Georges Di Scala

Flight induced by infusion of bicuculline methiodide into periventricular structures

Microinjections of different doses of bicuculline methiodide (BM) were performed into the mesencephalic central gray (CG), the medial hypothalamus (MH) and lateral hypothalamus (LH). Flight reactions could be induced by microinjections of BM into either the CG or the MH. However, the type of flight behavior was different whether the injection was made in the CG or the MH. Furthermore, microinjections of 35 ng of BM in either structure produced an increase in locomotor activity whose time course differed according to the injected structure, and an increase in rearings was induced at MH but not at CG sites. At lateral hypothalamic sites, BM produced an increase in locomotor activity and rearings but no jump. These effects were antagonized in a dose-dependent manner by a local pretreatment with 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP), a GABA agonist. These results suggest that (1) at the level of both the MH and the CG, a GABAergic link is involved in the inhibition of a substrate whose activation produces aversive effects, and (2) the aversive effect induced by CG BM microinjection seems to be different from that induced by MH BM microinjection.

Parallel Maturation of Goal-Directed Behavior and Dopaminergic Systems during Adolescence

Adolescence is a crucial developmental period characterized by specific behaviors reflecting the immaturity of decision-making abilities. However, the maturation of precise cognitive processes and their neurobiological correlates at this period remain poorly understood. Here, we investigate whether a differential developmental time course of dopamine (DA) pathways during late adolescence could explain the emergence of particular executive and motivational components of goal-directed behavior. First, using a contingency degradation protocol, we demonstrate that adolescent rats display a specific deficit when the causal relationship between their actions and their consequences is changed. When the rats become adults, this deficit disappears. In contrast, actions of adolescents remain sensitive to outcome devaluation or to the influence of a pavlovian-conditioned stimulus. This aspect of cognitive maturation parallels a delayed development of the DA system, especially the mesocortical pathway involved in action adaptation to rule changes. Unlike in striatal and nucleus accumbens regions, DA fibers and DA tissue content continue to increase in the medial prefrontal cortex from juvenile to adult age. Moreover, a sustained overexpression of DA receptors is observed in the prefrontal region until the end of adolescence. These findings highlight the relationship between the emergence of specific cognitive processes, in particular the adaptation to changes in action consequences, and the delayed maturation of the mesocortical DA pathway. Similar developmental processes in humans could contribute to the adolescent vulnerability to the emergence of several psychiatric disorders characterized by decision-making deficits.

Transient role of the rat prelimbic cortex in goal-directed behaviour

Lesion studies show that goal‐directed actions mediated by action‐outcome (A‐O) associations and habits mediated by stimulus‐response (S‐R) associations can be dissociated during instrumental training, with the prelimbic region of the medial prefrontal cortex being involved in the former and the infralimbic region in the latter. The present work further investigates the role of the prelimbic region in acquisition vs. expression of goal‐directed instrumental behaviour, using reversible neuronal inactivation and outcome devaluation procedures. In a first experiment, inactivating the prelimbic cortex at the time of testing did not alter the sensitivity to devaluation, indicating that this region was not essential for the expression of A‐O associations. In a second experiment, the prelimbic cortex was inactivated throughout the training phase. At the time of testing the performance was insensitive to devaluation, indicating that the acquired response was not goal‐directed but mediated by an S‐R association. These data challenge the view that the habit system replaces the goal‐directed system as training progresses. They show that the prelimbic cortex plays a transient but crucial role in the acquisition of goal‐directed responding and that the A‐O and S‐R systems can operate in a competitive fashion early in training.

A neuropharmacological study of the periventricular neural substrate involved in flight

This paper reviews results obtained in experiments concerning the neurochemical characteristics of the substrate involved in the control of flight reactions and the induction of aversive effects in the rat. These experiments investigated the behavioural effects produced by microinjecting into the periaqueductal grey matter (PAG) or the medial hypothalamus (MH) compounds known to interfere with the functioning of some neurotransmitter systems known to exist in these structures. The data obtained show that: the activity of the substrate involved in the production of flight reactions is tonically inhibited by the release of GABA (gamma-aminobutyric acid); the behavioural reactions produced by microinjecting GABA antagonists can be clearly distinguished, depending on whether such drugs were injected into the PAG or the MH, despite the fact that jumps were produced from either level; behavioural effects, comparable to some extent to those produced by microinjections of GABA antagonists, can be obtained by injecting drugs which act on non-GABAergic neurochemical substrates, namely opioidergic or cholinergic systems; and behavioural effects, comparable to those produced by injecting GABA antagonists into the PAG, can be obtained by injecting such drugs into various sites located in other parts of the tectum such as the inferior colliculus or adjacent structures.

What brain structures are active during emotions? Effects of brain stimulation elicited aversion on c-fos immunoreactivity and behavior

Aversive behavior is produced by stimulating some brain structures, such as the dorsal periaqueductal gray and the medial hypothalamus. We have used c-fos immunoreactivity to map brain areas which are influenced by stimulation of these two structures. Stimulation was produced in freely moving rats by electrical stimulation or by microinjections of either excitatory amino acids or GABA blocking drugs. Behavior was monitored to detect emotional changes. The effects on labeling induced by the stimulation of either structure were then compared. Structures labeled include the amygdala, the stria terminalis, the supramamillary area, the hypothalamus, the periaqueductal gray, the superior colliculus, the nucleus cuneiformis, and the locus coeruleus. Regardless whether chemical or electrical stimulation was used or the structure stimulated, there was a large overlap among the brain areas labeled. We then compared our results with data from the literature where other methods of inducing aversion have been used, including pain and stress. There was remarkable similarity in the patterning of labeling irrespective of the type of stimulation (central-peripheral, chemical-electrical). There was, however, one interesting difference produced by central vs. peripheral stimulation. Labeling was unilateral in the former case and bilateral in the latter case. Our results suggest that there is a neural substrate that mediates aversive behavior, no matter how it is produced. Nevertheless, that peripheral stimulation produces mainly bilateral activation of this substrate whereas central stimulation produces mainly unilateral activation suggests that natural peripheral stimuli are also integrated at a higher functional level. Future work could be directed toward explicit comparisons of central versus peripheral stimulation to identify the structures involved in higher level integration of aversive behavior.

A Cholinergic-Dependent Role for the Entorhinal Cortex in Trace Fear Conditioning

Trace conditioning is considered a model of higher cognitive involvement in simple associative tasks. Studies of trace conditioning have shown that cortical areas and the hippocampal formation are required to associate events that occur at different times. However, the mechanisms that bridge the trace interval during the acquisition of trace conditioning remain unknown. In four experiments with fear conditioning in rats, we explored the involvement of the entorhinal cortex (EC) in the acquisition of fear under a trace-30 s protocol. We first determined that pretraining neurotoxic lesions of the EC selectively impaired trace-, but not delay-conditioned fear as evaluated by freezing behavior. A local cholinergic deafferentation of the EC using 192-IgG-saporin did not replicate this deficit, presumably because cholinergic interneurons were spared by the toxin. However, pretraining local blockade of EC muscarinic receptors with the M1 antagonist pirenzepine yielded a specific and dose-dependent deficit in trace-conditioned responses. The same microinjections performed after conditioning were without effect on trace fear responses. These effects of blocking M1 receptors are consistent with the notion that conditioned stimulus (CS)-elicited, acetylcholine-dependent persistent activities in the EC are needed to maintain a representation of a tone CS across the trace interval during the acquisition of trace conditioning. This function of the EC is consistent with recent views of this region as a short-term stimulus buffer.

Differential contribution of dorsal and ventral hippocampus to trace and delay fear conditioning.

Trace conditioning relies on the maintained representation of a stimulus across a trace interval, and may involve a persistent trace of the conditioned stimulus (CS) and/or a contribution of contextual conditioning. The role of hippocampal structures in these two types of conditioning was studied by means of pretraining lesions and reversible inactivation of the hippocampus in rats. Similar levels of conditioning to a tone CS and to the context were obtained with a trace interval of 30 s. Neurotoxic lesions of the whole hippocampus or reversible muscimol inactivation of the ventral hippocampus impaired both contextual and tone freezing in both trace‐ and delay‐conditioned rats. Dorsal hippocampal injections impaired contextual freezing and trace conditioning, but not delay conditioning. No dissociation between trace and contextual conditioning was observed under any of these conditions. Altogether, these data indicate that the ventral and dorsal parts of the hippocampus compute different aspects of trace conditioning, with the ventral hippocampus being involved in fear and anxiety processes, and the dorsal hippocampus in the temporal and contextual aspects of event representation.

A Role for Medial Prefrontal Dopaminergic Innervation in Instrumental Conditioning

To investigate the involvement of dopaminergic projections to the prelimbic and infralimbic cortex in the control of goal-directed responses, a first experiment examined the effect of pretraining 6-OHDA lesions of these cortices. We used outcome devaluation and contingency degradation procedures to separately assess the representation of the outcome as a goal or the encoding of the contingency between the action and its outcome. All groups acquired the instrumental response at a normal rate, indicating that dopaminergic activity in the medial prefrontal cortex is not necessary for the acquisition of instrumental learning. Sham-operated animals showed sensitivity to both outcome devaluation and contingency degradation. Animals with dopaminergic lesions of the prelimbic cortex, but not the infralimbic cortex, failed to adapt their instrumental response to changes in contingency, whereas their response remained sensitive to outcome devaluation. In a second experiment, aimed at determining whether dopamine was specifically needed during contingency changes, we performed microinfusions of the dopamine D1/D2 receptor antagonist flupenthixol in the prelimbic cortex only before contingency degradation sessions. Animals with infusions of flupenthixol failed to adapt their response to changes in contingency, thus replicating the deficit of animals with dopaminergic lesions in Experiment 1. These results demonstrate that dissociable neurobiological mechanisms support action–outcome relationships and goal representation, dopamine signaling in the prelimbic cortex being necessary for the former but not the latter.

Behavioural, pharmacological and biochemical effects of acute and chronic administration of ketamine in the rat

The effects of N-methyl-D-aspartate (NMDA) antagonist ketamine given acutely or chronically were investigated on dopamine-related motor functions. Acute administration (15, 22.5, 30 mg/kg, i.p.) reversed the catalepsy induced by a dopamine (DA) antagonist (haloperidol, 0.25 mg/kg, i.p.) in the rat. When given orally and chronically (15 mg/kg per day) during at least 60 days, no alteration of spontaneous motor behaviour was observed, but the responsiveness to a DA agonist (apomorphine, 0.125 or 0.25 mg/kg s.c.) and to haloperidol was enhanced, suggesting an hypersensitivity of the DA receptors following the chronic blockade of NMDA receptors. However, following prolonged administration of ketamine there were no alteration of DA levels and turnover. Taken together these results suggest that the mechanisms involved in this DA receptor hypersensitivity should be postsynaptic.

Effects of unilateral microinjections of gabaergic drugs into the inferior colliculus on auditory evoked potentials and on audiogenic seizure susceptibility

Alteration of GABAergic neurotransmission within the inferior colliculus (IC) appears to be involved in the generation of the audiogenic seizure (AGS) susceptibility. In the present study, we provide evidence indicating that this susceptibility may result from IC neuronal hyperexcitability to sound induced by a decreased GABAergic inhibition. In a first experiment, a unilateral microinjection of bicuculline, a GABAa antagonist, into the IC of normal rats increased the amplitude of the collicular auditory evoked potential, while the microinjection of THIP, a GABAa agonist, decreased this response. In a second experiment, a unilateral microinjection of bicuculline into the IC induced AGS susceptibility in normal rats.