Center for Behavioral Brain Sciences

Schizophrenia encompasses positive, negative, and cognitive symptoms, and accumulating evidence suggests that the orexin system may modulate circuits relevant to these domains. Here, we investigated whether orexin-related interventions influence schizophrenia-like behaviors induced by the NMDA receptor antagonist dizocilpine in female and male mice. Two distinct approaches were used: nasal orexin A administration and chemogenetic activation of orexin neurons via DREADDs. Behavioral assessments included prepulse inhibition (PPI), locomotion and exploratory activity in the open field, social behavior, and working memory in the Y-maze. Overall, dizocilpine robustly induced schizophrenia-like phenotypes across these paradigms. Nasal orexin A exacerbated the dizocilpine-induced PPI deficit but attenuated the associated increase in startle reactivity, did not modify dizocilpine-induced hyperactivity, and partially rescued working memory impairments. Chemogenetic activation reproduced the PPI pattern observed with nasal orexin A, increased locomotion in both control- and dizocilpine-treated mice, induced anxiolytic-like effects in the open field, restored exploratory rearing, facilitated social recognition, and fully rescued working memory deficits. In some cases, the effects of these orexin-related interventions were differently pronounced in the two sexes. These findings indicate that activating the orexin system may worsen behavioral endophenotypes related to positive symptoms while alleviating those associated with negative and cognitive symptoms. However, substantial variability across assays, potentially related to the dosing of dizocilpine, orexin A, and CNO, as well as protocol-dependent constraints in some behavioral paradigms, limits definitive interpretation. Nevertheless, the present data reveal novel and domain-specific effects of orexin signaling in schizophrenia-relevant behavioral circuits and highlight the importance of exploring interventions with intermediate efficacy, including newly emerging orexin receptor agonists, to more precisely delineate orexin-dependent mechanisms and their therapeutic potential for negative and cognitive symptom domains.

Animal responses to fear cues are shaped by competing motivations such as hunger, access to mates and safety. In our previous work, wild mice (Apodemus spp.) showed little reaction to non-native predator scents. To test if native predator scents would elicit stronger reactions, we deployed fully enclosed laboratory chambers alongside a highly palatable food and olfactory cues from native foxes and cats and three types of controls, an herbivore scent (deer) and two procedural controls of wet and dry scent probes (the substrate on which we presented the scents) in the field. Despite using ontogenetically and evolutionarily relevant predator scents, mice showed no overt fear responses at any time, and only trivial behavioral differences between treatments. However, response variance was markedly higher for wet and dry controls compared to those exposed to animal-derived scents, suggesting a relatively greater perception of safety in chambers without scents. Collectively, these findings indicate that increased motivation for food and shelter during winter months buffered measurable responses to native predator scents. We conclude that the interpretation of risk sensitive behavior under natural conditions must account for ecological context, including shelter and food resources embedded within experimental assays, as well as seasonal tradeoffs associated with foraging decisions.

Adverse childhood experiences (ACE) have been linked to reduced cognitive functioning in adulthood. This cross-sectional online study refines this picture by including emotional and physical domains of childhood trauma. A total of 262 individuals completed the German version of the Childhood Trauma Questionnaire (CTQ) to operationalize ACE. Sustained attention was measured using the gradual onset Continuous Performance Task (gradCPT). Multivariate linear regressions modeled sustained attention parameters (d', RT, RTCoV, criterion) based on total CTQ score and emotional / physical subscores. Higher CTQ Total Scores predicted lower discrimination performance (d') and increased reaction time variability (RTCoV). No significant effects were found for the emotional and physical trauma subscores. These findings suggest lasting, negative ACE effects on sustained attention in adulthood. Additionally, the fully online design proved to be a reliable method for detecting subtle variations in sustained attention.

This systematic review and meta-analysis aimed to examine the effects of eccentric resistance training (ERT) versus traditional resistance training (TRT) on muscle strength, power, hypertrophy, and functional capacity in healthy older adults. Eleven randomized-controlled-trials were included. Between-group analysis for strength demonstrated a small but significant effect in favour of ERT over TRT (standardized-mean-difference [SMD]=0.27). No significant differences were found for functional capacity (SMD=0.12), muscle power (SMD=0.20), or hypertrophy (SMD=-0.03). Within-group analyses for ERT indicated large, significant effects for strength (SMD=0.96) and functional capacity (SMD=1.09) with no significant effects for power and hypertrophy. For TRT, large and moderate significant effects were found for functional capacity (SMD=0.94) and strength (SMD=0.59), respectively, with no significant effects for power and hypertrophy. Meta-regression analysis indicated that longer intervention durations were approaching-significance in their association with greater muscle strength gains with ERT than TRT (p = 0.09). With ERT, increasing age was significantly associated with greater muscle power gains (p = 0.04) and more sessions were approaching-significance in their association with hypertrophy (p = 0.08). Regarding TRT, a higher proportion of female participants was approaching-significance in its association with greater functional capacity gains (p = 0.09). In summary, ERT yields slightly greater muscle strength gains than TRT in older adults, while both produced comparable effects on functional capacity, muscle power, and hypertrophy. The two training modalities elicit moderate-to-large within-group improvements in strength and functional capacity but not in power or hypertrophy. ERT outcomes appear to be moderated by training duration, session number, and age, whereas TRT effects relate to female proportion. Overall, both modalities are effective for older adults, with a slight strength advantage for ERT.

BackgroundPupil dilation (PD) is an indirect and non‐exclusive marker of firing of the noradrenergic locus coeruleus (LC‐NA) system. The LC‐NA system undergoes both structural and functional decline in healthy and pathological aging. PD is known to increase with cognitive load or effort as well as an increased allocation of attentional resources. Findings on age‐related differences are mixed, with some evidence showing greater or more sustained pupil responses in older adults with increasing cognitive load, possibly reflecting compensatory mechanisms, while others show reduced or blunted responses. This study aimed to investigate whether changes in pupil size are associated with task‐dependent variations in performance in older and younger adults.Method40 healthy younger adults (20‐30 years old) and 27 healthy older adults (60‐75 years old) completed three experimental tasks during eye‐tracking recordings. The tasks assessed different types of cognitive abilities and employed cube structure stimuli with varying levels of difficulty: a) a mental rotation tasks with varying levels of angle disparity; b) a perceptual decision task with varying levels of stimulus sizes; c) a working memory tasks with varying levels of memory load.ResultIn both groups, behavioural performance was modulated by task difficulty with higher accuracy and faster responses in easier as compared to difficult conditions in all the tasks. Across all three tasks, older adults were slower and committed more errors than younger adults. Interestingly, age‐related differences in pupil dilation were detected only in the working memory task, where older participants showed greater pupil responses than younger participants. Furthermore, in the working memory tasks, pupil dilation was larger in difficult conditions.ConclusionOur findings suggest that pupil dilation is not a general marker of cognitive effort but can be specifically sensitive to memory load. Moreover, the results are in line with the idea that larger PD may reflect age‐related compensatory mechanisms, occurring in a task‐specific fashion. In conclusion, the study offers novel hypotheses on the role of the LC‐NA system in cognitive function and its decline.

BackgroundAlzheimer's Disease (AD) pathology accumulates early in the medial temporal lobe (MTL), crucial for spatial navigation. As spatial navigation is among the first cognitive functions affected by AD, it may benefit from targeted behavioral interventions. We investigated the potential of a novel smartphone‐assisted real‐world wayfinding training, tailored for healthy older adults, to improve their spatial abilities and explored associations with hippocampal vascularization and AD biomarkers.Method38 cognitively healthy older adults (62–84 years; 18 females) participated in a 3‐week navigation training, using our smartphone application “Explore” (Figure 1). Training involved finding several locations displayed on a map in the medical campus area of Magdeburg, Germany, while GPS data were recorded. Pre‐ and post‐training, participants underwent fMRI, performed a pointing task in a virtual campus version, and completed the VWLT. At pre‐assessment, AD pathology was characterized by plasma sampling (Abeta1‐42/1‐40, Ptau217) and [18F]PI‐2620 PET in a subsample. Hippocampal vascularization was assessed by 7T angiography. Performance in the virtual pointing task and a map drawing test was compared to a control group (n = 20) who performed a walking task of equal length without a navigational component. Additionally, changes in different mobile wayfinding performance indicators and their associations with AD biomarkers and hippocampal vascularization (i.e., mean distance of hippocampus to surrounding vessels) were examined.ResultPerformance in the pointing task and map drawing, but not in the VWLT (p = .321), significantly improved due to the training (all p < .001; Figure 2A C). The control group showed no improvements in navigation. Training benefits were also evident in the mobile data (all p ≤.017; Figure 3A‐E). Better wayfinding efficiency was associated with less vessel distance to hippocampus, r=.44, p = .012, and the number of orientation stops was negatively related to pTau217, r=‐.38, p = .019 (Figure 3F).ConclusionWe provide evidence that a remotely administered real‐world wayfinding training enhances wayfinding abilities and improves spatial memory in older adults. Importantly, hippocampal vascularization may benefit wayfinding efficiency. Higher pTau217 was related to fewer orientation stops during navigation. As a next step, potential mediating effects between vascularization and AD pathology on wayfinding performance will be investigated.

The brain’s perineuronal extracellular matrix (ECM) is a crucial factor in maintaining the stability of mature brain circuitry. However, how activity-induced synaptic plasticity is achieved in the adult brain with a dense ECM is unclear. We hypothesized that neuronal activity induces cleavage of ECM, creating conditions for synaptic rearrangements. To test this hypothesis, we investigated neuronal activity-dependent proteolytic cleavage of brevican, a prototypical ECM proteoglycan, and the importance of this process for functional and structural synaptic plasticity in the rat hippocampus ex vivo. Our findings reveal that chemical long-term potentiation (cLTP) triggers rapid brevican cleavage in perisynaptic regions through the activation of an extracellular proteolytic cascade involving proprotein convertases and ADAMTS-4 and ADAMTS-5. This process requires NMDA receptor activation and involves astrocytes. Interfering with cLTP-induced brevican cleavage prevents the formation of new dendritic protrusions in CA1 but does not impact LTP induction by theta-burst stimulation of CA3-CA1 synapses. Our data reveal a mechanism of activity-dependent ECM remodeling and suggest that ECM degradation is essential for structural synaptic plasticity.

BackgroundFragile X syndrome (FXS) is the most common inherited intellectual disability, caused by the loss of fragile X mental retardation protein (FMRP), which regulates neuronal signaling and plasticity. FXS patients and Fmr1 knockout (KO) mice exhibit sensory hypersensitivity, hyperarousal, and hippocampus-dependent learning deficits. Dysregulated metabotropic glutamate receptor (mGluR) and muscarinic acetylcholine receptor (mAChR) signaling, along with reduced kainate receptor (KAR) function, have been implicated in FXS pathophysiology. Activation of these signaling pathways induce gamma-frequency network oscillations hippocampal slices in vitro. However, their specific contribution to aberrant gamma oscillations in FXS remains unclear.MethodsWe recorded local field potential (LFP) gamma oscillations in vitro in hippocampal CA3 from wild-type (WT) and Fmr1 KO mice. Oscillations were induced pharmacologically using carbachol (CCh), the group I mGluR agonist dihydroxyphenylglycine (DHPG), or kainate (KA). In addition, we quantified synaptic protein expression of mAChR M1, mGluR1, mGluR5, GluK1, and GluK2-receptors involved in gamma oscillation generation under these conditions.ResultsFmr1 KO slices exhibited increased integrated gamma power (20–80 Hz) in response to DHPG and CCh, suggesting higher network synchronization through mGluR and mAChR pathways. In contrast, KA-induced oscillations showed reduced synchrony and gamma peak power, indicating disrupted network coordination. Aberrant spiking activity during both CCh- and KA-induced oscillations further supports impaired temporal coordination in Fmr1 KO mice. These physiological changes were only partially reflected by altered expression of the corresponding receptor proteins.LimitationsIn the current study, we found aberrant gamma oscillation power in in vitro hippocampal slices of Fmr1 KO mice. It remains to be determined whether these oscillatory changes extend to pharmacologically induced gamma oscillations in cortical slice preparations in vitro.ConclusionsOur findings demonstrate that hippocampal gamma oscillations are differentially affected by distinct neuromodulatory pathways in Fmr1 KO mice. Enhanced responsiveness to cholinergic and mGluR activation and reduced coherence of KA-induced rhythms suggest that multiple dysregulated mechanisms contribute to gamma oscillopathies in FXS.Supplementary informationThe online version contains supplementary material available at 10.1186/s13229-025-00687-9.