Sex-dependent association between immune function and paw preference in two substrains of C3H mice

Asymmetry in brain modulation of the immune system has been previously described in mice. Paw preference is known to be associated with immune reactivity but the respective roles of sex and genetic background in this association remain to be elucidaded. In this work, made and female mice of the C3H/He and C3H/OuJIco substrains were selected as right- and left-handers. Mitogen-induced lymphoproliferation and natural killer cell activity were then tested. Left-handed female mice of both C3H substrains exhibited higher mitogenesis than right-handers but no association between paw preference and NK cell activity was found in females. Conversely, in males of both substrains, right-handers showed enhanced NK cell activity compared to left-handers but no association between paw preference and mitogenesis was observed in males. Only small differences in the strength, but not in the direction, of the association between paw preference and immune functions were observed between the two C3H substrains. These results show that the association between paw preference and immune reactivity in mice varies according to the immune parameters tested and is a sex-dependent phenomenon in which the genetic background may be involved.     

Natural killer cell activity is associated with brain asymmetry in male mice

The brain is known to modulate the immune system in an asymmetrical way. In mice, there is an association between handedness and immune response and it has also been shown that hemicortical ablation has opposite effects on some immune parameters. An association between autoantibody production and paw preference was previously observed in female mice, but not in males, suggesting that the association between immune reactivity and functional brain asymmetry is a sex-dependent phenomenon. In three independent experiments, natural killer (NK) cell activity, lymphocyte subset distribution, and mitogen-induced lymphoproliferation were assessed in male C3H/OuJIco mice selected for handedness and after unilateral cortical ablation. Handedness was shown to be associated with NK cell activity but not with lymphocyte subset distribution or lymphoproliferation. Left-handers exhibited lower NK cell activity compared to right-handed or ambidextrous animals. In contrast to previous results in female mice, mitogen-induced lymphoproliferation was not associated with handedness in males. Left cortical ablations depressed NK cell activity, while right lesions had no effect. Neither left or right lesions affected lymphocyte subsets. No interaction between paw preference and side of the lesion was found in the modulation of NK cell activity. These and previous data show that the association between paw preference and immune reactivity varies according to the sex of the animal and the immunological parameters studied. This indicates that the brain may modulate different components of the immune system in different ways, through mechanisms apparently involving sex hormones.     

Asymmetrical distribution of brain interleukin-6 depends on lateralization in mice

The central nervous system can regulate the peripheral immune system. Moreover, differences between left and right hemispheres (neurochemical brain asymmetries) and behavioral lateralization (functional brain asymmetries) affect immune responses. The molecular basis of brain-immune interactions remains insufficiently understood. Cytokines regulate immune responses, possibly through activation of the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis activities are related to behavioral lateralization and brain asymmetry. Given IL-6 plays a role in asymmetrical brain immunomodulation, one might expect the IL-6 distribution in brain to be asymmetrical and to depend on behavioral lateralization. In order to start to test this hypothesis, male C57BL/6J mice were selected for paw preference and assessed for IL-6 levels in right and left cortex and hippocampus by enzyme linked immunosorbent assay. The results showed asymmetrical distribution of brain IL-6 in left-pawed animals and ambidextrous animals, but not in right-pawed animals, both in cortex and hippocampus. Furthermore, we found a correlation between IL-6 hemispheric distribution and the degree of behavioral lateralization both in cortex and hippocampus. Altogether, these results suggest that brain IL-6 could be a mediator of asymmetrical immunomodulation by the central nervous system.     

Activation of the hypothalamic-pituitary-adrenal axis in IL-1 beta-converting enzyme-deficient mice

Interleukin-1beta (IL-1beta) plays a key role in immune, behavioral and neuroendocrine responses to inflammation or infection. IL-1beta could also be involved in the response of the hypothalamic-pituitary-adrenal (HPA) axis during stress. Mature IL-1beta derives from a 31-kD precursor (pro-IL-1beta) that is processed by IL-1beta-converting enzyme (ICE). Mice in which the ICE gene has been nullated by homologous recombination were used to investigate the role of IL-1beta in the HPA axis response. Plasma levels of corticosterone and adrenocorticotropic hormone (ACTH) in response to an intraperitoneal injection of 5 microg lipopolysaccharide (LPS) were similar in ICE-deficient mice and wild-type (WT) controls. In contrast, plasma ACTH response to restraint or to 200 ng of rat recombinant IL-1beta (rrIL-1beta) was higher in ICE-deficient mice as compared to WT animals. This hyperreactivity of the HPA axis in ICE knockout mice appears not to be related to the production of plasma IL-1beta or IL-6, which was similar to that of WT mice after rrIL-1beta injection. After lipopolysaccharide, ICE-deficient mice exhibited a smaller increase in plasma-immunoreactive IL-1beta and IL-6 as compared to WT controls. After restraint stress neither increase in plasma IL-1beta nor IL-6 was observed. The mechanisms responsible for the increased reactivity of the HPA axis in ICE-deficient mice may result from a higher sensitivity of the HPA axis to inflammatory cytokines or to cleavage products of pro-IL-1beta processed by non-ICE proteases.     

The Role of the Endocannabinoid System in the Regulation of Hypothalamic-Pituitary-Adrenal Axis Activity

The endocannabinoid system (ECS) is a recently identified neuromodulatory system, which is involved in several physiological processes and in disease. For example, the ECS not only represents the biological substrate of marijuana's effects, but also is known to modulate several neuroendocrine axes, including the hypothalamic-pituitary-adrenal (HPA) axis. Although previous pharmacological studies using plant-derived or synthetic cannabinoids have implied a stimulating action on the HPA axis, more recent findings have led to the conclusion that an endogenous cannabinoid tone might exist, which is actually inhibiting the release of both adrenocorticotrophic hormone and glucocorticoids. Studies using mice lacking cannabinoid receptor CB₁ have demonstrated that presence and activity of these receptors is essential for the regulation of HPA axis activity. Interestingly, the effects of endocannabinoids on the HPA axis are consistent with their neuromodulatory action on brain neurotransmitter systems. Endocannabinoids have been found to mediate the nongenomic glucocorticoid-induced inhibition of the release of corticotrophin-releasing factor within the paraventricular nucleus of the hypothalamus. Altogether, these observations suggest that alterations of the endocannabinoid tone might be associated with the development of stress-related diseases, including anxiety, depression and obesity.     

Differential immune responses in mice with left- and right-turning preference.

Humoral and cell-mediated immune responses of inbred BALB/c male mice were assayed for differential reactivities associated with behavioral sidedness, which was evaluated by spontaneous rotational behavior in a circular cage model system. Mice with left-turning preference had lower in vivo primary IgM and IgG anti-Keyhole Limpet Hemocyanin (KLH) antibody responses, delayed-type hypersensitivity (DTH) responses, and host-resistance against the intracellular bacteria, Listeria monocytogenes, than mice with right-turning preference. The only immune parameter not shown to be associated with turning preference was the secondary humoral immune response to KLH. The weak innate immune response of left-turners for clearance of Listeria showed close intercorrelation with elevated serum IL-6 levels. Serum corticosterone and splenic norepinephrine levels were differentially increased and decreased by infection, respectively. We suggest that the observed differential immune reactivities of individual animals with same age, gender, and genetic background are associated with functional asymmetries within the brain, that the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic innervation are involved in the regulatory brain: immune interconnection after infection, and that the HPA axis and sympathetic nervous system are involved in the brain laterality effects on immune responses.     

Differential changes in the hypothalamic-pituitary-adrenal axis and prolactin responses to stress in early pregnant mice

Stress can cause pregnancy failure but it is unclear how the mother's neuroendocrine system responds to stress to impair mechanisms establishing implantation. We analysed stress-evoked hypothalamic-pituitary-adrenal (HPA) axis responses in early pregnant mice. HPA axis secretory responses to immune stress in early-mid pregnancy were strong and similar to that in virgins, although activation of hypothalamic vasopressin neurones, rather than corticotrophin-releasing hormone neurones, may be more important in the stress response in pregnancy. The site and mode of detrimental glucocorticoid action in pregnancy is not established. Because circulating prolactin is important for progesterone secretion and pregnancy establishment, we also hypothesised that stress negatively impacts on prolactin and its neuroendocrine control systems in early pregnant mice. Basal prolactin secretion was profoundly inhibited by either immune or fasting stress in early pregnancy. Prolactin release is inhibited by tonic dopamine release from tuberoinfundibular (TIDA) neurones. However, immune stress did not increase TIDA neurone activity in the median eminence in pregnant mice [measured by 3,4-dihydroxyphenylacetic acid (DOPAC) content and the DOPAC:dopamine ratio]. By contrast, both immune stress and fasting caused weak induction of Fos in TIDA neurones. However, Fos induction does not always reflect dopamine secretion. Taken together, the data suggest that the stress-evoked profound reduction in prolactin secretion does not involve substantially increased dopamine activity as anticipated. In pregnancy, there was also attenuated recruitment of parvocellular paraventricular nucleus neurones and increased activation of brainstem noradrenergic nuclei after immune stress, indicating that other mechanisms may be involved in the suppression of prolactin secretion. In summary, low prolactin and increased circulating glucocorticoids together may partly explain how a mother's endocrine system mediates stress-induced pregnancy failure.     

HPA axis dysregulation in mice overexpressing corticotropin releasing hormone.

BACKGROUND: Hypersecretion of corticotropin-releasing hormone (CRH) in the brain has been implicated in stress-related human pathologies. We developed a transgenic mouse line overexpressing CRH (CRH-OE) exclusively in neural tissues to assess the effect of long-term CRH overproduction on regulation of the hypothalamic-pituitary-adrenal (HPA) axis. METHODS: Male transgenic CRH-OE(2122) mice on a C57BL/6J background were used. Littermate wildtype mice served as control animals. Basal plasma corticotropin and corticosterone concentrations were measured, and adrenal gland weight was determined. A dexamethasone suppression test measured the effects of long-term CRH hypersecretion on negative feedback control. Additionally, we measured plasma corticosterone concentrations in reaction to stress. RESULTS: CRH-OE(2122) mice showed elevated basal plasma corticosterone concentrations, hypertrophy of the adrenal gland, and dexamethasone nonsuppression. Basal plasma ACTH concentrations of wildtype and CRH-OE(2122) mice did not differ significantly. In reaction to stress, CRH-OE(2122) mice showed a normal corticosterone response. CONCLUSIONS: The HPA axis abnormalities observed in CRH-OE(2122) mice suggest that long-term hypersecretion of CRH in the brain can be a main cause of HPA axis dysregulation. The alterations in HPA axis regulation are reminiscent of changes reported in major depressive disorder. As such, these CRH -OE(2122) mice may model the neuroendocrine changes observed in major depressive disorder.     

Functional brain asymmetry and lymphocyte proliferation in female mice: effects of right and left cortical ablation

Brain immunomodulation may be lateralized as evidenced by two experimental approaches. Using a behavioral paradigm, we have reported an association between asymmetrical brain function and lymphocyte reactivity in mice selected for right- and left-paw preference. Left-handed mice, in comparison to right-handers, exhibit higher mitogen-induced T-lymphocyte proliferation. Using a cortical lesion paradigm in mice, it has been previously shown that each hemicortex modulates in opposite directions lymphocyte reactivity. In these experiments, the role of the brain cortex in the association between paw preference and immune reactivity was assessed by studying mitogen-induced lymphoproliferation in left- and right-handed mice after right or left-cortical ablation. The difference in T-lymphocyte responsiveness between right- and left-handed mice persisted after right lesions but was abolished after left lesions. This immunological effect of left cortical ablation is hypothesized to involve the hypothalamic dopaminergic neurons.     

Differential disinhibition of the neonatal hypothalamic- pituitary-adrenal axis in brain-specific CRH receptor 1-knockout mice

In the adult, corticotropin-releasing hormone (CRH) is the key mediator for the behavioural and neuroendocrine response to stress. It has also been hypothesized that, during postnatal development of the stress system, CRH controls the activity of the HPA axis and mediates the effects of early disturbances, e.g. 24 h of maternal deprivation. In the current study we investigated the function of specific brain corticotropin-releasing hormone receptor type 1 (CRHR1) subpopulations in the control of the HPA axis during postnatal development under basal conditions as well as after 24 h of maternal deprivation. We used two conditional CRHR1-deficient mouse lines which lack this receptor, either specifically in forebrain and limbic structures (Cam-CRHR1) or in all neurons (Nes-CRHR1). Basal circulating corticosterone was increased in Nes-CRHR1 mice compared to controls. Corticosterone response to maternal deprivation was significantly increased in both CRHR1-deficient lines. In the paraventricular nucleus, Cam-CRHR1 animals displayed enhanced CRH and decreased vasopressin expression levels. In contrast, gene expression in Nes-CRHR1 pups was strikingly similar to that in maternally deprived control pups. Furthermore, maternal deprivation resulted in an enhanced response of Cam-CRHR1 pups in the brain, while expression levels in Nes-CRHR1 mouse pups were mostly unchanged. Our results demonstrate that brainstem and/or hypothalamic CRHR1 contribute to the suppression of basal corticosterone secretion in the neonate, while limbic and/or forebrain CRHR1 dampen the activation of the neonatal HPA axis induced by maternal deprivation.     

Inhibitory Function of the Dorsomedial Hypothalamic Nucleus on the Hypothalamic–Pituitary–Adrenal Axis Response to an Emotional Stressor but not Immune Challenge

Accumulating evidence implicates the dorsomedial hypothalamic nucleus (DMH) in the regulation of autonomic and neuroendocrine stress responses. However, although projections from the DMH to the paraventricular hypothalamic nucleus (PVN), which is the critical site of the neuroendocrine stress axis, have been described, the impact of DMH neurones in the modulation of hypothalamic‐pituitary‐adrenal (HPA) axis activation during stress is not fully understood. The present study aimed to investigate the role of the DMH in HPA axis responses to different types of stimuli. Male Sprague–Dawley rats fitted with a chronic jugular venous catheter were exposed to either an emotional stressor (elevated platform‐exposure) or immune challenge (systemic interleukin‐1β administration). Bilateral electrolytic lesions of the DMH disinhibited HPA axis responses to the emotional stressor, as indicated by higher plasma adrenocorticotrophic hormone levels during and after elevated platform exposure in lesioned animals compared to sham‐lesioned controls. Moreover, DMH‐lesioned animals showed increased neuronal activation in the PVN, as indicated by a higher c‐Fos expression after elevated‐platform exposure compared to controls. By contrast, DMH‐lesions had no effects on HPA axis responses to immune challenge. Taken together, our data suggest an inhibitory role of DMH neurones on stress‐induced HPA axis activation that is dependent upon the nature of the stimulus being important in response to an emotional stressor but not to immune challenge.     

The dynamics of the hypothalamic-pituitary-adrenal axis during maternal deprivation

A close contact between the dam and the litter is essential for the normal development of the hypothalamic-pituitary-adrenal (HPA) axis in rats and mice. Maternal signals, as licking and feeding, have been shown to sustain the HPA axis of the pups in a hypo-responsive state. Disruption of this mother-pup interaction by 24 h of maternal deprivation activates the otherwise quiescent stress system of the neonates, resulting in an enhanced adrenal sensitivity to adrenocorticotropic hormone (ACTH) and a decreased expression of central HPA markers, such as corticotropin-releasing hormone (CRH). However, the dynamics of these central and peripheral changes over the 24h period are largely unknown. In this study, we examined the time course of some of the central and peripheral indices of HPA activity during 24 h of maternal deprivation. We measured corticosterone and ACTH in the blood as well as CRH, mineralocorticoid and glucocorticoid receptor expression in the brain. Our results demonstrate that each of the components of the HPA axis responds to maternal deprivation at different time points following removal of the mother and with a very specific time course. The main activation of the HPA axis occurred between 4 h and 8 h of maternal absence. By contrast, during the second half of the deprivation period, negativefeedback mechanisms restrained the further increase in ACTH and corticosterone release. We conclude that maternal deprivation triggers a cascade of sequential changes at the various levels of the stress system, and that measuring only one aspect of the system at one time point does not accurately reflect the dynamic alterations of the HPA axis.     

IL-10 as a mediator in the HPA axis and brain

Certain functional interactions between the nervous, endocrine, and immune systems are mediated by cytokines. The pro-inflammatory cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF) were among the first to be recognized in this regard. A modulator of these cytokines, IL-10, has been shown to have a wide range of activities in the immune system; in this review, we describe its production and actions in the hypothalamic–pituitary–adrenal (HPA) axis. IL-10 is produced in pituitary, hypothalamic, and neural tissues in addition to lymphocytes. IL-10 enhances corticotropin releasing factor (CRF) and corticotropin (ACTH) production in hypothalamic and pituitary tissues, respectively. Further downstream in the HPA axis endogenous IL-10 has the potential to contribute to regulation of glucocorticosteroid production both tonically and following stressors. Our studies and those of others reviewed here indicate that IL-10 may be an important endogenous regulator in HPA axis activity and in CNS pathologies such as multiple sclerosis. Thus, in addition to its more widely recognized role in immunity, IL-10's neuroendocrine activities described here point to its role as an important regulator in communication between the immune and neuroendocrine systems.     

The hypothalamic-neurohypophysial system regulates the hypothalamic-pituitary-adrenal axis under stress: an old concept revisited

Mammals respond to challenging situations with characteristic changes in their behaviour as well as in autonomic and neuroendocrine parameters aimed at reinstating their disturbed homeostasis. Among such so-called coping strategies, alterations of the hypothalamic-pituitary-adrenal (HPA) axis play a crucial role. Today it is generally accepted that parvocellular neurones of the hypothalamic paraventricular nucleus control the secretion of corticotropin and corticosterone by synthesising and releasing both the corticotropin-releasing hormone and vasopressin (AVP). Recent evidence supports and embellishes the old hypothesis that AVP and the structurally related neuropeptide, oxytocin, originating from the hypothalamic-neurohypophysial system (HNS) might directly affect HPA axis activity. This review presents data supporting the concept of HNS effects on HPA axis activity and outlines their possible impact on some aspects of behavioural regulation and psychopathology.     

Lateralization and catecholaminergic neuroimmunomodulation: prazosin,an alpha1/alpha2-adrenergic receptor antagonist,suppresses interleukin-1 and increases interleukin-10 production induced by lipopolysaccharides

OBJECTIVE: The brain has previously been shown to asymmetrically modulate neurochemical, neuroendocrine and immune responses to lipopolysaccharides (LPS). As these responses are reversed by a chemical sympathectomy, it can be hypothesized that the asymmetry in the functioning of the sympathetic nervous system may be one of the mechanisms by which the brain hemispheres asymmetrically modulate immune reactivity. METHODS: The effects of prazosin, an alpha1/alpha2-adrenergic receptor antagonist, on the production of interleukin (IL)-1beta and IL-10 induced by LPS was studied in mice selected for their paw preference. RESULTS: Two hours after intraperitoneal injection of 5 microg of LPS, plasma levels of IL-1beta were higher in right-pawed mice as compared to left-pawed or ambidextrous animals. No lateralization effect was observed for LPS-induced plasma IL-10 levels. Prazosin, 10 mg/kg, injected intraperitoneally half an hour before LPS, reduced plasma levels of IL-1beta and abolished the effect of lateralization. By contrast, prazosin drastically increased plasma levels of IL-10 in response to LPS and the production of corticosterone in untreated controls. CONCLUSIONS: These results suggest that the catecholaminergic modulation of immune reactivity depends on lateralization. This work further demonstrates that prazosin is endowed with anti-inflammatory properties that may be considered side effects of this drug, which is widely prescribed in the treatment of hypertension.     

Mice selected for high versus low stress reactivity: a new animal model for affective disorders

Affective disorders such as major depression are among the most prevalent and costly diseases of the central nervous system, but the underlying mechanisms are still poorly understood. In recent years, it has become evident that alterations of the stress hormone system, in particular dysfunctions (hyper- or hypo-activity) of the hypothalamic-pituitary-adrenal (HPA) axis, play a prominent role in the development of major depressive disorders. Therefore, we aimed to generate a new animal model comprising these neuroendocrine core symptoms in order to unravel parameters underlying increased or decreased stress reactivity. Starting from a population of outbred mice (parental generation: 100 males and 100 females of the CD-1 strain), two breeding lines were established according to the outcome of a 'stress reactivity test' (SRT), consisting of a 15-min restraint period and tail blood samplings immediately before and after exposure to the stressor. Mice showing a very high or a very low secretion of corticosterone in the SRT, i.e. animals expressing a hyper- or a hypo-reactivity of the HPA axis, were selected for the 'high reactivity' (HR) and the 'low reactivity' (LR) breeding line, respectively. Additionally, a third breeding line was established consisting of animals with an 'intermediate reactivity' (IR) in the SRT. Already in the first generation, i.e. animals derived from breeding pairs selected from the parental generation, significant differences in the reactivity of the HPA axis between HR, IR, and LR mice were observed. Moreover, these differences were found across all subsequent generations and could be increased by selective breeding, which indicates a genetic basis of the respective phenotype. Repeated testing of individuals in the SRT furthermore proved that the observed differences in stress responsiveness are present already early in life and can be regarded as a robust genetic predisposition. Tests investigating the animal's emotionality including anxiety-related behavior, exploratory drive, locomotor activity, and depression-like behavior point to phenotypic similarities with behavioral changes observed in depressive patients. In general, HR males and females were 'hyperactive' in some behavioral paradigms, resembling symptoms of restlessness and agitation often seen in melancholic depression. LR mice, on the other hand, showed more passive-aggressive coping styles, corresponding to signs of retardation and retreat observed in atypical depression. Several morphometric and neuroendocrine findings further support this view. For example, monitoring the circadian rhythm of glucocorticoid secretion revealed clearly increased trough levels in HR mice, resulting in a flattened diurnal rhythm, again adding to the neuroendocrine similarities to patients suffering from melancholic depression. Taken together, our results suggest that distinct mechanisms influencing the function and regulation of the HPA axis are involved in the respective behavioral and neurobiological endophenotypes. Thus, the generated HR/IR/LR mouse lines can be a valuable model to elucidate molecular genetic, neuroendocrine, and behavioral parameters associated with altered stress reactivity, thereby improving our understanding of affective disorders, presumably including the symptomatology and pathophysiology of specific subtypes of major depression.     

NEUROENDOCRINE PERSPECTIVES ON SOCIAL ATTACHMENT AND LOVE

The purpose of this paper is to review existing behavioral and neuroendocrine perspectives on social attachment and love. Both love and social attachments function to facilitate reproduction, provide a sense of safety, and reduce anxiety or stress. Because social attachment is an essential component of love, understanding attachment formation is an important step toward identifying the neurobiological substrates of love. Studies of pair bonding in monogamous rodents, such as prairie voles, and maternal attachment in precocial ungulates offer the most accessible animal models for the study of mechanisms underlying selective social attachments and the propensity to develop social bonds. Parental behavior and sexual behavior, even in the absence of selective social behaviors, are associated with the concept of love; the analysis of reproductive behaviors, which is far more extensive than our understanding of social attachment, also suggests neuroendocrine substrates for love. A review of these literatures reveals a recurrent association between high levels of activity in the hypothalamic–pituitary–adrenal (HPA) axis and the subsequent expression of social behaviors and attachments. Positive social behaviors, including social bonds, may reduce HPA axis activity, while in some cases negative social interactions can have the opposite effect. Central neuropeptides, and especially oxytocin and vasopressin have been implicated both in social bonding and in the central control of the HPA axis. In prairie voles, which show clear evidence of pair bonds, oxytocin is capable of increasing positive social behaviors and both oxytocin and social interactions reduce activity in the HPA axis. Social interactions and attachment involve endocrine systems capable of decreasing HPA reactivity and modulating the autonomic nervous system, perhaps accounting for health benefits that are attributed to loving relationships. © 1998 Elsevier Science Ltd. All rights reserved.     

Reduced anxiety‐like behavior and central neurochemical change in germ‐free mice

Background There is increasing interest in the gut‐brain axis and the role intestinal microbiota may play in communication between these two systems. Acquisition of intestinal microbiota in the immediate postnatal period has a defining impact on the development and function of the gastrointestinal, immune, neuroendocrine and metabolic systems. For example, the presence of gut microbiota regulates the set point for hypothalamic‐pituitary‐adrenal (HPA) axis activity. Methods We investigated basal behavior of adult germ‐free (GF), Swiss Webster female mice in the elevated plus maze (EPM) and compared this to conventionally reared specific pathogen free (SPF) mice. Additionally, we measured brain mRNA expression of genes implicated in anxiety and stress‐reactivity. Key Results Germ‐free mice, compared to SPF mice, exhibited basal behavior in the EPM that can be interpreted as anxiolytic. Altered GF behavior was accompanied by a decrease in the N‐methyl‐D‐aspartate receptor subunit NR2B mRNA expression in the central amygdala, increased brain‐derived neurotrophic factor expression and decreased serotonin receptor 1A (5HT1A) expression in the dentate granule layer of the hippocampus. Conclusions & Inferences We conclude that the presence or absence of conventional intestinal microbiota influences the development of behavior, and is accompanied by neurochemical changes in the brain.     

Fatigue and regulation of the hypothalamo-pituitary-adrenal axis in multiple sclerosis

BACKGROUND: Fatigue is a common and disabling symptom in patients with multiple sclerosis (MS). Underlying mechanisms postulated so far have involved localization of brain lesions and abnormalities of the neuroendocrine system and cytokine regulation. OBJECTIVE: To investigate the relationship between fatigue and the hypothalamo-pituitary-adrenal (HPA) axis in patients with MS. DESIGN: A prospective survey. SETTING: Outpatient and inpatient study at the Max Planck Institute of Psychiatry, Munich, Germany. PATIENTS: Thirty-one patients with clinically definite MS, a relapsing-remitting disease course, and without MS-specific treatment. INTERVENTIONS: Assessment of fatigue with 3 questionnaires: the Fatigue Severity Scale (FSS), the Modified Fatigue Impact Scale (MFIS), and the Visual Analog Scale. Assessment of HPA axis regulation with the combined dexamethasone-corticotropin releasing hormone (Dex-CRH) test. RESULTS: The FSS score was significantly correlated with the MFIS score. Patients with fatigue had significantly elevated adrenocorticotropin (ACTH) levels in the combined Dex-CRH test. CONCLUSIONS: In contrast to results for chronic fatigue syndrome, where a hyporeactivity of the HPA axis has been shown, MS patients with fatigue exhibited a higher activity of the HPA axis than those without fatigue, as evidenced by significantly increased ACTH concentrations. Proinflammatory cytokines, known to be elevated in patients with MS, may cause both HPA axis alterations and fatigue.