Publications by authors named "Bastian Hengerer"

63 Publications

Effects of pro-depressant and immunomodulatory drugs on biases in decision-making in the rat judgement bias task.

Eur J Neurosci 2021 Jan 27. Epub 2021 Jan 27.

Faculty of Biomedical Sciences, School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK.

Studies in human and non-human species suggest that decision-making behaviour can be biased by an affective state, also termed an affective bias. To study these behaviours in non-human species, judgement bias tasks (JBT) have been developed. Animals are trained to associate specific cues (tones) with a positive or negative/less positive outcome. Animals are then presented with intermediate ambiguous cues and affective biases quantified by observing whether animals make more optimistic or more pessimistic choices. Here we use a high versus low reward JBT and test whether pharmacologically distinct compounds, which induce negative biases in learning and memory, have similar effects on decision-making: tetrabenazine (0.0-1.0 mg/kg), retinoic acid (0.0-10.0 mg/kg), and rimonabant (0.0-10.0 mg/kg). We also tested immunomodulatory compounds: interferon-α (0-100 units/kg), lipopolysaccharide (0.0-10.0 μg/kg), and corticosterone (0.0-10.0 mg/kg). We observed no specific effects in the JBT with any acute treatment except corticosterone which induced a negative bias. We have previously observed a similar lack of effect with acute but not chronic psychosocial stress and so next tested decision-making behaviour following chronic interferon-alpha. Animals developed a negative bias which was sustained even after treatment was ended. These data suggest that decision-making behaviour in the task is sensitive to chronic but not acute effects of most pro-depressant drugs or immunomodulators, but the exogenous administration of acute corticosterone induces pessimistic behaviour. This work supports our hypothesis that biases in decision-making develop over a different temporal scale to those seen with learning and memory which may be relevant in the development and perpetuation of mood disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejn.15127DOI Listing
January 2021

Activation of the medial preoptic area (MPOA) ameliorates loss of maternal behavior in a Shank2 mouse model for autism.

EMBO J 2021 Mar 25;40(5):e104267. Epub 2021 Jan 25.

Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany.

Impairments in social relationships and awareness are features observed in autism spectrum disorders (ASDs). However, the underlying mechanisms remain poorly understood. Shank2 is a high-confidence ASD candidate gene and localizes primarily to postsynaptic densities (PSDs) of excitatory synapses in the central nervous system (CNS). We show here that loss of Shank2 in mice leads to a lack of social attachment and bonding behavior towards pubs independent of hormonal, cognitive, or sensitive deficits. Shank2 mice display functional changes in nuclei of the social attachment circuit that were most prominent in the medial preoptic area (MPOA) of the hypothalamus. Selective enhancement of MPOA activity by DREADD technology re-established social bonding behavior in Shank2 mice, providing evidence that the identified circuit might be crucial for explaining how social deficits in ASD can arise.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15252/embj.2019104267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917557PMC
March 2021

FKBP5 polymorphisms induce differential glucocorticoid responsiveness in primary CNS cells - First insights from novel humanized mice.

Eur J Neurosci 2021 Jan 27;53(2):402-415. Epub 2020 Oct 27.

Boehringer Ingelheim Pharma GmbH & Co KG, CNSDR, Ingelheim, Germany.

The brain is a central hub for integration of internal and external conditions and, thus, a regulator of the stress response. Glucocorticoids are the essential communicators of this response. Aberrations in glucocorticoid signaling are a common symptom in patients with psychiatric disorders. The gene FKBP5 encodes a chaperone protein that functionally inhibits glucocorticoid signaling and, thus, contributes to the regulation of stress. In the context of childhood trauma, differential expression of FKBP5 has been found in psychiatric patients compared to controls. These variations in expression levels of FKBP5 were reported to be associated with differences in stress responsiveness in human carriers of the single nucleotide polymorphism (SNP) rs1360780. Understanding the mechanisms underlying FKBP5 polymorphism-associated glucocorticoid responsiveness in the CNS will lead to a better understanding of stress regulation or associated pathology. To study these mechanisms, two novel humanized mouse lines were generated. The lines carried either the risk (A/T) allele or the resilient (C/G) allele of rs1360780. Primary cells from CNS (astrocytes, microglia, and neurons) were analyzed for their basal expression levels of FKBP5 and their responsiveness to glucocorticoids. Differential expression of FKBP5 was found for these cell types and negatively correlated with the cellular glucocorticoid responsiveness. Astrocytes revealed the strongest transcriptional response, followed by microglia and neurons. Furthermore, the risk allele (A/T) was associated with greater induction of FKBP5 than the resilience allele. Novel FKBP5-humanized mice display differential glucocorticoid responsiveness due to a single intronic SNP. The vulnerability to stress signaling in the shape of glucocorticoids in the brain correlated with FKBP5 expression levels. The strong responsiveness of astrocytes to glucocorticoids implies astrocytes play a prominent role in the stress response, and in FKBP5-related differences in glucocorticoid signaling. The novel humanized mouse lines will allow for further study of the role that FKBP5 SNPs have in risk and resilience to stress pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejn.14999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894319PMC
January 2021

Proteomic analysis reveals a biosignature of decreased synaptic protein in cerebrospinal fluid of major depressive disorder.

Transl Psychiatry 2020 05 12;10(1):144. Epub 2020 May 12.

Department of Neurology, Ulm University, Ulm, Germany.

Major depressive disorder (MDD) is a leading cause of morbidity with a lifetime prevalence of 10%. There is increasing evidence suggesting synaptic dysfunction and impaired integrity of certain brain circuits in MDD. Here we investigate the cerebrospinal fluid proteome of psychiatric patients focusing on MDD by deep proteomic profiling approach combined with a further validation step using targeted mass spectrometry. We demonstrate profound CSF proteomic changes during on-going depression episodes in MDD patients (n = 40) in comparison to controls (n = 27), schizophrenia spectrum disorder (n = 13), and bipolar disorder patients (n = 11). The discovery analysis with isobaric tags for relative and absolute quantitation (iTRAQ) reveals changes in proteins associated with synaptic transmission, myelination, and Wnt signaling in CSF of MDD. The multiple reaction monitoring (MRM) validation analysis confirms significantly decreased levels of eight proteins including the membrane synaptic proteins neurexin 3 (NRXN3), contactin-associated protein-like 4 (CNTNAP4), and glutamate ionotropic receptor AMPA type subunit 4 (GRIA4) in the CSF of MDD patients in comparison to the controls. Overall, the study demonstrates proteins that constitute an MDD biosignature for further validation studies and provides insight into the pathophysiology of MDD and other psychiatric disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41398-020-0825-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217933PMC
May 2020

Cross-site Reproducibility of Social Deficits in Group-housed BTBR Mice Using Automated Longitudinal Behavioural Monitoring.

Neuroscience 2020 10 5;445:95-108. Epub 2020 May 5.

Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands. Electronic address:

Social withdrawal is associated with a variety of neuropsychiatric disorders, including neurodevelopmental disorders. Rodent studies provide the opportunity to study neurobiological mechanisms underlying social withdrawal, however, homologous paradigms to increase translatability of social behaviour between human and animal observation are needed. Standard behavioural rodent assays have limited ethological validity in terms of number of interaction partners, type of behaviour, duration of observation and environmental conditions. In addition, reproducibility of behavioural findings in rodents is further limited by manual and subjective behavioural scoring. Using a newly developed automated tracking tool for longitudinal monitoring of freely moving mice, we assessed social behaviours (approach, sniff, follow and leave) over seven consecutive days in colonies of BTBR and of C57BL/6J mice in two independent laboratories. Results from both laboratories confirmed previous findings of reduced social interaction in BTBR mice revealing a high level of reproducibility for this mouse phenotype using longitudinal colony assessments. In addition, we showed that detector settings contribute to laboratory specific findings as part of the behavioural data analysis procedure. Our cross-site study demonstrates reproducibility and robustness of reduced social interaction in BTBR mice using automated analysis in an ethologically relevant context.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuroscience.2020.04.045DOI Listing
October 2020

S-ketamine induces acute changes in the proteome of the mouse amygdala.

J Proteomics 2020 03 4;216:103679. Epub 2020 Feb 4.

Department of Neurology, Ulm University, Ulm, Germany. Electronic address:

Current understanding of the molecular mechanisms underlying ketamine's antidepressant effect remains largely incomplete. Recent imaging studies provide evidence for ketamine effects on amygdalo-hippocampal. This study in mice aimed to investigate acute proteomic changes after ketamine administration in various brain regions including amygdala and hippocampus. One hour after administration of s-ketamine, the brain-region tissues of interest were dissected out and analyzed using label-free shotgun proteomics. The deep proteomic analysis of amygdala and hippocampus identified 89,526 peptides corresponding to 8000 proteins. The analysis revealed a pronounced proteomic signature of the acute ketamine effect in the amygdala. We anticipate that this proteomic dataset will improve understanding of the mechanism of action of ketamine and identification of new drug targets. SIGNIFICANCE: Major depressive disorder (MDD) is the leading cause of global disability and it presents a significant challenge to human health. S-ketamine has been proposed as a rapid acting antidepressant and, indeed, the FDA recently approved it for treatment of resistant MDD. However, the mechanism of action of s-ketamine as an antidepressant is still elusive. In this context, we investigated the short-term proteomic changes after ketamine administration in mouse brain regions previously related to ketamine effects such as amygdala and hippocampus. We anticipate that this proteomic dataset will provide highly useful information to improve our understanding of the mechanism of action of ketamine and identification of new drug targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jprot.2020.103679DOI Listing
March 2020

A New Mouse Line Reporting the Translation of Brain-Derived Neurotrophic Factor Using Green Fluorescent Protein.

eNeuro 2020 Jan/Feb;7(1). Epub 2020 Jan 9.

School of Biosciences, Cardiff University, Cardiff CF10 3AX, United Kingdom

While BDNF is receiving considerable attention for its role in synaptic plasticity and in nervous system dysfunction, identifying brain circuits involving BDNF-expressing neurons has been challenging. BDNF levels are very low in most brain areas, except for the large mossy fiber terminals in the hippocampus where BDNF accumulates at readily detectable levels. This report describes the generation of a mouse line allowing the detection of single brain cells synthesizing BDNF. A bicistronic construct encoding BDNF tagged with a P2A sequence preceding GFP allows the translation of BDNF and GFP as separate proteins. Following its validation with transfected cells, this construct was used to replace the endogenous gene. Viable and fertile homozygote animals were generated, with the GFP signal marking neuronal cell bodies translating the mRNA. Importantly, the distribution of immunoreactive BDNF remained unchanged, as exemplified by its accumulation in mossy fiber terminals in the transgenic animals. GFP-labeled neurons could be readily visualized in distinct layers in the cerebral cortex where BDNF has been difficult to detect with currently available reagents. In the hippocampal formation, quantification of the GFP signal revealed that <10% of the neurons do not translate the mRNA at detectable levels, with the highest proportion of strongly labeled neurons found in CA3.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/ENEURO.0462-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957309PMC
January 2020

RFID-supported video tracking for automated analysis of social behaviour in groups of mice.

J Neurosci Methods 2019 09 27;325:108323. Epub 2019 Jun 27.

Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach an der Riss, Germany.

Background: Deficits in social behaviour, e.g. social withdrawal, appear as an early sign of many neuropsychiatric disorders. Investigation of the biological basis of social withdrawal and development of new targets for treatment requires reliable quantification methods of social behaviour.

New Method: In order to study behavioural deficits in preclinical rodent models, we developed a tracking and analysis tool for behavioural observations in groups of mice. RFID-Assisted SocialScan is based on video tracking supported by radio-frequency identification (RFID). For this purpose, mice were labelled with RFID tags providing unique animal identity and location in the arena. An integrated software package enables automatic detection of predefined behavioural events, which are extracted from video recordings. We designed a social arena that can be flexibly adapted for various behavioural experiments.

Results: We demonstrate the utility of our newly developed tracking tool by monitoring colonies of C57BL/6 J mice. We assessed social (approach, contact, follow, leave) and locomotor activities over multiple days.

Comparison With Other Existing Methods: RFID-Assisted SocialScan is an automated tracking and analysis tool for long-term behavioural observations of multiple freely moving mice housed in ethologically relevant environment.

Conclusions: Here, we demonstrate the performance of a newly developed behavioural tracking system that can be used for long-term translational studies of social behaviour in groups of freely moving mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jneumeth.2019.108323DOI Listing
September 2019

Neurofilament light chain as a blood biomarker to differentiate psychiatric disorders from behavioural variant frontotemporal dementia.

J Psychiatr Res 2019 06 24;113:137-140. Epub 2019 Mar 24.

Department of Neurology, Ulm University, Ulm, Germany. Electronic address:

The overlapping symptoms of behavioural variant frontotemporal dementia (bvFTD) and primary psychiatric disorders (such as depressive disorder, schizophrenia spectrum, and bipolar disorder) present a challenge for the differential diagnosis of bvFTD in middle and older-aged people. Neurofilaments are cytoskeletal proteins in the neurons, and several studies have reported elevated levels of neurofilament light chain (NfL) in cerebrospinal fluid of neurodegenerative as well as psychiatric disorders. The study aims to determine the utility of serum NfL levels as a biomarker to differentiate between bvFTD and psychiatric disorder. In our study, we investigated the levels of NfL in the serum of schizophrenia (n = 11), depression (n = 28), bipolar (n = 11), bvFTD (n = 20) patients and controls (n = 27) by single molecule array (Simoa) technology. The schizophrenia, depression and bipolar patients did not show significant changes in serum NfL levels in comparison to the control group (p > 0.99). The serum NfL levels were significantly elevated in bvFTD patients in comparison to the control cohort (p < 0.0001), depression (p < 0.0001), schizophrenia (p < 0.0002) and bipolar patients (p < 0.0083). We propose serum NfL as a biomarker to differentiate bvFTD from psychiatric disorders and to rule out neurodegeneration in the course of psychiatric disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpsychires.2019.03.019DOI Listing
June 2019

The reverse translation of a quantitative neuropsychiatric framework into preclinical studies: Focus on social interaction and behavior.

Neurosci Biobehav Rev 2019 02 16;97:96-111. Epub 2019 Jan 16.

Boehringer Ingelheim Pharma GmbH & Co. KG, CNS Diseases, Birkendorfer Straße 65, 88397, Biberach an der Riss, Germany. Electronic address:

Following the Research Domain Criteria (RDoC) concept, major brain circuits are conserved in evolution and malfunctioning of a brain circuit will lead to specific behavioral symptoms. Reverse translation of patient-based findings from Alzheimer's disease (AD), schizophrenia (SZ) and major depression (MD) patients to preclinical models accordingly can be a starting point for developing a deeper understanding of the functional circuit biology and contribute to the validation of new hypotheses for therapeutic intervention in patients. In the context of the EU funded PRISM project, a preclinical test battery of tasks has been selected and aligned with the clinical test battery. It allows for assessment of social functioning, sensory processing, attention and working memory and is designed for validation of biological substrates from human molecular landscaping of social withdrawal. This review will broadly summarize the available literature on tasks for studying social behavior in rodents and outline the development of a preclinical test battery for the PRISM project by reverse translation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neubiorev.2018.07.018DOI Listing
February 2019

Riluzole Attenuates L-DOPA-Induced Abnormal Involuntary Movements Through Decreasing CREB1 Activity: Insights from a Rat Model.

Mol Neurobiol 2019 Jul 27;56(7):5111-5121. Epub 2018 Nov 27.

Department of Human Genetics, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.

Chronic administration of L-DOPA, the first-line treatment of dystonic symptoms in childhood or in Parkinson's disease, often leads to the development of abnormal involuntary movements (AIMs), which represent an important clinical problem. Although it is known that Riluzole attenuates L-DOPA-induced AIMs, the molecular mechanisms underlying this effect are not understood. Therefore, we studied the behavior and performed RNA sequencing of the striatum in three groups of rats that all received a unilateral lesion with 6-hydroxydopamine in their medial forebrain bundle, followed by the administration of saline, L-DOPA, or L-DOPA combined with Riluzole. First, we provide evidence that Riluzole attenuates AIMs in this rat model. Subsequently, analysis of the transcriptomics data revealed that Riluzole is predicted to reduce the activity of CREB1, a transcription factor that regulates the expression of multiple proteins that interact in a molecular landscape involved in apoptosis. Although this mechanism underlying the beneficial effect of Riluzole on AIMs needs to be confirmed, it provides clues towards novel or existing compounds for the treatment of AIMs that modulate the activity of CREB1 and, hence, its downstream targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12035-018-1433-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647536PMC
July 2019

Chronic Social Stress Leads to Reduced Gustatory Reward Salience and Effort Valuation in Mice.

Front Behav Neurosci 2018 10;12:134. Epub 2018 Jul 10.

Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland.

Pathology of reward processing is a major clinical feature of stress-related neuropsychiatric disorders including depression. Several dimensions of reward processing can be impacted, including reward valuation/salience, learning, expectancy and effort valuation. To establish the causal relationships between stress, brain changes, and reward processing pathologies, valid animal models are essential. Here, we present mouse experiments investigating behavioral effects of chronic social stress (CSS) in association learning tests of gustatory reward salience and effort valuation. The reward salience test (RST) comprised Pavlovian pairing of a tone with gustatory reward. The effort valuation test (EVT) comprised operant responding for gustatory reinforcement on a progressive ratio schedule (PRS). All testing was conducted with mice at 100% baseline body weight (BBW). In one experiment, mice underwent 15-day CSS or control handling (CON) and testing was conducted using sucrose pellets. In the RST on days 16-17, CSS mice made fewer feeder responses and had a longer tone response latency, than CON mice. In a shallow EVT on days 19-20, CSS mice attained a lower final ratio than CON mice. In a second CSS experiment, mice underwent CSS or CON and testing was conducted with chocolate pellets and in the presence of standard diet (low effort/low reward). In the RST on days 16-18, CSS mice made fewer feeder responses and had a longer tone response latency, than CON mice. In a steep EVT on days 19-20, CSS and CON mice attained less pellets than in the RST, and CSS mice attained a lower final ratio than CON mice. At day 21, blood levels of glucose and the satiety adipokine leptin were similar in CSS and CON mice. Therefore, CSS leads to consistent reductions in reward salience and effort valuation in tests based on association learning. These reward pathology models are being applied to identify the underlying neurobiology and putative molecular targets for therapeutic pharmacology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnbeh.2018.00134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053640PMC
July 2018

Altered dopaminergic regulation of the dorsal striatum is able to induce tic-like movements in juvenile rats.

PLoS One 2018 26;13(4):e0196515. Epub 2018 Apr 26.

CNS Department, Boehringer Ingelheim Pharma GmbH& Co. KG, Biberach an der Riss, Germany.

Motor tics are sudden, repetitive, involuntary movements representing the hallmark behaviors of the neurodevelopmental disease Tourette's syndrome (TS). The primary cause of TS remains unclear. The initial observation that dopaminergic antagonists alleviate tics led to the development of a dopaminergic theory of TS etiology which is supported by post mortem and in vivo studies indicating that non-physiological activation of the striatum could generate tics. The striatum controls movement execution through the balanced activity of dopamine receptor D1 and D2-expressing medium spiny neurons of the direct and indirect pathway, respectively. Different neurotransmitters can activate or repress striatal activity and among them, dopamine plays a major role. In this study we introduced a chronic dopaminergic alteration in juvenile rats, in order to modify the delicate balance between direct and indirect pathway. This manipulation was done in the dorsal striatum, that had been associated with tic-like movements generation in animal models. The results were movements resembling tics, which were categorized and scored according to a newly developed rating scale and were reduced by clonidine and riluzole treatment. Finally, post mortem analyses revealed altered RNA expression of dopaminergic receptors D1 and D2, suggesting an imbalanced dopaminergic regulation of medium spiny neuron activity as being causally related to the observed phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0196515PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919623PMC
July 2018

Aripiprazole Selectively Reduces Motor Tics in a Young Animal Model for Tourette's Syndrome and Comorbid Attention Deficit and Hyperactivity Disorder.

Front Neurol 2018 13;9:59. Epub 2018 Feb 13.

Institute of Anatomy and Cell Biology, Ulm University, Ulm, Germany.

Tourette's syndrome (TS) is a neurodevelopmental disorder characterized primarily by motor and vocal tics. Comorbidities such as attention deficit and hyperactivity disorder (ADHD) are observed in over 50% of TS patients. We applied aripiprazole in a juvenile rat model that displays motor tics and hyperactivity. We additionally assessed the amount of ultrasonic vocalizations (USVs) as an indicator for the presence of vocal tics and evaluated the changes in the striatal neurometabolism using proton magnetic resonance spectroscopy (1H-MRS) at 11.7T. Thirty-one juvenile spontaneously hypertensive rats (SHRs) underwent bicuculline striatal microinjection and treatment with either aripiprazole or vehicle. Control groups were sham operated and sham injected. Behavior, USVs, and striatal neurochemical profile were analyzed at early, middle, and late adolescence (postnatal days 35 to 50). Bicuculline microinjections in the dorsolateral striatum induced motor tics in SHR juvenile rats. Acute aripiprazole administration selectively reduced both tic frequency and latency, whereas stereotypies, USVs, and hyperactivity remained unaltered. The striatal neurochemical profile was only moderately altered after tic-induction and was not affected by systemic drug treatment. When applied to a young rat model that provides high degrees of construct, face, and predictive validity for TS and comorbid ADHD, aripiprazole selectively reduces motor tics, revealing that tics and stereotypies are distinct phenomena in line with clinical treatment of patients. Finally, our 1H-MRS results suggest a critical revision of the striatal role in the hypothesized cortico-striatal dysregulation in TS pathophysiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2018.00059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5816975PMC
February 2018

Treatment with HC-070, a potent inhibitor of TRPC4 and TRPC5, leads to anxiolytic and antidepressant effects in mice.

PLoS One 2018 31;13(1):e0191225. Epub 2018 Jan 31.

Hydra Biosciences, Cambridge, Massachusetts, United States of America.

Background: Forty million adults in the US suffer from anxiety disorders, making these the most common forms of mental illness. Transient receptor potential channel canonical subfamily (TRPC) members 4 and 5 are non-selective cation channels highly expressed in regions of the cortex and amygdala, areas thought to be important in regulating anxiety. Previous work with null mice suggests that inhibition of TRPC4 and TRPC5 may have anxiolytic effects.

Hc-070 In Vitro: To assess the potential of TRPC4/5 inhibitors as an avenue for treatment, we invented a highly potent, small molecule antagonist of TRPC4 and TRPC5 which we call HC-070. HC-070 inhibits recombinant TRPC4 and TRPC5 homomultimers in heterologous expression systems with nanomolar potency. It also inhibits TRPC1/5 and TRPC1/4 heteromultimers with similar potency and reduces responses evoked by cholecystokinin tetrapeptide (CCK-4) in the amygdala. The compound is >400-fold selective over a wide range of molecular targets including ion channels, receptors, and kinases.

Hc-070 In Vivo: Upon oral dosing in mice, HC-070 achieves exposure levels in the brain and plasma deemed sufficient to test behavioral activity. Treatment with HC-070 attenuates the anxiogenic effect of CCK-4 in the elevated plus maze (EPM). The compound recapitulates the phenotype observed in both null TRPC4 and TRPC5 mice in a standard EPM. Anxiolytic and anti-depressant effects of HC-070 are also observed in pharmacological in vivo tests including marble burying, tail suspension and forced swim. Furthermore, HC-070 ameliorates the increased fear memory induced by chronic social stress. A careful evaluation of the pharmacokinetic-pharmacodynamic relationship reveals that substantial efficacy is observed at unbound brain levels similar to, or even lower than, the 50% inhibitory concentration (IC50) recorded in vitro, increasing confidence that the observed effects are indeed mediated by TRPC4 and/or TRPC5 inhibition. Together, this experimental data set introduces a novel, high quality, small molecule antagonist of TRPC4 and TRPC5 containing channels and supports the targeting of TRPC4 and TRPC5 channels as a new mechanism of action for the treatment of psychiatric symptoms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191225PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791972PMC
February 2018

Trial watch: Tracing investment in drug development for Alzheimer disease.

Nat Rev Drug Discov 2017 12 23;16(12):819. Epub 2017 Oct 23.

Fraunhofer Institute for Algorithms and Scientific Computing, Sankt Augustin 53754, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nrd.2017.169DOI Listing
December 2017

Proteasome impairment by α-synuclein.

PLoS One 2017 25;12(9):e0184040. Epub 2017 Sep 25.

Neurology Department, Ulm University, Ulm, Germany.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide and characterized by the loss of dopaminergic neurons in the patients' midbrains. Both the presence of the protein α-synuclein in intracellular protein aggregates in surviving neurons and the genetic linking of the α-synuclein encoding gene point towards a major role of α-synuclein in PD etiology. The exact pathogenic mechanisms of PD development are not entirely described to date, neither is the specific role of α-synuclein in this context. Previous studies indicate that one aspect of α-synuclein-related cellular toxicity might be direct proteasome impairment. The 20/26S proteasomal machinery is an important instrument of intracellular protein degradation. Thus, direct proteasome impairment by α-synuclein might explain or at least contribute to the formation of intracellular protein aggregates. Therefore this study investigates direct proteasomal impairment by α-synuclein both in vitro using recombinant α-synuclein and isolated proteasomes as well as in living cells. Our experiments demonstrate that the impairment of proteasome activity by α-synuclein is highly dependent upon the cellular background and origin. We show that recombinant α-synuclein oligomers and fibrils scarcely affect 20S proteasome function in vitro, neither does transient α-synuclein expression in U2OS ps 2042 (Ubi(G76V)-GFP) cells. However, stable expression of both wild-type and mutant α-synuclein in dopaminergic SH-SY5Y and PC12 cells results in a prominent impairment of the chymotrypsin-like 20S/26S proteasomal protein cleavage. Thus, our results support the idea that α-synuclein in a specific cellular environment, potentially present in dopaminergic cells, cannot be processed by the proteasome and thus contributes to a selective vulnerability of dopaminergic cells to α-synuclein pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184040PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5612461PMC
October 2017

Novel Blood-Based Biomarkers of Cognition, Stress, and Physical or Cognitive Training in Older Adults at Risk of Dementia: Preliminary Evidence for a Role of BDNF, Irisin, and the Kynurenine Pathway.

J Alzheimers Dis 2017 ;59(3):1097-1111

Department of Neurology, Ulm University, Germany.

 Psychosocial stress and physical, cognitive, and social activity predict the risk of cognitive decline and dementia. The aim of this study was to elucidate brain-derived neurotrophic factor (BDNF), irisin, and the kynurenine pathway (KP) as potential underlying biological correlates. We evaluated associations of irisin and the KP with BDNF in serum and with cognition, stress, and activities. Furthermore, changes in serum concentrations of BDNF, irisin, and KP metabolites were investigated after physical or cognitive training. Forty-seven older adults at risk of dementia were assigned to 10 weeks of physical training, cognitive training, or a wait-list control condition. Previous physical, cognitive, and social activities and stressful life events were recorded; global cognition, episodic memory, and executive functions were assessed. Serum levels of L-kynurenine, kynurenic acid, 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN) were determined by validated assays based on liquid chromatography coupled to tandem mass spectrometry. BDNF and irisin serum levels were determined with enzyme-linked immunosorbent assays. BDNF and irisin correlated positively with global cognition and episodic memory, while the neurotoxic metabolite QUIN correlated negatively with executive functions. Stressful life events were associated with reduced BDNF and increased 3-HK. 3-HK decreased after cognitive training, while BDNF tended to increase after physical training. This suggests that psychosocial stress as well as cognitive and physical training may impact BDNF serum levels and the KP. Irisin and QUIN may constitute novel serum biomarkers of cognitive impairment, in addition to BDNF. Larger scale trials are needed to replicate and extend these novel findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-170447DOI Listing
April 2018

Major depressive disorder: insight into candidate cerebrospinal fluid protein biomarkers from proteomics studies.

Expert Rev Proteomics 2017 06;14(6):499-514

a Department of Neurology , Ulm University , Ulm , Germany.

Introduction: Major Depressive Disorder (MDD) is the leading cause of global disability, and an increasing body of literature suggests different cerebrospinal fluid (CSF) proteins as biomarkers of MDD. The aim of this review is to summarize the suggested CSF biomarkers and to analyze the MDD proteomics studies of CSF and brain tissues for promising biomarker candidates. Areas covered: The review includes the human studies found by a PubMed search using the following terms: 'depression cerebrospinal fluid biomarker', 'major depression biomarker CSF', 'depression CSF biomarker', 'proteomics depression', 'proteomics biomarkers in depression', 'proteomics CSF biomarker in depression', and 'major depressive disorder CSF'. The literature analysis highlights promising biomarker candidates and demonstrates conflicting results on others. It reveals 42 differentially regulated proteins in MDD that were identified in more than one proteomics study. It discusses the diagnostic potential of the biomarker candidates and their association with the suggested pathologies. Expert commentary: One ultimate goal of finding biomarkers for MDD is to improve the diagnostic accuracy to achieve better treatment outcomes; due to the heterogeneous nature of MDD, using bio-signatures could be a good strategy to differentiate MDD from other neuropsychiatric disorders. Notably, further validation studies of the suggested biomarkers are still needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14789450.2017.1336435DOI Listing
June 2017

TS-EUROTRAIN: A European-Wide Investigation and Training Network on the Etiology and Pathophysiology of Gilles de la Tourette Syndrome.

Front Neurosci 2016 23;10:384. Epub 2016 Aug 23.

Department of Molecular Biology and Genetics, Democritus University of Thrace Alexandropoulos, Greece.

Gilles de la Tourette Syndrome (GTS) is characterized by the presence of multiple motor and phonic tics with a fluctuating course of intensity, frequency, and severity. Up to 90% of patients with GTS present with comorbid conditions, most commonly attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD), thus providing an excellent model for the exploration of shared etiology across disorders. TS-EUROTRAIN (FP7-PEOPLE-2012-ITN, Grant Agr.No. 316978) is a Marie Curie Initial Training Network (http://ts-eurotrain.eu) that aims to elucidate the complex etiology of the onset and clinical course of GTS, investigate the neurobiological underpinnings of GTS and related disorders, translate research findings into clinical applications, and establish a pan-European infrastructure for the study of GTS. This includes the challenges of (i) assembling a large genetic database for the evaluation of the genetic architecture with high statistical power; (ii) exploring the role of gene-environment interactions including the effects of epigenetic phenomena; (iii) employing endophenotype-based approaches to understand the shared etiology between GTS, OCD, and ADHD; (iv) establishing a developmental animal model for GTS; (v) gaining new insights into the neurobiological mechanisms of GTS via cross-sectional and longitudinal neuroimaging studies; and (vi) partaking in outreach activities including the dissemination of scientific knowledge about GTS to the public. Fifteen partners from academia and industry and 12 PhD candidates pursue the project. Here, we aim to share the design of an interdisciplinary project, showcasing the potential of large-scale collaborative efforts in the field of GTS. Our ultimate aims are to elucidate the complex etiology and neurobiological underpinnings of GTS, translate research findings into clinical applications, and establish Pan-European infrastructure for the study of GTS and associated disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnins.2016.00384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4994475PMC
September 2016

Telomere shortening leads to an acceleration of synucleinopathy and impaired microglia response in a genetic mouse model.

Acta Neuropathol Commun 2016 08 22;4(1):87. Epub 2016 Aug 22.

Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, 9713 AV, Groningen, The Netherlands.

Parkinson's disease is one of the most common neurodegenerative disorders of the elderly and ageing hence described to be a major risk factor. Telomere shortening as a result of the inability to fully replicate the ends of linear chromosomes is one of the hallmarks of ageing. The role of telomere dysfunction in neurological diseases and the ageing brain is not clarified and there is an ongoing discussion whether telomere shortening is linked to Parkinson's disease. Here we studied a mouse model of Parkinson's disease (Thy-1 [A30P] α-synuclein transgenic mouse model) in the background of telomere shortening (Terc knockout mouse model). α-synuclein transgenic mice with short telomeres (αSYN(tg/tg) G3Terc(-/-)) developed an accelerated disease with significantly decreased survival. This accelerated phenotype of mice with short telomeres was characterized by a declined motor performance and an increased formation of α-synuclein aggregates. Immunohistochemical analysis and mRNA expression studies revealed that the disease end-stage brain stem microglia showed an impaired response in αSYN(tg/tg) G3Terc(-/-) microglia animals. These results provide the first experimental data that telomere shortening accelerates α-synuclein pathology that is linked to limited microglia function in the brainstem.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40478-016-0364-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4994259PMC
August 2016

LC-MS/MS-based quantification of kynurenine metabolites, tryptophan, monoamines and neopterin in plasma, cerebrospinal fluid and brain.

Bioanalysis 2016 Sep 15;8(18):1903-17. Epub 2016 Aug 15.

CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88397 Biberach an der Riss, Germany.

Aim: The kynurenine (KYN) pathway is implicated in diseases such as cancer, psychiatric, neurodegenerative and autoimmune disorders. Measurement of KYN metabolite levels will help elucidating the involvement of the KYN pathway in the disease pathology and inform drug development.

Methodology: Samples of plasma, cerebrospinal fluid or brain tissue were spiked with deuterated internal standards, processed and analyzed by LC-MS/MS; analytes were chromatographically separated by gradient elution on a C18 reversed phase analytical column without derivatization.

Conclusion: We established an LC-MS/MS method to measure 11 molecules, namely tryptophan, KYN, 3-OH-KYN, 3-OH-anthranilic acid, quinolinic acid, picolinic acid, kynurenic acid, xanthurenic acid, serotonin, dopamine and neopterin within 5.5 min, with sufficient sensitivity to quantify these molecules in small sample volumes of plasma, cerebrospinal fluid and brain tissue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4155/bio-2016-0111DOI Listing
September 2016

Addressing the Complexity of Tourette's Syndrome through the Use of Animal Models.

Front Neurosci 2016 8;10:133. Epub 2016 Apr 8.

Department of Child and Adolescence Psychiatry/Psychotherapy, University of Ulm Ulm, Germany.

Tourette's syndrome (TS) is a neurodevelopmental disorder characterized by fluctuating motor and vocal tics, usually preceded by sensory premonitions, called premonitory urges. Besides tics, the vast majority-up to 90%-of TS patients suffer from psychiatric comorbidities, mainly attention deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). The etiology of TS remains elusive. Genetics is believed to play an important role, but it is clear that other factors contribute to TS, possibly altering brain functioning and architecture during a sensitive phase of neural development. Clinical brain imaging and genetic studies have contributed to elucidate TS pathophysiology and disease mechanisms; however, TS disease etiology still is poorly understood. Findings from genetic studies led to the development of genetic animal models, but they poorly reflect the pathophysiology of TS. Addressing the role of neurotransmission, brain regions, and brain circuits in TS disease pathomechanisms is another focus area for preclinical TS model development. We are now in an interesting moment in time when numerous innovative animal models are continuously brought to the attention of the public. Due to the diverse and largely unknown etiology of TS, there is no single preclinical model featuring all different aspects of TS symptomatology. TS has been dissected into its key symptomst hat have been investigated separately, in line with the Research Domain Criteria concept. The different rationales used to develop the respective animal models are critically reviewed, to discuss the potential of the contribution of animal models to elucidate TS disease mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnins.2016.00133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824761PMC
April 2016

Peripheral monocytes are functionally altered and invade the CNS in ALS patients.

Acta Neuropathol 2016 09 24;132(3):391-411. Epub 2016 Feb 24.

Department of Neurology, Ulm University, Albert-Einstein Allee 11, O25, Niveau 5, 89081, Ulm, Germany.

Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease affecting primarily the upper and lower motor neurons. A common feature of all ALS cases is a well-characterized neuroinflammatory reaction within the central nervous system (CNS). However, much less is known about the role of the peripheral immune system and its interplay with CNS resident immune cells in motor neuron degeneration. Here, we characterized peripheral monocytes in both temporal and spatial dimensions of ALS pathogenesis. We found the circulating monocytes to be deregulated in ALS regarding subtype constitution, function and gene expression. Moreover, we show that CNS infiltration of peripheral monocytes correlates with improved motor neuron survival in a genetic ALS mouse model. Furthermore, application of human immunoglobulins or fusion proteins containing only the human Fc, but not the Fab antibody fragment, increased CNS invasion of peripheral monocytes and delayed the disease onset. Our results underline the importance of peripheral monocytes in ALS pathogenesis and are in agreement with a protective role of monocytes in the early phase of the disease. The possibility to boost this beneficial function of peripheral monocytes by application of human immunoglobulins should be evaluated in clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-016-1548-yDOI Listing
September 2016

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase.

Brain Behav Immun 2016 May 24;54:59-72. Epub 2015 Dec 24.

Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center, University and ETH Zurich, Switzerland. Electronic address:

Psychosocial stress is a major risk factor for mood and anxiety disorders, in which excessive reactivity to aversive events/stimuli is a major psychopathology. In terms of pathophysiology, immune-inflammation is an important candidate, including high blood and brain levels of metabolites belonging to the kynurenine pathway. Animal models are needed to study causality between psychosocial stress, immune-inflammation and hyper-reactivity to aversive stimuli. The present mouse study investigated effects of psychosocial stress as chronic social defeat (CSD) versus control-handling (CON) on: Pavlovian tone-shock fear conditioning, activation of the kynurenine pathway, and efficacy of a specific inhibitor (IDOInh) of the tryptophan-kynurenine catabolising enzyme indoleamine 2,3-dioxygenase (IDO1), in reversing CSD effects on the kynurenine pathway and fear. CSD led to excessive fear learning and memory, whilst repeated oral escitalopram (antidepressant and anxiolytic) reversed excessive fear memory, indicating predictive validity of the model. CSD led to higher blood levels of TNF-α, IFN-γ, kynurenine (KYN), 3-hydroxykynurenine (3-HK) and kynurenic acid, and higher KYN and 3-HK in amygdala and hippocampus. CSD was without effect on IDO1 gene or protein expression in spleen, ileum and liver, whilst increasing liver TDO2 gene expression. Nonetheless, oral IDOInh reduced blood and brain levels of KYN and 3-HK in CSD mice to CON levels, and we therefore infer that CSD increases IDO1 activity by increasing its post-translational activation. Furthermore, repeated oral IDOInh reversed excessive fear memory in CSD mice to CON levels. IDOInh reversal of CSD-induced hyper-activity in the kynurenine pathway and fear system contributes significantly to the evidence for a causal pathway between psychosocial stress, immune-inflammation and the excessive fearfulness that is a major psychopathology in stress-related neuropsychiatric disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbi.2015.12.020DOI Listing
May 2016

Age-dependent defects of alpha-synuclein oligomer uptake in microglia and monocytes.

Acta Neuropathol 2016 Mar 17;131(3):379-91. Epub 2015 Nov 17.

Department of Neurology, Ulm University, Albert Einstein Allee 11, 89081, Ulm, Germany.

Extracellular alpha-synuclein (αsyn) oligomers, associated to exosomes or free, play an important role in the pathogenesis of Parkinson's disease (PD). Increasing evidence suggests that these extracellular moieties activate microglia leading to enhanced neuronal damage. Despite extensive efforts on studying neuroinflammation in PD, little is known about the impact of age on microglial activation and phagocytosis, especially of extracellular αsyn oligomers. Here, we show that microglia isolated from adult mice, in contrast to microglia from young mice, display phagocytosis deficits of free and exosome-associated αsyn oligomers combined with enhanced TNFα secretion. In addition, we describe a dysregulation of monocyte subpopulations with age in mice and humans. Accordingly, human monocytes from elderly donors also show reduced phagocytic activity of extracellular αsyn. These findings suggest that these age-related alterations may contribute to an increased susceptibility to pathogens or abnormally folded proteins with age in neurodegenerative diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-015-1504-2DOI Listing
March 2016

CD40-TNF activation in mice induces extended sickness behavior syndrome co-incident with but not dependent on activation of the kynurenine pathway.

Brain Behav Immun 2015 Nov 11;50:125-140. Epub 2015 Jul 11.

Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy & Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center, University and ETH Zurich, Switzerland. Electronic address:

The similarity between sickness behavior syndrome (SBS) in infection and autoimmune disorders and certain symptoms in major depressive disorder (MDD), and the high co-morbidity of autoimmune disorders and MDD, constitutes some of the major evidence for the immune-inflammation hypothesis of MDD. CD40 ligand-CD40 immune-activation is important in host response to infection and in development of autoimmunity. Mice given a single intra-peritoneal injection of CD40 agonist antibody (CD40AB) develop SBS for 2-3days characterized by weight loss and increased sleep, effects that are dependent on the cytokine, tumor necrosis factor (TNF). Here we report that CD40AB also induces behavioral effects that extend beyond acute SBS and co-occur with but are not mediated by kynurenine pathway activation and recovery. CD40AB led to decreased saccharin drinking (days 1-7) and decreased Pavlovian fear conditioning (days 5-6), and was without effect on physical fatigue (day 5). These behavioral effects co-occurred with increased plasma and brain levels of kynurenine and its metabolites (days 1-7/8). Co-injection of TNF blocker etanercept with CD40AB prevented each of SBS, reduced saccharin drinking, and kynurenine pathway activation in plasma and brain. Repeated oral administration of a selective indoleamine 2,3-dioxygenase (IDO) inhibitor blocked activation of the kynurenine pathway but was without effect on SBS and saccharin drinking. This study provides novel evidence that CD40-TNF activation induces deficits in saccharin drinking and Pavlovian fear learning and activates the kynurenine pathway, and that CD40-TNF activation of the kynurenine pathway is not necessary for induction of the acute or extended SBS effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbi.2015.06.184DOI Listing
November 2015

Inflammatory dysregulation of blood monocytes in Parkinson's disease patients.

Acta Neuropathol 2014 Nov 5;128(5):651-63. Epub 2014 Oct 5.

Department of Neurology, Ulm University, Albert Einstein Allee 11, 89081, Ulm, Germany.

Despite extensive effort on studying inflammatory processes in the CNS of Parkinson's disease (PD) patients, implications of peripheral monocytes are still poorly understood. Here, we set out to obtain a comprehensive picture of circulating myeloid cells in PD patients. We applied a human primary monocyte culture system and flow cytometry-based techniques to determine the state of monocytes from PD patients during disease. We found that the classical monocytes are enriched in the blood of PD patients along with an increase in the monocyte-recruiting chemoattractant protein CCL2. Moreover, we found that monocytes from PD patients display a pathological hyperactivity in response to LPS stimulation that correlates with disease severity. Inflammatory pre-conditioning was also reflected on the transcriptome in PD monocytes using next-generation sequencing. Further, we identified the CD95/CD95L as a key regulator for the PD-associated alteration of circulating monocytes. Pharmacological neutralization of CD95L reverses the dysregulation of monocytic subpopulations in favor of non-classical monocytes. Our results suggest that PD monocytes are in an inflammatory predisposition responding with hyperactivation to a "second hit". These results provide the first direct evidence that circulating human peripheral blood monocytes are altered in terms of their function and composition in PD patients. This study provides insights into monocyte biology in PD and establishes a basis for future studies on peripheral inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-014-1345-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201759PMC
November 2014

Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function.

Neuropharmacology 2014 Oct 5;85:328-41. Epub 2014 Jun 5.

Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich and ETH Zurich, Switzerland. Electronic address:

In neuropsychiatry, animal studies demonstrating causal effects of environmental manipulations relevant to human aetiology on behaviours relevant to human psychopathologies are valuable. Such valid models can improve understanding of aetio-pathophysiology and preclinical discovery and development of new treatments. In depression, specific uncontrollable stressful life events are major aetiological factors, and subsequent generalized increases in fearfulness, helplessness and fatigue are core symptoms or features. Here we exposed adult male C57BL/6 mice to 15-day psychosocial stress with loss of social control but minimal physical wounding. One cohort was assessed in a 3-day test paradigm of motor activity, fear conditioning and 2-way avoid-escape behaviour on days 16-18, and a second cohort was assessed in a treadmill fatigue paradigm on days 19 and 29, followed by the 3-day paradigm on days 30-32. All tests used a physical aversive stimulus, namely mild, brief electroshocks. Socially stressed mice displayed decreased motor activity, increased fear acquisition, decreased 2-way avoid-escape responding (increased helplessness) and increased fatigue. They also displayed increased plasma TNF and spleen hypertrophy, and adrenal hypertrophy without hyper-corticoidism. In a third cohort, psychosocial stress effects on brain gene expression were assessed using next generation sequencing. Gene expression was altered in pathways of inflammation and G-protein coupled receptors in prefrontal cortex and amygdala; in the latter, expression of genes important in dopamine function were de-regulated including down-regulated Drd2, Adora2a and Darpp-32. This model can be applied to identify targets for treating psychopathologies such as helplessness or fatigue, and to screen compounds/biologics developed to act at these targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuropharm.2014.05.039DOI Listing
October 2014

Identification and affinity-quantification of ß-amyloid and α-synuclein polypeptides using on-line SAW-biosensor-mass spectrometry.

J Am Soc Mass Spectrom 2014 Aug 21;25(8):1472-81. Epub 2014 May 21.

Laboratory of Analytical Chemistry and Steinbeis Center for Biopolymer Structure Analysis, University of Konstanz, 78457, Konstanz, Germany.

Bioaffinity analysis using a variety of biosensors has become an established tool for detection and quantification of biomolecular interactions. Biosensors, however, are generally limited by the lack of chemical structure information of affinity-bound ligands. On-line bioaffinity-mass spectrometry using a surface-acoustic wave biosensor (SAW-MS) is a new combination providing the simultaneous affinity detection, quantification, and mass spectrometric structural characterization of ligands. We describe here an on-line SAW-MS combination for direct identification and affinity determination, using a new interface for MS of the affinity-isolated ligand eluate. Key element of the SAW-MS combination is a microfluidic interface that integrates affinity-isolation on a gold chip, in-situ sample concentration, and desalting with a microcolumn for MS of the ligand eluate from the biosensor. Suitable MS-acquisition software has been developed that provides coupling of the SAW-MS interface to a Bruker Daltonics ion trap-MS, FTICR-MS, and Waters Synapt-QTOF- MS systems. Applications are presented for mass spectrometric identifications and affinity (K(D)) determinations of the neurodegenerative polypeptides, ß-amyloid (Aß), and pathophysiological and physiological synucleins (α- and ß-synucleins), two key polypeptide systems for Alzheimer's disease and Parkinson's disease, respectively. Moreover, first in vivo applications of αSyn polypeptides from brain homogenate show the feasibility of on-line affinity-MS to the direct analysis of biological material. These results demonstrate on-line SAW-bioaffinity-MS as a powerful tool for structural and quantitative analysis of biopolymer interactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13361-014-0904-1DOI Listing
August 2014