Dopamine modulates temporal dynamics of feedforward inhibition in rat prefrontal cortex in vivo.

Midbrain dopamine (DA) neurons project to pyramidal cells and interneurons of the prefrontal cortex (PFC). At the microcircuit level, interneurons gate inputs to a network and regulate/pattern its outputs. Whereas several in vitro studies have examined the role of DA on PFC interneurons, few in vivo data are available. In this study, we show that DA influences the timing of interneuron firing. In particular, DA had a reductive influence on interneuron spontaneous firing, which in the context of the excitatory response of interneurons to hippocampal electrical stimulation, lead to a temporal focalization of the interneuron response. This suggests that the reductive influence of DA on interneuron excitability is responsible for filtering out weak excitatory inputs. The increase in the temporal precision of interneuron firing is a mechanism by which DA can modulate the temporal dynamics of feedforward inhibition in PFC circuits and can thereby influence cognitive information processing.

Hippocampo-prefrontal cortex pathway: anatomical and electrophysiological characteristics.

The hippocampus, the prefrontal cortex, and interconnected neural circuits are implicated in several aspects of cognitive and memory processes. The present review is dedicated to the description of the anatomo-functional characteristics of the hippocampo-prefrontal pathway and related neuronal circuits in the rat. This pathway, which originates from the hippocampal CA1/subiculum fields, innervates the prelimbic/medial orbital areas of the prefrontal cortex (PL/MO). Its synaptic influence on cortical pyramidal neurons consists in an early monosynaptic excitation followed by an inhibition and, in some cases, a late excitation. These later effects are likely due to the subsequent activation of the local cortical network. PL/MO areas and the CA1/subiculum both send projections to the nucleus accumbens, a region of the ventral striatum which is particularly implicated in goal-directed behavior. Therefore, emphasis is placed on respective projections from PL/MO areas and from the CA1/subiculum on the "core" and the "shell" regions of the nucleus accumbens, as well as on their interconnected circuits. Signals which are directed to the prefrontal cortex through these circuits might modulate hippocampo-prefrontal inputs. Finally, the direct and/or indirect relationships of the hippocampus, prefrontal cortex, and nucleus accumbens with the ventral tegmental area/substantia nigra pars compacta complex (VTA/SNC) (where dopamine neurons are located) will also be described, because these neurons are known to modulate synaptic transmission and plasticity in their target structures and to play a fundamental role in motivational processes.

Nicotinic receptors in the rat prefrontal cortex: increase in glutamate release and facilitation of mediodorsal thalamo-cortical transmission.

The modulatory influence of nicotinic acetylcholine receptor (nAChRs) on thalamocortical transmission was characterized in the prelimbic area (PrL) of the rat prefrontal cortex. In the first experiment, rats received a unilateral excitotoxic lesion centred on the mediodorsal thalamic nucleus (MD), and were sacrificed 1 week later. The lesion resulted in a 40% reduction of 3H-nicotine autoradiographic labelling in the ipsilateral prefrontal cortex, particularly in areas that are innervated by the MD. Electrophysiological experiments were subsequently performed in non-lesioned anaesthetized animals, in order to study modulation of short- and long-latency responses of PrL neurons evoked by electrical stimulation of the MD. The short-latency responses result from activation of the MD-PrL pathway and are mediated via AMPA-type glutamatergic receptors, whereas the long-latency responses reflect activation of the recurrent collaterals of cortical pyramidal neurons, Iontophoretic application of nicotinic agonists (nicotine, DMPP) facilitated both types of response. Local application of the nAChR antagonists dihydro-beta-erythroidine, mecamylamine and methyllycaconitine, prevented both kinds of facilitation. Finally, intracerebral microdialysis experiments were performed in order to test for nicotinic modulation of extracellular glutamate concentrations in the PrL. Direct application of nicotine via the dialysis probe increased glutamate levels in a dose-dependent manner. This effect was blocked by local perfusion of dihydro-beta-erythroidine. These findings therefore provide anatomical and functional evidence for nAChR-mediated modulation of thalamocortical input to the prefrontal cortex. Such a mechanism may be relevant to the cognitive effects of nicotine and nicotinic antagonists.

Alpha1-adrenergic, D1, and D2 receptors interactions in the prefrontal cortex: implications for the modality of action of different types of neuroleptics.

The activation of rat mesocortical dopaminergic (DA) neurons evoked by the electrical stimulation of the ventral tegmental area (VTA) induces a marked inhibition of the spontaneous activity of prefrontocortical cells. In the present study, it was first shown that systemic administration of either clozapine (a mixed antagonist of D1, D2, and alpha1-adrenergic receptors) (3-5 mg/kg, i.v.), prazosin (an alpha1-adrenergic antagonist) (0.2 mg/kg, i.v.), or sulpiride (a D2 antagonist) (30 mg/kg, i.v.), but not SCH 23390 (a D1 antagonist) (0.2 mg/kg, i.v.), reversed this cortical inhibition. Second, it was found that following the systemic administration of prazosin, the VTA-induced cortical inhibition reappeared when either SCH 23390 or sulpiride was applied by iontophoresis into the prefrontal cortex. Third, it was seen that, whereas haloperidol (0.2 mg/kg, i.v.), a D2 antagonist which also blocks alpha1-adrenergic receptors, failed to reverse the VTA-induced inhibition, the systemic administration of haloperidol plus SCH 23390 (0.2 mg/kg, i.v.) blocked this inhibition. Finally, it was verified that the cortical inhibitions obtained following treatments with either "prazosin plus sulpiride" or "prazosin plus SCH 23390" were blocked by a superimposed administration of either SCH 23390 or sulpiride, respectively. These data indicate that complex interactions between cortical D2, D1, and alpha1-adrenergic receptors are involved in the regulation of the activity of prefrontocortical cells innervated by the VTA neurons. They confirm that the physiological stimulation of cortical alpha1-adrenergic receptors hampers the functional activity of cortical D1 receptors and suggest that the stimulations of cortical D1 and D2 receptors exert mutual inhibition on each other's transmission.

Search for the structures initiating seizures triggered by intraventricular injection of the mu opioid agonist dermorphin in rats.

Free-moving rats received intraventricular (i.c.v.) or intravenous (i.v.) injections of the mu opioid agonist dermorphin (DRM). The EEG activity of the cortex and of several structures near the injected lateral ventricle was recorded. The intravenous injections of DRM did not induce epileptiform activity. The intracerebroventricular injections of DRM triggered several types of electrical seizures and interictal spikes. With the aim of determining which structure gave rise to the epileptiform discharges, we compared the time relationships of epileptiform phenomena occurring in different structures. Epileptiform discharges, at once generalized, appeared first in the CA3 area of the ventral hippocampus, with involvement of the CA1 area of ventral hippocampus, the entorhinal cortex and the amygdala following immediately. We conclude that, after intracerebroventricular injection of a mu opiate agonist, epileptiform activity originates in the CA3 area of the ventral hippocampus.

Intracerebral microinjections of dermorphin: search for the epileptic induction thresholds.

To test the different sensitivity of several central structures to the epileptogenic action of mu opiate agonists, intracerebral microinjections of the selective mu agonist dermorphin were delivered into different areas of the rat dorsal and ventral hippocampus, septum, amygdala, entorhinal cortex, thalamus, striatum and neocortex. The dose of dermorphin (up to 6 nmol) necessary to trigger electrical epileptic events in each of these regions was studied. Epileptic discharges were triggered only in the ventral hippocampus (CA1 and CA3 areas), amygdala and entorhinal cortex. The epileptic induction threshold was the lowest in the CA1 area of the ventral hippocampus. The results suggest that when a mu opiate agonist is injected intraventricularly, the epileptic activity originates in the ventral hippocampus.

Distribution of [3H]clonidine binding sites in the brain of the convulsive mutant quaking mouse: a radioautographic analysis.

The radioautographic analysis of [3H]clonidine binding was performed on brain slices from the convulsive mutant mice quaking and their controls of the same strain. In the quaking mice significant increases were observed mostly in the brainstem and the cerebellum, but also in a few regions of the forebrain, such as the lateral and medial thalamic nuclei, the medial geniculate nucleus, the amygdala and the hypothalamus. Other regions, such as the cerebral cortex and the hippocampus, which are classically involved in various models of epilepsy, but not in the quaking mice, did not show any modification of [3H]clonidine binding. A high degree of correlation was found between the structures with an increased density of alpha 2-adrenoceptor binding sites and the distribution of regions from which seizures can be elicited by intracerebral electrical stimulation in head-restrained quaking mice. This comparison emphasizes the role of noradrenaline acting at the level of alpha 2-adrenoceptors in the epileptic syndrome of the quaking mutants.

Seizures can be triggered by stimulating non-cortical structures in the quaking mutant mouse.

Mutant Quaking mice (C57BL/6J) display convulsive tonic-clonic seizures that can be either spontaneous or triggered by manipulation of the animal or by auditory stimulation. Several abnormalities have been found (especially in the noradrenergic system) in the brainstem of this mutant strain. We first verified by electrophysiological recording that the cerebral cortex was not involved in the generation or in the development of these fits. Then we showed that tonic-clonic seizures similar to those obtained in the freely moving animal were triggered by low-threshold (LT, 5-50 microA) or high-threshold (HT, 55-150 microA) stimuli performed during head restraint. LT stimuli were mostly efficient in a number of ponto-bulbar and mesencephalic structures, including several reticular nuclei, the locus coeruleus, the nucleus subcoeruleus and the red nucleus, whereas HT stimuli were generally necessary to trigger fits by stimulating the nuclei pontis, the substantia nigra, the central gray area and the cerebellar nuclei. Seizures were also provoked at the diencephalic level with LT stimulation delivered in the medial thalamic area, the nucleus reticularis thalami and some subthalamic regions (zona incerta, H field of Forel). In contrast, no fits were obtained by stimulating the cerebellar cortex and the inferior colliculus, the ventral and lateral groups of thalamic nuclei or the telencephalic regions (hippocampus, amygdala, caudate nucleus, putamen and cerebral cortex), with the exception of the globus pallidus.

Intracerebroventricular dermorphin, but not dermenkephalin, is epileptogenic in the rat.

The effects of intracerebroventricular administration of dermorphin (mu agonist) and dermenkephalin (delta agonist) were studied at the electrocorticographic (ECoG) and electromyographic (EMG) levels in free-moving rats. A very low dose of dermorphin (125 pmol) induced ECoG spiking, occasional myoclonic jerks, wet-dog shakes and catalepsy. In addition, electrical seizures were triggered with doses of 250 to 500 pmol. These signs were reversed by an i.p. injection of naloxone (1 mg kg-1). However, no epileptic-like phenomena were seen after administration of dermenkephalin up to 1 nmol. These results indicate that mu but not delta receptors are involved in the epileptogenic effect of intraventricularly administered opiates.

Cortical mapping and laminar analysis of the cutaneous and proprioceptive inputs from the rat foreleg: an extra- and intra-cellular study.

The foreleg proprioceptive and cutaneous representations, in the Sm cortex of urethane-anesthetized rats was studied. Natural or electrical stimulations and stretches of single forearm muscles were used. Multiunitary, unitary or intra-cellular recordings were performed in the contra-lateral Sm cortex. The aims of the study were: 1- to compare the proprioceptive and cutaneous maps 2- to analyse the characteristics of the unitary responses and 3- to study the laminar distribution of cutaneous and muscular inputs. It is shown that: 1- the proprioceptive and cutaneous representations overlapped, except in the anterior part where only proprioceptive (mainly articular) responses were obtained. The representation of each stretched muscle extended over the whole cutaneous area, showing a total overlap between inputs from these muscles. 2- 46% of the intracellularly recorded cells (n = 215) responded to peripheral stimulation, and 30.7% were influenced by (at least) muscle stretch. The majority of excited cells showed cross-modal convergence, and among neurons responding to muscle stretch, 60% received inputs from the two muscles stretched. Two categories of EPSPs were found, and four neurons responded to cutaneous or muscular stimulation with a burst. 19% of the responding cells were inhibited by peripheral--mainly cutaneous--stimulation. 3- Excited neurons were recorded in all layers, with just over half located in layer IV, whereas IPSPs were obtained mainly in layer V. The cells excited by cutaneous and muscular inputs (convergent neurons) were preponderant in layers IV to VI. This work shows that the cutaneous and muscular inputs reach the same area in Sm cortex, and that a majority of excited cells are "convergent". The results are not in favor of an area 3a (by analogy with cats and monkeys) in the rat.

Penicillin epileptogenic focus in the rat: requisites for transcortical reflex triggering.

Epileptiform discharges elicited by natural or electrical stimulations, proprioceptive or cutaneous, were studied in the rat with an experimental acute focus induced by penicillin application in the motor area. EEG paroxystic spikes were easily triggered with restricted foci (0.5 to 1 mm2) located in the representation area of the stimulated region. However, despite the large overlap of sensory and motor cortical limb areas in the rat, EEG spikes, either spontaneous or triggered, were followed by muscular jerks only with much larger foci: at least 2 and 4 mm2, respectively, for anterior and posterior limb areas. Cutaneous stimulations were the most efficient in discharge production; however, discharges were triggered indifferently by muscular or cutaneous afferent fibers in about three-fourths of the cases. The temporal relation between EEG spike and myoclonic jerk were very close. A latency analysis (delay between triggered EEG spike and EMG response, parallel latency fluctuation of both phenomena, delay between spontaneous EEG spike and jerk) supported the hypothesis that a transcortical reflex mechanism, rather than a spinal excitability rebound, was involved in the jerk genesis. Iontophoretic ejection of penicillin within layers III-IV resulted in the development of electroclinical paroxysms. However, similar penicillin ejection within layer V, did not allow efferent discharge production. It is concluded that the involvement of a large surface or volume of cortical tissue is required to produce efferent discharges following EEG paroxysms. This observation is likely related to the unexpectedly wide representation of individual muscles at the motor cortical level.

A reappraisal of rat motor cortex organization by intracortical microstimulation.

The organization of the motor cortex was reinvestigated with intracortical microstimulation, in light-anaesthetized (ketamine) rats. A posterolateral (PL) vibrissae area was found in addition to the rostral one, and blinks of the contralateral eyelids were elicited from a part of this PL area. Several cortical representations such as neck or tail were largely overlapping with neighbouring areas. Vegetative effects (mainly myosis and swallowing) were obtained from a medial cortical strip. Within the PL vibrissae area, a topical arrangement related to the vibrissal rows was observed, whereas in the leg areas, no individual representation of muscles could be evidenced. These results are compared with the maps previously published, and discussed in terms of specificity, musculotopy and overlapping of motor areas.

The transcortical reflex triggered by cutaneous or muscle stimulation in the cat with a penicillin epileptic focus: relative importance of regions 3a and 4.

After establishment of a cortical penicillin epileptic focus in the cat, stimulation of an anterior paw muscle can evoke a late myographic response (LMR) in the same muscle via a transcortical reflex. It is shown here that (1) an LMR can also be obtained with cutaneous stimulation in the region of the muscle; (2) an LMR cannot be elicited when the focus in on area 3a; (3) after inactivation of area 3a by TTX, the motor cortex evoked potential and spike thresholds are increased for proprioceptive but not for cutaneous stimulation, and the LMR persists. It is concluded that area 4 is the critically important structure for the triggering of an LMR. The results concerning area 3a are discussed in terms of this region's efferent connections to the motor cortex and to the spinal cord.

[Proprioceptive afferents of the transcortical reflex in motor epilepsy:localisation of their thalamic relay in the cat (author's transl)]. / Afférences proprioceptives du réflexe transcortical dans l'épilepsie motrice: localisation du relais thalamique chez le chat.

In the Cat with a penicillin motor focus, a transcortical reflex (RTC) can be triggered by stimulation of the muscle or the cutaneous branch of the radial nerve (DR - SR). We tried here to identify at a suprabulbar level, the proprioceptive pathway involved in triggering RTC. Cerebellar ablation did not modify the reflex. On the other hand reversibly inactivation of a rostral-dorso-medial part of VPL (VPLr) receiving short latency proprioceptive afferents, reversibly abolished the TRC elicited through DR stimulation, while SR stimulation was still effective. It is thus assumed that muscle and cutaneous afferents responsible for eliciting the RTC run in parallel pathways with distinct relay zones within the VPL nucleus.U

[Transcortical reflexes of proprioceptive origin and motor epilepsy (author's transl)]. / Reflexes transcorticaux d'origine proprioceptive et epilepsie motrice.

The long-loop reflex involved in the triggering of paroxysmal activities by proprioceptive afferents is examined in monkeys with a chronic alumina focus and in cats with an acute penicillin focus. Electrical stimulation of a tibial nerve in monkeys as well as muscle stretch in cats elicit a cortical 'evoked spike', i.e., an evoked potential followed by an epileptic spike, accompanied by one or two motor bursts in the muscles concerned. With a very small acute focus, this transcortical reflex is shown to be quite topical: muscles in the vicinity are not affected. Relationships between evoked spike and myoclonic jerk are examined and it is shown that motor efferents usually follow the pyramidal tract. The concept of a transcortical reflex of proprioceptive origin is discussed on the basis of data collected from these models.

Modulation of proprioceptive transcortical reflexes in the cat with a penicillin epileptic motor focus.

Mechanisms responsible for the triggering of paroxysmal events by proprioceptive afferents, previously described in the monkey with a chronic epileptic focus, were studied in more detail in the cat with a penicillin focus. To analyse the topical organization of this reflex triggering, the focus was restricted to very small areas of the motor cortex; in this study only pericruciate areas were considered in which stimulation elicited a motor response in one of the several forelimb muscles tested, and which received afferents from that muscle. When the focus was located in the post-sigmoid gyrus, stimulation (usually by stretch) of the given (target) muscle first elicited a cortical spike following the evoked response, and secondly a late phasic EMG response (about 40 msec latency) quite distinct from purely spinal reflexes. Cortical spikes and late EMG responses were closely correlated, especially considering their probability of occurrence or their parallel latency fluctuations. In most cases, this effect was limited to the muscle whose motor area had been treated with penicillin: stretching muscles in the vicinity was ineffective, nor were these muscles activated when the target muscle was stimulated. Evidence is given for the participation of a transcortical reflex in the generation of the late phasic response and for the involvement of the pyramidal tract in this reflex.

A study of geniculate unit activity during cryogenic blockade of the primary visual cortex in the cat.

In cats under nembutal or chloralose anesthesia, unilateral temporary cryogenic blockades of the primary visual cortex were performed and their influence on unitary responses to restricted light spots was tested in the ipsilateral geniculate nucleus. No significant effect could thus be observed, at variance with previous positive results obtained by our group in structures like superior colliculus and pulvinar complex using the same experimental procedure.