Stereotypy in neocortical microcircuits

A central debate regarding neocortical function concerns the degree to which the underlying microcircuitry is stereotypically organized. Stereotypy reflects invariance in structure and function, as a result of common genetic templates and environmental conditions, whereas uniqueness can be caused by genetic variations, differences in environmental conditions as well as random processes. Stereotypy is an appealing concept because it provides strong support for determinism in the formation of neuronal microcircuits and in the relationship between their specific structure and function.     

GABAergic microcircuits in the neostriatum

The vast majority of neostriatal neurons and intrinsic intrastriatal synapses are GABAergic, the latter arising from axon collaterals of spiny projection neurons and from GABAergic interneurons. An important feature of the functional organization of the neostriatum has long been assumed to be the existence of a widespread lateral inhibitory network mediated by the axon collaterals of spiny projection neurons. However, these collateral connections have recently been demonstrated electrophysiologically to be relatively weak--in contrast to feedforward interneuronal inhibition, which exerts strong effects on spike timing in spiny neurons. These new data are incompatible with current "winner-take-all" models of lateral inhibitory function in the neostriatum, and they force a modification of established concepts of the functional roles of feedback inhibition in this nucleus.     

Synaptic pathways in neural microcircuits

The functions performed by different neural microcircuits depend on the anatomical and physiological properties of the various synaptic pathways connecting neurons. Neural microcircuits across various species and brain regions are similar in terms of their repertoire of neurotransmitters, their synaptic kinetics, their short-term and long-term plasticity, and the target-specificity of their synaptic connections. However, microcircuits can be fundamentally different in terms of the precise recurrent design used to achieve a specific functionality. In this review, which is part of the TINS Microcircuits Special Feature, we compare the connectivity designs in spinal, hippocampal, neocortical and cerebellar microcircuits, and discuss the different computational challenges that each microcircuit faces.     

Glomerular microcircuits in the olfactory bulb

Microcircuits in the olfactory bulb have long received particular attention from both experimentalists and theoreticians, due in part to an abundance of dendrodendritic interactions and other specialized modifications to the canonical cortical circuit architecture. Recent experimental and theoretical results have elucidated the mechanisms and function of these circuits and their presumed contributions to olfactory stimulus processing and odor perception. We here review the architecture and functionality of a prominent olfactory bulb microcircuit: the glomerular network.     

Cholinergic modulation of striatal microcircuits

The purpose of this review is to bridge the gap between earlier literature on striatal cholinergic interneurons and mechanisms of microcircuit interaction demonstrated with the use of newly available tools. It is well known that the main source of the high level of acetylcholine in the striatum, compared to other brain regions, is the cholinergic interneurons. These interneurons provide an extensive local innervation that suggests they may be a key modulator of striatal microcircuits. Supporting this idea requires the consideration of functional properties of these interneurons, their influence on medium spiny neurons, other interneurons, and interactions with other synaptic regulators. Here, we underline the effects of intrastriatal and extrastriatal afferents onto cholinergic interneurons and discuss the activation of pre‐ and postsynaptic muscarinic and nicotinic receptors that participate in the modulation of intrastriatal neuronal interactions. We further address recent findings about corelease of other transmitters in cholinergic interneurons and actions of these interneurons in striosome and matrix compartments. In addition, we summarize recent evidence on acetylcholine‐mediated striatal synaptic plasticity and propose roles for cholinergic interneurons in normal striatal physiology. A short examination of their role in neurological disorders such as Parkinson's, Huntington's, and Tourette's pathologies and dystonia is also included.     

Cortical microcircuits in schizophrenia--the dopamine hypothesis revisited

Strong evidence exists for disturbed functional connectivity of cortical microcircuits--particularly of prefrontal cortex. Dopamine, long implicated in antipsychotic drug effects, is crucially involved in optimizing signal-to-noise ratio of local cortical micro-circuits. This action of dopamine is achieved by means of D1- and D2-receptor-mediated effects on pyramidal and local circuit neurons, which mediate recurrent inhibition and thus contribute to the stability of cortical representations of external and internal stimuli. In schizophrenia, a diminished cortical dopamine D1/D2 activation ratio--in concert with altered GABAergic and glutamatergic transmission--appear to critically interfere with this process.     

Hippocampus, microcircuits and associative memory

The hippocampus is one of the most widely studied brain region. One of its functional roles is the storage and recall of declarative memories. Recent hippocampus research has yielded a wealth of data on network architecture, cell types, the anatomy and membrane properties of pyramidal cells and interneurons, and synaptic plasticity. Understanding the functional roles of different families of hippocampal neurons in information processing, synaptic plasticity and network oscillations poses a great challenge but also promises deep insight into one of the major brain systems. Computational and mathematical models play an instrumental role in exploring such functions. In this paper, we provide an overview of abstract and biophysical models of associative memory with particular emphasis on the operations performed by the diverse (inter)neurons in encoding and retrieval of memories in the hippocampus.     

Morphological evidence for local microcircuits in rat vestibular maculae

Previous studies suggested that intramacular, unmyelinated segments of vestibular afferent nerve fibers and their large afferent endings (calyces) on type I hair cells branch. Many of the branches (processes) contain vesicles and are presynaptic to type II hair cells, other processes, intramacular nerve fibers, and calyces. This study used serial section transmission electron microscopy and three-dimensional reconstruction methods to document the origins and distributions of presynaptic processes of afferents in the medial part of the adult rat utricular macula. The ultrastructural research focused on presynaptic processes whose origin and termination could be observed in a single micrograph. Results showed that calyces had 1) vesiculated, spine-like processes that invaginated type I cells and 2) other, elongate processes that ended on type II cells pre- as well as postsynaptically. Intramacular, unmyelinated segments of afferent nerve fibers gave origin to branches that were presynaptic to type II cells, calyces, calyceal processes, and other nerve fibers in the macula. Synapses with type II cells occurred opposite subsynaptic cisternae (C synapses); all other synapses were asymmetric. Vesicles were pleomorphic but were differentially distributed according to process origin. Small, clear-centered vesicles, ˜40–60 nm in diameter, predominated in processes originating from afferent nerve fibers and basal parts of calyces. Larger vesicles ˜70–120 nm in diameter having ˜40–80 nm electron-opaque cores were dominant in processes originating from the necks of calyces. Results are interpreted to indicate the existence of a complex system of intrinsic feedforward (postsynaptic)-feedback (presynaptic) connections in a network of direct and local microcircuits. The morphological findings support the concept that maculae dynamically preprocess linear acceleratory information before its transmission to the central nervous system. J. Comp. Neurol. 379:333–346, 1997. © 1997 Wiley-Liss, Inc.     

Biophysically detailed modelling of microcircuits and beyond

Realistic bottom-up modelling has been seminal to understanding which properties of microcircuits control their dynamic behaviour, such as the locomotor rhythms generated by central pattern generators. In this article of the TINS Microcircuits Special Feature, we review recent modelling work on the leech-heartbeat and lamprey-swimming pattern generators as examples. Top-down mathematical modelling also has an important role in analyzing microcircuit properties but it has not always been easy to reconcile results from the two modelling approaches. Most realistic microcircuit models are relatively simple and need to be made more detailed to represent complex processes more accurately. We review methods to add neuromechanical feedback, biochemical pathways or full dendritic morphologies to microcircuit models. Finally, we consider the advantages and challenges of full-scale simulation of networks of microcircuits.     

Changing microcircuits in the subplate of the developing cortex

Subplate neurons (SPNs) are a population of neurons in the mammalian cerebral cortex that exist predominantly in the prenatal and early postnatal period. Loss of SPNs prevents the functional maturation of the cerebral cortex. SPNs receive subcortical input from the thalamus and relay this information to the developing cortical plate and thereby can influence cortical activity in a feedforward manner. Little is known about potential feedback projections from the cortical plate to SPNs. Thus, we investigated the spatial distribution of intracortical synaptic inputs to SPNs in vitro in mouse auditory cortex by photostimulation. We find that SPNs fell into two broad classes based on their distinct spatial patterns of synaptic inputs. The first class of SPNs receives inputs from only deep cortical layers, while the second class of SPNs receives inputs from deep as well as superficial layers including layer 4. We find that superficial cortical inputs to SPNs emerge in the second postnatal week and that SPNs that receive superficial cortical input are located more superficially than those that do not. Our data thus suggest that distinct circuits are present in the subplate and that, while SPNs participate in an early feedforward circuit, they are also involved in a feedback circuit at older ages. Together, our results show that SPNs are tightly integrated into the developing thalamocortical and intracortical circuit. The feedback projections from the cortical plate might enable SPNs to amplify thalamic inputs to SPNs.     

Power-efficient simulation of detailed cortical microcircuits on SpiNNaker

Numerous brain structures are composed of distinct layers and such stratification has a profound effect on extracellular diffusion transport in these structures. We have derived a more general form of diffusion equation incorporating inhomogeneities in both the extracellular volume fraction (α) and diffusion permeability (θ). A numerical solution of this equation for a special case of layered environment was employed to analyze diffusion in the CA1 region of hippocampus where stratum pyramidale occupied by the bodies of principal neurons is flanked by stratum radiatum and stratum oriens. Extracellular diffusion in the CA1 region was measured in vitro by real-time iontophoretic and real-time pressure methods, and numerical analysis found that stratum pyramidale had a significantly smaller extracellular volume fraction (α = 0.127) and lower diffusion permeability (θ = 0.327) than the other two layers (α = 0.218, θ = 0.447). Stratum pyramidale thus functioned as a diffusion barrier for molecules attempting to cross it. We also demonstrate that unless the detailed properties of all layers are taken into account when diffusion experiments are interpreted, the extracted apparent parameters of the extracellular space lose their physical meaning and capacity to describe any individual layer. Such apparent parameters depend on diffusion distance and direction, giving a false impression of microscopic anisotropy and non-Gaussian behavior. This finding has implications for all diffusion mediated physiological processes as well as for other diffusion methods including integrative optical imaging and diffusion-weighted magnetic resonance imaging.     

Functional features of the rat subicular microcircuits studied in vitro

The subiculum has a strategic position in controlling hippocampal activity and is now receiving much experimental attention. However, information regarding this structure remains fragmented and there are important gaps in our knowledge between what we know about the subicular architecture and its biological function. In recent years a substantial amount of in vitro experimentation has explored many aspects of the functional organization of the subicular microcircuits. Here we review these recent findings. We aim to identify the rules that govern the operation of subicular microcircuits in vitro and to relate these to the role of the subiculum in the intact brain.     

Central inhibitory microcircuits controlling spike propagation into sensory terminals

The phenomenon of afferent presynaptic inhibition has been intensively studied in the sensory neurons of the chordotonal organ from the coxobasal joint (CBCO) of the crayfish leg. This has revealed that it has a number of discrete roles in these afferents, mediated by distinct populations of interneurons. Here we examine further the effect of presynaptic inhibition on action potentials in the CBCO afferents and investigate the nature of the synapses that mediate it. In the presence of picrotoxin, the action potential amplitude is increased and its half-width decreased, and a late depolarizing potential following the spike is increased in amplitude. Ultrastructural examination of the afferent terminals reveals that synaptic contacts on terminal branches are particularly abundant in the neuropil close to the main axon. Many of the presynaptic terminals contain small agranular vesicles, are of large diameter, and are immunoreactive for gamma-aminobutyric acid (GABA). These terminals are sometimes seen to make reciprocal connections with the afferents. Synaptic contacts from processes immunoreactive for glutamate are found on small-diameter afferent terminals. A few of the presynaptic processes contain numerous large granular vesicles and are immunoreactive for neither GABA nor glutamate. The effect that the observed reciprocal synapses might have was investigated by using a multicompartmental model of the afferent terminal.     

Cellular and field potential properties of epileptogenic hippocampal slices

Epileptogenic activity was induced in hippocampal slices by addition of penicillin (2.0 mM) to the binding medium. Field potential epileptiform events were recorded and single cell bursts studied with intracellular electrodes. Epileptogenic activity was seen in areas CA1 and CA3 of the slice, with bursts in CA3 always leading CA1 bursts; a cut between CA1 and CA3 abolished spontaneous bursting in CA1 but not in CA3. Increased [Mg²⁺] and decreased [Ca²⁺] abolished epileptiform discharge, thus demonstrating its dependence on synaptic activity; burst occurrence was also sensitive to [K⁺]. Measurements of single cell resting potentials, resistance, and time constant in CA1 cells revealed no difference between cells in normal medium and cells made epileptogenic by penicillin. Depolarization shifts in CA1 neurons during epileptogenesis did not behave like ‘giant EPSPs’ but rather were complexes to which depolarizing spike after-potentials, fast prepotentials, and underlying slow depolarizing events all contributed.     

Changes to interneuron-driven striatal microcircuits in a rat model of Parkinson's disease

Striatal interneurons play key roles in basal ganglia function and related disorders by modulating the activity of striatal projection neurons. Here we have injected rabies virus (RV) into either the rat substantia nigra pars reticulata or the globus pallidus and took advantage of the trans-synaptic spread of RV to unequivocally identify the interneurons connected to striatonigral- or striatopallidal-projecting neurons, respectively. Large numbers of RV-infected parvalbumin (PV+/RV+) and cholinergic (ChAT+/RV+) interneurons were detected in control conditions, and they showed marked changes following intranigral 6-hydroxydopamine injection. The number of ChAT+/RV+ interneurons innervating striatopallidal neurons increased concomitant with a reduction in the number of PV+/RV+ interneurons, while the two interneuron populations connected to striatonigral neurons were clearly reduced. These data provide the first evidence of synaptic reorganization between striatal interneurons and projection neurons, notably a switch of cholinergic innervation onto striatopallidal neurons, which could contribute to imbalanced striatal outflow in parkinsonian state.     

Dissecting functional connectivity of neuronal microcircuits: experimental and theoretical insights

Structure-function studies of neuronal networks have recently benefited from considerable progress in different areas of investigation. Advances in molecular genetics and imaging have allowed for the dissection of neuronal connectivity with unprecedented detail whereas in vivo recordings are providing much needed clues as to how sensory, motor and cognitive function is encoded in neuronal firing. However, bridging the gap between the cellular and behavioral levels will ultimately require an understanding of the functional organization of the underlying neuronal circuits. One way to unravel the complexity of neuronal networks is to understand how their connectivity emerges during brain maturation. In this review, we will describe how graph theory provides experimentalists with novel concepts that can be used to describe and interpret these developing connectivity schemes.     

Tuning the network: modulation of neuronal microcircuits in the spinal cord and hippocampus

Adaptation of an organism to its changing environment ultimately depends on the modification of neuronal activity. The dynamic interaction between cellular components within neuronal networks relies on fast synaptic interaction via ionotropic receptors. However, neuronal networks are also subject to modulation mediated by various metabotropic G-protein-coupled receptors that modify synaptic and neuronal function. Modulation increases the functional complexity of a network, because the same cellular components can produce different outputs depending on the behavioural state of the animal. This review, which is part of the TINS Microcircuits Special Feature, provides an overview of neuromodulation in two neuronal circuits that both produce oscillatory activity but differ fundamentally in function. Hippocampal circuits are compared with the spinal networks generating locomotion, with a view to exploring common principles of neuromodulatory activity.     

Transient microcircuits formed by subplate neurons and their role in functional development of thalamocortical connections

Subplate neurons are a transient population of neurons in the brain forming one of the first functional cortical circuits. Past experiments have demonstrated their importance in growth of thalamocortical afferents into the cortical plate and later segregation of thalamocortical afferents. Recently, subplate neurons have been shown to be required for the functional maturation of both thalamocortical connections and mature visual responses in visual cortex. These findings suggest that thalamocortical afferents might not segregate properly in the absence of subplate neurons because the thalamocortical synapse does not mature. Subplate neurons are unique in that they form a circuit that appears to promote synaptic scaling and maturation. Although the precise contribution of subplate neurons within the context of cortical development is unknown, they might play an early role in providing thalamic input to cortex that then interacts with learning rules governing synaptic strengthening at the thalamocortical synapse. Because they appear to play multiple key roles at different stages of development, subplate neurons might also play a role in the pathology of developmental disorders, such as epilepsy and schizophrenia.