Reward circuitry is perturbed in the absence of the serotonin transporter

The serotonin transporter (SERT) modulates the entire serotonergic system in the brain and influences both the dopaminergic and norepinephrinergic systems. These three systems are intimately involved in normal physiological functioning of the brain and implicated in numerous pathological conditions. Here we use high-resolution magnetic resonance imaging (MRI) and spectroscopy to elucidate the effects of disruption of the serotonin transporter in an animal model system: the SERT knock-out mouse. Employing manganese-enhanced MRI, we injected Mn^(2+) into the prefrontal cortex and obtained 3D MR images at specific time points in cohorts of SERT and normal mice. Statistical analysis of co-registered datasets demonstrated that active circuitry originating in the prefrontal cortex in the SERT knock-out is dramatically altered, with a bias towards more posterior areas (substantia nigra, ventral tegmental area, and Raphé nuclei) directly involved in the reward circuit. Injection site and tracing were confirmed with traditional track tracers by optical microscopy. In contrast, metabolite levels were essentially normal in the SERT knock-out by in vivo magnetic resonance spectroscopy and little or no anatomical differences between SERT knock-out and normal mice were detected by MRI. These findings point to modulation of the limbic cortical–ventral striatopallidal by disruption of SERT function. Thus, molecular disruptions of SERT that produce behavioral changes also alter the functional anatomy of the reward circuitry in which all the monoamine systems are involved

Estrogen treatment prevents gray matter atrophy in experimental autoimmune encephalomyelitis

Gray matter atrophy is an important correlate to clinical disability in multiple sclerosis (MS), and many treatment trials include atrophy as an outcome measure. Atrophy has been shown to occur in experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model of MS. The clinical severity of EAE is reduced in estrogen-reated mice, but it remains unknown whether estrogen treatment can reduce gray matter atrophy in EAE. In this study, mice with EAE were treated with either estrogen receptor (ER)-α ligand or ER-β ligand, and diffusion tensor images (DTI) were collected and neuropathology was performed. DTI showed atrophy in the cerebellar gray matter of vehicle-treated EAE mice compared with healthy controls but not in ER-α or ER-β ligand-treated EAE mice. Neuropathology demonstrated that Purkinje cell numbers were decreased in vehicle-treated EAE mice, whereas neither ER ligand-treated EAE groups showed a decrease. This is the first report of a neuroprotective therapy in EAE that unambiguously prevents gray matter atrophy while sparing a major neuronal cell type. Fractional anisotropy (FA) in the cerebellar white matter was decreased in vehicle- and ER-β ligand-treated but not in ER-α ligand-treated EAE mice. Inflammatory cell infiltration was increased in vehicle- and ER-β ligand-treated but not in ER-α ligand-treated EAE mice. Myelin staining was decreased in vehicle-treated EAE mice and was spared in both ER ligand-treated groups. This is consistent with decreased FA as a potential biomarker for inflammation rather than myelination or axonal damage in the cerebellum in EAE

Altered Neurocircuitry in the Dopamine Transporter Knockout Mouse Brain

The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn^(2+) into the prefrontal cortex indicated that DAT KO mice have a truncated Mn^(2+) distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn^(2+) transport into more posterior midbrain nuclei and contralateral mesolimbic structures at 26 hr post-injection. Thus, DAT KO mice appear, at this level of anatomic resolution, to have preserved cortico-striatal-thalamic connectivity but diminished robustness of reward-modulating circuitry distal to the thalamus. This is in contradistinction to the state of this circuitry in serotonin transporter KO mice where we observed more robust connectivity in more posterior brain regions using methods identical to those employed here

Cross relaxation in magnetic resonance: an extension of the Solomon equations for a consistent description of saturation

In magnetic resonance studies of cross relaxation or Overhauser effects by steady-state continuous irradn., it is shown that the Solomon equations do not allow one to obtain a consistent picture of the expectation values of various magnetization components. The contradictions can be resolved if, in addn. to the Zeeman polarizations, one takes into account a transverse magnetization component that is assocd. with the spin which is being irradiated. [on SciFinder (R)

Measurement of proton relaxation rates in proteins

Five different types of expt. are described which make it possible to measure various relaxation rates of selected protons in crowded spectra of macromols. such as proteins: longitudinal spin-lattice relaxation rates rt = 1/T1, transverse relaxation rates rt = 1/T2 measured under conditions of free precession, transverse relaxation rates rLOCKt = 1/T1r measured under conditions of spin-locking, and transverse relaxation rates rDQC = 1/T2DQC and rZQC = 1/T2ZQC of double- and zero-quantum coherences. The surprisingly large discrepancy between the transverse rates rt and rLOCKt is discussed in detail. To sep. overlapping proton signals, the exptl. schemes involve one or several magnetization transfer steps, using a doubly selective homonuclear Hartmann-Hahn method. Numerous variants of the basic ideas can be conceived, depending on the extent of signal overlap and on the topol. of the networks of scalar couplings. Applications are shown to He and Hd of Tyr23, to Ha, Hb and Hb' of Cys30, and to Ha and Hb of Ala24 in bovine pancreatic trypsin inhibitor (BPTI). [on SciFinder (R)

Le monde du génie industriel au XXe siècle : autour de Pierre Bézier et des machines-outils

International audiencePierre Bézier (1910-1999) est une figure remarquable quoique relativement peu connue de l’histoire des technologies industrielles du xxe siècle. Le grand public ne sait pas grand chose de cet ingénieur français qui a pourtant été tour à tour, artisan en France d’une forme originale d’automation (les machines transfert électromécaniques), promoteur des commandes numériques (les robots), puis père, à l’échelle mondiale, de l’informatique industrielle (la conception et fabrication assistée par ordinateur : CFAO). Il est encore aujourd’hui renommé dans le milieu des informaticiens pour les « courbes et surfaces » auxquelles il a donné son nom et qui ont « redessiné » le monde virtuel. Il est universellement connu parmi les ingénieurs de l’automobile et des arts mécaniques qui ont institué un prix en son honneur. Il a marqué les cadres et techniciens de la Régie Renault qui l’ont connu au cours de sa longue carrière (1933-1975) chez le constructeur automobile. Sa thèse d’Etat de mathématiques, soutenue en 1977 au début d’une retraite active, a été un coup de tonnerre dans le milieu des sciences appliquées.Le présent ouvrage souhaite contribuer à une meilleure connaissance de l’histoire de ce grand ingénieur-innovateur en replaçant ses principales réalisations dans le contexte international des extraordinaires bouleversements industriels de son époque et, tout particulièrement, dans le secteur de la machine-outil

Le monde du génie industriel au XXe siècle : autour de Pierre Bézier et des machines-outils

International audiencePierre Bézier (1910-1999) est une figure remarquable quoique relativement peu connue de l’histoire des technologies industrielles du xxe siècle. Le grand public ne sait pas grand chose de cet ingénieur français qui a pourtant été tour à tour, artisan en France d’une forme originale d’automation (les machines transfert électromécaniques), promoteur des commandes numériques (les robots), puis père, à l’échelle mondiale, de l’informatique industrielle (la conception et fabrication assistée par ordinateur : CFAO). Il est encore aujourd’hui renommé dans le milieu des informaticiens pour les « courbes et surfaces » auxquelles il a donné son nom et qui ont « redessiné » le monde virtuel. Il est universellement connu parmi les ingénieurs de l’automobile et des arts mécaniques qui ont institué un prix en son honneur. Il a marqué les cadres et techniciens de la Régie Renault qui l’ont connu au cours de sa longue carrière (1933-1975) chez le constructeur automobile. Sa thèse d’Etat de mathématiques, soutenue en 1977 au début d’une retraite active, a été un coup de tonnerre dans le milieu des sciences appliquées.Le présent ouvrage souhaite contribuer à une meilleure connaissance de l’histoire de ce grand ingénieur-innovateur en replaçant ses principales réalisations dans le contexte international des extraordinaires bouleversements industriels de son époque et, tout particulièrement, dans le secteur de la machine-outil

Measurement of overhauser effects in magnetic resonance of proteins by synchronous nutation

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Measurement of relaxation rates in crowded NMR spectra by selective coherence transfer

In crowded NMR spectra, it is shown how longitudinal relaxation rates (lab.-frame rates 1/T1) can be measured by selective inversion-recovery of a chosen site A followed by selective transfer of magnetization to another site X through a scalar coupling JAX, prior to observation of the signal. Relaxation rates in the presence of spin-locking (rotating frame rates 1/T1r) can be measured by first transferring transverse magnetization selectively from site X to A, followed by selective spin-locking of the magnetization of A, which can then be obsd. after partial decay. In both cases, the transfer can be achieved by a doubly-selective homonuclear Hartmann-Hahn method that uses simultaneous spin-locking of the transverse magnetization components of sites A and X by sidebands of an audio-modulated radio-frequency field. Provided the A-X cross-peak multiplet in a two-dimensional correlation (\"COSY\") spectrum does not suffer from overlap, there is no ambiguity in the one-dimensional spectra resulting from the novel methods. The techniques make it possible to measure accurate self-relaxation rates r or rt (diagonal elements of the Solomon matrixes), which are important for a quant. anal. of Overhauser effects in either lab. or rotating frames. The methods are applied to the protein bovine pancreatic trypsin inhibitor (BPTI) and to the cyclic undecapeptide cyclosporin A (CsA). [on SciFinder (R)

Measurement of cross relaxation between two selected nuclei by synchronous nutation of magnetization in nuclear magnetic resonance

A novel technique is described that allows one to measure cross-relaxation rates (Overhauser effects) between two selected nuclei in high-resolution NMR. The two chosen sites are irradiated simultaneously with the sidebands of an amplitude-modulated radio-frequency field, so that their magnetization vectors are forced to undergo a simultaneous motion, which is referred to as "synchronous nutation." From the time-dependence observed for different initial conditions, one may derive cross-relaxation rates, and hence determine internuclear distances. The scalar interactions between the selected spins and other spins belonging to the same coupling network are effectively decoupled. Furthermore, cross relaxation to other spins in the environment does not affect the transient response of the selected spins, which are therefore in effect isolated from their environment in terms of dipolar interactions. The method is particularly suitable to study cases where normal Overhauser effects are perturbed by spin-diffusion effects due to the presence of further spins. The technique is applied to the protein bovine pancreatic trypsin inhibitor. © 1993 American Institute of Physics.SCOPUS: ar.jinfo:eu-repo/semantics/publishe