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.
References (58)
- et al.
The serotonin-1A receptor in anxiety disorders
Biol. Psychiatry
(2009) A fast diffeomorphic image registration algorithm
NeuroImage
(2007)- et al.
Computing average shaped tissue probability templates
NeuroImage
(2009) Modern views on an ancient chemical: serotonin effects on cell proliferation, maturation, and apoptosis
Brain Res. Bull.
(2001)- et al.
Decoding the epigenetic language of neuronal plasticity
Neuron
(2008) - et al.
Biological parametric mapping: a statistical toolbox for multimodality brain image analysis
NeuroImage
(2007) - et al.
Serotonin: a regulator of neuronal morphology and circuitry
Trends Neurosci.
(2010) Serotonin and hippocampal neurogenesis
Neuropsychopharmacology
(1999)- et al.
Autoradiographic localization of 5-HT1A receptors in the post-mortem human brain using [3H]WAY-100635 and [11C]way-100635
Brain Res.
(1997) - et al.
Evaluation of 14 nonlinear deformation algorithms applied to human brain MRI registration
NeuroImage
(2009)
Where in-vivo imaging meets cytoarchitectonics: the relationship between cortical thickness and neuronal density measured with high-resolution [18F]flumazenil-PET
NeuroImage
Reduced serotonin-1A receptor binding in social anxiety disorder
Biol. Psychiatry
Experience-dependent structural plasticity in the adult human brain
Trends Cogn. Sci.
Neuroplasticity failure in Alzheimer's disease: bridging the gap between plaques and tangles
Neuron
The role of 5-HT(1A) receptors in learning and memory
Behav. Brain Res.
5-HT1A receptor-regulated signal transduction pathways in brain
Cell. Signal.
Prefrontal cortical abnormalities in currently depressed versus currently remitted patients with major depressive disorder
NeuroImage
Imaging phenotypes of major depressive disorder: genetic correlates
Neuroscience
5-HT(1A) receptor function in major depressive disorder
Prog. Neurobiol.
Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain
NeuroImage
Serotonin and brain development: role in human developmental diseases
Brain Res. Bull.
Serotonin regulates synaptic connections in the dentate molecular layer of adult rats via 5-HT1a receptors: evidence for a glial mechanism
Brain Res.
Cerebral morphology and dopamine D2/D3 receptor distribution in humans: a combined [18F]fallypride and voxel-based morphometry study
NeuroImage
5-HT1a receptors mediate the neurotrophic effect of serotonin on developing dentate granule cells
Brain Res. Dev. Brain Res.
Small G protein signaling in neuronal plasticity and memory formation: the specific role of ras family proteins
Neuron
Co-expression and in vivo interaction of serotonin1A and serotonin2A receptors in pyramidal neurons of prefrontal cortex
Cereb. Cortex
Serotonin depletion hampers survival and proliferation in neurospheres derived from adult neural stem cells
Neuropsychopharmacology
Presynaptic 5-HT1A is related to 5-HTT receptor density in the human brain
Neuropsychopharmacology
Synaptic plasticity: multiple forms, functions, and mechanisms
Neuropsychopharmacology
Cited by (23)
Convergent molecular and structural neuroimaging signatures of first-episode depression
2023, Journal of Affective DisordersCerebral grey matter density is associated with neuroreceptor and neurotransporter availability: A combined PET and MRI study
2021, NeuroImageCitation Excerpt :The effects remained essentially unchanged even when controlling for age and sex, which are known to influence both GM and the neuroreceptor systems (Kantonen et al., 2020; Resnick et al., 2003). In comparison with previous investigations on GM density and radiotracer uptake, we also observed effects with significantly larger number of regions likely due to improved statistical power (Kraus et al., 2012; Woodward et al., 2009). In general, the association between GMD and BPND were of moderate magnitude.
Gray matter reorganization underpinnings of antidepressant treatment of persistent depressive disorder
2021, European NeuropsychopharmacologyCitation Excerpt :For example, Vaidya et al have reported that administration of the serotonin2A-agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) leads to a significant increase of BDNF-expression in frontal and parietal cortex within layers II/III and V/VI, areas which were shown to be particularly affected by reductions of neuronal and glial cell density that observed in postmortem brains of depressed patients(Vaidya et al., 1997); Vetencourt et al have reported that antidepressants can reinstate adult visual neuroplasticity and increase cortical neurons by reduced intracortical inhibition and increased expression of a brain-derived neurotrophic factor in the visual cortex (Maya Vetencourt et al., 2008). In terms of macroscopic brain morphology, it has been demonstrated that the antidepressants with serotonin or/and norepinephrine transmitter effects, namely selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), have a significant impact on grey matter volume (GMV), which can be detected after 10 days of antidepressant administration (Kraus et al., 2014, 2012). Emerging findings from structural MRI studies have reported altered GMV in the middle frontal cortex (Kong et al., 2014b), dorsolateral prefrontal cortex (Smith et al., 2014), posterior cingulate cortex (Kraus et al., 2014), and the visual areas (Jung et al., 2014) after antidepressant treatment.
Imaging the neuroplastic effects of ketamine with VBM and the necessity of placebo control
2017, NeuroImageCitation Excerpt :Consecutive microdialysis in these monkeys further showed an increase of serotonin levels in the extracellular fluid of the prefrontal cortex (Yamamoto et al., 2013). The influence of ketamine on serotonergic transmission might further influence neuroplasticity as serotonin has been demonstrated to have a significant impact on grey matter volume (Kraus et al., 2014, 2012). In line with this, it has been reported that administration of the serotonin2A-agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) leads to a significant increase of BDNF-expression in frontal and parietal cortex of rats within layer II/III and V/VI which were shown to be particularly affected by reductions of neuronal and glial cell density and enlargements of glial nuclei in postmortem brains of depressed patients (Vaidya et al., 1997).
Magnetic Resonance and Molecular Imaging in Psychiatry
2015, International Encyclopedia of the Social & Behavioral Sciences: Second Edition