High-frequency oscillations (above 30 Hz) have been observed in sensory and higher-order brain areas, and are believed to constitute a general hallmark of functional neuronal activation. Fast inhibition in interneuronal networks has been suggested as a general mechanism for the generation of high-frequency oscillations. Certain classes of interneurons exhibit subthreshold oscillations, but the effect of this intrinsic neuronal property on the population rhythm is not completely understood. We study the influence of intrinsic damped subthreshold oscillations in the emergence of collective high-frequency oscillations, and elucidate the dynamical mechanisms that underlie this phenomenon. We simulate neuronal networks composed of either Integrate-and-Fire (IF) or Generalized Integrate-and-Fire (GIF) neurons. The IF model displays purely passive subthreshold dynamics, while the GIF model exhibits subthreshold damped oscillations. Individual neurons receive inhibitory synaptic currents mediated by spiking activity in their neighbors as well as noisy synaptic bombardment, and fire irregularly at a lower rate than population frequency. We identify three factors that affect the influence of single-neuron properties on synchronization mediated by inhibition: i) the firing rate response to the noisy background input, ii) the membrane potential distribution, and iii) the shape of Inhibitory Post-Synaptic Potentials (IPSPs). For hyperpolarizing inhibition, the GIF IPSP profile (factor iii)) exhibits post-inhibitory rebound, which induces a coherent spike-mediated depolarization across cells that greatly facilitates synchronous oscillations. This effect dominates the network dynamics, hence GIF networks display stronger oscillations than IF networks. However, the restorative current in the GIF neuron lowers firing rates and narrows the membrane potential distribution (factors i) and ii), respectively), which tend to decrease synchrony. If inhibition is shunting instead of hyperpolarizing, post-inhibitory rebound is not elicited and factors i) and ii) dominate, yielding lower synchrony in GIF networks than in IF networks.
Neurons in the brain engage in collective oscillations at different frequencies. Gamma and high-gamma oscillations (30–100 Hz and higher) have been associated with cognitive functions, and are altered in psychiatric disorders such as schizophrenia and autism. Our understanding of how high-frequency oscillations are orchestrated in the brain is still limited, but it is necessary for the development of effective clinical approaches to the treatment of these disorders. Some neuron types exhibit dynamical properties that can favour synchronization. The theory of weakly coupled oscillators showed how the phase response of individual neurons can predict the patterns of phase relationships that are observed at the network level. However, neurons in vivo do not behave like regular oscillators, but fire irregularly in a regime dominated by fluctuations. Hence, which intrinsic dynamical properties matter for synchronization, and in which regime, is still an open question. Here, we show how single-cell damped subthreshold oscillations enhance synchrony in interneuronal networks by introducing a depolarizing component, mediated by post-inhibitory rebound, that is correlated among neurons due to common inhibitory input.
Neuronal synchrony in the basolateral amygdala (BLA) is critical for emotional behavior. Coordinated theta-frequency oscillations between the BLA and the hippocampus and precisely timed integration of salient sensory stimuli in the BLA are involved in fear conditioning. We characterized GABAergic interneuron types of the BLA and determined their contribution to shaping these network activities. Using in vivo recordings in rats combined with the anatomical identification of neurons, we found that the firing of BLA interneurons associated with network activities was cell type specific. The firing of calbindin-positive interneurons targeting dendrites was precisely theta-modulated, but other cell types were heterogeneously modulated, including parvalbumin-positive basket cells. Salient sensory stimuli selectively triggered axo-axonic cells firing and inhibited firing of a disctinct projecting interneuron type. Thus, GABA is released onto BLA principal neurons in a time-, domain-, and sensory-specific manner. These specific synaptic actions likely cooperate to promote amygdalo-hippocampal synchrony involved in emotional memory formation.
► Comprehensive definition of interneuron types of the basolateral amygdala ► Identification of the target subcellular domains of each cell type ► GABAergic cell-type-specific coding of hippocampal theta rhythm and sensory stimuli ► Axo-axonic interneurons are excited by salient sensory stimuli
Bienvenu et al. provide a comprehensive characterization and in vivo recordings of basolateral amygdala interneurons. Their findings suggest that GABA is released onto BLA principal neurons in a time-, subcellular domain-, and sensory-dependent manner.
Dynamic balance of excitation and inhibition is crucial for network stability and cortical processing, but it is unclear how this balance is achieved at different membrane potentials (Vm) of cortical neurons, as found during persistent activity or slow Vm oscillation. Here we report that a Vm-dependent modulation of recurrent inhibition between pyramidal cells (PCs) contributes to the excitation-inhibition balance. Whole-cell recording from paired layer-5 PCs in rat somatosensory cortical slices revealed that both the slow and the fast disynaptic IPSPs, presumably mediated by low-threshold spiking and fast spiking interneurons, respectively, were modulated by changes in presynaptic Vm. Somatic depolarization (>5 mV) of the presynaptic PC substantially increased the amplitude and shortened the onset latency of the slow disynaptic IPSPs in neighboring PCs, leading to a narrowed time window for EPSP integration. A similar increase in the amplitude of the fast disynaptic IPSPs in response to presynaptic depolarization was also observed. Further paired recording from PCs and interneurons revealed that PC depolarization increases EPSP amplitude and thus elevates interneuronal firing and inhibition of neighboring PCs, a reflection of the analog mode of excitatory synaptic transmission between PCs and interneurons. Together, these results revealed an immediate Vm-dependent modulation of cortical inhibition, a key strategy through which the cortex dynamically maintains the balance of excitation and inhibition at different states of cortical activity.
Proper functioning of the neocortex requires a balance between excitation and inhibition. This balance can be achieved through the operation of cortical microcircuits interweaved by excitatory and inhibitory neurons. Since the membrane potentials (Vm) of cortical neurons fluctuate at different levels during cortical activities, it is important to know how the balance of excitation and inhibition is dynamically maintained at different Vm. Recurrent inhibition between excitatory pyramidal cells is mediated by two distinct types of inhibitory interneurons. Here, we show that the amount of recurrent inhibition depends on the Vm levels of presynaptic pyramidal cells. Modest depolarization of a pyramidal cell substantially increases, and sometimes turns on, disynaptic inhibition on its neighboring pyramidal cells. We find that this effect is due to an increase in the strength of synaptic connections from the pyramidal cell to inhibitory interneurons and a consequent elevation of interneuronal firing. The depolarization-induced increase in synaptic strength from the pyramidal cell therefore reflects “analog-mode” signaling in cortical excitatory synapses. We thus reveal a profound impact of analog-mode signaling on the operation of cortical microcircuits and provide a new mechanism for dynamic control of the balance of cortical excitation and inhibition.
High concentrations of enflurane will induce a characteristic electroencephalogram pattern consisting of periods of suppression alternating with large short paroxysmal epileptiform discharges (PEDs). In this study, we compared a theoretical computer model of this activity with real local field potential data obtained from anesthetized rats.
After implantation of a high-density 8x8 electrode array in the visual cortex, the patterns of local field potential and multiunit spike activity were recorded in rats during 0.5, 1.0, 1.5 and 2.0 minimum alveolar anesthetic concentration (MAC) enflurane anesthesia. These recordings were compared with computer simulations from a mean field model of neocortical dynamics. The neuronal effect of increasing enflurane concentration was simulated by prolonging the decay time constant of the inhibitory postsynaptic potential (IPSP). The amplitude of the excitatory postsynaptic potential (EPSP) was modulated, inverse to the neocortical firing rate.
In the anesthetized rats, increasing enflurane concentrations consistently caused the appearance of suppression pattern (>1.5MAC) in the local field potential recordings. The mean rate of multiunit spike activity decreased from 2.54/s (0.5MAC) to 0.19/s (2.0MAC). At high MAC the majority of the multiunit action potential events became synchronous with the PED. In the theoretical model, prolongation of the IPSP decay time and activity-dependent EPSP modulation resulted in output that was similar in morphology to that obtained from the experimental data. The propensity for rhythmic seizure-like activity in the model could be determined by analysis of the eigenvalues of the equations.
It is possible to use a mean field theory of neocortical dynamics to replicate the PED pattern observed in local field potentials in rats under enflurane anesthesia. This pattern requires a combination of a moderately increased total area under the IPSP, prolonged IPSP decay time, and also activity-dependent modulation of EPSP amplitude.
An unusual feature of the cerebellar cortex is that its output neurons, Purkinje cells, are GABAergic. Their high intrinsic firing rates1 (50 Hz) and extensive convergence2,3 predict that that target neurons in the cerebellar nuclei would be largely inhibited unless Purkinje cells pause their spiking, yet Purkinje and nuclear neuron firing rates do not always vary inversely4. A potential clue to how these synapses transmit information is that populations of Purkinje neurons synchronize their spikes during cerebellar behaviors5–11. If nuclear neurons respond to Purkinje synchrony, they may encode signals from subsets of inhibitory inputs7,12–14. Here we show in weanling and adult mice that nuclear neurons transmit the timing of synchronous Purkinje afferent spikes, owing to modest Purkinje-to-nuclear convergence ratios (~40:1), fast IPSC kinetics (τdecay=2.5 ms), and high intrinsic firing rates (~90 Hz). In vitro, dynamically clamped asynchronous IPSPs mimicking Purkinje afferents suppress nuclear cell spiking, whereas synchronous IPSPs entrain nuclear cell spiking. With partial synchrony, nuclear neurons time-lock their spikes to the synchronous subpopulation of inputs, even when only 2 of 40 afferents synchronize. In vivo, nuclear neurons reliably phase-lock to regular trains of molecular layer stimulation. Thus, cerebellar nuclear neurons can preferentially relay the spike timing of synchronized Purkinje cells to downstream premotor areas.
The medial septum (MS) is required for theta rhythmic oscillations and grid cell firing in the medial entorhinal cortex (MEC). While GABAergic, glutamatergic, and cholinergic neurons project from the MS to the MEC, their synaptic targets are unknown. To investigate whether MS neurons innervate specific layers and cell types in the MEC, we expressed channelrhodopsin-2 in mouse MS neurons and used patch-clamp recording in brain slices to determine the response to light activation of identified cells in the MEC. Following activation of MS axons, we observed fast monosynaptic GABAergic IPSPs in the majority (>60%) of fast-spiking (FS) and low-threshold-spiking (LTS) interneurons in all layers of the MEC, but in only 1.5% of nonstellate principal cells (NSPCs) and in no stellate cells. We also observed fast glutamatergic responses to MS activation in a minority (<5%) of NSPCs, FS, and LTS interneurons. During stimulation of MS inputs at theta frequency (10 Hz), the amplitude of GABAergic IPSPs was maintained, and spike output from LTS and FS interneurons was entrained at low (25–60 Hz) and high (60–180 Hz) gamma frequencies, respectively. By demonstrating cell type-specific targeting of the GABAergic projection from the MS to the MEC, our results support the idea that the MS controls theta frequency activity in the MEC through coordination of inhibitory circuits.
gamma; interneuron; lamina organization; medial entorhinal cortex; medial septum; theta
An activity-dependent long-lasting asynchronous release of GABA from identified fast-spiking inhibitory neurons in the neocortex can impair the reliability and temporal precision of activity in a cortical network.
Networks of specific inhibitory interneurons regulate principal cell firing in several forms of neocortical activity. Fast-spiking (FS) interneurons are potently self-inhibited by GABAergic autaptic transmission, allowing them to precisely control their own firing dynamics and timing. Here we show that in FS interneurons, high-frequency trains of action potentials can generate a delayed and prolonged GABAergic self-inhibition due to sustained asynchronous release at FS-cell autapses. Asynchronous release of GABA is simultaneously recorded in connected pyramidal (P) neurons. Asynchronous and synchronous autaptic release show differential presynaptic Ca2+ sensitivity, suggesting that they rely on different Ca2+ sensors and/or involve distinct pools of vesicles. In addition, asynchronous release is modulated by the endogenous Ca2+ buffer parvalbumin. Functionally, asynchronous release decreases FS-cell spike reliability and reduces the ability of P neurons to integrate incoming stimuli into precise firing. Since each FS cell contacts many P neurons, asynchronous release from a single interneuron may desynchronize a large portion of the local network and disrupt cortical information processing.
In the cerebral cortex (neocortex) of the brain, fast-spiking (FS) inhibitory cells contact many principal pyramidal (P) neurons on their cell bodies, which allows the FS cells to control the generation of action potentials (neuronal output). FS-cell-mediated rhythmic and synchronous inhibition drives coherent network oscillations of large ensembles of P neurons, indicating that FS interneurons are needed for the precise timing of cortical circuits. Interestingly, FS cells are self-innervated by GABAergic autaptic contacts, whose synchronous activation regulates FS-cell precise firing. Here we report that high-frequency firing in FS interneurons results in a massive (>10-fold), delayed, and prolonged (for seconds) increase in inhibitory events, occurring at both autaptic (FS–FS) and synaptic (FS–P) sites. This increased inhibition is due to asynchronous release of GABA from presynaptic FS cells. Delayed and disorganized asynchronous inhibitory responses significantly affected the input–output properties of both FS and P neurons, suggesting that asynchronous release of GABA might promote network desynchronization. FS interneurons can fire at high frequency (>100 Hz) in vitro and in vivo, and are known for their reliable and precise signaling. Our results show an unprecedented action of these cells, by which their tight temporal control of cortical circuits can be broken when they are driven to fire above certain frequencies.
The ability of spiking neurons to synchronize their activity in a network depends on the response behavior of these neurons as quantified by the phase response curve (PRC) and on coupling properties. The PRC characterizes the effects of transient inputs on spike timing and can be measured experimentally. Here we use the adaptive exponential integrate-and-fire (aEIF) neuron model to determine how subthreshold and spike-triggered slow adaptation currents shape the PRC. Based on that, we predict how synchrony and phase locked states of coupled neurons change in presence of synaptic delays and unequal coupling strengths. We find that increased subthreshold adaptation currents cause a transition of the PRC from only phase advances to phase advances and delays in response to excitatory perturbations. Increased spike-triggered adaptation currents on the other hand predominantly skew the PRC to the right. Both adaptation induced changes of the PRC are modulated by spike frequency, being more prominent at lower frequencies. Applying phase reduction theory, we show that subthreshold adaptation stabilizes synchrony for pairs of coupled excitatory neurons, while spike-triggered adaptation causes locking with a small phase difference, as long as synaptic heterogeneities are negligible. For inhibitory pairs synchrony is stable and robust against conduction delays, and adaptation can mediate bistability of in-phase and anti-phase locking. We further demonstrate that stable synchrony and bistable in/anti-phase locking of pairs carry over to synchronization and clustering of larger networks. The effects of adaptation in aEIF neurons on PRCs and network dynamics qualitatively reflect those of biophysical adaptation currents in detailed Hodgkin-Huxley-based neurons, which underscores the utility of the aEIF model for investigating the dynamical behavior of networks. Our results suggest neuronal spike frequency adaptation as a mechanism synchronizing low frequency oscillations in local excitatory networks, but indicate that inhibition rather than excitation generates coherent rhythms at higher frequencies.
Synchronization of neuronal spiking in the brain is related to cognitive functions, such as perception, attention, and memory. It is therefore important to determine which properties of neurons influence their collective behavior in a network and to understand how. A prominent feature of many cortical neurons is spike frequency adaptation, which is caused by slow transmembrane currents. We investigated how these adaptation currents affect the synchronization tendency of coupled model neurons. Using the efficient adaptive exponential integrate-and-fire (aEIF) model and a biophysically detailed neuron model for validation, we found that increased adaptation currents promote synchronization of coupled excitatory neurons at lower spike frequencies, as long as the conduction delays between the neurons are negligible. Inhibitory neurons on the other hand synchronize in presence of conduction delays, with or without adaptation currents. Our results emphasize the utility of the aEIF model for computational studies of neuronal network dynamics. We conclude that adaptation currents provide a mechanism to generate low frequency oscillations in local populations of excitatory neurons, while faster rhythms seem to be caused by inhibition rather than excitation.
Vestibulo-ocular reflex (VOR) gain adaptation, a longstanding experimental model of cerebellar learning, utilizes sites of plasticity in both cerebellar cortex and brainstem. However, the mechanisms by which the activity of cortical Purkinje cells may guide synaptic plasticity in brainstem vestibular neurons are unclear. Theoretical analyses indicate that vestibular plasticity should depend upon the correlation between Purkinje cell and vestibular afferent inputs, so that, in gain-down learning for example, increased cortical activity should induce long-term depression (LTD) at vestibular synapses.
Here we expressed this correlational learning rule in its simplest form, as an anti-Hebbian, heterosynaptic spike-timing dependent plasticity interaction between excitatory (vestibular) and inhibitory (floccular) inputs converging on medial vestibular nucleus (MVN) neurons (input-spike-timing dependent plasticity, iSTDP). To test this rule, we stimulated vestibular afferents to evoke EPSCs in rat MVN neurons in vitro. Control EPSC recordings were followed by an induction protocol where membrane hyperpolarizing pulses, mimicking IPSPs evoked by flocculus inputs, were paired with single vestibular nerve stimuli. A robust LTD developed at vestibular synapses when the afferent EPSPs coincided with membrane hyperpolarisation, while EPSPs occurring before or after the simulated IPSPs induced no lasting change. Furthermore, the iSTDP rule also successfully predicted the effects of a complex protocol using EPSP trains designed to mimic classical conditioning.
These results, in strong support of theoretical predictions, suggest that the cerebellum alters the strength of vestibular synapses on MVN neurons through hetero-synaptic, anti-Hebbian iSTDP. Since the iSTDP rule does not depend on post-synaptic firing, it suggests a possible mechanism for VOR adaptation without compromising gaze-holding and VOR performance in vivo.
Synchronization of 30–80 Hz oscillatory activity of the principle neurons in the olfactory bulb (mitral cells) is believed to be important for odor discrimination. Previous theoretical studies of these fast rhythms in other brain areas have proposed that principle neuron synchrony can be mediated by short-latency, rapidly decaying inhibition. This phasic inhibition provides a narrow time window for the principle neurons to fire, thus promoting synchrony. However, in the olfactory bulb, the inhibitory granule cells produce long lasting, small amplitude, asynchronous and aperiodic inhibitory input and thus the narrow time window that is required to synchronize spiking does not exist. Instead, it has been suggested that correlated output of the granule cells could serve to synchronize uncoupled mitral cells through a mechanism called “stochastic synchronization”, wherein the synchronization arises through correlation of inputs to two neural oscillators. Almost all work on synchrony due to correlations presumes that the correlation is imposed and fixed. Building on theory and experiments that we and others have developed, we show that increased synchrony in the mitral cells could produce an increase in granule cell activity for those granule cells that share a synchronous group of mitral cells. Common granule cell input increases the input correlation to the mitral cells and hence their synchrony by providing a positive feedback loop in correlation. Thus we demonstrate the emergence and temporal evolution of input correlation in recurrent networks with feedback. We explore several theoretical models of this idea, ranging from spiking models to an analytically tractable model.
Neurons in many parts of the brain fire spikes rhythmically and synchronously in many behaviorally and functionally relevant contexts. There are many mechanisms for producing oscillatory synchronization between populations of biological oscillators. One way to produce synchrony is that the population of oscillators receives common correlated input. In this paper, we study a population of oscillating neurons (mitral cells) that are not directly coupled to each other but receive broadband correlated input from a second population of neurons (granule cells). The granule cell population, in turn, receives inputs from the mitral cells; hence, the mitral and granule cells are reciprocally connected. Correlated input to the oscillating mitral cells produces tighter synchrony in the activity of the mitral cell population. We hypothesize that this increased mitral cell synchrony will evoke greater activity in specific groups of granule cells and that these specific granule cells, in turn, become the source of the correlated input to the mitral cells. That is, the synchronous input from the mitral cells increases the fraction of correlated feedback. Thus, we close the correlation loop. We show through analysis and simulations that this feedback mechanism can lead to the spontaneous appearance of highly synchronous activity within the mitral cells. We show that there is good experimental support for this mechanism in the circuitry of the olfactory bulb. We speculate that such mechanisms could also arise in other parts of the brain.
Electrical coupling between some subclasses of interneurons is thought to promote coordinated firing that generates rhythmic synchronous activity in cortical regions. Synaptic activity of cholecystokinin (CCK) interneurons which co-express cannabinoid type-1 (CB1) receptors are powerful modulators of network activity via the actions of endocannabinoids. We investigated the modulatory actions of endocannabinoids between chemically and electrically connected synapses of CCK cells using paired whole-cell recordings combined with biocytin and double immunofluorescence labeling in acute slices of rat hippocampus at P18–20 days. CA1 stratum radiatum CCK Schaffer collateral-associated cells were coupled electrically with each other as well as CCK basket cells and CCK cells with axonal projections expanding to dentate gyrus. Approximately 50% of electrically coupled cells received facilitating, asynchronously released inhibitory postsynaptic potential (IPSPs) that curtailed the steady-state coupling coefficient by 57%. Tonic CB1 receptor activity which reduces inhibition enhanced electrical coupling between cells that were connected via chemical and electrical synapses. Blocking CB1 receptors with antagonist, AM-251 (5 μM) resulted in the synchronized release of larger IPSPs and this enhanced inhibition further reduced the steady-state coupling coefficient by 85%. Depolarization induced suppression of inhibition (DSI), maintained the asynchronicity of IPSP latency, but reduced IPSP amplitudes by 95% and enhanced the steady-state coupling coefficient by 104% and IPSP duration by 200%. However, DSI did not did not enhance electrical coupling at purely electrical synapses. These data suggest that different morphological subclasses of CCK interneurons are interconnected via gap junctions. The synergy between the chemical and electrical coupling between CCK cells probably plays a role in activity-dependent endocannabinoid modulation of rhythmic synchronization.
CA1; CB1; CCK; DSI; electrically coupled; endocannabinoids; interneurons
Many studies have reported long-range synchronization of neuronal activity between brain areas, in particular in the beta and gamma bands with frequencies in the range of 14–30 and 40–80 Hz, respectively. Several studies have reported synchrony with zero phase lag, which is remarkable considering the synaptic and conduction delays inherent in the connections between distant brain areas. This result has led to many speculations about the possible functional role of zero-lag synchrony, such as for neuronal communication, attention, memory, and feature binding. However, recent studies using recordings of single-unit activity and local field potentials report that neuronal synchronization may occur with non-zero phase lags. This raises the questions whether zero-lag synchrony can occur in the brain and, if so, under which conditions. We used analytical methods and computer simulations to investigate which connectivity between neuronal populations allows or prohibits zero-lag synchrony. We did so for a model where two oscillators interact via a relay oscillator. Analytical results and computer simulations were obtained for both type I Mirollo–Strogatz neurons and type II Hodgkin–Huxley neurons. We have investigated the dynamics of the model for various types of synaptic coupling and importantly considered the potential impact of Spike-Timing Dependent Plasticity (STDP) and its learning window. We confirm previous results that zero-lag synchrony can be achieved in this configuration. This is much easier to achieve with Hodgkin–Huxley neurons, which have a biphasic phase response curve, than for type I neurons. STDP facilitates zero-lag synchrony as it adjusts the synaptic strengths such that zero-lag synchrony is feasible for a much larger range of parameters than without STDP.
long-range synchronization; spike-timing dependent plasticity; zero-lag synchronization
Development and maintenance of whisker-specific patterns along the rodent trigeminal pathway depends on an intact sensory periphery during the sensitive/critical period in development. Barrelette cells of the brain stem trigeminal nuclei are the first set of neurons to develop whisker-specific patterns. Those in the principal sensory nucleus (PrV) relay these patterns to the ventrobasal thalamus, and consequently, to the somatosensory cortex. Thus PrV barrelette cells are among the first group of central neurons susceptible to the effects of peripheral damage. Previously we showed that membrane properties of barrelette cells are distinct as early as postnatal day 1 (PND 1) and remain unchanged following peripheral denervation in newborn rat pups (Lo and Erzurumlu 2001). In the present study, we investigated the changes in synaptic transmission. In barrelette cells of normal PND 1 rats, weak stimulation of the trigeminal tract (TrV) that was subthreshold for inducing Na+ spikes evoked an excitatory postsynaptic potential–inhibitory postsynaptic potential (EPSP-IPSP) sequence that was similar to the responses seen in older rats (Lo et al. 1999). Infraorbital nerve transection at birth did not alter excitatory and inhibitory synaptic connections of the barrelette cells. These observations suggested that local neuronal circuits are already established in PrV at birth and remain intact after deafferentation. Strong stimulation of the TrV induced a sustained depolarization (plateau potential) in denervated but not in normal barrelette neurons. The plateau potential was distinct from the EPSP-IPSP sequence by 1) a sustained (>80 ms) depolarization above −40 mV; 2) a slow decline slope (<0.1 mV/ms); 3) partially or totally inactivated Na+ spikes on the plateau; and 4) a termination by a steep decay (> 1 mV/ms) to a hyperpolarizing membrane level. The plateau potential was mediated by L-type Ca2+ channels and triggered by a N-methyl-d-aspartate (NMDA) receptor-mediated EPSP. γ-aminobutyric acid-A (GABAA) receptor-mediated IPSP dynamically regulated the latency and duration of the plateau potential. These results indicate that after neonatal peripheral damage, central trigeminal inputs cause a large and longlasting Ca2+ influx through L-type Ca2+ channels in barrelette neurons. Increased Ca2+ entry may play a key role in injury-induced structural remodeling, and/or transsynaptic cell death.
Selective serotonin reuptake inhibitors (SSRIs) are used extensively in the treatment of depression and anxiety disorders. The therapeutic benefits of SSRIs typically require several weeks of continuous treatment. Intriguingly, according to clinical reports, symptoms of anxiety may actually increase during the early stages of treatment although more prolonged treatment alleviates affective symptoms. Consistent with earlier studies that have used animal models to capture this paradoxical effect of SSRIs, we find that rats exhibit enhanced anxiety-like behavior on the elevated plus-maze 1 h after a single injection of the SSRI fluoxetine. Next we investigated the potential neural substrates underlying the acute anxiogenic effects by analyzing the morphological and physiological impact of acute fluoxetine treatment on principal neurons of the basolateral amygdala (BLA), a brain area that plays a pivotal role in fear and anxiety. Although earlier studies have shown that behavioral or genetic perturbations that are anxiogenic for rodents also increase dendritic spine density in the BLA, we find that a single injection of fluoxetine does not cause spinogenesis on proximal apical dendritic segments on BLA principal neurons an hour later. However, at the same time point when a single dose of fluoxetine caused enhanced anxiety, it also enhanced action potential firing in BLA neurons in ex vivo slices. Consistent with this finding, in vitro bath application of fluoxetine caused higher spiking frequency and this increase in excitability was correlated with an increase in the input resistance of these neurons. Our results suggest that enhanced excitability of amygdala neurons may contribute to the increase in anxiety-like behavior observed following acute fluoxetine treatment.
amygdala; anxiety; neuronal excitability; SSRI; fluoxetine; dendritic spines
We investigated possible alterations of pharmacologically-isolated, evoked GABAA inhibitory postsynaptic potentials (eIPSPs) and miniature GABAA inhibitory postsynaptic currents (mIPSCs) in the rat central amygdala (CeA) elicited by acute application of μ-opioid receptor (MOR) agonists (DAMGO and morphine; 1 μM) and by chronic morphine treatment with morphine pellets. The acute activation of MORs decreased the amplitudes of eIPSPs, increased paired-pulse facilitation (PPF) of eIPSPs and decreased the frequency (but not the amplitude) of mIPSCs in a majority of CeA neurons, suggesting that acute MOR-dependent modulation of this GABAergic transmission is mediated predominantly via presynaptic inhibition of GABA release. We observed no significant changes in the membrane properties, eIPSPs, PPF or mIPSCs of CeA neurons during chronic morphine treatment compared to CeA of naïve or sham rats. Superfusion of the MOR antagonist CTOP (1 μM) increased the mean amplitude of eIPSPs in a majority of CeA neurons to the same degree in both naïve/sham and morphine-treated rats, suggesting a tonic activation of MORs in both conditions. Superfusion of DAMGO decreased eIPSP amplitudes and the frequency of mIPSCs equally in both naïve/sham and morphine-treated rats but decreased the amplitude of mIPSCs only in morphine treated rats, an apparent postsynaptic action. Our combined findings suggest the development of tolerance of the CeA GABAergic system to inhibitory effects of acute activation of MORs on presynaptic GABA release and possible alteration of MOR-dependent postsynaptic mechanisms that may represent important neuroadaptations of the GABAergic and MOR systems during chronic morphine treatment.
addiction; drug abuse; electrophysiology; extended amygdala; opiate; tolerance
Beta frequency oscillations (10–35 Hz) in motor regions of cerebral cortex play an important role in stabilising and suppressing unwanted movements, and become intensified during the pathological akinesia of Parkinson's Disease. We have used a cortical slice preparation of rat brain, combined with concurrent intracellular and field recordings from the primary motor cortex (M1), to explore the cellular basis of the persistent beta frequency (27–30 Hz) oscillations manifest in local field potentials (LFP) in layers II and V of M1 produced by continuous perfusion of kainic acid (100 nM) and carbachol (5 µM). Spontaneous depolarizing GABA-ergic IPSPs in layer V cells, intracellularly dialyzed with KCl and IEM1460 (to block glutamatergic EPSCs), were recorded at −80 mV. IPSPs showed a highly significant (P< 0.01) beta frequency component, which was highly significantly coherent with both the Layer II and V LFP oscillation (which were in antiphase to each other). Both IPSPs and the LFP beta oscillations were abolished by the GABAA antagonist bicuculline. Layer V cells at rest fired spontaneous action potentials at sub-beta frequencies (mean of 7.1+1.2 Hz; n = 27) which were phase-locked to the layer V LFP beta oscillation, preceding the peak of the LFP beta oscillation by some 20 ms. We propose that M1 beta oscillations, in common with other oscillations in other brain regions, can arise from synchronous hyperpolarization of pyramidal cells driven by synaptic inputs from a GABA-ergic interneuronal network (or networks) entrained by recurrent excitation derived from pyramidal cells. This mechanism plays an important role in both the physiology and pathophysiology of control of voluntary movement generation.
Fast-spiking (FS) cells in the neocortex are interconnected both by inhibitory chemical synapses and by electrical synapses, or gap-junctions. Synchronized firing of FS neurons is important in the generation of gamma oscillations, at frequencies between 30 and 80 Hz. To understand how these synaptic interactions control synchronization, artificial synaptic conductances were injected in FS cells, and the synaptic phase-resetting function (SPRF), describing how the compound synaptic input perturbs the phase of gamma-frequency spiking as a function of the phase at which it is applied, was measured. GABAergic and gap junctional conductances made distinct contributions to the SPRF, which had a surprisingly simple piecewise linear form, with a sharp midcycle break between phase delay and advance. Analysis of the SPRF showed how the intrinsic biophysical properties of FS neurons and their interconnections allow entrainment of firing over a wide gamma frequency band, whose upper and lower frequency limits are controlled by electrical synapses and GABAergic inhibition respectively.
Oscillations of the electrical field in the brain at 30–80 Hz (gamma oscillations) reflect coordinated firing of neurons during cognitive, sensory, and motor activity, and are thought to be a key phenomenon in the organization of neural processing in the cortex. Synchronous firing of a particular type of neuron, the inhibitory fast-spiking (FS) cell, imposes the gamma rhythm on other cells in the network. FS cells are highly interconnected by both gap junctions and chemical inhibition. In this study, we probed FS cells with a synthetic conductance stimulus which mimics the electrical effect of these complex connections in a controlled way, and directly measured how the timing of their firing should be affected by nearby FS neighbours. We were able to fit a mathematically simple but accurate model to these measurements, the “synaptic phase-resetting function”, which predicts how FS neurons synchronize at different frequencies, noise levels, and synaptic connection strengths. This model gives us deeper insight into how the FS cells synchronize so effectively at gamma oscillations, and will be a building-block in large-scale simulations of the FS cell network aimed at understanding the onset and stability of patterns of gamma oscillation in the cortex.
Synchronous firing is commonly observed in the brain, but its underlying mechanisms and neurobiological meaning remain debated. Most commonly, synchrony is attributed either to electrical coupling by gap junctions or to shared excitatory inputs. In the cerebral cortex and hippocampus, fast-spiking (FS) or somatostatin–containing (SOM) inhibitory interneurons are electrically coupled to same-type neighbors, and each subtype-specific network tends to fire in synchrony. Electrical coupling across subtypes is weak or absent, but SOM-FS and FS-FS pairs are often connected by inhibitory synapses. Theoretical studies suggest that purely inhibitory coupling can also promote synchrony; however, this has not been confirmed experimentally. We recorded from 74 pairs of electrically non-coupled layer 4 interneurons in mouse somatosensory cortex in vitro, and found that tonically depolarized FS-FS and SOM-FS pairs connected by uni- or bidirectional inhibitory synapses often fired within one millisecond of each other. Using a novel, jitter-based measure of synchrony, we found that synchrony correlated with inhibitory coupling strength. Importantly, synchrony was resistant to ionotropic glutamate receptors antagonists but was strongly reduced when GABAA receptors were blocked, confirming that in our experimental system IPSPs were both necessary and sufficient for synchrony. Submillisecond firing lags emerged in a computer simulation of pairs of spiking neurons, in which the only assumed interaction between neurons was by inhibitory synapses. We conclude that cortical interneurons are capable of synchronizing both within and across subtypes, and that submillisecond coordination of firing can arise by mutual synaptic inhibition alone, with neither shared inputs nor electrical coupling.
The neural circuitry that processes natural rewards converges with that engaged by addictive drugs. Because of this common neurocircuitry, drugs of abuse have been able to engage the hedonic mechanisms normally associated with the processing of natural rewards. Ghrelin is an orexigenic peptide that stimulates food intake by activating GHS-R1A receptors in the hypothalamus. However, ghrelin also activates GHS-R1A receptors on extrahypothalamic targets that mediate alcohol reward. The central nucleus of the amygdala (CeA) has a critical role in regulating ethanol consumption and the response to ethanol withdrawal. We previously demonstrated that rat CeA GABAergic transmission is enhanced by acute and chronic ethanol treatment. Here, we used quantitative RT-PCR (qRT-PCR) to detect Ghsr mRNA in the CeA and performed electrophysiological recordings to measure ghrelin effects on GABA transmission in this brain region. Furthermore, we examined whether acute or chronic ethanol treatment would alter these electrophysiological effects. Our qRT-PCR studies show the presence of Ghsr mRNA in the CeA. In naive animals, superfusion of ghrelin increased the amplitude of evoked inhibitory postsynaptic potentials (IPSPs) and the frequency of miniature inhibitory postsynaptic currents (mIPSCs). Coapplication of ethanol further increased the ghrelin-induced enhancement of IPSP amplitude, but to a lesser extent than ethanol alone. When applied alone, ethanol significantly increased IPSP amplitude, but this effect was attenuated by the application of ghrelin. In neurons from chronic ethanol-treated (CET) animals, the magnitude of ghrelin-induced increases in IPSP amplitude was not significantly different from that in naive animals, but the ethanol-induced increase in amplitude was abolished. Superfusion of the GHS-R1A antagonists 𝒟-Lys3-GHRP-6 and JMV 3002 decreased evoked IPSP and mIPSC frequency, revealing tonic ghrelin activity in the CeA. 𝒟-Lys3-GHRP-6 and JMV 3002 also blocked ghrelin-induced increases in GABAergic responses. Furthermore, 𝒟-Lys3-GHRP-6 did not affect ethanol-induced increases in IPSP amplitude. These studies implicate a potential role for the ghrelin system in regulating GABAergic transmission and a complex interaction with ethanol at CeA GABAergic synapses.
Alcohol & Alcoholism; Electrophysiology; GABA; Molecular & Cellular Neurobiology; Neuropharmacology; electrophysiology; neuroadaptation; central nucleus of the amygdala; ghrelin; ethanol; alcohol dependence
The basolateral amygdala (BLA) has a fundamental role in affective processing. In vivo studies have revealed rhythmic population activity of a similar type to that seen in the hippocampus and cortical areas during learning tasks. The amygdala contains densely interconnected networks of inhibitory interneurons similar to those responsible for fast network activity generation in the hippocampus and other cortical structures. Here we report that neuronal networks of the BLA in isolation generate persistent, gamma frequency (30–80 Hz) oscillations upon kainate receptor activation with kainic acid. We show that, like other cortical structures, BLA oscillations are completely dependent upon γ-aminobutyric acid (GABA)ergic inhibition. GABAA receptor blockade abolished all oscillations, and the activity was also sensitive to the barbiturate, pentobarbital. Blockade of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors or N-methyl-d-aspartate (NMDA) receptors had no significant effect on gamma activity. However, the GluR5-containing kainate receptor-specific antagonist (S)-1-(2-amino-2-carboxyethyl)-3-(2-carboxybenzyl) pyrimidine-2,4-dione (UBP302) abolished oscillations–evidence that glutamatergic receptor involvement is predominantly kainate receptor mediated. The mixed AMPA/kainate receptor antagonist 6-nitro-7-sulphamoylbenzo[f]quinoxalone-2,3-dione disodium (NBQX) abolished all oscillatory activity in 8/14 of slices tested. In the remaining slices, gamma frequency activity was abolished to reveal a low-amplitude, NMDA receptor-dependent, beta frequency (10–20 Hz) oscillation. Gamma oscillations are abolished by gap junction blockade. While these data show the BLA capable of generating gamma rhythms in common with other cortical areas studied to date, the network mechanisms appear to be different, suggesting a unique network structure underlies amygdala rhythmogenesis. Understanding how BLA networks produce synchronous activity is paramount to understanding how the BLA executes influence on important cognitive processes such as emotional learning.
BLA; gamma oscillations; gap junction; glutamate
Theta oscillations are considered crucial mechanisms in neuronal communication across brain areas, required for consolidation and retrieval of fear memories. One form of inhibitory learning allowing adaptive control of fear memory is extinction, a deficit of which leads to maladaptive fear expression potentially leading to anxiety disorders. Behavioral responses after extinction training are thought to reflect a balance of recall from extinction memory and initial fear memory traces. Therefore, we hypothesized that the initial fear memory circuits impact behavioral fear after extinction, and more specifically, that the dynamics of theta synchrony in these pathways signal the individual fear response. Simultaneous multi-channel local field and unit recordings were obtained from the infralimbic prefrontal cortex, the hippocampal CA1 and the lateral amygdala in mice. Data revealed that the pattern of theta coherence and directionality within and across regions correlated with individual behavioral responses. Upon conditioned freezing, units were phase-locked to synchronized theta oscillations in these pathways, characterizing states of fear memory retrieval. When the conditioned stimulus evoked no fear during extinction recall, theta interactions were directional with prefrontal cortical spike firing leading hippocampal and amygdalar theta oscillations. These results indicate that the directional dynamics of theta-entrained activity across these areas guide changes in appraisal of threatening stimuli during fear memory and extinction retrieval. Given that exposure therapy involves procedures and pathways similar to those during extinction of conditioned fear, one therapeutical extension might be useful that imposes artificial theta activity to prefrontal cortical-amygdalo-hippocampal pathways that mimics the directionality signaling successful extinction recall.
Varicosities immunoreactive for nitric oxide synthase (NOS) make synaptic connections with submucosal neurons in the guinea-pig small intestine, but the effects of nitric oxide (NO) on these neurons are unknown. We used intracellular recording to characterize effects of sodium nitroprusside (SNP, NO donor) and nitro-l-arginine (NOLA, NOS inhibitor), on inhibitory synaptic potentials (IPSPs), slow excitatory synaptic potentials (EPSPs) and action potential firing in submucosal neurons of guinea-pig ileum in vitro. Recordings were made from neurons with the characteristic IPSPs of non-cholinergic secretomotor neurons. SNP (100 μM) markedly enhanced IPSPs evoked by single stimuli applied to intermodal strands and IPSPs evoked by trains of 2–10 pulses (30 Hz). Both noradrenergic (idazoxan-sensitive) and non-adrenergic (idazoxan-insensitive) IPSPs were affected. SNP enhanced hyperpolarizations evoked by locally applied noradrenaline or somatostatin. SNP did not affect slow EPSPs evoked by single stimuli, but depressed slow EPSPs evoked by stimulus trains. NOLA (100 μM) depressed IPSPs evoked by one to three stimulus pulses and enhanced slow EPSPs evoked by trains of two to three stimuli (30 Hz). SNP also increased the number of action potentials and the duration of firing evoked by prolonged (500 or 1000 ms) depolarizing current pulses, but NOLA had no consistent effect on action potential firing. We conclude that neurally released NO acts post-synaptically to enhance IPSPs and depress slow EPSPs, but may enhance the intrinsic excitability of these neurons. Thus, NOS neurons may locally regulate several secretomotor pathways ending on common neurons.
nitric oxide; secretomotor neurons; IPSPs; slow EPSPs; somatostatin; noradrenaline; neuronal excitability
Central among the brain regions that regulate fear/anxiety behaviors is the lateral/basolateral amygdala (BLA). BLA output is tightly controlled by the relative activity of two populations of inhibitory GABAergic interneurons, local feed-back cells distributed throughout the nucleus and feed-forward cells found along the lateral paracapsular border of this subdivision. Recent studies suggest that dopamine can modulate the BLA GABAergic system thus linking fear/anxiety-states with mesolimbic reward/attentional processes. However, the precise dopaminergic mechanisms regulating the activity of the two BLA GABAergic neuron populations have not been fully explored. We therefore examined the effects of dopamine (DA) D3-like receptors on BLA-dependent anxiety-like behavior and neurophysiology. After confirming the presence of D3-like receptors within the BLA, we found that microinjection of a D3-selective antagonist into the BLA decreased anxiety-like behavior expressed in both the light/dark transition test and the elevated plus maze. Consistent with this, we found that in vitro D3-like receptor activation selectively inhibits synaptic transmission at both BLA feed-back and feed-forward GABAergic interneuron populations, with no effect on glutamatergic transmission. This inhibition of GABAergic transmission is a result of a D3-like receptor-mediated, dynamin-dependent process that presumably reflects endocytosis of postsynaptic GABAA receptors found on principal BLA neurons. Because environmental cues alter both DA release and relative activity states of the BLA, our data strongly suggest that DA, potentially acting through D3-like receptors, may suppress the relative contribution by inhibitory processes in the BLA and modify the expression of BLA-related behaviors.
anxiety; dopamine; electrophysiology; GABAergic synapse; U99194; endocytosis
Central among the brain regions that regulate fear/anxiety behaviors is the lateral/basolateral amygdala (BLA). BLA output is tightly controlled by the relative activity of two populations of inhibitory GABAergic interneurons, local feedback cells distributed throughout the nucleus, and feedforward cells found along the lateral paracapsular border of this subdivision. Recent studies suggest that dopamine (DA) can modulate the BLA GABAergic system, thus linking fear/anxiety states with mesolimbic reward/attentional processes. However, the precise dopaminergic mechanisms regulating the activity of the two BLA GABAergic neuron populations have not been fully explored. We therefore examined the effects of DA D3-like receptors on BLA-dependent anxiety-like behavior and neurophysiology. After confirming the presence of D3-like receptors within the BLA, we found that microinjection of a D3-selective antagonist into the BLA decreased anxiety-like behavior expressed in both the light/dark transition test and the elevated plus maze. Consistent with this, we found that in vitro D3-like receptor activation selectively inhibits synaptic transmission at both BLA feedback and feedforward GABAergic interneuron populations, with no effect on glutamatergic transmission. This inhibition of GABAergic transmission is a result of a D3-like receptor-mediated, dynamin-dependent process that presumably reflects endocytosis of postsynaptic GABAA receptors found on principal BLA neurons. Because environmental cues alter both DA release and relative activity states of the BLA, our data strongly suggest that DA, potentially acting through D3-like receptors, may suppress the relative contribution by inhibitory processes in the BLA and modify the expression of BLA-related behaviors.
anxiety; dopamine; electrophysiology; GABAergic synapse; U99194; endocytosis; ; ;
Recordings from area V4 of monkeys have revealed that when the focus of attention is on a visual stimulus within the receptive field of a cortical neuron, two distinct changes can occur: The firing rate of the neuron can change and there can be an increase in the coherence between spikes and the local field potential (LFP) in the gamma-frequency range (30–50 Hz). The hypothesis explored here is that these observed effects of attention could be a consequence of changes in the synchrony of local interneuron networks. We performed computer simulations of a Hodgkin-Huxley type neuron driven by a constant depolarizing current, I, representing visual stimulation and a modulatory inhibitory input representing the effects of attention via local interneuron networks. We observed that the neuron’s firing rate and the coherence of its output spike train with the synaptic inputs was modulated by the degree of synchrony of the inhibitory inputs. When inhibitory synchrony increased, the coherence of spiking model neurons with the synaptic input increased, but the firing rate either increased or remained the same. The mean number of synchronous inhibitory inputs was a key determinant of the shape of the firing rate versus current (f–I) curves. For a large number of inhibitory inputs (~50), the f–I curve saturated for large I and an increase in input synchrony resulted in a shift of sensitivity—the model neuron responded to weaker inputs I. For a small number (~10), the f–I curves were non-saturating and an increase in input synchrony led to an increase in the gain of the response—the firing rate in response to the same input was multiplied by an approximately constant factor. The firing rate modulation with inhibitory synchrony was highest when the input network oscillated in the gamma frequency range. Thus, the observed changes in firing rate and coherence of neurons in the visual cortex could be controlled by top-down inputs that regulated the coherence in the activity of a local inhibitory network discharging at gamma frequencies.
Selective attention; Synchrony; Noise; Gamma oscillation; Gain modulation; Computer model