Neurochemical Changes in the Mouse Hippocampus Underlying the Antidepressant Effect of Genetic Deletion of P2X7 Receptors.

Recent investigations have revealed that the genetic deletion of P2X7 receptors (P2rx7) results in an antidepressant phenotype in mice. However, the link between the deficiency of P2rx7 and changes in behavior has not yet been explored. In the present study, we studied the effect of genetic deletion of P2rx7 on neurochemical changes in the hippocampus that might underlie the antidepressant phenotype. P2X7 receptor deficient mice (P2rx7-/-) displayed decreased immobility in the tail suspension test (TST) and an attenuated anhedonia response in the sucrose preference test (SPT) following bacterial endotoxin (LPS) challenge. The attenuated anhedonia was reproduced through systemic treatments with P2rx7 antagonists. The activation of P2rx7 resulted in the concentration-dependent release of [3H]glutamate in P2rx7+/+ but not P2rx7-/- mice, and the NR2B subunit mRNA and protein was upregulated in the hippocampus of P2rx7-/- mice. The brain-derived neurotrophic factor (BDNF) expression was higher in saline but not LPS-treated P2rx7-/- mice; the P2rx7 antagonist Brilliant blue G elevated and the P2rx7 agonist benzoylbenzoyl ATP (BzATP) reduced BDNF level. This effect was dependent on the activation of NMDA and non-NMDA receptors but not on Group I metabotropic glutamate receptors (mGluR1,5). An increased 5-bromo-2-deoxyuridine (BrdU) incorporation was also observed in the dentate gyrus derived from P2rx7-/- mice. Basal level of 5-HT was increased, whereas the 5HIAA/5-HT ratio was lower in the hippocampus of P2rx7-/- mice, which accompanied the increased uptake of [3H]5-HT and an elevated number of [3H]citalopram binding sites. The LPS-induced elevation of 5-HT level was absent in P2rx7-/- mice. In conclusion there are several potential mechanisms for the antidepressant phenotype of P2rx7-/- mice, such as the absence of P2rx7-mediated glutamate release, elevated basal BDNF production, enhanced neurogenesis and increased 5-HT bioavailability in the hippocampus

The Brain Reaction to Viewing Faces of Opposite- and Same-Sex Romantic Partners

We pursued our functional magnetic resonance imaging (fMRI) studies of the neural correlates of romantic love in 24 subjects, half of whom were female (6 heterosexual and 6 homosexual) and half male (6 heterosexual and 6 homosexual). We compared the pattern of activity produced in their brains when they viewed the faces of their loved partners with that produced when they viewed the faces of friends of the same sex to whom they were romantically indifferent. The pattern of activation and de-activation was very similar in the brains of males and females, and heterosexuals and homosexuals. We could therefore detect no difference in activation patterns between these groups

Enhanced catecholamine transporter binding in the locus coeruleus of patients with early Parkinson disease

<p>Abstract</p> <p>Background</p> <p>Studies in animals suggest that the noradrenergic system arising from the locus coeruleus (LC) and dopaminergic pathways mutually influence each other. Little is known however, about the functional state of the LC in patients with Parkinson disease (PD).</p> <p>Methods</p> <p>We retrospectively reviewed clinical and imaging data of 94 subjects with PD at an early clinical stage (Hoehn and Yahr stage 1-2) who underwent single photon computed tomography imaging with FP-CIT ([¹²³I] N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane). FP-CIT binding values from the patients were compared with 15 healthy subjects: using both a voxel-based whole brain analysis and a volume of interest analysis of <it>a priori </it>defined brain regions.</p> <p>Results</p> <p>Average FP-CIT binding in the putamen and caudate nucleus was significantly reduced in PD subjects (43% and 57% on average, respectively; p < 0.001). In contrast, subjects with PD showed an increased binding in the LC (166% on average; p < 0.001) in both analyses. LC-binding correlated negatively with striatal FP-CIT binding values (caudate: contralateral, ρ = -0.28, p < 0.01 and ipsilateral ρ = -0.26, p < 0.01; putamen: contralateral, ρ = -0.29, p < 0.01 and ipsilateral ρ = -0.29, p < 0.01).</p> <p>Conclusions</p> <p>These findings are consistent with an up-regulation of noradrenaline reuptake in the LC area of patients with early stage PD, compatible with enhanced noradrenaline release, and a compensating activity for degeneration of dopaminergic nigrostriatal projections.</p

Microstructural Abnormalities in Subcortical Reward Circuitry of Subjects with Major Depressive Disorder

Previous studies of major depressive disorder (MDD) have focused on abnormalities in the prefrontal cortex and medial temporal regions. There has been little investigation in MDD of midbrain and subcortical regions central to reward/aversion function, such as the ventral tegmental area/substantia nigra (VTA/SN), and medial forebrain bundle (MFB).We investigated the microstructural integrity of this circuitry using diffusion tensor imaging (DTI) in 22 MDD subjects and compared them with 22 matched healthy control subjects. Fractional anisotropy (FA) values were increased in the right VT and reduced in dorsolateral prefrontal white matter in MDD subjects. Follow-up analysis suggested two distinct subgroups of MDD patients, which exhibited non-overlapping abnormalities in reward/aversion circuitry. The MDD subgroup with abnormal FA values in VT exhibited significantly greater trait anxiety than the subgroup with normal FA values in VT, but the subgroups did not differ in levels of anhedonia, sadness, or overall depression severity.These findings suggest that MDD may be associated with abnormal microstructure in brain reward/aversion regions, and that there may be at least two subtypes of microstructural abnormalities which each impact core symptoms of depression

Abnormal development of monoaminergic neurons is implicated in mood fluctuations and bipolar disorder

Subtle mood fluctuations are normal emotional experiences, whereas drastic mood swings can be a manifestation of bipolar disorder (BPD). Despite their importance for normal and pathological behavior, the mechanisms underlying endogenous mood instability are largely unknown. During embryogenesis, the transcription factor Otx2 orchestrates the genetic networks directing the specification of dopaminergic (DA) and serotonergic (5-HT) neurons. Here we behaviorally phenotyped mouse mutants overexpressing Otx2 in the hindbrain, resulting in an increased number of DA neurons and a decreased number of 5-HT neurons in both developing and mature animals. Over the course of 1 month, control animals exhibited stable locomotor activity in their home cages, whereas mutants showed extended periods of elevated or decreased activity relative to their individual average. Additional behavioral paradigms, testing for manic-and depressive-like behavior, demonstrated that mutants showed an increase in intra-individual fluctuations in locomotor activity, habituation, risk-taking behavioral parameters, social interaction, and hedonic-like behavior. Olanzapine, lithium, and carbamazepine ameliorated the behavioral alterations of the mutants, as did the mixed serotonin receptor agonist quipazine and the specific 5-HT 2C receptor agonist CP-809101. Testing the relevance of the genetic networks specifying monoaminergic neurons for BPD in humans, we applied an interval-based enrichment analysis tool for genome-wide association studies. We observed that the genes specifying DA and 5-HT neurons exhibit a significant level of aggregated association with BPD but not with schizophrenia or major depressive disorder. The results of our translational study suggest that aberrant development of monoaminergic neurons leads to mood fluctuations and may be associated with BPD

Apelin controls emotional behavior in age- and metabolic state-dependent manner

International audienceApelin is a small peptide secreted by the adipose tissue notably in conditions of obesity-induced hyper-insulinemia. Apelin exerts a range of physiological functions at the periphery including the improvement of insulin sensitivity and the increase of muscle strength or cardiac contractibility. Interestingly, the brain is endowed with a high density of APJ, the single target of apelin, and growing evidence suggests various central actions of this adipokine. Recent studies reported that the intracerebroventricular infusion of apelin modulates emotional states in middle age stressed animals. However, results are so far been mixed and have not allowed for definitive conclusions about the impact of apelin on anxio-depressive-like phenotype. This study aims 1) to evaluate whether serum apelin levels are associated with mood in older adults and 2) to determine the impact of the genetic apelin inactivation in 12-month old mice fed a standard diet (STD) or in 6-month old mice fed a high fat diet (HFD). A higher plasma apelin level was associated with higher depressive symptoms in older adults. In line with these clinical findings, 12-month old apelin knock-out (Ap-/-) mice displayed a spontaneous antidepressant-like phenotype. In a marked contrast, 6-month old Ap-/- mice harbored a higher degree of peripheral insulin resistance than wild-types in response to HFD and were more prone to develop anxiety while the depressive-like state was not modified. We also provided evidence that such anxious behavior was associated with an impairment of central serotonergic and dopaminergic neuronal activities. Finally, although the insulin sensitizing drug metformin failed to reverse HFD-induced insulin resistance in 6-month old Ap-/- mice, it reversed their anxious phenotype. These results emphasize a complex contribution of apelin in the regulation of emotional state that might depend on the age and the metabolic status of the animals. Further investigations are warranted to highlight the therapeutic potential of manipulating the apelinergic system in mood-related disorders

Behavioral and serotonergic consequences of decreasing or increasing hippocampus brain-derived neurotrophic factor protein levels in mice.

Antidepressants such as Selective Serotonin Reuptake Inhibitors (SSRI) act as indirect agonists of serotonin (5-HT) receptors. Although these drugs produce a rapid blockade of serotonin transporters (SERTs) in vitro, several weeks of treatment are necessary to observe clinical benefits. This paradox has not been solved yet. Recent studies have identified modifications of intracellular signaling proteins and target genes that could contribute to antidepressant-like activity of SSRI (e.g., increases in neurogenesis and BDNF protein levels), and may explain, at least in part, their long delay of action. Although these data suggest a positive regulation of 5-HT on the expression of the gene coding for BDNF, the reciprocal effects of BDNF on brain 5-HT neurotransmission remains poorly documented. To study the impact of BDNF on serotonergic activity, a dual experimental strategy was used to analyze neurochemical and behavioral consequences of its decrease (strategy 1) or increase (strategy 2) in the brain of adult male mice. (1) In heterozygous BDNF+/- mice in which brain BDNF protein levels were decreased by half, an enhancement of basal extracellular 5-HT levels (5-HText) that induced a down-regulation of SERT, i.e., a decrease in its capacity to reuptake 5-HT, was found in the hippocampus. In addition, the SSRI, paroxetine, failed to increase hippocampal 5-HText in BDNF+/- mice, while it produces robust effects in wild-type littermates. Thus, BDNF+/- mice can be viewed as an animal model of genetic resistance to serotonergic antidepressant drugs. (2) In wild-type BDNF+/+ mice, the effects of intra-hippocampal (vHi) injection of BDNF (100 ng) in combination with a SSRI was examined by using intracerebral microdialysis and behavioral paradigms that predict an antidepressant- and anxiolytic-like activity of a molecule [the forced swim test (FST) and the open field paradigm (OF) respectively]. BDNF induced a rapid and transient increase in paroxetine response on 5-HText in the adult hippocampus, which was correlated with a potentiation of its antidepressant-like activity in the FST. The effects of BDNF were selectively blocked by K252a, an antagonist of its high-affinity TrkB receptor. Such a correlation between neurochemical and behavioral effects of [BDNF+SSRI] co-administration suggests that its antidepressant-like activity is linked to the activation of 5-HT neurotransmission in the adult hippocampus. BDNF also had a facilitatory effect on anxiety-like behavior in the OF test, and paroxetine prevented this anxiogenesis. What was the mechanism by which BDNF exerted these latter effects? Surprisingly, by using zero net flux method of quantitative microdialysis in vivo, we found that an intra-hippocampal BDNF injection in wild-type mice decreased the functional activity of SERT as observed in BDNF+/- mice. However, the decreased capacity of SERT to reuptake 5-HT was not associated to an increase in basal 5-HText in the hippocampus of WT mice. Interestingly, using in situ hybridization experiments indicated that TrkB receptor mRNA was expressed in the hippocampus and dorsal raphe nucleus in adult mice suggesting that the neurochemical and behavioral effects of intra-hippocampal BDNF injection can mobilize both pre- and post-synaptic elements of the brain 5-HT neurotransmission. Taken together, these set of experiments unveiled a relative opposition of neurochemical and behavioral responses following either a decrease (in BDNF+/- mutant mice) or an increase in brain BDNF levels (bilateral intra-hippocampal injection) in adult mice. In view of developing new antidepressant drug strategy, a poly-therapy combining BDNF with a chronic SSRI treatment could thus improve the efficacy of current medications

Characterization of 5-HT(1A/1B)-/- mice: an animal model sensitive to anxiolytic treatments.

Selective serotonin (5-HT) re-uptake inhibitors (SSRIs) are commonly used in the treatment of generalized anxiety disorder in Humans. However, because only few animal models display overt anxious-like behavior, detailed preclinical studies of the anxiolytic properties of antidepressants are still lacking. Here, we studied the neurochemical and behavioral effects of a double 5-HT(1A/1B) receptor knockout in mice (5-HT(1A/1B)-/-) as compared to their wild-type littermates (5-HT(1A/1B)+/+). It is known that single deletion of either 5-HT(1A) or 5-HT(1B) receptor induces behavioral changes that are not correlated with differences in brain serotonergic tone. Deletion of both receptors resulted in (i) higher emotionality of animals, as observed in three unconditioned paradigms of anxiety (open field, elevated plus maze and novelty suppressed feeding tests); (ii) a ≈200% increase in the mean spontaneous firing rate of 5-HT neurons in the dorsal raphe nucleus (DRN) compared to 5-HT(1A/1B)+/+ mice; (iii) elevated basal dialysate levels of 5-HT in the DRN and frontal cortex; (iv) an exaggerated response to acute paroxetine administration in microdialysis experiments, and (v) increased basal core body temperature. These findings suggest that the deletion of both autoreceptors induces a strong anxious-like behavioral state associated with increased 5-HT neurotransmission. Interestingly, 5-HT(1A/1B)-/- mice are still sensitive to the acute administration of diazepam. Moreover, while deletion of both receptors impacted on the response to acute SSRI treatment in the forced swim test, anxiolytic-like effects of a chronic SSRI treatment were still observed in 5-HT(1A/1B)-/- mice. Thus, the 5-HT(1A/1B)-/- mouse model could be of great interest to unveil the mechanisms of action of the anxiolytic effects of SSRIs

Consequences of changes in BDNF levels on serotonin neurotransmission, 5-HT transporter expression and function: studies in adult mice hippocampus.

In vivo intracerebral microdialysis is an important neurochemical technique that has been applied extensively in genetic and pharmacological studies aimed at investigating the relationship between neurotransmitters. Among the main interests of microdialysis application is the infusion of drugs through the microdialysis probe (reverse dialysis) in awake, freely moving animals. As an example of the relevance of intracerebral microdialysis, this review will focus on our recent neurochemical results showing the impact of Brain-Derived Neurotrophic Factor (BDNF) on serotonergic neurotransmission in basal and stimulated conditions. Indeed, although the elevation of 5-HT outflow induced by chronic administration of selective serotonin reuptake inhibitors (SSRIs) causes an increase in BDNF protein levels and expression (mRNA) in the hippocampus of rodents, the reciprocal interaction has not been demonstrated yet. Thus, the neurochemical sight of this question will be addressed here by examining the consequences of either a constitutive decrease or increase in brain BDNF protein levels on hippocampal extracellular levels of 5-HT in conscious mice