Paul J. Lucassen

BACKGROUND: Cognitive resilience to Alzheimer’s disease (AD) can be modelled in amyloid-expressing rodents through early handling (EH). This study investigated how EH and sex affect cognition and pathology over time. METHODS: We assessed cognition (open field, object recognition test, Barnes maze) in 6- and 12-month-old APP/PS1 and WT mice (N=180, EH/Ctrl×M/F), performed biochemical and histological analyses of several brain areas to assess effects on Aβ, glial cells, and other markers of pathology, and investigated how behavior correlates with pathology. RESULTS: EH improved non-spatial memory at 6 months, consistent with a reduction of hippocampal microglia density, and normalized locomotor activity at 12 months (both p<0.05). Females demonstrated similar (6 & 12 months) or better (12 months) cognition, despite greater pathology across timepoints. Correlations implicated microglial recruitment in EH-related effects, supported by morphological analysis of prefrontal regions (p<0.05). CONCLUSION: Our findings highlight the critical role of early postnatal experiences and sex in shaping resilience in the context of AD pathology.

Regular physical activity promotes brain health, yet the underlying mechanisms remain incompletely understood. Repetitive activation of neurons results in accumulation of the transcription factor ΔFOSB, a long-lived splice variant of FOSB. Long-term voluntary wheel running (VWR), a behavioral paradigm that mimics human exercise training, altered brain ΔFOSB immunoreactivity signatures and reorganized coactivation networks in Wistar rats. Here, we used a similar approach to determine large-scale ΔFOSB brain signatures following long-term VWR in mice. Young-adult individually housed male and female C57BL/6J ^OlaHsd mice were allowed to run for 4 weeks on horizontal saucer-like wheels, after which ΔFOSB immunoreactivity was quantified in 46 brain regions associated with stress regulation and cognition- and reward-related behavior. Network analysis was applied to assess VWR-mediated changes in interregional ΔFOSB coactivation patterns and network topology. Male and female mice ran equal distances, and VWR blunted body weight gain and terminal gonadal white adipose tissue mass in both sexes. VWR modulated ΔFOSB immunoreactivity across several cortical, striatal, hippocampal, and thalamic regions. Network analysis revealed substantial network reorganizations, with reduced overall network density and increased cortical centrality in males, and greater global efficiency (i.e., small-worldness) in females. Thus, VWR induced large-scale adaptations in brain (in)activation, reshaping network organization in distinct ways in both sexes. Because ΔFOSB regulates many target genes, impacting, e.g., neuron excitability, our findings suggest that long-term VWR induces widespread transcriptional alterations throughout the mouse brain. Functional and mechanistic follow-up studies are necessary to determine the impact of these alterations on stress regulation and cognition- and reward-related behavior.

Neurodegenerative disorders impose a major burden on patients and their families worldwide, and finding effective ways to treat or prevent these disorders

Exercise training promotes brain health, yet the underlying mechanisms remain unclear. ∆FOSB, a transcription factor involved in neuroplasticity, stress-, cognition- and reward-related behavior, accumulates in response to repetitive neuronal stimulation due to its unusual protein stability and can thus serve as a proxy for chronic neuronal activation. This study employed voluntary wheel running (VWR), an animal model for exercise training, in male and female Wistar rats to quantify VWR-induction of ∆FOSB in 44 brain regions implicated in stress, cognition and reward. Using network analysis, we examined broader patterns of co-activation and changes in network topology (e.g. centrality, small-world-likeness) of this comprehensive map of brain regions. Four weeks of VWR improved metabolic health, independent of sex, and females ran more than males. Notably, semi-automated quantification of ∆FOSB-immunoreactivity revealed VWR regulation of ∆FOSB in several cortical, striatal, hippocampal, hypothalamic and midbrain regions, which was more pronounced in females. VWR altered several parameters of ∆FOSB co-activation networks, decreasing network density while increasing global efficiency in both sexes, and was associated with greater cortical centrality. These findings demonstrate that VWR-mediated chronic neuronal activation extends beyond previously studied brain regions and that habitual VWR shifts hierarchy to more cortical regions. Because ∆FOSB overexpression is associated with lower neuronal excitability, the current ∆FOSB brain atlas and network co-activation dataset extends our understanding of the impact of VWR on brain neuroplasticity and provides a framework for future mechanistic studies into ∆FOSB-mediated changes in neuronal excitability during habitual VWR and subsequent effects on stress-, cognition- and reward-related behavior.

Physical exercise training promotes brain health, yet the underlying mechanisms remain incompletely understood. Repeated neuronal activation results in accumulation of the transcription factor ΔFOSB, a long-lived splice variant of FOSB. We have previously demonstrated in rats that long-term voluntary wheel running (VWR), a behavioral paradigm that mimics exercise training in humans, altered ΔFOSB expression in a brain-wide manner, and that it reorganized co-activation networks. Here, we used a similar approach, now in mice, to map neuronal activation patterns following long-term VWR. Young-adult male and female C57BL/6J ^OlaHsd mice were allowed to run for four weeks on horizontal wheels, after which ΔFOSB immunoreactivity was quantified across 46 brain regions associated with stress regulation, cognition and reward-related behavior. Subsequently, network analysis was applied to assess VWR-mediated changes in patterns of interregional ΔFOSB co-activation and network topology. Male and female mice ran equal distances and VWR blunted bodyweight gain and final fat mass in both sexes. VWR modulated ΔFOSB expression across several cortical, striatal, hippocampal and thalamic regions. Network analysis revealed a sex-specific network reorganization, with reduced overall network density and increased cortical centrality in males, and greater global efficiency ( i.e. small-worldness) in females. Thus, VWR induced large-scale, sex-dependent adaptations in brain (in)activation, reshaping network organization in distinct ways across sexes. Because ΔFOSB regulates many target genes, our findings indicate that long-term VWR induces widespread transcriptional alterations throughout the mouse brain. More focused follow-up studies are required to investigate the impact of these specific alterations on stress regulation, cognition and reward-related behavior. SIGNIFICANCE STATEMENT: Exercise training promotes brain health, but the underlying mechanisms remain elusive. Here, we studied ΔFOSB, a very stable transcription factor involved in neuroplasticity, after four weeks of running in mice. We show this altered ΔFOSB expression in a subset of 46 brain regions implicated in stress regulation, cognition and reward, notably with sex-specific signatures. This was accompanied by specific changes in ΔFOSB co-activation networks, including decreased network density and increased cortical centrality in males, and greater network efficiency in females. Our mouse ΔFOSB brain map following running improves our understanding of how exercise training impacts brain plasticity and offers a framework for more mechanistic future studies into running-mediated changes in stress regulation, cognition and reward-related behavior.

Physical exercise exerts several positive effects on the brain and is emerging as an approach for mitigating age-related functional decline. One benefit of exercise is the increase in adult hippocampal neurogenesis (AHN). However, physical exercise may not always be feasible in individuals due to physical or medical constraints which are more common in older age, highlighting the importance of understanding regulators of exercise-induced AHN. We demonstrate that Rasal1, a GTPase-activating protein, is downregulated in the dentate gyrus (DG) by voluntary running exercise in young adult rats. Middle age is recognised as a period of the lifespan prognostic of cognitive health in older age, and amenable to intervention. Lentiviral knockdown of Rasal1 in the DG promoted AHN and neurite growth in middle-aged rats that were otherwise reluctant to run. Treatment of hippocampal neuroprogenitor cells in vitro with serum from exercising animals mimicked the exercise-induced downregulation of Rasal1 and was associated with neuroprogenitor expansion. Lastly, multi-omic analysis of sera in conjunction with brain proteomics identified possible systemic mediators of Rasal1 downregulation. Taken together, our findings highlight Rasal1 as a novel candidate regulator of the pro-neurogenic effects of exercise. Identifying systemic factors underlying the Rasal1-driven effects of exercise could inform new therapies to enhance AHN and hippocampal function.

Paul Lucassen leads the Brain Plasticity group at the Swammerdam Institute for Life Sciences at the University of Amsterdam. Following his biomedical training, he completed his PhD with Dick Swaab at the Netherlands Institute for Neuroscience in 1995, followed by a postdoc with Ron De Kloet in Leiden, after which he joined Marian Joels at UvA in 1998, where he was appointed full professor in 2011. His Brain Plasticity group aims to understand how our brain adapts to a changing, and often challenging, environment, studying the hippocampus, amygdala, and hypothalamus, brain regions involved in cognition, stress, homeostasis, and in various disorders. Plasticity is approached from the molecular, structural, functional, and behavioural levels, focusing on how brain plasticity is modified by lifestyle factors, including early-life stress, nutrition, inflammation, physical exercise, enriched environment, and psychoactive drugs, and on how plasticity is involved in metabolic and brain disorders such as TBI, depression, and dementia. A key interest is adult neurogenesis, a unique form of structural plasticity in which stem cells continue to produce new neurons in the adult brains of various species, including humans, and are involved in various aspects of brain function. Lucassen's group combines molecular, cellular, and omics analyses with in vitro and rodent models, human brain imaging, human postmortem brain, and cohort studies. He serves as WP co-lead of the Alzheimer consortium MODEM, co-recipient of the Urban Mental Health grant, and the ME/CFS consortium on chronic fatigue, and co-recipient of a Gravitation grant for the Institute for Chemical Neuroscience on molecular mechanisms underlying psychiatric disorders.

The hypothalamic suprachiasmatic nucleus (SCN), the circadian pacemaker of the mammalian brain, integrates both environmental and endogenous information to modulate various physiological and behavioral processes. Both light and physical activity entrain SCN circadian rhythmicity, but the underlying molecular mechanisms for physical activity remain elusive. Repetitive neuronal stimulation results in accumulation of the stable transcription factor ΔFOSB, that has been implicated in long-term brain plasticity, altered neuronal excitability, and changes in behavior. In rodents, voluntary wheel running (VWR) mimics aspects of exercise training and increases ΔFOSB in several brain regions. Whether VWR also alters ΔFOSB in the SCN is unexplored. Here, young-adult male and female Wistar rats were housed sedentary or allowed to run for four weeks followed by quantification of ΔFOSB in the SCN. VWR lowered SCN ΔFOSB-positive cell numbers in males and females compared to sedentary housing. Total running distance did not correlate with ΔFOSB suppression. Analysis taking estrous cycle into account revealed that ΔFOSB-positive cell numbers were cyclic in sedentary females, being lowest during proestrus and highest during diestrus. Remarkably, this cyclicity was absent in runners, where ΔFOSB-positive cell numbers remained comparable to those observed during proestrus in sedentary controls. Finally, estradiol replacement following ovariectomy in sedentary females lowered SCN ΔFOSB-positive cell numbers. Thus, VWR and estrous cycle, via, at least in part, estradiol, modulate SCN ΔFOSB. Given its role in long-term plasticity and behavioral adaptations, ΔFOSB may provide a molecular link between VWR and/or estrous cycle and the output of the SCN and its related behavioral adaptations.

Background Electroconvulsive therapy (ECT) is an effective treatment for major depressive episodes, though its mechanisms remain unclear. Its use is limited due to stigma and possible cognitive side-effects. Repeated magnetic resonance imaging (MRI) could provide further insights into the brain changes associated with ECT’s efficacy and cognitive outcomes. Methods We analyzed prospective longitudinal repeated MRI, cognitive, and efficacy data of depressed ECT-patients. Structural and diffusion tensor imaging (DTI) MRI scans were conducted at baseline, directly after initial ECT-sessions, within two weeks after the course and at three months follow-up. Test-retest effects were controlled by including 26 matched healthy controls (n=26). Linear and nonlinear changes in grey matter (GM) volume, white matter (WM) volume, mean diffusivity (MD) and fractional anisotropy (FA) were assessed. Early brain changes were associated with cognitive and efficacy outcomes. Results After the 3^rd ECT-session (n=19), subcortical GM volumes increased, accompanied by right lateralized decrease of MD in those areas. Two weeks post-ECT (n=30), cortical GM volume increased which returned to baseline after three months. In WM, MD linearly increased post-ECT, without widespread FA changes, and MD did not return to baseline after three months (n=30). ECT decreased verbal learning transiently, letter fluency, and animal category fluency tests (n=23, p_bonferroni = 0.04; n=22, p_bonferroni = 0.04; n=62, p_bonferroni = 0.02). Early brain changes were not associated with cognitive performance or efficacy. Conclusions These results suggest that ECT induces rapid changes in brain microstructure and macrostructure. But while macroscopic increases are temporary, microscopic changes in brain structure are longer-lasting.