Leading role of the piriform cortex over the neocortex in the generation of spontaneous interictal spikes during block of GABA(A) receptors.

Interictal spikes are generated in the cerebral cortex during certain pathological conditions. In normal tissue, interictal spikes are triggered by blocking GABA(A) receptors. We studied the propensity of different areas of the cerebral cortex (including neocortex and piriform cortex) to generate spontaneous interictal spikes during block of GABA(A) receptors in slices of adult mice. Ten sequential brain slices were studied spanning most of the cerebral hemisphere. During block of GABA(A) receptors spontaneous interictal spikes were observed in all slices. Interestingly, interictal spikes recurred at different frequencies in different slices; posterior slices had a higher rate than the frontal slices (approximately 0.2 vs. 0.1 Hz, posterior vs. frontal). Multi-site recordings allowed to monitor discharges traveling across each slice and to derive cross-correlations. It became apparent that for the slices with higher frequency (i.e. posterior slices) the discharges originated in the piriform cortex and spread to the neocortex. A correlation between the frequency of the spontaneous discharges and the probability of events originating from piriform cortex was positive and significant. A further demonstration of this site of origin was provided by severing the connections between the neocortex and the piriform cortex. After interrupting these connections all the neocortical sites in the posterior slices displayed a lower frequency of discharges; similar to slower frontal slices. Meanwhile, the isolated piriform cortex of the posterior slices continued to produce higher frequency discharges. Thus, the higher frequency activity displayed by the posterior slices is intrinsically generated in the posterior piriform cortex from where it spreads to the neocortex. The results indicate that the neocortex and the piriform cortex have a distinct propensity to generate spontaneous interictal spikes, and that the more prone areas impose their activity on the less prone areas during disinhibition.

[Thalamocortical dynamics: how do the thalamus and the neocortex communicate during the processing of information?]. / Dinamismo talamocortical: ¿cómo se comunican el tálamo y la neocorteza durante los estados de procesamiento de información?

INTRODUCTION AND DEVELOPMENT: The thalamus is the gateway to the neocortex. Most of the information that reaches the neocortex is transmitted through thalamocortical fibres. The neocortex, in turn, sends massive feedback to the thalamus through corticothalamic fibres. The sensory input reaches the thalamus by means of the primary sensory fibres. When the properties of these pathways are explored, they are found to present specific response characteristics. These studies have generally been conducted during anaesthesia or other quiescent states. Yet when the properties of these synaptic connections are explored in the active states typical of information processing, their responses are substantially different. CONCLUSION: These changes appear to be necessary to set the pathways of the thalamocortical system in a state of sensory input processing and, therefore, could account for the transformations that take place in order to sustain attentional and perceptive processes.

Input-specific effects of acetylcholine on sensory and intracortical evoked responses in the "barrel cortex" in vivo.

The somatosensory neocortex processes extrinsic information from the thalamus and intrinsic information from local circuits. We compared the effects of acetylcholine (Ach) on neocortical field potential responses evoked by stimulation of the whiskers and by local electrical stimulation in the upper layers of the neocortex vibrissae representation ("barrel cortex") of adult rats anesthetized with urethane. In the barrel cortex, the cholinergic system was manipulated using microdialysis by exogenous application of Ach, by increasing the endogenous levels of Ach with physostigmine and by applying specific cholinergic agonists. The results revealed that Ach selectively enhances the sensory response relative to the intracortical response. Thus, pathways in the barrel cortex are differentially regulated by cholinergic inputs.

Cortico-cortical connectivity of the human mid-dorsolateral frontal cortex and its modulation by repetitive transcranial magnetic stimulation.

Modulation of cortico-cortical connectivity in specific neural circuits might underlie some of the behavioural effects observed following repetitive transcranial magnetic stimulation (rTMS) of the human frontal cortex. This possibility was tested by applying rTMS to the left mid-dorsolateral frontal cortex (MDL-FC) and subsequently measuring functional connectivity of this region with positron emission tomography (PET) and TMS. The results showed a strong rTMS-related modulation of brain activity in the fronto-cingulate circuit. These results were confirmed in a parallel experiment in the rat using electrical stimulation and field-potential recordings. Future studies are needed to provide a direct link between the rTMS-induced modulation of cortical connectivity and its effects on specific behaviours.

High-pass filtering of corticothalamic activity by neuromodulators released in the thalamus during arousal: in vitro and in vivo.

The thalamus is the principal relay station of sensory information to the neocortex. In return, the neocortex sends a massive feedback projection back to the thalamus. The thalamus also receives neuromodulatory inputs from the brain stem reticular formation, which is vigorously activated during arousal. We investigated the effects of two neuromodulators, acetylcholine and norepinephrine, on corticothalamic responses in vitro and in vivo. Results from rodent slices in vitro showed that acetylcholine and norepinephrine depress the efficacy of corticothalamic synapses while enhancing their frequency-dependent facilitation. This produces a stronger depression of low-frequency responses than of high-frequency responses. The effects of acetylcholine and norepinephrine were mimicked by muscarinic and alpha(2)-adrenergic receptor agonists and blocked by muscarinic and alpha-adrenergic antagonists, respectively. Stimulation of the brain stem reticular formation in vivo also strongly depressed corticothalamic responses. The suppression was very strong for low-frequency responses, which do not produce synaptic facilitation, but absent for high-frequency corticothalamic responses. As in vitro, application of muscarinic and alpha-adrenergic antagonists into the thalamus in vivo abolished the suppression of corticothalamic responses induced by stimulating the reticular formation. In conclusion, cholinergic and noradrenergic activation during arousal high-pass filters corticothalamic activity. Thus, during arousal only high-frequency inputs from the neocortex are allowed to reach the thalamus. Neuromodulators acting on corticothalamic synapses gate the flow of cortical activity to the thalamus as dictated by behavioral state.

Origin of synchronized oscillations induced by neocortical disinhibition in vivo.

During disinhibition, the neocortex generates synchronous activities. Block of GABA(A) receptors in neocortex transforms cortical slow-wave oscillations into large-amplitude approximately 1 Hz discharges consisting of a negative spike or multiple negative spikes riding on a positive wave. Further block of GABA(B) receptors in neocortex slows the discharges to approximately 0.5 Hz and increments the number of negative spikes forming rhythmic approximately 10 Hz neocortical oscillations. Although the thalamus responds robustly to these neocortical discharges, these are unaffected by thalamic inactivation using tetrodotoxin. Thus, an important problem relates to the origin of these activities within the neocortex. Current source density analysis and intracellular recordings revealed that the first negative spike in a discharge corresponded to a current sink that reflected a paroxysmal depolarizing shift (PDS) and could originate in the lower layers or in the upper layers. Regardless of the origin (upper or lower layer), the initial current sink always spreads to the same site in upper layer V-IV. In contrast, the approximately 10 Hz oscillation that follows the initial negative spike corresponds to current sinks that always originate in the lower layers but do not spread to upper layer V-IV, jumping directly to the upper layers. Each current sink in the approximately 10 Hz oscillation reflects a small PDS and is followed by a current source that reflects the repolarization after each PDS.

Presynaptic long-term potentiation in corticothalamic synapses.

The thalamus and neocortex are two highly organized and complex brain structures that work in concert with each other. The largest synaptic input to the thalamus arrives from the neocortex via corticothalamic fibers. Using brain slices, we describe long-term potentiation (LTP) in corticothalamic fibers contacting the ventrobasal thalamus. Corticothalamic LTP is input-specific, NMDA receptor-independent, and reversible. The induction of corticothalamic LTP is entirely presynaptic and Ca(2+)-dependent. The expression of corticothalamic LTP is associated with a decrease in paired-pulse facilitation (PPF) and blocked by an inhibitor of the cAMP-dependent protein kinase A (PKA). Consistent with an involvement of cAMP and PKA, activation of adenylyl cyclase induced a synaptic enhancement that was associated with a decrease in PPF and occluded LTP. Corticothalamic LTP may serve to enhance the efficacy of cortico-cortical communication via the thalamus and/or to mediate experience-dependent long-term modifications of thalamocortical receptive fields.

Neocortical synchronized oscillations induced by thalamic disinhibition in vivo.

Thalamocortical circuits are recognized as the main elements involved in the genesis of synchronized oscillations typical of certain generalized seizures. We addressed the capability of thalamic disinhibition to generate synchronized oscillations in neocortex. Microdialysis was used to infuse GABA(A) and GABA(B) receptor antagonists directly into the thalamus of anesthetized rats while recording cortical field potentials from 16 sites aligned perpendicular to the cortical surface, using 100 microm spaced linear array silicon probes. The results demonstrate that block of thalamic GABA(A) receptors induces continuous 3 Hz discharges in neocortex and that thalamic GABA(B) receptors mediate this activity. Also, during thalamic disinhibition sporadic long-lasting discharges at 12 Hz occur that do not depend on GABA(B) receptors. Current source density analysis of these activities revealed that the dynamics of sinks and sources for the 3 and 12 Hz discharges was quite distinct, in a way that suggests a different active involvement of the neocortex. The results indicate that intrathalamic inhibitory processes play an essential role in the generation of neocortical synchronized oscillatory activity that may be related to certain forms of generalized seizures.

Distinct forms of short-term plasticity at excitatory synapses of hippocampus and neocortex.

The expression of short- and long-term synaptic plasticity varies strongly across pathways in the central nervous system. Differences in the properties of transmitter release may underlie some of this variability. Here we compared the short-term plasticity displayed by a neocortical and a hippocampal pathway in vitro, and observed dramatic differences. Conditions known to increase transmitter release probability were more effective in hippocampus, while conditions known to decrease release probability were similarly effective in both pathways. The effects of the irreversible open-channel blocker of N-methyl-D-aspartate receptors, MK-801, implied that synapses in the neocortical pathway have a relatively high probability of transmitter release as compared with synapses in the hippocampal pathway. Differences in release probability may explain the pathway-specific variance in short- and long-term synaptic plasticity.

Thalamocortical synapses.

Thalamocortical synapses inform the cerebral neocortex about the external and internal worlds. The thalamus produces myriad thalamocortical pathways that vary in morphological, physiological, pharmacological and functional properties. All these features are of great importance for understanding how information is acquired, integrated, processed, stored and retrieved by the thalamocortical system. This paper reviews the properties of the afferents from thalamus to cortex, and identifies some of the gaps in our knowledge of thalamocortical pathways.

Short-term plasticity in thalamocortical pathways: cellular mechanisms and functional roles.

Information reaches the neocortex through different types of thalamocortical pathways. These differ in many morphological and physiological properties. One interesting aspect in which thalamocortical pathways differ is in their temporal dynamics, such as their short-term plasticity. Primary pathways display frequency-dependent depression, while secondary pathways display frequency-dependent enhancement. The cellular mechanisms underlying these dynamic responses involve pre- and post-synaptic and circuit properties. They may serve to synchronize, amplify and/or filter neural activity in neocortex depending on behavioral demands, and thus to adapt each pathway to its specific function.

Cellular mechanisms of the augmenting response: short-term plasticity in a thalamocortical pathway.

Some thalamocortical pathways display an "augmenting response" when stimuli are delivered at frequencies between 7 and 14 Hz. Cortical responses to the first three stimuli of a series increase progressively in amplitude and are relatively stable thereafter. We have investigated the cellular mechanisms of the augmenting response using extracellular and intracellular recordings in vivo and in slices of the sensorimotor neocortex of the rat. Single stimuli to the ventrolateral (VL) nucleus of the thalamus generate EPSPs followed by feedforward IPSPs that hyperpolarize cells in layer V. A long-latency depolarization interrupts the IPSP with a peak at approximately 200 msec. A second VL stimulus delivered during the hyperpolarization and before the peak of the long-latency depolarization yields an augmenting response. The shortest latency for augmenting responses occurs in cells of layer V, and they appear in dendrites and somata recorded in upper layers approximately 5 msec later. Recordings in vitro show that some layer V cells have hyperpolarization-activated and deinactivated conductances that may serve to increase their excitability after IPSPs. Also in vitro, cells from layer V, but not from layer III, generated augmenting responses at the same stimulation frequencies that were effective in vivo. Control experiments indicated that neither paired-pulse depression of IPSPs nor presynaptically mediated facilitation can account for the augmenting response. Active dendritic conductances contribute to the spread of augmenting responses into upper layers by way of back-propagating fast spikes, which attenuate with repetition, and long-lasting spikes, which enhance in parallel with the augmenting response. In conclusion, we propose that the initiation of augmenting responses depends on an interaction between inhibition, intrinsic membrane properties, and synaptic interconnections of layer V pyramidal neurons.

Spatiotemporal properties of short-term plasticity sensorimotor thalamocortical pathways of the rat.

Each region of neocortex receives synaptic input from several thalamic nuclei, but the response properties of thalamocortical pathways may differ. We have studied the frontoparietal (motor and somatosensory) neocortex of the rat and have examined the responses induced by stimulating two convergent thalamocortical projections originating in the ventrolateral (VL) nucleus and ventroposterior lateral (VPL) nucleus. Depth recordings and current-source density (CSD) analysis revealed two primary responses with different laminar and temporal patterns when VL and VPL were stimulated. Single shocks to VL produced a characteristic small current sink in layer V, which strongly enhanced in response to a second pulse delivered within a 50-200 msec interval (i.e., the augmenting response). In contrast, a shock to VPL evoked a large current sink that originated in layer IV, spread strongly into the supragranular layers, and was almost abolished in response to a second pulse at intervals of <200 msec (i.e., the decremental response). Control experiments determined that these responses could not be attributed to the antidromic firing of corticothalamic cells, intrathalamic mechanisms, or anesthesia. Topographic response maps were obtained from a grid of 30 sites across frontoparietal cortex. One shock to VL excited a very limited cortical region, but an augmenting response evoked 50-200 msec later spread at approximately 1 m/sec to synchronize the activity across an area up to 25 times larger. In contrast, a single shock to VPL activated a relatively large area, but the area activated by a second shock delivered within 200 msec was much smaller. We conclude that overlapping thalamocortical projections, originating in different thalamic nuclei, have distinct spatiotemporal response characteristics that may serve the functional specializations of these pathways.

Short-term plasticity of a thalamocortical pathway dynamically modulated by behavioral state.

The neocortex receives information about the environment and the rest of the brain through pathways from the thalamus. These pathways have frequency-dependent properties that can strongly influence their effect on the neocortex. In 1943 Morison and Dempsey described "augmenting responses," a form of short-term plasticity in some thalamocortical pathways that is triggered by 8- to 15-hertz activation. Results from anesthetized rats showed that the augmenting response is initiated by pyramidal cells in layer V. The augmenting response was also observed in awake, unrestrained animals and was found to be dynamically modulated by their behavioral state.

Involvement of protein kinase C and nitric oxide in the modulation by insulin-like growth factor-I of glutamate-induced GABA release in the cerebellum.

Insulin-like growth factor-I elicits a long-term depression of the glutamate-induced GABA release in the adult rat cerebellum that lasts at least several hours. We studied whether protein kinase C and nitric oxide may be involved in this effect of insulin-like growth factor-I on GABA release since both signalling pathways have been implicated in other forms of neuromodulation in the cerebellum. By using microdialysis in the adult rat cerebellum, we found that either an inhibitor of protein kinase C (staurosporine) or of nitric oxide synthase (Nw-nitro-L-arginine methyl ester) counteracted the long-term, but not the acute effects of insulin-like growth factor-I on glutamate-induced GABA release. On the contrary, when either an activator of protein kinase C (phorbol ester), or an nitric oxide donor (L-arginine), were given with glutamate, they mimicked only the acute effects of insulin-like growth factor-I on glutamate-induced GABA release. Finally, when both protein kinase C and nitric oxide-synthase were simultaneously inhibited by conjoint administration of staurosporine and Nw-nitro-L-arginine methyl ester, a complete blockage of both the short and the long-term effects of insulin-like growth factor-I on GABA release was obtained. These results, indicate that: (i) activation by insulin-like growth factor-I of either the protein kinase C or nitric oxide-signalling pathways is sufficient for the short-term inhibition of glutamate-induced GABA release; and (ii) simultaneous activation of both the protein kinase C and the nitric oxide signalling pathways is necessary for insulin-like growth factor-I to induce a long-term depression of GABA responses to glutamate. Thus, long-term depression of glutamate-induced GABA release by insulin-like growth factor-I in the cerebellum is mediated by simultaneous activation of both protein kinase C and nitric oxide-signalling pathways.

Short-term synaptic enhancement and long-term potentiation in neocortex.

Repetitive stimuli reliably induce long-term potentiation (LTP) of synapses in the upper layers of the granular somatosensory cortex but not the agranular motor cortex of rats. Herein we examine, in these same cortical areas, short-term changes in synaptic strength that occur during the LTP induction period. theta-Burst stimulation produced a strong short-term enhancement of synapses in the granular area but only weak enhancement in the agranular area. The magnitude of enhancement during stimulation was strongly correlated with the magnitude of LTP subsequently expressed. Short-term enhancement was abolished by an antagonist of N-methyl-D-aspartate (NMDA) receptors but remained in the presence of a non-NMDA receptor antagonist. Inhibitory postsynaptic potentials of the granular and agranular areas displayed similar frequency sensitivity, but the frequency sensitivity of NMDA receptor-dependent excitatory postsynaptic potentials differed significantly between areas. We propose that pathway-specific differences in short-term enhancement are due to variations in the frequency dependence of NMDA currents; different capacities for short-term enhancement may explain why repetitive stimulation more readily induces LTP in the somatosensory cortex than in the motor cortex.

Functional recovery of forelimb response capacity after forelimb primary motor cortex damage in the rat is due to the reorganization of adjacent areas of cortex.

Functional recovery after brain damage has been described frequently and different mechanisms have been proposed to account for the observed recovery. One possible mechanism involves the capacity of one part of the brain to take over the function of another. A possible area for this to take place is in the cerebral cortex, where a variety of reorganizational processes have been described after different manipulations. We show in the present study that the forelimb force and response capacity of the rat, which becomes highly impaired after the bilateral ablation of the forelimb primary motor cortex, is recovered when the animals receive an electrical stimulation in the ventral tegmental nucleus contingent to each forelimb response in the task. Microstimulation mapping of the cortical areas adjacent to the forelimb primary motor cortex revealed the appearance of an area located caudolaterally to the forelimb primary motor cortex, where forelimb movements could be evoked in recovered animals but to a lesser extent in non-recovered animals. A positive and significant correlation was observed between the size of the reorganized forelimb area and the behavioral performance of the animals. Ablation of the forelimb reorganized area in recovered animals reinstated the forelimb behavioral impairment, while the same lesion in normal animals had no effect on the behavioral performance. The results indicate that recovery after bilateral forelimb primary motor cortex ablation may be due to the organization of specific adjacent areas in the cortex.

Different forms of synaptic plasticity in somatosensory and motor areas of the neocortex.

We have studied vertical synaptic pathways in two cytoarchitectonically distinct areas of rat neocortex--the granular primary somatosensory (SI) area and the agranular primary motor (MI) area--and tested their propensity to generate long-term potentiation (LTP), long-term depression (LTD), and related forms of synaptic plasticity. Extracellular and intracellular responses were recorded in layer II/III of slices in vitro while stimulating in middle cortical layers (in or around layer IV). Under control conditions, 5 Hz theta-burst stimulation produced LTP in the granular area, but not in the agranular area. Agranular cortex did generate short-term potentiation that decayed within 20 min. Varying the inter-burst frequency from 2 Hz to 10 Hz reliably yielded LTP of 21-34% above control levels in granular cortex, but no lasting changes were induced in agranular cortex. However, the agranular cortex was capable of generating LTP if a GABAA receptor antagonist was applied locally at the recording site during the induction phase. In contrast to LTP, an identical form of homosynaptic LTD could be induced in both granular and agranular areas by applying low frequency stimulation (1 Hz for 15 min) to the middle layers. Under control conditions, both LTP and LTD were synapse-specific; theta-burst or low-frequency stimulation in the vertical pathway did not induce changes in responses to stimulation of a layer II/III horizontal pathway. Application of the NMDA receptor antagonist D-2-amino-5-phosphonovaleric acid (AP5) blocked the induction of both LTP and LTD in granular and agranular cortex. In the presence of AP5, low-frequency conditioning stimuli yielded a short-term depression in both areas that decayed within 10-15 min. Nifedipine, which blocks L-type, voltage-sensitive calcium channels, slightly depressed the magnitudes of LTP and LTD but did not abolish them. Synaptic responses evoked during theta-burst stimulation were strikingly different in granular and agranular areas. Responses in granular cortex were progressively facilitated during each sequence of 10 theta-bursts, and from sequence-to-sequence; in contrast, responses in agranular cortex were stable during an entire theta-burst tetanus. The results suggest that vertical pathways in primary somatosensory cortex and primary motor cortex express several forms of synaptic plasticity. They were equally capable of generating LTD, but the pathways in somatosensory cortex much more reliably generated LTP, unless inhibition was reduced. LTP may be more easily produced in sensory cortex because of the pronounced synaptic facilitation that occurs there during repetitive stimulation of the induction phase.(ABSTRACT TRUNCATED AT 400 WORDS)

Contribution of NMDA and nonNMDA glutamate receptors to synchronized excitation and cortical output in the primary motor cortex of the rat.

Application of a GABA (gamma-aminobutyric acid) type A receptor antagonist through a microdialysis probe into the forelimb primary motor cortex (MI) of ketamine anesthetized rats induced the appearance of paroxysmal field potentials recorded in the supragranular layers of the MI and concomitant electromyographic (EMG) activity in the contralateral forelimb. Application of a nonNMDA (N-methyl-D-aspartate) glutamate receptor antagonist in conjunction with the GABA type A receptor antagonist completely blocked the paroxysmal field potentials and the EMG activity of the contralateral forelimb, while a NMDA receptor antagonist had no effect. The results indicate that the spread of activity within the primary motor cortex and the motor cortex output are mediated by nonNMDA receptors.