Persistent Firing Research Articles

Tonic inhibition sets the state of excitability in olfactory bulb granule cells

GABAergic granule cells (GCs) regulate, via mitral cells, the final output from the olfactory bulb to piriform cortex and are central for the speed and accuracy of odour discrimination. However, little is known about the local circuits in which GCs are embedded and how GCs respond during functional network activity. We recorded inhibitory and excitatory currents evoked during a single sniff-like odour presentation in GCs in vivo. We found that synaptic excitation was extensively activated across cells, whereas phasic inhibition was rare. Furthermore, our analysis indicates that GCs are innervated by a persistent firing of deep short axon cells that mediated the inhibitory evoked responses. Blockade of GABAergic synaptic input onto GCs revealed a tonic inhibitory current mediated by furosemide-sensitive GABA(A) receptors. The average current associated with this tonic GABAergic conductance was 3-fold larger than that of phasic inhibitory postsynaptic currents. We show that the pharmacological blockage of tonic inhibition markedly increased the occurrence of supra-threshold responses during an odour-stimulated sniff. Our findings suggest that GCs mediate recurrent or lateral inhibition, depending on the ambient level of extracellular GABA.

Metabotropic Glutamate Receptors Drive Global Persistent Inhibition in the Visual Thalamus

Within the dorsal lateral geniculate nucleus (dLGN) of the thalamus, retinal ganglion cell (RGC) projections excite thalamocortical (TC) cells that in turn relay visual information to the cortex. Local interneurons in the dLGN regulate the output of TC cells by releasing GABA from their axonal boutons and specialized dendritic spines. Here we examine the functional role of these highly specialized interneurons and how they inhibit TC cells in mouse brain slices. It was widely thought that activation of metabotropic glutamate receptor type 5 (mGluR5) on interneuron spines leads to local GABA release restricted to sites receiving active RGC inputs. We reexamined experiments that supported this view, and found that in the presence of TTX, mGluR5 agonists evoked GABA release that could instead be explained by interneuron depolarization and widespread intracellular calcium increases. We also examined GABA release evoked by RGC activation and found that high-frequency stimulation induces a long-lasting subthreshold afterdepolarization, persistent firing, or prolonged plateau potentials in interneurons and evokes sustained GABA release. mGluR5 antagonists virtually eliminated sustained spiking and the resulting widespread calcium-signals, and reduced inhibition by >50%. The remaining inhibition appeared to be mediated by a fraction of interneurons in which plateau potentials produced large and widespread calcium increases. Local calcium signals required for local GABA release were not observed. These findings indicate that, contrary to the previous view, RGC activation does not simply evoke localized GABA release by activating mGluR5, rather, synaptic activation of mGluR5 acts primarily by depolarizing interneurons and evoking widespread dendritic GABA release.

NMDA Receptors Subserve Persistent Neuronal Firing during Working Memory in Dorsolateral Prefrontal Cortex

Neurons in the primate dorsolateral prefrontal cortex (dlPFC) generate persistent firing in the absence of sensory stimulation, the foundation of mental representation. Persistent firing arises from recurrent excitation within a network of pyramidal Delay cells. Here, we examined glutamate receptor influences underlying persistent firing in primate dlPFC during a spatial working memory task. Computational models predicted dependence on NMDA receptor (NMDAR) NR2B stimulation, and Delay cell persistent firing was abolished by local NR2B NMDAR blockade or by systemic ketamine administration. AMPA receptors (AMPARs) contributed background depolarization to sustain network firing. In contrast, many Response cells were sensitive to AMPAR blockade and increased firing after systemic ketamine, indicating that models of ketamine actions should be refined to reflect neuronal heterogeneity. The reliance of Delay cells on NMDAR may explain why insults to NMDARs in schizophrenia or Alzheimer's disease profoundly impair cognition.

NMDA and GABAB(KIR) Conductances: The “Perfect Couple” for Bistability

Networks that produce persistent firing in response to novel input patterns are thought to be important in working memory and other information storage functions. One possible mechanism for maintaining persistent firing is dendritic voltage bistability in which the depolarized state depends on the voltage dependence of the NMDA conductance at recurrent synapses. In previous models, the hyperpolarized state is dependent on voltage-independent conductances, including GABA(A). The interplay of these conductances leads to bistability, but its robustness is limited by the fact that the conductance ratio must be within a narrow range. The GABA(B) component of inhibitory transmission was not considered in previous analyses. Here, we show that the voltage dependence of the inwardly rectifying potassium (KIR) conductance activated by GABA(B) receptors adds substantial robustness to network simulations of bistability and the persistent firing that it underlies. The hyperpolarized state is robust because, at hyperpolarized potentials, the GABA(B)/KIR conductance is high and the NMDA conductance is low; the depolarized state is robust because, at depolarized potentials, the NMDA conductance is high and the GABA(B)/KIR conductance is low. Our results suggest that this complementary voltage dependence of GABA(B)/KIR and NMDA conductances makes them a "perfect couple" for producing voltage bistability.

Muscarinic Receptors in Amygdala Control Trace Fear Conditioning

Intelligent behavior requires transient memory, which entails the ability to retain information over short time periods. A newly-emerging hypothesis posits that endogenous persistent firing (EPF) is the neurophysiological foundation for aspects or types of transient memory. EPF is enabled by the activation of muscarinic acetylcholine receptors (mAChRs) and is triggered by suprathreshold stimulation. EPF occurs in several brain regions, including the lateral amygdala (LA). The present study examined the role of amygdalar mAChRs in trace fear conditioning, a paradigm that requires transient memory. If mAChR-dependent EPF selectively supports transient memory, then blocking amygdalar mAChRs should impair trace conditioning, while sparing delay and context conditioning, which presumably do not rely upon transient memory. To test the EPF hypothesis, LA was bilaterally infused, prior to trace or delay conditioning, with either a mAChR antagonist (scopolamine) or saline. Computerized video analysis quantified the amount of freezing elicited by the cue and by the training context. Scopolamine infusion profoundly reduced freezing in the trace conditioning group but had no significant effect on delay or context conditioning. This pattern of results was uniquely anticipated by the EPF hypothesis. The present findings are discussed in terms of a systems-level theory of how EPF in LA and several other brain regions might help support trace fear conditioning.

PRESYNAPTIC LEARNING AND MEMORY WITH A PERSISTENT FIRING NEURON AND A HABITUATING SYNAPSE: A MODEL OF SHORT TERM PERSISTENT HABITUATION

Our paper explores the interaction of persistent firing axonal and presynaptic processes in the generation of short term memory for habituation. We first propose a model of a sensory neuron whose axon is able to switch between passive conduction and persistent firing states, thereby triggering short term retention to the stimulus. Then we propose a model of a habituating synapse and explore all nine of the behavioral characteristics of short term habituation in a two neuron circuit. We couple the persistent firing neuron to the habituation synapse and investigate the behavior of short term retention of habituating response. Simulations show that, depending on the amount of synaptic resources, persistent firing either results in continued habituation or maintains the response, both leading to longer recovery times. The effectiveness of the model as an element in a bio-inspired memory system is discussed.

Balanced cortical microcircuitry for maintaining short-term memory

Persistent patterns of neural activity that last long after the offset of a stimulus are thought to be the neural substrate for short-term memory. Because the observed decay of persistent activity in memory circuits is much slower than the typical decay time constants associated with synaptic or intrinsic neuronal dynamics, it has been suggested that network interactions must be used to prolong the duration of persistent activity. Most often, these network interactions have been assumed to mediate positive feedback between neurons that supports a long-lasting reverberation of activity. However, most positive feedback models do not naturally fit the architecture of working memory-storing structures in neocortex that have been suggested to exhibit a close balance between excitation and inhibition. Furthermore, positive feedback models of analog memory storage are highly non-robust against commonly studied perturbations in network connectivity. Here, we suggest a complementary mechanism for generating persistent activity based on the principle of corrective negative-feedback: an error-correcting signal of the form of a time-derivative of activity reduces memory slip when it occurs. Using analytic calculations, we show that neocortical circuit models with the observed balance in strength, but with different kinetics, between excitatory and inhibitory synaptic inputs, produce a negative-derivative feedback signal that counteracts drifts in persistent activity. The networks maintain a continuum of stable firing rates even in the presence of intrinsic input-output nonlinearity, while still remaining responsive to external memory inputs. More generally, the networks act as temporal integrators of their inputs, for example converting step-like input into linearly ramping activity. Memory networks operating in this balanced regime are robust against many commonly studied perturbations to synaptic weights that grossly disrupt the performance of persistent activity circuits based on positive feedback. Specifically, in response to uniform changes in synaptic excitation, synaptic inhibition, intrinsic neuronal gains or loss of a fraction of excitatory or inhibitory neurons, there is minimal decay or instability in persistent firing. Furthermore, spiking network models implementing derivative feedback generate persistent firing with Poisson-like statistics, as has been observed experimentally. This observed highly irregular activity occurs across a graded range of firing rates, and arises because the close balance between excitation and inhibition results in spikes being triggered primarily by fluctuations in, rather than means levels of, synaptic inputs. To generate experimental predictions that distinguish among different mechanisms for short-term memory, we compared the correlation structure of excitatory and inhibitory inputs in the negative-derivative feedback models to that of typical analog memory models based on positive feedback. Negative-derivative feedback models exhibit a strong positive correlation between inhibitory and excitatory synaptic inputs, as suggested by recent experiments. By contrast, similarly responding neurons in positive feedback models either exhibited anti-correlations or weak correlations between their excitatory and inhibitory inputs. Altogether, this work suggests a new paradigm for short-term memory storage based upon a balanced network with cortical-like architecture. Stabilization of responses through negative feedback is a common principle in engineering control systems. Our work suggests that a similar principle might be inherent to the circuitry of working memory systems.

Selectivity and persistent firing responses to social vocalizations in the basolateral amygdala

This study examined responsiveness to acoustic stimuli among neurons of the basolateral amygdala. While recording from single neurons in awake mustached bats (Pteronotus parnellii), we presented a wide range of acoustic stimuli including tonal, noise, and vocal signals. While many neurons displayed phasic or sustained responses locked to effective auditory stimuli, the majority of neurons (n=58) displayed a persistent excitatory discharge that lasted well beyond stimulus duration and filled the interval between successive stimuli. Persistent firing usually began seconds (median value, 5.4s) after the initiation of a train of repeated stimuli and lasted, in the majority of neurons, for at least 2min after the end of the stimulus train. Auditory-responsive amygdalar neurons were generally excited by one stimulus or very few stimuli. Most neurons did not respond well to synthetic stimuli including tones, noise bursts or frequency-modulated sweeps, but instead responded only to vocal stimuli (82 of 87 neurons). Furthermore, most neurons were highly selective among vocal stimuli. On average, neurons responded to 1.7 of 15 different syllables or syllable sequences. The largest percentage of neurons responded to a hiss-like rectangular broadband noise burst (rBNB) call associated with aggressive interactions. Responsiveness to effective vocal stimuli was reduced or eliminated when the spectrotemporal features of the stimuli were altered in a subset of neurons. Chemical activation of the medial geniculate body (MG) increased both background and evoked firing. Among 39 histologically localized recording sites, we saw no evidence of topographic organization in terms of temporal response pattern, habituation, or the affect of calls to which neurons responded. Overall, these studies demonstrate that amygdalar neurons in the mustached bat show high selectivity to vocal stimuli, and suggest that persistent firing may be an important feature of amygdalar responses to social vocalizations.

Predictive Features of Persistent Activity Emergence in Regular Spiking and Intrinsic Bursting Model Neurons

Proper functioning of working memory involves the expression of stimulus-selective persistent activity in pyramidal neurons of the prefrontal cortex (PFC), which refers to neural activity that persists for seconds beyond the end of the stimulus. The mechanisms which PFC pyramidal neurons use to discriminate between preferred vs. neutral inputs at the cellular level are largely unknown. Moreover, the presence of pyramidal cell subtypes with different firing patterns, such as regular spiking and intrinsic bursting, raises the question as to what their distinct role might be in persistent firing in the PFC. Here, we use a compartmental modeling approach to search for discriminatory features in the properties of incoming stimuli to a PFC pyramidal neuron and/or its response that signal which of these stimuli will result in persistent activity emergence. Furthermore, we use our modeling approach to study cell-type specific differences in persistent activity properties, via implementing a regular spiking (RS) and an intrinsic bursting (IB) model neuron. We identify synaptic location within the basal dendrites as a feature of stimulus selectivity. Specifically, persistent activity-inducing stimuli consist of activated synapses that are located more distally from the soma compared to non-inducing stimuli, in both model cells. In addition, the action potential (AP) latency and the first few inter-spike-intervals of the neuronal response can be used to reliably detect inducing vs. non-inducing inputs, suggesting a potential mechanism by which downstream neurons can rapidly decode the upcoming emergence of persistent activity. While the two model neurons did not differ in the coding features of persistent activity emergence, the properties of persistent activity, such as the firing pattern and the duration of temporally-restricted persistent activity were distinct. Collectively, our results pinpoint to specific features of the neuronal response to a given stimulus that code for its ability to induce persistent activity and predict differential roles of RS and IB neurons in persistent activity expression.

Synaptic Activity Unmasks Dopamine D2 Receptor Modulation of a Specific Class of Layer V Pyramidal Neurons in Prefrontal Cortex

Dopamine D2 receptors (D2Rs) play a major role in the function of the prefrontal cortex (PFC), and may contribute to prefrontal dysfunction in conditions such as schizophrenia. Here we report that in mouse PFC, D2Rs are selectively expressed by a subtype of layer V pyramidal neurons that have thick apical tufts, prominent h-current, and subcortical projections. Within this subpopulation, the D2R agonist quinpirole elicits a novel afterdepolarization that generates voltage fluctuations and spiking for hundreds of milliseconds. Surprisingly, this afterdepolarization is masked in quiescent brain slices, but is readily unmasked by physiologic levels of synaptic input which activate NMDA receptors, possibly explaining why this phenomenon has not been reported previously. Notably, we could still elicit this afterdepolarization for some time after the cessation of synaptic stimulation. In addition to NMDA receptors, the quinpirole-induced afterdepolarization also depended on L-type Ca(2+) channels and was blocked by the selective L-type antagonist nimodipine. To confirm that D2Rs can elicit this afterdepolarization by enhancing Ca(2+) (and Ca(2+)-dependent) currents, we measured whole-cell Ca(2+) potentials that occur after blocking Na(+) and K(+) channels, and found quinpirole enhanced these potentials, while the selective D2R antagonist sulpiride had the opposite effect. Thus, D2Rs can elicit a Ca(2+)-channel-dependent afterdepolarization that powerfully modulates activity in specific prefrontal neurons. Through this mechanism, D2Rs might enhance outputs to subcortical structures, contribute to reward-related persistent firing, or increase the level of noise in prefrontal circuits.

Persistent Neuronal Firing in Primary Somatosensory Cortex in the Absence of Working Memory of Trial-specific Features of the Sample Stimuli in a Haptic Working Memory Task

Previous studies suggested that primary somatosensory (SI) neurons in well-trained monkeys participated in the haptic-haptic unimodal delayed matching-to-sample (DMS) task. In this study, 585 SI neurons were recorded in monkeys performing a task that was identical to that in the previous studies but without requiring discrimination and active memorization of specific features of a tactile or visual memorandum. A substantial number of those cells significantly changed their firing rate in the delay compared with the baseline, and some of them showed differential delay activity. These firing changes are similar to those recorded from monkeys engaged in active (working) memory. We conclude that the delay activity is not necessarily only observed as was generally thought in the situation of active memorization of different features between memoranda after those features have been actively discriminated. The delay activity observed in this study appears to be an intrinsic property of SI neurons and suggests that there exists a neural network in SI (the primary sensory cortex) for haptic working memory no matter whether the difference in features of memoranda needs to be memorized in the task or not. Over 400 SI neurons were also recorded in monkeys well-trained to discriminate two memoranda in the haptic-haptic DMS task for comparison of delay firing of SI neurons between the two different working memory tasks used in this study. The similarity observed in those two situations suggests that working memory uses already-existing memory apparatus by activating it temporarily. Our data also suggest that, through training (repetitive exposure to the stimulus), SI neurons may increase their involvement in the working memory of the memorandum.

Cholinergic modulation of the CAN current may adjust neural dynamics for active memory maintenance, spatial navigation and time-compressed replay

Suppression of cholinergic receptors and inactivation of the septum impair short-term memory, and disrupt place cell and grid cell activity in the medial temporal lobe (MTL). Location-dependent hippocampal place cell firing during active waking, when the acetylcholine level is high, switches to time-compressed replay activity during quiet waking and slow-wave-sleep (SWS), when the acetylcholine level is low. However, it remains largely unknown how acetylcholine supports short-term memory, spatial navigation, and the functional switch to replay mode in the MTL. In this paper, we focus on the role of the calcium-activated non-specific cationic (CAN) current which is activated by acetylcholine. The CAN current is known to underlie persistent firing, which could serve as a memory trace in many neurons in the MTL. Here, we review the CAN current and discuss possible roles of the CAN current in short-term memory and spatial navigation. We further propose a novel theoretical model where the CAN current switches the hippocampal place cell activity between real-time and time-compressed sequential activity during encoding and consolidation, respectively.

Neurogliaform and Ivy Cells: A Major Family of nNOS Expressing GABAergic Neurons.

Neurogliaform and Ivy cells are members of an abundant family of neuronal nitric oxide synthase (nNOS) expressing GABAergic interneurons found in diverse brain regions. These cells have a defining dense local axonal plexus, and display unique synaptic properties including a biphasic postsynaptic response with both a slow GABAA component and a GABAB component following even a single action potential. The type of transmission displayed by these cells has been termed “volume transmission,” distinct from both tonic and classical synaptic transmission. Electrical connections are also notable in that, unlike other GABAergic cell types, neurogliaform family cells will form gap junctions not only with other neurogliaform cells, but also with non-neurogliaform family GABAergic cells. In this review, we focus on neurogliaform and Ivy cells throughout the hippocampal formation, where recent studies highlight their role in feedforward inhibition, uncover their ability to display a phenomenon called persistent firing, and reveal their modulation by opioids. The unique properties of this family of cells, their abundance, rich connectivity, and modulation by clinically relevant drugs make them an attractive target for future studies in vivo during different behavioral and pharmacological conditions.

Effects of acetylcholine on neuronal properties in entorhinal cortex.

The entorhinal cortex (EC) receives prominent cholinergic innervation from the medial septum and the vertical limb of the diagonal band of Broca (MSDB). To understand how cholinergic neurotransmission can modulate behavior, research has been directed toward identification of the specific cellular mechanisms in EC that can be modulated through cholinergic activity. This review focuses on intrinsic cellular properties of neurons in EC that may underlie functions such as working memory, spatial processing, and episodic memory. In particular, the study of stellate cells (SCs) in medial entorhinal has resulted in discovery of correlations between physiological properties of these neurons and properties of the unique spatial representation that is demonstrated through unit recordings of neurons in medial entorhinal cortex (mEC) from awake-behaving animals. A separate line of investigation has demonstrated persistent firing behavior among neurons in EC that is enhanced by cholinergic activity and could underlie working memory. There is also evidence that acetylcholine plays a role in modulation of synaptic transmission that could also enhance mnemonic function in EC. Finally, the local circuits of EC demonstrate a variety of interneuron physiology, which is also subject to cholinergic modulation. Together these effects alter the dynamics of EC to underlie the functional role of acetylcholine in memory.

A novel coding mechanism for social vocalizations in the lateral amygdala

The amygdala plays a central role in evaluating the significance of acoustic signals and coordinating the appropriate behavioral responses. To understand how amygdalar responses modulate auditory processing and drive emotional expression, we assessed how neurons respond to and encode information that is carried within complex acoustic stimuli. We characterized responses of single neurons in the lateral nucleus of the amygdala to social vocalizations and synthetic acoustic stimuli in awake big brown bats. Neurons typically responded to most of the social vocalizations presented (mean = nine of 11 vocalizations) but differentially modulated both firing rate and response duration. Surprisingly, response duration provided substantially more information about vocalizations than did spike rate. In most neurons, variation in response duration depended, in part, on persistent excitatory discharge that extended beyond stimulus duration. Information in persistent firing duration was significantly greater than in spike rate, and the majority of neurons displayed more information in persistent firing, which was more likely to be observed in response to aggressive vocalizations (64%) than appeasement vocalizations (25%), suggesting that persistent firing may relate to the behavioral context of vocalizations. These findings suggest that the amygdala uses a novel coding strategy for discriminating among vocalizations and underscore the importance of persistent firing in the general functioning of the amygdala.

Ivy and Neurogliaform Interneurons Are a Major Target of μ-Opioid Receptor Modulation

μ-Opioid receptors (μORs) are selectively expressed on interneurons in area CA1 of the hippocampus. Fast-spiking, parvalbumin-expressing, basket cells express μORs, but circumstantial evidence suggests that another major, unidentified, GABAergic cell class must also be modulated by μORs. Here we report that the abundant, dendritically targeting, neurogliaform family of cells (Ivy and neurogliaform cells) is a previously unrecognized target of direct modulation by μORs. Ivy and neurogliaform cells are not only numerous but also have unique properties, including promiscuous gap junctions formed with various interneuronal subtypes, volume transmission, and the ability to produce a postsynaptic GABA(B) response after a single presynaptic spike. Using a mouse line expressing green fluorescent protein under the neuropeptide Y promoter, we find that, across all layers of CA1, activation of μORs hyperpolarizes Ivy and neurogliaform cells. Furthermore, paired recordings between synaptically coupled Ivy and pyramidal cells show that Ivy cell terminals are dramatically inhibited by μOR activation. Effects in Ivy and neurogliaform cells are seen at similar concentrations of agonist as those producing inhibition in fast-spiking parvalbumin basket cells. We also report that Ivy cells display the recently described phenomenon of persistent firing, a state of continued firing in the absence of continued input, and that induction of persistent firing is inhibited by μOR activation. Together, these findings identify a major, previously unrecognized, target of μOR modulation. Given the prominence of this cell type in and beyond CA1, as well as its unique role in microcircuitry, opioid modulation of neurogliaform cells has wide implications.

Muscarinic receptor activation enables persistent firing in pyramidal neurons from superficial layers of dorsal perirhinal cortex

Persistent-firing neurons in the entorhinal cortex (EC) and the lateral nucleus of the amygdala (LA) continue to discharge long after the termination of the original, spike-initiating current. An emerging theory proposes that endogenous persistent firing helps support a transient memory system. This study demonstrated that persistent-firing neurons are also prevalent in rat perirhinal cortex (PR), which lies immediately adjacent to and is reciprocally connected with EC and LA. Several characteristics of persistent-firing neurons in PR were similar to those previously reported in LA and EC. Persistent firing in PR was enabled by the application of carbachol, a nonselective cholinergic agonist, and it was induced by injecting a suprathreshold current or by stimulating suprathreshold excitatory synaptic inputs to the neuron. Once induced, persistent firing lasted for seconds to minutes. Persistent firing could always be terminated by a sufficiently large and prolonged hyperpolarizing current; it was prevented by antagonists of muscarinic cholinergic receptors (mAChRs); and it was blocked by flufenamic acid. The latter has been suggested to inhibit a Ca(2+) -activated nonspecific cation conductance (G(CAN) ) that normally furnishes the sustained depolarization during persistent firing. In many PR neurons, the discharge rate during persistent firing was a graded function of depolarizing and/or hyperpolarizing inputs. Persistent firing was not prevented by blocking fast excitatory and inhibitory synaptic transmission, demonstrating that it can be generated endogenously. We suggest that persistent-firing neurons in PR, EC, LA, and certain other brain regions may cooperate in support of a transient-memory system.

Alison Munro Elliman

Within the dorsal lateral geniculate nucleus (dLGN) of the thalamus, retinal ganglion cell (RGC) projections excite thalamocortical (TC) cells that in turn relay visual information to the cortex. Local interneurons...

Spatial gradients and multidimensional dynamics in a neural integrator circuit

In a neural integrator, the variability and topographical organization of neuronal firing rate persistence can provide information about the circuit’s functional architecture. Here we use optical recording to measure the time constant of decay of persistent firing (“persistence time”) across a population of neurons comprising the larval zebrafish oculomotor velocity-to-position neural integrator. We find extensive persistence time variation (10-fold; coefficients of variation 0.58–1.20) across cells within individual larvae. We also find that the similarity in firing between two neurons decreased as the distance between them increased and that a gradient in persistence time was mapped along the rostrocaudal and dorsoventral axes. This topography is consistent with the emergence of persistence time heterogeneity from a circuit architecture in which nearby neurons are more strongly interconnected than distant ones. Collectively, our results can be accounted for by integrator circuit models characterized by multiple dimensions of slow firing rate dynamics.

Variability of spike firing during theta-coupled replay of memories in a simulated attractor network

Simulation work has recently shown that attractor networks can reproduce Poisson-like variability of single cell spiking, with coefficient of variation (Cv2) around unity, consistent with cortical data. However, the use of local variability (Lv) measures has revealed area- and layer-specific deviations from Poisson-like firing. In order to test these findings in silico we used a biophysically detailed attractor network model. We show that Lv well above 1, specifically found in superficial cortical layers and prefrontal areas, can indeed be reproduced in such networks and is consistent with periodic replay rather than persistent firing. The memory replay at the theta time scale provides a framework for a multi-item memory storage in the model.This article is part of a Special Issue entitled Neural Coding.