Pyramidal Cell Pairs Research Articles

Fast-spiking Interneurons Contribute to Propofol-induced Facilitation of Firing Synchrony in Pyramidal Neurons of the Rat Insular Cortex.

The general anesthetic propofol induces frontal alpha rhythm in the cerebral cortex at a dose sufficient to induce loss of consciousness. The authors hypothesized that propofol-induced facilitation of unitary inhibitory postsynaptic currents would result in firing synchrony among postsynaptic pyramidal neurons that receive inhibition from the same presynaptic inhibitory fast-spiking neurons. Multiple whole cell patch clamp recordings were performed from one fast-spiking neuron and two or three pyramidal neurons with at least two inhibitory connections in rat insular cortical slices. The authors examined how inhibitory inputs from a presynaptic fast-spiking neuron modulate the timing of spontaneous repetitive spike firing among pyramidal neurons before and during 10 μM propofol application. Responding to activation of a fast-spiking neuron with 150-ms intervals, pyramidal cell pairs that received common inhibitory inputs from the presynaptic fast-spiking neuron showed propofol-dependent decreases in average distance from the line of identity, which evaluates the coefficient of variation in spike timing among pyramidal neurons: average distance from the line of identity just after the first activation of fast-spiking neuron was 29.2 ± 24.1 (mean ± SD, absolute value) in control and 19.7 ± 19.2 during propofol application (P < 0.001). Propofol did not change average distance from the line of identity without activating fast-spiking neurons and in pyramidal neuron pairs without common inhibitory inputs from presynaptic fast-spiking neurons. The synchronization index, which reflects the degree of spike synchronization among pyramidal neurons, was increased by propofol from 1.4 ± 0.5 to 2.3 ± 1.5 (absolute value, P = 0.004) and from 1.5 ± 0.5 to 2.2 ± 1.0 (P = 0.030) when a presynaptic fast-spiking neuron was activated at 6.7 and 10 Hz, respectively, but not at 1, 4, and 13.3 Hz. These results suggest that propofol facilitates pyramidal neuron firing synchrony by enhancing inhibitory inputs from fast-spiking neurons. This synchrony of pyramidal neurons may contribute to the alpha rhythm associated with propofol-induced loss of consciousness.

Dynamic Recovery from Depression Enables Rate Encoding in Inhibitory Synapses.

SummaryParvalbumin-expressing fast-spiking interneurons (PV-INs) control network firing and the gain of cortical response to sensory stimulation. Crucial for these functions, PV-INs can sustain high-frequency firing with no accommodation. However, PV-INs also exhibit short-term depression (STD) during sustained activation, largely due to the depletion of synaptic resources (vesicles). In most synapses the rate of replenishment of depleted vesicles is constant, determining an inverse relationship between depression levels and the activation rate, which theoretically, severely limits rate-coding capabilities. We examined STD of the PV-IN to pyramidal cell synapse in the mouse visual cortex and found that in these synapses the recovery from depression is not constant but increases linearly with the frequency of use. By combining modeling, dynamic clamp, and optogenetics, we demonstrated that this recovery enables PV-INs to reduce pyramidal cell firing in a linear manner, which theoretically is crucial for controlling the gain of cortical visual responses.

Reliable Sequential Activation of Neural Assemblies by Single Pyramidal Cells in a Three-Layered Cortex

Recent studies reveal the occasional impact of single neurons on surround firing statistics and even simple behaviors. Exploiting the advantages of a simple cortex, we examined the influence of single pyramidal neurons on surrounding cortical circuits. Brief activation of single neurons triggered reliable sequences of firing in tens of other excitatory and inhibitory cortical neurons, reflecting cascading activity through local networks, as indicated by delayed yet precisely timed polysynaptic subthreshold potentials. The evoked patterns were specific to the pyramidal cell of origin, extended over hundreds of micrometers from their source, and unfolded over up to 200ms. Simultaneous activation of pyramidal cell pairs indicated balanced control of population activity, preventing paroxysmal amplification. Single cortical pyramidal neurons can thus trigger reliable postsynaptic activity that can propagate in a reliable fashion through cortex, generating rapidly evolving and non-random firing sequences reminiscent of those observed in mammalian hippocampus during "replay" and in avian song circuits.

Differential Regulation of Evoked and Spontaneous Release by Presynaptic NMDA Receptors

Presynaptic NMDA receptors (preNMDARs) control synaptic release, but it is not well understood how. Rab3-interacting molecules (RIMs) provide scaffolding at presynaptic active zones and are involved in vesicle priming. Moreover, c-Jun N-terminal kinase (JNK) has been implicated in regulation of spontaneous release. We demonstrate that, at connected layer 5 pyramidal cell pairs of developing mouse visual cortex, Mg2+-sensitive preNMDAR signaling upregulates replenishment of the readily releasable vesicle pool during high-frequency firing. In conditional RIM1αβ deletion mice, preNMDAR upregulation of vesicle replenishment was abolished, yet preNMDAR control of spontaneous release was unaffected. Conversely, JNK2 blockade prevented Mg2+-insensitive preNMDAR signaling from regulating spontaneous release, but preNMDAR control of evoked release remained intact. We thus discovered that preNMDARs signal differentially to control evoked and spontaneous release by independent and non-overlapping mechanisms. Our findings suggest that preNMDARs may sometimes signal metabotropically and support the emerging principle that evoked and spontaneous release are distinct processes. VIDEO ABSTRACT.

In Vitro Investigation of Synaptic Plasticity.

A classical in vitro model for investigation of information storage in the brain is based on the acute hippocampal slice. Here, repeated high-frequency stimulation of excitatory Schaeffer collaterals making synapses onto pyramidal cells in the hippocampal CA1 region leads to strengthening of evoked field-recording responses-long-term potentiation (LTP)-in keeping with Hebb's postulate. This model remains tremendously influential for its reliability, specificity, and relative ease of use. More recent plasticity studies have explored various other brain regions including the neocortex, which often requires more laborious whole-cell recordings of synaptically connected pairs of neurons, to ensure that the identities of recorded cells are known. In addition, with this experimental approach, the spiking activity can be controlled with millisecond precision, which is necessary for the study of spike-timing-dependent plasticity (STDP). Here, we provide protocols for in vitro study of hippocampal CA1 LTP using field recordings, and of STDP in synaptically connected pairs of layer-5 pyramidal cells in acute slices of rodent neocortex.

Synchronized gamma-frequency inhibition in neocortex depends on excitatory-inhibitory interactions but not electrical synapses.

Synaptic inhibition plays a crucial role in the precise timing of spiking activity in the cerebral cortex. Synchronized, rhythmic inhibitory activity in the gamma (30-80 Hz) range is thought to be especially important for the active, information-processing neocortex, but the circuit mechanisms that give rise to synchronized inhibition are uncertain. In particular, the relative contributions of reciprocal inhibitory connections, excitatory-inhibitory interactions, and electrical synapses to precise spike synchrony among inhibitory interneurons are not well understood. Here we describe experiments on mouse barrel cortex in vitro as it spontaneously generates slow (<1 Hz) oscillations (Up and Down states). During Up states, inhibitory postsynaptic currents (IPSCs) are generated at gamma frequencies and are more synchronized than excitatory postsynaptic currents (EPSCs) among neighboring pyramidal cells. Furthermore, spikes in homotypic pairs of interneurons are more synchronized than in pairs of pyramidal cells. Comparing connexin36 knockout and wild-type animals, we found that electrical synapses make a minimal contribution to synchronized inhibition during Up states. Estimations of the delays between EPSCs and IPSCs in single pyramidal cells showed that excitation often preceded inhibition by a few milliseconds. Finally, tonic optogenetic activation of different interneuron subtypes in the absence of excitation led to only weak synchrony of IPSCs in pairs of pyramidal neurons. Our results suggest that phasic excitatory inputs are indispensable for synchronized spiking in inhibitory interneurons during Up states and that electrical synapses play a minimal role.

Mechanisms for synchronized burst firing in pyramidal cells using oscillatory inhibition: a model for attentional control

Pyramidal cells have two different action potential initiation sites; one at the soma, which receives inputs from synapses contacting the basal dendrites or the soma, and one at the distal apical dendrite and tuft [1]. At the latter, calcium spikes can be elicited resulting in a plateau potential due to the influx of calcium that causes the pyramidal cell to fire bursts of action potentials [2]. This mechanism can be used to enhance the effect of top-down synaptic inputs that are received on the distal apical dendrite and tuft on activating its downstream targets. Calcium spikes can be elicited either by convergence of forward-propagating inputs at the tuft or by simultaneous depolarization from back-propagating action potentials and excitation at the tuft [3], referred to as FAC and BAC, respectively. We investigated whether these two firing patterns can be synchronized by oscillatory inhibition in order to transmit top-down or combined top-down and bottom-up information to different brain areas. We hypothesize this mechanism as an explanation for the synchronization of burst spiking to distant local field potentials at beta frequencies (12-20 Hz) that was recorded in the prefrontal cortex and the anterior cingulate cortex during attentional control [4]. We simulated the behavior of pyramidal cells stimulated by oscillatory inhibition at the tuft and noisy excitatory inputs at the basal dendrite and tuft. First, we investigated the occurrence and phase-locking of FAC and BAC firing in one cell as function of the ratio of excitatory basal and tuft inputs. Second, we examined the synchronization of a population of pyramidal cells downstream to oscillatory inhibition with frequencies in the beta range. The pyramidal cells were modeled using four compartments and including calcium dynamics in the apical dendrite and tuft [5]. For single pyramidal cells FACs predominantly occur when the tuft receives stronger excitation than the basal dendrites, while BACs occur predominantly when the tuft and basal dendrites are excited equally strong. Both mechanisms have in common that they dominate the behavior of the pyramidal cell only when oscillatory inhibition is in the lower frequency range (2-20 Hz). For a 1:2 ratio between excitatory basal and tuft input FACs accounted for up to 85% of all spike events, whereas for a ratio of 1:1 BACs constituted up to 68%. Bursts activated by FACs and BACs were strongly phase-locked to the inhibitory drive, while bursts activated by other mechanisms had a lower coherence. The synchrony between pairs of pyramidal cells was quantified using the Schreiber measure [6] with the smoothing parameter set to σ=5 ms. When stimulated in the beta frequency range the synchrony between pairs of pyramidal cells was on average 0.78. Taken together, the results show that FAC and BAC firing can be used in conjunction with oscillatory inhibition to produce synchronized burst firing in pyramidal cells. This provides an effective means to transmit top-down or combined top-down and bottom-up information downstream.

Monosynaptic excitatory transmission from the hippocampal CA1 region to the subiculum

The subiculum is a major output region of the hippocampus, receiving inputs from the CA1 region. We obtained paired patch-clamp recordings from synaptically coupled pairs of CA1 pyramidal cells (CA1PCs) and subicular principal cells (SubPCs), using rat hippocampal organotypic slice cultures. A single action potential in a presynaptic CA1PC evoked a unitary excitatory postsynaptic current in a SubPC (EPSCCA1→Sub). The failure rate of the monosynaptic transmission was remarkably low (0.08). Paired-pulse depression in SubPCs was apparent when an interval of presynaptic action potentials was shorter than 50ms. When trains of action potentials were induced in a CA1PC, EPSCCA1→Sub was significantly depressed with increasing spike frequency (20–100Hz). Thus the unitary monosynaptic transmission from a CA1PC to a SubPC is reliable, and depressed in response to frequent inputs, suggesting that the subiculum may function as a low pass filter to provide the downstream brain regions with appropriate information.

Presynaptic cholinergic neuromodulation alters the temporal dynamics of short-term depression at parvalbumin-positive basket cell synapses from juvenile CA1 mouse hippocampus

Parvalbumin-positive basket cells (PV BCs) of the CA1 hippocampus are active participants in theta (5-12 Hz) and gamma (20-80 Hz) oscillations in vivo. When PV BCs are driven at these frequencies in vitro, inhibitory postsynaptic currents (IPSCs) in synaptically connected CA1 pyramidal cells exhibit paired-pulse depression (PPD) and multiple-pulse depression (MPD). Moreover, PV BCs express presynaptic muscarinic acetylcholine receptors (mAChRs) that may be activated by synaptically released acetylcholine during learning behaviors in vivo. Using acute hippocampal slices from the CA1 hippocampus of juvenile PV-GFP mice, we performed whole cell recordings from synaptically connected PV BC-CA1 pyramidal cell pairs to investigate how bath application of 10 μM muscarine impacts PPD and MPD at CA1 PV BC-pyramidal cell synapses. In accordance with previous studies, PPD and MPD magnitude increased with stimulation frequency. mAChR activation reduced IPSC amplitude and transiently reduced PPD, but MPD was largely maintained. Consistent with a reduction in release probability (pr), MPD and mAChR activation increased both the coefficient of variation of IPSC amplitudes and the fraction of failures. Using variance-mean analysis, we converted MPD trains to pr functions and developed a kinetic model that optimally fit six distinct pr conditions. The model revealed that vesicular depletion caused MPD and that recovery from depression was dependent on calcium. mAChR activation reduced the presynaptic calcium transient fourfold and initial pr twofold, thereby reducing PPD. However, mAChR activation slowed calcium-dependent recovery from depression during sustained repetitive activity, thereby preserving MPD. Thus the activation of presynaptic mAChRs optimally protects PV BCs from vesicular depletion during short bursts of high-frequency activity.

Activation of parallel fiber feedback by spatially diffuse stimuli reduces signal and noise correlations via independent mechanisms in a cerebellum-like structure.

Correlations between the activities of neighboring neurons are observed ubiquitously across systems and species and are dynamically regulated by several factors such as the stimulus' spatiotemporal extent as well as by the brain's internal state. Using the electrosensory system of gymnotiform weakly electric fish, we recorded the activities of pyramidal cell pairs within the electrosensory lateral line lobe (ELL) under spatially localized and diffuse stimulation. We found that both signal and noise correlations were markedly reduced (>40%) under the latter stimulation. Through a network model incorporating key anatomical features of the ELL, we reveal how activation of diffuse parallel fiber feedback from granule cells by spatially diffuse stimulation can explain both the reduction in signal as well as the reduction in noise correlations seen experimentally through independent mechanisms. First, we show that burst-timing dependent plasticity, which leads to a negative image of the stimulus and thereby reduces single neuron responses, decreases signal but not noise correlations. Second, we show trial-to-trial variability in the responses of single granule cells to sensory input reduces noise but not signal correlations. Thus, our model predicts that the same feedback pathway can simultaneously reduce both signal and noise correlations through independent mechanisms. To test this prediction experimentally, we pharmacologically inactivated parallel fiber feedback onto ELL pyramidal cells. In agreement with modeling predictions, we found that inactivation increased both signal and noise correlations but that there was no significant relationship between magnitude of the increase in signal correlations and the magnitude of the increase in noise correlations. The mechanisms reported in this study are expected to be generally applicable to the cerebellum as well as other cerebellum-like structures. We further discuss the implications of such decorrelation on the neural coding strategies used by the electrosensory and by other systems to process natural stimuli.

Paired whole cell recordings in organotypic hippocampal slices.

Pair recordings involve simultaneous whole cell patch clamp recordings from two synaptically connected neurons, enabling not only direct electrophysiological characterization of the synaptic connections between individual neurons, but also pharmacological manipulation of either the presynaptic or the postsynaptic neuron. When carried out in organotypic hippocampal slice cultures, the probability that two neurons are synaptically connected is significantly increased. This preparation readily enables identification of cell types, and the neurons maintain their morphology and properties of synaptic function similar to that in native brain tissue. A major advantage of paired whole cell recordings is the highly precise information it can provide on the properties of synaptic transmission and plasticity that are not possible with other more crude techniques utilizing extracellular axonal stimulation. Paired whole cell recordings are often perceived as too challenging to perform. While there are challenging aspects to this technique, paired recordings can be performed by anyone trained in whole cell patch clamping provided specific hardware and methodological criteria are followed. The probability of attaining synaptically connected paired recordings significantly increases with healthy organotypic slices and stable micromanipulation allowing independent attainment of pre- and postsynaptic whole cell recordings. While CA3-CA3 pyramidal cell pairs are most widely used in the organotypic slice hippocampal preparation, this technique has also been successful in CA3-CA1 pairs and can be adapted to any neurons that are synaptically connected in the same slice preparation. In this manuscript we provide the detailed methodology and requirements for establishing this technique in any laboratory equipped for electrophysiology.

Mechanism underlying unaltered cortical inhibitory synaptic transmission in contrast with enhanced excitatory transmission in CaV2.1 knockin migraine mice

Familial hemiplegic migraine type 1 (FHM1), a monogenic subtype of migraine with aura, is caused by gain-of-function mutations in CaV2.1 (P/Q-type) calcium channels. In FHM1 knockin mice, excitatory neurotransmission at cortical pyramidal cell synapses is enhanced, but inhibitory neurotransmission at connected pairs of fast-spiking (FS) interneurons and pyramidal cells is unaltered, despite being initiated by CaV2.1 channels. The mechanism underlying the unaltered GABA release at cortical FS interneuron synapses remains unknown. Here, we show that the FHM1 R192Q mutation does not affect inhibitory transmission at autapses of cortical FS and other types of multipolar interneurons in microculture from R192Q knockin mice, and investigate the underlying mechanism. Lowering the extracellular [Ca2+] did not reveal gain-of-function of evoked transmission neither in control nor after prolongation of the action potential (AP) with tetraethylammonium, indicating unaltered AP-evoked presynaptic calcium influx at inhibitory autapses in FHM1 KI mice. Neither saturation of the presynaptic calcium sensor nor short duration of the AP can explain the unaltered inhibitory transmission in the mutant mice. Recordings of the P/Q-type calcium current in multipolar interneurons in microculture revealed that the current density and the gating properties of the CaV2.1 channels expressed in these interneurons are barely affected by the FHM1 mutation, in contrast with the enhanced current density and left-shifted activation gating of mutant CaV2.1 channels in cortical pyramidal cells. Our findings suggest that expression of specific CaV2.1 channels differentially sensitive to modulation by FHM1 mutations in inhibitory and excitatory cortical neurons underlies the gain-of-function of excitatory but unaltered inhibitory synaptic transmission and the likely consequent dysregulation of the cortical excitatory–inhibitory balance in FHM1.

Recurrent synapses and circuits in the CA3 region of the hippocampus: an associative network

In the CA3 region of the hippocampus, pyramidal cells excite other pyramidal cells and interneurons. The axons of CA3 pyramidal cells spread throughout most of the region to form an associative network. These connections were first drawn by Cajal and Lorente de No. Their physiological properties were explored to understand epileptiform discharges generated in the region. Synapses between pairs of pyramidal cells involve one or few release sites and are weaker than connections made by mossy fibers on CA3 pyramidal cells. Synapses with interneurons are rather effective, as needed to control unchecked excitation. We examine contributions of recurrent synapses to epileptiform synchrony, to the genesis of sharp waves in the CA3 region and to population oscillations at theta and gamma frequencies. Recurrent connections in CA3, as other associative cortices, have a lower connectivity spread over a larger area than in primary sensory cortices. This sparse, but wide-ranging connectivity serves the functions of an associative network, including acquisition of neuronal representations as activity in groups of CA3 cells and completion involving the recall from partial cues of these ensemble firing patterns.

REM Sleep Reorganizes Hippocampal Excitability

Sleep is composed of an alternating sequence of REM and non-REM episodes, but their respective roles are not known. We found that the overall firing rates of hippocampal CA1 neurons decreased across sleep concurrent with an increase in the recruitment of neuronal spiking to brief "ripple" episodes, resulting in a net increase in neural synchrony. Unexpectedly, within non-REM episodes, overall firing rates gradually increased together with a decrease in the recruitment of spiking to ripples. The rate increase within non-REM episodes was counteracted bya larger and more rapid decrease of discharge frequency within the interleaved REM episodes. Both the decrease in firing rates and the increase in synchrony during the course of sleep were correlated with the power of theta activity during REM episodes. These findings assign a prominent role of REM sleep in sleep-related neuronal plasticity.

Heterogeneity and independency of unitary synaptic outputs from hippocampal CA3 pyramidal cells

The variation of individual synaptic transmission impacts the dynamics of complex neural circuits. We performed whole-cell recordings from monosynaptically connected hippocampal neurons in rat organotypic slice cultures using a synapse mapping method. The amplitude of unitary excitatory postsynaptic current (uEPSC) varied from trial to trial and was independent of the physical distance between cell pairs. To investigate the source of the transmission variability, we obtained patch-clamp recordings from intact axons. Axonal action potentials (APs) were reliably transmitted throughout the axonal arbour and showed modest changes in width. In contrast, calcium imaging from presynaptic boutons revealed that the amplitude of AP-evoked calcium transients exhibited large variations both among different boutons at a given trial and among trials in a given bouton. These results suggest that a factor contributing to the uEPSC fluctuations is the variability in calcium dynamics at presynaptic terminals. Finally, we acquired triple whole-cell recordings from divergent circuit motifs with one presynaptic neuron projecting to two postsynaptic neurons. Consistent with the independency of calcium dynamics among axonal boutons, a series of uEPSC fluctuations was not correlated between the two postsynaptic cells, indicating that different synapses even from the same neuron act independently.We conclude that the intra-bouton and inter-bouton variability in AP-induced calcium dynamics determine the heterogeneity and independency of uEPSCs.

Ih modulates theta rhythm and synchrony in computer model of CA3

Although the contributions of different hippocampal cell classes to oscillatory activity has been studied, the intrinsic membrane mechanisms contributing to the oscillations and neuronal synchronization are not well understood. The hyperpolarization-activated cation (HCN) channel is a voltage-gated ion channel potentially implicated in epilepsy. Ih, the current produced by HCN channels, plays an important role in regulating neuronal excitability, particularly in hippocampal and neocortical pyramidal neurons. Changes in HCN conductance have been associated with epilepsy, manifesting as discharges with aberrant synchrony [1]. In this study we investigated the role of Ih in pacing network oscillations and synchronizing activity. We studied the effects of modulating both the Ih time-constant and the Ih conductance level in a biophysical computer model of the CA3 region of the hippocampus using the NEURON simulator. Some of the manipulations could be realized in-vitro with pharmacological manipulation via the Ih blocker, ZD7288. Our network consisted of 800 five-compartment pyramidal cells, 200 one-compartment basket cell interneurons, and 200 one-compartment oriens lacunosum-moleculare (O-LM) interneurons. All cells contained leak current, transient sodium current and delayed rectifier current. Additionally, pyramidal cells contained potassium type A current and pyramidal and OLM cells had Ih current. Cell classes were interconnected probabilistically with AMPA/NMDA, and two classes of GABAA synapses. The O-LM cells formed synapses on the distal dendrites of pyramidal cells, while the basket cells synapsed proximally on pyramidal and other basket cells. Pyramidal cells synapsed on both types of interneurons with AMPA/NMDA synapses. All synapses were bombarded with external Poisson inputs to generate network activity. We used Kendall’s tau correlation to measure the synchrony between pairs of pyramidal cells and performed FFT analysis on local field potentials generated by the pyramidal cells to measure rhythmic activity. At baseline, OLM cells fired preferentially at the theta frequency, causing periodic inhibition/disinhibition of pyramidal cells [2]. Although lowering the Ih conductance of pyramidal cell distal dendrites did not change average firing rates of pyramidal cells, the delay to pyramidal cell synchronization increased. Delayed synchronization was associated with a delay in the emergence of pyramidal interneuron network gamma (PING; in PING, pyramidal cells drive basket cells via AMPA/NMDA receptors and basket cells in turn inhibit the pyramidal cells through GABAergic synapses). This mechanism depends on stabilization via pyramidal cell synchronization. Analysis of the simulated local field potential spectral power showed that Ih conductance level correlated with the peak theta rhythm, from ~6.5 - 8.5 Hz. Our model demonstrates that changes in conductance of HCN channels can modulate hippocampal network rhythms and synchrony. These effects could be tested in-vivo and in-vitro, under neuromodulatory or pharmacological control. Our model also predicts that hippocampal networks may become more prone towards epilepsy with alterations in the level of HCN channel expression.

Closing the loop in primate prefrontal cortex: inter-laminar processing

Prefrontal cortical (PFC) activity in the primate brain emerging from minicolumnar microcircuits plays a critical role in cognitive processes dealing with executive control of behavior. However, the specific operations of columnar laminar processing in prefrontal cortex (PFC) are not completely understood. Here we show via implementation of unique microanatomical recording and stimulating arrays, that minicolumns in PFC are involved in the executive control of behavior in rhesus macaque nonhuman primates (NHPs) performing a delayed-match-to-sample (DMS) task. PFC neurons demonstrate functional interactions between pairs of putative pyramidal cells within specified cortical layers via anatomically oriented minicolumns. Results reveal target-specific, spatially tuned firing between inter-laminar (layer 2/3 and layer 5) pairs of neurons participating in the gating of information during the decision making phase of the task with differential correlations between activity in layer 2/3 and layer 5 in the integration of spatial vs. object-specific information for correct task performance. Such inter-laminar processing was exploited by the interfacing of an online model which delivered stimulation to layer 5 locations in a pattern associated with successful performance thereby closing the columnar loop externally in a manner that mimicked normal processing in the same task. These unique technologies demonstrate that PFC neurons encode and process information via minicolumns which provides a closed loop form of “executive function,” hence disruption of such inter-laminar processing could form the bases for cognitive dysfunction in primate brain.

Exact firing-rate response of the integrate-and-fire neuron receiving finite amplitude excitatory and inhibitory post-synaptic potentials

Neurons in active networks are subject to a fluctuating synaptic drive comprising excitatory and inhibitory post-synaptic potentials arriving at high rates relative to the integration time of the cell. The standard approach for treating stochastic synaptic currents and conductances has been to approximate them by a Gaussian white-noise or coloured-noise process in which the amplitudes of the underlying post-synaptic potentials are considered small. Importantly, this diffusion approximation has allowed for various firing-rate properties of populations of fluctuation-driven neurons to be calculated using Johanessma’s [1] and Ricciardi’s [2] Fokker-Planck framework. This framework in turn has proven to be a powerful theoretical tool for deriving the emergent states of coupled neuronal networks as a function of the properties of constituent neurons. The Gaussian/diffusion model of fluctuating synaptic conductance is in widespread use theoretically, computationally and experimentally and, in many cases, is an excellent approximation to the synaptic drive experienced by neurons in active networks in vitro or in vivo. The typical synaptic coupling between neurons in many brain regions, however, is often sufficiently strong such that relatively few synchronous synaptic events are required to bring a neuron from rest to the spiking threshold. For example, pairs of neocortical layer-5 pyramidal cells form synaptic connections with amplitudes in the range 0.5mV-6mV with a mean of 1.3mV [2] and, when correlations are taken into account, near-synchronous pre-synaptic activity will lead to even stronger aggregate EPSPs. Given that the difference between rest and threshold is around 10mV for this class of cell [3] it is likely that finite-amplitude effects missed by the standard Gaussian/diffusion approximation will play an important role in shaping the steady-state and response properties of neurons in vivo. Here we present a significant generalization of the standard Gaussian/diffusion approach to treating synaptic fluctuations by exactly solving the firing-rate response for a neuron receiving finite-amplitude Poissonian excitatory and inhibitory post-synaptic potentials [5]. The mathematical framework involves the solution of a master equation and can be applied to synaptic-amplitude distributions decomposable into combinations of exponential functions -similar to those seen in experiment. It will be shown that this more general mathematical description of the neuronal response to stochastic synaptic dynamics is significantly richer and qualitatively distinct from that predicted by the Gaussian/diffusion approximation. As well as providing analytical solutions for the firing-rate response of the leaky integrate-and-fire model, it will be demonstrated how an efficient numerical scheme can be used to calculate, numerically but exactly, the response properties of non-linear integrate-and-fire neurons and also to better capture the effects of synaptic reversal potentials.

Distinct synaptic properties of perisomatic inhibitory cell types and their different modulation by cholinergic receptor activation in the CA3 region of the mouse hippocampus.

Perisomatic inhibition originates from three types of GABAergic interneurons in cortical structures, including parvalbumin-containing fast-spiking basket cells (FSBCs) and axo-axonic cells (AACs), as well as cholecystokinin-expressing regular-spiking basket cells (RSBCs). These interneurons may have significant impact in various cognitive processes, and are subjects of cholinergic modulation. However, it is largely unknown how cholinergic receptor activation modulates the function of perisomatic inhibitory cells. Therefore, we performed paired recordings from anatomically identified perisomatic interneurons and pyramidal cells in the CA3 region of the mouse hippocampus. We determined the basic properties of unitary inhibitory postsynaptic currents (uIPSCs) and found that they differed among cell types, e.g. GABA released from axon endings of AACs evoked uIPSCs with the largest amplitude and with the longest decay measured at room temperature. RSBCs could also release GABA asynchronously, the magnitude of the release increasing with the discharge frequency of the presynaptic interneuron. Cholinergic receptor activation by carbachol significantly decreased the uIPSC amplitude in all three types of cell pairs, but to different extents. M2-type muscarinic receptors were responsible for the reduction in uIPSC amplitudes in FSBC– and AAC–pyramidal cell pairs, while an antagonist of CB1 cannabinoid receptors recovered the suppression in RSBC–pyramidal cell pairs. In addition, carbachol suppressed or even eliminated the short-term depression of uIPSCs in FSBC– and AAC–pyramidal cell pairs in a frequency-dependent manner. These findings suggest that not only are the basic synaptic properties of perisomatic inhibitory cells distinct, but acetylcholine can differentially control the impact of perisomatic inhibition from different sources.

Restoring the “Young” Brain

Restoring the “Young” Brain