Smad-dependent alterations of PPT cholinergic neurons as a pathophysiological mechanism of age-related sleep-dependent memory impairments.

In humans, memory impairments are highly prevalent in the aged population, but their functional and structural origins are still unknown. We hypothesized that circadian rhythm alterations may predict spatial memory impairment in aged rats. We demonstrate an association between sleep/wake circadian rhythm disturbances (non-REM sleep fragmentation) and spatial memory impairments in aged rats. We show by light and electron microscopy that these age-related disruptions in circadian rhythm and spatial memory are also associated with degeneration of cholinergic neurons of the pedunculopontine nucleus (PPT), a structure known to be involved in sleep and cognitive functions and which is altered during aging. Finally, we demonstrate that a trophic deregulation of the PPT occur in aged impaired rats, involving an over activation of the TGFbeta-Smad cascade, a signalling pathway involved in neurodegeneration. In conclusion these results provide a new pathophysiological mechanism for age-related sleep-dependent memory impairments opening the ground for the development of new therapeutic approaches of these pathologies.

Pregnenolone sulfate enhances neurogenesis and PSA-NCAM in young and aged hippocampus.

Age-dependent cognitive impairments have been correlated with functional and structural modifications in the hippocampal formation. In particular, the brain endogenous steroid pregnenolone-sulfate (Preg-S) is a cognitive enhancer whose hippocampal levels have been linked physiologically to cognitive performance in senescent animals. However, the mechanism of its actions remains unknown. Because neurogenesis is sensitive to hormonal influences, we examined the effect of Preg-S on neurogenesis, a novel form of plasticity, in young and old rats. We demonstrate that in vivo infusion of Preg-S stimulates neurogenesis and the expression of the polysialylated forms of NCAM, PSA-NCAM, in the dentate gyrus of 3- and 20-month-old rats. These influences on hippocampal plasticity are mediated by the modulation of the gamma-aminobutyric acid receptor complex A (GABA(A)) receptors present on hippocampal neuroblasts. In vitro, Preg-S stimulates the division of adult-derived spheres suggesting a direct influence on progenitors. These data provide evidence that neurosteroids represent one of the local secreted signals controlling hippocampal neurogenesis. Thus, therapies which stimulate neurosteroidogenesis could preserve hippocampal plasticity and prevent the appearance of age-related cognitive disturbances.

Interindividual differences in active and passive behaviors in the forced-swimming test: implications for animal models of psychopathology.

BACKGROUND: In common with other animal models of psychopathology, the forced-swimming test (FST) suffers from the fact that it involves normal animals. Moreover, powerful antidepressant drugs such as the selective serotonin reuptake inhibitors have been found to give false negatives in this behavioral test. METHODS: To circumvent these theoretical and practical difficulties, we studied the interindividual variability of the behavioral reactivity of rats in the FST. The effects of fluoxetine treatment or of a stressful experience (repeated testing in the FST) were analyzed on various behavioral responses. RESULTS: The following observations were made in replicated experiments: 1) a dimensional behavioral response from passivity to high reactivity in the FST; 2) an antidepressant-like effect of fluoxetine only in a subgroup of animals categorized as low responders on the dimension of passivity-reactivity; and 3) a switch toward passive responses following a past experience of stress, which was corrected by fluoxetine treatment. CONCLUSIONS: It is concluded that a dimensional approach could improve the screening of antidepressant drugs and could aid the development of new ones by identifying the biobehavioral characteristics of responder and nonresponder subjects.

Higher and longer stress-induced increase in dopamine concentrations in the nucleus accumbens of animals predisposed to amphetamine self-administration. A microdialysis study.

Individual vulnerability to the reinforcing effects of drugs appears to be a crucial factor in the development of addiction in humans. In the rat, individuals at risk for psychostimulant self-administration (SA) may be identified from their locomotor reactivity to a stress situation such as exposure to a novel environment. Animals with high locomotor responses to novelty (high responders, HR) acquire amphetamine SA, while animals with low responses (low responders, LR) do not. In this study we examined by microdialysis whether stress-induced extracellular dopamine (DA) concentrations in the nucleus accumbens differed between these two groups of animals. This neurotransmitter was studied because it is thought to be involved in the reinforcing effects of psychostimulants. Furthermore, previous studies have shown that HR animals have a higher basal DOPAC/DA ratio in the nucleus accumbens and higher extracellular concentrations of dopamine in this structure in response to cocaine. The stress procedure used in this experiment consisted of a 10 min tail-pinch. HR animals displayed a higher and longer stress-induced changes in DA concentrations than the LR group. Regression analysis showed that stress-induced changes in DA levels accounted for 75% of the variance observed in the locomotor response to a novel environment. Since higher DA activity in the nucleus accumbens has been reported in animals in which the propensity to psychostimulant SA is induced by brain lesions or life events, this biochemical modification may be one neurobiological substrate of the predisposition to acquire psychostimulant self-administration.

Memory disturbances following ibotenic acid injections in the nucleus basalis magnocellularis of the rat.

The behavioral effects of lesions of the nucleus basalis magnocellularis (NBM) on two spatial discrimination tasks (place navigation and cross maze) were examined in the rat. These tasks were designed to test reference memory. Lesions by bilateral injection of ibotenic acid into the NBM led to a severe and permanent impairment in the learning of the cross maze task. In the learning of the place navigation task, the rats with lesions showed only a transient deficit. Immediately after the removal of the platform, the rats with lesions explored the quadrant (NE) previously containing the platform as long as controls and above chance levels. The rats with lesions did not extinguish exploration like the controls, seen as a reduction both in time spent in the NE quadrant and in swimming activity. Taken together, the results showed that (1) NBM lesions impair reference memory, but (2) spare other aspects of memory. On the basis of the results in the place navigation task, procedural memory was assumed to remain intact after lesion of the NBM. Biochemical assays of choline acetyltransferase (ChAT) in various brain regions in the lesioned animals demonstrated a reduced ChAT activity in the neocortical projections of the NBM but not in the hippocampus. However, it cannot be decided from this work whether behavioral deficits result from the lesion of cholinergic or of non-cholinergic cells in the NBM.

Catecholamines and conditioned blocking: effects of ventral tegmental, septal and frontal 6-hydroxydopamine lesions in rats.

The performance of rats on the conditioned blocking test of learned inattention was measured in a two-way shuttle avoidance task after sham and dopamine (DA)-depleting lesions of the frontal cortex, septum and ventral tegmental area (VTA). Animals were trained on two sessions with tone and/or light as conditioned stimuli. One group was trained with both stimuli on both sessions. A second group was trained on the first session with one stimulus and on the second with both stimuli. The blocking of conditioning to the added stimulus (b) was tested by presenting the stimuli (a and b) separately and measuring the blocking ratio (avoidance to b/a + b) and response latencies. No deficits were recorded on tests of sensory and motor ability. The VTA group alone showed a hyperlocomotor response to apomorphine treatment and did not acquire the avoidance response. The appearance of blocking in the septal group was delayed until the end of the test session. Blocking was mildly attenuated in the frontal group. DA levels were depleted by about 80% and noradrenaline (NA) levels by, respectively, 20 and 50% in frontal and septal areas. This suggests that the level of DA activity or the balance between the activity of DA and NA in frontal and limbic regions can contribute to efficient associative conditioning and/or the normal ability of rats not to attend to a redundant stimulus.

The in vitro production of anti-nuclear antibodies by human peripheral blood mononuclear cells. Demonstration of T cell requirement and soluble inducing factor(s) for anti-nuclear antibodies triggering in patients with systemic lupus erythematosus.

Peripheral blood mononuclear cells (PBMC) of 29 patients with systemic lupus erythematosus (SLE) and 14 normal individuals were investigated for the in vitro production of anti-nuclear antibodies (ANA). Twenty-eight of 29 SLE patients but only one control spontaneously produced ANA in unstimulated PBMC. Pokeweed mitogen induced ANA synthesis in six controls. No detectable ANA was observed in B cell enriched fraction except in two cases of SLE. Recombination of B + T cell enriched fractions and PBMC supernatants from SLE patients could induce B cells to synthesize ANA. These results indicate that: (1) SLE patients spontaneously produced ANA in vitro whereas controls rarely did; (2) autoreactive clones exist in normal individuals but are kept under control and (3) T cell help is required for ANA triggering.

The in vitro production and regulation of anti-double stranded DNA antibodies by peripheral blood mononuclear cells from normals and patients with systemic lupus erythematosus.

The in vitro production of anti-double stranded DNA antibodies (anti-DNA) by peripheral blood mononuclear cells (PBMC) was investigated in 19 patients with systemic lupus erythematosus (SLE) and in 12 normal individuals, using a micro solid phase enzyme immunoassay. PBMC from SLE patients spontaneously produced anti-DNA with a higher frequency (16 of 19) than did PBMC of controls (three of 12). In addition SLE patients produced predominantly IgG antibodies. PWM and DNA enhanced anti-DNA synthesis is spontaneously low and non-producers, but acted as inhibitors in spontaneously high producers. The partial removal of T cells decreased or abolished anti-DNA synthesis in four of nine SLE patients. In contrast the B cell enriched fractions of five of nine SLE and five of seven normal patients produced the same or higher anti-DNA levels than did the corresponding unseparated PBMC. These results suggest evidence for autoreactive B cells in SLE as well as in normals, and therefore the combination of these autoreactive B cells with helper and/or suppressor T cell disorders could lead to the over production of anti-DNA seen in different patients with SLE.