Dynamics of spontaneous activity in random networks with multiple neuron subtypes and synaptic noise

During slow-wave sleep, brain electrical activity is dominated by the slow (< 1 Hz) electroencephalogram (EEG) oscillations characterized by the periodic transitions between active (or Up) and silent (or Down) states in the membrane voltage of the cortical and thalamic neurons. Sleep slow oscillation is believed to play critical role in consolidation of recent memories. Past computational studies, based on the Hodgkin-Huxley type neuronal models, revealed possible intracellular and network mechanisms of the neuronal activity during sleep, however, they failed to explore the large-scale cortical network dynamics depending on collective behavior in the large populations of neurons. In this new study, we developed a novel class of reduced discrete time spiking neuron models for large-scale network simulations of wake and sleep dynamics. In addition to the spiking mechanism, the new model implemented nonlinearities capturing effects of the leak current, the Ca²⁺ dependent K⁺ current and the persistent Na⁺ current that were found to be critical for transitions between Up and Down states of the slow oscillation. We applied the new model to study large-scale two-dimensional cortical network activity during slow-wave sleep. Our study explained traveling wave dynamics and characteristic synchronization properties of transitions between Up and Down states of the slow oscillation as observed in vivo in recordings from cats. We further predict a critical role of synaptic noise and slow adaptive currents for spike sequence replay as found during sleep related memory consolidation.     

Neuronal plasticity in thalamocortical networks during sleep and waking oscillations

Spontaneous brain oscillations during states of vigilance are associated with neuronal plasticity due to rhythmic spike bursts and spike trains fired by thalamic and neocortical neurons during low-frequency rhythms that characterize slow-wave sleep and fast rhythms occurring during waking and REM sleep. Intracellular recordings from thalamic and related cortical neurons in vivo demonstrate that, during natural slow-wave sleep oscillations or their experimental models, both thalamic and cortical neurons progressively enhance their responsiveness. This potentiation lasts for several minutes after the end of oscillatory periods. Cortical neurons display self-sustained activity, similar to responses evoked during previous epochs of stimulation, despite the fact that thalamic neurons remain under a powerful hyperpolarizing pressure. These data suggest that, far from being a quiescent state during which the cortex and subcortical structures are globally inhibited, slow-wave sleep may consolidate memory traces acquired during wakefulness in corticothalamic networks. Similar phenomena occur as a consequence of fast oscillations during brain-activated states.     

The dynamical stability of reverberatory neural circuits

The concept of reverberation proposed by Lorente de Nó and Hebb is key to understanding strongly recurrent cortical networks. In particular, synaptic reverberation is now viewed as a likely mechanism for the active maintenance of working memory in the prefrontal cortex. Theoretically, this has spurred a debate as to how such a potentially explosive mechanism can provide stable working-memory function given the synaptic and cellular mechanisms at play in the cerebral cortex. We present here new evidence for the participation of NMDA receptors in the stabilization of persistent delay activity in a biophysical network model of conductance-based neurons. We show that the stability of working-memory function, and the required NMDA/AMPA ratio at recurrent excitatory synapses, depend on physiological properties of neurons and synaptic interactions, such as the time constants of excitation and inhibition, mutual inhibition between interneurons, differential NMDA receptor participation at excitatory projections to pyramidal neurons and interneurons, or the presence of slow intrinsic ion currents in pyramidal neurons. We review other mechanisms proposed to enhance the dynamical stability of synaptically generated attractor states of a reverberatory circuit. This recent work represents a necessary and significant step towards testing attractor network models by cortical electrophysiology.     

Active neocortical processes during quiescent sleep

The neocortex and the thalamus constitute a unified oscillatory machine during different states of vigilance. The cortically generated slow sleep oscillation has the virtue of grouping other sleep rhythms, including those arising in the thalamus, within complex wave-sequences. Despite the coherent oscillatory activity in corticothalamic circuits, on the functional side there is dissociation between thalamus and neocortex during sleep. While dorsal thalamic neurons undergo inhibitory processes induced by prolonged spikebursts of GABAergic thalamic reticular neurons, the cortex displays, periodically, a rich spontaneous activity and preserves the capacity to process internally generated signals. Simultaneous intracellular recordings from thalamic and cortical neurons show that short-term plasticity processes occur after prolonged and rhythmic spike-bursts fired by thalamic and cortical neurons during slow-wave sleep oscillations. This may serve to support resonant phenomena and reorganize corticothalamic circuitry.     

Transcranial electrical currents to probe EEG brain rhythms and memory consolidation during sleep in humans

Previously the application of a weak electric anodal current oscillating with a frequency of the sleep slow oscillation (～0.75 Hz) during non-rapid eye movement sleep (NonREM) sleep boosted endogenous slow oscillation activity and enhanced sleep-associated memory consolidation. The slow oscillations occurring during NonREM sleep and theta oscillations present during REM sleep have been considered of critical relevance for memory formation. Here transcranial direct current stimulation (tDCS) oscillating at 5 Hz, i.e., within the theta frequency range (theta-tDCS) is applied during NonREM and REM sleep. Theta-tDCS during NonREM sleep produced a global decrease in slow oscillatory activity conjoint with a local reduction of frontal slow EEG spindle power (8-12 Hz) and a decrement in consolidation of declarative memory, underlining the relevance of these cortical oscillations for sleep-dependent memory consolidation. In contrast, during REM sleep theta-tDCS appears to increase global gamma (25-45 Hz) activity, indicating a clear brain state-dependency of theta-tDCS. More generally, results demonstrate the suitability of oscillating-tDCS as a tool to analyze functions of endogenous EEG rhythms and underlying endogenous electric fields as well as the interactions between EEG rhythms of different frequencies.     

Serotonin and Prefrontal Cortex Function: Neurons,Networks, and Circuits

Higher-order executive tasks such as learning, working memory, and behavioral flexibility depend on the prefrontal cortex (PFC), the brain region most elaborated in primates. The prominent innervation by serotonin neurons and the dense expression of serotonergic receptors in the PFC suggest that serotonin is a major modulator of its function. The most abundant serotonin receptors in the PFC, 5-HT1A, 5-HT2A and 5-HT3A receptors, are selectively expressed in distinct populations of pyramidal neurons and inhibitory interneurons, and play a critical role in modulating cortical activity and neural oscillations (brain waves). Serotonergic signaling is altered in many psychiatric disorders such as schizophrenia and depression, where parallel changes in receptor expression and brain waves have been observed. Furthermore, many psychiatric drug treatments target serotonergic receptors in the PFC. Thus, understanding the role of serotonergic neurotransmission in PFC function is of major clinical importance. Here, we review recent findings concerning the powerful influences of serotonin on single neurons, neural networks, and cortical circuits in the PFC of the rat, where the effects of serotonin have been most thoroughly studied.     

Maturation of GABAergic Inhibition Promotes Strengthening of Temporally Coherent Inputs among Convergent Pathways

Spike-timing-dependent plasticity (STDP), a form of Hebbian plasticity, is inherently stabilizing. Whether and how GABAergic inhibition influences STDP is not well understood. Using a model neuron driven by converging inputs modifiable by STDP, we determined that a sufficient level of inhibition was critical to ensure that temporal coherence (correlation among presynaptic spike times) of synaptic inputs, rather than initial strength or number of inputs within a pathway, controlled postsynaptic spike timing. Inhibition exerted this effect by preferentially reducing synaptic efficacy, the ability of inputs to evoke postsynaptic action potentials, of the less coherent inputs. In visual cortical slices, inhibition potently reduced synaptic efficacy at ages during but not before the critical period of ocular dominance (OD) plasticity. Whole-cell recordings revealed that the amplitude of unitary IPSCs from parvalbumin positive (Pv+) interneurons to pyramidal neurons increased during the critical period, while the synaptic decay time-constant decreased. In addition, intrinsic properties of Pv+ interneurons matured, resulting in an increase in instantaneous firing rate. Our results suggest that maturation of inhibition in visual cortex ensures that the temporally coherent inputs (e.g. those from the open eye during monocular deprivation) control postsynaptic spike times of binocular neurons, a prerequisite for Hebbian mechanisms to induce OD plasticity.     

Role of the basal ganglia in the occurrence of paradoxical sleep dreams (hypothetical mechanism)

A hypothetical mechanism of the basal ganglia involvement in the occurrence of paradoxical sleep dreams and rapid eye movements is proposed. According to this mechanism, paradoxical sleep is provided by facilitation of activation of cholinergic neurons in the pedunculopontine nucleus as a result of suppression of their inhibition from the output basal ganglia nuclei. This disinhibition is promoted by activation of dopaminergic cells by pedunculopontine neurons, subsequent rise in dopamine concentration in the input basal ganglia structure. striatum, and modulation of the efficacy of cortico-striatal inputs. In the absence of signals from retina, a disinhibition of neurons in the pedunculopontine nucleus and superior colliculus allows them to excite neurons in the lateral geniculate body and other thalamic nuclei projecting to the primary and higher visual cortical areas, prefrontal cortex and back into the striatum. Dreams as visual images and "motor hallucinations" are the result of an increase in activity of definitely selected groups of thalamic and neocortical neurons. This selection is caused by modifiable action of dopamine on long-term changes in the efficacy of synaptic transmission during circulation of signals in closed interconnected loops, each of which includes one of the visual cortical areas (motor cortex), one of the thalamic nuclei, limbic and one of the visual areas (motor area) of the basal ganglia. pedunculopontine nucleus, and superior colliculus. Simultaneous modification and modulation of synapses in diverse units of neuronal loops is provided by PGO waves. Disinhibition of superioir colliculus neurons and their excitation by pedunculopontine nucleus lead to an appearance of rapid eye movements during paradoxical sleep.     

Circadian rhythms and memory: not so simple as cogs and gears

The influence of circadian rhythms on memory has long been studied; however, the molecular prerequisites for their interaction remain elusive. The hippocampus, which is a region of the brain important for long‐term memory formation and temporary maintenance, shows circadian rhythmicity in pathways central to the memory‐consolidation process. As neuronal plasticity is the translation of numerous inputs, illuminating the direct molecular links between circadian rhythms and memory consolidation remains a daunting task. However, the elucidation of how clock genes contribute to synaptic plasticity could provide such a link. Furthermore, the idea that memory training could actually function as a zeitgeber for hippocampal neurons is worth consideration, based on our knowledge of the entrainment of the circadian clock system. The integration of many inputs in the hippocampus affects memory consolidation at both the cellular and the systems level, leaving the molecular connections between circadian rhythmicity and memory relatively obscure but ripe for investigation.     

System principles in the organization of neurons carrying out cortical inhibition

Some new data on neuronal and synaptic organization of sensorimotor cortical area in cat are obtained by a complex of morphological and electrophysiological methods. These data permit considering that direct afferent inhibition is ensured by thalamo-cortical neurons and neurons forming the callosal and association links. The recurrent and lateral inhibition are structurally realized through the ascending recurrent axon collaterals of pyramidal neurons forming links either with short-axon or with long-axon interneurons. Cortico-thalamic (cortico-fugal) inhibition may be performed either via descending cortico-thalamic neurons or via cortico-cortical ipsi- and contralateral neurons. The above mentioned neuronal chains may be considered as structural elements of more complex neuronal sets which ensure the inhibition at the cortical inputs, outputs and intracortically.     

Modeling the effect of sleep regulation on a neural mass model

In mammals, sleep is categorized by two main sleep stages, rapid eye movement (REM) and non-REM (NREM) sleep that are known to fulfill different functional roles, the most notable being the consolidation of memory. While REM sleep is characterized by brain activity similar to wakefulness, the EEG activity changes drastically with the emergence of K-complexes, sleep spindles and slow oscillations during NREM sleep. These changes are regulated by circadian and ultradian rhythms, which emerge from an intricate interplay between multiple neuronal populations in the brainstem, forebrain and hypothalamus and the resulting varying levels of neuromodulators. Recently, there has been progress in the understanding of those rhythms both from a physiological as well as theoretical perspective. However, how these neuromodulators affect the generation of the different EEG patterns and their temporal dynamics is poorly understood. Here, we build upon previous work on a neural mass model of the sleeping cortex and investigate the effect of those neuromodulators on the dynamics of the cortex and the corresponding transition between wakefulness and the different sleep stages. We show that our simplified model is sufficient to generate the essential features of human EEG over a full day. This approach builds a bridge between sleep regulatory networks and EEG generating neural mass models and provides a valuable tool for model validation.     

Study of role of inhibitory interneurons in mechanisms of regulation of sensory synapses formed by thalamic and cortical inputs on pyramidal cells of the dorsolateral amygdala nucleus

The work deals with study of role of inhibitory interneurons in the process of regulation of sensory currents converging on soma of pyramidal cells of the dorsolateral amygdala nucleus as well as of role of these interneurons in mechanism of regulation of plasticity of amygdala synapses. It has been shown that the part of the spontaneous inhibitory postsynaptic currents recorded on the dorsolateral amygdala pyramidal cells is relatively high and amounts to about a half of the total amount of the recorded events. Analysis of the evoked postsynaptic responses has shown the interneurons to regulate activity and duration of these responses due to the postsynaptic membrane hyperpolarization as a result of activation of GABA_A-receptors. Also studied was role of interneurons in providing mechanisms of the long-term potentiation of the synaptic responses evoked by stimulation of cortical and thalamic inputs. Block of effect of interneurons with help of picrotoxin has been shown to lead to an increase of evoked potentiation of synaptic responses.     

Hippocampal ripples and memory consolidation

During slow wave sleep and quiet wakefulness, the hippocampus generates high frequency field oscillations (ripples) during which pyramidal neurons replay previous waking activity in a temporally compressed manner. As a result, reactivated firing patterns occur within shorter time windows propitious for synaptic plasticity within the hippocampal network and in downstream neocortical structures. This is consistent with the long-held view that ripples participate in strengthening and reorganizing memory traces, possibly by mediating information transfer to neocortical areas. Recent studies have confirmed that ripples and associated neuronal reactivations play a causal role in memory consolidation during sleep and rest. However, further research will be necessary to better understand the neurophysiological mechanisms of memory consolidation, in particular the selection of reactivated assemblies, and the functional specificity of awake ripples.     

Perisomatic inhibition and cortical circuit dysfunction in schizophrenia

Deficits of cognitive control in schizophrenia are associated with altered gamma oscillations in the prefrontal cortex. Paralbumin basket interneurons, which innervate the perisomatic region of pyramidal neurons, appear to play a key role in generating cortical gamma oscillations. In the prefrontal cortex of subjects with schizophrenia, alterations are present in both pre- and post-synaptic markers of the strength of GABA inputs from parvalbumin basket neurons to pyramidal neurons. These alterations may contribute to the neural substrate for impaired gamma oscillations in schizophrenia.     

Norepinephrine-induced expression of cytokines in isolated biventricular working rat hearts

Whereas ATP consumption increases with neural activity and is buffered by phosphocreatine (PCr), it is not known whether PCr synthesis by ubiquitous mitochondrial creatine kinase (uMtCK) supports energy metabolism in all neurons. To explore the possibility that uMtCK expression in neurons is modulated by activity and during development, we used immunocytochemistry to detect uMtCK-containing mitochondria. In the adult brain, subsets of neurons including layer Va pyramidal cells, most thalamic nuclei, cerebellar Purkinje cells, olfactory mitral cells and hippocampal interneurons strongly express uMtCK. uMtCK is transiently expressed by a larger group of neurons at birth. Neurons in all cortical layers express uMtCK at birth (P0), but uMtCK is restricted to layer Va by P12. uMtCK is detected in cerebellar Purkinje cells at birth, but localization to dendrites is only observed after P5 and is maximal on P14. Hippocampal CA1 and CA3 pyramidal neurons contain uMtCK-positive mitochondria at birth, but this pattern becomes progressively restricted to interneurons. Seizures induced uMtCK expression in cortical layers II–III and CA1 pyramidal neurons. In the cortex, but not in CA1, blockade of seizures prevented the induction of uMtCK. These findings support the concept that uMtCK expression in neurons is (1) developmentally regulated in post-natal life, (2) constitutively restricted in the adult brain, and (3) regulated by activity in the cortex and hippocampus. This implies that mitochondrial synthesis of PCr is restricted to those neurons that express uMtCK and may contribute to protect these cells during periods of increased energy demands.     

PROX1: A Lineage Tracer for Cortical Interneurons Originating in the Lateral/Caudal Ganglionic Eminence and Preoptic Area

The homeobox-encoding gene Prox1 and its Drosophila homologue prospero are key regulators of cell fate-specification. In the developing rodent cortex a sparse population of cells thought to correspond to late-generated cortical pyramidal neuron precursors expresses PROX1. Using a series of transgenic mice that mark cell lineages in the subcortical telencephalon and, more specifically, different populations of cortical interneurons, we demonstrate that neurons expressing PROX1 do not represent pyramidal neurons or their precursors but are instead subsets of cortical interneurons. These correspond to interneurons originating in the lateral/caudal ganglionic eminence (LGE/CGE) and a small number of preoptic area (POA)-derived neurons. Expression within the cortex can be detected from late embryonic stages onwards when cortical interneurons are still migrating. There is persistent expression in postmitotic cells in the mature brain mainly in the outer cortical layers. PROX1^+ve interneurons express neurochemical markers such as calretinin, neuropeptide Y, reelin and vasoactive intestinal peptide, all of which are enriched in LGE/CGE- and some POA-derived cells. Unlike in the cortex, in the striatum PROX1 marks nearly all interneurons regardless of their origin. Weak expression of PROX1 can also be detected in oligodendrocyte lineage cells throughout the forebrain. Our data show that PROX1 can be used as a genetic lineage tracer of nearly all LGE/CGE- and subsets POA-derived cortical interneurons at all developmental and postnatal stages in vivo.     

Coupling of Thalamocortical Sleep Oscillations Are Important for Memory Consolidation in Humans

Sleep, specifically non-rapid eye movement (NREM) sleep, is thought to play a critical role in the consolidation of recent memories. Two main oscillatory activities observed during NREM, cortical slow oscillations (SO, 0.5–1.0Hz) and thalamic spindles (12–15Hz), have been shown to independently correlate with memory improvement. Yet, it is not known how these thalamocortical events interact, or the significance of this interaction, during the consolidation process. Here, we found that systemic administration of the GABAergic drug (zolpidem) increased both the phase-amplitude coupling between SO and spindles, and verbal memory improvement in humans. These results suggest that thalamic spindles that occur during transitions to the cortical SO Up state are optimal for memory consolidation. Our study predicts that the timely interactions between cortical and thalamic events during consolidation, contribute to memory improvement and is mediated by the level of inhibitory neurotransmission.     

Specificity in the functional architecture of primate prefrontal cortex

Multiple lines of evidence indicate that the performance of complex cognitive processes, such as those involving working memory, depend upon the functional properties of the circuitry of the prefrontal cortex (PFC). In primates, working memory has been proposed to be dependent upon the sustained activity of specific populations of PFC pyramidal cells, with this activity regulated by certain types of GABAergic interneurons. Thus, knowledge of the connectivity between PFC pyramidal cells and interneurons is crucial to the understanding the neural mechanisms that subserve working memory. This paper reviews recent findings that reveal specificity in the spatial organization, synaptic targets and postnatal development of pyramidal cells and interneurons in the primate prefrontal cortex, and considers the relevance of these findings for the neural circuitry that subserves working memory.     

Interneurons of the motor region of the neocortex]

Interneurons of motor area in the brain cortex have been studied in cats and monkeys. The greatest attention has been paid to pyramidal interneurons, among which six cell types have been described according to their axonal composition. Unlike stellate interneurons, all types of pyramidal interneurons possess less developed axonal collaterals. Interneuronal contacts are situated on dendrites or cell bodies of middle and large long-axonal pyramids. Functional role of cortical interneurons seems to be different. Some of them are of inhibitory nature (basket cells and, perhaps, other types of long-axonal stellate neurons), others are exciting elements. The latter include short-axonal stellate neurons and, perhaps, pyramidal interneurons. While comparing the cortex in cats and monkeys, it is evident that the neocortex in monkeys, especially its lower layers, is rich in pyramidal interneurons.