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

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


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.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Attention Deficit Disorder with Hyperactivity / pathology*
  • Brain Mapping
  • Cerebral Cortex / diagnostic imaging
  • Cerebral Cortex / physiopathology*
  • Disease Models, Animal
  • Electroencephalography
  • Hippocampus / diagnostic imaging
  • Hippocampus / physiopathology*
  • Image Processing, Computer-Assisted
  • Magnetic Resonance Imaging
  • Male
  • Neural Pathways / diagnostic imaging
  • Neural Pathways / physiopathology*
  • Oxygen / blood
  • Rats
  • Rats, Inbred Strains
  • Rats, Sprague-Dawley
  • Rest*


  • Oxygen