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PubMed2005

Microcircuits in action--from CPGs to neocortex.

To understand the interface between global brain function and molecular neuroscience--that is, the microcircuit level--a major challenge. Such understanding is prerequisite if we are to account for neural function in cellular terms. Very few vertebrate microcircuits are yet understood because their analysis is demanding technically. In this review of the TINS Microcircuits Special Feature, we attempt to shed light on the problem by comparing the operation of four types of microcircuit, to identify common molecular and cellular components. Central pattern generator (CPG) networks underlying rhythmic movements and hippocampal microcircuits that generate gamma and theta rhythms are compared with the neocortical microcircuits used in cognitive tasks and a cerebellar network. The long-term goal is to identify the components of a molecular and synaptic tool kit for the design of different microcircuits.

Animals↗
PubMed2001

Environmental context modulates the ability of cocaine and amphetamine to induce c-fos mRNA expression in the neocortex, caudate nucleus, and nucleus accumbens.

We reported previously that environmental novelty enhances the acute psychomotor activating effects of amphetamine, its ability to induce behavioral sensitization, and its ability to induce c-fos mRNA in the striatum and other structures, relative to when amphetamine is given in the home cage. The purpose of the present experiment was 2-fold: to determine (1) whether environmental novelty has a similar effect on the ability of cocaine to induce c-fos mRNA, and (2) whether this effect is seen in neurologically-intact rats (in previous experiments we studied the intact hemisphere of rats with a unilateral 6-OHDA lesion). In the dorsal portion of the caudate putamen, core and shell of the nucleus accumbens, and in several cortical regions, both amphetamine (1.5 mg/kg) and cocaine (15 mg/kg) induced higher levels of c-fos mRNA expression when administered in a novel environment, relative to when they were administered in the home cage. The ability of environmental context to modulate psychostimulant drug-induced immediate early gene expression may be related to its ability to modulate forms of drug experience-dependent plasticity, such as behavioral sensitization.

Amphetamine↗
PubMed2002

The ability of amphetamine to evoke arc (Arg 3.1) mRNA expression in the caudate, nucleus accumbens and neocortex is modulated by environmental context.

The ability of amphetamine or cocaine to induce the expression of c-fos mRNA in a number of brain regions is greatly enhanced when these drugs are administered in a distinct and relatively novel environment, relative to when they are given in the home cage. The purpose of this study was to determine if environmental context has a similar effect on the ability of amphetamine to induce the expression of arc (also known as Arg 3.1), an "effector" immediate early gene (IEG) thought to play a direct role in cellular plasticity. Rats were administered either saline or amphetamine (0.5 mg/kg, i.v.), in their home cage or in a distinct test environment. Fifty minutes later, they were decapitated and their brains processed for in situ hybridization histochemistry. In the prefrontal cortex, caudate-putamen and core of the nucleus accumbens, amphetamine significantly increased arc mRNA expression under both conditions, but the level of expression was significantly enhanced when amphetamine was given in a distinct environment. In the shell of the nucleus accumbens amphetamine significantly increased the expression of arc mRNA only when it was administered in the distinct environment. Thus, the ability of amphetamine to induce the expression of arc varies as a function of the environmental context in which it is administered. This could contribute to the ability of environmental context to modulate forms of drug experience-dependent neuroplasticity, including behavioral sensitization.

Amphetamine↗
PubMed2003

Proliferation and death of conditionally immortalized neural cells from murine neocortex: p53 alters the ability of neuron-like cells to re-enter the cell cycle.

Neurons are distinctive in that they are generally considered to be permanently post-mitotic cells. The oncoprotein p53 is a key regulator in neuronal development, notably in cell proliferation and neuronal death. We hypothesize that p53 maintains the post-mitotic characteristic of differentiated neurons. New lines of conditionally immortalized cortical cells were generated to test this hypothesis. Populations of cells were obtained from the neocortices of dual transgenic mice that were null for p53 and expressed a temperature-sensitive SV40 large T antigen. At a permissive temperature (32 degrees C), the cells continued to proliferate and most expressed nestin and proteins associated with glia. At a non-permissive temperature (39 degrees C), the cells expressed cytoskeletal proteins associated with differentiated neurons such as microtubule associated protein 2 and neurofilament 200. Under permissive conditions, both p53(+/-) and p53(-/-) cells exhibited similar cycling behaviors; the length of the cell cycle was 13-15 h and >85% of the cells were actively cycling. In non-permissive conditions, most p53(+/-) cells stopped dividing, whereas the p53(-/-) cells continued to proliferate. The survival of the cells also differed. In the non-permissive conditions, many p53(+/-) cells died following treatment with a neurotoxin (ethanol, 400 mg/dl), whereas the p53(-/-) cells did not. After re-introduction to the permissive conditions, both cell lines expressed neuron-like characteristics, but only the p53(-/-) cells retained their ability to cycle. Therefore, p53-mediated activities appear to be involved in the proliferation, survival, and post-mitotic nature of neuron-like cells.

Animals↗
PubMed1997

The fates of the callosal neurons in neocortex after bisection of the corpus callosum, using the technique of retrograde neuronal labeling with two fluorescent dyes.

The fate of callosal neurons after callosotomy is yet unclear although this has become a common surgical procedure for intractable generalized epilepsies. Using retrograde neuronal labeling with two fluorescent dyes, we demonstrated that callosal neurons in the parietal cortex of the adult rat survive up to 20 weeks after callosotomy. Our data suggest that these neurons possess numerous ipsilateral axon collaterals with indispensable functions in the ipsilateral hemisphere.

Amidines↗
PubMed1999

Regulation of cyclic AMP level by progesterone in ovariectomized rat neocortex.

Exposure of neocortical slices to progesterone, without prior treatment with estrogen, augmented forskolin-induced cyclic AMP within 15 min. 30 nM progesterone produced approximately 1/2 the maximal effect but as little as 10 nM progesterone produced a detectable increase in cyclic AMP. When forskolin was replaced by dideoxyforskolin, an analog that does not directly stimulate adenylyl cyclase but shares many of its other actions, progesterone did not augment cyclic AMP. Progesterone also failed to affect increased cyclic AMP that followed exposure to norepinephrine or isoproterenol. The effect of progesterone upon cyclic AMP was also evident when tetrodotoxin was added to block voltage-dependent sodium channels, suggesting that intercellular communication that is dependent upon action potentials was not necessary. The effect of progesterone was at least partially blocked by antagonists of GABAA receptor action, suggesting the involvement of GABAA or GABAA-like receptors. The effect of progesterone was also not homogeneous over the neo cortex. While forskolin-stimulated cyclic AMP was augmented by progesterone in the parietal and occipital regions, it was suppressed in the frontal region. These results are envisioned as a progesterone action upon a small and perhaps compartmentalized component of the cellular cyclic AMP system, an effect that is made detectable in our whole-tissue assay by the well known ability of forskolin to potentiate many hormonal effects upon cyclic AMP.

Animals↗
PubMed2002

Arylalkylamines are a novel class of positive allosteric modulators at GABA(B) receptors in rat neocortex.

Using grease-gap recording from rat neocortical slices, the gamma-aminobutyric acid(B) (GABA(B)) receptor agonists baclofen (3-100 microM) and SKF 97541 (3-aminopropyl-methylphosphinic acid) (1-30 microM) elicited reversible and concentration-dependent hyperpolarizing responses, with EC(50) values of 10 and 3 microM, respectively. The hyperpolarizations were antagonised by the GABA(B) receptor antagonist Sch 50911 ((+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid) (1, 5 and 10 microM). Fendiline (N-[3,3-diphenylpropyl)-alpha-methylbenzylamine) (5-50 microM) and its congeners, prenylamine (N-[3,3-diphenylpropyl)-alpha-methylphenylethylamine) (10-100 microM) and F551 (N-[3,3-diphenylpropyl)-alpha-methyl-3-methoxybenzylamine) (1-30 microM) reversibly enhanced hyperpolarizing responses to the agonists; such effects were reduced by Sch 50911. These arylalkylamines produced leftward shifts of the concentration-response curves, with a marked increase in the maximal hyperpolarization obtained, compared with the agonists alone, F551 being the most potent. These findings suggest that these arylalkylamines represent a new class of positive modulators of GABA(B) receptor-mediated function.

Animals↗
PubMed2003

Potentiation of metabotropic GABAB receptors by L-amino acids and dipeptides in rat neocortex.

Selected neutral L-alpha-amino acids, and their dipeptides, were reversible, stereospecific, potentiators of GABA(B) receptor-mediated hyperpolarizing responses to baclofen (3-100 microM) in rat neocortical slices. These responses were sensitive to the GABA(B) receptor antagonist (+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid (Sch50911) (30 microM). Most potent were L-Leu, L-Ile and L-Phe, as were the dipeptides L-Phe-Phe and L-Phe-Leu, and less potent were L-Met, L-Val, L-Cys, L-Cystine, L-Tyr, L-Thr, L-Arg and L-Ser. Inactive were L-Trp, L-His, L-Lys and L-Pro. These potentiators gave leftward shifts of the baclofen concentration-response curves with a Hill slope of 2, and a marked increase in the maximal hyperpolarizing responses. Selected L-amino acids and dipeptides are a class of naturally occurring GABA(B) potentiators, which may be allosteric modulators.

Allosteric Regulation↗
PubMed2003

Hippocampal kindling epileptogenesis upregulates neuronal cyclooxygenase-2 expression in neocortex.

Recurrent and spontaneous seizures in epilepsy result from poorly defined cell signaling aberrations thought to include synaptic and extracellular matrix remodeling. Here we have used a rat hippocampal kindling model to study cyclooxygenase-2 (COX-2) gene expression in epileptogenesis. COX-2, encoded in an early-response gene, increases in a synaptic activity-dependent fashion and also during kainic acid-induced hippocampal damage. We found that during kindling, COX-2 induction occurred initially only in hippocampal neurons, and then spread to neocortical neurons. When rats were rekindled 34 days later, this spreading of COX-2 expression persisted. Induction of hippocampal and neocortical cytosolic phospholipase A(2) (cPLA(2)), an enzyme that catalyzes the synthesis of COX-2 substrate arachidonic acid (AA), occurred after 4 days of stimulation during kindling and rekindling. Moreover the COX-2 selective inhibitor nimesulide attenuated kindling development. We conclude that neuronal COX-2 gene induction and cPLA(2) activation are key signaling events in epileptogenesis.

Animals↗
PubMed2002

Inhibition of neuronal Ca(2+) influx by gabapentin and pregabalin in the human neocortex.

Gabapentin and pregabalin (S-(+)-3-isobutylgaba) produced concentration-dependent inhibitions of the K(+)-induced [Ca(2+)](i) increase in fura-2-loaded human neocortical synaptosomes (IC(50)=17 microM for both compounds; respective maximal inhibitions of 37 and 35%). The weaker enantiomer of pregabalin, R-(-)-3-isobutylgaba, was inactive. These findings were consistent with the potency of these drugs to inhibit [(3)H]-gabapentin binding to human neocortical membranes. The inhibitory effect of gabapentin on the K(+)-induced [Ca(2+)](i) increase was prevented by the P/Q-type voltage-gated Ca(2+) channel blocker omega-agatoxin IVA. The alpha 2 delta-1, alpha 2 delta-2, and alpha 2 delta-3 subunits of voltage-gated Ca(2+) channels, presumed sites of gabapentin and pregabalin action, were detected with immunoblots of human neocortical synaptosomes. The K(+)-evoked release of [(3)H]-noradrenaline from human neocortical slices was inhibited by gabapentin (maximal inhibition of 31%); this effect was prevented by the AMPA receptor antagonist NBQX (2,3-dioxo-6-nitro-1,2,3,4-tetrahydro[f]quinoxaline-7-sulphonamide). Gabapentin and pregabalin may bind to the Ca(2+) channel alpha 2 delta subunit to selectively attenuate depolarization-induced Ca(2+) influx of presynaptic P/Q-type Ca(2+) channels; this results in decreased glutamate/aspartate release from excitatory amino acid nerve terminals leading to a reduced activation of AMPA heteroreceptors on noradrenergic nerve terminals.

Acetates↗
PubMed2003

Perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin alters activity-dependent expression of BDNF mRNA in the neocortex and male rat sexual behavior in adulthood.

Dioxin and its related compounds are suspected to cause neurological and nueroendocrinological disruption in human and laboratory animal offspring upon in utero and lactational exposure during growth and development. We tested the hypothesis by utilizing Long-Evans Hooded rats that perinatal exposure to dioxins affects the neocortical function and expression of sexual behavior in adulthood. In the sexual behavior test, perinatal exposure to TCDD significantly reduced the number of mounts and intromissions. The mRNA semi-quantification in in situ hybridization showed that the mating stimulus in control males induced c-fos mRNA expression in the preoptic area (POA) and the brain derived neurotrophic factor (BDNF) mRNA upregulation in the frontal cortex. In contrast, perinatal exposure to TCDD lowered the upregulation of BDNF mRNA in the frontal cortex but not that of c-fos mRNA in the POA. The volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) was not affected. The results suggest that perinatal TCDD affects the neocortical function independently from the brain sexual differentiation and alters the expression of sexual behavior.

Animals↗
PubMed2001

Developmental characteristics of epileptiform activity in immature rat neocortex: a comparison of four in vitro seizure models.

New-onset seizures and epilepsy have a relatively high incidence in infants and children. A leading hypothesis to explain an increased seizure susceptibility of the immature nervous system involves ontogenetic changes in different neurotransmitter systems, such as specific glutamate and GABA receptors. However, few studies have directly tested this hypothesis in a systematic fashion, especially in neocortical structures, where seizures in pediatric patients frequently arise. The present study investigated developmental changes in epileptiform activity in rat neocortical slices from four age groups (postnatal days P4--7, P13--16, P23--26, P41--47) due to four pharmacological conditions (4-aminopyridine, low magnesium, picrotoxin, CGP-35348) that differentially modulate glutamate and GABA systems. A characteristic age-dependence of the incidence of epileptiform activity was observed. In all pharmacological conditions, no epileptiform activity occurred in neocortical slices from P4--7 rats. Interictal discharges, ictal events, and spreading depression had a maximal incidence at P13--16 and decreased progressively in later age groups. 4-Aminopyridine, low magnesium, and picrotoxin induced all types of epileptiform activity with a similar age-dependent pattern, despite minor differences in quantitative characteristics of epileptiform activity between these three conditions. The GABA(B) antagonist, CGP-35348, did not elicit epileptiform activity in any age group, but could potentiate synaptic potentials. These findings establish that isolated neocortical tissue intrinsically displays ontogenetic changes in seizure susceptibility independent of systemic factors. The similar age-dependent patterns of epileptiform activity with multiple drugs support a concept of global developmental changes in excitability not specifically linked to any particular neurotransmitter system.

4-Aminopyridine↗
PubMed2002

Age-dependent occurrence of synchronized population oscillation suggestive of a developing functional coupling between NMDA and ryanodine receptors in the neocortex.

Synchronized population oscillation of delta to alpha range frequencies was synaptically induced in rat visual cortex neurons, depending on (1) the extent of N-methyl-D-aspartate (NMDA) receptor activation, (2) occurrence of calcium-induced calcium release (CICR), and (3) the age of animals. In adult slices bathed with 0.1 mM Mg(2+), as white matter stimulation continued, solitary synaptic potentials gradually became enlarged and overridden by small wavelets oscillating at alpha range frequencies. The calcium store depeletor thapsigargin prevented appearance of these wavelets. When Mg(2+) block of NMDA receptors was intensified with 0.5 or 2.0 mM Mg(2+), the oscillation failed to be induced, but became inducible by caffeine, which facilitates CICR. NMDA receptor blockade abolished induction of the oscillation even under caffeine application. In immature slices, the induction of oscillation was possible only with 0.1 mM Mg(2+) and bath-applied caffeine, but failed with 0.5 mM Mg(2+) or without caffeine. The oscillation induced in immature tissue was smaller in amplitude and frequency (delta-theta; range) than in adult tissue (alpha range). Immature tissue thus requires more restricted conditions for inducing the oscillation. We propose that NMDA and ryanodine receptors become coupled during maturation to enhance synaptically induced intracellular calcium releases, thereby facilitating induction of the oscillation at later stages.

Age Factors↗
PubMed1998

Ontogeny of cation-Cl- cotransporter expression in rat neocortex.

Neuronal precursors and immature cortical neurons actively accumulate Cl- and as a consequence depolarize in response to GABAA receptor activation. With maturity, intracellular Cl- decreases resulting in a shift towards GABAA inhibition. These observations suggest that changes in expression of cation-Cl- cotransporters may have a significant role in the ontogeny of neuronal Cl- homeostasis. Using ribonuclease protection analysis and in situ hybridization we examined the developmental expression of all presently known members of the cation-Cl- cotransporter gene family in rat brain. Of the inwardly directed cotransporters, NKCC-1, NKCC-2, and NCC-1, only NKCC-1 was detected at significant levels in brain. NKCC-1 was expressed in neurons, appearing first in cortical plate but not in ventricular or subventricular zone. Expression levels peaked by the third postnatal week and were maintained into adulthood. The outwardly directed cotransporters, KCC-1 and KCC-2, demonstrated significantly different levels and time courses of expression. KCC-1 was expressed prenatally at very low levels which increased little over the course of development. In contrast, KCC-2 expression appeared perinatally and increased dramatically after the first week of postnatal life. Differential changes in expression of this gene family occurred during periods of critical shifts in chloride homeostasis and GABA response suggestive of a role in these processes. Furthermore the absence of expression of known inwardly directed cotransporters in Cl- accumulating neuroepithelia and lack of evidence for glial expression suggests that as yet unidentified members of this gene family may be involved in chloride homeostasis in immature neuronal precursors and neuroglia.

Animals↗
PubMed2001

Neuromodulatory control of interacting medial temporal lobe and neocortex in memory consolidation and working memory.

A model of the interacting medial temporal lobe and neocortical association areas is formulated and applied to memory consolidation and working memory. A simplified connectivity in terms of superassemblies and assemblies of neurons representing types and values, respectively, of object features is underlying the model. Realistic low-dimensional model neurons, developed in particular to take neuronal adaptation into account, are employed. Observed short- and long-term potentiation and depression of plastic synaptic couplings are incorporated. It is shown that memory consolidation by long-term potentiation, based on repeated activations of neocortical patterns, may be guided by neuromodulated dynamics of the medial temporal lobe via short-term couplings acting as pointers. Bifurcations, i.e. transitions between different modes of network dynamics, with respect to developing synaptic couplings are shown to depend on the adaptivity of excitatory neurons in the medial temporal lobe and thus to be under neuromodulatory control. At weak adaptivity, after an initial temporal segmentation of several objects accounting for the capacity of working memory to resolve several items, attention is selectively focused on a single object according to the model. At intermediate adaptivity, reactivations may persist and long-term synaptic couplings gradually develop. At strong adaptivity, the model predicts attention and memory consolidation to be subsequently terminated. The neuromodulatory control of the interacting medial temporal lobe and neocortical system via the adaptivity of excitatory neurons may account for several observations on the influence of neuromodulators on various cognitive processes and brain disorders.

Animals↗
PubMed1999

Calbindin immunoreactivity in the hippocampal formation and neocortex of schizophrenics.

1. The authors studied the morphology of CalbindinD28K (CaBp) immunoreactive cells and processes in the hippocampal formation and the prefrontal cortex of schizophrenics using the immunohistochemical technique of avidin-biotin-complex method (ABC method), and the results were compared with those from normal human brains. 2. In the hippocampal formation area CA2 of schizophrenics, many CaBp-immunopositive cell bodies and fibers were disordered in their arrangement compared to normal control brains. 3. In the prefrontal cortex (Brodmann area 9) of schizophrenics, many immunopositive cell bodies were exhibited irregular axis arrangement and fiber disarray. 4. The altered distribution pattern of CaBp-immunopositive structures in the hippocampal formation and the prefrontal cortex might indicate the existence of GABA(gamma-aminobutyric acid)ergic dysfunction in the brain of schizophrenic patients.

Aged↗