Publications by authors named "Alon Chen"

120 Publications

Differential chronic social stress models in male and female mice.

Eur J Neurosci 2021 Sep 29. Epub 2021 Sep 29.

Department of Neurobiology, The Ruhman Family Laboratory for Research on the Neurobiology of Stress, Weizmann Institute of Science, Rehovot, Israel.

Chronic stress creates an allostatic overload that may lead to mood disorders such as anxiety and depression. Modern causes of chronic stress in humans are mostly social in nature, relating to work and relationship stress. Research into neural and molecular mechanisms of vulnerability and resilience following chronic social stress (CSS) is ongoing and uses animal models to discover efficient prevention strategies and treatments. To date, most CSS studies have neglected the female sex and used male-focused aggression-based animal models such as chronic social defeat stress (CSDS). Accumulating evidence on sex differences suggests differences in the stress response, the prevalence of stress-related illness and in response to treatment, indicating that researchers should expand CSS investigation to include female-focused protocols alongside the popular CSDS protocols. Here, we describe a novel female mouse model of CSS and a parallel modified male mouse model of CSDS in C57BL/6 mice. These new models enable the investigation of vulnerability, coping and downstream effectors mediating short-term and long-term consequences of CSS in both sexes. Our data demonstrate differential effects on male and female mice during, soon after, and many weeks after CSS. Female mice are more prone to body weight loss during CSS and hyperactive anxious behaviour following CSS. Both sexes show reduced social interaction, but only stressed male mice show long-term changes in emotional memory and neuroendocrine function. We further discuss future avenues of research using these models to investigate mechanisms pertaining to sensitivity to CSS and treatment response profiles, in a sex-appropriate manner.
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http://dx.doi.org/10.1111/ejn.15481DOI Listing
September 2021

Stress-related emotional and behavioural impact following the first COVID-19 outbreak peak.

Mol Psychiatry 2021 Aug 4. Epub 2021 Aug 4.

The Ruhman Family Laboratory for Research on the Neurobiology of Stress, Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.

The COVID-19 pandemic poses multiple psychologically stressful challenges and is associated with an increased risk for mental illness. Previous studies have focused on the psychopathological symptoms associated with the outbreak peak. Here, we examined the behavioural and mental-health impact of the pandemic in Israel using an online survey, during the six weeks encompassing the end of the first outbreak and the beginning of the second. We used clinically validated instruments to assess anxiety- and depression-related emotional distress, symptoms, and coping strategies, as well as questions designed to specifically assess COVID-19-related concerns. Higher emotional burden was associated with being female, younger, unemployed, living in high socioeconomic status localities, having prior medical conditions, encountering more people, and experiencing physiological symptoms. Our findings highlight the environmental context and its importance in understanding individual ability to cope with the long-term stressful challenges of the pandemic.
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http://dx.doi.org/10.1038/s41380-021-01219-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335462PMC
August 2021

Structural correlates of trauma-induced hyperarousal in mice.

Prog Neuropsychopharmacol Biol Psychiatry 2021 Dec 22;111:110404. Epub 2021 Jul 22.

Research Group Neuronal Plasticity, Max Planck Institute of Psychiatry, 80804 Munich, Germany; Max Planck School of Cognition, 04103 Leipzig, Germany; Central Nervous System Diseases Research (CNSDR), Boehringer Ingelheim Pharma GmbH & Co KG, 88397, Biberach an der Riss, Germany. Electronic address:

Post-traumatic stress disorder (PTSD) is a chronic disease caused by traumatic incidents. Numerous studies have revealed grey matter volume differences in affected individuals. The nature of the disease renders it difficult to distinguish between a priori versus a posteriori changes. To overcome this difficulty, we studied the consequences of a traumatic event on brain morphology in mice before and 4 weeks after exposure to brief foot shocks (or sham treatment), and correlated morphology with symptoms of hyperarousal. In the latter context, we assessed hyperarousal upon confrontation with acoustic, visual, or composite (acoustic/visual/tactile) threats and integrated the individual readouts into a single Hyperarousal Score using logistic regression analysis. MRI scans with subsequent whole-brain deformation-based morphometry (DBM) analysis revealed a volume decrease of the dorsal hippocampus and an increase of the reticular nucleus in shocked mice when compared to non-shocked controls. Using the Hyperarousal Score as regressor for the post-exposure MRI measurement, we observed negative correlations with several brain structures including the dorsal hippocampus. If the development of changes with respect to the basal MRI was considered, reduction in globus pallidus volume reflected hyperarousal severity. Our findings demonstrate that a brief traumatic incident can cause volume changes in defined brain structures and suggest the globus pallidus as an important hub for the control of fear responses to threatening stimuli of different sensory modalities.
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http://dx.doi.org/10.1016/j.pnpbp.2021.110404DOI Listing
December 2021

The role of TET proteins in stress-induced neuroepigenetic and behavioural adaptations.

Authors:
Alec Dick Alon Chen

Neurobiol Stress 2021 Nov 11;15:100352. Epub 2021 Jun 11.

Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.

Over the past decade, critical, non-redundant roles of the ten-eleven translocation (TET) family of dioxygenase enzymes have been identified in the brain during developmental and postnatal stages. Specifically, TET-mediated active demethylation, involving the iterative oxidation of 5-methylcytosine to 5-hydroxymethylcytosine and subsequent oxidative derivatives, is dynamically regulated in response to environmental stimuli such as neuronal activity, learning and memory processes, and stressor exposure. Such changes may therefore perpetuate stable and dynamic transcriptional patterns within neuronal populations required for neuroplasticity and behavioural adaptation. In this review, we will highlight recent evidence supporting a role of TET protein function and active demethylation in stress-induced neuroepigenetic and behavioural adaptations. We further explore potential mechanisms by which TET proteins may mediate both the basal and pathological embedding of stressful life experiences within the brain of relevance to stress-related psychiatric disorders.
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http://dx.doi.org/10.1016/j.ynstr.2021.100352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220100PMC
November 2021

The relationship between the plasma proinflammatory cytokine levels of depressed/anxious children and their parents.

Sci Rep 2021 06 3;11(1):11798. Epub 2021 Jun 3.

Department of Psychological Medicine, Schneider Children's Medical Center of Israel, 14 Kaplan Street, 4920235, Petach Tikva, Israel.

Recent studies suggest immune function dysregulation in depression and anxiety disorders. Elevated pro-inflammatory cytokines may be a marker for immune system dysregulation. No study assessed the correlation between the levels of cytokines in children and adolescents with depression/anxiety disorders and their parents. In this study, 92 children and adolescents (mean age 13.90 ± 2.41 years) with depression and/or anxiety disorders were treated with fluoxetine. Blood samples were collected before initiation of treatment. One hundred and sixty-four of their parents (mean age 50.6 ± 6.2 years) and 25 parents of healthy children (mean age 38.5 ± 6.2 years) also gave blood samples. Plasma levels of three pro-inflammatory cytokine (TNF-α, IL-6, IL-1β) were measured by enzyme linked immunosorbent assays (ELISA) and compared between depressed/anxious children and their parents. We also compared cytokine levels between parents of children with depression/anxiety and control parents. Mothers of depressed children had higher TNF-α levels than mothers of controls. No significant difference was detected in the fathers. A positive correlation was found between the IL-1β levels of the depressed/anxious boys and their mothers. No such correlation was observed in the fathers. Our conclusions are that higher levels of proinflammatory cytokines may indicate immune system activation in mothers in response to the distress associated with having depressed/anxious offspring. The correlation between IL-1β levels in the mothers and their depressed/anxious children may indicate familial vulnerability to depression and anxiety. Our observation highlights the need for a better understanding of sexual dimorphism in inflammatory responses to stress.
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http://dx.doi.org/10.1038/s41598-021-90971-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175361PMC
June 2021

Oligonucleotides as therapeutic tools for brain disorders: Focus on major depressive disorder and Parkinson's disease.

Pharmacol Ther 2021 Nov 27;227:107873. Epub 2021 Apr 27.

Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), 08036 Barcelona, Spain; Institut d'Investigacions August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain.

Remarkable advances in understanding the role of RNA in health and disease have expanded considerably in the last decade. RNA is becoming an increasingly important target for therapeutic intervention; therefore, it is critical to develop strategies for therapeutic modulation of RNA function. Oligonucleotides, including antisense oligonucleotide (ASO), small interfering RNA (siRNA), microRNA mimic (miRNA), and anti-microRNA (antagomir) are perhaps the most direct therapeutic strategies for addressing RNA. Among other mechanisms, most oligonucleotide designs involve the formation of a hybrid with RNA that promotes its degradation by activation of endogenous enzymes such as RNase-H (e.g., ASO) or the RISC complex (e.g. RNA interference - RNAi for siRNA and miRNA). However, the use of oligonucleotides for the treatment of brain disorders is seriously compromised by two main limitations: i) how to deliver oligonucleotides to the brain compartment, avoiding the action of peripheral RNAses? and once there, ii) how to target specific neuronal populations? We review the main molecular pathways in major depressive disorder (MDD) and Parkinson's disease (PD), and discuss the challenges associated with the development of novel oligonucleotide therapeutics. We pay special attention to the use of conjugated ligand-oligonucleotide approach in which the oligonucleotide sequence is covalently bound to monoamine transporter inhibitors (e.g. sertraline, reboxetine, indatraline). This strategy allows their selective accumulation in the monoamine neurons of mice and monkeys after their intranasal or intracerebroventricular administration, evoking preclinical changes predictive of a clinical therapeutic action after knocking-down disease-related genes. In addition, recent advances in oligonucleotide therapeutic clinical trials are also reviewed.
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http://dx.doi.org/10.1016/j.pharmthera.2021.107873DOI Listing
November 2021

Circulating microRNA Expression in Cushing's Syndrome.

Front Endocrinol (Lausanne) 2021 22;12:620012. Epub 2021 Feb 22.

Department of Endocrinology, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-University, Munich, Germany.

Context: Cushing's syndrome (CS) is a rare disease of endogenous hypercortisolism associated with high morbidity and mortality. Diagnosis and classification of CS is still challenging.

Objective: Circulating microRNAs (miRNAs) are minimally invasive diagnostic markers. Our aim was to characterize the circulating miRNA profiles of CS patients and to identify distinct profiles between the two major CS subtypes.

Methods: We included three groups of patients from the German Cushing's registry: ACTH-independent CS (Cortisol-Producing-Adenoma; CPA), ACTH-dependent pituitary CS (Cushing's Disease; CD), and patients in whom CS had been ruled out (controls). Profiling of miRNAs was performed by next-generation-sequencing (NGS) in serum samples of 15 CS patients (each before and after curative surgery) and 10 controls. Significant miRNAs were first validated by qPCR in the discovery cohort and then in an independent validation cohort of 20 CS patients and 11 controls.

Results: NGS identified 411 circulating miRNAs. Differential expression of 14 miRNAs were found in the pre- and postoperative groups. qPCR in the discovery cohort validated 5 of the significant miRNAs from the preoperative group analyses. Only, miR-182-5p was found to be significantly upregulated in the CD group of the validation cohort. Comparing all CS samples as a group with the controls did not reveal any significant differences in expression.

Outcome: In conclusion, our study identified miR-182-5p as a possible biomarker for CD, which has to be validated in a prospective cohort. Furthermore, our results suggest that presence or absence of ACTH might be at least as relevant for miRNA expression as hypercortisolism itself.
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http://dx.doi.org/10.3389/fendo.2021.620012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937959PMC
February 2021

The neural circuitry of social homeostasis: Consequences of acute versus chronic social isolation.

Cell 2021 03 9;184(6):1500-1516. Epub 2021 Mar 9.

The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address:

Social homeostasis is the ability of individuals to detect the quantity and quality of social contact, compare it to an established set-point in a command center, and adjust the effort expended to seek the optimal social contact expressed via an effector system. Social contact becomes a positive or negative valence stimulus when it is deficient or in excess, respectively. Chronic deficits lead to set-point adaptations such that reintroduction to the previous optimum is experienced as a surplus. Here, we build upon previous models for social homeostasis to include adaptations to lasting changes in environmental conditions, such as with chronic isolation.
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http://dx.doi.org/10.1016/j.cell.2021.02.028DOI Listing
March 2021

The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus of male mice.

Mol Psychiatry 2021 Jul 1;26(7):3060-3076. Epub 2021 Mar 1.

Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, Munich, Germany.

Disturbed activation or regulation of the stress response through the hypothalamic-pituitary-adrenal (HPA) axis is a fundamental component of multiple stress-related diseases, including psychiatric, metabolic, and immune disorders. The FK506 binding protein 51 (FKBP5) is a negative regulator of the glucocorticoid receptor (GR), the main driver of HPA axis regulation, and FKBP5 polymorphisms have been repeatedly linked to stress-related disorders in humans. However, the specific role of Fkbp5 in the paraventricular nucleus of the hypothalamus (PVN) in shaping HPA axis (re)activity remains to be elucidated. We here demonstrate that the deletion of Fkbp5 in Sim1 neurons dampens the acute stress response and increases GR sensitivity. In contrast, Fkbp5 overexpression in the PVN results in a chronic HPA axis over-activation, and a PVN-specific rescue of Fkbp5 expression in full Fkbp5 KO mice normalizes the HPA axis phenotype. Single-cell RNA sequencing revealed the cell-type-specific expression pattern of Fkbp5 in the PVN and showed that Fkbp5 expression is specifically upregulated in Crh neurons after stress. Finally, Crh-specific Fkbp5 overexpression alters Crh neuron activity, but only partially recapitulates the PVN-specific Fkbp5 overexpression phenotype. Together, the data establish the central and cell-type-specific importance of Fkbp5 in the PVN in shaping HPA axis regulation and the acute stress response.
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http://dx.doi.org/10.1038/s41380-021-01044-xDOI Listing
July 2021

Single-cell molecular profiling of all three components of the HPA axis reveals adrenal ABCB1 as a regulator of stress adaptation.

Sci Adv 2021 Jan 27;7(5). Epub 2021 Jan 27.

Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Bavaria 80804, Germany.

Chronic activation and dysregulation of the neuroendocrine stress response have severe physiological and psychological consequences, including the development of metabolic and stress-related psychiatric disorders. We provide the first unbiased, cell type-specific, molecular characterization of all three components of the hypothalamic-pituitary-adrenal axis, under baseline and chronic stress conditions. Among others, we identified a previously unreported subpopulation of cells involved in stress adaptation in the adrenal gland. We validated our findings in a mouse stress model, adrenal tissues from patients with Cushing's syndrome, adrenocortical cell lines, and peripheral cortisol and genotyping data from depressed patients. This extensive dataset provides a valuable resource for researchers and clinicians interested in the organism's nervous and endocrine responses to stress and the interplay between these tissues. Our findings raise the possibility that modulating ABCB1 function may be important in the development of treatment strategies for patients suffering from metabolic and stress-related psychiatric disorders.
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http://dx.doi.org/10.1126/sciadv.abe4497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840126PMC
January 2021

miR-323a regulates ERBB4 and is involved in depression.

Mol Psychiatry 2020 Nov 20. Epub 2020 Nov 20.

Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, QC, Canada.

Major depressive disorder (MDD) is a complex and debilitating illness whose etiology remains unclear. Small RNA molecules, such as micro RNAs (miRNAs) have been implicated in MDD, where they display differential expression in the brain and the periphery. In this study, we quantified miRNA expression by small RNA sequencing in the anterior cingulate cortex and habenula of individuals with MDD and psychiatrically-healthy controls. Thirty-two miRNAs showed significantly correlated expression between the two regions (False Discovery Rate < 0.05), of which four, miR-204-5p, miR-320b, miR-323a-3p, and miR-331-3p, displayed upregulated expression in MDD. We assessed the expression of predicted target genes of differentially expressed miRNAs in the brain, and found that the expression of erb-b2 receptor tyrosine kinase 4 (ERBB4), a gene encoding a neuregulin receptor, was downregulated in both regions, and was influenced by miR-323a-3p in vitro. Finally, we assessed the effects of manipulating miRNA expression in the mouse ACC on anxiety- and depressive-like behaviors. Mice in which miR-323-3p was overexpressed or knocked-down displayed increased and decreased emotionality, respectively. Additionally, these mice displayed significantly downregulated and upregulated expression of Erbb4, respectively. Overall, our findings indicate the importance of brain miRNAs in the pathology of MDD, and emphasize the involvement of miR-323a-3p and ERBB4 in this phenotype. Future studies further characterizing miR-323a-3p and neuregulin signaling in depression are warranted.
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http://dx.doi.org/10.1038/s41380-020-00953-7DOI Listing
November 2020

Hippocampal neurons with stable excitatory connectivity become part of neuronal representations.

PLoS Biol 2020 11 3;18(11):e3000928. Epub 2020 Nov 3.

Max Planck Institute of Psychiatry, Munich, Germany.

Experiences are represented in the brain by patterns of neuronal activity. Ensembles of neurons representing experience undergo activity-dependent plasticity and are important for learning and recall. They are thus considered cellular engrams of memory. Yet, the cellular events that bias neurons to become part of a neuronal representation are largely unknown. In rodents, turnover of structural connectivity has been proposed to underlie the turnover of neuronal representations and also to be a cellular mechanism defining the time duration for which memories are stored in the hippocampus. If these hypotheses are true, structural dynamics of connectivity should be involved in the formation of neuronal representations and concurrently important for learning and recall. To tackle these questions, we used deep-brain 2-photon (2P) time-lapse imaging in transgenic mice in which neurons expressing the Immediate Early Gene (IEG) Arc (activity-regulated cytoskeleton-associated protein) could be permanently labeled during a specific time window. This enabled us to investigate the dynamics of excitatory synaptic connectivity-using dendritic spines as proxies-of hippocampal CA1 (cornu ammonis 1) pyramidal neurons (PNs) becoming part of neuronal representations exploiting Arc as an indicator of being part of neuronal representations. We discovered that neurons that will prospectively express Arc have slower turnover of synaptic connectivity, thus suggesting that synaptic stability prior to experience can bias neurons to become part of representations or possibly engrams. We also found a negative correlation between stability of structural synaptic connectivity and the ability to recall features of a hippocampal-dependent memory, which suggests that faster structural turnover in hippocampal CA1 might be functional for memory.
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http://dx.doi.org/10.1371/journal.pbio.3000928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665705PMC
November 2020

Social dominance mediates behavioral adaptation to chronic stress in a sex-specific manner.

Elife 2020 10 9;9. Epub 2020 Oct 9.

Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.

Sex differences and social context independently contribute to the development of stress-related disorders. However, less is known about how their interplay might influence behavior and physiology. Here we focused on social hierarchy status, a major component of the social environment in mice, and whether it influences behavioral adaptation to chronic stress in a sex-specific manner. We used a high-throughput automated behavioral monitoring system to assess social dominance in same-sex, group-living mice. We found that position in the social hierarchy at baseline was a significant predictor of multiple behavioral outcomes following exposure to chronic stress. Crucially, this association carried opposite consequences for the two sexes. This work demonstrates the importance of recognizing the interplay between sex and social factors and enhances our understating of how individual differences shape the stress response.
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http://dx.doi.org/10.7554/eLife.58723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679136PMC
October 2020

Loss of the psychiatric risk factor SLC6A15 is associated with increased metabolic functions in primary hippocampal neurons.

Eur J Neurosci 2021 01 19;53(2):390-401. Epub 2020 Oct 19.

Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, Munich, Germany.

Major depressive disorder (MDD) is one of the most severe global health problems with millions of people affected, however, the mechanisms underlying this disorder is still poorly understood. Genome-wide association studies have highlighted a link between the neutral amino acid transporter SLC6A15 and MDD. Additionally, a number of preclinical studies support the function of this transporter in modulating levels of brain neurotransmitters, stress system regulation and behavioural phenotypes related to MDD. However, the molecular and functional mechanisms involved in this interaction are still unresolved. Therefore, to investigate the effects of the SLC6A15 transporter, we used hippocampal tissue from Slc6a15-KO and wild-type mice, together with several in-vitro assays in primary hippocampal neurons. Utilizing a proteomics approach we identified differentially regulated proteins that formed a regulatory network and pathway analysis indicated significantly affected cellular domains, including metabolic, mitochondrial and structural functions. Furthermore, we observed reduced release probability at glutamatergic synapses, increased mitochondrial function, higher GSH/GSSG redox ratio and an improved neurite outgrowth in primary neurons lacking SLC6A15. In summary, we hypothesize that by controlling the intracellular concentrations of neutral amino acids, SLC6A15 affects mitochondrial activity, which could lead to alterations in neuronal structure and activity. These data provide further indication that a pharmacological or genetic reduction of SLC6A15 activity may indeed be a promising approach for antidepressant therapy.
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http://dx.doi.org/10.1111/ejn.14990DOI Listing
January 2021

Loss of the psychiatric risk factor SLC6A15 is associated with increased metabolic functions in primary hippocampal neurons.

Eur J Neurosci 2021 01 19;53(2):390-401. Epub 2020 Oct 19.

Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, Munich, Germany.

Major depressive disorder (MDD) is one of the most severe global health problems with millions of people affected, however, the mechanisms underlying this disorder is still poorly understood. Genome-wide association studies have highlighted a link between the neutral amino acid transporter SLC6A15 and MDD. Additionally, a number of preclinical studies support the function of this transporter in modulating levels of brain neurotransmitters, stress system regulation and behavioural phenotypes related to MDD. However, the molecular and functional mechanisms involved in this interaction are still unresolved. Therefore, to investigate the effects of the SLC6A15 transporter, we used hippocampal tissue from Slc6a15-KO and wild-type mice, together with several in-vitro assays in primary hippocampal neurons. Utilizing a proteomics approach we identified differentially regulated proteins that formed a regulatory network and pathway analysis indicated significantly affected cellular domains, including metabolic, mitochondrial and structural functions. Furthermore, we observed reduced release probability at glutamatergic synapses, increased mitochondrial function, higher GSH/GSSG redox ratio and an improved neurite outgrowth in primary neurons lacking SLC6A15. In summary, we hypothesize that by controlling the intracellular concentrations of neutral amino acids, SLC6A15 affects mitochondrial activity, which could lead to alterations in neuronal structure and activity. These data provide further indication that a pharmacological or genetic reduction of SLC6A15 activity may indeed be a promising approach for antidepressant therapy.
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http://dx.doi.org/10.1111/ejn.14990DOI Listing
January 2021

INSPIRE: A European training network to foster research and training in cardiovascular safety pharmacology.

J Pharmacol Toxicol Methods 2020 Sep 18;105:106889. Epub 2020 Jun 18.

National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), London, UK.

Safety pharmacology is an essential part of drug development aiming to identify, evaluate and investigate undesirable pharmacodynamic properties of a drug primarily prior to clinical trials. In particular, cardiovascular adverse drug reactions (ADR) have halted many drug development programs. Safety pharmacology has successfully implemented a screening strategy to detect cardiovascular liabilities, but there is room for further refinement. In this setting, we present the INSPIRE project, a European Training Network in safety pharmacology for Early Stage Researchers (ESRs), funded by the European Commission's H2020-MSCA-ITN programme. INSPIRE has recruited 15 ESR fellows that will conduct an individual PhD-research project for a period of 36 months. INSPIRE aims to be complementary to ongoing research initiatives. With this as a goal, an inventory of collaborative research initiatives in safety pharmacology was created and the ESR projects have been designed to be complementary to this roadmap. Overall, INSPIRE aims to improve cardiovascular safety evaluation, either by investigating technological innovations or by adding mechanistic insight in emerging safety concerns, as observed in the field of cardio-oncology. Finally, in addition to its hands-on research pillar, INSPIRE will organize a number of summer schools and workshops that will be open to the wider community as well. In summary, INSPIRE aims to foster both research and training in safety pharmacology and hopes to inspire the future generation of safety scientists.
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http://dx.doi.org/10.1016/j.vascn.2020.106889DOI Listing
September 2020

Wireless Optogenetic Stimulation of Oxytocin Neurons in a Semi-natural Setup Dynamically Elevates Both Pro-social and Agonistic Behaviors.

Neuron 2020 08 15;107(4):644-655.e7. Epub 2020 Jun 15.

Department of Neurobiology, Weizmann Institute of Science, Rehovot 7610001, Israel; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich 80804, Germany. Electronic address:

Complex behavioral phenotyping techniques are becoming more prevalent in the field of behavioral neuroscience, and thus methods for manipulating neuronal activity must be adapted to fit into such paradigms. Here, we present a head-mounted, magnetically activated device for wireless optogenetic manipulation that is compact, simple to construct, and suitable for use in group-living mice in an enriched semi-natural arena over several days. Using this device, we demonstrate that repeated activation of oxytocin neurons in male mice can have different effects on pro-social and agonistic behaviors, depending on the social context. Our findings support the social salience hypothesis of oxytocin and emphasize the importance of the environment in the study of social neuromodulators. Our wireless optogenetic device can be easily adapted for use in a variety of behavioral paradigms, which are normally hindered by tethered light delivery or a limited environment.
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http://dx.doi.org/10.1016/j.neuron.2020.05.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447984PMC
August 2020

Wireless Optogenetic Stimulation of Oxytocin Neurons in a Semi-natural Setup Dynamically Elevates Both Pro-social and Agonistic Behaviors.

Neuron 2020 08 15;107(4):644-655.e7. Epub 2020 Jun 15.

Department of Neurobiology, Weizmann Institute of Science, Rehovot 7610001, Israel; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich 80804, Germany. Electronic address:

Complex behavioral phenotyping techniques are becoming more prevalent in the field of behavioral neuroscience, and thus methods for manipulating neuronal activity must be adapted to fit into such paradigms. Here, we present a head-mounted, magnetically activated device for wireless optogenetic manipulation that is compact, simple to construct, and suitable for use in group-living mice in an enriched semi-natural arena over several days. Using this device, we demonstrate that repeated activation of oxytocin neurons in male mice can have different effects on pro-social and agonistic behaviors, depending on the social context. Our findings support the social salience hypothesis of oxytocin and emphasize the importance of the environment in the study of social neuromodulators. Our wireless optogenetic device can be easily adapted for use in a variety of behavioral paradigms, which are normally hindered by tethered light delivery or a limited environment.
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http://dx.doi.org/10.1016/j.neuron.2020.05.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447984PMC
August 2020

Wireless Optogenetic Stimulation of Oxytocin Neurons in a Semi-natural Setup Dynamically Elevates Both Pro-social and Agonistic Behaviors.

Neuron 2020 08 15;107(4):644-655.e7. Epub 2020 Jun 15.

Department of Neurobiology, Weizmann Institute of Science, Rehovot 7610001, Israel; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich 80804, Germany. Electronic address:

Complex behavioral phenotyping techniques are becoming more prevalent in the field of behavioral neuroscience, and thus methods for manipulating neuronal activity must be adapted to fit into such paradigms. Here, we present a head-mounted, magnetically activated device for wireless optogenetic manipulation that is compact, simple to construct, and suitable for use in group-living mice in an enriched semi-natural arena over several days. Using this device, we demonstrate that repeated activation of oxytocin neurons in male mice can have different effects on pro-social and agonistic behaviors, depending on the social context. Our findings support the social salience hypothesis of oxytocin and emphasize the importance of the environment in the study of social neuromodulators. Our wireless optogenetic device can be easily adapted for use in a variety of behavioral paradigms, which are normally hindered by tethered light delivery or a limited environment.
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http://dx.doi.org/10.1016/j.neuron.2020.05.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447984PMC
August 2020

ASL Metabolically Regulates Tyrosine Hydroxylase in the Nucleus Locus Coeruleus.

Cell Rep 2019 11;29(8):2144-2153.e7

Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel. Electronic address:

Patients with germline mutations in the urea-cycle enzyme argininosuccinate lyase (ASL) are at risk for developing neurobehavioral and cognitive deficits. We find that ASL is prominently expressed in the nucleus locus coeruleus (LC), the central source of norepinephrine. Using natural history data, we show that individuals with ASL deficiency are at risk for developing attention deficits. By generating LC-ASL-conditional knockout (cKO) mice, we further demonstrate altered response to stressful stimuli with increased seizure reactivity in LC-ASL-cKO mice. Depletion of ASL in LC neurons leads to reduced amount and activity of tyrosine hydroxylase (TH) and to decreased catecholamines synthesis, due to decreased nitric oxide (NO) signaling. NO donors normalize catecholamine levels in the LC, seizure sensitivity, and the stress response in LC-ASL-cKO mice. Our data emphasize ASL importance for the metabolic regulation of LC function with translational relevance for ASL deficiency (ASLD) patients as well as for LC-related pathologies.
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http://dx.doi.org/10.1016/j.celrep.2019.10.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902269PMC
November 2019

Identity domains capture individual differences from across the behavioral repertoire.

Nat Neurosci 2019 12 4;22(12):2023-2028. Epub 2019 Nov 4.

Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.

Personality traits can offer considerable insight into the biological basis of individual differences. However, existing approaches toward understanding personality across species rely on subjective criteria and limited sets of behavioral readouts, which result in noisy and often inconsistent outcomes. Here we introduce a mathematical framework for describing individual differences along dimensions with maximum consistency and discriminative power. We validate this framework in mice, using data from a system for high-throughput longitudinal monitoring of group-housed male mice that yields a variety of readouts from across the behavioral repertoire of individual animals. We demonstrate a set of stable traits that capture variability in behavior and gene expression in the brain, allowing for better-informed mechanistic investigations into the biology of individual differences.
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http://dx.doi.org/10.1038/s41593-019-0516-yDOI Listing
December 2019

Social context and dominance status contribute to sleep patterns and quality in groups of freely-moving mice.

Sci Rep 2019 10 23;9(1):15190. Epub 2019 Oct 23.

Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804, Germany.

In socially-living species, sleep patterns are often subject to group influences, as individuals adjust to the presence, daily rhythms, and social pressures of cohabitation. However, sleep studies in mice are typically conducted in single-housed individuals. Here, we investigated sleep in a semi-naturalistic environment with freely-moving, group-housed mice using wireless electroencephalographic (EEG) monitoring and video tracking. We found evidence of in-group synchrony of sleep state patterns and effects of social dominance status on sleep quality. These findings highlight the importance of exploring sleep in a social context and are a step toward more informative research on the interplay between social functioning and sleep.
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http://dx.doi.org/10.1038/s41598-019-51375-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811636PMC
October 2019

Multi-omics analysis identifies mitochondrial pathways associated with anxiety-related behavior.

PLoS Genet 2019 09 26;15(9):e1008358. Epub 2019 Sep 26.

Molecular and Integrative Biosciences Research Program, University of Helsinki, Helsinki, Finland.

Stressful life events are major environmental risk factors for anxiety disorders, although not all individuals exposed to stress develop clinical anxiety. The molecular mechanisms underlying the influence of environmental effects on anxiety are largely unknown. To identify biological pathways mediating stress-related anxiety and resilience to it, we used the chronic social defeat stress (CSDS) paradigm in male mice of two inbred strains, C57BL/6NCrl (B6) and DBA/2NCrl (D2), that differ in their susceptibility to stress. Using a multi-omics approach, we identified differential mRNA, miRNA and protein expression changes in the bed nucleus of the stria terminalis (BNST) and blood cells after chronic stress. Integrative gene set enrichment analysis revealed enrichment of mitochondrial-related genes in the BNST and blood of stressed mice. To translate these results to human anxiety, we investigated blood gene expression changes associated with exposure-induced panic attacks. Remarkably, we found reduced expression of mitochondrial-related genes in D2 stress-susceptible mice and in exposure-induced panic attacks in humans, but increased expression of these genes in B6 stress-susceptible mice. Moreover, stress-susceptible vs. stress-resilient B6 mice displayed more mitochondrial cross-sections in the post-synaptic compartment after CSDS. Our findings demonstrate mitochondrial-related alterations in gene expression as an evolutionarily conserved response in stress-related behaviors and validate the use of cross-species approaches in investigating the biological mechanisms underlying anxiety disorders.
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http://dx.doi.org/10.1371/journal.pgen.1008358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6762065PMC
September 2019

Glucocorticoid-induced leucine zipper "quantifies" stressors and increases male susceptibility to PTSD.

Transl Psychiatry 2019 07 25;9(1):178. Epub 2019 Jul 25.

Department of Neurobiology, Weizmann Institute of Science, 76100, Rehovot, Israel.

Post-traumatic stress disorder (PTSD) selectively develops in some individuals exposed to a traumatic event. Genetic and epigenetic changes in glucocorticoid pathway sensitivity may be essential for understanding individual susceptibility to PTSD. This study focuses on PTSD markers in the glucocorticoid pathway, spotlighting glucocorticoid-induced leucine zipper (GILZ), a transcription factor encoded by the gene Tsc22d3 on the X chromosome. We propose that GILZ uniquely "quantifies" exposure to stressors experienced from late gestation to adulthood and that low levels of GILZ predispose individuals to PTSD in males only. GILZ mRNA and methylation were measured in 396 male and female human blood samples from the Grady Trauma Project cohort (exposed to multiple traumatic events). In mice, changes in glucocorticoid pathway genes were assessed following exposure to stressors at distinct time points: (i) CRF-induced prenatal stress (PNS) with, or without, additional exposure to (ii) PTSD induction protocol in adulthood, which induces PTSD-like behaviors in a subset of mice. In humans, the number of traumatic events correlated negatively with GILZ mRNA levels and positively with % methylation of GILZ in males only. In male mice, we observed a threefold increase in the number of offspring exhibiting PTSD-like behaviors in those exposed to both PNS and PTSD induction. This susceptibility was associated with reduced GILZ mRNA levels and epigenetic changes, not found in females. Furthermore, virus-mediated shRNA knockdown of amygdalar GILZ increased susceptibility to PTSD. Mouse and human data confirm that dramatic alterations in GILZ occur in those exposed to a stressor in early life, adulthood or both. Therefore, GILZ levels may help identify at-risk populations for PTSD prior to additional traumatic exposures.
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http://dx.doi.org/10.1038/s41398-019-0509-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658561PMC
July 2019

Longitudinal Two-Photon Imaging of Dorsal Hippocampal CA1 in Live Mice.

J Vis Exp 2019 06 19(148). Epub 2019 Jun 19.

Dept. of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry;

Two-photon microscopy is a fundamental tool for neuroscience as it permits investigation of the brain of live animals at spatial scales ranging from subcellular to network levels and at temporal scales from milliseconds to weeks. In addition, two-photon imaging can be combined with a variety of behavioral tasks to explore the causal relationships between brain function and behavior. However, in mammals, limited penetration and scattering of light have limited two-photon intravital imaging mostly to superficial brain regions, thus precluding longitudinal investigation of deep-brain areas such as the hippocampus. The hippocampus is involved in spatial navigation and episodic memory and is a long-standing model used to study cellular as well as cognitive processes important for learning and recall, both in health and disease. Here, a preparation that enables chronic optical access to the dorsal hippocampus in living mice is detailed. This preparation can be combined with two-photon optical imaging at cellular and subcellular resolution in head fixed, anesthetized live mice over several weeks. These techniques enable repeated imaging of neuronal structure or activity-evoked plasticity in tens to hundreds of neurons in the dorsal hippocampal CA1. Furthermore, this chronic preparation can be used in combination with other techniques such as micro-endoscopy, head-mounted wide field microscopy or three-photon microscopy, thus greatly expanding the toolbox to study cellular and network processes involved in learning and memory.
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http://dx.doi.org/10.3791/59598DOI Listing
June 2019

Adenosine-to-Inosine RNA Editing Within Corticolimbic Brain Regions Is Regulated in Response to Chronic Social Defeat Stress in Mice.

Front Psychiatry 2019 26;10:277. Epub 2019 Apr 26.

Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.

Adenosine-to-inosine (A-to-I) RNA editing is a co-/posttranscriptional modification of double-stranded RNA, catalyzed by the adenosine deaminase acting on RNA (ADAR) family of enzymes, which results in recognition of inosine as guanosine by translational and splicing machinery causing potential recoding events in amino acid sequences. A-to-I editing is prominent within brain-specific transcripts, and dysregulation of editing at several well-studied loci (e.g., , ) has been implicated in acute and chronic stress in rodents as well as neurological (e.g., Alzheimer's) and psychopathological disorders such as schizophrenia and major depressive disorder. However, only a small fraction of recoding sites has been investigated within the brain following stress, and our understanding of the role of RNA editing in transcriptome regulation following environmental stimuli remains poorly understood. Thus, we aimed to investigate A-to-I editing at hundreds of loci following chronic social defeat stress (CSDS) in mice within corticolimbic regions responsive to chronic stress regulation. Adult male mice were subjected to CSDS or control conditions for 21 days and dynamic regulation of A-to-I editing was investigated 2 and 8 days following the final defeat within both the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA). Employing a targeted resequencing approach, which utilizes microfluidics-based multiplex polymerase chain reaction (PCR) coupled with next-generation sequencing, we analyzed A-to-I editing at ∼100 high-confidence editing sites within the mouse brain. CSDS resulted in acute regulation of transcripts encoding several ADAR enzymes, which normalized 8 days following the final defeat and was specific for susceptible mice. In contrast, sequencing analysis revealed modest and dynamic regulation of A-to-I editing within numerous transcripts in both the mPFC and BLA of resilient and susceptible mice at both 2 and 8 days following CSDS with minimal overlap between regions and time points. Editing within the transcript and relative abundance of messenger RNA (mRNA)variants were also observed within the BLA of susceptible mice 2 days following CSDS. These results indicate dynamic RNA editing within discrete brain regions following CSDS in mice, further implicating A-to-I editing as a stress-sensitive molecular mechanism within the brain of potential relevance to resiliency and susceptibility to CSDS.
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http://dx.doi.org/10.3389/fpsyt.2019.00277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512728PMC
April 2019

Stress at its best: the 1st Munich Winter Conference On Stress.

Stress 2018 09;21(5):382-383

a Department of Stress Neurobiology and Neurogenetics , Max Planck Institute of Psychiatry , Munich , Germany.

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http://dx.doi.org/10.1080/10253890.2018.1509814DOI Listing
September 2018

Sex dependent impact of gestational stress on predisposition to eating disorders and metabolic disease.

Mol Metab 2018 11 20;17:1-16. Epub 2018 Aug 20.

Department of Neurobiology, Weizmann Institute of Science, Rehovot, 76100, Israel; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804, Germany. Electronic address:

Objective: Vulnerability to eating disorders (EDs) is broadly assumed to be associated with early life stress. However, a careful examination of the literature shows that susceptibility to EDs may depend on the type, severity and timing of the stressor and the sex of the individual. We aimed at exploring the link between chronic prenatal stress and predisposition to EDs and metabolic disease.

Methods: We used a chronic variable stress protocol during gestation to explore the metabolic response of male and female offspring to food restriction (FR), activity-based anorexia (ABA), binge eating (BE) and exposure to high fat (HF) diet.

Results: Contrary to controls, prenatally stressed (PNS) female offspring showed resistance to ABA and BE and displayed a lower metabolic rate leading to hyperadiposity and obesity on HF diet. Male PNS offspring showed healthy responses to FR and ABA, increased propensity to binge and improved coping with HF compared to controls. We found that long-lasting abnormal responses to metabolic challenge are linked to fetal programming and adult hypothalamic dysregulation in PNS females, resulting from sexually dimorphic adaptations in placental methylation and gene expression.

Conclusions: Our results show that maternal stress may have variable and even opposing effects on ED risk, depending on the ED and the sex of the offspring.
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http://dx.doi.org/10.1016/j.molmet.2018.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197785PMC
November 2018

The Corticotropin-Releasing Factor Family: Physiology of the Stress Response.

Physiol Rev 2018 10;98(4):2225-2286

Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry , Munich , Germany ; and Department of Neurobiology, Weizmann Institute of Science , Rehovot , Israel.

The physiological stress response is responsible for the maintenance of homeostasis in the presence of real or perceived challenges. In this function, the brain activates adaptive responses that involve numerous neural circuits and effector molecules to adapt to the current and future demands. A maladaptive stress response has been linked to the etiology of a variety of disorders, such as anxiety and mood disorders, eating disorders, and the metabolic syndrome. The neuropeptide corticotropin-releasing factor (CRF) and its relatives, the urocortins 1-3, in concert with their receptors (CRFR1, CRFR2), have emerged as central components of the physiological stress response. This central peptidergic system impinges on a broad spectrum of physiological processes that are the basis for successful adaptation and concomitantly integrate autonomic, neuroendocrine, and behavioral stress responses. This review focuses on the physiology of CRF-related peptides and their cognate receptors with the aim of providing a comprehensive up-to-date overview of the field. We describe the major molecular features covering aspects of gene expression and regulation, structural properties, and molecular interactions, as well as mechanisms of signal transduction and their surveillance. In addition, we discuss the large body of published experimental studies focusing on state-of-the-art genetic approaches with high temporal and spatial precision, which collectively aimed to dissect the contribution of CRF-related ligands and receptors to different levels of the stress response. We discuss the controversies in the field and unravel knowledge gaps that might pave the way for future research directions and open up novel opportunities for therapeutic intervention.
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http://dx.doi.org/10.1152/physrev.00042.2017DOI Listing
October 2018
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