We demonstrate a technique for mapping brain activity that combines molecular specificity and spatial coverage using a neurotransmitter sensor detectable by magnetic resonance imaging (MRI). This molecular functional MRI (fMRI) method yielded time-resolved volumetric measurements of dopamine release evoked by reward-related lateral hypothalamic brain stimulation of rats injected with the neurotransmitter sensor. Peak dopamine concentrations and release rates were observed in the anterior nucleus accumbens core. Substantial dopamine transients were also present in more caudal areas. Dopamine-release amplitudes correlated with the rostrocaudal stimulation coordinate, suggesting participation of hypothalamic circuitry in modulating dopamine responses. This work provides a foundation for development and application of quantitative molecular fMRI techniques targeted toward numerous components of neural physiology.

The notion of uncontrollable stress causing reduced hippocampal size remains controversial in the posttraumatic stress disorder literature because human studies cannot discern the causality of effect. Here, we addressed this issue by employing structural magnetic resonance imaging in rats to measure the hippocampus and other brain regions before and after stress. Chronic restraint stress produced approximately 3% reduction in hippocampal volume, which was not observed in control rats. This decrease was not signficantly correlated with baseline hippocampal volume or body weight. Total forebrain volume and the sizes of the other brain regions and adrenal glands were all unaffected by stress. This longitudinal, within-subjects design study provides direct evidence that the hippocampus is differentially vulnerable and sensitive to chronic stress.

Multi-drug resistant efflux transporters found in Blood-Brain Barrier (BBB) acts as a functional barrier, by pumping out most of the drugs into the blood. Previous studies showed focused ultrasound (FUS) induced microbubble oscillation can disrupt the BBB by loosening the tight junctions in the brain endothelial cells; however, no study was performed to investigate its impact on the functional barrier of the BBB. In this study, the BBB in rat brains were disrupted using the MRI guided FUS and microbubbles. The immunofluorescence study evaluated the expression of the P-glycoprotein (P-gp), the most dominant multi-drug resistant protein found in the BBB. Intensity of the P-gp expression at the BBB disruption (BBBD) regions was significantly reduced (63.2 ± 18.4%) compared to the control area. The magnitude of the BBBD and the level of the P-gp down-regulation were significantly correlated. Both the immunofluorescence and histologic analysis at the BBBD regions revealed no apparent damage in the brain endothelial cells. The results demonstrate that the FUS and microbubbles can induce a localized down-regulation of P-gp expression in rat brain. The study suggests a clinically translation of this method to treat neural diseases through targeted delivery of the wide ranges of brain disorder related drugs.

SUMMARY Magnetic resonance imaging (MRI) with molecular probes offers the potential to monitor physiological parameters with comparatively high spatial and temporal resolution in living subjects. For detection of intracellular analytes, construction of cell-permeable imaging agents remains a challenge. Here we show that a porphyrin-based MRI molecular imaging agent, Mn-(DPA-C2)2-TPPS3, effectively penetrates cells and persistently stains living brain tissue in intracranially injected rats. Chromogenicity of the probe permitted direct visualization of its distribution by histology, in addition to MRI. Distribution was concentrated in cell bodies after hippocampal infusion. Mn-(DPA-C2)2-TPPS3 was designed to sense zinc ions, and contrast enhancement was more pronounced in the hippocampus, a zinc-rich brain region, than in the caudate nucleus, which contains relatively little labile Zn2+. Membrane permeability, optical activity, and high relaxivity of porphyrin-based contrast agents offer exceptional functionality for in vivo imaging.

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Reuptake of neurotransmitters from the brain interstitium shapes chemical signaling processes and is disrupted in several pathologies. Serotonin reuptake in particular is important for mood regulation and is inhibited by first-line drugs for treatment of depression. Here we introduce a molecular-level fMRI technique for micron-scale mapping of serotonin transport in live animals. Intracranial injection of an MRI-detectable serotonin sensor complexed with serotonin, together with serial imaging and compartmental analysis, permits neurotransmitter transport to be quantified as serotonin dissociates from the probe. Application of this strategy to much of the striatum and surrounding areas reveals widespread non-saturating serotonin removal with maximal rates in lateral septum. The serotonin reuptake inhibitor fluoxetine selectively suppresses serotonin removal in septal subregions, whereas both fluoxetine and a dopamine transporter blocker depress reuptake in striatum. These results highlight promiscuous pharmacological influences on the serotonergic system and demonstrate utility of molecular fMRI for characterization of neurochemical dynamics.

Subcortical vascular dementia(SVaD) is associated with white matter damage, lacunar infarction, and degeneration of cerebral microcirculation. Currently available mouse models can mimic only partial aspects of human SVaD features. Here, we combined bilateral common carotid artery stenosis (BCAS) with a hyperlipidaemia model in order to develop a mouse model of SVaD; 10- to 12-week-old apolipoprotein E (ApoE)-deficient or wild-type C57BL/6J mice were subjected to sham operation or chronic cerebral hypoperfusion with BCAS using micro-coils. Behavioural performance (locomotion, spatial working memory, and recognition memory), histopathological findings (white matter damage, microinfarctions, astrogliosis), and cerebral microcirculation (microvascular density and blood-brain barrier (BBB) integrity) were investigated. ApoE-deficient mice subjected to BCAS showed impaired locomotion, spatial working memory, and recognition memory. They also showed white matter damage, multiple microinfarctions, astrogliosis, reduction in microvascular density, and BBB breakdown. The combination of chronic cerebral hypoperfusion and ApoE deficiency induced cognitive decline and cerebrovascular pathology, including white matter damage, multiple microinfarctions, and degeneration of cerebral microcirculation. Together, these features are all compatible with those of patients with SVaD. Thus, the proposed animal model is plausible for investigating SVaD pathophysiology and for application in preclinical drug studies.

In this study, we designed and synthesized a highly stable manganese (Mn 2+ )-based hepatobiliary complex by tethering an ethoxybenzyl (EOB) moiety with an ethylenediaminetetraacetic acid (EDTA) coordination cage as an alternative to the well-established hepatobiliary gadolinium (Gd 3+ ) chelates and evaluated its usage as a T 1 hepatobiliary magnetic resonance imaging (MRI) contrast agent (CA). This new complex exhibits higher r 1 relaxivity (2.3 mM −1 s −1 ) than clinically approved Mn 2+ -based hepatobiliary complex Mn-DPDP (1.6 mM −1 s −1 ) at 1.5 T. Mn-EDTA-EOB shows much higher kinetic inertness than that of clinically approved Gd 3+ -based hepatobiliary MRI CAs, such as Gd-DTPA-EOB and Gd-BOPTA. In addition, in vivo biodistribution and MRI enhancement patterns of this new Mn 2+ chelate are comparable to those of Gd 3+ -based hepatobiliary MRI CAs. The diagnostic efficacy of the new complex was demonstrated by its enhanced tumor detection sensitivity in a liver cancer model using in vivo MRI.