The project will investigate the mechanistic basis of maladaptation in stress and PTSD at the micro, meso and macro circuit levels. A particular focus will be on the underlying plasticity mechanisms at the synapse and circuit level as well as on transferable imaging methods that will be examined across scales, bridging animal and human research.

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While the investigation of mental illnesses typically focuses on the impaired functionality of an index person (patient), many mental disorders are characterized by a pronounced disturbance in social interaction. The goal of TP3 is to examine functional and dysfunctional relationship patterns, as well as their neural, peripheral-physiological and behavioral correlates, as predictors and endpoints of mental disorders. Building on the first funding period, we will realize four work packages (WPs). The first will examine neural and behavioral synchronization in healthy, impaired, and pathological social interactions, exploring their function as predictors of mental illness and their modifiability through therapy and intervention. In the second WP, we will investigate bidirectional empathic stress contagion within dyads and families, studying not only established hormonal markers but also neurological and behavioral indices of stress contagion. Identifying the familial “epicentres” of stress transmission will be one central goal of WP2. In the third WP we will focus on brain activity and neuropeptide roles in group interactions within 'mouse cities,' echoing questions raised in human studies. Our preliminary results indicate stable prosocial personalities in mouse groups, and we will now investigate how chronic stress affects behaviour activity on a brain-wide level as well as in defined peptidergic circuits associated with resilience.
Our human subprojects interact through overlapping personnel and similar methodologies, creating synergies, but also through the development of a toolbox for social behaviour measures, as well as the aim to develop a theory of social process synchronization under allostatic load. They are informed by specific biomarkers, circuits and behaviours identified in relevant mouse models in WP3, while the animal models will be further refined by the tools and theories developed in the human social interaction studies

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Orexinergic neurons are a central component of the wake-promoting system. Their activity displays a strong circadian rhythm and may help to explain circadian fluctuations in cognitive performance. In this project, we aim to explore the potential of orexinergic neuromodulation in mobilising cognitive resource by stimulating prefrontal cortex (PFC)-to-hippocampus signalling and in modifying available resources in intrahippocampal microcircuit function. Probing the circuitry by acute phase delay in mice as a physiologically relevant circadian strain, we previously demonstrated deficits in hippocampal memory retrieval that affect the formation of cellular engrams in the dentate gyrus (DG). Acute phase delay further activated orexinergic neurons in the lateral hypothalamus and neuronal populations in the supramammillary nucleus (SUM). We identified SUM relay neurons connecting the PFC and the dentate gyrus (DG), as well as mossy cells in the hilus of the DG as prime candidates for an orexin-mediated modulation, likely via Orexin receptor type 1. Building on these findings, we now aim to determine the precise circuit mechanisms involved in orexinergic modulation of this circuitry and to explore its potential for targeted intervention to mobilise cognitive resource. To this end we investigate (1) the role of local mossy cell circuits and SUM-to-DG projections in resource mobilisation, (2) the state-specific modulation of cognitive resources by orexin and its interaction with ageing, and (3) together with C04 explore the potency of pharmacological orexin manipulation to enhance cognitive function in translational paradigms aligned between mice and humans.

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The mammalian brain has an enormous capacity for structural and functional plasticity adjusting behavior to an ever-changing environment. This ability requires highly coordinated signaling, synchronized (de-)construction of synapses and adjustment of proteostasis in functional neuronal circuits. Maladaptive changes, arising from early-life adverse experiences, traumatic stress or neurodegenerative processes, can lead to neuropsychiatric conditions such as post-traumatic stress disorder (PTSD), depression or dementia.
Neuropeptide Y (NPY) is well established as an anxiolytic and stress-reducing factor and NPY transmission in the dorsal dentate gyrus (DG) has been demonstrated by us and others to control fear memory salience and traumatic stress resilience. Moreover, recent evidence suggests that NPY might play a key role in synaptic preoteostasis, by regulating neuronal autophagy both in vertebrates and invertebrates and that this might explain its capacity to modulate long-term cellular changes in neural circuitry. In this project we will therefore study the role of NPY-induced autophagy in a local circuit relevant for stress adaptation and emotional and cognitive information processing.
Specifically, in the DG-to-cornu ammonis (CA)3 system we will address mechanisms of behavioral induced autophagy in DG mossy fibers (MF) and their associated local NPY-secreting interneurons. The role of postsynaptic NPY-Y1 and pre-synaptic/autoregulatory NPY-Y2 receptors as well as intracellular and local circuitry signals will be examined. In addition, we will investigate the behavioral consequences of disturbed NPY-induced autophagy in these cells and ultimately aim to identify molecular and cellular processes that mediate NPY-induced adaptive changes and stress resilience. Our project intends to bridge a cellular and molecular analysis of autophagy to its involvement in adaptive cognitive and emotional brain function and is thereby interwoven with various other research projects of Syntophagy.

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Proinflammatory interleukins (ILs) such as IL-6 or TNFalpha are discussed as biomarkers for stress-related diseases such as depression or anxiety disorders. They can influence the metabolism and function of neurons in glial cells in the nervous system and also regulate neuronal plasticity via the direct and indirect activation of certain intracellular signaling pathways. In this project, we are collaborating to investigate how IL-6 and its related molecule IL-11 can alter the expression of plasticity-related proteins in the mouse hippocampus and what effects this may have on the structure and function of the hippocampus in vitro and in vivo. The aim is to gain a better understanding of the causal mechanisms of IL for learning and memory, but also for neuropsychiatric disorders of these processes.

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In this project will bridge animal and human research on the dynamic processes of adult stress response following early life adversity, with a focus on underlying plasticity mechanisms at the synapse and circuit level and translatable imaging and blood and physiological markers. The methodological points will be: (i) analysis of neural circuits at the micro- and mesoscale, (ii) opto- and chemogenetic interventions (iii) the use of data science and computational approaches and finally (iv) behavioral stratification in order to identify new neural access points for diagnosis and therapeutic intervention.

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Evidence from human but also rodent studies suggest that stress can be transmitted between people and thereby impact our health and wellbeing. We will translate established behavioral paradigms from the human to a mouse model in order to pinpoint the bio-behavioral correlates, neural circuits (both on the individual and group levels), and neuro-immunological health consequences of empathic stress as one aspect of maladaptive social interaction. Identified biomarkers, circuits, behaviors and interaction patterns will subsequently allow to detect resilient individuals and develop targeted intervention strategies for at-risk humans. Overall, this project will deliver in-depth translational knowledge about synchronized circuits in an allostatic state.

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Chronic inflammatory skin diseases such as atopic dermatitis (AD) and psoriasis are associated with a high co-morbidity of neuropsychiatric disorders like anxiety and depression, suggesting a link between pathophysiological processes in the skin and the brain. G-protein coupled receptors, such as the Hydroxy-Carboxylic Acid Receptor (HCA2R), which is expressed on brain, skin and immune cells, could mitigate such interactions.
In this ongoing study, we investigate cytokine expression profiles and neuroinflammation in HCA2R deficient mice (HCA2-/- mice), with and without a chronic skin treatment with the hapten DNFB (1-fluoro-2,4-dinitrobenzene) that leads to an AD-like skin inflammation.
Gene expression analysis of cytokines and microglia markers by qPCR revealed increased levels of IFNg and the IFNg-dependent chemokine CCl8 in the hippocampus of wildtype mice. Such a proinflammatory response was further elevated in HCA2-/- mice.
Moreover, inflammation-naïve HCA2-/- mice displayed enhanced expression levels of IL4 in the dorsal hippocampus and an increased immunhistochemical density of the microglia marker Iba1 in sublayers of this brain region A first assessment of emotion-related behavior in tn HCA2-/- mice revealed altered anxiety-like behavior and generalized tone-dependent fear memory in these m animals.
Together, our first results indicate a modulation of proinflammatory responses to peripheral skin stimuli by the HCA2 receptors. HCA2 receptor deficiency may lead to altered glial function, thereby affecting inflammatory responses in brain areas important for emotion and memory. Ultimately, the HCA2 receptor may provide an interesting target for treatment options of anxiety-related co-morbidities of skin inflammations.

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Orexinergic neurons are potent mediators of circadian fluctuation in cognitive function. In the proposed
project, we aim to explore the potential of orexinergic neuromodulation and the associated wakefulness
promoting system to mobilise neural resources by stimulating prefrontal cortex (PFC)-tohippocampus
signalling and to build up resources through increasing neural plasticity in the hippocampus.
We will impose circadian disturbances together with pharmacological and viral interventions
to dissect the circuit mechanisms that underlie the circadian neuromodulation of memory formation,
pattern recognition and cognitive flexibility. Engram labelling, slice physiology and molecular analysis
will be utilised to determine the cellular mechanisms of resource formation within hippocampal microcircuits.
Our project will closely connect with other CRC projects that target cellular and circuit mechanism
of resource management and ultimately aims to investigate the potential of orexinergic modulation
for the mobilisation of cognitive reserve beyond circadian modulation. Thus, the interactive approach
within the CRC will provide fundamental insights into neuronal circuits and cellular mechanism
that may be utilised to battle cognitive decline, e.g. during ageing

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In the proposed project, we aim to explore the potential of orexinergic neuromodulation and the associated wakefulness promoting system to mobilize neural resources by stimulating prefrontal cortex (PFC)-to hippocampus signaling and to build up resources through increasing neural plasticity in the hippocampus. To dissect the underlying neuronal mechanisms, we will use behavioral, pharmacological and viral interventions. In close connection to other CRC projects we expect to gain insight in to the neuronal circuits and cellular mechanism that may be utilized to battle cognitive decline.

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This project aims to gain an understanding of the neural circuit functions underlying the impact of early childhood experiences, stress and trauma on the development of post-traumatic stress disorder (PTSD). In a preclinical research approach, neuronal networks and mechanisms are identified that harbor an increased vulnerability to this disease and thus pose a risk to maintaining mental health. With behavioral modelling, imaging analysis of functional circuits and optogenetics, we not only map these comprehensively, but also examine the molecular and cellular factors involved for their suitability as potential new biomarkers for mental disorders. The extensive characterization in this system will allow us to translate our findings directly into the study of human circuit function within the Center for Mental Health

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Autophagy in lysosomes is one of the major pathways for cellular protein degradation. Disturbances in these processes are particularly devastating for neuronal cells, leading to protein accumulation to toxic levels with subsequent functional impairments and neuronal loss. Such processes are involved in the pathogenesis of neurodegenerative diseases and measures to enhance autophagic flux have been, therefore, implicated in counteracting Alzheimer’s and Parkinson’s diseases, for instance. 
However, recent studies demonstrate that autophagy may play a much broader role in the brain’s response to external challenges: while on a cellular level autophagy promotes cytoprotection and the maintenance of synaptic function under stress in vitro, autophagy in vivo is associated with the success of various antidepressive treatments in the context of stress-induced psychopathologies. 
However, the exact mechanisms of autophagy contributions to synapse development and function as well as to stress resilience on a cellular and neuronal network level are not well understood. Therefore, in the current project, we will investigate fundamental molecular and cellular mechanisms of autophagy by utilizing neuronal cell cultures in vitro and their role in an established stress model in vivo. Using different cellular stress models, we set out to analyse molecular mechanisms of autophagy dynamics and their impact on protein translation in vitro. Identified molecular candidates will be then tested for a regulation of the response to stress on a behavioural level in vivo. Thereby, we hope to reveal starting points for a pharmacological treatment of autophagy-dependent diseases of the nervous system.

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Memories for stressful and fear-inducing events are of vital importance for behavioral adaptation to a potentially dangerous environment. However, exaggerated fear memories can develop following the experience of a traumatic stressor and lead to diseases such as post-traumatic stress disorder. Thus, experimental fear conditioning paradigms have been instrumental in resolving fundamental mechanisms of information storage in the nervous system and in studying the development of stress-induced psychopathology.

The dentate gyrus as a gateway to the hippocampal formation plays a critical role in the formation and retrieval of contextual fear memory. Activity and plasticity in the dentate gyrus are modulated by stress and are under control of stress-responsive neural circuits. GABAergic local circuit neurons appear to play a pivotal role in this regulation, controlling information flow and excitability in the dentate gyrus in a stress-dependent manner.
In the proposed project we aim to determine how two populations of GABAergic interneurons and their associated neuropeptides, neuropeptide Y and cholecystokinin, control adaptive and maladaptive fear memory formation. In specific pre-experiments to this project we found that stress exposure induces lasting expression alterations in these two neuropeptides, which are not only markers for distinct populations of interneurons but themselves act as potent modifiers of anxiety state.
We will therefore utilize an established animal model of juvenile stress-induced pathological fear in combination with a novel behavioral profiling approach to determine how individual fear levels relate to the expression and function of neuropeptide Y and cholecystokinin in the dentate gyrus. The partners in this project combine their expertise in the analysis of molecular and physiological mechanisms of fear in order to delineate and functionally characterize the interneuron circuits that utilize these peptides and their recruitment by different stress experiences. We will determine how psychological parameters, in particular of controllability as a predisposing factor for maladaptive fear memory, act on local circuit components and may lead to pathology or lasting adaptation. Activation mechanisms acting on these interneuron populations will be examined with high resolution profiling of receptor expression and through amygdala priming experiments that we have previously shown to simulate stress-related modification of dentate gyrus activity and plasticity. Finally, we will recruit specific and selective molecular intervention tools to examine the function of those neuropeptides in the local circuitry and their control of fear behavior and fear memory.
We expect that this interdisciplinary study will yield critical understanding of the neural mechanisms of fear adaptation, the individual vulnerability to stress and stress-related psychopathology.

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The project uses biochemical analysis and functional morphology to investigate the intestinal and systemic adaptation of the organism to toxin exposure in the diet on an interdisciplinary basis. Since the mechanism of action of the mycotoxin deoxinivalenol is unclear, the function of the organism after toxin administration is also analyzed under the stress of an inflammatory stimulus by LPS.
This text was translated with DeepL on 27/03/2026

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The use of antibiotics in pigs is still widespread and is used to control enteric infectious diseases. This practice can spread antibiotic resistance in the agricultural sector and pose a threat to consumer health. PiGutNet will establish the first european network to address this issue, with specialists in all areas of research. the network coordinates databases and designs innovative tools to define the status of enteric eubiosis in pigs. The main outputs are genome/metabolome-wide association studies and the provision of a roadmap to increase pig resistance to Git infections, leading to improved animal health and welfare, consumer protection and competitive advantage for European agriculture.

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Tierhaltung erfolgt normalerweise nicht unter spezifiziert-pathogenfreien Bedingungen (SPF). Das Verbot von Antibiotika im Tierfutter (sog. Leistungsförderer), das die Europäische Union durchgesetzt hat, führt dazu, dass junge Schweine in der Aufzucht einer großen Anzahl von Bakterien ausgesetzt sind. Durch diese natürlichen Bedingungen muss sich der Organismus an die Umwelt anpassen und seine eigenen Abwehrmechanismen und eine effektive Darmfunktion entwickeln. Aber auch der Darm selbst reguliert die bakterielle Besiedlung - es kommt zu einer engen Interaktion zwischen Wirt und Darmbakterien - daher auch der Projektname ?Interplay?. Das Projekt wird einerseits die genaue Zusammensetzung der Darmbakterien charakterisieren, andererseits die Regulation des Darmepithels und des Abwehrsystems der Darmwand und des gesamten Organismus untersuchen. Wir wollen verstehen, wie die frühe Besiedlung des Darmes durch Bakterien die Gesamtentwicklung des Tieres beeinflusst und erwarten, dass bei genauer Kenntnis dieser Prozesse eine nachhaltige Tierhaltung ermöglicht wird.

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Throughout Europe it is normal commercial practice that pigs are weaned at an age much less than that which occurs in the wild. This causes gastrointestinal disturbances and an increased susceptibility to infection, resulting in large economic losses to the pig industry. Whilst it is clear that many interacting factors may play a role in the increased susceptibility to infection current methods of control rely on the very wide use of antibiotics. The aim of these proposals is to examine the potential of using plant extracts and other natural substances, not considered harmful for human or animal health, as alternatives to antimicrobials in reducing losses from post-weaning infection, and improving productivity. Experimental approaches shown to modify gut health will be characterised in detail with respect to their mode of action and effect on the host immune system and gut function. The Magdeburg contribution includes morphological and functional studies to analyse intestinal immune functions after application of the test substances.

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In dem Projekt wird mittels biochemischer Analytik und funktioneller Morphologie die intestinale und systemische Anpassung des Organismus an eine Toxinbelastung in der Nahrung interdisziplinär untersucht.

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In dem Projekt werden die Dendritische Zellen im Immunsystem des Schweines als Zielstruktur für Antigenstimulation phänotypisch und funktionell charakterisiert.

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