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Limited studies in humans and in animal models have investigated the neurotoxic risks related to a gestational exposure to diesel exhaust particles (DEP) on the embryonic brain, especially those regarding monoaminergic systems linked to neurocognitive disorders. We previously showed that exposure to DEP alters monoaminergic neurotransmission in fetal olfactory bulbs and modifies tissue morphology along with behavioral consequences at birth in a rabbit model. Given the anatomical and functional connections between olfactory and central brain structures, we further characterized their impacts in brain regions associated with monoaminergic neurotransmission. At gestational day 28 (GD28), fetal rabbit brains were collected from dams exposed by nose-only to either a clean air or filtered DEP for 2 h/day, 5 days/week, from GD3 to GD27. HPLC dosage and histochemical analyses of the main monoaminergic systems, i.e., dopamine (DA), noradrenaline (NA), and serotonin (5-HT) and their metabolites were conducted in microdissected fetal brain regions. DEP exposure increased the level of DA and decreased the dopaminergic metabolites ratios in the prefrontal cortex (PFC), together with sex-specific alterations in the hippocampus (Hp). In addition, HVA level was increased in the temporal cortex (TCx). Serotonin and 5-HIAA levels were decreased in the fetal Hp. However, DEP exposure did not significantly modify NA levels, tyrosine hydroxylase, tryptophan hydroxylase or AChE enzymatic activity in fetal brain. Exposure to DEP during fetal life results in dopaminergic and serotonergic changes in critical brain regions that might lead to detrimental potential short-term neural disturbances as precursors of long-term neurocognitive consequences., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Strokes are becoming less severe due to increased numbers of intensive care units and improved treatments. As patients survive longer, post-stroke cognitive impairment (PSCI) has become a major health public issue. Diabetes has been identified as an independent predictive factor for PSCI. Here, we characterized a clinically relevant mouse model of PSCI, induced by permanent cerebral artery occlusion in diabetic mice, and investigated whether a reliable biomarker of PSCI may emerge from the kynurenine pathway which has been linked to inflammatory processes., Methods: Cortical infarct was induced by permanent middle cerebral artery occlusion in male diabetic mice (streptozotocin IP). Six weeks later, cognitive assessment was performed using the Barnes maze, hippocampi long-term potentiation using microelectrodes array recordings, and neuronal death, white matter rarefaction and microglia/macrophages density assessed in both hemispheres using imunohistochemistry. Brain and serum metabolites of the kynurenin pathway were measured using HPLC and mass fragmentography. At last, these same metabolites were measured in the patient's serum, at the acute phase of stroke, to determine if they could predict PSCI 3 months later., Results: We found long-term spatial memory was impaired in diabetic mice 6 weeks after stroke induction. Synaptic plasticity was completely suppressed in both hippocampi along with increased neuronal death, white matter rarefaction in both striatum, and increased microglial/macrophage density in the ipsilateral hemisphere. Brain and serum quinolinic acid concentrations and quinolinic acid over kynurenic acid ratios were significantly increased compared to control, diabetic and non-diabetic ischemic mice, where PSCI was absent. These putative serum biomarkers were strongly correlated with degradation of long-term memory, neuronal death, microglia/macrophage infiltration and white matter rarefaction. Moreover, we identified these same serum biomarkers as potential predictors of PSCI in a pilot study of stroke patients., Conclusions: we have established and characterized a new model of PSCI, functionally and structurally, and we have shown that the QUIN/KYNA ratio could be used as a surrogate biomarker of PSCI, which may now be tested in large prospective studies of stroke patients.

One of the hallmarks of decision-making processes is the inter-individual variability between healthy subjects. These behavioral patterns could constitute risk factors for the development of psychiatric disorders. Therefore, finding predictive markers of safe or risky decision-making is an important challenge for psychiatry research. We set up a mouse gambling task (MGT)-adapted from the human Iowa gambling task with uncertain contingencies between response and outcome that furthermore enables the emergence of inter-individual differences. Mice (n = 54) were further individually characterized for locomotive, emotional and cognitive behavior. Individual basal rates of monoamines and brain activation after the MGT were assessed in brain regions related to reward, emotion or cognition. In a large healthy mice population, 44 % showed a balanced strategy with limited risk-taking and flexible choices, 29 % showed a safe but rigid strategy, while 27 % adopted risky behavior. Risky mice took also more risks in other apparatus behavioral devices and were less sensitive to reward. No difference existed between groups regarding anxiety, working memory, locomotion and impulsivity. Safe/rigid mice exhibited a hypoactivation of prefrontal subareas, a high level of serotonin in the orbitofrontal cortex combined with a low level of dopamine in the putamen that predicted the emergence of rigid behavior. By contrast, high levels of dopamine, serotonin and noradrenalin in the hippocampus predicted the emergence of more exploratory and risky behaviors. The coping of C57bl/6J mice in MGT enables the determination of extreme patterns of choices either safe/rigid or risky/flexible, related to specific neurochemical and behavioral markers., Competing Interests: The authors report no biomedical financial interests or potential conflicts of interest.

We use Astyanax mexicanus, a single species with surface-dwelling forms (SF) and blind de-pigmented cave forms (CF), to study mechanisms underlying the evolution of brain and behaviour. In CF, the origin of changes in complex motivated behaviours (social, feeding, sleeping, exploratory) is unknown. Here we find a hyper-aminergic phenotype in CF brains, including high levels and neurotransmission indexes for serotonin, dopamine and noradrenaline, and low monoamine oxidase (MAO) activity. Although MAO expression is unchanged in CF, a pro106leu mutation is identified in the MAO coding sequence. This mutation is responsible for low MAO activity and high serotonin neurotransmission index in CF brains. We find the same mutated allele in several natural CF populations, some being independently evolved. Such occurrence of the same allele in several caves may suggest that low MAO activity is advantageous for cave life. These results provide a genetic basis for several aspects of the cavefish 'behavioural syndrome'.

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication of mice is a standard model of Parkinson's disease (PD). However, it does not reproduce functionally PD. Given the occurrence of PD during aging, symptoms might only be detected in MPTP-intoxicated mice after aging. To address this, mice injected with MPTP at 2.5 months were followed up to a maximum age of 21 months. There was no loss of dopamine cells with aging in control mice; moreover, the initial post-MPTP intoxication decrease in dopamine cell was no longer significant at 21 months. With aging, striatal dopamine level remained constant, but concentrations of the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were markedly reduced in both groups. There was also a late impairment of fine motor skills. After MPTP intoxication, hyperactivity was immediately detected and it became greater than in control mice from 14 months of age; fine motor skills were also more impaired; both these symptoms were correlated with striatal dopamine, DOPAC and HVA concentrations. In bothgroups, neither motor symptoms nor dopamine changes worsened with age. These findings do not support the notion that PD develops with age in mice after MPTP intoxication and that the motor deficits seen are because of an aging process., (© 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.)

We previously reported that confronting mice to the Unpredictable Chronic Mild Stress procedure (UCMS) resulted in peripheral and cerebral alterations of the kynurenine pathway (KP). The present study tested whether KP disturbances are associated with differences in anxiety- and depressive-like behaviors in both naïve and UCMS mice. Non-stressed and UCMS mice were subjected to the elevated plus maze test and to the forced swim test. Mice were then sacrificed for quantification of tryptophan (TRP)-serotonin (5-HT) and TRP-kynurenine (KYN) metabolites in two corticolimbic structures involved in the regulation of mood (cingulate cortex=CC; amygdala=AMY). We showed that an elevated peripheral (lung) KYN/TRP ratio is correlated to the magnitude of anxiodepressive-like phenotypes only in UCMS mice. We also observed, in UCMS mice, that a high peripheral (lung) KYN/TRP ratio is associated with an increased metabolism of 5-HT in CC and a reduced level of kynurenic acid (KYNA) in AMY. Our results suggest that elevated peripheral KP might underlie cerebral biochemical changes and might consequently be involved in the modulation of behavior but only in UCMS mice. These findings make more complete the comprehension of the KP involvement in behavioral changes induced by chronic stress and suggest that it could play a crucial role in the modulation of emotional states., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Occurring both peripherally and centrally, the kynurenine pathway (KP) - an alternative pathway to 5-HT synthesis from tryptophan (TRP) - could be of particular value to better understand the link between peripheral changes of circulating levels of glucocorticoids (GC)/proinflammatory cytokines and altered neurotransmission observed in depressed patients. Indeed, it is activated by these mediators of stress and can produce several neuroactive compounds like quinolinic acid (QUIN) and kynurenic acid (KYNA) that can respectively increase and decrease glutamate concentration in brain. In order to characterize the role of both the peripheral and cerebral KP in the pathophysiology of depressive disorders, we used the Unpredictable Chronic Mild Stress (UCMS) to induce a depressive-like syndrome and we then measured the level of relevant TRP-KYN pathway metabolites: KYN, 3-hydroxykynurenine (3HK; precursor of QUIN) and KYNA. We also measured TRP-5HT pathway metabolites: TRP, 5-HT, 5-HIAA. We showed that UCMS increased TRP catabolism along the KP in the periphery. 5-HT and KYN were found to be strongly negatively correlated in all brain structures of control mice and of UCMS mice except in the hippocampus. More importantly we found that KYN was preferentially metabolized along the QUIN pathway at the subcortical level (amygdala/striatum) whereas, at the cortical level (cingulate cortex), the QUIN pathway was reduced. Considering the role of these metabolites on the glutamatergic neurotransmission, we propose that such KP alterations could participate to the cortical/subcortical glutamatergic alterations reported in depressed patients.

Parkinson disease (PD) is a neurodegenerative disorder characterized by a loss of dopamine-containing neurons. Mounting evidence suggests that dopaminergic cell death is influenced by the innate immune system. However, the pathogenic role of the adaptive immune system in PD remains enigmatic. Here we showed that CD8+ and CD4+ T cells but not B cells had invaded the brain in both postmortem human PD specimens and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD during the course of neuronal degeneration. We further demonstrated that MPTP-induced dopaminergic cell death was markedly attenuated in the absence of mature T lymphocytes in 2 different immunodeficient mouse strains (Rag1-/- and Tcrb-/- mice). Importantly, similar attenuation of MPTP-induced dopaminergic cell death was seen in mice lacking CD4 as well as in Rag1-/- mice reconstituted with FasL-deficient splenocytes. However, mice lacking CD8 and Rag1-/- mice reconstituted with IFN-gamma-deficient splenocytes were not protected. These data indicate that T cell-mediated dopaminergic toxicity is almost exclusively arbitrated by CD4+ T cells and requires the expression of FasL but not IFNgamma. Further, our data may provide a rationale for targeting the adaptive arm of the immune system as a therapeutic strategy in PD.

Organic cation transporters (OCTs) are carrier-type polyspecific permeases known to participate in low-affinity extraneuronal catecholamine uptake in peripheral tissues. OCT3 is the OCT subtype most represented in the brain, yet its implication in central aminergic neurotransmission in vivo had not been directly demonstrated. In a detailed immunohistochemistry study, we show that OCT3 is expressed in aminergic pathways in the mouse brain, particularly in dopaminergic neurons of the substantia nigra compacta, non-aminergic neurons of the ventral tegmental area, substantia nigra reticulata (SNr), locus coeruleus, hippocampus and cortex. Although OCT3 was found mainly in neurons, it was also occasionally detected in astrocytes in the SNr, hippocampus and several hypothalamic nuclei. In agreement with this distribution, OCT3/Slc22a3-deficient mice show evidence of altered monoamine neurotransmission in the brain, with decreased intracellular content and increased turnover of aminergic transmitters. The behavioral characterization of these mutants reveal subtle behavioral alterations such as increased sensitivity to psychostimulants and increased levels of anxiety and stress. Altogether our data support a role of OCT3 in the homeostatic regulation of aminergic neurotransmission in the brain.

Neurochemical studies performed in vivo have suggested that serotonin-containing and -synthesizing nerves, originating in the raphe nuclei, directly innervate pial blood vessels. Nerve fibres of these vessels have been shown by immunocytochemistry to contain tryptophan hydroxylase (the rate-limiting enzyme of serotonin synthesis) but no serotonin. The present study examines this contradiction by measuring in vitro the tryptophan hydroxylase activity of rat cerebral vessels and femoral arteries (which also contain tryptophan hydroxylase-immunopositive nerves), and comparing them to the tryptophan hydroxylase activity of the rat pineal body, raphe nuclei and brain cortex under identical conditions. Oxygenated incubation solutions contained either [14C]- or "cold" L-tryptophan (2 x 10(-5) to 5 x 10(-4) M) and NSD-1015 (3-hydroxybenzylhydrazine) which inhibits the decarboxylation of 5-hydroxytryptophan, the second step of serotonin synthesis. Tissue fragments were incubated for 35-60 min. High-performance liquid chromatography (on tissue extracts and incubation solutions) as well as determination of 14C activity in the 5-hydroxytryptophan fraction of elution from tissue extracts showed that the pineal body, the raphe nuclei and cortical slices synthesize various amounts of 5-hydroxytryptophan under our experimental conditions. All these tissues contained serotonin. Femoral arteries, but not cerebral vessels, also contained small amounts of serotonin stored before incubation, probably in mast cells. In contrast to brain tissues, no measurable amounts of "cold" or [14C]5-hydroxytryptophan were found in cerebral blood vessel and femoral artery extracts or incubation solutions. Under identical experimental conditions, sympathetic nerves of both types of vessels were able to synthesize large amounts of L-DOPA when incubation solutions contained L-tyrosine instead of L-tryptophan.(ABSTRACT TRUNCATED AT 250 WORDS)