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Preclinical and some clinical studies suggest a relationship between perturbation in magnesium (Mg2+) homeostasis and pathological anxiety, although the underlying mechanisms remain largely unknown. Since there is evidence that Mg2+ modulates the hypothalamic-pituitary adrenal (HPA) axis, we tested whether enhanced anxiety-like behaviour can be reliably elicited by dietary Mg2+ deficiency and whether Mg2+ deficiency is associated with altered HPA axis function. Compared with controls, Mg2+ deficient mice did indeed display enhanced anxiety-related behaviour in a battery of established anxiety tests. The enhanced anxiety-related behaviour of Mg2+ deficient mice was sensitive to chronic desipramine treatment in the hyponeophagia test and to acute diazepam treatment in the open arm exposure test. Mg2+ deficiency caused an increase in the transcription of the corticotropin releasing hormone in the paraventricular hypothalamic nucleus (PVN), and elevated ACTH plasma levels, pointing to an enhanced set-point of the HPA axis. Chronic treatment with desipramine reversed the identified abnormalities of the stress axis. Functional mapping of neuronal activity using c-Fos revealed hyper-excitability in the PVN of anxious Mg2+ deficient mice and its normalisation through diazepam treatment. Overall, the present findings demonstrate the robustness and validity of the Mg2+ deficiency model as a mouse model of enhanced anxiety, showing sensitivity to treatment with anxiolytics and antidepressants. It is further suggested that dysregulations in the HPA axis may contribute to the hyper-emotionality in response to dietary induced hypomagnesaemia. This article is part of a Special Issue entitled ‘Anxiety and Depression’., Highlights ► Robustness and validity of the Mg2+ deficiency model of enhanced anxiety is shown. ► The Mg2+ deficiency model is sensitive to anxiolytic/antidepressant treatments. ► We suggest an inverse relationship between Mg2+ and anxiety. ► An aberrant HPA axis may contribute to the hyper-emotionality of Mg2+ deficiency.

A relationship between zinc (Zn)-deficiency and mood disorders has been suspected. Here we examined for the first time whether experimentally-induced Zn-deficiency in mice would alter depression- and anxiety-related behaviour assessed in established tests and whether these alterations would be sensitive to antidepressant treatment. Mice receiving a Zn-deficient diet (40% of daily requirement) had similar homecage and open field activity compared to normally fed mice, but displayed enhanced depression-like behaviour in both the forced swim and tail suspension tests which was reversed by chronic desipramine treatment. An anxiogenic effect of Zn-deficiency prevented by chronic desipramine and Hypericum perforatum treatment was observed in the novelty suppressed feeding test, but not in other anxiety tests performed. Zn-deficient mice showed exaggerated stress-evoked immediate-early gene expression in the amygdala which was normalised following DMI treatment. Taken together these data support the link between low Zn levels and depression-like behaviour and suggest experimentally-induced Zn deficiency as a putative model of depression in mice.

Hypersecretion of central corticotropin-releasing hormone (CRH) has been implicated in the pathophysiology of affective disorders. Both, basic and clinical studies suggested that disrupting CRH signaling through CRH type 1 receptors (CRH-R1) can ameliorate stress-related clinical conditions. To study the effects of CRH-R1 blockade upon CRH-elicited behavioral and neurochemical changes we created different mouse lines overexpressing CRH in distinct spatially restricted patterns. CRH overexpression in the entire central nervous system, but not when overexpressed in specific forebrain regions, resulted in stress-induced hypersecretion of stress hormones and increased active stress-coping behavior reflected by reduced immobility in the forced swim test and tail suspension test. These changes were related to acute effects of overexpressed CRH as they were normalized by CRH-R1 antagonist treatment and recapitulated the effect of stress-induced activation of the endogenous CRH system. Moreover, we identified enhanced noradrenergic activity as potential molecular mechanism underlying increased active stress-coping behavior observed in these animals. Thus, these transgenic mouse lines may serve as animal models for stress-elicited pathologies and treatments that target the central CRH system.

BACKGROUND. In the immature developing fetal brain, amino acids (such as γ-aminobutyric acid, and taurine) and monoamines (serotonin, noradrenaline, and dopamine) act as developmental signals or regulators. In subjects with Down syndrome, dysfunctional brain development is evident from birth as reduction in brain weight, as well as volume reductions in specific brain regions, and an altered number of neurons, dendrites, and dendritic branching is observed. However, mechanisms that underlie the observed dysfunctional brain development in Down syndrome are not clear. OBJECTIVES. Because diverse amino acids and monoamines are critical for normal brain development, we wanted to determine whether dysfunctional brain development observed in subjects with Down syndrome is associated with altered brain amino acid and/or monoamine levels. DESIGN/METHODS. We quantified tissue concentrations of diverse amino acids, including γ-aminobutyric acid and taurine, and the monoamines serotonin, noradrenaline, and dopamine in the frontal cortex of fetal Down syndrome tissue at a gestational age of ∼20 weeks versus age-matched control aborted fetuses. RESULTS. Fetal Down syndrome brains showed reductions in the levels of serotonin, γ-aminobutyric acid, taurine, and dopamine in the frontal cortex. No alteration in the levels of arginine, aspartate, glutamine, glutamate, glycine, histidine, serine, or noradrenaline was observed. CONCLUSIONS. Serotonin, γ-aminobutyric acid, taurine, and dopamine are critical for the acquisition of brain morphologic features, neuronal and glia proliferation, and synapse formation. The detected reductions in the levels of these neurotransmitters may indicate potential mechanisms for the observed dysfunctional neuronal development in the Down syndrome fetal brain.

Antagonists of the substance P (SP) preferring neurokinin 1 receptor (NK1R) represent a promising novel class of drugs for the treatment of stress-related disorders such as depression and anxiety disorders; however, the involved neuronal pathways releasing SP in response to stressors are ill defined. By using in vivo microdialysis in combination with a highly sensitive and selective radioimmunoassay we found that exposure to forced swim stress increased SP release in the rat lateral septum (LS), a key area in processing emotions and stress responses. Acute administration of the selective NK1R antagonist L-822429 injected either systemically or locally into the LS reduced passive and facilitated active stress-coping strategies in the forced swim test. This effect seems to be mediated by enhanced intraseptal serotonergic transmission via serotonin (5-HT)1A receptors since NK1R blockade reversed the swim stress-induced decrease to an increase in extracellular 5-HT efflux, and furthermore the behavioral effects of L-822429 were blocked by intraseptal 5-HT1A receptor antagonism. A direct heterosynaptic regulation by NK1R on 5-HT release from serotonergic fibers was ruled out by immunocytochemistry at the light and electron microscopic level indicating involvement of GABAergic interneuron(s) in this interaction. Taken together, our data identify the LS as a critical brain area for the involvement of SP transmission in the modulation of stress responses and demonstrate that NK1R blockade can elicit a functionally significant facilitatory effect on 5-HT transmission, which does not necessarily involve the previously proposed interaction with neuronal firing at the cell body level of raphe neurons.

Reduced daily intake of magnesium (Mg(2+)) is suggested to contribute to depression. Indeed, preclinical studies show dietary magnesium restriction (MgR) elicits enhanced depression-like behaviour establishing a causal relationship. Amongst other mechanisms, Mg(2+) gates the activity of N-methyl-D-asparte (NMDA) receptors; however, it is not known whether reduced dietary Mg(2+) intake can indeed affect brain NMDA receptor complexes. Thus, the aim of the current study was to reveal whether MgR induces changes in brain NMDA receptor subunit composition that would indicate altered NMDA receptor regulation. The results revealed that enhanced depression-like behaviour elicited by MgR was associated with reduced amygdala-hypothalamic protein levels of GluN1-containing NMDA complexes. No change in GluN1 mRNA levels was observed indicating posttranslational changes were induced by dietary Mg(2+) restriction. To reveal possible protein interaction partners, GluN1 immunoprecipitation and proximity ligation assays were carried out revealing the expected GluN1 subunit association with GluN2A, GluN2B, but also novel interactions with GluA1, GluA2 in addition to known downstream signalling proteins. Chronic paroxetine treatment in MgR mice normalized enhanced depression-like behaviour, but did not alter protein levels of GluN1-containing NMDA receptors, indicating targets downstream of the NMDA receptor. Collectively, present data demonstrate that dietary MgR alters brain levels of GluN1-containing NMDA receptor complexes, containing GluN2A, GluN2B, AMPA receptors GluA1, GluA2 and several protein kinases. These data indicate that the modulation of dietary Mg(2+) intake may alter the function and signalling of this receptor complex indicating its involvement in the enhanced depression-like behaviour elicited by MgR.

There is evidence to suggest that low levels of magnesium (Mg) are associated with affective disorders, however, causality and central neurobiological mechanisms of this link are largely unproven. We have recently shown that mice fed a low Mg-containing diet (10% of daily requirement) display enhanced depression-like behavior sensitive to chronic antidepressant treatment. The aim of the present study was to utilize this model to gain insight into underlying mechanisms by quantifying amygdala/hypothalamus protein expression using gel-based proteomics and correlating changes in protein expression with changes in depression-like behavior. Mice fed Mg-restricted diet displayed reduced brain Mg tissue levels and altered expression of four proteins, N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (DDAH1), manganese-superoxide dismutase (MnSOD), glutamate dehydrogenase 1 (GDH1) and voltage-dependent anion channel 1. The observed alterations in protein expression may indicate increased nitric oxide production, increased anti-oxidant response to increased oxidative stress and potential alteration in energy metabolism. Aberrant expressions of DDAH1, MnSOD and GDH1 were normalized by chronic paroxetine treatment which also normalized the enhanced depression-like behavior, strengthening the link between the changes in these proteins and depression-like behavior. Collectively, these findings provide first evidence of low magnesium-induced alteration in brain protein levels and biochemical pathways, contributing to central dysregulation in affective disorders.

Background Preclinical and some clinical studies suggest a relationship between perturbation in magnesium homeostasis and pathological anxiety, although the underlying mechanisms remain largely unknown. Since there is evidence that Mg modulates the hypothalamic-pituitary-adrenal (HPA) axis, we tested whether enhanced anxiety-like behaviour can be reliably elicited by dietary Mg restriction and whether Mg deficiency is associated with altered HPA axis function.

Pathological fear and anxiety are highly debilitating and, despite considerable advances in psychotherapy and pharmacotherapy they remain insufficiently treated in many patients with PTSD, phobias, panic and other anxiety disorders. Increasing preclinical and clinical evidence indicates that pharmacological treatments including cognitive enhancers, when given as adjuncts to psychotherapeutic approaches [cognitive behavioral therapy including extinction-based exposure therapy] enhance treatment efficacy, while using anxiolytics such as benzodiazepines as adjuncts can undermine long-term treatment success. The purpose of this review is to outline the literature showing how pharmacological interventions targeting neurotransmitter systems including serotonin, dopamine, noradrenaline, histamine, glutamate, GABA, cannabinoids, neuropeptides (oxytocin, neuropeptides Y and S, opioids) and other targets (neurotrophins BDNF and FGF2, glucocorticoids, L-type-calcium channels, epigenetic modifications) as well as their downstream signaling pathways, can augment fear extinction and strengthen extinction memory persistently in preclinical models. Particularly promising approaches are discussed in regard to their effects on specific aspects of fear extinction namely, acquisition, consolidation and retrieval, including long-term protection from return of fear (relapse) phenomena like spontaneous recovery, reinstatement and renewal of fear. We also highlight the promising translational value of the preclinial research and the clinical potential of targeting certain neurochemical systems with, for example d-cycloserine, yohimbine, cortisol, and L-DOPA. The current body of research reveals important new insights into the neurobiology and neurochemistry of fear extinction and holds significant promise for pharmacologically-augmented psychotherapy as an improved approach to treat trauma and anxiety-related disorders in a more efficient and persistent way promoting enhanced symptom remission and recovery.

We describe a case of primary myelofibrosis which terminated in an acute megakaryoblastic leukaemia with massive marrow fibrosis and osteosclerosis. The megakaryocyte lineage of the terminal phase was confirmed by ultrastructural and surface marker studies of the blast cells. The leukaemic phase was associated with the presence of large numbers of progressively more immature megakaryocyte progenitors in the peripheral blood. The expression of c-sis mRNA in these blast cells was significantly higher than in normal mononuclear cells. Activation of the c-sis protooncogene leading to increased production of platelet-derived growth factor could be related to the progressive fibrosis observed.

Methods and results The present experiments firstly tested whether deficits in extinguishing emotional responses in S1 extends to contextual extinction. No reduction in emotional responses to the context was observed during an extinction training session which indicates generalised inability of S1 to engage associative fear extinction mechanisms. This was in contrast to mice of another 129 strain, 129S6/SvEvTac (S6), which showed contextual (and cued) extinction of emotional responding. Importantly, S1 and S6 showed identical responses on the flinch/jump test, which indicated that the results obtained were not an artefact of altered sensitivity to the unconditioned stimulus (US). Evidence that S1 mice can engage non-associative mechanisms to extinguish emotional responses was revealed as complete abolishment of contextual emotional expression was observed following US habituation (devaluing emotional responding to the US). We next investigated whether impaired cued emotional extinction persisted following also very “weak” conditioning paradigms. Results revealed that under these conditions, S1 mice displayed cued emotional (within) extinction when extinction training was performed using massed-CS presentations. This result indicates that the strength of the conditioning determines the ability of S1 to engage associative mechanisms to extinguish emotional responding. Using this paradigm it was possible to reveal impaired extinction consolidation in S1, as no between-session extinction was observed. Post extinction training application of D-cycloserine (an NMDA receptor agonist) and MS-275 (an HDAC inhibitor) rescued impaired extinction consolidation in S1. Finally, using “weak” conditioning, an enhanced sensitivity in S1 to incubate emotional responses was observed. During extinction training, temporally spaced CS presentations increased emotional responding in S1, but not the comparator strain C57BL6, revealing that S1 display an increased propensity over “normally” behaving mice to incubate emotional responses (via nonassociative mechanisms) following weak trauma.