Biology subjects

Lessmann, V.

Publications and source records attributed to Lessmann, V..

4 recordsLinked to original sources

bioRxiv2026

Ferulic acid eicosyl ester enhances cognitive flexibility and modulates arousal-related neural circuits in mice

Cognitive deficits are a major contributor to disability in numerous neuropsychiatric and neurodegenerative disorders, yet effective pharmacological treatments remain limited. Ferulic acid eicosyl ester (FAE-20), a natural constituent of the plant Rhodiola rosea, has previously been identified as an enhancer of simple forms of Pavlovian conditioning in flies, bees, and mice. Here, we investigated whether FAE-20 has further potential to enhance cognitive flexibility, working memory, or spatial learning in mice, and explored potential neurobiological mechanisms underlying such enhancement. Cognitive flexibility was assessed using the attentional set-shifting task (ASST). Subchronic FAE-20 treatment significantly improved ASST performance in both male and female young adult mice, indicating enhanced cognitive flexibility. In contrast, no effects were observed on spatial working memory, assessed by spontaneous alternations in the Y-maze, or on spatial learning in the Barnes maze in either young or aged mice. Notably, FAE-20 enabled spatial learning in the Barnes maze in a subgroup of aged mice that failed to learn the task under vehicle treatment. Histological analyses using c-Fos immunohistochemistry as a marker of neural activity and doublecortin expression and spine density as markers of hippocampal plasticity revealed sex-specific effects on components of the ascending arousal system. FAE-20 increased the activation of orexinergic neurons in the lateral hypothalamus of male mice, whereas it reduced the activity of cholinergic neurons in the laterodorsal tegmental nucleus of females. No effects were detected on hippocampal neurogenesis or dendritic spine density. These findings suggest that the cognitive effects of FAE-20 are selective, depending on the cognitive demands of the task and the baseline cognitive abilities of the animals, and may be mediated, at least in part, by modulation of arousal-related neural circuits. HighlightsO_LIFAE-20 enhanced cognitive flexibility in young adult mice C_LIO_LIEffects of FAE-20 were strongest in demanding cognitive tasks C_LIO_LIAged poor learners benefited from FAE-20 treatment C_LIO_LIFAE-20 activated hypothalamic orexin neurons in male mice C_LIO_LIFAE-20 modulated ascending arousal systems in a sex-specific manner C_LI

neuroscience↗

bioRxiv2026

The S1PR modulator Ozanimod reverses spine deficits, Amyloid-β plaques deposition and neuroinflammation in aged APP/PS1 mice

Innovative therapeutic approaches providing clinically effective medication for Alzheimers disease (AD) patients are urgently needed. In recent years, monoclonal antibodies against Amyloid-{beta} (A{beta}) oligomers were approved as the first disease modifying AD therapies. However, their effects on cognitive decline of AD patients are still limited - most likely because neuroinflammatory processes downstream of A{beta} plaques remain activated, even when plaques are depleted. Accordingly, anti-inflammatory drugs are currently considered as valuable (co-)treatments to target A{beta} associated neuro-inflammation. The anti-inflammatory sphingosine-1-phosphate receptor (S1PR) modulator fingolimod (FTY720) has been shown to alleviate synaptic and cognitive deficits in numerous mouse models of AD. Whether other S1PR modulators exert similar beneficial effects is largely unknown. Here we used a transgenic APP/PS1 AD mouse model to investigate whether the S1PR modulator Ozanimod (RPC1063) can rescue AD pathology and synaptic dysfunctions even when treatment is initiated at 16-17 months of age, which is 10 months after onset of cognitive deficits. We performed quantitative dendritic spine analysis in hippocampal CA1 pyramidal neurons and immunohistochemical labelling of Iba1-positive activated microglia, GFAP-positive reactive astrocytes, and A{beta} plaques in hippocampus and neocortex. Our results reveal that 6 weeks of Ozanimod treatment via drinking water rescues synaptic spine deficits, counteracts A{beta} pathology and reduces neuro-inflammation in the hippocampus and neocortex of APP/PS1 mice. Therefore, it might hold promise to examine a potential disease-modifying effect of S1PR modulators in clinical trials with AD patients.

neuroscience↗

bioRxiv2019

Anti-inflammatory treatment with FTY720 starting after onset of symptoms reverses synaptic and memory deficits in an AD mouse model

Therapeutical approaches providing effective medication for Alzheimers disease (AD) patients after disease onset are urgently needed. Repurposing FDA approved drugs like fingolimod (FTY720) for treatment of AD is a promising way to reduce the time to bring such medication into clinical practice. Previous studies in AD mouse models suggested that physical exercise or changed lifestyle can delay AD related synaptic and memory dysfunctions when treatment started in juvenile animals long before onset of disease symptoms. Here, we addressed whether the FDA approved drug fingolimod rescues AD related synaptic deficits and memory dysfunction in an APP/PS1 AD mouse model when medication starts after onset of symptoms (at 5 months). Male mice received intraperitoneal injections of fingolimod for 1-2 months starting at 5-6 months. This treatment rescued spine density as well as long-term potentiation in hippocampal CA1 pyramidal neurons, and ameliorated dysfunctional hippocampus-dependent memory that was observed in untreated APP/PS1 animals at 6-7 months of age. Immunohistochemical analysis with markers of microgliosis (Iba1) and astrogliosis (GFAP) revealed that our fingolimod treatment regime strongly down regulated neuro-inflammation in the hippocampus and cortex of this AD model. These effects were accompanied by a moderate reduction of A{beta} accumulation in hippocampus and cortex. Our results suggest that fingolimod, when applied after onset of disease symptoms in an APP/PS1 mouse model, rescues synaptic pathology and related memory performance deficits observed in untreated AD mice, and that this beneficial effect is mediated via anti-neuroinflammatory actions of the drug on microglia and astrocytes.

neuroscience↗

bioRxiv2019

Calcium-permeable AMPA receptors mediate timing-dependent LTP elicited by six coincident action potentials at Schaffer collateral-CA1 synapses

High-frequency stimulation induced long-term potentiation (LTP), or low frequency stimulation induced LTD are considered as cellular models of memory formation. Interestingly, spike timing-dependent plasticity (STDP) can induce equally robust timing-dependent LTP (t-LTP) and t-LTD in response to low frequency repeats of coincident action potential (AP) firing in presynaptic and postsynaptic cells. Commonly, STDP paradigms relying on 25-100 repeats of coincident AP firing are used to elicit t-LTP or t-LTD, but the minimum number of repeats required for successful STDP is barely explored. However, systematic investigation of physiologically relevant low repeat STDP paradigms is of utmost importance to explain learning mechanisms in vivo. Here, we examined low repeat STDP at Schaffer collateral-CA1 synapses by pairing one presynaptic AP with either one postsynaptic AP (1:1 t-LTP), or a burst of 4 APs (1:4 t-LTP) and found 3-6 repeats to be sufficient to elicit t-LTP. 6x 1:1 t-LTP required postsynaptic Ca2+ influx via NMDARs and L-type VGCCs and was mediated by increased presynaptic glutamate release. In contrast, 1:4 t-LTP depended on postsynaptic metabotropic GluRs and ryanodine receptor signaling, and was mediated by postsynaptic insertion of AMPA receptors. Unexpectedly, both 6x t-LTP variants were strictly dependent on activation of postsynaptic Ca2+-permeable AMPARs but were differentially regulated by dopamine receptor signaling. Our data show that synaptic changes induced by only 3-6 repeats of mild STDP stimulation occurring in [≤] 10 s can take place on time scales observed also during single trial learning.

neuroscience↗