Functional and structural neural network characterization of serotonin transporter knockout rats

PLoS One. 2013;8(2):e57780. doi: 10.1371/journal.pone.0057780. Epub 2013 Feb 25.

Abstract

Brain serotonin homeostasis is crucially maintained by the serotonin transporter (5-HTT), and its down-regulation has been linked to increased vulnerability for anxiety- and depression-related behavior. Studies in 5-HTT knockout (5-HTT(-/-)) rodents have associated inherited reduced functional expression of 5-HTT with increased sensitivity to adverse as well as rewarding environmental stimuli, and in particular cocaine hyperresponsivity. 5-HTT down-regulation may affect normal neuronal wiring of implicated corticolimbic cerebral structures. To further our understanding of its contribution to potential alterations in basal functional and structural properties of neural network configurations, we applied resting-state functional MRI (fMRI), pharmacological MRI of cocaine-induced activation, and diffusion tensor imaging (DTI) in 5-HTT(-/-) rats and wild-type controls (5-HTT(+/+)). We found that baseline functional connectivity values and cocaine-induced neural activity within the corticolimbic network was not significantly altered in 5-HTT(-/-) versus 5-HTT(+/+) rats. Similarly, DTI revealed mostly intact white matter structural integrity, except for a reduced fractional anisotropy in the genu of the corpus callosum of 5-HTT(-/-) rats. At the macroscopic level, analyses of complex graphs constructed from either functional connectivity values or structural DTI-based tractography results revealed that key properties of brain network organization were essentially similar between 5-HTT(+/+) and 5-HTT(-/-) rats. The individual tests for differences between 5-HTT(+/+) and 5-HTT(-/-) rats were capable of detecting significant effects ranging from 5.8% (fractional anisotropy) to 26.1% (pharmacological MRI) and 29.3% (functional connectivity). Tentatively, lower fractional anisotropy in the genu of the corpus callosum could indicate a reduced capacity for information integration across hemispheres in 5-HTT(-/-) rats. Overall, the comparison of 5-HTT(-/-) and wild-type rats suggests mostly limited effects of 5-HTT genotype on MRI-based measures of brain morphology and function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Mapping / methods
  • Corpus Callosum / metabolism*
  • Diffusion Tensor Imaging / methods
  • Magnetic Resonance Imaging / methods
  • Male
  • Nerve Net / metabolism*
  • Neural Pathways / metabolism*
  • Neurons / metabolism
  • Neurons / physiology
  • Rats
  • Rats, Wistar
  • Serotonin / metabolism*
  • Serotonin Plasma Membrane Transport Proteins / metabolism*

Substances

  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin

Grants and funding

This work has been financially supported by a grant of the Netherlands Brain Foundation (15F07(2).20) (JRH), and Utrecht University's High Potential program (RMD). The grant providers had no further role in the design of the study, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication.