Biology subjects

Steffen, J.

Publications and source records attributed to Steffen, J..

11 recordsLinked to original sources

bioRxiv2026

Reduced planning depth and stronger probability discounting in alcohol and tobacco use disorder

Background: Substance use disorders (SUDs) are associated with impaired goal-directed decision-making, but the specific cognitive mechanisms underlying these deficits remain unclear. Forward planning, a key component of goal-directed control, requires strategies to contain computational demand and ensure feasibility through heuristics such as reducing planning depth, pruning unlikely options, and discounting probabilistic outcomes. This study investigated whether individuals with alcohol use disorder (AUD) and tobacco use disorder (TUD) differ from healthy controls in their use of these heuristics during sequential decision-making. Methods: We examined participants from the general population meeting criteria for at least moderate AUD (n = 45), TUD (n = 49), or both (n = 45), and compared them with matched healthy control groups. To assess forward planning, we used a previously published probabilistic three-step Markov decision task. Computational modeling was used to infer individual planning depths and compare model variants incorporating low-probability pruning, probability discounting, or both. Results: A combined model including both low-probability pruning and probability discounting best explained participants' behavior and was subsequently used for analysis. Compared to matched healthy controls, all groups with SUD exhibited significantly reduced planning depth. Moreover, individuals with SUD tended to show stronger probability discounting, with this effect reaching statistical significance in the comorbid group. Conclusion: Individuals with AUD and/or TUD engaged in forward planning using similar strategies as healthy controls but exhibited reduced planning depth and a tendency toward stronger probability discounting. These findings suggest the presence of altered planning processes in SUD, which could contribute to maladaptive decision-making. Future research is needed to clarify whether such differences reflect pre-existing cognitive traits, consequences of substance use, or both, and to explore their potential relevance for intervention.

neuroscience↗

bioRxiv2026

Dynamin-2 promotes Atg9A retrieval from phagophores during autophagy.

Autophagy involves the rapid growth of phagophores through membrane addition. This growth is triggered by vesicles containing the Atg9A protein. However, Atg9A is not incorporated into mature autophagosomes. We now demonstrate that Dynamin-2 (Dnm2) colocalizes with the BAR domain protein Endophilin-B1 (EndoB1/Bif-1/SH3GLB1) and other autophagy proteins when autophagy is induced. Our data suggest that Atg9A is retrieved from phagophores via fission, with Dnm2 acting as the membrane scission protein. Blocking Atg9A recycling, either by mutating Dnm2, using RNA interference, or applying chemical inhibitors, results in Atg9A remaining in autophagosomes and being degraded during autophagy. Overall, these findings provide new insights into the roles of membrane-scission proteins in autophagy.

cell biology↗

bioRxiv2024

Deficiency of actin depolymerizing factors ADF/Cfl1 in microglia decreases motility and impairs memory

Microglia are highly motile cells that play a crucial role in the central nervous system in health and disease. Here we show that actin depolymerizing factors ADF and Cofilin1 (Cfl1) are key factors of microglia integrity and function. We found a profound morphological phenotype in absence of ADF and Cfl1 in microglia. In vivo two-photon imaging of microglia with ADF/Cfl1-KO revealed reduced microglial fine processes motility and impaired microglia migration towards a laser-induced lesion. We found increased accumulation of stabilized F-actin and altered microtubule dynamics in ADF/Cfl1-KO microglia, indicating that ADF/Cfl1 are necessary for microglial cytoskeleton dynamics. Interestingly, microglial ADF/Cfl1-deficiency decreased learning and memory, suggesting that impaired microglial cytoskeleton dynamics affect neuronal functions relevant for cognition. Our results reveal a fundamental role of ADF/Cfl1 in microglia function and underscore the importance of these innate immune cells for higher cognitive functions.

neuroscience↗

bioRxiv2024

CX3CR1 modulates migration of resident microglia towards brain injury

Microglia are innate immune cells of the central nervous system (CNS). They extend their processes towards and migrate towards injuries in vivo. However, whether the fractalkine receptor (CX3CR1) influences microglial migration remains unknown. Label-free proteomic profiling predicted changes in RHO-signaling activity that hint at dysregulated cytoskeleton signaling in Cx3cr1-deficient murine cortex tissue. To further investigate microglial migration, we carried out 4-hour interval two-photon in vivo imaging for 72 hours after a laser lesion in the cortex. Cx3cr1-deficient microglia showed enhanced migration towards the lesion. Additionally, length and velocity of microglial fine processes extending towards the lesion were increased in Cx3cr1-deficient microglia. Migration remained unchanged in Ccr2-deficient mice, indicating that monocyte-derived macrophages/microglia did not contribute to microglia accumulation around the lesion. These results demonstrate microglia migration towards CNS injury and suggest CX3CR1 as a modulator of this. Manipulating microglia migration via CX3CR1 therefore is a potential target for treatment of CNS-injury.

neuroscience↗

bioRxiv2022

Forward planning under uncertainty in a population-based alcohol use disorder sample

BackgroundEtiological theories of addictive behavior postulate a key role for decision-making mechanisms. However, current research is lacking clear computational models for decision-making in multi-step forward planning scenarios to identify underlying mechanisms and make derived hypotheses testable. MethodsWe used a recently developed planning task and computational model to investigate performance, planning time and inferred forward planning parameters like planning depth and decision noise in 30 individuals diagnosed with mostly mild-to-moderate alcohol use disorder (AUD) relative to 32 healthy control participants, both sampled from the general population. ResultsContrary to our hypothesis, we did not observe reduced planning depth in participants with AUD but found that participants with AUD showed a higher performance in the planning task. Group differences could be explained by planning time and general cognitive performance. Importantly, participants with AUD invested more time for planning, showed a higher correlation of planning depth with incentive value and showed lower response noise, potentially indicative of higher choice consistency. ConclusionThe significant differences in planning time, moderation of planning depth by incentive value and choice consistency may reflect higher motivation and willingness to exert effort among participants with AUD compared to healthy controls. Overall, our findings do not support the notion that mild-to-moderate alcohol use disorder is associated with impairments in forward planning across multiple steps.

neuroscience↗

bioRxiv2021

Influenza A virus (H1N1) infection induces microglia activation and temporal dysbalance in glutamatergic synaptic transmission.

3.Influenza A virus (IAV) causes respiratory tract disease and is responsible for seasonal and reoccurring epidemics affecting all age groups. Next to typical disease symptoms such as fever and fatigue, IAV infection has been associated with behavioral alterations presumably contributing to the development of major depression. Previous experiments using IAV/H1N1 infection models have shown impaired hippocampal neuronal morphology and cognitive abilities, but the underlying pathways have not been fully described. In this study, we demonstrate that infection with a low dose non-neurotrophic H1N1 strain of IAV causes ample peripheral immune response followed by a temporary blood-brain-barrier disturbance. Although histological examination did not reveal obvious pathological processes in the brains of IAV-infected mice, detailed multidimensional flow cytometric characterization of immune cells uncovered subtle alterations in the activation status of microglia cells. More specifically, we detected an altered expression pattern of major histocompatibility complex class I and II, CD80, and F4/80 accompanied by elevated mRNA levels of CD36, CD68, C1QA, and C3, suggesting evolved synaptic pruning. To closer evaluate how these profound changes affect synaptic balance, we established a highly sensitive multiplex flow cytometry-based approach called Flow Synaptometry. The introduction of this novel technique enabled us to simultaneously quantify the abundance of pre- and postsynapses from distinct brain regions. Our data reveal a significant reduction of VGLUT1 in excitatory presynaptic terminals in the Cortex and Hippocampus, identifying a subtle dysbalance in glutamatergic synapse transmission upon H1N1 infection in mice. In conclusion, our results highlight the consequences of systemic IAV-triggered inflammation on the central nervous system and the induction and progression of neuronal alterations.

immunology↗

bioRxiv2020

Hippocampal hyperactivity in a rat model of Alzheimers disease

Neuronal network dysfunction is a hallmark of Alzheimers disease (AD). However, the underlying pathomechanisms remain unknown. We analyzed the hippocampal micronetwork in a rat model of AD at an early disease stage at the beginning of extracellular amyloid beta (A{beta}) deposition. We established two-photon Ca2+-imaging in vivo in the hippocampus of rats and found hyperactivity of CA1 neurons. Patch-clamp recordings in brain slices in vitro revealed changes in the passive properties and intrinsic excitability of CA1 pyramidal neurons. Furthermore, we observed increased neuronal input resistance and prolonged action potential width in CA1 pyramidal neurons. Surprisingly, all parameters measured to quantify synaptic inhibition and excitation onto CA1 pyramidal neurons were intact suggesting a cell immanent deficit. Our data support the view that altered intrinsic excitability of CA1 neurons may precede inhibitory dysfunction at an early stage of disease progression.

neuroscience↗

bioRxiv2019

Microglia motility depends on neuronal activity andpromotes structural plasticity in the hippocampus

Microglia, the resident immune cells of the brain, play a complex role in health and disease. They actively survey the brain parenchyma by physically interacting with other cells and structurally shaping the brain. Yet, the mechanisms underlying microglia motility and their significance for synapse stability, especially during adulthood, remain widely unresolved. Here we investigated the impact of neuronal activity on microglia motility and its implication for synapse formation and survival. We used repetitive two-photon in vivo imaging in the hippocampus of awake mice to simultaneously study microglia motility and their interaction with synapses. We found that microglia process motility depended on neuronal activity. Simultaneously, more dendritic spines emerged in awake compared to anesthetized mice. Interestingly, microglia contact rates with individual dendritic spines were associated with their stability. These results suggest that microglia are not only sensing neuronal activity, but participate in synaptic rewiring of the hippocampus during adulthood, which has profound relevance for learning and memory processes.

neuroscience↗

bioRxiv2018

Restoring memory by optogenetic synchronization of hippocampal oscillations in an Alzheimer’s disease mouse model

Disrupted neural oscillations are a feature of Alzheimers disease (AD). We observed reduced frequency of theta oscillations in the hippocampal local field potential (LFP) in a mouse model of beta-amyloidosis. By restoring the temporal organization of theta oscillations using LFP-guided closed-loop optogenetic stimulation of parvalbumin-positive interneurons, we could rescue memory deficits of APP/PS1 mice in the novel object recognition test.

neuroscience↗

bioRxiv2018

Memory trace superimposition impairs recall in a mouse model of AD

Learning and memory processes depend on the hippocampus and are impaired in Alzheimers disease (AD). Active neuronal ensembles form an engram by encoding information during learning. Their reactivation is required for memory recall. However, it remains unresolved whether the engram in CA1 principal neurons is impaired under AD-like conditions. We used two-photon in vivo imaging to visualize the expression of the immediate early gene c-fos within CA1 neurons during contextual fear conditioning and retrieval. Surprisingly, we identified engrams in wild-type mice and in the mouse model of AD indicating intact memory formation. However, under AD-like conditions engrams were superimposed by a high number of newly recruited fosGFP+ neurons during memory recall. This superimposition resembled the network configuration of wild-type mice exposed to a novel context. Artificial superimposition of the memory trace during recall in wild-type mice was sufficient to induce memory impairment. Thus, we propose superimposition of the CA1 memory trace as a mechanism for memory impairment in a mouse model of AD.\n\nHighlightsO_LIDecreased fosGFP expression in direct vicinity to amyloid-{beta} plaques\nC_LIO_LIIntact engram in CA1 of APP/PS1 mice\nC_LIO_LIImpurity of the retrieval network in CA1 is sufficient to impair memory recall\nC_LI\n\nPoll et al. present a novel mechanism for memory impairment in a mouse model of AD. The potential memory trace was found intact in the CA1 region of the hippocampus. However, excessive neuronal activity during retrieval, was superimposing the memory trace in a mouse model of AD.

neuroscience↗

bioRxiv2018

Dynamin-2 facilitates Atg9 recycling from nascent autophagosomes

Autophagy involves rapid growth of phagophores through membrane addition. Newly added membranes are derived from other organelles through vesicles carrying the Atg9 protein. Membrane is delivered by fusing these vesicles with the phagophores. Atg9 is, nevertheless, not incorporated in autophagosomes. We now show that this protein is retrieved from phagophores by fission utilizing Dynamin-2 (Dnm2) as the membrane scission protein. Blocking Atg9 recycling by interfering with Dnm2 helps retain Atg9 in autophagosomes and degrades this protein by autophagy. Dnm2 colocalizes with the BAR domain protein Endophilin-B1 (EndoB1/Bif-1) when autophagy is induced, consistent with transient interactions during Atg9 retrieval. EndoB1 and Dnm2 also control the downstream fusion of phagophores to late endosomes, thus ensuring the completion of phagophores before proceeding to the next stage in the autophagy process. These data provide novel insights into the roles of membrane scission proteins during autophagy.

cell biology↗