Characteristics of cortical inhibitory neurons

Spikes were recorded extracellularly and IPSPs intracellularly from auditory cortical neurons of cats immobilized with D-tubocurarine in response to stimulation of geniculo-cortical fibers. Fibers whose stimulation induces IPSPs in auditory cortical neurons mainly have low thresholds. When two stimuli, each of which separately evoked an IPSP of maximal amplitude, were applied to them the shortest interval at which the second stimulus evoked an effect was 2.5–3 msec. This effect consisted of an increase in the duration of the integral IPSP, the amplitude of which either remained unchanged or increased under these circumstances by only 5–10%. The interval at which a separate IPSP appeared in response to the second stimulus depended on the duration of the ascending phase of the IPSP and varied from 4 to 22 msec for different neurons. The amplitude of the second IPSP in this case depended on the interval between stimuli. Under moderately deep pentobarbital anesthesia the number of neurons responding to stimulation of the geniculo-cortical fibers by spikes fell sharply but the number of neurons responding by primary IPSPs remained almost unchanged. Under very deep pentobarbital anesthesia, when spike responses of the cortical neurons completely disappeared, the IPSPs also were completely suppressed. It is concluded that inhibitory neurons of the auditory cortex are excited by thick low-threshold fibers, they have a short refractory period, and they are resistant to the narcotic action of pentobarbital.     

Exciting information for inhibitory neurons

One unsolved issue in brain development is how interneurons migrating tangentially into the cortex acquire their regional addresses and laminar positions. The study by Lodato et al. in this issue shows that projection neurons regulate the laminar fates of cortical interneurons.     

Cortical modulation of cholinergic neurons in the striatum

Previous reports suggest the existence of a cortico-striatal pathway which might use glutamate as the transmitter. In the present study, the possible influence of this pathway on striatal cholinergic neurons was investigated. Two weeks following surgical destruction of the cerebral cortex, the high affinity uptake of glutamate and choline into striatal synaptosomes was significantly reduced whereas GABA uptake was unaffected. In acute experiments (1 hour following decortication), only choline uptake was significantly reduced while the uptake of glutamate and GABA were not altered. Acute injection (2 minutes) of kainic acid into the striatum, 1 hour after decortication, reversed the effect of the decortication on choline uptake, perhaps by simulating an excitatory input to the striatum which was presumably removed by the cortical ablation. These observations are consistent with the existence of a cortical input (perhaps glutamatergic) to the striatum and suggest that striatal cholinergic neurons can be influenced by this cortico-striatal pathway.     

Monosynaptic inhibitory postsynaptic potentials of cortical neurons

Monopolar intracortical stimulation of the auditory cortex was carried out in cats immobilized with D-tubocurarine. A macroelectrode (tip diameter 100 µ) or a microelectrode (tip diameter 10–15 µ) was used for stimulation. In both cases, besides excitatory responses, primary IPSPs with latent periods of 0.4–1.2 and 1.4–6.0 msec were recorded in cortical neurons close to the point of stimulation. The first group of IPSPs are considered to be generated in response to direct stimulation of bodies or axons of inhibitory cortical neurons, i.e., monosynaptically. The amplitude of these IPSPs varied in different neurons from 3 to 15 mV, and their duration from 4 to 150 msec. Additional later inhibitory responses were superposed on many of them. Of the IPSPs generated in auditory cortical neurons in response to stimulation of geniculocortical fibers 1.5% had a latency of 0.8–1.3 msec. They also are assumed to be monosynaptic. It is concluded that the duration of synaptic delay of IPSPs in cortical neurons and spinal motoneurons is the same, namely 0.3–0.4 msec. Axons of auditory cortical inhibitory neurons may be 1.5 mm long. The velocity of impulse conduction along these axons is 1.6–2.8 m/sec. The genesis of some special features of IPSPs of cortical neurons is discussed.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 7, No. 5, pp. 458–467, September–October, 1975.     

Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons

Leptin acts in the brain to prevent obesity. The underlying neurocircuitry responsible for this is poorly understood, in part because of incomplete knowledge regarding first-order, leptin-responsive neurons. To address this, we and others have been removing leptin receptors from candidate first-order neurons. While functionally relevant neurons have been identified, the observed effects have been small, suggesting that most first-order neurons remain unidentified. Here we take an alternative approach and test whether first-order neurons are inhibitory (GABAergic, VGAT?) or excitatory (glutamatergic, VGLUT2?). Remarkably, the vast majority of leptin's antiobesity effects are mediated by GABAergic neurons; glutamatergic neurons play only a minor role. Leptin, working directly on presynaptic GABAergic neurons, many of which appear not to express AgRP, reduces inhibitory tone to postsynaptic POMC neurons. As POMC neurons prevent obesity, their disinhibition by leptin action on presynaptic GABAergic neurons probably mediates, at least in part, leptin's antiobesity effects.     

Energy coding in neural network with inhibitory neurons

This paper aimed at assessing and comparing the effects of the inhibitory neurons in the neural network on the neural energy distribution, and the network activities in the absence of the inhibitory neurons to understand the nature of neural energy distribution and neural energy coding. Stimulus, synchronous oscillation has significant difference between neural networks with and without inhibitory neurons, and this difference can be quantitatively evaluated by the characteristic energy distribution. In addition, the synchronous oscillation difference of the neural activity can be quantitatively described by change of the energy distribution if the network parameters are gradually adjusted. Compared with traditional method of correlation coefficient analysis, the quantitative indicators based on nervous energy distribution characteristics are more effective in reflecting the dynamic features of the neural network activities. Meanwhile, this neural coding method from a global perspective of neural activity effectively avoids the current defects of neural encoding and decoding theory and enormous difficulties encountered. Our studies have shown that neural energy coding is a new coding theory with high efficiency and great potential.     

Excitatory and inhibitory interactions in localized populations of model neurons

Coupled nonlinear differential equations are derived for the dynamics of spatially localized populations containing both excitatory and inhibitory model neurons. Phase plane methods and numerical solutions are then used to investigate population responses to various types of stimuli. The results obtained show simple and multiple hysteresis phenomena and limit cycle activity. The latter is particularly interesting since the frequency of the limit cycle oscillation is found to be a monotonic function of stimulus intensity. Finally, it is proved that the existence of limit cycle dynamics in response to one class of stimuli implies the existence of multiple stable states and hysteresis in response to a different class of stimuli. The relation between these findings and a number of experiments is discussed.     

Dynamics of networks of randomly connected excitatory and inhibitory spiking neurons

Recent advances in the understanding of the dynamics of populations of spiking neurones are reviewed. These studies shed light on how a population of neurones can follow arbitrary variations in input stimuli, how the dynamics of the population depends on the type of noise, and how recurrent connections influence the dynamics. The importance of inhibitory feedback for the generation of irregularity in single cell behaviour is emphasized. Examples of computation that recurrent networks with excitatory and inhibitory cells can perform are then discussed. Maintenance of a network state as an attractor of the system is discussed as a model for working memory function, in both object and spatial modalities. These models can be used to interpret and make predictions about electrophysiological data in the awake monkey.     

Analysis of stability of neural network with inhibitory neurons

Phase coding in a neural network composed of neural oscillators with inhibitory neurons was studied based on the theory of stochastic phase dynamics. We found that with increasing the coupling coefficients of inhibitory neural oscillators, the firing density in excitatory population transits to a critical state. In this case, when we increase the inhibitory coupling, the firing density will come into dynamic balance again and tend to a fixed value gradually. According to the phenomenon, in the paper we found parameter regions to exhibit those different population states, called dividing zones including flat fading zone, rapid fading zone and critical zone. Based on the dividing zones we can choose the number ratio between inhibitory neurons and excitatory neurons in the neural network, and estimate the coupling action of inhibitory population and excitatory population. Our research also shows that the balance value, enabling the firing density to reach the dynamic balance, does not depend on initial conditions. In addition, the critical value in critical state is only related to the number ratio between inhibitory neurons and excitatory neurons, but is independent of inhibitory coupling and excitatory coupling.     

On the dynamics of electrically-coupled neurons with inhibitory synapses

We study the dynamics and bifurcations of noise-free neurons coupled by gap junctions and inhibitory synapses, using both delayed delta functions and alpha functions to model the latter. We focus on the case of two cells, as in the studies of Chow and Kopell (2000) and Lewis and Rinzel (2003), but also show that stable asynchronous splay states exist for globally coupled networks of N cells dominated by subthreshold electrical coupling. Our results agree with those of Lewis and Rinzel (2003) in the weak coupling range, but our Poincaré map analysis yields more information about global behavior and domains of attraction, and we show that the explicit discontinuous maps derived using delayed delta functions compare well with the continuous history-dependent, implicitly-defined maps derived from alpha functions. We find that increased bias currents, super-threshold electrical coupling and synaptic delays promote synchrony, while sub-threshold electrical coupling and fast synapses promote asynchrony. We compare our analytical results with simulations of an ionic current model of spiking cells, and briefly discuss implications for stimulus response modes of locus coeruleus and for central pattern generators. Action Editor: F. Skinner     

Cortical neurons express PSI,a novel isoform of phosphacan/RPTPbeta

Phosphacan is a chondroitin sulfate proteoglycan representing the secreted extracellular part of a transmembrane receptor protein tyrosine phosphatase (RPTP-). These isoforms have been implicated in cell-extracellular matrix signaling events associated with myelination, axon growth, and cell migration in the developing central nervous system and may play critical roles in the context of brain pathologies. Recently, we have reported the identification of a new isoform of phosphacan, the phosphacan short isoform (PSI), the expression of which peaks in the second postnatal week. PSI interacts with the neuronal receptors L1 and F3/contactin and can promote neurite growth of cortical neurons. In this study, we have assessed, by in situ hybridization, the expression profile of PSI in the rat brain at postnatal day 7. PSI is largely expressed in the gray matter of the developing cerebral cortex in which it colocalizes with phosphacan, whereas the expression of RPTPbeta receptor forms is restricted to the ventricular area in which PSI has not been observed. Neurons from all layers of the cortex express PSI. In the cerebellum, on the other hand, no expression of PSI has been detected, although the other phosphacan/RPTP-beta isoforms show strong PSI expression here. Overall, our study suggests that PSI is expressed during the postnatal period in differentiated neurons of the cortex but is absent from structures in which proliferation and migration occur. The significance of these observations is discussed in the context of previous models of phosphacan/RPTP-beta functions.The authors thank the German Research Council (DFG) for grant support (SFB 509 and SPP 1048 to A.F.) and for a graduate training grant to Alice Klausmeyer (GK 736).     

Effect of picamilon on inhibitory postsynaptic responses of cortical neurons

In experiments on immobilized anesthetized rats, we intracellularly recorded neuronal responses in the motor cortex before and after application of picamilon (PM) on the cortical surface; the responses were evoked by intracortical stimulation. Aplications of PM in the 5, 20, 50, and 100 μM concentrations noticeably increased, while that in the 10 μM concentration decreased the amplitude of IPSP in the cortical neurons. Probable mechanisms of the effect of PM on a cellular level are discussed.     

Glutamate-induced suppression of inhibitory synaptic transmission in cultivated hippocampal neurons

In a dissociated culture of rat hippocampal neurons (14 to 24 daysin vitro), modulation effects of glutamate on GABA_A-ergic inhibitory transmission were studied with the use of simultaneous patch-clamp whole-cell recording from monosynaptically connected neuron pairs. In all experiments (n=49), 1.5-min-long or longer extracellular application of 0.5 to 100 μM glutamate suppressed evoked inhibitory postsynaptic currents (IPSC). This suppression usually included fast (seconds) and slow (τ=1.3 min) phases. In 83.7% of the cases studied, IPSC did not return to the control values during the entire subsequent recording period (from 10 to 64 min). When glutamate was applied in the presence of blockers of glutamate ionotropic receptors, DL-APV or CNQX, the fast phase of the effect was removed, while some suppression of inhibitory neuronal responses, although weaker, was preserved (n=19); in most cases (73.3%) this residual suppression was slow and long-lasting. It is concluded that both types of glutamate receptors, ionotropic and metabotropic, are involved in modulation of GABA_A-ergic synaptic transmission. The first above receptor type provides fast and reversible suppression, while the effect provided by the second type is slow and long-lasting.     

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     

A Cdk5 inhibitory peptide reduces tau hyperphosphorylation and apoptosis in neurons

The extracellular aggregation of amyloid beta (Abeta) peptides and the intracellular hyperphosphorylation of tau at specific epitopes are pathological hallmarks of neurodegenerative diseases such as Alzheimer's disease (AD). Cdk5 phosphorylates tau at AD-specific phospho-epitopes when it associates with p25. p25 is a truncated activator, which is produced from the physiological Cdk5 activator p35 upon exposure to Abeta peptides. We show that neuronal infections with Cdk5 inhibitory peptide (CIP) selectively inhibit p25/Cdk5 activity and suppress the aberrant tau phosphorylation in cortical neurons. Furthermore, Abeta(1-42)-induced apoptosis of these cortical neurons was also reduced by coinfection with CIP. Of particular importance is our finding that CIP did not inhibit endogenous or transfected p35/Cdk5 activity, nor did it inhibit the other cyclin-dependent kinases such as Cdc2, Cdk2, Cdk4 and Cdk6. These results, therefore, provide a strategy to address, and possibly ameliorate, the pathology of neurodegenerative diseases that may be a consequence of aberrant p25 activation of Cdk5, without affecting 'normal' Cdk5 activity.     

Non-participation of bulbar inspiratory neurons in the esophago-diaphragmatic inhibitory reflex

The effects of the distension of the lower oesophageal sphincter were studied on the inspiratory activity of 96 medullary neurons located either in the dorsal or in the ventral respiratory groups and on the inspiratory activity of the costal and crural parts of the diaphragm in barbiturate anaesthetized cat. Inhibition of the inspiratory activity of the crural part of the diaphragm during oesophageal distension was never associated with significant changes of the medullary inspiratory neuron discharge. These results suggest that the observed crural inhibition is due to reflex loop that does not include the inspiratory neurons belonging to the dorsal and the ventral respiratory groups.     

Cellular and subcellular localization of the inhibitory glycine receptor in hippocampal neurons

Inhibitory glycine receptors are most abundant in spinal cord and brainstem, and glycinergic synapses have a well-established role in the regulation of locomotor behavior. Little is known about the function of glycine receptors in cortex and hippocampus, where GABA plays a dominant role in synaptic inhibition. Therefore, we have investigated tissue and cellular expression of glycine receptor alpha-subunits. Western blot and immunohistochemical analyses reveal the presence of glycine receptors in hippocampal tissue. Immunocytochemical experiments in hippocampal cultures show prominent cellular expression of glycine receptors in pyramidal neurons and GAD-positive interneurons similar to the calcium-binding protein VILIP-1 with widespread hippocampal distribution. On the subcellular level we found co-staining of GlyR and the presynaptic marker synapsin I. Furthermore, co-staining with GAD at synaptic terminals indicated partial co-localization of GABA- and glycine receptors.     

Switching mechanisms and bout times in a pair of reciprocally inhibitory neurons

Within the appropriate parameter regime, a deterministic model of a pair of mutually inhibitory neurons receiving excitatory driving currents exhibits bistability—each of the two stable states corresponds to one neuron being active and the other being quiescent. The presence of noise in the driving currents results in a system that randomly switches back and forth between these two states, causing alternating bouts of spiking activity. In this work, we examine the random bout durations of the two neurons and dependence on system parameters. We find that bout durations of each neuron are exponentially distributed, with changes in system parameters altering only the mean of the distribution. Synaptic inhibition independently controls the bout durations of the two neurons—the mean bout time of a neuron is a function of efferent (or outgoing) inhibition, and is independent of afferent (or incoming) inhibition. Furthermore, we find that the mean bout time of a neuron exhibits a critical dependence on the time course (rather than amplitude) of efferent inhibition—mean bout time of a neuron grows exponentially with the time course of efferent inhibition, and the growth rate of this exponential function depends only on the excitatory driving current to that neuron (and not on any other system parameters). We discuss the relevance of our results to the regulation of sleep-wake cycling by medullary and pontine structures within the brain.     

Cortical influences on neurons of the lateral reticular nucleus responding to noxious stimuli

The effect of frontoparietal sensorimotor (FPSM) cortex stimulation on both the spontaneous and the noxious evoked activity of neurons in the lateral reticular nucleus (LRN) was tested in barbiturate-anesthetized rats. Ninety-three LRN neurons that responded to a noxious heat stimulus (HS) were recorded (72% antidromically fired from the cerebellum). Of these, 66 neurons altered their spontaneous firing rates in response to cortical stimulation. Two patterns of responses were found: either an excitation followed by a suppression of spontaneous activity (52 neurons), or a pure suppression of spontaneous activity lasting 50-400 msec (14 neurons). In 46 of these neurons, it was found that cortical stimulation reduced HS-evoked activity to near the baseline level. Furthermore, it was found that when applied after a prolonged cortical stimulation, the HS was ineffective. It is concluded that FPSM cortex can influence nociceptive information in LRN neurons that respond to its stimulation, possibly interfering with the mechanisms underlying stimulation-produced analgesia (SPA). In this context, it is proposed that the cortex can modulate the activity of LRN neurons that activate, through local loops, a descending antinociceptive system and also a separate projection system to the cerebellum.