Differential modulation of the default mode network via serotonin-1A receptors

Department of Psychiatry and Psychotherapy, Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, 1090 Vienna, Austria.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2012; 109(7):2619-24. DOI: 10.1073/pnas.1117104109
Source: PubMed


Reflecting one's mental self is a fundamental process for evaluating the personal relevance of life events and for moral decision making and future envisioning. Although the corresponding network has been receiving growing attention, the driving neurochemical mechanisms of the default mode network (DMN) remain unknown. Here we combined positron emission tomography and functional magnetic resonance imaging to investigate modulations of the DMN via serotonin-1A receptors (5-HT(1A)), separated for 5-HT autoinhibition (dorsal raphe nucleus) and local inhibition (heteroreceptors in projection areas). Using two independent approaches, regional 5-HT(1A) binding consistently predicted DMN activity in the retrosplenial cortex for resting-state functional magnetic resonance imaging and the Tower of London task. On the other hand, both local and autoinhibitory 5-HT(1A) binding inversely modulated the posterior cingulate cortex, the strongest hub in the resting human brain. In the frontal part of the DMN, a negative association was found between the dorsal medial prefrontal cortex and local 5-HT(1A) inhibition. Our results indicate a modulation of key areas involved in self-referential processing by serotonergic neurotransmission, whereas variations in 5-HT(1A) binding explained a considerable amount of the individual variability in the DMN. Moreover, the brain regions associated with distinct introspective functions seem to be specifically regulated by the different 5-HT(1A) binding sites. Together with previously reported modulations of dopamine and GABA, this regional specialization suggests complex interactions of several neurotransmitters driving the default mode network.

Download full-text


Available from: Cécile Philippe, Oct 03, 2015
302 Reads
  • Source
    • "Decreasing 5HT1A neurotransmission caused a very significant effect in the orbitofrontal network. The frontal cortex shows a very high density of 5HT receptors and is important for memory functions, emotional behavior, attention and introspective processing (Hahn et al. 2012). 5HT1A inhibition additionally decreased FC within the thalamic, caudate putamen , somatosensory and nucleus accumbens networks, consistent with the known involvement of serotonin in motor activity, sensory gating, and motivated behavior (Bishop et al. 2009; Clissold et al. 2013; van den Buuse 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Resting-state functional MRI (rsfMRI) is a widely implemented technique used to investigate large-scale topology in the human brain during health and disease. Studies in mice provide additional advantages, including the possibility to flexibly modulate the brain by pharmacological or genetic manipulations in combination with high-throughput functional connectivity (FC) investigations. Pharmacological modulations that target specific neurotransmitter systems, partly mimicking the effect of pathological events, could allow discriminating the effect of specific systems on functional network disruptions. The current study investigated the effect of cholinergic and serotonergic antagonists on large-scale brain networks in mice. The cholinergic system is involved in cognitive functions and is impaired in, e.g., Alzheimer's disease, while the serotonergic system is involved in emotional and introspective functions and is impaired in, e.g., Alzheimer's disease, depression and autism. Specific interest goes to the default-mode-network (DMN), which is studied extensively in humans and is affected in many neurological disorders. The results show that both cholinergic and serotonergic antagonists impaired the mouse DMN-like network similarly, except that cholinergic modulation additionally affected the retrosplenial cortex. This suggests that both neurotransmitter systems are involved in maintaining integrity of FC within the DMN-like network in mice. Cholinergic and serotonergic modulations also affected other functional networks, however, serotonergic modulation impaired the frontal and thalamus networks more extensively. In conclusion, this study demonstrates the utility of pharmacological rsfMRI in animal models to provide insights into the role of specific neurotransmitter systems on functional networks in neurological disorders.
    Brain Structure and Function 07/2015; DOI:10.1007/s00429-015-1087-7 · 5.62 Impact Factor
  • Source
    • "The latter means that the concentration of a biochemical constituent, as measured by MRS, may predict activity in either the same region, i.e., intra-regionally, and/or another region, i.e., trans-regionally [27]. There is, for example, evidence which suggests the existence of complex interactions between neurotransmitters and the activity of the DMN [28]. Similarly, glutamate measured in the ACC was found to be related with the resting state activity in the same region [29]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The role of neurotransmitters in the activity of resting state networks has been gaining attention and has become a field of research with magnetic resonance spectroscopy (MRS) being one of the key techniques. MRS permits the measurement of c-aminobutyric acid (GABA) and glutamate levels, the central biochemical constituents of the excitation-inhibition balance in vivo. The inhibitory effects of GABA in the brain have been largely investigated in relation to the activity of resting state networks in functional magnetic resonance imaging (fMRI). In this study GABA concentration in the posterior cingulate cortex (PCC) was measured using single voxel spectra acquired with standard point resolved spectroscopy (PRESS) from 20 healthy male volunteers at 3 T. Resting state fMRI was consecutively measured and the values of GABA/Creatine+ Phosphocreatine ratio (GABA ratio) were included in a general linear model matrix as a step of dual regression analysis in order to identify voxels whose neuroimaging metrics during rest were related to individual levels of the GABA ratio. Our data show that the connection strength of putamen to the default-mode network during resting state has a negative linear relationship with the GABA ratio measured in the PCC. These findings highlight the role of PCC and GABA in segregation of the motor input, which is an inherent condition that characterises resting state.
    PLoS ONE 09/2014; 9(9):e106609. DOI:10.1371/journal.pone.0106609 · 3.23 Impact Factor
  • Source
    • "Therefore, these tasks typically did not directly measure planning ability and are referred to in this paper as tests of problem-solving ability. aspects (Baker et al., 1996; Boghi et al., 2006; Wagner et al., 2006; Just et al., 2007; Den Braber et al., 2008; Fitzgerald et al., 2008; Campbell et al., 2009; Zhu et al., 2010; De Ruiter et al., 2011; Kaller et al., 2011; Stokes et al., 2011; Hahn et al., 2012). Activation was also routinely observed in a number of other cortical and subcortical regions, including the parietal cortex, premotor region, anterior cingulate cortex, insular cortex, caudate, and thalamus (Baker et al., 1996; Beauchamp et al., 2003; Cazalis et al., 2006; Just et al., 2007; Campbell et al., 2009; Den Braber et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Problem-solving is an executive function subserved by a network of neural structures of which the dorsolateral prefrontal cortex (DLPFC) is central. Whereas several studies have evaluated the role of the DLPFC in problem-solving, few standardized tasks have been developed specifically for use with functional neuroimaging. The current study adapted a measure with established validity for the assessment of problem-solving abilities to design a test more suitable for functional neuroimaging protocols. The Scarborough adaptation of the Tower of London (S-TOL) was administered to 38 healthy adults while hemodynamic oxygenation of the PFC was measured using 16-channel continuous-wave functional near-infrared spectroscopy (fNIRS). Compared to a baseline condition, problems that required two or three steps to achieve a goal configuration were associated with higher activation in the left DLPFC and deactivation in the medial PFC. Individuals scoring higher in trait deliberation showed consistently higher activation in the left DLPFC regardless of task difficulty, whereas individuals lower in this trait displayed less activation when solving simple problems. Based on these results, the S-TOL may serve as a standardized task to evaluate problem-solving abilities in functional neuroimaging studies.
    Frontiers in Human Neuroscience 03/2014; 8:185. DOI:10.3389/fnhum.2014.00185 · 2.99 Impact Factor
Show more