Stress-induced hippocampus Npas4 mRNA expression relates to specific psychophysiological patterns of stress response.

Neuronal Per-Arnt-Sim (PAS) domain protein 4 (Npas4) is a key protein that intervenes in GABA synapse scaling and neurotrophicity enhancing. Since GABA and neurotrophicity are implicated in stress response and Npas4-deficient rodents exhibit behavioral alterations, an investigation was designed in rats to verify whether stress-induced spontaneous hippocampus Npas4 mRNA expression would be associated with specific patterns of stress response. The rats were exposed to one of three stressor levels: no stress (CTL, n = 15), exposure to a footshock apparatus (Sham, S, n = 40) and footshock (F, n = 80). After stress exposure the S and F rats were tested in an activity cage, and subsequently in an elevated plus maze (EPM), just prior to the sacrifice. Using cluster analysis, the animals already assigned to a stress level were also distributed into 2 subgroups depending on their Npas4 mRNA levels. The low (L) and high (H) Npas4 expression subgroups were identified in the S and F groups, the CTL group being independent of the Npas4 levels. The Npas4 effect was studied through the interaction between stress (S and F) and Npas4 level (L and H). The biological stress response was similar in H and L rats, except blood corticosterone that was slightly lower in the H rats. The H rats were more active in the actimetry cage and presented higher levels of exploration in the EPM. They also exhibited higher hippocampus activation, as assessed by the c-fos, Egr1 and Arc mRNA levels. Therefore high Npas4 expression favors stress management.

Metyrapone effects on systemic and cerebral energy metabolism.

Metyrapone is a cytochrome P(450) inhibitor that protects against ischemia- and excitotoxicity-induced brain damages in rodents. This study examines whether metyrapone would act on energy metabolism in a manner congruent with its neuroprotective effect. In a first investigation, the rats instrumented with telemetric devices measuring abdominal temperature, received i.p. injection of either metyrapone or saline. One hour after injection, their blood and hippocampus were sampled. Hippocampus metabolite concentrations were measured using (1)H high-resolution magic angle spinning-magnetic resonance spectroscopy ((1)H HRMAS-MRS). The hippocampus levels in phosphorylated mammalian target of rapamycin (mTOR) and adenosine monophosphate-activated protein kinase (AMPK) were measured by Western Blot analysis and those of c-fos and HSP70-2 mRNA were quantified by RT-PCR. In a second investigation, the rats received the same treatment and were sacrificed 1h after. The functioning of mitochondria was immediately studied on their whole brain. Metyrapone provoked a slight hypothermia which was correlated to the increase in blood glucose concentration. Metyrapone also increased blood lactate concentrations without modifying hippocampus lactate content. In the hippocampus, metyrapone decreased γ-aminobutyric acid (GABA) and glutamate levels but increased glutamine and N-acetyl-aspartate contents (NAA). Phosphorylated mTOR and AMPK and the c-fos and HSP70-2 mRNA levels were similar between treatment groups. Metyrapone did not modify blood corticosterone levels. Mitochondrial oxygen consumption was similar in both groups whatever the substrate used. These metabolic modifications, which take place without modifying blood glucocorticoid levels, are consistent with the neuroprotective properties of metyrapone as demonstrated in animal models.

The relationship between locomotion and heat tolerance in heat exposed rats.

Low spontaneous locomotor activity (SA) represents a thermoregulatory behaviour that aims at improving heat tolerance. However, high SA is observed during heat exposure. We hypothesized that high SA could be associated to brain dysfunction. Eighty male Sprague-Dawley rats were heat exposed for 90-min under a continuous assessment of SA and abdominal temperature (T(abd)) using telemetry. The time course analysis showed two SA peaks. The first one was related to exposure to novel environment, the second to heat. The maximal SA level reached in the second peak served to distribute the rats into three groups (LOW, MED and HIGH). In each SA pattern group, heat tolerance was estimated from T(abd) values. At the end of heat exposure, frontal cortex activation was assessed using c-fos, Hsp70 and IkappaBalpha mRNA expressions. The LOW rats exhibited the lowest T(abd), a slight increase in c-fos and Hsp70 mRNA expressions and a robust increase in IkappaBalpha mRNA expression. The HIGH rats exhibited the highest T(abd) and a robust increase in c-fos and Hsp70 mRNA expressions without any change in IkappaBalpha mRNA expression. The c-fos and Hsp70 mRNA expressions were positively correlated to the highest SA levels occurring 45 min before sacrifice, suggesting that high SA and frontal cortex activation are related. In conclusion, high SA is associated to decreased heat tolerance and frontal cortex activation. It may represent a marker of inadequate stress reaction.

Metyrapone blunts stress-induced hyperthermia and increased locomotor activity independently of glucocorticoids and neurosteroids.

Metyrapone, a cytochrome P(450) inhibitor used to inhibit corticosterone synthesis, triggers biological markers of stress and also reduces stress-induced anxiety-like behaviors. To address these controversial effects, 6 separate investigations were carried out. In a first set of investigations, abdominal temperature (T(abd)), spontaneous locomotor activity (A(S)) and electroencephalogram (EEG) were recorded in freely moving rats treated with either saline or 150 mg kg(-1) metyrapone. An increase in T(abd) and A(S) occurred in saline rats, while, metyrapone rats exhibited an immediate decrease, both variables returning to basal values 5h later. Concomitantly, the EEG spectral power increased in the gamma and beta 2 bands and decreased in the alpha frequency band, and the EMG spectral power increased. This finding suggests that metyrapone depressed stress-induced physiological response while arousing the animal. In a second step, restraint stress was applied 5h after injection. Metyrapone significantly blunted the stress-induced T(abd) and A(S) rise, without affecting the brain c-fos mRNA increase. Corticosterone (5 and 40 mg kg(-1)) injected concomitantly to metyrapone failed to reverse the observed metyrapone-induced effects in T(abd) and A(S). Finasteride (50 mg kg(-1)), which blocks neurosteroid production, was also unable to block these effects. In conclusion, metyrapone acutely reduced stress-induced physiological response in freely behaving rats independently from glucocorticoids and neurosteroids.

[The sleep of Africans and Europeans in the Ivory Coast: questionnaire study]. / Le Sommeil d'Africains et d'Européens en Côte d'lvoire: étude par questionnaires.

Sleep behaviour has been extensively studied with questionnaires in industrialised countries to investigate the epidemiology of sleep-wake disorders. However, only few attempts have yet been made to examine sleep behaviour of people living in Africa. Although, a large number of studies in hot or cold environments have used short-term exposures, reporting disrupted sleep for most of them, long-term exposures to stressful thermal environments are rare in the literature. Prior to the present investigation, we used questionnaires to analyse the effects of seasonal heat increase on perceived sleep behaviour and sleep quality in young native African students in Niger [7], even though these methods of investigation are by no means as accurate as polysomnographic recordings. The hypothesis was that sleep behaviour may be influenced by climatic variations in a hot dry tropical climate. Such climatic variations have been shown to induce seasonal heat acclimatisation marked by changes in body temperature rhythms in the hot versus the cool season [13]. Sleep behaviour was examined during two 7-day periods in January ("cool-dry" season, 88 subjects) and May ("hot-dry" season, 53 subjects). The questionnaire was completed after night sleep and/or naps. The subjects slept an average of 7 1/2 hours a day, most of them having afternoon naps. They experienced no major seasonal variation in their sleep behaviour, but for an increased number of awakenings during the hot season. Restorative quality of sleep scored lower after a nap than after nocturnal sleep. Therefore, general sleep characteristics were not modified by seasonal temperature variations in African native students, perhaps because of the limited changes in daylight under the low latitude of Niamey. Another investigation was carried out using the same 12-item questionnaire in Abidjan on 78 medical students who did not have a nap [9]. Contrary to the Niamey students, the Abidjan subjects adopted short duration sleep schedules, without any effect on the subjective quality of the restorative properties of their sleep.