency predominated, and the intensity of the periodic processes increased. The command "look" evoked a high degree of synchronous synphasic relations of biopotentials in the parietal-occipital cortical parts of both hemispheres; oscillations with 6 osc/sec frequency predominated; their intensity rose; synphasic relations of oscillations in parietal and motor and temporal centres grew more manifest, while the rhythmic activity in the parietal zones preceded the potentials in the frontal lobes of both hemispheres.     

Synaptic plasticity at archicortical and neocortical levels

Research carried out by the author and his collaborators, devoted to analysis of the properties and neurophysiological mechanisms of long-term (for several hours) potentiation, is surveyed. Long-term potentiation of focal potentials and unitary responses of strictly hippocampal structures (areas CA₁ and CA₃) in the unanesthetized rabbit is described. Enhancement of excitatory (EPSPs) and inhibitory (IPSPs) postsynaptic potentials was found after tetanization. No corresponding changes of sensitivity to acetylcholine or acetylcholinesterase activity were found by microiontophoretic and histochemical methods during long-term potentiation. Statistical analysis of EPSPs evoked by microstimulation, based on the quantal hypothesis of synaptic transmission, showed an increase in the number of quanta of transmitter release during potentiation. Long-term potentiation of focal potentials during stimulation of the subcortical white matter in surviving neocortical slices and also long-term potentiation of focal and unitary responses of the sensomotor cortex of the unanesthetized rabbit are described. Potentiation of the "indirect" component of the global response of the pyramidal tract was found. The data suggest the presence of long-term potentiation of monosynaptic neocortical responses. It is concluded that the main mechanism of both hippocampal and neocortical long-term potentiation is increased efficiency of excitatory synapses. It is postulated that synapses modified in this way are used in the formation of memory traces.Brain Institute, All-Union Mental Health Research Center, Academy of Medical Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 16, No. 5, pp. 651–665, September–October, 1984.     

Activation of glutamate ionotropic connections of sensorimotor cortex neurons during conditioning

Changes in conditioned impulse reactions of neurons in sensorimotor cortex were studied during microiontophoretic application of glutamatergic and GABA ergic agonistic and antagonistic drugs. It was shown that ionotropic glutamate receptors (AMPA and NMDA) are activated by a conditioned stimulus. Not only large pyramidal neurons of deep cortical layers but surrounding short-axon inhibitory interneurons are involved in the reaction. It was shown that the activity of pyramidal neurons is under a constant inhibitory control from surrounding interneurons. This inhibition is involved in organization of excitatory cortical responses during conditioning.     

Encoding of Naturalistic Stimuli by Local Field Potential Spectra in Networks of Excitatory and Inhibitory Neurons

Recordings of local field potentials (LFPs) reveal that the sensory cortex displays rhythmic activity and fluctuations over a wide range of frequencies and amplitudes. Yet, the role of this kind of activity in encoding sensory information remains largely unknown. To understand the rules of translation between the structure of sensory stimuli and the fluctuations of cortical responses, we simulated a sparsely connected network of excitatory and inhibitory neurons modeling a local cortical population, and we determined how the LFPs generated by the network encode information about input stimuli. We first considered simple static and periodic stimuli and then naturalistic input stimuli based on electrophysiological recordings from the thalamus of anesthetized monkeys watching natural movie scenes. We found that the simulated network produced stimulus-related LFP changes that were in striking agreement with the LFPs obtained from the primary visual cortex. Moreover, our results demonstrate that the network encoded static input spike rates into gamma-range oscillations generated by inhibitory–excitatory neural interactions and encoded slow dynamic features of the input into slow LFP fluctuations mediated by stimulus–neural interactions. The model cortical network processed dynamic stimuli with naturalistic temporal structure by using low and high response frequencies as independent communication channels, again in agreement with recent reports from visual cortex responses to naturalistic movies. One potential function of this frequency decomposition into independent information channels operated by the cortical network may be that of enhancing the capacity of the cortical column to encode our complex sensory environment.     

The modulation of sensory transmission through the medullary dorsal horn during cortically driven mastication

During mastication, reflexes are modulated and sensory transmission is altered in interneurons and ascending pathways of the rostral trigeminal sensory complex. The current experiment examines the modulation of sensory transmission through the most caudal part of the trigeminal sensory system, the medullary dorsal horn, during fictive mastication produced by cortical stimulation. Extracellular single unit activity was recorded from the medullary dorsal horn, and multiple unit activity was recorded from the trigeminal motor nucleus in anesthetized, paralyzed rabbits. The masticatory area of sensorimotor cortex was stimulated to produce rhythmic activity in the trigeminal motor nucleus (fictive mastication). Activity in the dorsal horn was compared in the presence and absence of cortical stimulation. Fifty-two percent of neurons classified as low threshold and 83% of neurons receiving noxious inputs were influenced by cortical stimulation. The cortical effects were mainly inhibitory, but 21% of wide dynamic range and 6% of low threshold cells were excited by cortical stimulation. The modulation produced by cortical stimulation, whether inhibitory or excitatory, was not phasically related to the masticatory cycle. It is likely that, when masticatory movements are commanded by the sensorimotor cortex, the program includes tonic changes in sensory transmission through the medullary dorsal horn.     

Long-latency responses to conditioned stimulus in the cat motor cortex can be generated through the enhancement of efficiency excitatory collaterals of pyramidal neuron

The long-latency excitatory components are the characteristic feature of neuronal responses to conditional stimuli in the motor cortex of the cat. The data presented suggest that the neuronal machine that generates these reactions is that, generating long-latency epileptiform discharges in epileptogenic cortex. The long-latency component generation is based on NMDA-receptor activation in the recurrent excitatory collaterals of the cortical pyramidal neurons. The response delay is dependent on initial activation of inhibitory GABA(A) receptors. The emergence of the late components in the course of motor learning take place as a result of efficiency enhancement of recurrent collaterals synaptic linkage with pyramidal neurons.     

Driving oscillatory activity in the human cortex enhances motor performance

Voluntary movement is accompanied by changes in the degree to which neurons in the brain synchronize their activity within discrete frequency ranges. Two patterns of movement-related oscillatory activity stand out in human cortical motor areas. Activity in the beta frequency (15-30 Hz) band is prominent during tonic contractions but is attenuated prior to and during voluntary movement. Without such attenuation, movement may be slowed, leading to the suggestion that beta activity promotes postural and tonic contraction, possibly at a cost to the generation of new movements. In contrast, activity in the gamma (60-90 Hz) band increases during movement. The direction of change suggests that gamma activity might facilitate motor processing. In correspondence with this, increased frontal gamma activity is related with reduced reaction times. Yet the possibility remains that these functional correlations reflect an epiphenomenal rather than causal relationship. Here we provide strong evidence that oscillatory activities at the cortical level are mechanistically involved in determining motor behavior and can even improve performance. By driving cortical oscillations using noninvasive electrical stimulation, we show opposing effects at beta and gamma frequencies and interactions with motor task that reveal the potential quantitative importance of oscillations in motor behavior.     

Attentional modulation of firing rate and synchrony in a model cortical network

The response of a neuron in the visual cortex to stimuli of different contrast placed in its receptive field is commonly characterized using the contrast response curve. When attention is directed into the receptive field of a V4 neuron, its contrast response curve is shifted to lower contrast values (Reynolds et al., 2000). The neuron will thus be able to respond to weaker stimuli than it responded to without attention. Attention also increases the coherence between neurons responding to the same stimulus (Fries et al., 2001). We studied how the firing rate and synchrony of a densely interconnected cortical network varied with contrast and how they were modulated by attention. The changes in contrast and attention were modeled as changes in driving current to the network neurons. We found that an increased driving current to the excitatory neurons increased the overall firing rate of the network, whereas variation of the driving current to inhibitory neurons modulated the synchrony of the network. We explain the synchrony modulation in terms of a locking phenomenon during which the ratio of excitatory to inhibitory firing rates is approximately constant for a range of driving current values. We explored the hypothesis that contrast is represented primarily as a drive to the excitatory neurons, whereas attention corresponds to a reduction in driving current to the inhibitory neurons. Using this hypothesis, the model reproduces the following experimental observations: (1) the firing rate of the excitatory neurons increases with contrast; (2) for high contrast stimuli, the firing rate saturates and the network synchronizes; (3) attention shifts the contrast response curve to lower contrast values; (4) attention leads to stronger synchronization that starts at a lower value of the contrast compared with the attend-away condition. In addition, it predicts that attention increases the delay between the inhibitory and excitatory synchronous volleys produced by the network, allowing the stimulus to recruit more downstream neurons. Action Editor: David Golomb     

Functional implications of temporal structure in primate cortical information processing

Processing of information in the cerebral cortex of primates is characterized by distributed representations and processing in neuronal assemblies rather than by detector neurons, cardinal cells or command neurons. Responses of individual neurons in sensory cortical areas contain limited and ambiguous information on common features of the natural environment which is disambiguated by comparison with the responses of other, related neurons. Distributed representations are also capable to represent the enormous complexity and variability of the natural environment by the large number of possible combinations of neurons that can engage in the representation of a stimulus or other content. A critical problem of distributed representation and processing is the superposition of several assemblies activated at the same time since interpretation and processing of a population code requires that the responses related to a single representation can be identified and distinguished from other, related activity. A possible mechanism which tags related responses is the synchronization of neuronal responses of the same assembly with a precision in the millisecond range. This mechanism also supports the separate processing of distributed activity and dynamic assembly formation. Experimental evidence from electrophysiological investigations of non-human primates and human subjects shows that synchronous activity can be found in visual, auditory and motor areas of the cortex. Simultaneous recordings of neurons in the visual cortex indicate that individual neurons synchronize their activity with each other, if they respond to the same stimulus but not if they are part of different assemblies representing different contents. Furthermore, evidence for synchronous activity related to perception, expectation, memory, and attention has been observed.