Marie-Christine Pardon

Stress reactivity of the brain noradrenergic system in three rat strains differing in their neuroendocrine and behavioral responses to stress: Implications for susceptibility to stress-related neuropsychiatric disorders

The brain noradrenergic system is activated by stress, modulating the activity of forebrain regions involved in behavioral and neuroendocrine responses to stress. In this study, we characterized brain noradrenergic reactivity to acute immobilization stress in three rat strains that differ in their neuroendocrine stress response: the inbred Lewis (Lew) and Wistar-Kyoto (WKY) rats, and outbred Sprague-Dawley (SD) rats. Noradrenergic reactivity was assessed by measuring tyrosine hydroxylase mRNA expression in locus coeruleus, and norepinephrine release in the lateral bed nucleus of the stria terminalis. Behavioral measures of arousal and acute stress responsivity included locomotion in a novel environment, fear-potentiated startle, and stress-induced reductions in social interaction and open-arm exploration on the elevated-plus maze. Neuroendocrine responses were assessed by plasma adrenocorticotropic hormone. Compared to SD, adrenocorticotropic hormone responses of Lew rats were blunted, whereas those of WKY were enhanced. The behavioral effects of stress were similar in Lew and SD rats, despite baseline differences. Lew had similar elevations of tyrosine hydroxylase mRNA, and initially greater norepinephrine release in the lateral bed nucleus of the stria terminalis during stress, although both noradrenergic responses returned toward baseline more rapidly than in SD rats. WKY rats showed depressed baseline startle and lower baseline exploratory and social behavior than SD. However, unlike the Lew or SD rats, WKY exhibited a lack both of fear potentiation of the startle response and of stress-induced reductions in exploratory and social behavior, indicating attenuated stress responsivity. Acute noradrenergic reactivity to stress, measured by either tyrosine hydroxylase mRNA levels or norepinephrine release, was also attenuated in WKY rats. Thus, reduced arousal and behavioral responsivity in WKY rats may be related to deficient brain noradrenergic reactivity. This deficit may alter their ability to cope with stress, resulting in the exaggerated neuroendocrine responses and increased susceptibility to stress-related pathology exhibited by this strain.

5-HT1A autoreceptor desensitization by chronic ultramild stress in mice.

Electrophysiological and biochemical approaches were used to assess possible changes in central 5-HT neurotransmission in mice that had been subjected to chronic ultramild stress for 8 weeks. This treatment produced a significant decrease in the potency of the 5-HT1A agonist ipsapirone to inhibit the electrical activity of serotoninergic neurons in the dorsal raphe nucleus, without modifying 5-HT1A receptor binding in various brain areas. These data demonstrate that chronic ultramild stress triggers a long term and durable functional desensitization of somatodendritic 5-HT1A autoreceptors in mice.

Chronic cold stress sensitizes brain noradrenergic reactivity and noradrenergic facilitation of the HPA stress response in Wistar Kyoto rats

Many psychiatric disorders, including depression, post-traumatic stress disorder and other anxiety disorders, result from an interaction between genetic factors and exposure to a sufficiently sensitizing environmental stressor. The inbred Wistar Kyoto (WKY) rat strain has been proposed as a model of stress vulnerability, exhibiting an exaggerated hypothalamic-pituitary-adrenal (HPA) response to stress and susceptibility to gastric ulceration. Previously, we showed that stress-activation of the brain noradrenergic system was deficient in WKY rats, and they lacked noradrenergic facilitation of the HPA response in the lateral bed nucleus of the stria terminalis (BSTL), compared to outbred Sprague-Dawley (SD) controls. Deficient modulatory function of the noradrenergic system may contribute to the stress susceptibility of WKY rats. Thus, we investigated the influence of a sensitizing stimulus, chronic intermittent cold exposure, on neuroendocrine and noradrenergic stress reactivity, and on noradrenergic facilitation of the HPA response in these two strains. Chronic cold exposure (7 days, 4 h/day, 4 degrees C) potentiated activation of the HPA axis by acute immobilization stress, assessed by measuring plasma adrenocorticotropic hormone (ACTH), in both strains, although to a greater extent in WKY rats, and enhanced stress-induced norepinephrine (NE) release in BSTL of WKY but not SD rats. We then compared the influence of chronic cold exposure on noradrenergic modulation of the HPA stress response in BSTL, by measuring changes in acute stress-induced elevation of plasma ACTH after microinjecting the alpha(1)-adrenoreceptor antagonist benoxathian into the BSTL. As shown previously, benoxathian attenuated stress-induced ACTH secretion in control SD but not control WKY rats. After chronic cold, the ACTH response to acute stress was attenuated by benoxathian administration into BSTL of both strains, such that the WKY response was not different from that of SD rats. Thus, chronic cold not only sensitized the release of NE in BSTL of WKY rats, but also restored noradrenergic facilitation of their already-elevated HPA response. Such functional sensitization of a previously-deficient facilitatory system may be one mechanism whereby exposure to repeated or severe stress may induce pathologic dysregulation of the stress response in susceptible individuals, resulting in psychiatric illness.

What do we know about the long-term consequences of stress on ageing and the progression of age-related neurodegenerative disorders?

The aim of this paper is to review evidences that stressful events throughout life can have a long-term impact on ageing and the progression of Alzheimers disease. As early as the prenatal or neonatal period, stress can alter the rate of cognitive decline and neurodegenerative changes in the brain in a stressor-dependent manner, with prenatal restraint and maternal separation usually causing damage to the brain, whereas neonatal handling was found protective. The occurrence of negative outcomes of early stress can, however, be reversed by subsequent events known to be beneficial to the ageing process. After the early developmental period, it is currently unknown how stress will impact on the ageing process, due to a lack of studies. On the other hand, there is evidence of a lack of plasticity of the brain monoaminergic systems in response to stress with age, and of age-dependent changes in the immediate impact of stress, which is greater in subjects vulnerable to age-related cognitive decline. In addition, vulnerability to stress enhances the risk of developing Alzheimers disease in humans and chronic substantial stress in animal models of the disease accelerates both the onset and progression of pathological markers in the brain. In an attempt to integrate these findings, a hypothesis is presented here whereby stress, in susceptible individuals, would precipitate age-related cognitive decline and hippocampal integrity during normal and pathological ageing, but will only affect the progression of pathological markers of Alzheimers disease in the presence of other risk factors to this neuropathological disorder.

Regulation of the norepinephrine transporter by chronic administration of antidepressants

BACKGROUND Downregulation of serotonin transporter was observed previously after chronic treatment with selective serotonin reuptake inhibitors (SSRIs) but not selective norepinephrine reuptake inhibitors (NRIs). This study investigated if chronic treatment of rats with selective NRIs or SSRIs also affected the norepinephrine transporter (NET). METHODS Rats were treated for 3 to 6 weeks by osmotic minipumps with either the selective NRIs, desipramine, or the SSRI paroxetine. RESULTS [(3)H]nisoxetine binding sites as well as [(3)H]norepinephrine uptake were decreased in hippocampus and cortex after treatment with desipramine. By contrast, paroxetine-treated rats showed no alteration in either [(3)H]nisoxetine binding or [(3)H]norepinephrine uptake. NET messenger RNA levels in the locus coeruleus were unchanged by desipramine treatment. CONCLUSIONS These results demonstrate that the marked decrease in NET density 1) is not a consequence of a decrease in gene expression; 2) was caused only by a selective NRI; and 3) was associated with a parallel decrease in norepinephrine uptake.

Social threat and novel cage stress-induced sustained extracellular-regulated kinase1/2 (ERK1/2) phosphorylation but differential modulation of brain-derived neurotrophic factor (BDNF) expression in the hippocampus of NMRI mice.

The extracellular signal-regulated kinase1/2 (ERK1/2) pathway has a key role in cell survival and brain plasticity, processes that are impaired following exposure to stressful situations. We have recently validated two repeated intermittent stress procedures in male NMRI mice, social threat and repeated exposure to a novel cage, which result in clear behavioral effects following 4 weeks of application. The present results demonstrate that both repeated intermittent stress procedures alter the activity of the ERK1/2 pathway in the brain, as shown by changes in phosphorylated ERK1/2 (phospho-ERK1/2) protein expression and in the expression of downstream proteins: phosphorylated cAMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF), in the hippocampus, the frontal cortex and the hypothalamus. The hippocampus showed greater responsiveness to stress as the two stressors increased phospho-ERK1/2 and BDNF expression under acute condition. Following repeated stress, hyperphosphorylation of ERK1/2 was associated with up-regulation of hippocampal BDNF expression in the social threat group but not in mice exposed to novel cage. This lack of a pro-survival effect of ERK1/2 with repeated novel cage exposure may constitute an early event in stress-mediated brain pathology. The sustained BDNF up-regulation in the hippocampi of mice subjected to repeated social threat could be related to rewarding aspects of aggressive interactions, suggested by our previous studies.

Role of neurotrophic factors in behavioral processes: implications for the treatment of psychiatric and neurodegenerative disorders.

Neurotrophins are important regulators of neuronal function in the developing and adult brain and thus play a critical role in sustaining normal behavioral function. Brain-derived neurotrophic factor (BDNF) has been the most widely studied neurotrophin because of its important role as modulator of synaptic plasticity, which is essential to the regulation of experience-dependent behavior. Extensive work implicates BDNF in hippocampus-dependent forms of learning and memory, although it also regulates other cognitive processes. A role for BDNF in anxiety-related disorders and aggressive behavior can also be suspected. More importantly, BDNF signaling has recently emerged as a key player in the development of drug addiction and is well known to be involved in adaptation to stress and stress-related disorders. NGF in the other hand is thought to be involved in aggression and alcohol dependence. Finally, BDNF appears to participate in the therapeutic effects of drugs and interventions capable of reversing or attenuating behavioral disturbances relevant to psychiatric and neurodegenerative disorders. Compounds mimicking BDNF signaling, however, are unlikely to be used in a clinical context, given their adverse side effects and pharmacokinetic limitations.

Effects of Ginkgo biloba extract (EGb 761) on learning and possible actions on aging

A study of the effect of Ginkgo biloba extract (EGb 761) has shown enhancing effects on training in adult and aged Swiss mice. An analysis of inbred mice has confirmed this sensitivity to EGb 761, but depending on the strains, with different effects at different ages. The most interesting results are related to improvements in performances observed with aged mice of the DBA/2J strain. The results obtained with inbred strains in the study of the mossy fibers of the hippocampus make it possible to suggest a link between the improvements in training and the histological structure of the hippocampus. This possibility, which can be confirmed by further studies, is presented here.

Repeated sensory contact with aggressive mice rapidly leads to an anticipatory increase in core body temperature and physical activity that precedes the onset of aversive responding.

The present study investigated whether the ‘psychological threat’ induced by sensory contact with an aggressive conspecific would be a sufficient factor in inducing behavioural and physiological disturbances. Repeated sensory contact with an aggressive mouse (social threat) in a partitioned cage was compared with repeated exposure to a novel partitioned cage in male NMRI mice. We first examined parameters of stress responsiveness (body weight, plasma corticosterone levels, frequency of self‐grooming and defecation). The temperature and physical activity responses to stress were also recorded during and after the 4 weeks of stress using radiotelemetry. Finally, cognitivo‐emotional performance was assessed after acute stress and 2 and 4 weeks of stress by measuring decision making, sequential alternation performance and behaviour in the elevated T‐maze. Social threat had a greater impact than novel cage exposure on most parameters of stress responsiveness, although mice did not habituate to either stressor. Social threat rapidly led to an anticipatory rise in core body temperature and physical activity before the scheduled stress sessions. Such anticipation developed within the first week and persisted for 9 days after ending the stress procedure. Some memory impairment in the sequential alternation test was found in stressed mice, independent of the stressor. After 4 weeks of stress, inhibitory avoidance in the elevated T‐maze was enhanced in socially stressed mice and reduced in novel cage mice. The sustained anticipation of stress in the social threat group preceded aversive responding. It remains to be established whether anticipation contributes to the development of aversive responses.

Age-dependent effects of a chronic ultramild stress procedure on open-field behaviour in B6D2F1 female mice

Few studies have been devoted to the interaction between age and stress. However, in view of the age-related changes in various components of the stress responses, the effects of stress may not be constant with age. In this study, we used a dimensional approach to compare open-field behaviour of B6D2F1 female mice, aged 5-6, 11-12, 17-18 and 23-24 months, exposed to a chronic ultramild stress (CUMS) procedure, solely based on nonnociceptive socioenvironmental stressors. Three behavioural dimensions emerged from the principal-component analysis; these were labelled as motor reactivity, exploratory activity, and emotional reactivity. Despite a major effect of age on the three dimensions, we could not conclude that CUMS had any influence as a function the age of the subjects. At all ages, CUMS increased motor activity and had no clear-cut effect on emotional reactivity and exploratory activity. The results are discussed in terms of the influence of the nature of the stressors on behavioural responses to novelty.