Institute of Physiology and Pathophysiology, University of Mainz, Duesbergweg 6, D-55128 Mainz, Germany
Address correspondence to Heiko J. Luhmann, Institute of Physiology and Pathophysiology, University of Mainz, Duesbergweg 6, D-55128 Mainz, Germany. Email: luhmann{at}uni-mainz.de.
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Abstract |
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Introduction |
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Material and Methods |
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All experiments were conducted in accordance with national laws for the use of animals in research and approved by the local ethical committee. Neonatal Wistar rats [postnatal day (P) 07; day of birth = P0] were deeply anesthetized by hypothermia and decapitated. The brain was rapidly removed and transferred to oxygenated (95% O2/5% CO2), ice-cold (25°C) artificial cerebrospinal fluid (ACSF) of the following composition (in mM): 124 NaCl; 5 KCl; 1.6 CaCl2; 1 MgSO4; 26 NaHCO3; 1.25 NaH2PO4; and 10 glucose (pH 7.4). The subsequent preparation was performed in oxygenated, ice-cold ACSF and lasted 1015 min. The two hemispheres were separated by a scalpel cut through the midline and all subcortical structures, including the hippocampus, were removed in one hemisphere. The pial membranes were carefully removed and the intact cerebral cortex of one hemisphere was transferred into a conventional fully submerged chamber superfused with ACSF at 3233°C at a rate of 810 ml/min (Khalilov et al., 1997; Luhmann et al., 2000a
). The tissue was placed on a plastic mesh with the medial side down and fixed to the silgard bottom using three entomological needles.
Conventional 400600 mm thick neocortical slices from P57 rats were prepared as described previously (Kilb and Luhmann 2000; Luhmann et al., 2000b
). In brief, coronal slices including the fronto-parietal cortex were prepared in oxygenated, ice-cold ACSF on a vibroslicer (TPI, St Louis, MO) and transferred to an incubation chamber containing ACSF at 3233°C. After an incubation period of at least 1 h, slices were transferred to a recording chamber (volume <2 ml) mounted on the fixed stage of an Axioskop microscope (Zeiss, Jena, Germany), where they were continuously superfused at a rate of 2 ml/min with ACSF at 3233°C.
Multi-site Extracellular and Whole-cell Recordings
Extracellular multi-site recordings were performed with five tungsten 45 M microelectrodes (FHC, Bowdoinham, ME, USA) positioned in different cortical areas or in fronto-parietal cortex along a row in rostrocaudal direction with a an electrode tip separation of
0.5 mm. Signals were AC recorded with extracellular amplifiers, low-pass filtered at 3 kHz, stored and analyzed with an eight-channel PC-based software program (WinTida, Heka, Lambrecht, Germany). CCh (Sigma-Aldrich, Steinheim, Germany) was added to the bathing solution in a concentration of 1200 mM. The CCh-induced oscillations were analyzed in the extra-cellular recordings in their onset latency (interval between CCh washing and occurrence of first oscillatory activity), duration (interval between beginning and end of one complete oscillatory cycle) and maximal amplitude (voltage between the positive- and negative-going peaks). Furthermore, fast Fourier transformation (FFT) spectra were calculated by the use of the WinTida program and CCh-induced oscillations were analyzed in their maximal frequency and power.
Blind whole-cell recordings in the supragranular layers of the intact cortex were performed according to the methods described previously (Blanton et al., 1989). In conventional cortical slices, whole-cell recordings were performed from visually identified pyramidal neurons in upper cortical layers using video enhanced infrared Normarski optics. Recording pipettes were pulled from borosilicate glass tubing (CG200F8P, Science Products, Hofheim, Germany) on a vertical puller (PP83, Narishige, Tokyo, Japan) and filled with the following solution (in mM): 117 K-gluconate; 13 KCl; 1 CaCl2; 2 MgCl2; 11 EGTA; 10 K-HEPES; 2 NaATP; and 0.5 NaGTP. This solution was adjusted to pH 7.4 with 1 M KOH and to an osmolarity of 306 mOsm with sucrose. In all experiments 0.5% biocytin (Sigma-Aldrich) was included in the patch electrode solutions for later cell identification. The patch pipettes with resistances of 612 M
were connected to the headstage of a discontinuous voltage-clamp/current-clamp amplifier (SEC-05L; NPI, Tamm, Germany) and signals were amplified, low-pass filtered at 3 kHz, digitized online with an AD/DA-board (ITC-16; Heka) and analyzed using WinTida software. For experiments involving whole-cell recordings, extracellular MgSO4 was substituted by MgCl2 and all recordings were corrected for liquid junction potentials with 10 mV (Kilb and Luhmann, 2000
).
Intra- and Extracellular Biocytin Staining Histology
Intact cortices containing biocytin-filled neurons were fixed for at least 2 days in 4% paraformaldehyde at 4°C, subsequently cryoprotected overnight with 30% sucrose and coronal sections of 100 mm thickness were cut on a cryotome. Conventional coronal slices were treated in the same way, but not resectioned. For extracellular labelling, a small crystal of biocytin was injected into the upper layers of the primary somatosensory cortex (S1) of the intact cerebral cortex in vitro. After 68 h at 3233°C, the tissue was removed from the submerged chamber, carefully flattened between two layers of tissue paper, fixed overnight, cryoprotected and tangential section of 75100 µm thickness were cut. Sections were stained as described previously (Schröder and Luhmann, 1997). Sections were preincubated for 60 min in phosphate-buffered saline (PBS) containing 0.5% H2O2 to saturate endogenous peroxidase, followed by incubation overnight in avidin-coupled peroxidase (ABC kit; Vectorlabs, Burlingame, CA). After wash in PBS and Tris the slices were incubated for 30 min in 3,3-diaminobenzidine (DAB; Sigma-Aldrich) and for 10 min in DAB containing 0.01% H2O2. The reaction product was intensified by 23 min incubation in 0.5% OsO4. Finally, the slices were rinsed in TRIS and distilled water, dehydrated in ethanol and embedded in Durcopan (Fluka, Buchs, Switzerland). Digital photographs of biocytin labelled sections were taken with a Nikon Coolpix 990 camera (Nikon, Düsseldorf, Germany) attached to a Zeiss microscope.
Drugs
The sodium channel blocker tetrodotoxin citrate (TTX; RBI, Natick, MA) was applied in a concentration of 0.11 mM and 10 mM atropine sulfate (RBI) was used to block muscarinic acetylcholine receptors. Gamma-amino butyric acid type A (GABA-A) receptors were blocked with 20 mM bicuculline methiodide (BMI; Sigma-Aldrich) or 100 mM gabazine (SR-95531; RBI). The broad spectrum glutamate receptor antagonist kynurenic acid (KA, Sigma-Aldrich) was dissolved freshly at 500 mM in ACSF. The -amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA)/ kainate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; RBI) was bath applied at 10 mM and N-methyl-D-aspartate (NMDA) receptors were blocked with (±)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP, 20 µM; RBI) or the non-competitive antagonist (+)-MK-801 hydrogen maleate (MK-801, 20 mM; RBI).
Statistics
Statistical analyses were performed with Systat version 9 (SPSS Inc., Chicago, IL) and Auto Signal version 1.5 (SPSS Inc.). Cross-correlograms for 1 ms binwidth were calculated and the strength of the correlation between the neural activity recorded at two different sites was quantified by measuring the peak cross-correlation coefficient (Eggermont, 2000). Values throughout this report are given as mean ± SEM. For statistical comparisons, a paired samples t-test was performed.
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Results |
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The intact neocortex in vitro preparation proofed to be most valuable to study large-scale network activities in cortical structures [see also Schwartz et al. (Schwartz et al., 1998) for details on spontaneous neuronal activity in the whole hemisphere preparation]. Intact cortices were analyzed with extra- and intracellular recording techniques over periods of 68 h and did not reveal any signs of functional abnormalities. Transient oscillatory network activity occurring 34 ± 2.9 s after washing of CCh could be observed with extracellular recording electrodes in all 70 intact cortices prepared from P0P7 rats. In normal bathing solution these transient oscillations had a duration of 4.6 ± 0.2 s (n = 68) and a maximal amplitude of 123 ± 7.4 µV (n = 128; Fig. 1A
). Color-coded spectrograms (Fig. 1B
) and fast Fourier transformations (FFT; Fig. 1C
) of the signals indicate that the CCh-induced activity consists of oscillations in the beta (1230 Hz) and to a lesser extent in the lower gamma (3080 Hz) frequency range. Whereas the initial oscillation lasting 12 s is dominated by higher frequencies in the range of 2040 Hz, the subsequent activity is characterized by a gradual decrease in oscillatory frequency to 1015 Hz (Fig. 1B
). The FFT spectra revealed the maximal power at an average frequency of 17.7 ± 0.5 Hz (n = 128). In contrast to the persistent CCh-induced network oscillations in adult rat hippocampal slices (Fisahn et al., 1998
), oscillatory activity in the intact cerebral cortex of the neonatal rat was primarily restricted to the washing phase of CCh (
30 µM) and repetitive periods of network oscillations could be observed only rarely at intervals of 3040 min.
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We first addressed the question of whether the CCh-induced oscillations were mediated by action potential-dependent synaptic interactions. TTX blocked the oscillatory activity in six out of six experiments and this effect was reversible after washing out TTX for >45 min (Fig. 4A). The network activity was also blocked by atropine (n = 6), indicating that muscarinic receptors play an essential role in CCh-induced cortical oscillations (Fig. 4B
). The participation of GABA-A receptors in the cholinergically induced activity was studied by bath application of the specific antagonist BMI or gabazine (Table 1
). BMI caused a reversible increase in the response amplitude and maximal FFT power of the CCh-induced oscillations (Fig. 4C
), but these effects were not significant at the P < 0.05 level. Gabazine had similar, but non-reversible effects (Fig. 4D
). Both GABA-A antagonists did neither change the peak frequency nor the propagation pattern of the network activity. These results suggest that GABA-A receptor blockade amplifies, rather than inhibits, the CCh-induced oscillations.
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The spatial and temporal coupling of the oscillations was studied in nine intact cortices by performing cross-correlation analyses of the responses recorded with five extracellular electrodes, which were separated by 0.52 mm (Fig. 6). CCh-induced beta rhythms support robust synchronization between sites separated horizontally by
1 mm and for delays of 28 ms (Fig. 6A,B
). At a distance of 0.5 mm, the average cross-correlation coefficient estimated 0.558 ± 0.056 (n = 20 pairs). At 1.0 mm, the cross-correlation coefficient decreased to 0.366 ± 0.069 (n = 15 pairs) and at distances of
1.5 mm no significant correlation coefficients could be detected (at 1.5 mm, 0.162 ± 0.031, n = 10 and at 2.0 mm 0.075 ± 0.031, n = 5; Fig. 6C,D
). These data indicate that local circuits synchronize in the range of a few milliseconds over distances of up to 1 mm already in the very immature cerebral cortex.
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To examine in more detail the cellular responses to CCh application, we performed whole-cell current-clamp recordings from visually identified and biocytin-labelled pyramidal neurons (Fig. 8A) and simultaneous extracellular recordings in 14 coronal slices of P57 rat fronto-parietal cortex. The average resting membrane potential was 63.6 ± 1.5 mV and the input resistance 582 ± 52.6 M
(n = 17). In all of these cells, bath application of CCh increased the spontaneous synaptic activity and in 13 neurons a prominent membrane depolarization by 24.3 ± 3.8 mV could be observed (Fig. 8B
), which in 70% of the cells was sufficient to trigger action potentials. In the remaining four cells, CCh induced a small membrane hyperpolarization by 5.6 ± 1.4 mV. In contrast to our observations in the intact cerebral cortex, CCh-induced network oscillations recorded with extracellular electrodes in slices occurred less frequently and were smaller in amplitude (<120 µV; Fig. 8C
). Furthermore, CCh-induced oscillations in the field potential recordings (12.4 ± 1.8 Hz, n = 5) and in single cells (10.8 ± 3.7 Hz, n = 4) were smaller in their maximal frequency (Fig. 8D
) in slices as compared to the intact cortex. However, a smaller peak in the lower beta frequency range could be also observed (arrow in Fig. 8D
). These data indicate that a sufficiently large network of intra-cortical excitatory connections is essential for the generation of robust CCh-induced beta oscillations and that this network is only partially preserved in the cortical slice preparation.
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Extracellular biocytin injections into the upper layers of S1 in the intact cerebral cortex of 10 P47 rats revealed a dense network of anterogradely labelled horizontal fibers and retrogradely stained neurons organized in discrete clusters up to 2.7 mm from the center of the injection site (Fig. 12A). The majority of these cells resembled in their morphology pyramidal neurons (Fig. 12B,C
), although an unequivocal identification of the cells in tangential slices is difficult. These data indicate that intracortical horizontal connections of considerable extent are capable to synchronize the CCh-induced oscillations over spatial dimensions of at least 1 mm.
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Discussion |
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Anatomical Substrate of Spatio-temporal Correlation
Previous studies in developing cat visual cortex have already demonstrated horizontal intrinsic connections ranging over several millimeters (Luhmann et al., 1986, 1990
; Assal and Innocenti, 1993
; Galuske and Singer, 1996
) and our previous studies in neonatal rat cortical slices have shown lateral axonal projections up to 2 mm [see Fig. 4A
in Luhmann et al. (Luhmann et al., 1999
)]. Since horizontal intrinsic connections in rat cerebral cortex conduct at 0.150.55 m/s (Murakoshi et al., 1993
), monosynaptic interactions over 1 mm should reveal a latency of 1.86.7 ms. This value is exactly in the range of our results in the cross-correlograms (28 ms). Therefore, lateral intracortical connections probably form the anatomical substrate of synchronized CCh-induced rhythmic activity in newborn rat cortex. Recently Chiu and Weliky (Chiu and Weliky, 2001
) demonstrated in developing ferret visual cortex in vivo clusters of correlated spontaneous activity that were separated by
1 mm and proposed that this pattern is generated by horizontal patchy connections.
But why does the neonatal cortical network oscillate in the beta frequency range? Kopell et al. (Kopell et al., 2000) suggested on the basis of their computational network model that synchronization over long distances and long conduction delays is mainly supported by beta rhythms. This hypothesis is supported by experimental data demonstrating synchronized activity in the beta frequency range between widely spaced cortical areas of awake cats during a visuomotor task (Roelfsema et al., 1997
). In the newborn rat cortex, synchronization processes are restricted to
1 mm, but due to the slow kinetics of passive and active membrane properties at this age (Luhmann et al., 2000b
), long conduction delays occur even over these relatively small distances. The beta rhythm seems to be most suited to mediate synchronization of CCh-induced oscillatory activity in the neonatal cerebral cortex. During further development and maturation of faster membrane kinetics and synaptic properties, the system may use faster rhythms (i.e. in the gamma range) to synchronize intracortical activity at nearby sites (Buhl et al., 1998
; Dickson et al., 2000
). Steriade et al. (Steriade et al., 1996
) demonstrated in adult cat cortex, that during the transition from sleep to wakefulness fast oscillations (3040 Hz) are not only synchronized between neighboring (12 mm) sites, but also between different cortical areas separated by >5 mm.
Cellular Basis of CCh-induced Network Oscillations
Beierlein et al. (Beierlein et al., 2000) have recently demonstrated in P1421 rats that a network of low-threshold-spiking inhibitory interneurons, when activated by muscarinic or metabotropic glutamate receptor agonists, can coordinate the firing pattern of neocortical neurons over a distance of
400 µm. This widespread synchronous inhibition is critically depending on electrical synapses containing the gap junction protein Cx36 (Deans et al., 2001
). Gap junctions in combination with GABAergic synaptic connections are also capable of synchronizing action potential generation in regular spiking nonpyramidal neurons at beta and gamma frequencies (Szabadics et al., 2001
). These data indicate that cortical networks of inhibitory interneurons connected by electrical (and chemical) synapses are well suited to synchronize neuronal activity and to generate different cortical rhythms (Galarreta and Hestrin, 2001
). In contrast, the CCh-induced network oscillations observed in the newborn rat cerebral cortex are mediated by chemical synapses and are not dependent on intact GABAergic synaptic transmission. In agreement with previous observations in neonatal rat hippocampus (Reece and Schwartzkroin, 1991
; Avignone and Cherubini, 1999
), application of CCh to the intact cerebral cortex of the newborn rat produced an increase in synaptic network activity and most often a prominent membrane depolarization. The ascending cholinergic projection from the basal forebrain (Dinopoulos et al., 1989
; Calarco and Robertson, 1995
; Mechawar and Descarries, 2001
) and muscarinic receptors on cortical neurons (Buwalda et al., 1995
; Hohmann et al., 1995
) are clearly present in the perinatal rat and an important function of the cholinergic system and of muscarinic receptors in cortical morphogenesis has been previously demonstrated in various studies (Hohmann and Berger-Sweeney, 1998
). Our data imply that a network with sufficient recurrent excitatory connections can generate oscillatory activity by itself as long as the neuronal activity exceeds a critical threshold, which is surpassed by the combined activation of muscarinic and NMDA receptors (Fig. 13
). Activation of muscarinic or NMDA receptors induces in newborn rat cortical neurons an intracellular calcium rise (Yuste and Katz, 1991
) and Peinado (Peinado, 2000
) recently demonstrated that cholinergically induced calcium waves propagate in newborn cortex over many millimeters. In contrast to the spontaneous neuronal domains in developing neocortex, which are insensitive to TTX, propagate locally at
100 µm/s and are abolished by gap junction blockers (Yuste et al., 1992
, 1995
), the CCh-induced propagating calcium waves are blocked by TTX (Peinado, 2000
). In the newborn rat cortex, large-scale oscillatory calcium waves propagating at 2.1 mm/s require action potentials and activation of AMPA and NMDA (Garaschuk et al., 2000
). Although AMPA receptor blockade caused a decrease in the average amplitude and FFT power of the CCh-induced oscillatory activity (Table 1
), our observations in the intact cerebral cortex suggest that NMDA receptors play a primary role in cholinergically induced oscillations. Application of NMDA antagonists only reduced the CCh-induced membrane depolarization, but completely blocked the oscillatory network activity. These data indicate that NMDA receptors are required to reach the critical threshold for eliciting the network oscillations and that the CCh-induced increase in synaptic activity is insufficient to trigger the oscillations.
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The cholinergic system plays an important role in the maturation and in developmental plasticity of the cerebral cortex (Hohmann and Berger-Sweeney, 1998). Numerous studies in rodent somatosensory cortex (Hohmann et al., 1988
) and cat visual cortex (Bear and Singer, 1986
) have demonstrated that an impairment in cholinergic function results in a deficit of cortical morphogenesis or early synaptic plasticity. Our data indicate that cholinergically induced oscillatory activity may influence these processes during the early stages of corticogenesis. The synchronization of CCh-induced oscillatory activity between neighboring neocortical modules is sustained by an excitatory circuit involving AMPA/kainate receptors and critically depending on NMDA receptors (Fig. 13
). The crucial role of NMDA receptors during early neocortical development, i.e. in pattern formation, has been well documented in the cat visual (Kleinschmidt et al., 1987
) and mouse somatosensory cortex (Iwasato et al., 1997
, 2000
). During the first postnatal week, a large number of glutamatergic synapses in rat cortical structures are exclusively mediated by NMDA receptors (Isaac et al., 1997
; Rumpel et al., 1998
) and activity-dependent modifications in synaptic strength require NMDA receptor activation (Crair and Malenka, 1995
; Durand et al., 1996
). Furthermore, during early postnatal development NMDA currents in rat cerebral cortex show an activity-dependent decrease in duration (Carmignoto and Vicini, 1992
) by upregulation of the NR2A subunit (Flint et al., 1997
), further supporting the hypothesis that NMDA receptors mediate activity-dependent plasticity during neonatal stages (Crair, 1999
). Since in the rat hippocampal CA1 region, NMDA receptors are also critically involved in synaptic plasticity during CCh-induced theta oscillation (Huerta and Lisman, 1993
, 1995
), we expected activity-dependent modifications in the synchronization process between neighboring networks over repeated CCh applications. Whereas in the olfactory system of insects, odor-evoked synchronized oscillations increase in spike time precision and coherence over repeated odor stimulations (Stopfer and Laurent, 1999
), CCh-induced beta oscillations in the neonatal rat cortex are characterized by their stability of synchronization. Probably additional synaptic activity arising from the sensory periphery is required for modifying these synaptic connections according to Hebbian (Hebb, 1949
) rules (Singer, 1995
; Katz and Shatz, 1996
; Sur et al., 1999
).
We suggest that in the neonatal cerebral cortex in vivo the three following prerequisites have to be fulfilled in order to induce physiologically relevant synaptic modifications between spatially separated cortical modules (Fig. 13). (i) The neuronal network has to be connected over considerable distances via horizontal axonal fibers, which mainly use NMDA receptor synapses. (ii) Ascending modulatory systems, as the cholinergic system, have to convert the neocortical network into an oscillatory mode with a preference in the beta frequency range, which tolerates long conduction delays. (iii) Patterned synaptic inputs provide the decisive signal to modify horizontal connections between functionally related sites in an experience-dependent manner and according to Hebbian rules. However, whether the early formation of cortical circuits and patterns involving lateral interactions critically depends on these three conditions can be tested only under in vivo conditions or in intact in vitro preparations.
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Footnotes |
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