Serotonin-1A receptor binding is positively associated with gray matter volume — A multimodal neuroimaging study combining PET and structural MRI
Highlights
► Multimodal assessment using structural MRI and PET with [carbonyl-11C]WAY - 100635. ► 5-HT1A binding is positively associated with GMV in hippocampi and temporal cortices. ► 5-HT1A receptor binding in the midbrain is associated with gray matter in forebrain. ► Neuroplastic properties of 5-HT1A receptors might be involved.
Introduction
Growing evidence shows distinctive neuromodulatory properties of serotonin (5-hydroxytryptamine, 5-HT) in developing and mature brain networks (Daubert and Condron, 2010, Gaspar et al., 2003). Early alterations in the 5-HT system are associated with life-long changes in cognitive and behavioral functioning and the neuronal organization in neuropsychiatric diseases (Gaspar et al., 2003). The 5-HT1A receptor, one of at least 16 receptors in the serotonergic system, is directly linked to signaling cascades mediating neuroplasticity (Azmitia, 2001). Structural neuroimaging techniques revealed increased amounts of gray matter volume (GMV) as surrogate for enhanced neuroplasticity in relation to motoric training, cognitive performance or treatment with the antidepressant fluoxetine, a selective serotonin reuptake inhibitor (Draganski et al., 2004, Kanai and Rees, 2011, Vetencourt et al., 2008). On the other side, GMV loss as measured with high-resolution structural magnetic resonance imaging (MRI), is a key feature of neuropsychiatric brain disorders, whereby the hippocampal formation was demonstrated to be especially vulnerable to volumetric alterations (Benninghoff et al., 2010, Geuze et al., 2005).
Serotonin-1A autoreceptors are located presynaptically on serotonergic neurons in the raphe nuclei where they reduce tonic cell firing, thus autoinhibiting 5-HT release (Hall et al., 1997). Postsynaptically, 5-HT1A heteroreceptors are expressed on glutamatergic and GABAergic neurons and mediate an inhibitory serotonergic response (Amargós-Bosch et al., 2004, Hall et al., 1997, Puig et al., 2005). Neurobiological studies identified a vast number of second messenger pathways that exert neuroplastic changes (Citri and Malenka, 2008, Pittenger and Duman, 2008) triggered by 5-HT via 5-HT1A receptors (Azmitia, 2001, Tardito et al., 2006). To sum up, 5-HT1A receptors might be involved in altering GMV, thereby offering a possible explanation for gray matter atrophy observed in several brain disorders.
Dysfunctional neuronal organization is an important contributor to the pathogenesis of Alzheimer's disease (Mesulam, 1999), schizophrenia (Lewis and González-Burgos, 2008) and depressive disorder (Pittenger and Duman, 2008), however the underlying molecular mechanisms, leading to gray matter loss in these disorders are complex and not fully understood. Interestingly, positron emission tomography (PET) studies demonstrated alterations of 5-HT1A receptors in patients suffering from these disorders (Kasper et al., 2002, Kepe et al., 2006, Lanzenberger et al., 2007, Mamo et al., 2007, Savitz et al., 2009). This congruence and a lack of data in human brains in vivo lead us to investigate the relationship between 5-HT1A receptor concentration and GMV with a multimodal neuroimaging approach.
Section snippets
Participants
We examined 35 healthy adults, 18 males and 17 females (age range = 21–52, mean = 26.6 ± 6.8 years, Table 1), with at least general qualification for university entrance as lowest educational level. All subjects were recruited via advertisement at the Medical University of Vienna, Austria and underwent a general physical and neurological examination at the screening visit including medical history, electrocardiogram and routine laboratory tests. Inclusion criteria were age between 18 and 60, ability
5-HT1A receptor binding positively correlated with gray matter volumes within distinctive brain regions
In this pooled study sample, male study subjects significantly differed from females in GMV, weight and total injected radiotracer dose (Table 1). In line with previous results of our group, 5-HT1A BPND, an index for receptor density, peaked in the parahippocampal gyri, the temporal poles and the insula (Figs. 1A and 3, Table S1 and Stein et al., 2008).
Serotonin-1A BPND strongly correlated with GMV in the hippocampus (the cluster in the right hippocampus spread from the posterior hippocampus to
Discussion
Our results demonstrate positive associations between 5-HT1A receptor binding and gray matter. In distinctive regions of both hemispheres, as in the hippocampi and in temporal cortices, 5-HT1A receptor binding was strongly correlated with gray matter. These results were not just based on a priori higher regional values of gray matter, because we demonstrated that in regions such as the insula, in contrast to the hippocampus, there were no significant positive associations, although having
Conclusions
Our results demonstrate that 5-HT1A receptor binding is positively associated with gray matter in specific regions such as the hippocampus and the temporal cortices in both hemispheres. Furthermore 5-HT1A autoreceptor binding in the midbrain is positively associated with gray matter in the anterior cingulate cortex. Currently, it is hard to pin down the molecular mechanisms underlying our results, mostly because, there are no exact models which cellular compounds correspond to the signal
Acknowledgments
This research was partly supported by grants from the Austrian Science Fund, and the Austrian National Bank (P 11468) to R. L. A. Hahn is recipient of a DOC-fellowship of the Austrian Academy of Sciences at the Department of Psychiatry and Psychotherapy. We are grateful to the technical and medical teams of the PET and High-Field MRI Centre, Medical University of Vienna, especially to K. Kletter, R. Dudczak, E. Moser, L.-K. Mien, and F. Gerstl. Furthermore, we would like to thank U. Moser, M.
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