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PubMed1996

Regional cerebral blood flow in schizophrenia and the local circuit neurons hypothesis.

It has been suggested that nitric oxide, a nonconventional intra- and intercellular messenger involved in various biological and nervous system functions, may play a crucial role in a sophisticated cerebral microvascular system that regulates cerebral blood flow (CBF) under resting and activated conditions. A review of regional cerebral blood flow (rCBF) studies is schizophrenia shows that in schizophrenia patients this microvascular regulatory system may be deficient, failing to selectively raise rCBF in areas of the frontal and temporal lobes to respond to the physiological load placed on brain cells in these areas during certain neuropsychological tasks. A hypothesis about the more general role of local circuit neurons (LCNs) in the pathophysiology of schizophrenia is revised in light of recent information about both the characterization of LCN subpopulations and the interactions of multiple neuro-transmitter systems in midbrain, striatum, and cortex. This revision helps explain the subtle rCBF regulatory failure, as well as other failures in information processing, in schizophrenia patients and points to interneurons as likely sites for the action of both typical and atypical antipsychotic drugs.

Brain↗
PubMed2004

Neuronal circuits of the neocortex.

We explore the extent to which neocortical circuits generalize, i.e., to what extent can neocortical neurons and the circuits they form be considered as canonical? We find that, as has long been suspected by cortical neuroanatomists, the same basic laminar and tangential organization of the excitatory neurons of the neocortex is evident wherever it has been sought. Similarly, the inhibitory neurons show characteristic morphology and patterns of connections throughout the neocortex. We offer a simple model of cortical processing that is consistent with the major features of cortical circuits: The superficial layer neurons within local patches of cortex, and within areas, cooperate to explore all possible interpretations of different cortical input and cooperatively select an interpretation consistent with their various cortical and subcortical inputs.

Animals↗
PubMed1994

Prevention of Ca(2+)-mediated action potentials in GABAergic local circuit neurones of rat thalamus by a transient K+ current.

1. Neurones enzymatically dissociated from the rat dorsal lateral geniculate nucleus (LGN) were identified as GABAergic local circuit interneurones and geniculocortical relay cells, based upon quantitative analysis of soma profiles, immunohistochemical detection of GABA or glutamic acid decarboxylase, and basic electrogenic behaviour. 2. During whole-cell current-clamp recording, isolated LGN neurones generated firing patterns resembling those in intact tissue, with the most striking difference relating to the presence in relay cells of a Ca2+ action potential with a low threshold of activation, capable of triggering fast spikes, and the absence of a regenerative Ca2+ response with a low threshold of activation in local circuit cells. 3. Whole-cell voltage-clamp experiments demonstrated that both classes of LGN neurones possess at least two voltage-dependent membrane currents which operate in a range of membrane potentials negative to the threshold for generation of Na(+)-K(+)-mediated spikes: the T-type Ca2+ current (IT) and an A-type K+ current (IA). Taking into account the differences in membrane surface area, the average size of IT was similar in the two types of neurones, and interneurones possessed a slightly larger A-conductance. 4. In local circuit neurones, the ranges of steady-state inactivation and activation of IT and IA were largely overlapping (VH = 81.1 vs. -82.8 mV), both currents activated at around -70 mV, and they rapidly increased in amplitude with further depolarization. In relay cells, the inactivation curve of IT was negatively shifted along the voltage axis by about 20 mV compared with that of IA (Vh = -86.1 vs. -69.2 mV), and the activation threshold for IT (at -80 mV) was 20 mV more negative than that for IA. In interneurones, the activation range of IT was shifted to values more positive than that in relay cells (Vh = -54.9 vs. -64.5 mV), whereas the activation range of IA was more negative (Vh = -25.2 vs. -14.5 mV). 5. Under whole-cell voltage-clamp conditions that allowed the combined activation of Ca2+ and K+ currents, depolarizing voltage steps from -110 mV evoked inward currents resembling IT in relay cells and small outward currents indicative of IA in local circuit neurones. After blockade of IA with 4-aminopyridine (4-AP), the same pulse protocol produced IT in both types of neurones. Under current clamp, 4-AP unmasked a regenerative membrane depolarization with a low threshold of activation capable of triggering fast spikes in local circuit neurones.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1999

Local disinhibition of neocortical neuronal circuits causes augmentation of glutamatergic and GABAergic synaptic transmission in the rat neostriatum in vitro.

Intra- and extracellular recordings were performed to investigate the influence of local disinhibition of neocortical circuits on corticostriatal synaptic transmission. In rat brain slices with preserved corticostriatal connections, electrical stimulation of the neocortex elicited composed postsynaptic responses in neostriatal neurons consisting of glutamatergic excitatory postsynaptic potentials (EPSPs) and weakly expressed GABAA receptor-mediated inhibitory postsynaptic potentials (IPSPs). Following local application of the GABAA receptor antagonist bicuculline to the neocortex, neocortical neurons responded to intracortical stimulation with transient paroxysmal depolarizations. Simultaneously, the amplitude of neocortically evoked EPSPs recorded from neostriatal neurons was found to be enhanced without changes in duration. Similarly, the amplitude of IPSPs increased following disinhibition of neocortical circuits. In addition and in contrast to EPSPs, the duration of the IPSPs was found to be markedly prolonged. The results demonstrate that local disinhibition of neocortical neuronal circuits potentiates both excitatory and inhibitory synaptic transmission in striatal neurons. However, compared to AMPA receptor-mediated excitation, GABAA receptor-mediated inhibition becomes more efficient due to a marked prolongation of IPSPs. The pronounced augmentation of inhibition can be attributed to a strong activation of inhibitory interneurons within the striatum.

Animals↗
PubMed1989

Structure-function relationships in rat brainstem subnucleus interpolaris: III. Local circuit neurons.

Intracellular recording, electrical stimulation, receptive field mapping, and intracellular injection of horseradish peroxidase were used to assess the response properties, collateral projections, and morphology of 44 local circuit (LC) neurons in the subnucleus interpolaris (Sp Vi) of the trigeminal brainstem complex of the rat. LC neurons were defined as those with axons restricted to brainstem areas receiving trigeminal primary afferent fibers. Thus, none were antidromically activated from the thalamus, tectum, or cerebellum, and their axons could be seen terminating exclusively within the trigeminal brainstem complex or reticular formation. All neurons sampled were discharged by innocuous or noxious mechanical stimulation of a restricted portion of the face or mouth. They were classified functionally as sensitive to vibrissae (N = 22), nociceptors (N = 9), guard hairs (N = 7), hairy skin (N = 3), or periodontia (N = 3). Fifty percent of the stained neurons were vibrissa sensitive. Twenty-one of these 22 responded to deflection of only one vibrissa. The remaining functional groups also had small receptive fields. Intracellular staining revealed a consistency in vibrissa-sensitive LC morphology. Somata were small to medium in size and multipolar. Their axons had an initial transverse trajectory and gave off recurrent collaterals which arborized extensively in the region of the soma. The parent axon then bifurcated. One branch traveled rostrally to subnucleus principalis while the other branch traveled caudally to subnucleus caudalis. The branches periodically sent collaterals into regions of the trigeminal complex corresponding to the transverse position of the soma. Dendrites extended 440 +/- 140 microns rostrocaudally, forming a tree with a transverse perimeter of 459 +/- 226 microns. Distal dendrites were thin and sinuous, had few spines, and extensively arborized adjacent to the soma. They ended in multiple swellings connected by slender processes. The stereotyped morphology of vibrissa-sensitive LC neurons differed from the variable morphologies of LC neurons activated by nociceptors, guard hairs, hairy skin, or periodontia. Although no group of neurons in one of these categories displayed a distinguishing morphological characteristic, they collectively had features which distinguished them from the vibrissa-sensitive neurons. Non-vibrissa-responsive neurons generally had more expansive, but less circular, dendritic and recurrent axonal arbors; dendrites had more spines, and axons often sent endings into the reticular formation.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed2004

Reward, memory and substance abuse: functional neuronal circuits in the nucleus accumbens.

The firing patterns of neurons in the nucleus accumbens (NA) are examined and discussed with respect to different types of rewards and reward conditions. Comparisons and contrasts between individually identified NA neuron responses to cocaine self-administration and water reinforcement are presented with an emphasis on the fact that the same neurons do not respond in a phasic manner to both types of rewards. However, the phasic firing patterns, even though segregated for each reinforcer, are quite similar, suggesting that the method of differentiation between rewarding stimuli in the NA is by sorting cell populations into distinct ensembles or networks for each type of reinforcer. These neural networks appear to be 'tuned' to respond to particular associative behavioral contexts that couple response execution to reward delivery, and in the process acquire a reciprocity to firing within reward contexts. This maintains the specificity of each reinforcer for the response and associated stimuli that produce it and, makes it possible to attach different NA networks to different reinforcing circumstances. Comparisons of cocaine and water reinforced NA cell firing patterns during rapid switching between these two reinforcers suggests that the networks are negatively coupled and mutually inhibit each other to maintain accurate encoding of immediately experienced, as well as expected (i.e. future) reward contingencies.

Action Potentials↗
PubMed1988

Computer simulation of neuronal circuit models of rhythmic behavior in the electroencephalogram.

A computer program for modeling some features of the electroencephalogram (EEG) recorded by scalp electrodes in terms of the time- and space-dependent interactions of populations of neurons in different hypothetical brain configurations was developed. The input of the model consists of: (1) geometric and anatomic data characterizing the brain configuration; (2) physiologic features characterizing neurons; and (3) functions describing the time-dependent afferent impulses to the brain configuration under study. The output of the model consists of plots of selected intracellular and extracellular potentials as a function of time. In application of the model to various brain configurations, some configurations were sufficiently compact spatially that propagation times of action potentials between elements were either taken to be constant or were nearly independent of distance within the accuracy of the calculations. Other configurations represented cerebral cortex alone or a combined thalamocortical system in which many elements interacted via global interconnections. The basic requirement for rhythmic behavior is the existence of circuits containing inhibitory neurons. The characteristic frequencies of rhythmic oscillations are primarily determined by the local circuit parameters and are relatively independent of global circuit parameters.

Action Potentials↗
PubMed2001

A sequential protocol combining dual neuroanatomical tract-tracing with the visualization of local circuit neurons within the striatum.

We describe here an experimental approach designed to aid in the identification of complex brain circuits within the rat corpus striatum. Our aim was to characterize in a single section (i) striatal thalamic afferents, (ii) striatopallidal projection neurons and (iii) striatal local circuit interneurons. To this end, we have combined anterograde tracing using biotinylated dextran amine and retrograde neuroanatomical tracing with Fluoro-Gold. This dual tracing protocol was further implemented with the visualization of different subpopulations of striatal interneurons. The subsequent use of three different peroxidase substrates enabled us to unequivocally detect structures that were labeled within a three-color paradigm.

3,3'-Diaminobenzidine↗
PubMed2006

Systems-level modeling of neuronal circuits for leech swimming.

This paper describes a mathematical model of the neuronal central pattern generator (CPG) that controls the rhythmic body motion of the swimming leech. The systems approach is employed to capture the neuronal dynamics essential for generating coordinated oscillations of cell membrane potentials by a simple CPG architecture with a minimal number of parameters. Based on input/output data from physiological experiments, dynamical components (neurons and synaptic interactions) are first modeled individually and then integrated into a chain of nonlinear oscillators to form a CPG. We show through numerical simulations that the values of a few parameters can be estimated within physiologically reasonable ranges to achieve good fit of the data with respect to the phase, amplitude, and period. This parameter estimation leads to predictions regarding the synaptic coupling strength and intrinsic period gradient along the nerve cord, the latter of which agrees qualitatively with experimental observations.

Algorithms↗
PubMedDate not supplied

The computational basis of an identified neuronal circuit for elementary motion detection in dipterous insects.

Based on comparative anatomical studies and electrophysiological experiments, we have identified a conserved subset of neurons in the lamina, medulla, and lobula of dipterous insects that are involved in retinotopic visual motion direction selectivity. Working from the photoreceptors inward, this neuronal subset includes lamina amacrine (alpha) cells, lamina monopolar (L2) cells, the basket T-cell (T1 or beta), the transmedullary cell Tm1, and the T5 bushy T-cell. Two GABA-immunoreactive neurons, the transmedullary cell Tm9 and a local interneuron at the level of T5 dendrites, are also implicated in the motion computation. We suggest that these neurons comprise the small-field elementary motion detector circuits the outputs of which are integrated by wide-field lobula plate tangential cells. We show that a computational model based on the available data about these neurons is consistent with existing models of biological elementary motion detection, and present a comparable version of the Hassenstein-Reichardt (HR) correlation model. Further, by using the model to synthesize a generic tangential cell, we show that it can account for the responses of lobula plate tangential cells to a wide range of transient stimuli, including responses which cannot be predicted using the HR model. This computational model of elementary motion detection is the first which derives specifically from the functional organization of a subset of retinotopic neurons supplying the lobula plate. A key prediction of this model is that elementary motion detector circuits respond quite differently to small-field transient stimulation than do spatially integrated motion processing neurons as observed in the lobula plate. In addition, this model suggests that the retinotopic motion information provided to wide-field motion-sensitive cells in the lobula is derived from a less refined stage of processing than motion inputs to the lobula plate.

Animals↗
PubMed1988

New evidence for a gating action of norepinephrine in central neuronal circuits of mammalian brain.

Many previous studies have examined the effects of norepinephrine (NE) on neuronal responsiveness to synaptic inputs and putative transmitter substances and have described differential depressant actions of NE on stimulus evoked versus spontaneous discharge such that the "signal to noise" ratio of threshold responses was increased. In the present studies, similar experimental strategies employing a combination of microiontophoresis, single unit recording and afferent pathway stimulation in intact anesthetized and brain tissue slice preparations have revealed noradrenergic "gating" actions whereby weak or subthreshold synaptic stimuli can evoke threshold neuronal responses in the presence of iontophoretically applied NE or following electrical stimulation of the locus coeruleus. Overall, these results suggest that potentially threshold excitatory and inhibitory synaptic inputs may normally arrive at central neurons but appear weak or absent except during behavioral conditions favoring the synaptic release of NE. As such, these findings provide evidence that signal to noise ratio may not be the only potential modulatory action expressed by NE in noradrenergic target circuits of the mammalian brain.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2002

Retrograde trans-synaptic transfer of green fluorescent protein allows the genetic mapping of neuronal circuits in transgenic mice.

The function of the nervous system is a consequence of the intricate synaptic connectivity of its neurons. Our understanding of these highly complex networks has profited enormously from methods used over the past two decades that are based on the mechanical injection of tracer molecules into brain regions. We have developed a genetic system for the mapping of synaptic connections during development of the mammalian central nervous system and in the mature brain. It is based on the transsynaptic transfer of green fluorescent protein (GFP) in the brains of mice using a fusion protein with a nontoxic fragment of tetanus toxin (TTC) expressed in defined neurons. These transgenic mice allowed us to visualize neurons, at single-cell resolution, that are in synaptic contact by the detection of GFP in interconnected circuits. Targeted genetic expression with a specific promoter permitted us to transfer GFP to defined subsets of neurons and brain regions. GFP-TTC is coexpressed with a lacZ reporter gene to discriminate neurons that produce the tracer from cells that have acquired it transneuronally. The marker shows selective transfer in the retrograde direction. We have used electron microscopic detection of GFP to define the ultrastructural features of the system. Our work opens up a range of possibilities for brain slice and in vivo studies taking advantage of the fluorescence of GFP. We point the way toward the use of powerful multiphoton technology and set the stage for the transsynaptic transfer of other proteins in the brains of mice.

Animals↗
PubMed2000

Activation of specific neuronal circuits by corticotropin releasing hormone as indicated by c-fos expression and glucose metabolism.

The neuropeptide corticotropin releasing hormone (CRH) is the central nervous system (CNS) transducer of stressful stimuli. Endogenous CRH is released from neuronal terminals in several central nervous system regions-for example, amygdala and hypothalamus-during stress, and exogenous CRH administration mimics stress-related behaviors and hormonal patterns. However, whereas the role of endogenous CRH as a stress neuromodulator has been established, recent findings suggest that the peptide also functions to influence cognitive, emotional, and neuroimmune functions by modulating neuronal communication in a number of circuits. Although anatomic and pharmacologic approaches have provided evidence for this wider spectrum of CRH actions, the discrete regions and specific circuits activated by CRH have not been fully elucidated. In this article, the authors report on the use of two complementary methods to discern specific regions and cell groups activated by the administration of CRH. Glucose metabolism analysis provided quantitative measures of CRH-induced activation, but at a regional resolution; expression of the immediate early gene c-fos permitted a single cell resolution, but underestimated the neuroanatomic extent of CRH-induced activation. Overlapping regions activated using both methods delineated discrete cortical, limbic. and motor pathways. Importantly, cell groups activated by CRH included those possessing either or both members of the CRH receptor family, suggesting that both receptors may mediate the effects of the endogenous ligand. In summary, CRH activates a broad but selective array of neuronal structures belonging to cortical, limbic, and motor circuits. These findings indicate that stress-related release of this peptide may contribute to a spectrum of important modulations of CNS function.

Animals↗
PubMed2000

Optical probing of neuronal circuits with calcium indicators.

An experimental difficulty in unraveling circuits in the mammalian nervous system is the identification of postsynaptic targets of a given neuron. Besides ultrastructural reconstructions, simultaneous recordings from pairs of cells in brain slices have been used to identify connected neurons. We describe in this paper a technique using calcium imaging that allows rapid identification of potential postsynaptic targets. This method consists of stimulating one neuron ("trigger") while imaging a population of cells to detect which other neurons ("followers") are activated by the trigger. By using bulk-loading of calcium indicators in slices of mouse visual cortex, we demonstrate that neurons that display somatic calcium transients time-locked to the spikes of a trigger neuron can be monosynaptically connected to it. This technique could be applied to reconstruct and assay circuits in the central nervous system.

Animals↗
PubMed1984

Changes in neuronal circuits during insect metamorphosis.

During metamorphosis insects undergo dramatic changes in both form and behaviour. Cell birth and death, as well as neurone respecification all contribute to the overall reorganization of the nervous system. Within the visual and chemosensory processing areas of the insect brain large numbers of newly-generated adult neurones are incorporated into the larval nervous system. In the abdominal ganglia, however, identified larval neurones are retained to assume a new adult role. This respecification of motor neurone function involves not only the acquisition of a new target muscle, but also the reorganization of dendritic morphology, and alterations in the interconnections between neurones. For example, an identified abdominal motor neurone in the hawkmoth, Manduca sexta, grows new dendritic processes and changes its synaptic relationship with an abdominal stretch receptor such that an interaction that was inhibitory during larval life, becomes excitatory in the adult. In another example, identified sensory neurones that evoke a larval flexion behaviour, later participate in the defense gin trap reflex that is characteristic of the pupa. In both instances the formation of new pathways is a two-step process in that the new circuits do not become behaviourally relevant as they are formed, but instead are activated abruptly at the appropriate time. For the gin trap reflex an identified peptide hormone is responsible for activating the circuit.

Abdomen↗
PubMed2005

Transcranial magnetic and electrical stimulation compared: does TES activate intracortical neuronal circuits?

OBJECTIVE: To determine whether, and under which conditions, transcranial electrical stimulation (TES) and transcranial magnetic stimulation (TMS) can activate similar neuronal structures of the human motor cortex, as indicated by electromyographic recordings. METHODS: Focal TMS was performed on three subjects inducing a postero-anterior directed current (p-a), TES with postero-anteriorly (p-a) and latero-medially (l-m) oriented electrodes. We analyzed the onset latencies and amplitudes (single-pulse) and intracortical inhibition and excitation (paired-pulse). RESULTS: TMS p-a and TES p-a produced muscle responses with the same onset latency, while TES l-m led to 1.4-1.9 ms shorter latencies. Paired-pulse TMS p-a and TES p-a induced inhibition at short inter-stimulus intervals (ISI) (maximum: 2-3 ms) and facilitation at longer ISIs (maximum: 10 ms). No inhibition but a strong facilitation was obtained from paired-pulse TES l-m (ISIs 1-5 ms). CONCLUSIONS: Our findings support the hypothesis, that current direction is the most relevant factor in determining the mode of activation for both TMS and TES: TMS p-a and TES p-a are likely to activate the corticospinal neurons indirectly. In contrast, TES l-m may preferentially activate the corticospinal fibres directly, distant of the neuronal body. SIGNIFICANCE: TES is a suitable tool to induce intracortical inhibition and excitation.

Adult↗