Molecular Imaging of the Brain Serotonergic Transmitter Systems - Links to Behaviour

Transcription

1 Molecular Imaging of the Brain Serotonergic Transmitter Systems - Links to Behaviour Gitte Moos Knudsen MD PhD Neurobiology Research Unit HR Rigshospitalet University of Copenhagen Denmark

2 Interindividual Differences in Complex Behaviour: Interaction between Genes & Environment

3 Research Strategy

4 Functions of serotonin, 5-HT Presynaptic autoreceptors. They act in an inhibitory way - when stimulated, further serotonin release and synthesis is inhibited The serotonin-transporter, SERT, is located presynaptically on serotonergic neurons and astrocytes. Plays an important role in the termination of the 5-HTtransmission More than 14 postsynaptic serotonin receptor subtypes are identified; they mediate the physiological functions of serotonin: e.g., anxiety, aggression, mood, sleep, appetite, cognitive functions

5 Serotonin System SSRI 4 SSRI Increased serotonin signaling

6 Serotonin Synthesis Serotonin Transporter Serotonin 1A Receptor Serotonin 2A Receptor Serotonin 1B Receptor Serotonin 4 Receptor

7 PET Brain Receptor Imaging Cyclotron Radiotracer PET scanning 11 C OH H OCH3 O 11 CH 3 F N BP CTX 1 Modelling analysis MRI / PET HIP registration 1 Input function

8 Brain anatomy heritability Thompson et al, 2001

9 Monozygotic vs. dizygotic brains Pinborg et al, 2008

10 Retest MZ twin B DZ twin B 5-HT 2A Receptor Binding is Genetically Determined ICC =0.92 ICC =0.87 ICC =0.67 BP1 (unitless) BP1 (unitless) BP1 (unitless) Test Pinborg et al, 2008 Frontal cortex Temporal cortex Parietal cortex Occipital cortex Orbitofrontal cortex Ant cingulate cortex MZ tw in A Frontal cortex Temporal cortex Parietal cortex Occipital cortex Orbitofrontal cortex Ant cingulate cortex DZ tw in A Frontal cortex Temporal cortex Parietal cortex Occipital cortex Orbitofrontal cortex Ant cingulate cortex

11 Correlation between Regions 5-HT 2A receptors (N=56) 5-HTT (N=56) Erritzoe et al, J Neurosci 2010

12 5-HT 1A receptor vs. 5-HTT binding Bose et al, Neuropsychopharm 2011

13 SERT vs 5-HT 2A receptor binding Erritzoe et al, J Neurosci 2010

14 Personlighed, interesser og holdninger er arvelige Correlations among monozygotic twins reared together (MZT) or reared apart (MZA) for physiological characteristics, personality traits, interests, and attitudes Kandel: Principles of Neuroscience

15 The Big Five - som udtrykt i NEO-PI-R Neuroticisme (angst, irritabilitet, depression, jegbevidsthed, impulsivitet, sårbarhed) Ekstroversion (varme, selskabstrang, dominans, aktivitet, spændingssøgen, positive emotioner) Åbenhed (fantasi, æstetisk sans, følelser, handlinger, ideer, værdier) Venlighed (tillidsfuldhed, ligefremhed, altruisme, efterrettelighed, beskedenhed, blødsødenhed) Samvittighedsfuldhed (kompetence, orden, pligtopfyldenhed, præstationsorientering, selvdisciplin, besindighed)

16 Personlighedstræk er associeret med sygdomsrisiko og levetid Positiv livsindstilling og høj samvittighedsfuldhed er forbundet med længere levetid Vrede og fjendtlige træk er forbundet med øget sygdomsrisiko (fx cardiovaskulær sygdom) Høj neuroticisme er forbundet med øget risiko for udvikling af depression

17 Cerebral 5-HT 2A receptor binding in MDD Meyer, 2007

18 Determine early surrogates Trait or state? Drug-induced alterations Related to disease pathogenesis or healthy counter-response Answer: Conduct at-risk studies, before disease evolves

19 5-HT 2A receptor binding is positively related to neuroticism and its facet vulnerability Examples: I often feel helpless and want someone else to solve my problems I often worry about things that can go wrong I tend to blame myself whenever something goes wrong Blue: p<0.05, green: p<0.01, red: p<0.001, N=83. Frokjaer et al, Biol Psych 2008

20 Neurotisism consists of six personality traits Vulnerability Anxiety Depression Impulsiveness Self-consciousness Angry hostility sensitivity to stress and trauma active reaction when faced with stress

21 High-Risk versus Low-Risk Twins Inclusion criterium: having (or for the low-risk: not having) a MZ or DZ co-twin with a diagnosis of affective disorder according to information from the Danish Psychiatric Central Research Register Exclusion criteria (SCAN interview): Prior depressive episode Prior manic episode Earlier medical treatment for an affective episode Severe organic brain disease Schizophrenia

22 5-HT 2A Binding in High-Risk vs Low-Risk Individuals Effect of familial risk on the association between frontolimbic 5-HT 2A receptor BP P and neuroticism, adjusted for BMI and age. P<0.03 N=38 Frokjaer et al, Neuropsychopharm, 2010

23 Conclusions Positive association between frontolimbic serotonin 2A receptor binding and neuroticism Familial risk of developing mood disorders modifies the positive association between frontolimbic serotonin 2A receptor binding and neuroticism The strong association between high neuroticism and high frontolimbic serotonin 2A receptor binding in individuals at high familiar risk may reflect an enhanced negative impact of stress The combination of high frontolimbic serotonin 2A receptor binding and high neuroticism may be particularly disadvantageous in the context of mood disorders

24 5-HTTLPR

25 5-HTTLPR and In Vivo Cerebral 5-HTT Binding In healthy individuals, 5-HTT binding as measured with 11 C-DASB is higher among homozygotic carriers of the long 5-HTTLPR allele who also have the A variation at rs25531: L A vs. (L G /L G + S/L G + SS) Praschak-Rieder et al, 2007 (putamen, n=43) Reimold et al, 2007 (midbrain, n=19) Kalbitzer et al, 2009 (caudate, n=50) Although a single study in 63 men could not find any difference (Murthy et al, 2010)

26 5-HTTLPR and affective disorder Kim J-M et al, 2007

27 The S-allele carriers Amygdala Structural and functional changes result in increased threat-related reactivity (Caspi et al 2010) More vulnerable to environmental changes Depression after stressful life events (Caspi et al 2003) More likely to score high on neuroticism (Young et al 1991) Seasonal affective disorder (Rosenthal et al 1998)

28 Seasonal Affective Disorder

29 Genotype Seasonality Interaction on 5-HTT binding Kalbitzer et al, 2010; Praschak-Rieder et al, 2008; Ruhe et al, HTT binding over seasons, adjusted for age and gender Kalbitzer et al. Biol Psych 2010

30 The Serotonergic Transmitter Systems Role in Seasonal Rhythms Are the fluctuating cerebral SERT levels counteracting seasonal fluctuations in interstitial serotonin levels, and thus an appropriate mechanism to maintain serotonergic tonus? Or is the primary event rather a fluctuation in cerebral SERT that leads to secondary changes in serotonin levels. Can the upregulation of SERT in winter time be counteracted by bright light therapy?

31 Block Face + Face Face Face sec 0.2 sec Run Fear Neutral Angry Neutral Angry Neutral... Session 12 sec Run 1 Run 2 6 min 24 sec 32 Neutral blocks 16 Fear blocks 16 Angry blocks Scan time: 12 mins 48 secs

32 Bright Light Therapy: fmri and Emotional Faces Aversive - Neutral Neutral - Aversive Low response of the amygdala to aversive neutral faces Large, negative response to aversive neutral faces within mpfc Fisher et al, in prep

33 Effects of Bright Light Therapy (BLT) Three weeks of bright light exposure is dose-dependently associated with a decline in amygdala activation to emotional faces

34 Summary Brain Imaging the 5-HT System Season dependent fluctuations are seen in SERT binding with a gene*environment effect Three weeks of exposure to bright light during the winter is dose-dependently associated with a decline in bilateral amygdala activation to emotional faces

35 Neurobiology Research Unit 2012 Funding: The Lundbeck Foundation

36 Is Depression Associated with Amyloid Deposition? Madsen et al, Neurobiol Ageing 2012