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.     

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.     

二甲双胍调节初级视觉皮层兴奋性和抑制性平衡及改善视觉功能的研究

大脑皮层中兴奋和抑制系统之间的动态平衡决定了皮层神经元对刺激的反应特性. 已有研究表明,二甲双胍能够诱导γ-氨基丁酸受体向突触后膜聚集,增强神经系统的抑制效果. 本课题进一步探讨了二甲双胍对初级视觉皮层兴奋和抑制系统平衡的调节作用,以及其改善小鼠视觉功能的潜力. 实验使用成年雄性小鼠,实验组（metformin）10只每天给予二甲双胍250 mg/kg,对照组（control）6只每天给予0.3 ml生理盐水,灌胃处理3周. 结果发现二甲双胍可以显著升高囊泡GABA转运蛋白VGAT和突触后抑制性递质受体相关蛋白Gephyrin的合成. 此外,它显著降低突触后兴奋性受体GluA1和GluN1的表达. 多通道电极电生理记录结果显示,二甲双胍作用下小鼠初级视觉皮层的自发放和诱发放显著降低,而信噪比、方向和方位选择性显著增加. 实验结果表明,二甲双胍可以通过降低兴奋突触、增强抑制突触,调节初级视皮层的兴奋——抑制平衡,提高信息处理能力,增强视觉功能.     

The function of the medial superior olive in small mammals: temporal receptive fields in auditory analysis

Traditionally, the medial superior olive, a mammalian auditory brainstem structure, is considered to encode interaural time differences, the main cue for localizing low-frequency sounds. Detection of binaural excitatory and inhibitory inputs are considered as an underlying mechanism. Most small mammals, however, hear high frequencies well beyond 50 kHz and have small interaural distances. Therefore, they can not use interaural time differences for sound localization and yet possess a medial superior olive. Physiological studies in bats revealed that medial superior olive cells show similar interaural time difference coding as in larger mammals tuned to low-frequency hearing. Their interaural time difference sensitivity, however, is far too coarse to serve in sound localization. Thus, interaural time difference sensitivity in medial superior olive of small mammals is an epiphenomenon. We propose that the original function of the medial superior olive is a binaural cooperation causing facilitation due to binaural excitation. Lagging inhibitory inputs, however, suppress reverberations and echoes from the acoustic background. Thereby, generation of antagonistically organized temporal fields is the basic and original function of the mammalian medial superior olive. Only later in evolution with the advent of larger mammals did interaural distances, and hence interaural time differences, became large enough to be used as cues for sound localization of low-frequency stimuli. Accepted: 28 February 2000     

蛙下丘听觉神经元对双耳强度差检测功能的建模和仿真

建立了蛙下丘听觉神经元对双耳刺激强度差检测功能的一个数学模型。按此模型所作的计算机仿真和相应实验结果比较的一致性支持了下列假设 :下丘中的EO神经元对同侧刺激不产生反应可能是由于接受了来自同侧的强烈抑制性输入 ,从而掩盖了它同时接受到的来自同侧耳的兴奋性输入。而来自同侧的抑制性输入 ,与来自对侧的兴奋性输入可能通过突触前抑制的相互作用 ,则导致了EE神经元的双耳抑制现象。     

GABA-mediated modulation of the discharge pattern and rate-level function of two simultaneously recorded neurons in the inferior colliculus of the big brown bat, Eptesicus fuscus

Neurons in the central nucleus of the inferior colliculus (IC) receive excitatory and inhibitory inputs from both lower and higher auditory nuclei. Interaction of these two opposing inputs shapes response properties of IC neurons. In this study, we examine the interaction of excitation and inhibition on the responses of two simultaneously recorded IC neurons using a probe and a masker under forward masking paradigm. We specifically study whether a sound that serves as a probe to elicit responses of one neuron might serve as a masker to suppress or facilitate the responses of the other neuron. For each pair of IC neurons, we deliver the probe at the best frequency (BF) of one neuron and the masker at the BF of the other neuron and vice versa. Among 33 pairs of IC neurons recorded, this forward masking produces response suppression in 29 pairs of IC neurons and response facilitation in 4 pairs of IC neurons. The degree of suppression decreases with recording depth, sound level and BF difference between each pair of IC neurons. During bicuculline application, the degree of response suppression decreases in the bicuculline-applied neuron but increases in the paired neuron. Our data indicate that the forward masking of responses of IC neurons observed in this study is mostly mediated through GABAergic inhibition which also shapes the discharge pattern of these neurons. These data suggest that interaction among individual IC neurons improves auditory sensitivity during auditory signal processing.     

A possible mechanism of influence of modifiable striatal lateral inhibition on the conditioned selection of motor activity

A mechanism of the influence of dopamine-evoked modulation of lateral inhibition in the striatum on a conditioned selection of motor activity is proposed. According to suggested modulation rules for inhibitory transmission, action of dopamine on postsynaptic D1 (D2) receptors on striatonigral (striatopallidal) cells promotes long-term depression (potentiation) of inhibitory inputs simultaneously with potentiation (depression) of "strong" excitatory inputs that open NMDA channels on these neurons. If excitatory inputs are "weak" and NMDA channels are closed, modulation rules have opposite signs. Activation of presynaptic D2 (D1) receptors results in a decrease (increase) in GABA release from striatopallidal (striatonigral) axon terminals that innervate striatonigral (striatopallidal) cells. Thereof, dopamine-evoked modulation of lateral inhibition simultaneously strengthens both potentiation (depression) of excitatory inputs to "strongly" activated striatonigral (striatopallidal) neurons rising (reducing) their activity, and depression (potentiation) of excitatory inputs to "weakly" activated striatonigral (striatopallidal) neurons reducing (rising) their activity. Subsequent reorganization of neuronal activity in the cortico-basal-ganglia-thalamocortical loop promotes a conditioned selection of motor reaction because of the further increase (decrease) in activity of those motocortical neurons that "strongly" ("weakly") activated the striatum during dopamine release in response to conditioned stimulus.     

Real-time imaging of neural activity during binaural interaction in the guinea pig auditory cortex

Spatio-temporal patterns of binaural interaction in the guinea pig auditory cortex (AC) were observed using optical recording with a 12 × 12 photodiode array and a voltage-sensitive dye. The amplitudes of the sound-induced light signals from the cortex were transformed into sequential two-dimensional images every 0.58 ms. Binaural sound stimuli evoked an excitatory response followed by a strong inhibition, and contralateral stimuli evoked a strong excitatory response followed by a weak inhibition. Ipsilateral sound stimuli evoked a weak response. Binaural stimulation induced two types of ipsilateral inhibition: a fast binaural inhibition which was detected only after the contralateral and ipsilateral responses were subtracted from the binaural responses, and which appeared 12–25 ms after the onset of stimulation, and a slow binaural inhibitory effect which was clearly observed in the binaural responses themselves, appearing 70–95 ms after the onset of stimulation. The fast binaural inhibition was observed in the same area as the contralateral excitatory response. The inhibited area became stronger and more widespread with increasing intensity of ipsilateral stimulation. We did not observe the specialized organization of binaural neurons as electrophysiologically found in the cat AC, in which binaural neurons of the same binaural response type are clustered together and alternate with clusters of other response types. Accepted: 14 August 1997     

GABA-mediated synaptic inhibition of projection neurons in the antennal lobes of the sphinx moth,Manduca sexta

Responses of neurons in the antennal lobe (AL) of the moth Manduca sexta to stimulation of the ipsilateral antenna by odors consist of excitatory and inhibitory synaptic potentials. Stimulation of primary afferent fibers by electrical shock of the antennal nerve causes a characteristic IPSP-EPSP synaptic response in AL projection neurons. The IPSP in projection neurons reverses below the resting potential, is sensitive to changes in external and internal chloride concentration, and thus is apparently mediated by an increase in chloride conductance. The IPSP is reversibly blocked by 100 microM picrotoxin or bicuculline. Many AL neurons respond to application of GABA with a strong hyperpolarization and an inhibition of spontaneous spiking activity. GABA responses are associated with an increase in neuronal input conductance and a reversal potential below the resting potential. Application of GABA blocks inhibitory synaptic inputs and reduces or blocks excitatory inputs. EPSPs can be protected from depression by application of GABA. Muscimol, a GABA analog that mimics GABA responses at GABAA receptors but not at GABAB receptors in the vertebrate CNS, inhibits many AL neurons in the moth.     

The amplitude sensitivity of mouse inferior collicular neurons in the presence of weak noise

Natural auditory environment consists of multiple sound sources that are embedded in ambient strong and weak noise. For effective sound communication and signal analysis, animals must somehow extract biologically relevant signals from the inevitable interference of ambient noise. The present study examined how a weak noise may affect the amplitude sensitivity of neurons in the mouse central nucleus of the inferior colliculus (IC) which receives convergent excitatory and inhibitory inputs from both lower and higher auditory centers. Specifically, we studied the amplitude sensitivity of IC neurons using a probe (best frequency pulse) and a masker (weak noise) under simultaneous masking paradigm. For most IC neurons, weak noise masking increases the minimum threshold and decreases the number of impulses. Noise masking also increased the slope and decreased the dynamic range of the rate amplitude function of these IC neurons. The strength of this noise masking was greater at low than at high sound amplitudes. This variation in the amplitude sensitivity of IC neurons in the presence of the weak noise was mostly mediated through GABAergic inhibition. These data indicate that in the real world the ambient weak noise improves amplitude sensitivity of IC neurons through GABAergic inhibition while inevitably decreases the range of overall auditory sensitivity of IC neurons.     

Lateral sharpening of cortical frequency tuning by approximately balanced inhibition

Cortical inhibition plays an important role in shaping neuronal processing. The underlying synaptic mechanisms remain controversial. Here, in vivo whole-cell recordings from neurons in the rat primary auditory cortex revealed that the frequency tuning curve of inhibitory input was broader than that of excitatory input. This results in relatively stronger inhibition in frequency domains flanking the preferred frequencies of the cell and a significant sharpening of the frequency tuning of membrane responses. The less selective inhibition can be attributed to a broader bandwidth and lower threshold of spike tonal receptive field of fast-spike inhibitory neurons than nearby excitatory neurons, although both types of neurons receive similar ranges of excitatory input and are organized into the same tonotopic map. Thus, the balance between excitation and inhibition is only approximate, and intracortical inhibition with high sensitivity and low selectivity can laterally sharpen the frequency tuning of neurons, ensuring their highly selective representation.     

Balancing feed-forward excitation and inhibition via Hebbian inhibitory synaptic plasticity

It has been suggested that excitatory and inhibitory inputs to cortical cells are balanced, and that this balance is important for the highly irregular firing observed in the cortex. There are two hypotheses as to the origin of this balance. One assumes that it results from a stable solution of the recurrent neuronal dynamics. This model can account for a balance of steady state excitation and inhibition without fine tuning of parameters, but not for transient inputs. The second hypothesis suggests that the feed forward excitatory and inhibitory inputs to a postsynaptic cell are already balanced. This latter hypothesis thus does account for the balance of transient inputs. However, it remains unclear what mechanism underlies the fine tuning required for balancing feed forward excitatory and inhibitory inputs. Here we investigated whether inhibitory synaptic plasticity is responsible for the balance of transient feed forward excitation and inhibition. We address this issue in the framework of a model characterizing the stochastic dynamics of temporally anti-symmetric Hebbian spike timing dependent plasticity of feed forward excitatory and inhibitory synaptic inputs to a single post-synaptic cell. Our analysis shows that inhibitory Hebbian plasticity generates 'negative feedback' that balances excitation and inhibition, which contrasts with the 'positive feedback' of excitatory Hebbian synaptic plasticity. As a result, this balance may increase the sensitivity of the learning dynamics to the correlation structure of the excitatory inputs.     

Activity-dependent matching of excitatory and inhibitory inputs during refinement of visual receptive fields

The receptive field (RF) of single visual neurons undergoes progressive refinement during development. It remains largely unknown how the excitatory and inhibitory inputs on single developing neurons are refined in a coordinated manner to allow the formation of functionally correct circuits. Using whole-cell voltage-clamp recording from Xenopus tectal neurons, we found that RFs determined by excitatory and inhibitory inputs in more mature tectal neurons are spatially matched, with each spot stimulus evoking balanced synaptic excitation and inhibition. This emerges during development through a gradual reduction in the RF size and a transition from disparate to matched topography of excitatory and inhibitory inputs to the tectal neurons. Altering normal spiking activity of tectal neurons by either blocking or elevating GABA(A) receptor activity significantly impeded the developmental reduction and topographic matching of RFs. Thus, appropriate inhibitory activity is essential for the coordinated refinement of excitatory and inhibitory connections.     

Structural Changes and Lack of HCN1 Channels in the Binaural Auditory Brainstem of the Naked Mole-Rat (Heterocephalus glaber)

Naked mole-rats (Heterocephalus glaber) live in large eu-social, underground colonies in narrow burrows and are exposed to a large repertoire of communication signals but negligible binaural sound localization cues, such as interaural time and intensity differences. We therefore asked whether monaural and binaural auditory brainstem nuclei in the naked mole-rat are differentially adjusted to this acoustic environment. Using antibody stainings against excitatory and inhibitory presynaptic structures, namely the vesicular glutamate transporter VGluT1 and the glycine transporter GlyT2 we identified all major auditory brainstem nuclei except the superior paraolivary nucleus in these animals. Naked mole-rats possess a well structured medial superior olive, with a similar synaptic arrangement to interaural-time-difference encoding animals. The neighboring lateral superior olive, which analyzes interaural intensity differences, is large and elongated, whereas the medial nucleus of the trapezoid body, which provides the contralateral inhibitory input to these binaural nuclei, is reduced in size. In contrast, the cochlear nucleus, the nuclei of the lateral lemniscus and the inferior colliculus are not considerably different when compared to other rodent species. Most interestingly, binaural auditory brainstem nuclei lack the membrane-bound hyperpolarization-activated channel HCN1, a voltage-gated ion channel that greatly contributes to the fast integration times in binaural nuclei of the superior olivary complex in other species. This suggests substantially lengthened membrane time constants and thus prolonged temporal integration of inputs in binaural auditory brainstem neurons and might be linked to the severely degenerated sound localization abilities in these animals.     

Perisomatic GABA release and thalamocortical integration onto neocortical excitatory cells are regulated by neuromodulators

Neuromodulators such as acetylcholine, serotonin, and noradrenaline are powerful regulators of neocortical activity. Although it is well established that cortical inhibition is the target of these modulations, little is known about their effects on GABA release from specific interneuron types. This knowledge is necessary to gain a mechanistic understanding of the actions of neuromodulators because different interneuron classes control specific aspects of excitatory cell function. Here, we report that GABA release from fast-spiking (FS) cells, the most prevalent interneuron subtype in neocortex, is robustly inhibited following activation of muscarinic, serotonin, adenosine, and GABA(B) receptors--an effect that regulates FS cell control of excitatory neuron firing. The potent muscarinic inhibition of GABA release from FS cells suppresses thalamocortical feedforward inhibition. This is supplemented by the muscarinic-mediated depolarization of thalamo-recipient excitatory neurons and the nicotinic enhancement of thalamic input onto these neurons to promote thalamocortical excitation.     

Asymmetric Excitatory Synaptic Dynamics Underlie Interaural Time Difference Processing in the Auditory System

Low-frequency sound localization depends on the neural computation of interaural time differences (ITD) and relies on neurons in the auditory brain stem that integrate synaptic inputs delivered by the ipsi- and contralateral auditory pathways that start at the two ears. The first auditory neurons that respond selectively to ITD are found in the medial superior olivary nucleus (MSO). We identified a new mechanism for ITD coding using a brain slice preparation that preserves the binaural inputs to the MSO. There was an internal latency difference for the two excitatory pathways that would, if left uncompensated, position the ITD response function too far outside the physiological range to be useful for estimating ITD. We demonstrate, and support using a biophysically based computational model, that a bilateral asymmetry in excitatory post-synaptic potential (EPSP) slopes provides a robust compensatory delay mechanism due to differential activation of low threshold potassium conductance on these inputs and permits MSO neurons to encode physiological ITDs. We suggest, more generally, that the dependence of spike probability on rate of depolarization, as in these auditory neurons, provides a mechanism for temporal order discrimination between EPSPs.     

The influence of neuromodulators on the synaptic plasticity in dopaminergic structures of the midbrain (hypothetical mechanism)

A mechanism underlying the effects of neuromodulators on long-term changes in the efficacy of excitatory and inhibitory inputs to dopaminergic and inhibitory cells of the substantia nigra and ventral tegmental area is suggested. According to this mechanism, activation of Gi/0 protein-coupled dopamine D2 autoreceptors and opioid kappa (mu) receptors on dopaminergic (inhibitory) cells promotes the LTD of excitatory inputs to these cells and decrease in their activity. Activation of Gq/11 protein-coupled alpha1 adrenoreceptors, muscarinic M1, neurokinin NK3 (alpha1, M3, NK1, serotonin 5-HT2) receptors on dopaminergic (inhibitory) cells as well as activation of Gs protein-coupled D1 receptors on inhibitory cells promotes the LTP of excitatory inputs to these cells and increase in their activity. Augmenting (lowering) GABA release can be provided by activation of presynaptic D1 and M3 receptors (mu, 5-HT1, and adenosine A1) receptors. Increase (decrease) in GABA concentration due to modulation of inhibitory cell activity and/or GABA release will promote the induction of LTD (LTP) of excitatory inputs to target dopamine cells. The model agree with known experimental data describing the involvement of neuromodulators in modification of dopamine cell activity and dopamine release. The suggested model can be useful in understanding the operation of neuronal networks, which include the basal ganglia.     

Golgi Cell-Mediated Activation of Postsynaptic GABA(B) Receptors Induces Disinhibition of the Golgi Cell-Granule Cell Synapse in Rat Cerebellum

In the cerebellar glomerulus, GABAergic synapses formed by Golgi cells regulate excitatory transmission from mossy fibers to granule cells through feed-forward and feedback mechanisms. In acute cerebellar slices, we found that stimulating Golgi cell axons with a train of 10 impulses at 100 Hz transiently inhibited both the phasic and the tonic components of inhibitory responses recorded in granule cells. This effect was blocked by the GABA(B) receptor blocker CGP35348, and could be mimicked by bath-application of baclofen (30 μM). This depression of IPSCs was prevented when granule cells were dialyzed with GDPβS. Furthermore, when synaptic transmission was blocked, GABA(A) currents induced in granule cells by localized muscimol application were inhibited by the GABA(B) receptor agonist baclofen. These findings indicate that postsynaptic GABA(B) receptors are primarily responsible for the depression of IPSCs. This inhibition of inhibitory events results in an unexpected excitatory action by Golgi cells on granule cell targets. The reduction of Golgi cell-mediated inhibition in the cerebellar glomerulus may represent a regulatory mechanism to shift the balance between excitation and inhibition in the glomerulus during cerebellar information processing.     

TrkB受体依赖的PV神经元调控小鼠视觉方位辨别能力的机制

神经营养因子-酪氨酸受体激酶B （tyrosine receptor kinase B,TrkB）信号通路在调控初级视皮层（primary visual cortex,V1）兴奋与抑制平衡上发挥着重要的作用,以往的研究揭示了其通过增加兴奋性传递效率来调控皮层兴奋性水平的机制,却并未阐明TrkB受体如何通过抑制系统来调控兴奋与抑制平衡,进而影响视觉皮层功能。为了探讨TrkB信号通路如何特异性地调控最主要的抑制性神经元——PV神经元进而对小鼠视觉皮层功能产生影响,本研究通过病毒特异性地降低V1区的PV神经元上TrkB受体的表达水平,并通过在体多通道电生理手段记录初级视皮层抑制性与兴奋性神经元功能变化,通过行为学实验测试小鼠的方位辨别能力改变。结果表明,初级视觉皮层中的PV抑制性神经元上的TrkB受体表达减少会显著增加兴奋性神经元的反应强度,减弱抑制性神经元与兴奋性神经元的方位辨别能力,增加二者的信噪比,但是小鼠个体水平的方位辨别能力出现下降。这些结果说明,TrkB信号通路并非单纯通过增加靶向PV神经元的兴奋性传递来调控PV神经元的功能,其对神经元信噪比的影响也并非由于抑制系统的增强所致。     

Excitatory actions of GABA in the cortex

Little is known about how GABAergic inputs interact with excitatory inputs under conditions that maintain physiological concentrations of intracellular anions. Using extracellular and gramicidin perforated-patch recording, we show that somatic and dendritic GABA responses in mature cortical pyramidal neurons are depolarizing from rest and can facilitate action potential generation when combined with proximal excitatory input. Dendritic GABA responses were excitatory regardless of timing, whereas somatic GABA responses were inhibitory when coincident with excitatory input but excitatory at earlier times. These excitatory actions of GABA occur even though the GABA reversal potential is below action potential threshold and largely uniform across the somato-dendritic axis, and arise when GABAergic inputs are temporally or spatially isolated from concurrent excitation. Our findings demonstrate that under certain circumstances GABA will have an excitatory role in synaptic integration in the cortex.