Mapping Functional Brain Activation Using [14C]-Iodoantipyrine in Male Serotonin Transporter Knockout Mice

Abstract

BackgroundSerotonin transporter knockout mice have been a powerful tool in understanding the role played by the serotonin transporter in modulating physiological function and behavior. However, little work has examined brain function in this mouse model. We tested the hypothesis that male knockout mice show exaggerated limbic activation during exposure to an emotional stressor, similar to human subjects with genetically reduced transcription of the serotonin transporter.Methodology/Principal FindingsFunctional brain mapping using [14C]-iodoantipyrine was performed during recall of a fear conditioned tone. Regional cerebral blood flow was analyzed by statistical parametric mapping from autoradiographs of the three-dimensionally reconstructed brains. During recall, knockout mice compared to wild-type mice showed increased freezing, increased regional cerebral blood flow of the amygdala, insula, and barrel field somatosensory cortex, decreased regional cerebral blood flow of the ventral hippocampus, and conditioning-dependent alterations in regional cerebral blood flow in the medial prefrontal cortex (prelimbic, infralimbic, and cingulate). Anxiety tests relying on sensorimotor exploration showed a small (open field) or paradoxical effect (marble burying) of loss of the serotonin transporter on anxiety behavior, which may reflect known abnormalities in the knockout animal's sensory system. Experiments evaluating whisker function showed that knockout mice displayed impaired whisker sensation in the spontaneous gap crossing task and appetitive gap cross training.ConclusionsThis study is the first to demonstrate altered functional activation in the serotonin transporter knockout mice of critical nodes of the fear conditioning circuit. Alterations in whisker sensation and functional activation of barrel field somatosensory cortex extend earlier reports of barrel field abnormalities, which may confound behavioral measures relying on sensorimotor exploration.

The Anterior Cingulate Cortex Is a Critical Hub for Pain-Induced Depression

“…However, a clinical study suggests a correlation between the activation of insula and the unpleasantness of tonic pain stimulus (41), and a recent preclinical study showed increased cerebral blood flow in the anterior part of insular cortex during anxiety-like behaviors (42). These observations differ in many variables from present work, such as the type of stimulus (acute versus chronic) or the targeted insular cortex subregion (anterior versus posterior).…”

Serotonin transporter knockout rats show improved strategy set-shifting and reduced latent inhibition

“…In analogy with the 5-HTTLPR findings, 5-HTT knockout (5-HTT 2/2 ) rats and mice show-next to increased anxiety-and depression-like behaviors (Kalueff et al 2010)-improved performance in a reversal learning task (Brigman et al 2010;Nonkes et al 2011) and functional changes in prefrontal areas subserving reversal learning (orbitofrontal cortex; OFC) and extradimensional set-shifting (medial prefrontal cortex; mPFC) (Ragozzino 2007;Wellman et al 2007;Nonkes et al 2010;Keeler and Robbins 2011;Pang et al 2011). Therefore we hypothesized that 5-HTT 2/2 rats also show improved extradimensional set-shifting.…”

“…Specifically, the orbitofrontal cortex (OFC) is implicated in reversal learning (McAlonan and Brown 2003;Ghods-Sharifi et al 2008), the medial prefrontal cortex (mPFC) in extradimensional (strategy) set-shifting (Ragozzino et al 1999;Floresco et al 2008), and latent inhibition paradigms (George et al 2010). As anatomical and task-related functional changes in these regions have been reported in 5-HTT 2/2 rodents (Wellman et al 2007;Nonkes et al 2010;Pang et al 2011), the observed genotype differences in reversal learning (Nonkes et al 2011) and the EDSS and latent inhibition paradigms (present study) might relate to altered OFC and mPFC function. In line, we specifically observed a genotype effect on mPFC-dependent perseverative errors, but not regressive or never-reinforced errors, which are thought to be more striatum-dependent (Floresco et al 2009).…”

Animal models for posttraumatic stress disorder: An overview of what is used in research

“…Other risk factors such as variation in 5-HTTLPR in humans, that affects the prevalence of several anxiety disorders including PTSD, can be assessed in this model as well [46][47][48] . 5-HTT knockout rats, displaying increased freezing and impaired fear extinction [49][50][51] or fear extinction recall [52][53][54] , have been used as model for the more PTSD-susceptible 5-HTTLPR genotype. The polymorphism results in differences in serotonin regulation that play an important role in anxiety disorders.…”