Alexandra Barbelivien

Environmental enrichment increases responding to contextual cues but decreases overall conditioned fear in the rat

This study aimed at investigating the effects of environmental enrichment on various aspects of contextual processing in adult female rats. In experiment 1, simple conditioning was studied using either a training procedure allowing overshadowing of the contextual cues by signalling footshock with a discrete tone or a training procedure allowing a reduction of this overshadowing by explicitly unpairing the footshock and the tone. In experiment 2, contextual discrimination and contextual occasion-setting were assessed. Rats were daily exposed to two different contexts. In one context, a footshock was delivered 30s after the offset of a tone, whereas in the other context the same tone was presented alone. Experiment 3 examined familiarization to a new context. Experiment 1 showed that environmental enrichment reduced the overshadowing of contextual cues by the tone and also reduced freezing to the more predictive cue according to the training procedure used. Experiment 2 showed that environmental enrichment increased the ability of rats to discriminate two contexts. Experiment 3 showed that enriched rats familiarized faster to a new context than standard rats. Taken together, these results suggest that environmental enrichment in adult rats enhances learning about contextual cues and reduces overall fear associated with aversive events.

The behavioral effects of enriched housing are not altered by serotonin depletion but enrichment alters hippocampal neurochemistry.

To assess a possible role for serotonin in the mediation of the behavioral changes induced by enriched housing conditions (EC), adult female Long-Evans rats sustaining a serotonin depletion (150 microg of 5,7-dihydroxytryptamine, icv) and sham-operated rats were housed postoperatively for 30 days in enriched (12 rats/large cage containing various objects) or standard housing conditions (2 rats/standard laboratory cage). Thereafter, anxiety responses (elevated plus-maze), locomotor activity (in the home-cage), sensori-motor capabilities (beam-walking task), and spatial memory (eight-arm radial maze) were assessed. Monoamine levels were subsequently measured in the frontoparietal cortex and the hippocampus. Overall, EC reduced anxiety-related responses, enhanced sensori-motor performance and improved the memory span in the initial stage of the spatial memory task. Despite a substantial reduction of serotonergic markers in the hippocampus (82%) and the cortex (74%), these positive effects of EC were not altered by the lesion. EC reduced the serotonin levels in the ventral hippocampus (particularly in unlesioned rats: -23%), increased serotonin turnover in the entire hippocampus (particularly in lesioned rats: +36%) and augmented the norepinephrine levels in the dorsal hippocampus (+68% in unlesioned and +49% in lesioned rats); no such alterations were found in the frontoparietal cortex. Our data suggest that an intact serotonergic system is not a prerequisite for the induction of positive behavioral effects by EC. The neurochemical changes found in the hippocampus of EC rats, however, show that the monoaminergic innervation of the hippocampus is a target of EC.

Rats with different profiles of impulsive choice behavior exhibit differences in responses to caffeine and d-amphetamine and in medial prefrontal cortex 5-HT utilization

This study investigated if sub-populations of rats characterized by their basal level of impulsivity (BLI) in a delayed-reinforcement task, displayed differences in the functioning of neurotransmitter systems modulating impulsive choice behavior. For this, the effects of various doses of caffeine and d-amphetamine were investigated in three sub-populations of rats displaying pronounced differences in their impulsive choice behavior and their post-mortem serotonergic and dopaminergic functions were assessed. Caffeine and d-amphetamine reduce impulsive choice behavior only in the Medium BLI sub-population. Dopamine utilization was similar in the three sub-populations, but serotonin utilization was lower in the prefrontal cortex of the Medium and Very high BLI sub-populations as compared to the low BLI one. These results suggest that anti-impulsive effects of caffeine and d-amphetamine are dependent on the BLI of rats and that a low serotonergic function in the prefrontal cortex may be a trait marker of impulsivity evaluated by impulsive choice behavior.

Selective cholinergic lesions in the rat nucleus basalis magnocellularis with limited damage in the medial septum specifically alter attention performance in the five-choice serial reaction time task

Selective immunotoxic cholinergic lesions in the nucleus basalis magnocellularis (NBM) impair visuospatial attention performance in a 5-choice serial reaction time task (5-CSRT task). The features of the reported deficits, however, do not perfectly match among studies, in which some lesions may have been too weak while others largely encroached onto the septal region. Using the 5-CSRT task, we therefore re-assessed the effects of NBM lesions that produced minimal septal damage. Long-Evans adult male rats were trained to stable 5-CSRT task performance (stimulus duration: 0.5 s) and subsequently subjected to intra-NBM injections of 192 IgG-saporin (200 ng/side). The lesions induced more than 90% loss of choline acetyltransferase-positive neurons in the NBM vs. only 28% in the medial septum. The decrease of the optical density of acetylcholinesterase reaction products was significant in the cortex (-91%), not in the hippocampus. In the 5-CSRT task, the lesions resulted in increased omissions (from 10% to 30%) and decreased correct responses (from 80% to 60%), with negligible or no effects on all other usually collected variables. This deficit disappeared with lengthened stimulus duration (i.e. 0.5-1 and then 5 s). Furthermore, overall performance levels decreased when the stimulus duration was shortened (i.e. 0.5-0.2 s) or its intensity attenuated, and rats with cholinergic lesions remained consistently impaired vs. controls. These results show that disruption of sustained visual attention functions by damage to the NBM cholinergic neurons can be evidenced despite weak or no effects on variables accounting for motivational, locomotion- or impulsivity-related biases. Discrepancies with previously reported results are discussed in terms of differences in lesion extent/specificity and training levels.

Contribution of corticosterone to cued versus contextual fear in rats

Several studies have suggested a positive relationship between circulating corticosterone levels and contextual conditioning. However, a positive relationship between circulating corticosterone levels and cued conditioning has also been reported. This study further investigates the relationship between corticosterone and fear conditioning by modulating the predictive value of contextual and discrete tone cues in separate groups of rats. In a first experiment in which training parameters were chosen to induce strong conditioning (five foot-shocks), we used a correlational approach and investigated whether post-training corticosterone levels were related to subsequent expression of contextual and/or tone fear. In a second experiment, in which training parameters were chosen to induce lower conditioning (one and two foot-shocks), we investigated whether a post-training corticosterone injection enhanced the consolidation of contextual and/or tone conditioning. In the first experiment, the highest post-training corticosterone levels were obtained in rats trained with paired tones and shocks. Post-training corticosterone levels tended to be positively correlated with freezing scores during the tone-fear test and were negatively correlated with freezing scores during training although not during the context-fear test. In the second experiment, a post-training injection of corticosterone (3mg/kg) had no effect on subsequent freezing to contextual cues and to a tone that did not predict shock, whereas it was efficient in increasing fear conditioned to a predictive tone. Globally, these results suggest that the predictive value of the conditioned stimulus may be the main determinant of the facilitatory action of acutely enhanced corticosterone in fear conditioning.

Specific in vivo binding in the rat brain of [18F]RP 62203: A selective 5-HT2A receptor radioligand for positron emission tomography

In vivo pharmacokinetic and brain binding characteristics of [18F]RP 62203, a selective high-affinity serotonergic 5-HT2A receptor antagonist, were assessed in the rat following intravenous injection of trace amount of the radioligand. The radioactive distribution profile observed in the brain 60 min after injection was characterized by greater than fourfold higher uptake in neocortex as compared to cerebellum (0.38 +/- 0.07% injected dose/g, % ID/g and 0.08 +/- 0.01 ID/g, respectively), consistent with in vivo specific binding to the 5-HT2A receptor. Furthermore, specific [18F]RP 62203 binding significantly correlated with the reported in vitro distribution of 5-HT2A receptors, but not with known concentration profiles of dopaminergic D2 or adrenergic alpha 1 receptors. Finally, detectable specific binding was abolished by pretreatment with large doses of ritanserin, a selective 5-HT2A antagonist, which resulted in uniform uptakes across cortical, striatal and cerebellar tissues. Thus, [18F]RP 62203 appears to be a promising selective tool to visualize and quantify 5-HT2A brain receptors in vivo with positron emission tomography.

The modulation of striatal dopamine release correlates with water-maze performance in aged rats.

Cluster analysis of performance during acquisition of a place-learning task in the water maze distinguished between subpopulations of aged rats (25-27 months) classified as moderately (AMI) or severely impaired (ASI) in comparison with young adults (3-5 months). Using a slice-superfusion device, electrically or nicotine-evoked release of dopamine from striatum was assessed in the presence of GR-55,562 (5-HT(1B) receptor antagonist), methiotepin (mixed 5-HT(1/2) receptor antagonist) and/or sulpiride (D(2)/D(3) receptor antagonist). The main neuropharmacological results demonstrated age-related alterations in the 5-HT(1B)- and D(2)/D(3)-mediated modulation of electrically evoked striatal dopamine release. Regression analyses indicated a possible contribution of such alterations to the age-related behavioural deficits: the larger the deficit, the weaker the electrically evoked release under 5-HT(1B) and D(2)/D(3) receptor blockade. Extending our recent report on the modulation of striatal acetylcholine release in aged rats [Cassel et al., 2007. Neurobiol. Aging 28, 1270-1285], these new findings make dopaminergic and serotonergic functional alterations potential candidates to participate in age-related deficits in the water maze, most probably in interaction with formerly described cholinergic dysfunctions.

Galanin inhibits the vasodilatatory basalocortical cholinergic system in the anaesthetized rat.

In order to test the putative interaction between galanin and the vasodilatatory basalocortical cholinergic system, anaesthetized ventilated rats received a microinjection into the substantia innominata of 0.9% NaCl, 50 nmol carbachol, 50 nmol carbachol and 200 ng galanin, or 200 ng galanin. Cerebral blood flow (CBF) was measured with [14C]iodoantipyrine by the tissue sampling technique immediately following the intracerebral infusions. Under coinjection conditions, the flow increases observed after carbachol microinjection in the ipsilateral temporal and frontoparietal cortices were found to be significantly reduced (−37%, p ≤ 0.02 and −25%, p ≤ 0.05 respectively) compared with carbachol stimulated rats. The infusion of galanin by itself had no effect on CBF. These results demonstrate that galanin inhibits the vasodilatatory basalocortical cholinergic system an thus may possibly influence CBF by indirect mechanisms.

Late enrichment maintains accurate recent and remote spatial memory only in aged rats that were unimpaired when middle aged

Exposure of rodents to a stimulating environment has beneficial effects on some cognitive functions that are impaired during physiological aging, and especially spatial reference memory. The present study investigated whether environmental enrichment rescues these functions in already declining subjects and/or protects them from subsequent decline. Subgroups of 17-mo-old female rats with unimpaired versus impaired performance in a spatial reference memory task (Morris water maze) were housed until the age of 24 mo in standard or enriched environment. They were then trained in a second reference memory task, conducted in a different room than the first, and recent (1 d) and remote (10 d) memory were assessed. In unimpaired subgroups, spatial memory declined from 17 to 24 mo in rats housed in standard conditions; an enriched environment during this period allowed maintenance of accurate recent and remote spatial memory. At 24 mo, rats impaired at the age of 17 mo housed in enriched environment learned the task and displayed substantial recent memory, but their performance remained lower than that of unimpaired rats, showing that enrichment failed to rescue spatial memory in already cognitively declining rats. Controls indicated carryover effects of the first water maze training, especially in aged rats housed in standard condition, and confirmed the beneficial effect of enrichment on remote memory of aged rats even if they performed poorly than young adults housed for the same duration in standard or enriched condition.