锐化蝙蝠听皮层神经元频率调谐的柱特征

用双声刺激和多管电极方法在 6只大棕蝠 (bigbrownbat,Eptesicusfuscus)的 98个神经元上研究了锐化 (sharpening)蝙蝠听皮层 (primaryauditorycortex ,AC)神经元频率调谐的柱特征。结果发现 ,电极直插在 1个电极通道内连续记录到多个神经元时 ,它们锐化频率调谐的抑制性调谐曲线或抑制区基本相似。电极与AC表面呈 45°斜向推入使其跨越多个功能柱时 ,可观察到锐化频率调谐的抑制区构成也随电极进入不同的功能柱而发生相应的改变。两种不同的电极插入方式均证明锐化AC神经元频率调谐的神经抑制呈柱状组构。这些神经元组合起来排列在同一听觉功能柱内 ,构成AC频率分析的基本功能组构单位“微频率处理器”。实验中还观察到多峰频率调谐曲线神经元 ,它们在声通讯和声定位中不同波谱区域的时间匹配中起作用。此外 ,也有理由认为多峰调谐神经元亦被用于作为复杂波谱信息的“高级调谐预处理器” ,从而极大地提高了神经元对频率分析的能力。为研究锐化频率调谐的神经抑制机制 ,用多管电极电泳γ -氨基丁酸 (γ aminobutyricacid ,GA BA)能a受体拮抗剂荷包牡丹碱 (bicuculline ,Bic)至所记录的神经元 ,发现能大部分或几乎全部取消抑制区 ,从而表明在正常情况下GABA能抑制参与构成锐化AC神经元频率调谐的抑制区 ,     

Direction-dependent corticofugal modulation of frequency-tuning curves of inferior collicular neurons in the big brown bat, Eptesicus fuscus

This study examined if corticofugal modulation of subcortical frequency-tuning curves varied with sound direction. Both excitatory and inhibitory frequency tuning curves of inferior collicular neurons of the big brown bat, Eptesicus fuscus were plotted before and during electrical stimulation in the auditory cortex at two sound directions (contra-40 degrees and ipsi-40 degrees). Most collicular neurons had broader excitatory frequency-tuning curves at contra-40 degrees but had broader inhibitory frequency-tuning curves at ipsi-40 degrees. Cortical electrical stimulation changed the excitatory minimum thresholds of most collicular neurons at a greater degree at ipsi-40 degrees than at contra-40 degrees. However, cortical electrical stimulation produced a greater increase in the sharpness of excitatory frequency-tuning curves of most corticofugally inhibited collicular neurons at contra-40 degrees but produced a greater decrease in the sharpness of excitatory frequency-tuning curves of most corticofugally facilitated collicular neurons at ipsi-40 degrees. Cortical electrical stimulation also produced a greater change in the sharpness of inhibitory frequency-tuning curves of most corticofugally inhibited collicular neurons at contra-40 degrees than at ipsi-40 degrees. Possible mechanisms for this direction-dependent corticofugal modulation of frequency-tuning curves of collicular neurons are discussed.     

GABAergic inhibition shapes frequency tuning and modifies response properties in the auditory midbrain of the leopard frog

The functional role of GABAergic inhibition in shaping the frequency tuning of 96 neurons in the torus semicircularis of the leopard frog, Rana pipiens, was studied using microiontophoresis of the GABA_A receptor antagonist, bicuculline methiodide. Bicuculline application abolished, or reduced in size, the inhibitory tuning curves of 72 neurons. In each case, there was a concommitant broadening of the excitatory tuning curve such that frequency-intensity combinations that were inhibitory under control conditions, became excitatory during disinhibition with bicuculline methiodide. These effects were observed irrespective of the excitatory tuning curve configuration prior to bicuculline methiodide application. Results indicate an important role for GABA-mediated inhibition in shaping the frequency selectivity of neurons in the torus semicircularis of the leopard frog. Bicuculline application also affected several other response properties of neurons in the leopard frog torus. Disinhibition with bicuculline methiodide increased both the spontaneous firing rate (18 cells) and stimulus-evoked discharge rate (81 cells) of torus neurons, decreased the minimum excitatory threshold for 18 cells, and altered the temporal discharge pattern of 47 neurons. Additional roles for GABAergic inhibition in monaural signal analysis are discussed. Accepted: 25 August 1999     

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     

Emergent oscillations in a realistic network: the role of inhibition and the effect of the spatiotemporal distribution of the input.

We have simulated a network of 10,000 two-compartment cells, spatially distributed on a two-dimensional sheet; 15% of the cells were inhibitory. The input to the network was spatially delimited. Global oscillations frequently were achieved with a simple set of connectivity rules. The inhibitory neurons paced the network, whereas the excitatory neurons amplified the input, permitting oscillations at low-input intensities. Inhibitory neurons were active over a greater area than excitatory ones, forming a ring of inhibition. The oscillation frequency was modulated to some extent by the input intensity, as has been shown experimentally in the striate cortex, but predominantly by the properties of the inhibitory neurons and their connections: the membrane and synaptic time constants and the distribution of delays. In networks that showed oscillations and in those that did not, widely distributed inputs could lead to the specific recruitment of the inhibitory neurons and to near zero activity of the excitatory cells. Hence the spatial distribution of excitatory inputs could provide a means of selectively exciting or inhibiting a target network. Finally, neither the presence of oscillations nor the global spike activity provided any reliable indication of the level of excitatory output from the network.     

Emergent Oscillations in a Realistic Network: The Role of Inhibition and the Effect of the Spatiotemporal Distribution of the Input

We have simulated a network of 10,000 two-compartment cells, spatially distributed on a two-dimensional sheet; 15% of the cells were inhibitory. The input to the network was spatially delimited. Global oscillations frequently were achieved with a simple set of connectivity rules. The inhibitory neurons paced the network, whereas the excitatory neurons amplified the input, permitting oscillations at low-input intensities. Inhibitory neurons were active over a greater area than excitatory ones, forming a ring of inhibition. The oscillation frequency was modulated to some extent by the input intensity, as has been shown experimentally in the striate cortex, but predominantly by the properties of the inhibitory neurons and their connections: the membrane and synaptic time constants and the distribution of delays.In networks that showed oscillations and in those that did not, widely distributed inputs could lead to the specific recruitment of the inhibitory neurons and to near zero activity of the excitatory cells. Hence the spatial distribution of excitatory inputs could provide a means of selectively exciting or inhibiting a target network. Finally, neither the presence of oscillations nor the global spike activity provided any reliable indication of the level of excitatory output from the network.     

Nonmonotonic synaptic excitation and imbalanced inhibition underlying cortical intensity tuning

Intensity-tuned neurons, characterized by their nonmonotonic response-level function, may play important roles in the encoding of sound intensity-related information. The synaptic mechanisms underlying intensity tuning remain unclear. Here, in vivo whole-cell recordings in rat auditory cortex revealed that intensity-tuned neurons, mostly clustered in a posterior zone, receive imbalanced tone-evoked excitatory and inhibitory synaptic inputs. Excitatory inputs exhibit nonmonotonic intensity tuning, whereas with tone intensity increments, the temporally delayed inhibitory inputs increase monotonically in strength. In addition, this delay reduces with the increase of intensity, resulting in an enhanced suppression of excitation at high intensities and a significant sharpening of intensity tuning. In contrast, non-intensity-tuned neurons exhibit covaried excitatory and inhibitory inputs, and the relative time interval between them is stable with intensity increments, resulting in monotonic response-level function. Thus, cortical intensity tuning is primarily determined by excitatory inputs and shaped by cortical inhibition through a dynamic control of excitatory and inhibitory timing.     

Robustness of neuronal tuning to binaural sound localization cues against age-related loss of inhibitory synaptic inputs

Sound localization relies on minute differences in the timing and intensity of sound arriving at both ears. Neurons of the lateral superior olive (LSO) in the brainstem process these interaural disparities by precisely detecting excitatory and inhibitory synaptic inputs. Aging generally induces selective loss of inhibitory synaptic transmission along the entire auditory pathways, including the reduction of inhibitory afferents to LSO. Electrophysiological recordings in animals, however, reported only minor functional changes in aged LSO. The perplexing discrepancy between anatomical and physiological observations suggests a role for activity-dependent plasticity that would help neurons retain their binaural tuning function despite loss of inhibitory inputs. To explore this hypothesis, we use a computational model of LSO to investigate mechanisms underlying the observed functional robustness against age-related loss of inhibitory inputs. The LSO model is an integrate-and-fire type enhanced with a small amount of low-voltage activated potassium conductance and driven with (in)homogeneous Poissonian inputs. Without synaptic input loss, model spike rates varied smoothly with interaural time and level differences, replicating empirical tuning properties of LSO. By reducing the number of inhibitory afferents to mimic age-related loss of inhibition, overall spike rates increased, which negatively impacted binaural tuning performance, measured as modulation depth and neuronal discriminability. To simulate a recovery process compensating for the loss of inhibitory fibers, the strength of remaining inhibitory inputs was increased. By this modification, effects of inhibition loss on binaural tuning were considerably weakened, leading to an improvement of functional performance. These neuron-level observations were further confirmed by population modeling, in which binaural tuning properties of multiple LSO neurons were varied according to empirical measurements. These results demonstrate the plausibility that homeostatic plasticity could effectively counteract known age-dependent loss of inhibitory fibers in LSO and suggest that behavioral degradation of sound localization might originate from changes occurring more centrally.     

Thalamocortical control of feed-forward inhibition in awake somatosensory 'barrel' cortex

Intracortical inhibition plays a role in shaping sensory cortical receptive fields and is mediated by both feed-forward and feedback mechanisms. Feed-forward inhibition is the faster of the two processes, being generated by inhibitory interneurons driven by monosynaptic thalamocortical (TC) input. In principle, feed-forward inhibition can prevent targeted cortical neurons from ever reaching threshold when TC input is weak. To do so, however, inhibitory interneurons must respond to TC input at low thresholds and generate spikes very quickly. A powerful feed-forward inhibition would sharpen the tuning characteristics of targeted cortical neurons, and interneurons with sensitive and broadly tuned receptive fields could mediate this process. Suspected inhibitory interneurons (SINs) with precisely these properties are found in layer 4 of the somatosensory (S1) 'barrel' cortex of rodents and rabbits. These interneurons lack the directional selectivity seen in most cortical spiny neurons and in ventrobasal TC afferents, but are much more sensitive than cortical spiny neurons to low-amplitude whisker displacements. This paper is concerned with the activation of S1 SINs by TC impulses, and with the consequences of this activation. Multiple TC neurons and multiple S1 SINs were simultaneously studied in awake rabbits, and cross-correlation methods were used to examine functional connectivity. The results demonstrate a potent, temporally precise, dynamic and highly convergent/divergent functional input from ventrobasal TC neurons to SINs of the topographically aligned S1 barrel. Whereas the extensive pooling of convergent TC inputs onto SINs generates sensitive and broadly tuned inhibitory receptive fields, the potent TC divergence onto many SINs generates sharply synchronous activity among these elements. This TC feed-forward inhibitory network is well suited to provide a fast, potent, sensitive and broadly tuned inhibition of targeted spiny neurons that will suppress spike generation following all but the most optimal feed-forward excitatory inputs.     

Inferior colliculus neuronal response abnormalities in genetically epilepsy-prone rats: evidence for a deficit of inhibition

The genetically epilepsy-prone rat (GEPR) is abnormally susceptible to induction of seizures by acoustic stimulation. The inferior colliculus (IC) is critically important to audiogenic seizure susceptibility. The GEPR is more susceptible to induction of audiogenic seizures at 12 kHz than at other pure tone frequencies. IC neurons in the GEPR exhibit significantly elevated response thresholds and broader tuning characteristics than normal. These findings along with previous neurophysiological and anatomical data suggest that a hearing deficit occurs in the GEPR. IC neurons in the GEPR exhibit a significantly elevated incidence of a response pattern with a peak of activity at the beginning and end of the stimulus, the onset-offset response. This response pattern occurs at 12 kHz and at characteristic frequency with high stimulus intensities and may represent an afterdischarge phenomenon. The onset-offset pattern may be a manifestation of central mechanisms developed to compensate for reduced peripheral auditory input that appears to be involved in the hearing deficit of the GEPR. Such compensatory mechanisms may involve alterations of the actions of neurotransmitters of the brain-stem auditory nuclei. GABA is implicated as an inhibitory transmitter in the IC. Iontophoretic application of GABA or a benzodiazepine produces significantly less inhibition of IC neurons of the GEPR than of the normal rat. Endogenous sound-induced (binaural) inhibition which is suggested to be GABA-mediated is also significantly reduced in IC neurons of the GEPR. Iontophoresis of the GABAA antagonist, bicuculline, often converts normal response patterns in the IC to onset-offset responses seen with high incidence in GEPR IC neurons, suggesting that the decreased effectiveness of GABA may lead to the onset-offset prevalence. This reduced effectiveness of inhibition may be unable to compensate for the rise in the putative excitatory transmitter, aspartate, in IC during high intensity acoustic stimulation in the GEPR. These altered transmitter actions may be important mechanisms subserving initiation of audiogenic seizures in the genetically epilepsy-prone rat.     

Network Models of Frequency Modulated Sweep Detection

Frequency modulated (FM) sweeps are common in species-specific vocalizations, including human speech. Auditory neurons selective for the direction and rate of frequency change in FM sweeps are present across species, but the synaptic mechanisms underlying such selectivity are only beginning to be understood. Even less is known about mechanisms of experience-dependent changes in FM sweep selectivity. We present three network models of synaptic mechanisms of FM sweep direction and rate selectivity that explains experimental data: (1) The ‘facilitation’ model contains frequency selective cells operating as coincidence detectors, summing up multiple excitatory inputs with different time delays. (2) The ‘duration tuned’ model depends on interactions between delayed excitation and early inhibition. The strength of delayed excitation determines the preferred duration. Inhibitory rebound can reinforce the delayed excitation. (3) The ‘inhibitory sideband’ model uses frequency selective inputs to a network of excitatory and inhibitory cells. The strength and asymmetry of these connections results in neurons responsive to sweeps in a single direction of sufficient sweep rate. Variations of these properties, can explain the diversity of rate-dependent direction selectivity seen across species. We show that the inhibitory sideband model can be trained using spike timing dependent plasticity (STDP) to develop direction selectivity from a non-selective network. These models provide a means to compare the proposed synaptic and spectrotemporal mechanisms of FM sweep processing and can be utilized to explore cellular mechanisms underlying experience- or training-dependent changes in spectrotemporal processing across animal models. Given the analogy between FM sweeps and visual motion, these models can serve a broader function in studying stimulus movement across sensory epithelia.     

Modeling inhibition of type II units in the dorsal cochlear nucleus

 Type II units in the dorsal cochlear nucleus (DCN) are characterized by vigorous but nonmonotonic responses to best frequency tones as a function of sound pressure level, and relatively weak responses to noise. A model of DCN neural circuitry was used to explore two hypothetical mechanisms by which neurons may be endowed with type II unit response properties. Both mechanisms assume that type II units receive excitatory input from auditory nerve (AN) fibers and inhibitory input from an unspecified class of cochlear nucleus interneurons that also receive excitatory AN input. The first mechanism, a lateral inhibition (LI) model, supposes that type II units receive inhibitory input from a number of narrowly tuned interneurons whose best frequencies (BFs) flank the BF of the type II unit. Tonal stimuli near BF result in only weak inhibitory input, but broadband stimuli recruit enough lateral inhibitors to greatly weaken the type II unit response. The second mechanism, a wideband inhibition (WBI) model, supposes that type II units receive inhibitory input from interneurons that are broadly tuned so that they respond more vigorously to broadband stimuli than to tones. Physiological and anatomical evidence points to the possible existence of such a class of neurons in the cochlear nucleus. The model extends an earlier computer model of an iso-frequency DCN patch to multiple frequency slices and adds a population of interneurons to provide the inhibition to model type II units (called I2-cells). The results show that both mechanisms accurately simulate responses of type II units to tones and noise. An experimental paradigm for distinguishing the two mechanisms is proposed. Received: 30 December 1996/Accepted in revised form: 13 March 1997     

A geometric model of orientation tuning dynamics in visual neurons]

A geometrical model for the dynamics of orientation tuning of visual neurones was proposed, which makes it possible to study the dynamics of configuration, localization, and weight of excitatory and inhibitory subzones of the receptive field. The model reproduces typical patterns of orientation tuning dynamics, observed in neurophysiological experiments on cat visual cortex neurones. The parameters of the model (size and mutual position of excitatory and inhibitory zones of the receptive field, their weight, and dynamics type) were estimated that correspond to the main types of orientation tuning dynamics in natural conditions. It is shown that selective and acute tuning of neurones can be formed and/or sharpened by intracotrical inhibition, while the dynamics of preferred orientation is due to changes in the geometry of the inhibitory subzone of the receptive field.     

A model study of the dynamic mechanisms of the double orientation tuning of the visual cortex neurons]

The dynamics of double orientation tuning of neurons in the visual cortex of cat was studied by means of computer simulation. It was possible to test the role of shape, relative localization and weight of the inhibitory and excitatory zones of a receptive field and the dynamics of these characteristics. It was shown that selective and acute double orientation tuning can be achieved only through changes in the weight of zones in the receptive fields with the end-stopping and lateral inhibitory zones whereas only the presence of the end-stopping inhibitory zone in the receptive field is sufficient during changes in zone localization and area.     

GABAergic inhibition shapes frequency tuning and modifies response properties in the superior olivary nucleus of the leopard frog

The role of gamma-aminobutyric acid (GABA)ergic inhibition in shaping the excitatory frequency tuning of 74 neurons in the superior olivary nucleus of the leopard frog, Rana pipiens, was studied using iontophoretic application of the GABA(A) receptor antagonist, bicuculline methiodide. For 37 neurons, bicuculline application broadened and/or changed the configuration of the excitatory frequency-tuning curve. Results indicate that GABA-mediated inhibition not only sharpens the tuning curves of neurons but also plays a critical role in creating new frequency tuning properties in the superior olivary nucleus. Bicuculline application affected other neuronal response properties as well. Spontaneous firing rate increased 11-338% for 18 of 59 neurons. For 32 of 58 neurons there was an increase in stimulus-evoked discharge rate and a change in rate-level function. There was no qualitative effect on the discharge pattern of 60 neurons, though 2 tonically responding neurons did show an increase (> 30%) in response duration. Additional roles for GABAergic inhibition in monaural signal analysis are discussed.     

Computer simulation of brainstem respiratory activity.

A mathematical model of the medullary respiratory oscillator, composed of two mutually inhibiting populations (inspiratory and expiratory) of computer-simulated neurons, is presented. Each population consists of randomly interconnected subpopulations of excitatory and inhibitory neurons, is presented. Each population consists of randomly interconnected subpopulations of excitatory and inhibitory neurons. Neuronal coupling is such that either the inspiratory or expiratory population alone is capable of cyclic activity. Weak inhibitory connections between inspiratory and expiratory populations provide satisfactory reciprocating activity independent of the natural frequency of either population alone. Initiation and persistence of rhythmic activity is dependent on a diffused noncyclic excitatory input. Vagal discharge, simulated by phasic inhibition of inspiratory neurons, results in increased respiratory frequency with decreased inspiratory activity. In the absence of simulated vagal discharge, uniform facilitation of synaptic connections increases averaged activities of inspiratory and expiratory populations, with minor effect on frequency. In the presence of simulated vagal discharge, facilitation of synaptic connections increases both frequency and amplitude. The simulated effects of synaptic facilitation, with and without vagal discharge, mimic the physiological response to CO2 in the intact and vagotimized animal.     

Recurrent circuitry dynamically shapes the activation of piriform cortex

In the piriform cortex, individual odorants activate a unique ensemble of neurons that are distributed without discernable spatial order. Piriform neurons receive convergent excitatory inputs from random collections of olfactory bulb glomeruli. Pyramidal cells also make extensive recurrent connections with other excitatory and inhibitory neurons. We introduced channelrhodopsin into the piriform cortex to characterize these intrinsic circuits and to examine their contribution to activity driven by afferent bulbar inputs. We demonstrated that individual pyramidal cells are sparsely interconnected by thousands of excitatory synaptic connections that extend, largely undiminished, across the piriform cortex, forming a large excitatory network that can dominate the bulbar input. Pyramidal cells also activate inhibitory interneurons that mediate strong, local feedback inhibition that scales with excitation. This recurrent network can enhance or suppress bulbar input, depending on whether the input arrives before or after the cortex is activated. This circuitry may shape the ensembles of piriform cells that encode odorant identity.     

Coexistence of lateral and co-tuned inhibitory configurations in cortical networks

The responses of neurons in sensory cortex depend on the summation of excitatory and inhibitory synaptic inputs. How the excitatory and inhibitory inputs scale with stimulus depends on the network architecture, which ranges from the lateral inhibitory configuration where excitatory inputs are more narrowly tuned than inhibitory inputs, to the co-tuned configuration where both are tuned equally. The underlying circuitry that gives rise to lateral inhibition and co-tuning is yet unclear. Using large-scale network simulations with experimentally determined connectivity patterns and simulations with rate models, we show that the spatial extent of the input determined the configuration: there was a smooth transition from lateral inhibition with narrow input to co-tuning with broad input. The transition from lateral inhibition to co-tuning was accompanied by shifts in overall gain (reduced), output firing pattern (from tonic to phasic) and rate-level functions (from non-monotonic to monotonically increasing). The results suggest that a single cortical network architecture could account for the extended range of experimentally observed response types between the extremes of lateral inhibitory versus co-tuned configurations.     

Reaction of neurons of the medial geniculate body to acoustic stimulation

Responses of medial geniculate body (MGB) neurons to pure tones and clicks were studied in acute experiments in immobilized cats, preliminary operations being performed under calypsol anaesthesia. MGB units were identified by their reactions to cortical zone AI and brachium of inferior colliculus stimulations. When tonal stimuli were applied relay neurons of pars principalis of MGB usually demonstrated either unimodal tuning curves with narrow frequency band or fragmental ones with several narrow bands. On-response with subsequent inhibition of the background activity or without such an inhibitory period was most frequent type of the reaction (66.6%) of relay MGB neurons to tonal stimulation. The group of relay neurons with the tonic type of reaction (9.1%) was classified for which the duration of tonic response depends on the duration of tonal stimulus. Change of the excitatory reaction to the inhibitory one when the characteristic tone frequency is changed by non-characteristic++ ones is supposed to be a mechanism supplying sharpness of tuning at relay MGB neurons. It is concluded that responses of acoustic cortical neurons to sound stimulation depend to a great extent on the pattern of impulsation that comes from MGB relay units.     

Synaptic mechanisms underlying auditory processing

In vivo voltage clamp recordings have provided new insights into the synaptic mechanisms that underlie processing in the primary auditory cortex. Of particular importance are the discoveries that excitatory and inhibitory inputs have similar frequency and intensity tuning, that excitation is followed by inhibition with a short delay, and that the duration of inhibition is briefer than expected. These findings challenge existing models of auditory processing in which broadly tuned lateral inhibition is used to limit excitatory receptive fields and suggest new mechanisms by which inhibition and short term plasticity shape neural responses.