Yves Gioanni

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. Hippocampus 10:411–419, 2000

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.

Influence of the hippocampus on interneurons of the rat prefrontal cortex

The hippocampus and prefrontal cortex (PFC), two structures implicated in learning and memory processes, are linked by a direct hippocampo‐prefrontal pathway. It has been shown that PFC pyramidal cells receive monosynaptic excitatory inputs from the hippocampus and, in this study, we sought to determine the influence of the hippocampus on PFC interneurons in anesthetized rats. Extracellular recordings were coupled to juxtacellular injections of neurobiotin or biotinylated dextran amine to morphologically differentiate interneurons from pyramidal cells. In all cases, the action potentials of labeled interneurons were of shorter duration (< 0.70 ms) than those of identified pyramidal cells (> 0.70 ms). Single pulse stimulation of the hippocampal CA1/subiculum region induced an excitatory response in 70% of recorded interneurons in the prelimbic and medial‐orbital areas of the PFC. In contrast to the one to two action potentials generated by pyramidal cells, an important group of interneurons fired a burst of action potentials in response to hippocampal stimulation. A large proportion of these excitatory responses was probably monosynaptic as their latency is consistent with the conduction time of the hippocampo‐prefrontal pathway. In addition, when both a pyramidal cell and an interneuron were simultaneously recorded and both responded to stimulation, the interneuron consistently fired before the pyramidal cell. In conclusion, the hippocampus exerts a direct excitatory influence on PFC interneurons and is thus capable of feedforward inhibition of pyramidal cells. Hippocampal output is spatially and temporally focalized via this inhibitory process and consequently could facilitate the synchronization of a specific subset of PFC neurons with hippocampal activity.

α1‐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 α1‐adrenergic receptors) (3–5 mg/ kg, i.v.), prazosin (an α1‐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 α1‐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 α1‐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 α1‐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 others transmission. Synapse 30:362–370, 1998.

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.

DOPAMINE FUNCTION IN THE PREFRONTAL CORTEX

Publisher Summary This chapter summarizes the influence of the mesocortical dopaminergic (DA) system on the excitatory responses induced in the prefrontal cortex (PFC) following electrical stimulation of the thalamic mediodorsal nucleus (MD). The DA innervation of the PFC that originates from the ventral tegmental area (VTA) has been shown to be crucial for its functions. The particularly high reactivity of the mesocortical DA system to stressful situations or anxiogenic drugs suggests that this system is involved in the control of emotional behavior. Moreover, the DA neurotransmission in the PFC contributes to the regulation of cognitive functions. The DA- and VTA-induced inhibition of efferent PFC neurons may result from a direct action of DA on pyramidal cells and/or an indirect effect involving GABA interneurons. Several observations also support a possible involvement of CABA interneurons in the inhibitory effect of DA on pyramidal cells. Moreover, the inhibitory GABAergic postsynaptic potentials recorded in pyramidal cells are increased by DA application on PFC slices. The in vivo study also suggests that part of the inhibitory responses of PFC cells induced by the activation of the mesocortical DA system involves a local GABAergic component. Electrical stimulation of the MD evokes excitatory responses in PFC neurons that result not only from the activation of the MD-PFC pathways, but also from the activation of recurrent collaterals of the antidromically driven PFC fibers projecting to the MD. The mesocortical DA system exerts a potent inhibitory control on the excitatory responses induced by the activation of intracortical recurrent collaterals of the PFC pyramidal cells that project to the MD. The complex but specific influence of DA on the transfer of information may explain the major role of the mesocortical DA system in the functions of the PFC.

Microscale impedance measurements suggest that ionic diffusion is implicated in generating extracellular potentials.

The genesis of the Local Field Potential (LFP) highly depends on the electric properties of the extracellular medium, but such properties are still subject to a controversy because of contradictory measurements. One possibility is that the use of metal electrodes as current sources in previous studies provides non-physiological results. We tested this possibility by performing impedance measurements in conditions as close as possible to physiological conditions. We generated single-cell LFPs by injecting subthreshold inputs in single neurons using patch-clamp recordings, combined with extracellular recordings with micropipettes. Various measurement configurations show that (1) the extracellular medium has strong low-pass filtering properties and cannot be accounted by a resistive medium; (2) the frequency scaling of the filtering, as well as its phase, show that the system seems intermediate between resistive and capacitive. The extracellular impedance was also measured from in vivo experiments in rats under anesthesia. In this case, recording with intracellular (whole-cell) electrodes, together with extracellular LFP, showed results consistent with the in vitro experiments. Finally, we developed a theoretical model based on Maxwell equations, which shows that all measurements can be explained if the extracellular medium is of diffusive type (Warburg impedance). This model predicts that the phase difference between intracellular and extracellular signals should provide a signature of the physical nature of the impedance, with 45 degrees phase difference for purely diffusive type. The experiments show that indeed, the phase is that of a RC soma in series with a diffusive impedance (between 0 and -45 degrees), therefore confirming the diffusive nature of the extracellular impedance. These findings have potentially important consequences for interpreting LFP measurements and source estimation such as CSD analysis.