Increased stress-induced intra-hippocampus corticosterone rise associated with memory impairments in middle-aged mice.

The present study investigates the relationships between hippocampal corticosterone concentrations and memory retrieval performance in stress and non-stress conditions, in both young (6 month-old) and middle-aged (16 month-old) mice. For this purpose, the time-course evolution of stress-induced corticosterone rise in the dorsal hippocampus (dHPC) was investigated in both young and middle-aged mice. In parallel, the evolution of memory retrieval patterns was assessed using a contextual serial discrimination task (CSD). Finally, metyrapone (corticosterone synthesis inhibitor) was administered in order to evaluate the stress-induced impact of corticosterone rise on contextual memory retrieval in middle-aged animals. Results showed that: (i) non-stressed middle-aged mice exhibited a memory retrieval pattern opposite to that of non-stressed young animals, but similar to that of stressed young mice; (ii) the impact of stress on memory performance was transient (90 min) in young, as compared to middle-aged mice (120 min); (iii) dHPC basal (non-stress) corticosterone level was significantly increased by ageing; (iv) acute stress induced a rapid (15 min) and transient (90 min) dHPC corticosterone rise in young mice, while exhibiting greater magnitude and duration (120 min) in middle-aged animals; and (v) both the stress-induced endocrinal and memory effects were blocked by metyrapone in young and middle-aged mice. Finally, to our knowledge, the present work is the first study to directly measure the corticosterone rise in the hippocampus following exposure to stress and to directly correlate the corticosterone changes in the hippocampus with memory performance in both young and middle-aged mice.

Rapid stress-induced corticosterone rise in the hippocampus reverses serial memory retrieval pattern.

We previously showed that an acute stress (electric footshocks) induced both a rapid plasma corticosterone rise and a reversal of serial memory retrieval pattern in a contextual serial discrimination (CSD) task. This study is aimed at determining (i) if the rapid stress effects on CSD performance are mediated by the hippocampus; (ii) if hippocampal corticosterone membrane receptor activation is involved in the rapid stress effects on CSD performance. In experiment 1, microdialysis in the dorsal hippocampus (dHPC) was used to measure the stress-induced corticosterone rise; in parallel, the effect of acute stress on CSD performance was evaluated. In addition, the functional involvement of corticosterone in the behavioral effects of stress was assessed by administering metyrapone, a corticosterone synthesis inhibitor, before stress. In experiment 2, the involvement of hippocampal corticosterone membrane receptors in the stress-induced reversal of CSD performance was studied by injecting corticosterone-bovine serum albumin (BSA) (a membrane-impermeable complex) in the dHPC in non stressed mice. Results showed that (i) the acute stress induced a rapid (15 min) and transitory (90 min) corticosterone rise into the hippocampus dHPC, and a reversal of serial memory retrieval pattern; (ii) both the endocrinal and memory stress-induced effects were blocked by metyrapone; (iii) corticosterone-BSA injection into the dHPC in non stressed mice mimicked the effects of stress on serial retrieval pattern. Overall, our study is first to show that (i) a rapid stress-induced corticosterone rise into the dHPC transitorily reverses serial memory retrieval pattern and (ii) hippocampal corticosterone membrane receptors activation is involved in the rapid effects of acute stress on serial memory retrieval.

Intrahippocampal cholinesterase inhibition induces epileptogenesis in mice without evidence of neurodegenerative events.

The mechanisms of epileptogenesis remain largely unknown and are probably diverse. The aim of this study was to investigate the role of focal cholinergic imbalance in epileptogenesis. To address this question, we monitored electroencephalogram (EEG) activity up to 12 weeks after the injection of a potent cholinesterase (ChE) inhibitor (soman) at different doses (0.53, 0.75, 1, 2, 2.8, 4 and 11 nmol) into the right dorsal hippocampus of C57BL/6 mice. Different parameters were used to choose the dose for a focal model of epileptogenesis (mainly electrographic patterns and peripheral ChE inhibition). The pattern of neuronal activation was studied by Fos immunohistochemistry (IHC). Brain damage was evaluated by hemalun-phloxin, neuronal nuclei antigen IHC and silver staining. Glial fibrillary acidic protein IHC was used to evaluate astroglial reaction. Finally, long-term behavioral consequences were characterized. At the highest dose (11 nmol), soman quickly evoked severe signs, including initial seizures and promoted epileptogenesis in the absence of tissue damage. With lower doses, late-onset seizures were evidenced, after 1-4 weeks depending on the dose, despite the absence of initial overt seizures and of brain damage. Only a weak astroglial reaction was observed. Following injection of 1 nmol, Fos changes were first evidenced in the ipsilateral hippocampus and then spread to extrahippocampal areas. A selective deficit in contextual fear conditioning was also evidenced two months after injection. Our data show that focal hypercholinergy may be a sufficient initial event to promote epilepsy and that major brain tissue changes (cellular damage, edema, neuroinflammation) are not necessary conditions.

Prefrontal cortex or basolateral amygdala lesions blocked the stress-induced inversion of serial memory retrieval pattern in mice.

Previous data from our team have shown that pre-test stress in mice reversed the pattern of memory retrieval in a contextual serial spatial task (CSD; Celerier, A., Pierard, C., Rachbauer, D., Sarrieau, A., & Beracochea, D. (2004). Contextual and serial discriminations: A new learning paradigm to assess simultaneously the effects of acute stress on retrieval of flexible or stable information in mice. Learning and Memory, 11, 196-204). The present study is aimed at determining brain areas which might be critically involved in mediating the stress effect on memory retrieval in the CSD task. For that purpose, we studied hereby the effects of ibotenic acid lesions of either the prefrontal cortex (PFC) or the basolateral amygdala (BLA) in Stressed or Non-Stressed Balb/c mice on memory retrieval in the CSD task. In that task, mice learned two successive spatial discriminations (D1 and D2) within two different internal contexts in a four-hole board. The stressor (electric footshocks) was delivered 5 min before test, occurring 24 h after acquisition. During test, mice were relocated either on the floor of the first or of the second discrimination. Results showed that (i) spatial memory was substantial and remained unaffected both by lesions and stress; (ii) Non-Stressed controls as well as Non-Stressed or Stressed PFC and BLA-lesioned mice remembered accurately D1 but not D2; and (iii) in contrast, Stressed controls accurately remembered D2 but not D1. In parallel to behavioral experiments, we also showed that PFC and BLA lesions did not affect the stress-induced increase of plasma corticosterone levels. All together, PFC and BLA integrity are not necessary for retrieval processes per se; in contrast, the PFC and BLA are critically involved in the mediation of the deleterious stress effects on serial order memory retrieval.

Effects of moderate and intensive training on functional activity of central 5-HT1B receptors in the rat substantia nigra.

The efficacy of the selective 5-HT1B receptor agonist CP 93,129 in inhibiting the forskolin-stimulated adenylyl cyclase activity in the rat substantia nigra was reduced by both moderate and intensive prolonged training compared with sedentary resting rats. The concentration-response curves of the agonist were shifted to the right with a sixfold increase of the half-maximal inhibitory concentration. A difference was observed between the two training exercises in regard to further changes in 5-HT1B receptor sensitivity induced by an acute restraint stress. This manipulation did not affect the functional response of the 5-HT1B receptors further in moderately trained rats, whereas an additional desensitization of the 5-HT1B receptors was observed in intensively trained rats. These results strongly suggest the existence of regulation mechanisms altering the functional efficacy of 5-HT1B receptors and, accordingly, affecting the serotonergic activity, since 5-HT1B receptors modulate the neuronal release of the amine.

Fluid shifts and endocrine responses during lower body negative pressure and dynamic arm exercise.

The use of lower body negative pressure (LBNP) is proposed as a means of reducing the effect of spaceflight on body water loss by stimulation of renin angiotensin aldosterone system (RAAS) activity. Seven subjects were successively submitted to LBNP exposure, arm cranking physical exercise, and to a combination of both procedures (LBNP + arm cranking) in order to check whether this combination enhances RAAS activity. The results showed that exposure to 40 min of LBNP to a level of -40 mm Hg was a more potent stimulus for renin secretion than submaximal and maximal arm cranking. The combination of LBNP with exercise does not further enhance the RAAS activity induced by LBNP alone. These data suggest that the fluid shift toward the lower body induced by LBNP counteracts triggering of renin secretion due to physical exercise.

Hypertension induced by repeated exposure to high sustained +Gz (HS + Gz) stress.

The purpose of this study was to determine whether repeated exposure to high sustained +Gz (HS + Gz) stress induced persistent changes in the functional state of the cardiovascular system. Three groups of rabbits--centrifuged, restrained, and control--were studied. After being placed in the restraining system of the centrifuge, the animals were submitted three times in a row to 8-9 +Gz sustained for 40 s. This exposure was repeated three times a week for 3-6 weeks. Restrained animals were not exposed to HS + Gz. Control animals were not restrained. The two types of stress (centrifuge + restraint; restraint alone) determined the appearance of two types of arterial hypertension. Systolic arterial pressure (AP) and left ventricular pressure (LVP) significantly increased in restrained animals. The function of the cardiovascular system was more perturbed in centrifuged rabbits since the significant changes affected not only systolic AP and LVP but alos systemic diastolic AP and the maximum rate of rise of LVP. The myocardium of rabbits repeatedly subjected to HS + Gz exposures, except for those that suffered a fracture of the lumbar spine, was significantly glycogen-depleted.