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Behav Brain Res. 2017 Aug 30;333:171-178. doi: 10.1016/j.bbr.2017.06.026. Epub 2017 Jun 26.

Enhanced limbic/impaired cortical-loop connection onto the hippocampus of NHE rats: Application of resting-state functional connectivity in a preclinical ADHD model.

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Cell Biology and Neurosciences Dept., Istituto Superiore di Sanità, Rome, Italy.
University of Campania "Luigi Vanvitelli", Naples, Italy.
Department of Biological Sciences, University of Cagliari, Cagliari, Italy.
Cell Biology and Neurosciences Dept., Istituto Superiore di Sanità, Rome, Italy. Electronic address:
Cell Biology and Neurosciences Dept., Istituto Superiore di Sanità, Rome, Italy; Present address: Preclinical MRI Unit, Core Facilities, Istituto Superiore di Sanità, Rome, Italy.


Due to a hyperfunctioning mesocorticolimbic system, Naples-High-Excitability (NHE) rats have been proposed to model for the meso-cortical variant of attention deficit/hyperactivity disorder (ADHD). Compared to Naples Random-Bred (NRB) controls, NHE rats show hyperactivity, impaired non-selective attention (Aspide et al., 1998), and impaired selective spatial attention (Ruocco et al., 2009a, 2014). Alteration in limbic functions has been proposed; however, resulting unbalance among forebrain areas has not been assessed yet. By resting-state functional Magnetic-Resonance Imaging (fMRI) in vivo, we investigated the connectivity of neuronal networks belonging to limbic vs. cortical loops in NHE and NRB rats (n=10 each). Notably, resting-state fMRI was applied using a multi-slice sagittal, gradient-echo sequence. Voxel-wise connectivity maps at rest, based on temporal correlation among fMRI time-series, were computed by seeding the hippocampus (Hip), nucleus accumbens (NAcc), dorsal striatum (dStr), amygdala (Amy) and dorsal/medial prefrontal cortex (PFC), both hemispheres. To summarize patterns of altered connection, clearly directional connectivity was evident within the cortical loop: bilaterally and specularly, from orbital and dorsal PFCs through dStr and hence towards Hip. Such network communication was reduced in NHE rats (also, with less mesencephalic/pontine innervation). Conversely, enhanced network activity emerged within the limbic loop of NHE rats: from left PFC, both through the NAcc and directly, to the Hip (all of which received greater ventral tegmental innervation, likely dopamine). Together with tuned-down cortical loop, this potentiated limbic loop may serve a major role in controlling ADHD-like behavioral symptoms in NHE rats.


ADHD; Amygdala; BOLD; Dopamine; Dorsal striatum; Hippocampus; Limbic/Cortical loop; NHE rats; Nucleus accumbens; OFC; PFC; Resting state fMRI

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