Neurobiology Research Unit

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Wickens J.R.,Neurobiology Research Unit | Arbuthnott G.W.,Okinawa Institute of Science and Technology
Handbook of Behavioral Neuroscience | Year: 2010

This chapter discusses that synaptic plasticity operating on the corticostriatal projection strengthens connections, which are active in association with dopamine release, and weakens connections that are active when there is no dopamine release. It suggests that such strengthening and weakening of connections between the cortex and striatum might be involved in the learning of stimulus-response associations. The activity of a cortical cell assembly is detected by one, or a number of, striatal cells, and this detection is accomplished with great accuracy. It also discusses that dopamine-dependent synaptic plasticity may reinforce the detection of cortical assemblies associated with positive outcomes. The convergence of different modalities particularly favors the detection of assemblies with both motor and sensory components, which might represent a combination of stimuli and responses, or more abstractly, actions, intentions, and strategies. Consideration of the anatomy and plasticity of the corticostriatal pathway suggests the spiny cell network may compute a value function with which to evaluate cortical propositions, and select the ones associated with reinforcement. © 2010 Elsevier Inc.


Frokjaer V.G.,Center for Integrated Molecular Brain Imaging | Frokjaer V.G.,Neurobiology Research Unit | Pinborg A.,Fertility Clinic | Pinborg A.,Copenhagen University | And 25 more authors.
Biological Psychiatry | Year: 2015

Background An adverse response to acute and pronounced changes in sex-hormone levels during, for example, the perimenopausal or postpartum period appears to heighten risk for major depression in women. The underlying risk mechanisms remain elusive but may include transiently compromised serotonergic brain signaling. Here, we modeled a biphasic ovarian sex hormone fluctuation using a gonadotropin-releasing hormone agonist (GnRHa) and evaluated if emergence of depressive symptoms was associated with change in cerebral serotonin transporter (SERT) binding following intervention. Methods A double-blind, randomized, placebo-controlled study included 63 healthy female volunteers (mean age 24.3 ± 4.9 years) with regular menstrual cycles between 23 and 35 days. Participants were randomized to active (goserelin [GnRHa] 3.6 mg implant) or placebo intervention. Sixty women completed follow-up and entered the analyses. Primary outcome measures were changes from baseline in depressive symptoms assessed on the 17-item Hamilton Depression Rating Scale and SERT binding as imaged by [11C]DASB positron emission tomography. Outcome measures were acquired at baseline in the follicular phase (cycle day 6.6 ± 2.2) and at follow-up (16.2 ± 2.6 days after intervention start). Results Sex hormone manipulation with GnRHa significantly triggered subclinical depressive symptoms within-group (p =.003) and relative to placebo (p =.02), which were positively associated with net decreases in estradiol levels (p =.02) from baseline within the GnRHa group. Depressive symptoms were associated with increases in neocortical SERT binding in the GnRHa group relative to placebo (p =.003). Conclusions Our data imply both serotonergic signaling and estradiol in the mechanisms by which sex-steroid hormone fluctuations provoke depressive symptoms and thus provide a rationale for future preventive strategies in high-risk groups. © 2015 Society of Biological Psychiatry.


Marner L.,Neurobiology Research Unit | Marner L.,Center for Integrated Molecular Brain Imaging | Frokjaer V.G.,Neurobiology Research Unit | Frokjaer V.G.,Center for Integrated Molecular Brain Imaging | And 12 more authors.
Neurobiology of Aging | Year: 2012

In patients with Alzheimer's disease (AD), postmortem and imaging studies have revealed early and prominent reductions in cerebral serotonin 2A (5-HT 2A) receptors. To establish if this was due to a selective disease process of the serotonin system, we investigated the cerebral 5-HT 2A receptor and the serotonin transporter binding, the latter as a measure of serotonergic projections and neurons. Twelve patients with AD (average Mini Mental State Examination [MMSE]: 24) and 11 healthy age-matched subjects underwent positron emission tomography (PET) scanning with [ 18F]altanserin and [ 11C]N,N-Dimethyl-2-(2-amino-4-cyanopheylthio)benzylamine ([ 11C]DASB). Overall [ 18F]altanserin binding was markedly reduced in AD by 28%-39% (p = 0.02), whereas the reductions in [ 11C]DASB binding were less prominent and mostly insignificant, except for a marked reduction of 33% in mesial temporal cortex (p = .0005). No change in [ 11C]DASB binding was found in the midbrain. We conclude that the prominent reduction in neocortical 5-HT 2A receptor binding in early AD is not caused by a primary loss of serotonergic neurons or their projections. © 2012 Elsevier Inc..


PubMed | Copenhagen University, Neurobiology Research Unit, Rigshospitalet, The Fertility Clinic and 2 more.
Type: Journal Article | Journal: Biological psychiatry | Year: 2015

An adverse response to acute and pronounced changes in sex-hormone levels during, for example, the perimenopausal or postpartum period appears to heighten risk for major depression in women. The underlying risk mechanisms remain elusive but may include transiently compromised serotonergic brain signaling. Here, we modeled a biphasic ovarian sex hormone fluctuation using a gonadotropin-releasing hormone agonist (GnRHa) and evaluated if emergence of depressive symptoms was associated with change in cerebral serotonin transporter (SERT) binding following intervention.A double-blind, randomized, placebo-controlled study included 63 healthy female volunteers (mean age 24.3 4.9 years) with regular menstrual cycles between 23 and 35 days. Participants were randomized to active (goserelin [GnRHa] 3.6 mg implant) or placebo intervention. Sixty women completed follow-up and entered the analyses. Primary outcome measures were changes from baseline in depressive symptoms assessed on the 17-item Hamilton Depression Rating Scale and SERT binding as imaged by [(11)C]DASB positron emission tomography. Outcome measures were acquired at baseline in the follicular phase (cycle day 6.6 2.2) and at follow-up (16.2 2.6 days after intervention start).Sex hormone manipulation with GnRHa significantly triggered subclinical depressive symptoms within-group (p = .003) and relative to placebo (p = .02), which were positively associated with net decreases in estradiol levels (p = .02) from baseline within the GnRHa group. Depressive symptoms were associated with increases in neocortical SERT binding in the GnRHa group relative to placebo (p = .003).Our data imply both serotonergic signaling and estradiol in the mechanisms by which sex-steroid hormone fluctuations provoke depressive symptoms and thus provide a rationale for future preventive strategies in high-risk groups.


Mehendale A.W.,Neurobiology Research Unit | Goldman M.P.,Neurobiology Research Unit | Mehendale R.P.,University of Texas at San Antonio
Journal of Opioid Management | Year: 2013

Throughout history, opioids have effectively alleviated pain but not without the risk of addiction and death. Seductive and dangerous, full of promise and destruction, opioids are both revered and feared by Western culture. Their exponential use in "developed countries" is now an enormous public health problem and requires us to harness their properties with scientific rigor and adequate safeguards. The use of opioids for the treatment of chronic nonterminal pain (CNTP) has been a relatively new phenomenon which has coincided with the proclamation by the Joint Commission on Accreditation of Health Care Organization in 2000 that pain assessment be the "fifth vital sign," notwithstanding the fact that pain is a symptom and not a sign. 1 Nonetheless, this resulted in a culture of a marked increase in use of opioids for acute and chronic pain management. Consequently, there are many unintended outcomes which include opioid-induced hyperalgesia increased diversion, addiction, and death. Understandably, this has resulted in many regulatory responses from such agencies such as the Drug Enforcement Administration (DHA) and state medical boards. This article proposes a clinically relevant paradigm of opioid overuse pain syndrome. The goal of this article is to inform the clinicians of the complicated neurobiology of opioids. It is our hope that scientists rather than government regulators dictate the appropriate response to the epidemic of over prescription of opioids. A similar designation of "medication overuse headache" has resulted in near extinction of excessive use of opioids in the field of headache medicine. © 2013 Journal of Opioid Management, All Rights Reserved.


Frokjaer V.G.,Copenhagen University | Frokjaer V.G.,Neurobiology Research Unit | Erritzoe D.,Copenhagen University | Erritzoe D.,Neurobiology Research Unit | And 15 more authors.
European Neuropsychopharmacology | Year: 2013

Stress sensitivity and serotonergic neurotransmission interact, e.g. individuals carrying the low-expressing variants (S and LG) of the 5-HTTLPR promoter polymorphism of the serotonin transporter (SERT) gene are at higher risk for developing mood disorders when exposed to severe stress and display higher cortisol responses when exposed to psychosocial stressors relative to high expressing 5-HTTLPR variants. However, it is not clear how the relation between SERT and cortisol output is reflected in the adult brain. We investigated the relation between cortisol response to awakening (CAR) and SERT binding in brain regions considered relevant to modify the cortisol awakening response. Methods: thirty-two healthy volunteers underwent in vivo SERT imaging with [11C]DASB-Positron Emission Tomography (PET), genotyping, and performed home-sampling of saliva to assess CAR. Results: CAR, defined as the area under curve with respect to increase from baseline, was positively coupled to prefrontal SERT binding (p=0.02), independent of adjustment for 5-HTTLPR genotype. Although S- and LG-allele carriers tended to show a larger CAR (p=0.07) than LA homozygous, 5-HTTLPR genotype did not modify the coupling between CAR and prefrontal SERT binding as tested by an interaction analysis (genotype x CAR). Conclusion: prefrontal SERT binding is. © 2012 Elsevier B.V. and ECNP.


Frokjaer V.G.,Neurobiology Research Unit | Vinberg M.,Copenhagen University | Erritzoe D.,Neurobiology Research Unit | Baare W.,Neurobiology Research Unit | And 10 more authors.
Neuropsychopharmacology | Year: 2010

Life stress is a robust risk factor for later development of mood disorders, particularly for individuals at familial risk. Likewise, scoring high on the personality trait neuroticism is associated with an increased risk for mood disorders. Neuroticism partly reflects stress vulnerability and is positively correlated to frontolimbic serotonin 2A (5-HT 2A) receptor binding. Here, we investigate whether neuroticism interacts with familial risk in relation to frontolimbic 5-HT 2A receptor binding. Twenty-one healthy twins with a co-twin history of mood disorder and 16 healthy twins without a co-twin history of mood disorder were included. They answered self-report personality questionnaires and underwent 18 Faltanserin positron emission tomography. We found a significant interaction between neuroticism and familial risk in predicting the frontolimbic 5-HT 2A receptor binding (p0.026) in an analysis adjusting for age and body mass index. Within the high-risk group only, neuroticism and frontolimbic 5-HT 2A receptor binding was positively associated (p0.0037). In conclusion, our data indicate that familial risk and neuroticism interact in their relation to frontolimbic 5-HT 2A receptor binding. These findings point at a plausible neurobiological link between genetic and personality risk factors and vulnerability to developing mood disorders. It contributes to our understanding of why some people at high risk develop mood disorders while others do not. We speculate that an increased stress reactivity in individuals at high familial risk for mood disorders might enhance the effect of neuroticism in shaping the impact of potential environmental stress and thereby influence serotonergic neurotransmission. © 2010 Nature Publishing Group All rights reserved.


Jakobsen G.R.,Neurobiology Research Unit | Jakobsen G.R.,Copenhagen University | Fisher P.M.,Neurobiology Research Unit | Dyssegaard A.,Neurobiology Research Unit | And 10 more authors.
Psychoneuroendocrinology | Year: 2016

Serotonin signalling is considered critical for an appropriate and dynamic adaptation to stress. Previously, we have shown that prefrontal serotonin transporter (SERT) binding is positively associated with the cortisol awakening response (CAR) (. Frokjaer et al., 2013), which is an index of hypothalamic-pituitary-adrenal (HPA)-axis output dynamics. Here, we investigated in healthy individuals if cerebral serotonin 4 receptor (5-HT4r) binding, reported to be a proxy for serotonin levels, is associated with CAR.Thirty healthy volunteers (25 males, age range 20-56 years) underwent 5-HT4r PET imaging with [11C]-SB207145, genotyping of the SERT-linked polymorphic region (5-HTTLPR), and performed serial home sampling of saliva (5 time points from 0 to 60 min from awakening) to assess CAR. The association between 5-HT4r binding in 4 regions of interest (prefrontal cortex, anterior cingulate cortex, pallidostriatum, and hippocampus) and CAR was tested using multiple linear regression with adjustment for age and 5-HTTLPR genotype. Finally, an exploratory voxel-based analysis of the association was performed.CAR was negatively associated with 5-HT4r binding in pallidostriatum (p = 0.01), prefrontal cortex (p = 0.03), and anterior cingulate cortex (p = 0.002), respectively, but showed no association in hippocampus. The results remained significant when taking into account other potentially relevant covariates.In conclusion, our finding reinforces an association between HPA-axis function and serotonin signaling in vivo in humans. We suggest that higher synaptic serotonin concentration, here indexed by lower 5-HT4r binding, supports HPA-axis dynamics, which in healthy volunteers is reflected by a robust CAR. © 2016 Elsevier Ltd.


Vinberg M.,Copenhagen University | Froekjaer V.G.,Neurobiology Research Unit | Kessing L.V.,Copenhagen University
Journal of Nervous and Mental Disease | Year: 2010

Coping styles may influence the perceived life stress experienced by an individual and, therefore, also be critical in the development of affective disorders. This study examined whether familial risk of affective disorder is associated with the use of maladaptive coping styles, in healthy individuals. One hundred twelve high-risk and 78 low-risk individuals were identified through nation-wide registers and invited to participate in an extensive psychiatric evaluation including the Coping Inventory for Stressful Situations. The high-risk individuals used more Emotion-oriented (p = 0.001) and Avoidance coping (p = 0.04) than individuals not at risk. Adjusted for gender, age, years of education, and recent stressful life events the high-risk individuals used more emotion-oriented coping (p = 0.03). In conclusion, maladaptive coping style may represent a trait marker for mood disorder improving maladaptive coping styles may be a target for selective prevention focusing on subgroups at high risk of developing an affective disorder. © 2010 by Lippincott Williams & Wilkins.


PubMed | Neurobiology Research Unit
Type: Comparative Study | Journal: Neurobiology of aging | Year: 2012

In patients with Alzheimers disease (AD), postmortem and imaging studies have revealed early and prominent reductions in cerebral serotonin 2A (5-HT(2A)) receptors. To establish if this was due to a selective disease process of the serotonin system, we investigated the cerebral 5-HT(2A) receptor and the serotonin transporter binding, the latter as a measure of serotonergic projections and neurons. Twelve patients with AD (average Mini Mental State Examination [MMSE]: 24) and 11 healthy age-matched subjects underwent positron emission tomography (PET) scanning with [(18)F]altanserin and [(11)C]N,N-Dimethyl-2-(2-amino-4-cyanopheylthio)benzylamine ([(11)C]DASB). Overall [(18)F]altanserin binding was markedly reduced in AD by 28%-39% (p = 0.02), whereas the reductions in [(11)C]DASB binding were less prominent and mostly insignificant, except for a marked reduction of 33% in mesial temporal cortex (p = .0005). No change in [(11)C]DASB binding was found in the midbrain. We conclude that the prominent reduction in neocortical 5-HT(2A) receptor binding in early AD is not caused by a primary loss of serotonergic neurons or their projections.

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