Papers by Bastian Hengerer
Fragmentation and aggregation of physiological and parkinson- synucleins revealed by ion mobility and affinity- mass spectrometry
Journal of Peptide Science, 2014
Author response for "Effects of pro‐depressant and immunomodulatory drugs on biases in decision‐making in the rat judgement bias task
European Journal of Neuroscience, Feb 21, 2021
This is an open access article under the terms of the Creative Commons Attribution License, which... more This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
The Journal of Neuroscience, Apr 23, 2008
Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) often leads t... more Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) often leads to debilitating involuntary movements, termed L-DOPA-induced dyskinesia (LID), about which the rodent analog, the abnormal involuntary movements (AIMs), has been associated consistently with an activation of the Ras-extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase signaling pathway. Previous studies have shown that lovastatin, a specific inhibitor of the rate-limiting enzyme in cholesterol biosynthesis, can also inhibit Ras isoprenylation and activity and subsequently the phosphorylation of ERK1/2 (pERK1/2). We hypothesized that lovastatin treatment-commenced previous L-DOPA exposure could reduce AIM incidence and severity in the 6-hydroxydopamine (6-OHDA) rat model of PD by secondarily preventing the L-DOPA/Benserazide-induced increase in pERK1 levels. The lovastatin-L-DOPA/Benserazide-treated 6-OHDA animals displayed less severe rotational behavior as well as a dramatic reduction in AIM severity than the L-DOPA/Benserazide-treated ones. Such lower AIM severity was associated with a decrease in L-DOPA-induced increase in the following: (1) striatal pERK1 and (2) ⌬FosB levels, and (3) theta/␣ oscillations of substantia nigra pas reticulata (SNr) neurons as well as (4) a normalization of SNr firing frequency. Those results strongly suggest that lovastatin might represent a treatment option for managing LID in PD.
Translational Psychiatry, Aug 1, 2017
Attention deficit hyperactivity disorder (ADHD), Tourette syndrome (TS) as well as obsessive comp... more Attention deficit hyperactivity disorder (ADHD), Tourette syndrome (TS) as well as obsessive compulsive disorder (OCD) are co-occurring neurodevelopmental diseases that share alterations of frontocortical neurometabolites. In this longitudinal study we investigated the behavioral and neurochemical effects of aripiprazole and riluzole treatment in juvenile spontaneously hypertensive rats (SHR), a model for ADHD. For neurochemical analysis we employed in vivo magnetic resonance spectroscopy (MRS). Spectra from voxels located at the central striatum and prefrontal cortex were acquired postnatally from day 35 to 50. In the SHR strain only, treatments reduced repetitive grooming and climbing behavior. The absolute quantification of cerebral metabolites in vivo using localized 1 H-MRS at 11.7T showed significant alterations in SHR rats compared to controls (including glutamine, aspartate and total NAA). In addition, drug treatment reduced the majority of the detected metabolites (glutamate and glutamine) in the SHR brain. Our results indicate that the drug treatments might influence the hypothesized 'hyperactive' state of the cortico-striatal-thalamocortical circuitries of the SHR strain. Furthermore, we could show that behavioral changes correlate with brain region-specific alterations in neurometabolite levels in vivo. These findings should serve as reference for animal studies and for the analysis of neurometabolites in selected human brain regions to further define neurochemical alterations in neuropsychiatric diseases.
Three-dimensional co-culture platform of human induced pluripotent stem cell-derived oligodendrocyte lineage cells and neurons for studying myelination
STAR protocols, Jun 1, 2023
Manipulating a brain circuit associated with sociability by a two-recombinase system
Neuroscience applied, 2022
Investigating neuropsychological and reward-related deficits in a chronic corticosterone-induced model of depression
Psychoneuroendocrinology, 2023
Increasing the Excitatory Drive Rescues Excitatory/Inhibitory Imbalance and Mismatch Negativity Deficit Caused by Parvalbumin Specific GluA1 Deletion
Neuroscience, Aug 1, 2022
Communications biology, Apr 15, 2023
Reduced reward interest/learning and reward-to-effort valuation are distinct, common symptoms in ... more Reduced reward interest/learning and reward-to-effort valuation are distinct, common symptoms in neuropsychiatric disorders for which chronic stress is a major aetiological factor. Glutamate neurons in basal amygdala (BA) project to various regions including nucleus accumbens (NAc). The BA-NAc neural pathway is activated by reward and aversion, with many neurons being monovalent. In adult male mice, chronic social stress (CSS) leads to reduced discriminative reward learning (DRL) associated with decreased BA-NAc activity, and to reduced reward-to-effort valuation (REV) associated, in contrast, with increased BA-NAc activity. Chronic tetanus toxin BA-NAc inhibition replicates the CSS-DRL effect and causes a mild REV reduction, whilst chronic DREADDs BA-NAc activation replicates the CSS effect on REV without affecting DRL. This study provides evidence that stress disruption of reward processing involves the BA-NAc neural pathway; the bi-directional effects implicate opposite activity changes in reward (learning) neurons and aversion (effort) neurons in the BA-NAc pathway following chronic stress.
Molecular Neurobiology, Nov 27, 2018
Chronic administration of L-DOPA, the first-line treatment of dystonic symptoms in childhood or i... more 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.
Molecular Psychiatry, Apr 22, 2022
The cumulative load of genetic predisposition, early life adversity (ELA) and lifestyle shapes th... more The cumulative load of genetic predisposition, early life adversity (ELA) and lifestyle shapes the prevalence of psychiatric disorders. Single nucleotide polymorphisms (SNPs) in the human FKBP5 gene were shown to modulate disease risk. To enable investigation of diseaserelated SNPs in behaviourally relevant context, we generated humanised mouse lines carrying either the risk (AT) or the resiliency (CG) allele of the rs1360780 locus and exposed litters of these mice to maternal separation. Behavioural and physiological aspects of their adult stress responsiveness displayed interactions of genotype, early life condition, and sex. In humanised females carrying the CG-but not the AT-allele, ELA led to altered HPA axis functioning, exploratory behaviour, and sociability. These changes correlated with differential expression of genes in the hypothalamus, where synaptic transmission, metabolism, and circadian entrainment pathways were deregulated. Our data suggest an integrative role of FKBP5 in shaping the sex-specific outcome of ELA in adulthood.
Neuropsychopharmacology, Aug 25, 2020
Major Depressive Disorder is a significant and costly cause of global disability. Until the disco... more Major Depressive Disorder is a significant and costly cause of global disability. Until the discovery of the rapid acting antidepressant (RAAD) effects of ketamine, treatments were limited to drugs that have delayed clinical benefits. The mechanism of action of ketamine is currently unclear but one hypothesis is that it may involve neuropsychological effects mediated through modulation of affective biases (where cognitive processes such as learning and memory and decision-making are modified by emotional state). Previous work has shown that affective biases in a rodent decision-making task are differentially altered by ketamine, compared to conventional, delayed onset antidepressants. This study sought to further investigate these effects by comparing ketamine with other NMDA antagonists using this decision-making task. We also investigated the subtype selective GluN2B antagonist, CP-101,606 and muscarinic antagonist scopolamine which have both been shown to have RAAD effects. Both CP-101,606 and scopolamine induced similar positive biases in decision-making to ketamine, but the same effects were not seen with other NMDA antagonists. Using targeted medial prefrontal cortex (mPFC) infusions, these effects were localised to the mPFC. In contrast, the GABA A agonist, muscimol, induced general disruptions to behaviour. These data suggest that ketamine and other RAADs mediate a specific effect on affective bias which involves the mPFC. Non-ketamine NMDA antagonists lacked efficacy and we also found that temporary inactivation of the mPFC did not fully recapitulate the effects of ketamine, suggesting a specific mechanism.
Three-dimensional co-culture platform of human induced pluripotent stem cell-derived oligodendrocyte lineage cells and neurons for studying myelination
STAR Protocols
Reduced reward interest/learning and reward-to-effort valuation are distinct, common symptoms in ... more Reduced reward interest/learning and reward-to-effort valuation are distinct, common symptoms in neuropsychiatric disorders for which chronic stress is a major aetiological factor. Glutamate neurons in basal amygdala (BA) project to various regions including nucleus accumbens (NAc). The BA-NAc neural pathway is activated by reward and aversion, with many neurons being monovalent. In adult male mice, chronic social stress (CSS) led to both reduced discriminative reward learning (DRL) associated with decreased BA-NAc activity, and reduced reward-to-effort valuation (REV) associated, in contrast, with increased BA-NAc activity. Chronic tetanus toxin BA-NAc inhibition replicated the CSS-DRL effect and caused a mild REV reduction, whilst chronic DREADDs BA-NAc activation replicated the CSS effect on REV without affecting DRL. This study provides novel evidence that stress disruption of reward processing involves the BA-NAc neural pathway; the bi-directional effects implicate opposite act...
The developmental nature of many neuropsychiatric disorders such as schizophrenia necessitates th... more The developmental nature of many neuropsychiatric disorders such as schizophrenia necessitates the detection of functional biomarkers during the prodromal phase of disease that can predict symptomatic conversion and outcomes. Structural chromosomal aberrations, such as copy number variants, confer high risk and penetrance of neuropsychiatric disorders. We used functional ultrasound imaging (fUS) to characterize the functional connectivity profile of the 15q13.3+/−copy number variant mouse model during major developmental milestones on post-natal day (p)35, 42, 60, and 90 in comparison to wild type littermates. We identified divergent trajectories for 15q13.3+/−mice and WT littermate controls where functional connectivity was reduced for both genotypes with age, but to a lesser extent for 15q13.3+/−mice. We were then able to isolate the distinct differences between genotypes to identify a large-scale network where 15q13.3+/−mice displayed global cortical hyperconnectivity and elevate...
Molecular Psychiatry
The cumulative load of genetic predisposition, early life adversity (ELA) and lifestyle shapes th... more The cumulative load of genetic predisposition, early life adversity (ELA) and lifestyle shapes the prevalence of psychiatric disorders. Single nucleotide polymorphisms (SNPs) in the human FKBP5 gene were shown to modulate disease risk. To enable investigation of disease-related SNPs in behaviourally relevant context, we generated humanised mouse lines carrying either the risk (AT) or the resiliency (CG) allele of the rs1360780 locus and exposed litters of these mice to maternal separation. Behavioural and physiological aspects of their adult stress responsiveness displayed interactions of genotype, early life condition, and sex. In humanised females carrying the CG- but not the AT-allele, ELA led to altered HPA axis functioning, exploratory behaviour, and sociability. These changes correlated with differential expression of genes in the hypothalamus, where synaptic transmission, metabolism, and circadian entrainment pathways were deregulated. Our data suggest an integrative role of ...
P.0254 TRPC4/5 inhibition reverses both stress-induced excessive aversion processing and attenuated reward processing in mice
European Neuropsychopharmacology, 2021
Nature Reviews Drug Discovery, 2017
Genes, Brain and Behavior, 2018
Oligodendrocyte gene expression is downregulated in stress-related neuropsychiatric disorders, in... more Oligodendrocyte gene expression is downregulated in stress-related neuropsychiatric disorders, including depression. In mice, chronic social stress (CSS) leads to depression-relevant changes in brain and emotional behavior, and the present study shows the involvement of oligodendrocytes in this model. In C57BL/6 (BL/6) mice, RNA-sequencing (RNA-Seq) was conducted with prefrontal cortex, amygdala and hippocampus from CSS and controls; a gene enrichment database for neurons, astrocytes and oligodendrocytes was used to identify cell origin of deregulated genes, and cell deconvolution was applied. To assess the potential causal contribution of reduced oligodendrocyte gene expression to CSS effects, mice heterozygous for the oligodendrocyte gene cyclic nucleotide phosphodiesterase (Cnp1) on a BL/6 background were studied; a 2 genotype (wildtype, Cnp1 +/−) × 2 environment (control, CSS) design was used to investigate effects on emotional behavior and amygdala microglia. In BL/6 mice, in prefrontal cortex and amygdala tissue comprising gray and white matter, CSS downregulated expression of multiple oligodendroycte genes encoding myelin and myelin-axon-integrity proteins, and cell deconvolution identified a lower proportion of oligodendrocytes in amygdala. Quantification of oligodendrocyte proteins in amygdala gray matter did not yield evidence for reduced translation, suggesting that CSS impacts primarily on white matter oligodendrocytes or the myelin transcriptome. In Cnp1 mice, social interaction was reduced by CSS in Cnp1 +/− mice specifically; using ionized calcium-binding adaptor molecule 1 (IBA1) expression, microglia activity was increased additively by Cnp1 +/− and CSS in amygdala gray and white matter. This study provides back-translational evidence that oligodendrocyte changes are relevant to the pathophysiology and potentially the treatment of stress-related neuropsychiatric disorders.
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Papers by Bastian Hengerer