Functional ultrasound imaging to study brain dynamics: Application of pharmaco-fUS to atomoxetine.

Functional ultrasound (fUS) is a new tool enabling the imaging of brain activity through the regional monitoring of cerebral blood volume (CBV) dynamics. This innovative technique has not yet demonstrated its full potential in pharmacological applications and drug development. In the current proof-of-concept study, the impact of atomoxetine (ATX), a potent norepinephrine reuptake inhibitor and non-stimulant treatment marketed in attention-deficit/hyperactivity-disorder, was evaluated in anesthetized rat using pharmacological functional ultrasound (pharmaco-fUS) at increasing doses (0.3, 1 and 3 mg/kg). Using regions of interest (acute changes of CBV and functional connectivity) or pixel-based (general linear modeling and independent component analysis) analysis, we here demonstrated that ATX consistently displayed a hemodynamic effect in the visual cortex, the dentate gyrus and thalamus, especially visual areas such as lateral posterior thalamic nuclei and lateral geniculate nuclei (LGN). The time profile of ATX effects was dose-dependent, with fastest CBV increases at the highest dose, and longer CBV increases at the intermediate dose. Standardizing the use of pharmaco-fUS could improve our understanding of the mechanism of action of drugs active in the brain and might constitute a new step to move forward in drug development for neurological disorders.

DCX-expressing cells in the vicinity of the hypothalamic neurogenic niche: a comparative study between mouse, sheep, and human tissues.

Neural stem and precursor cells persist postnatally throughout adulthood and are capable of responding to numerous endogenous and exogenous signals by modifying their proliferation and differentiation. Whereas adult neurogenesis has been extensively studied in the dentate gyrus of the hippocampal formation and in the subventricular zone adjacent to the wall of the lateral ventricles, we and others have recently reported constitutive adult neurogenesis in other brain structures, including the hypothalamus. In this study, we used immunohistochemistry to study the expression of the neuroblast marker doublecortin (DCX), and compared its expression pattern in adult ovine, mouse, and human hypothalamic tissues. Our results indicate that DCX-positive cells resembling immature and developing neurons occur in a wide range of hypothalamic nuclei in all three species, although with different distribution patterns. In addition, the morphology of DCX-positive cells varied depending on their location. DCX-positive cells near the third ventricle had the morphology of very immature neuroblasts, a round shape with no processes, whereas those located deeper in the parenchyma such as in the ventromedial nucleus were fusiform and showed a bipolar morphology. Extending this observation, we showed that among the cohort of immature neurons entering the ventromedial nucleus, some appeared to undergo maturation, as revealed by the partial colocalization of DCX with markers of more mature neurons, e.g., human neuronal protein C and D (HuC/D). This study provides further confirmation of the existence of an adult hypothalamic neurogenic niche and argues for the potential existence of a migratory path within the hypothalamus.