The extracellular matrix of the brain is a macromolecular aggregate composed of a great variety o... more The extracellular matrix of the brain is a macromolecular aggregate composed of a great variety of structurally diverse glycoproteins and proteoglycans serving as a microen- vironment for neurons and glial cells. Proteoglycans are large molecules consisting of a protein core and glycosaminoglycan (GAG) side chains. During morphogenesis and neural differentiation, the matrix undergoes dramatic changes in its composition and structure. Up to now, more than 20 different proteoglycan core proteins have been described to occur in the brain, most of them being developmentally regulated in their patterns of expression (1). Some of the brain proteoglycans are considered members of the aggrecan/ versican family, a group of chondroitin sulphate (CS) bearing secreted molecules with modular structures (for review see ref. 2). Fig. 1A gives a schematic overview of this proteoglycan family. Members of the family are aggrecan, known as the main aggregating proteoglycan of cartilage (3), versican, originally identified in fibroblasts (4), and the two neural-specific molecules neurocan (5) and brevican (6). All these proteoglycans share common structural features including N-terminal globular domains called proteoglycan tandem repeats (PTR) that are capable of binding hyaluronic acid (HA) and link protein. The central part of the molecules has a stretched architecture and carries the GAG side chains. In the C-terminal part, epidermal growth factor (EGF)-like domains, C-type lectin domains and a complement-regulatory protein (CRP)-motive are to be found. The putative HA-binding protein BEHAB (7) is identical to the N-terminus of brevican. Using antisera against a synaptic protein preparation from rat brain we have cloned rat brevican from a
The neural extracellular matrix (ECM) composition shapes the neuronal microenvironment and underg... more The neural extracellular matrix (ECM) composition shapes the neuronal microenvironment and undergoes substantial changes upon development and aging, but also due to cerebral pathologies. In search for potential biomarkers, cerebrospinal fluid (CSF) and serum concentrations of brain ECM molecules have been determined recently to assess ECM changes during neurological conditions including Alzheimer’s disease or vascular dementia. Here, we measured the levels of two signature proteoglycans of brain ECM, neurocan and brevican, in the CSF and serum of 96 neurological patients currently understudied regarding ECM alterations: 16 cases with amyotrophic lateral sclerosis (ALS), 26 epilepsy cases, 23 cerebral small vessel disease (CSVD) patients and 31 controls. Analysis of total brevican and neurocan was performed via sandwich Enzyme-linked immunosorbent assays (ELISAs). Major brevican and neurocan cleavage products were measured in the CSF using semiquantitative immunoblotting. Total brevi...
Neurons and glial cells in the central nervous system (CNS) are embedded in a dense and dynamic m... more Neurons and glial cells in the central nervous system (CNS) are embedded in a dense and dynamic meshwork of extracellular matrix (ECM). ECM components, which are synthesized and secreted by both neurons and glial cells, co-aggregate and form highly organized extracellular structures around cell somata, axon initial segments, dendrites and synapses, in particular, in the form of so-called perineuronal nets (PNNs).
The Met allele of the Val66Met SNP of the BDNF gene (rs6265) is associated with impaired activity... more The Met allele of the Val66Met SNP of the BDNF gene (rs6265) is associated with impaired activity-dependent release of brain-derived neurotrophic factor (BDNF), resulting in reduced synaptic plasticity, impaired glutamatergic neurotransmission, and morphological changes. While previous work has demonstrated Val66Met effects on magnetic resonance spectroscopy (MRS) markers of either glutamatergic metabolism (Glx) or neuronal integrity (NAA), no study has investigated Val66Met effects on these related processes simultaneously. As these metabolites share a metabolic pathway, the Glx/NAA ratio may be a more sensitive marker of changes associated with the Val66Met SNP. This ratio is increased in psychiatric disorders linked to decreased functioning in the anterior cingulate cortex (ACC). In this study, we investigated the correlation of the Val66Met polymorphism of the BDNF gene with Glx/NAA in the pregenual anterior cingulate cortex (pgACC) using MRS at 3 Tesla (T) (n = 30, all males) a...
Pavlovian biases influence the interaction between action and valence by coupling reward seeking ... more Pavlovian biases influence the interaction between action and valence by coupling reward seeking to action invigoration and punishment avoidance to action suppression. In this study we used an orthogonalised go/no-go task to investigate learning in 247 individuals across the human lifespan (7-80 years) to demonstrate that all participants, independently of age, demonstrated an influence of Pavlovian control. Computational modeling revealed peak performance in young adults was attributable to greater sensitivity to both rewards and punishment. However in children and adolescents an increased bias towards action but not reward sensitivity was observed. In contrast, reduced learning in midlife and older adults was accompanied with decreased reward sensitivity and especially punishment sensitivity. These findings reveal distinct learning capabilities across the human lifespan that cannot be probed using conventional go/reward no-go/punishment style paradigms that have important implicat...
In the brain, Hebbian-type and homeostatic forms of plasticity are affected by neuromodulators li... more In the brain, Hebbian-type and homeostatic forms of plasticity are affected by neuromodulators like dopamine (DA). Modifications of the perisynaptic extracellular matrix (ECM), controlling functions and mobility of synaptic receptors as well as diffusion of transmitters and neuromodulators in the extracellular space, are crucial for the manifestation of plasticity. Mechanistic links between synaptic activation and ECM modifications are largely unknown. Here, we report that neuromodulation via D1-type DA receptors can induce targeted ECM proteolysis specifically at excitatory synapses of rat cortical neurons via proteases ADAMTS-4 and -5. We show that receptor activation induces increased proteolysis of brevican (BC) and aggrecan, two major constituents of the adult ECM, in vivo and in vitro. ADAMTS immunoreactivity is detected near synapses, and shRNA-mediated knockdown reduced BC cleavage. We outline a molecular scenario how synaptic activity and neuromodulation are linked to ECM r...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 3, 2018
Anxiety disorders are common and debilitating conditions with higher prevalence in women. However... more Anxiety disorders are common and debilitating conditions with higher prevalence in women. However, factors that predispose women to anxiety phenotypes are not clarified. Here we investigated potential contribution of the single nucleotide polymorphism rs2236418 in gene to changes in regional inhibition/excitation balance, anxiety-like traits and related neural activity in both sexes. 105 healthy individuals were examined with high-field (7T) multimodal magnetic resonance imaging (MRI), including resting state fMRI in combination with assessment of GABA and Glutamate (Glu) levels via MR spectroscopy (MRS). Regional GABA/Glu levels in ACC subregions were assessed as mediators of gene-personality interaction for the trait harm avoidance and moderation by sex was tested. In AA homozygotes, with putatively lower promoter activity, we observed increased intrinsic neuronal activity and higher inhibition/excitation balance in pregenual ACC (pgACC), as compared to G carriers. The pgACC drove...
Dopamine is critically important in the neural manifestation of motivated behavior, and alteratio... more Dopamine is critically important in the neural manifestation of motivated behavior, and alterations in the human dopaminergic system have been implicated in the etiology of motivation-related psychiatric disorders, most prominently addiction. Patients with chronic addiction exhibit reduced dopamine D2 receptor (DRD2) availability in the striatum, and the DRD2 TaqIA (rs1800497) and C957T (rs6277) genetic polymorphisms have previously been linked to individual differences in striatal dopamine metabolism and clinical risk for alcohol and nicotine dependence. Here, we investigated the hypothesis that the variants of these polymorphisms would show increased reward-related memory formation, which has previously been shown to jointly engage the mesolimbic dopaminergic system and the hippocampus, as a potential intermediate phenotype for addiction memory. To this end, we performed functional magnetic resonance imaging (fMRI) in 62 young, healthy individuals genotyped for DRD2 TaqIA and C957...
Learning and memory processes are accompanied by rearrangements of synaptic protein networks. Whi... more Learning and memory processes are accompanied by rearrangements of synaptic protein networks. While various studies have demonstrated the regulation of individual synaptic proteins during these processes, much less is known about the complex regulation of synaptic proteomes. Recently, we reported that auditory discrimination learning in mice is associated with a relative down-regulation of proteins involved in the structural organization of synapses in various brain regions. Aiming at the identification of biological processes and signaling pathways involved in auditory memory formation, here, a label-free quantification approach was utilized to identify regulated synaptic junctional proteins and phosphoproteins in the auditory cortex, frontal cortex, hippocampus and striatum of mice 24 h after the learning experiment. Twenty proteins, including postsynaptic scaffolds, actin-remodeling proteins and RNA-binding proteins, were regulated in at least three brain regions pointing to comm...
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Jun 29, 2015
Cocaine-associated environmental cues sustain relapse vulnerability by reactivating long-lasting ... more Cocaine-associated environmental cues sustain relapse vulnerability by reactivating long-lasting memories of cocaine reward. Responding to cocaine cues can time-dependently intensify during periods of abstinence, a phenomenon referred to as 'incubation of cocaine craving'. Here, we investigated the role of the extracellular matrix protein brevican in recent (1 day after training) and remote (3 weeks after training) expression of cocaine conditioned place preference (CPP). Wild-type and Brevican heterozygous knock-out mice, which express brevican at ~50% of wild-type levels, received three cocaine-context pairings using a relatively low dose of cocaine (5 mg/kg). In a drug-free CPP test, heterozygous mice showed enhanced preference for the cocaine-associated context at the remote time-point compared with the recent time-point. This progressive increase was not observed in wild-type mice and it did not generalize to contextual-fear memory. Viral-mediated overexpression of brev...
Neural circuits can express different forms of plasticity. So far, Hebbian synaptic plasticity wa... more Neural circuits can express different forms of plasticity. So far, Hebbian synaptic plasticity was considered the most important plastic phenomenon, but over the last decade, homeostatic mechanisms gained more interest because they can explain how a neuronal network maintains stable baseline function despite multiple plastic challenges, like developmental plasticity, learning, or lesion. Such destabilizing influences can be counterbalanced by the mechanisms of homeostatic plasticity, which restore the stability of neuronal circuits. Synaptic scaling is a mechanism in which neurons can detect changes in their own firing rates through a set of molecular sensors that then regulate receptor trafficking to scale the accumulation of glutamate receptors at synaptic sites. Additional homeostatic mechanisms allow local changes in synaptic activation to generate local synaptic adaptations and network-wide changes in activity, which lead to adjustments in the balance between excitation and inh...
The extracellular matrix of the brain is a macromolecular aggregate composed of a great variety o... more The extracellular matrix of the brain is a macromolecular aggregate composed of a great variety of structurally diverse glycoproteins and proteoglycans serving as a microen- vironment for neurons and glial cells. Proteoglycans are large molecules consisting of a protein core and glycosaminoglycan (GAG) side chains. During morphogenesis and neural differentiation, the matrix undergoes dramatic changes in its composition and structure. Up to now, more than 20 different proteoglycan core proteins have been described to occur in the brain, most of them being developmentally regulated in their patterns of expression (1). Some of the brain proteoglycans are considered members of the aggrecan/ versican family, a group of chondroitin sulphate (CS) bearing secreted molecules with modular structures (for review see ref. 2). Fig. 1A gives a schematic overview of this proteoglycan family. Members of the family are aggrecan, known as the main aggregating proteoglycan of cartilage (3), versican, originally identified in fibroblasts (4), and the two neural-specific molecules neurocan (5) and brevican (6). All these proteoglycans share common structural features including N-terminal globular domains called proteoglycan tandem repeats (PTR) that are capable of binding hyaluronic acid (HA) and link protein. The central part of the molecules has a stretched architecture and carries the GAG side chains. In the C-terminal part, epidermal growth factor (EGF)-like domains, C-type lectin domains and a complement-regulatory protein (CRP)-motive are to be found. The putative HA-binding protein BEHAB (7) is identical to the N-terminus of brevican. Using antisera against a synaptic protein preparation from rat brain we have cloned rat brevican from a
The neural extracellular matrix (ECM) composition shapes the neuronal microenvironment and underg... more The neural extracellular matrix (ECM) composition shapes the neuronal microenvironment and undergoes substantial changes upon development and aging, but also due to cerebral pathologies. In search for potential biomarkers, cerebrospinal fluid (CSF) and serum concentrations of brain ECM molecules have been determined recently to assess ECM changes during neurological conditions including Alzheimer’s disease or vascular dementia. Here, we measured the levels of two signature proteoglycans of brain ECM, neurocan and brevican, in the CSF and serum of 96 neurological patients currently understudied regarding ECM alterations: 16 cases with amyotrophic lateral sclerosis (ALS), 26 epilepsy cases, 23 cerebral small vessel disease (CSVD) patients and 31 controls. Analysis of total brevican and neurocan was performed via sandwich Enzyme-linked immunosorbent assays (ELISAs). Major brevican and neurocan cleavage products were measured in the CSF using semiquantitative immunoblotting. Total brevi...
Neurons and glial cells in the central nervous system (CNS) are embedded in a dense and dynamic m... more Neurons and glial cells in the central nervous system (CNS) are embedded in a dense and dynamic meshwork of extracellular matrix (ECM). ECM components, which are synthesized and secreted by both neurons and glial cells, co-aggregate and form highly organized extracellular structures around cell somata, axon initial segments, dendrites and synapses, in particular, in the form of so-called perineuronal nets (PNNs).
The Met allele of the Val66Met SNP of the BDNF gene (rs6265) is associated with impaired activity... more The Met allele of the Val66Met SNP of the BDNF gene (rs6265) is associated with impaired activity-dependent release of brain-derived neurotrophic factor (BDNF), resulting in reduced synaptic plasticity, impaired glutamatergic neurotransmission, and morphological changes. While previous work has demonstrated Val66Met effects on magnetic resonance spectroscopy (MRS) markers of either glutamatergic metabolism (Glx) or neuronal integrity (NAA), no study has investigated Val66Met effects on these related processes simultaneously. As these metabolites share a metabolic pathway, the Glx/NAA ratio may be a more sensitive marker of changes associated with the Val66Met SNP. This ratio is increased in psychiatric disorders linked to decreased functioning in the anterior cingulate cortex (ACC). In this study, we investigated the correlation of the Val66Met polymorphism of the BDNF gene with Glx/NAA in the pregenual anterior cingulate cortex (pgACC) using MRS at 3 Tesla (T) (n = 30, all males) a...
Pavlovian biases influence the interaction between action and valence by coupling reward seeking ... more Pavlovian biases influence the interaction between action and valence by coupling reward seeking to action invigoration and punishment avoidance to action suppression. In this study we used an orthogonalised go/no-go task to investigate learning in 247 individuals across the human lifespan (7-80 years) to demonstrate that all participants, independently of age, demonstrated an influence of Pavlovian control. Computational modeling revealed peak performance in young adults was attributable to greater sensitivity to both rewards and punishment. However in children and adolescents an increased bias towards action but not reward sensitivity was observed. In contrast, reduced learning in midlife and older adults was accompanied with decreased reward sensitivity and especially punishment sensitivity. These findings reveal distinct learning capabilities across the human lifespan that cannot be probed using conventional go/reward no-go/punishment style paradigms that have important implicat...
In the brain, Hebbian-type and homeostatic forms of plasticity are affected by neuromodulators li... more In the brain, Hebbian-type and homeostatic forms of plasticity are affected by neuromodulators like dopamine (DA). Modifications of the perisynaptic extracellular matrix (ECM), controlling functions and mobility of synaptic receptors as well as diffusion of transmitters and neuromodulators in the extracellular space, are crucial for the manifestation of plasticity. Mechanistic links between synaptic activation and ECM modifications are largely unknown. Here, we report that neuromodulation via D1-type DA receptors can induce targeted ECM proteolysis specifically at excitatory synapses of rat cortical neurons via proteases ADAMTS-4 and -5. We show that receptor activation induces increased proteolysis of brevican (BC) and aggrecan, two major constituents of the adult ECM, in vivo and in vitro. ADAMTS immunoreactivity is detected near synapses, and shRNA-mediated knockdown reduced BC cleavage. We outline a molecular scenario how synaptic activity and neuromodulation are linked to ECM r...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 3, 2018
Anxiety disorders are common and debilitating conditions with higher prevalence in women. However... more Anxiety disorders are common and debilitating conditions with higher prevalence in women. However, factors that predispose women to anxiety phenotypes are not clarified. Here we investigated potential contribution of the single nucleotide polymorphism rs2236418 in gene to changes in regional inhibition/excitation balance, anxiety-like traits and related neural activity in both sexes. 105 healthy individuals were examined with high-field (7T) multimodal magnetic resonance imaging (MRI), including resting state fMRI in combination with assessment of GABA and Glutamate (Glu) levels via MR spectroscopy (MRS). Regional GABA/Glu levels in ACC subregions were assessed as mediators of gene-personality interaction for the trait harm avoidance and moderation by sex was tested. In AA homozygotes, with putatively lower promoter activity, we observed increased intrinsic neuronal activity and higher inhibition/excitation balance in pregenual ACC (pgACC), as compared to G carriers. The pgACC drove...
Dopamine is critically important in the neural manifestation of motivated behavior, and alteratio... more Dopamine is critically important in the neural manifestation of motivated behavior, and alterations in the human dopaminergic system have been implicated in the etiology of motivation-related psychiatric disorders, most prominently addiction. Patients with chronic addiction exhibit reduced dopamine D2 receptor (DRD2) availability in the striatum, and the DRD2 TaqIA (rs1800497) and C957T (rs6277) genetic polymorphisms have previously been linked to individual differences in striatal dopamine metabolism and clinical risk for alcohol and nicotine dependence. Here, we investigated the hypothesis that the variants of these polymorphisms would show increased reward-related memory formation, which has previously been shown to jointly engage the mesolimbic dopaminergic system and the hippocampus, as a potential intermediate phenotype for addiction memory. To this end, we performed functional magnetic resonance imaging (fMRI) in 62 young, healthy individuals genotyped for DRD2 TaqIA and C957...
Learning and memory processes are accompanied by rearrangements of synaptic protein networks. Whi... more Learning and memory processes are accompanied by rearrangements of synaptic protein networks. While various studies have demonstrated the regulation of individual synaptic proteins during these processes, much less is known about the complex regulation of synaptic proteomes. Recently, we reported that auditory discrimination learning in mice is associated with a relative down-regulation of proteins involved in the structural organization of synapses in various brain regions. Aiming at the identification of biological processes and signaling pathways involved in auditory memory formation, here, a label-free quantification approach was utilized to identify regulated synaptic junctional proteins and phosphoproteins in the auditory cortex, frontal cortex, hippocampus and striatum of mice 24 h after the learning experiment. Twenty proteins, including postsynaptic scaffolds, actin-remodeling proteins and RNA-binding proteins, were regulated in at least three brain regions pointing to comm...
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Jun 29, 2015
Cocaine-associated environmental cues sustain relapse vulnerability by reactivating long-lasting ... more Cocaine-associated environmental cues sustain relapse vulnerability by reactivating long-lasting memories of cocaine reward. Responding to cocaine cues can time-dependently intensify during periods of abstinence, a phenomenon referred to as 'incubation of cocaine craving'. Here, we investigated the role of the extracellular matrix protein brevican in recent (1 day after training) and remote (3 weeks after training) expression of cocaine conditioned place preference (CPP). Wild-type and Brevican heterozygous knock-out mice, which express brevican at ~50% of wild-type levels, received three cocaine-context pairings using a relatively low dose of cocaine (5 mg/kg). In a drug-free CPP test, heterozygous mice showed enhanced preference for the cocaine-associated context at the remote time-point compared with the recent time-point. This progressive increase was not observed in wild-type mice and it did not generalize to contextual-fear memory. Viral-mediated overexpression of brev...
Neural circuits can express different forms of plasticity. So far, Hebbian synaptic plasticity wa... more Neural circuits can express different forms of plasticity. So far, Hebbian synaptic plasticity was considered the most important plastic phenomenon, but over the last decade, homeostatic mechanisms gained more interest because they can explain how a neuronal network maintains stable baseline function despite multiple plastic challenges, like developmental plasticity, learning, or lesion. Such destabilizing influences can be counterbalanced by the mechanisms of homeostatic plasticity, which restore the stability of neuronal circuits. Synaptic scaling is a mechanism in which neurons can detect changes in their own firing rates through a set of molecular sensors that then regulate receptor trafficking to scale the accumulation of glutamate receptors at synaptic sites. Additional homeostatic mechanisms allow local changes in synaptic activation to generate local synaptic adaptations and network-wide changes in activity, which lead to adjustments in the balance between excitation and inh...
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