Influencing cognitive performance via social interactions: a novel therapeutic approach for brain disorders based on neuroanatomical mapping?

Many psychiatric and neurological disorders present deficits in both the social and cognitive domain. In this perspectives article, we provide an overview and the potential of the existence of an extensive neurobiological substrate underlying the close relationship between these two domains. By mapping the rodent brain regions involved in the social and/or cognitive domain, we show that the vast majority of brain regions involved in the cognitive domain are also involved in the social domain. The identified neuroanatomical overlap has an evolutionary basis, as complex social behavior requires cognitive skills, and aligns with the reported functional interactions of processes underlying cognitive and social performance. Based on the neuroanatomical mapping, recent (pre-)clinical findings, and the evolutionary perspective, we emphasize that the social domain requires more focus as an important treatment target and/or biomarker, especially considering the presently limited treatment strategies for these disorders.

Whole-body vibration ameliorates glial pathological changes in the hippocampus of hAPP transgenic mice, but does not affect plaque load.

BACKGROUND: Alzheimer's disease (AD) is the core cause of dementia in elderly populations. One of the main hallmarks of AD is extracellular amyloid beta (Aß) accumulation (APP-pathology) associated with glial-mediated neuroinflammation. Whole-Body Vibration (WBV) is a passive form of exercise, but its effects on AD pathology are still unknown. METHODS: Five months old male J20 mice (n = 26) and their wild type (WT) littermates (n = 24) were used to investigate the effect of WBV on amyloid pathology and the healthy brain. Both J20 and WT mice underwent WBV on a vibration platform or pseudo vibration treatment. The vibration intervention consisted of 2 WBV sessions of 10 min per day, five days per week for five consecutive weeks. After five weeks of WBV, the balance beam test was used to assess motor performance. Brain tissue was collected to quantify Aß deposition and immunomarkers of astrocytes and microglia. RESULTS: J20 mice have a limited number of plaques at this relatively young age. Amyloid plaque load was not affected by WBV. Microglia activation based on IBA1-immunostaining was significantly increased in the J20 animals compared to the WT littermates, whereas CD68 expression was not significantly altered. WBV treatment was effective to ameliorate microglia activation based on morphology in both J20 and WT animals in the Dentate Gyrus, but not so in the other subregions. Furthermore, GFAP expression based on coverage was reduced in J20 pseudo-treated mice compared to the WT littermates and it was significantly reserved in the J20 WBV vs. pseudo-treated animals. Further, only for the WT animals a tendency of improved motor performance was observed in the WBV group compared to the pseudo vibration group. CONCLUSION: In accordance with the literature, we detected an early plaque load, reduced GFAP expression and increased microglia activity in J20 mice at the age of ~ 6 months. Our findings indicate that WBV has beneficial effects on the early progression of brain pathology. WBV restored, above all, the morphology of GFAP positive astrocytes to the WT level that could be considered the non-pathological and hence "healthy" level. Next experiments need to be performed to determine whether WBV is also affective in J20 mice of older age or other AD mouse models.

Supporting Resilience of Older Adults with Cognitive Decline Requires a Multi-Level System Approach.

The concept of resilience, i.e., the capacity of a system to bounce back after a stressor, is gaining interest across many fields of science, policy, and practice. To date, resilience research in people with cognitive decline has predominantly addressed the early stages of decline. We propose that: (1) resilience is a relevant concept in all stages of cognitive decline; and (2) a socio-ecological, multisystem perspective on resilience is required to advance understanding of, and care and support for people with cognitive decline and their support networks. We substantiate our position with literature and examples. Resilience helps understand differences in response to risk factors of (further) cognitive decline and informs personalised prevention. In a curative context, interventions to strengthen resilience aim to boost recovery from cognitive decline. In care for people with dementia, resilience-focused interventions can strengthen coping mechanisms to maintain functioning and well-being of the individual and their support network. A good example of improving resilience in the social and policy context is the introduction of age-friendly cities and dementia-friendly communities. Good care for people with cognitive decline requires a health and social care system that can adapt to changes in demand. Given the interdependency of resilience at micro-, meso- and macro-levels, an integrative socio-ecological perspective is required. Applying the concept of resilience in the field of cognitive decline opens new horizons for research to improve understanding, predicting, intervening on health and social care needs for the increasing population with cognitive decline.

Elucidating the role of protein synthesis in hippocampus-dependent memory consolidation across the day and night.

It is widely acknowledged that de novo protein synthesis is crucial for the formation and consolidation of long-term memories. While the basal activity of many signaling cascades that modulate protein synthesis fluctuates in a circadian fashion, it is unclear whether the temporal dynamics of protein synthesis-dependent memory consolidation vary depending on the time of day. More specifically, it is unclear whether protein synthesis inhibition affects hippocampus-dependent memory consolidation in rodents differentially across the day (i.e., the inactive phase with an abundance of sleep) and night (i.e., the active phase with little sleep). To address this question, male and female C57Bl6/J mice were trained in a contextual fear conditioning task at the beginning or the end of the light phase. Animals received a single systemic injection with the protein synthesis inhibitor anisomycin or vehicle directly, 4, 8 hr, or 11.5 hr following training, and memory was assessed after 24 hr. Here, we show that protein synthesis inhibition impaired the consolidation of context-fear memories selectively when the protein synthesis inhibitor was administered at the first three time points, irrespective of timing of training. Even though the basal activity of signaling pathways regulating de novo protein synthesis may fluctuate across the 24-hr cycle, these results suggest that the temporal dynamics of protein synthesis-dependent memory consolidation are similar for day-time and night-time learning.

Correlations of blood and brain biochemistry in phenylketonuria: Results from the Pah-enu2 PKU mouse.

BACKGROUND: In phenylketonuria (PKU), treatment monitoring is based on frequent blood phenylalanine (Phe) measurements, as this is the predictor of neurocognitive and behavioural outcome by reflecting brain Phe concentrations and brain biochemical changes. Despite clinical studies describing the relevance of blood Phe to outcome in PKU patients, blood Phe does not explain the variance in neurocognitive and behavioural outcome completely. METHODS: In a PKU mouse model we investigated 1) the relationship between plasma Phe and brain biochemistry (Brain Phe and monoaminergic neurotransmitter concentrations), and 2) whether blood non-Phe Large Neutral Amino Acids (LNAA) would be of additional value to blood Phe concentrations to explain brain biochemistry. To this purpose, we assessed blood amino acid concentrations and brain Phe as well as monoaminergic neurotransmitter levels in in 114 Pah-Enu2 mice on both B6 and BTBR backgrounds using (multiple) linear regression analyses. RESULTS: Plasma Phe concentrations were strongly correlated to brain Phe concentrations, significantly negatively correlated to brain serotonin and norepinephrine concentrations and only weakly correlated to brain dopamine concentrations. From all blood markers, Phe showed the strongest correlation to brain biochemistry in PKU mice. Including non-Phe LNAA concentrations to the multiple regression model, in addition to plasma Phe, did not help explain brain biochemistry. CONCLUSION: This study showed that blood Phe is still the best amino acid predictor of brain biochemistry in PKU. Nevertheless, neurocognitive and behavioural outcome cannot fully be explained by blood or brain Phe concentrations, necessitating a search for other additional parameters. TAKE-HOME MESSAGE: Blood Phe is still the best amino acid predictor of brain biochemistry in PKU. Nevertheless, neurocognitive and behavioural outcome cannot fully be explained by blood or brain Phe concentrations, necessitating a search for other additional parameters.

A brief period of sleep deprivation causes spine loss in the dentate gyrus of mice.

Sleep and sleep loss have a profound impact on hippocampal function, leading to memory impairments. Modifications in the strength of synaptic connections directly influences neuronal communication, which is vital for normal brain function, as well as the processing and storage of information. In a recently published study, we found that as little as five hours of sleep deprivation impaired hippocampus-dependent memory consolidation, which was accompanied by a reduction in dendritic spine numbers in hippocampal area CA1. Surprisingly, loss of sleep did not alter the spine density of CA3 neurons. Although sleep deprivation has been reported to affect the function of the dentate gyrus, it is unclear whether a brief period of sleep deprivation impacts spine density in this region. Here, we investigated the impact of a brief period of sleep deprivation on dendritic structure in the dentate gyrus of the dorsal hippocampus. We found that five hours of sleep loss reduces spine density in the dentate gyrus with a prominent effect on branched spines. Interestingly, the inferior blade of the dentate gyrus seems to be more vulnerable in terms of spine loss than the superior blade. This decrease in spine density predominantly in the inferior blade of the dentate gyrus may contribute to the memory deficits observed after sleep loss, as structural reorganization of synaptic networks in this subregion is fundamental for cognitive processes.

Hippocampal microglia modifications in C57Bl/6 Pahenu2 and BTBR Pahenu2 phenylketonuria (PKU) mice depend on the genetic background, irrespective of disturbed sleep patterns.

Toxic levels of phenylalanine in blood and brain is a characteristic of (untreated) phenylketonuria (PKU), leading to cognitive deficits in PKU mice. In addition, our recent findings showed that PKU mice (as well as PKU patients) have a disturbed sleep/wake cycle. As a consequence, sleep loss may contribute to cognitive deficits in PKU. Sleep loss has been linked to increased activation of microglia in the hippocampus. In this study, we set out to examine morphological features of the microglia population in the hippocampus of the mouse PKU model, using both the C57Bl/6 and the BTBR strain and their wild-type controls (age 5.3 ±â€¯0.5 months; n = 16 per group, both males and females; n = 8 each). Microglial activation is reflected by retraction and thickening of the dendritic branches and an increase in cell body size of a microglial cell. Such morphological changes of microglia were studied by way of immunohistochemical staining for Iba-1, a microglia-specific calcium binding protein. We measured the number of microglia in seven subregions of the dorsal hippocampus. The level of microglial activation was determined, based on the ratio between the soma size and total cell size (soma size plus the area covered by the dendritic branches). Results showed subtle but statistical significant activation of hippocampal microglia in the C57Bl6, but not in the BTBR, PKU mice when compared with their wild-type controls. Also the total number of microglia was higher in the C57Bl/6 PKU (compared to the wild-type) mouse, but not in the BTBR PKU mouse. It is concluded that the C57Bl/6 PKU mouse has mildly higher microglia activity, which may support rather than hamper hippocampal homeostasis. The results further indicate that high levels of phenylalanine or disturbed sleep patterns do not consequently cause hippocampal microglial activation in the PKU mouse. It is currently unknown why the two PKU mouse strains show these differences in number and activation level of their hippocampal microglia, and to what extent it influences hippocampal functioning. Further scrutinizing the role of microglia functioning in the context of PKU is therefore warranted.

Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration.

Despite the recognized role of tumor necrosis factor (TNF) in inflammation and neuronal degeneration, anti-TNF therapeutics failed to treat neurodegenerative diseases. Animal disease models had revealed the antithetic effects of the two TNF receptors (TNFR) in the central nervous system, whereby TNFR1 has been associated with inflammatory degeneration and TNFR2 with neuroprotection. We here show the therapeutic potential of selective inhibition of TNFR1 and activation of TNFR2 by ATROSAB, a TNFR1-selective antagonistic antibody, and EHD2-scTNFR2, an agonistic TNFR2-selective TNF, respectively, in a mouse model of NMDA-induced acute neurodegeneration. Coadministration of either ATROSAB or EHD2-scTNFR2 into the magnocellular nucleus basalis significantly protected cholinergic neurons and their cortical projections against cell death, and reverted the neurodegeneration-associated memory impairment in a passive avoidance paradigm. Simultaneous blocking of TNFR1 and TNFR2 signaling, however, abrogated the therapeutic effect. Our results uncover an essential role of TNFR2 in neuroprotection. Accordingly, the therapeutic activity of ATROSAB is mediated by shifting the balance of the antithetic activity of endogenous TNF toward TNFR2, which appears essential for neuroprotection. Our data also explain earlier results showing that complete blocking of TNF activity by anti-TNF drugs was detrimental rather than protective and argue for the use of next-generation TNFR-selective TNF therapeutics as an effective approach in treating neurodegenerative diseases.

Passive exercise to improve quality of life, activities of daily living, care burden and cognitive functioning in institutionalized older adults with dementia - a randomized controlled trial study protocol.

BACKGROUND: Dementia affects cognitive functioning, physical functioning, activities of daily living (ADLs), and quality of life (QOL). Pharmacological treatments to manage, cure or prevent dementia remain controversial. Therefore development of non-pharmacological approaches to prevent, or at least delay the onset and progression of dementia is urgently needed. Passive exercise is proposed to be such a non-pharmacological alternative. This study primarily aims to investigate the effects of three different forms of passive exercise on QOL and ADLs of institutionalized patients with dementia. The secondary aims are to assess the effects of three different forms of passive exercise on cognitive functioning and physical functioning of institutionalized patients with dementia as well as on care burden of both the primary formal and primary informal caregivers of these patients. METHODS: This is a multicenter randomized controlled trial. Three forms of passive exercise are distinguished; motion simulation (MSim), whole body vibration (WBV), and a combination of both MSim + WBV. Intervention effects are compared to a control group receiving regular care. Institutionalized patients with dementia follow a six-week intervention program consisting of four 4-12 min sessions a week. The primary outcome measures QOL and ADLs and secondary outcome measure care burden are assessed with questionnaires filled in by the primary formal and informal caregivers of the patient. The other secondary outcome measures cognitive and physical functioning are assessed by individual testing. The four groups are compared at baseline, after 6 weeks of intervention, and 2 weeks after the intervention has ended. DISCUSSION: This study will provide insight in the effects of different forms of passive exercise on QOL, ADLs, cognitive and physical functioning and care burden of institutionalized patients with dementia and their primary formal and informal caregivers. The results of this study might support the idea that passive exercise can be an efficient alternative for physical activity for patients not able to be or stay involved in active physical exercise. TRIAL REGISTRATION: The Netherlands National Trial Register ( NTR6290 ). Retrospectively registered 29 March 2017.

Time-place learning over a lifetime: absence of memory loss in trained old mice.

Time-place learning (TPL) offers the possibility to study the functional interaction between cognition and the circadian system with aging. With TPL, animals link biological significant events with the location and the time of day. This what-where-when type of memory provides animals with an experience-based daily schedule. Mice were tested for TPL five times throughout their lifespan and showed (re)learning from below chance level at the age of 4, 7, 12, and 18 mo. In contrast, at the age of 22 mo these mice showed preservation of TPL memory (absence of memory loss), together with deficiencies in the ability to update time-of-day information. Conversely, the majority of untrained (naïve) mice at 17 mo of age were unable to acquire TPL, indicating that training had delayed TPL deficiencies in the mice trained over lifespan. Two out of seven naïve mice, however, compensated for correct performance loss by adapting an alternative learning strategy that is independent of the age-deteriorating circadian system and presumably less cognitively demanding. Together, these data show the age-sensitivity of TPL, and the positive effects of repeated training over a lifetime. In addition, these data shed new light on aging-related loss of behavioral flexibility to update time-of-day information.

BH4 treatment in BH4-responsive PKU patients: preliminary data on blood prolactin concentrations suggest increased cerebral dopamine concentrations.

In phenylketonuria (PKU), cerebral neurotransmitter deficiencies have been suggested to contribute to brain dysfunction. Present treatment aims to reduce blood phenylalanine concentrations by a phenylalanine-restricted diet, while in some patients blood phenylalanine concentrations also respond to cofactor treatment with tetrahydrobiopterin (BH4). Recently, a repurposing approach of BH4 was suggested to increase cerebral neurotransmitter synthesis. To investigate whether BH4 may improve cerebral dopamine concentrations in PKU patients beyond its effect through lowering blood phenylalanine concentrations, we investigated blood prolactin concentrations-as a parameter of brain dopamine availability. We retrospectively compared blood prolactin in relation to blood phenylalanine concentrations of nine (male) BH4-responsive PKU patients, when being treated without and with BH4. Blood prolactin concentrations positively correlated to blood phenylalanine concentrations (p=0.002), being significantly lower with than without BH4 treatment (p=0.047). In addition, even in this small number of male patients, blood prolactin concentrations tended to be lower at increasing BH4 dose (p=0.054), while taking blood phenylalanine concentrations into account (p=0.002). In individual BH4-responsive patients, median blood prolactin concentrations were significantly lower while using BH4 than before using BH4 treatment (p=0.024), whereas median blood phenylalanine concentrations tended to be lower, but this did not reach statistical significance (p=0.107). Therefore, these data show that high blood phenylalanine in BH4-responsive PKU male patients seems to be associated with increased blood prolactin concentrations, suggesting reduced cerebral dopamine availability. Moreover, these data suggest that BH4 treatment in itself could decrease blood prolactin concentrations in a dose-responsive way, independent of blood phenylalanine concentrations. We conclude that these preliminary data indicate that BH4 treatment may improve cerebral dopamine concentrations in PKU patients beyond its effect through lowering blood phenylalanine concentrations, possibly in a dose-dependent manner, but further research would be warranted.

Prior infection exacerbates postoperative cognitive dysfunction in aged rats.

Older patients may experience persisting postoperative cognitive dysfunction (POCD), which is considered to largely depend on surgery-induced (neuro)inflammation. We hypothesize that inflammatory events before surgery could predispose patients to POCD. When part of our aged rats developed Mycoplasma pulmonis, this presented the unique opportunity to investigate whether a pulmonary infection before surgery influences surgery-induced neuroinflammation and POCD. Male 18-mo-old Wistar rats that had recovered from an active mycoplasma infection (infection) and control rats (healthy) were subjected to abdominal surgery and jugular vein catheterization under general anesthesia (surgery) or remained naïve (control). In postoperative week 2, behavioral tests were performed to assess cognitive performance and exploratory behavior. The acute systemic inflammatory response was investigated by measuring plasma IL-6 and IL-12. In the hippocampus, prefrontal cortex and striatum, microglial activity, neurogenesis, and concentrations of IL-6, IL-12, IL1B, and brain-derived neurotropic factor on postoperative day 14 were determined. Rats still showed signs of increased neuroinflammatory activity, as well as cognitive and behavioral changes, 3 wk after the symptoms of infection had subsided. Rats that had experienced infection before surgery exhibited a more generalized and exacerbated postoperative cognitive impairment compared with healthy surgery rats, as well as a prolonged increase in systemic cytokine levels and increased microglial activation in the hippocampus and prefrontal cortex. These findings support the hypothesis that an infection before surgery under general anesthesia exacerbates POCD. Future studies are necessary to determine whether the found effects are aging specific and to investigate the magnitude and time course of this effect in a controlled manner.

Postoperative cognitive dysfunction and microglial activation in associated brain regions in old rats.

Research indicates that neuroinflammation plays a major role in postoperative cognitive dysfunction (POCD) in older patients. However, studies have mainly focused on hippocampal neuroinflammation and hippocampal-dependent learning and memory, which does not cover the whole spectrum of POCD. We hypothesized that regional differences in postoperative neuroinflammation in the brain may underlie variation in postoperative cognitive impairment. We aimed to investigate this hypothesis in a rat-model for POCD, by analyzing postoperative impairment in behavioral task performance and microglial activation in related brain areas. We subjected 25 months old Wistar rats to surgery and assessed spatial learning and memory, object and location recognition, reversal learning and exploratory behavior in the second postoperative week. The number and morphology of microglia were analyzed in the hippocampus, prefrontal cortex, striatum and amygdala on postoperative day 14. Control groups consisted of 3 and 25 months old rats that did not undergo surgery. We observed age related impairment in learning, memory and behavior, which was aggravated following surgery. Additionally, in old rats surgery was associated with signs of classical microglial activation in brain areas related to the impaired cognitive functions. These outcomes suggest that indeed neuroinflammation may be involved in POCD. Moreover, effects of age and surgery on cognition and microglial morphology seem to be area specific and hence cannot be generalized to the whole brain. This underpins the importance for expanding the research of POCD beyond the hippocampus.

Postoperative cognitive dysfunction: Involvement of neuroinflammation and neuronal functioning.

Postoperative cognitive dysfunction (POCD) has been hypothesized to be mediated by surgery-induced inflammatory processes, which may influence neuronal functioning either directly or through modulation of intraneuronal pathways, such as the brain derived neurotrophic factor (BDNF) mediated pathway. To study the time course of post-surgical (neuro)inflammation, changes in the BDNF-pathway and POCD, we subjected 3months old male Wistar rats to abdominal surgery and implanted a jugular vein catheter for timed blood sampling. Cognition, affective behavior and markers for (neuro)inflammation, BDNF and neurogenesis were assessed at 1, 2 and 3weeks following surgery. Rats displayed changes in exploratory activity shortly after surgery, associated with postoperatively elevated IL-6 plasma levels. Spatial learning and memory were temporarily impaired in the first 2weeks following surgery, whereas non-spatial cognitive functions seemed unaffected. Analysis of brain tissue revealed increased neuroinflammation (IL-1B and microgliosis) 7days following surgery, decreased BDNF levels on postoperative day 14 and 21, and decreased neurogenesis until at least 21days following surgery. These findings indicate that in young adult rats only spatial learning and memory is affected by surgery, suggesting hippocampal dependent cognition is especially vulnerable to surgery-induced impairment. The observed differences in time course following surgery and relation to plasma IL-6 suggest cognitive dysfunction and mood changes comprise distinct features of postoperative behavioral impairment. The postoperative changes in neuroinflammation, BDNF and neurogenesis may represent aspects of the underlying mechanism for POCD. Future research should be aimed to elucidate how these players interact.

Whole body vibration ameliorates anxiety-like behavior and memory functions in 30 months old senescent male rats.

Whole body vibration (WBV) is a form of passive exercise that offers an alternative physical training to aged individuals with limitations in their physical and mental capabilities. The aim of the present study was to explore the therapeutic potential of five weeks of WBV on anxiety-like behaviors as well as learning and memory abilities in senescent thirty months old rats. Animals were exposed to 5 min vibration twice per day, five times per week during the five consecutive weeks. Pseudo WBV treated animals served as controls. After five weeks of WBV treatment, animals were tested for anxiety-like behavior by the open field test and for spatial and object memory functions by the novel and spatial object recognition tests, respectively. As a result, anxiety-like and exploratory behaviors were significantly improved in the WBV treated group compared to the pseudo WBV group. Furthermore, WBV treatment increased discrimination performance in both spatial and object memory function testing. These results indicate that WBV treatment in thirty months old rats seems to have comparable beneficial effects on age-related emotional and cognitive performance as what has been reported in younger age groups.

Cognitive Deficits in human ApoE4 Knock-In Mice: A Systematic Review and Meta-Analysis.

Apolipoprotein-E4 (ApoE4) is an important genetic risk factor for Alzheimer's disease. The development of targeted-replacement human ApoE knock-in mice facilitates research into mechanisms by which ApoE4 affects the brain. We performed meta-analyses and meta-regression analyses to examine differences in cognitive performance between ApoE4 and ApoE3 mice. We included 61 studies in which at least one of the following tests was assessed: Morris Water Maze (MWM), novel object location (NL), novel object recognition (NO) and Fear Conditioning (FC) test. ApoE4 vs. ApoE3 mice performed significantly worse on the MWM (several outcomes, 0.17 ≤ g ≤ 0.60), NO (exploration, g=0.33; index, g=0.44) and FC (contextual, g=0.49). ApoE4 vs. ApoE3 differences were not systematically related to sex or age. We conclude that ApoE4 knock-in mice in a non-AD condition show some, but limited cognitive deficits, regardless of sex and age. These effects suggest an intrinsic vulnerability in ApoE4 mice that may become more pronounced under additional brain load, as seen in neurodegenerative diseases.

Whole-body vibration as a passive alternative to exercise after myocardial damage in middle-aged female rats: Effects on the heart, the brain, and behavior.

Background: Females with cardiovascular disease seem more vulnerable to develop concomitant mental problems, such as depression and cognitive decline. Although exercise is shown beneficial in cardiovascular disease as well as in mental functions, these patients may be incapable or unmotivated to perform exercise. Whole body vibration (WBV) could provide a passive alternative to exercise. Aim of the present study was to compare WBV to exercise after isoproterenol (ISO)-induced myocardial damage in female rats, regarding effects on heart, brain and behavior. Methods: One week after ISO (70 mg/kg s.c., on 2 consecutive days) or saline injections, 12 months old female rats were assigned to WBV (10 minutes daily), treadmill running (30 minutes daily) or pseudo intervention for 5 weeks. During the last 10 days, behavioral tests were performed regarding depressive-like behavior, cognitive function, and motor performance. Rats were sacrificed, brains and hearts were dissected for (immuno)histochemistry. Results: Significant ISO-induced cardiac collagen deposition (0.67 ± 0.10 vs 0.18 ± 0.03%) was absent after running (0.45 ± 0.26 vs 0.46 ± 0.08%), but not after WBV (0.83 ± 0.12 vs 0.41 ± 0.05%). However, WBV as well as running significantly reduced hippocampal (CA3) collagen content in ISO-treated rats. Significant regional differences in hippocampal microglia activity and brain derived neurotrophic factor (BDNF) expression were observed. Significant ISO-induced CA1 microglia activation was reduced after WBV as well as running, while opposite effects were observed in the CA3; significant reduction after ISO that was restored by WBV and running. Both WBV and running reversed the ISO-induced increased BDNF expression in the CA1, Dentate gyrus and Hilus, but not in the CA3 area. Whereas running had no significant effect on behavior in the ISO-treated rats, WBV may be associated with short-term spatial memory in the novel location recognition test. Conclusion: Although the female rats did not show the anticipated depressive-like behavior or cognitive decline after ISO, our data indicated regional effects on neuroinflammation and BDNF expression in the hippocampus, that were merely normalized by both WBV and exercise. Therefore, apart from the potential concern about the lack of cardiac collagen reduction, WBV may provide a relevant alternative for physical exercise.

Variation in Group Composition Alters an Early-Stage Social Phenotype in hAPP-Transgenic J20 Mice.

BACKGROUND: Altered social behavior is one of the symptoms of Alzheimer's disease (AD) that results in social withdrawal and loneliness and provides a major burden on patients and their relatives. Furthermore, loneliness is associated with an increased risk to develop AD and related dementias. OBJECTIVE: We aimed to investigate if altered social behavior is an early indicator of amyloid-ß (Aß) pathology in J20 mice, and if co-housing with wild type (WT) mice can positively influence this social phenotype. METHODS: The social phenotype of group-housed mice was assessed using an automated behavioral scoring system for longitudinal recordings. Female mice were housed in a same-genotype (4 J20 or WT mice per colony) or mixed-genotype (2 J20 mice + 2 WT mice) colony. At 10 weeks of age, their behavior was assessed for five consecutive days. RESULTS: J20 mice showed increased locomotor activity and social sniffing, and reduced social contact compared to WT mice housed in same-genotype colonies. Mixed-genotype housing reduced the social sniffing duration of J20 mice, increased social contact frequency of J20 mice, and increased nest hide by WT mice. CONCLUSION: Thus, altered social behavior can be used as an early indicator of Aß-pathology in female J20 mice. Additionally, when co-housed with WT mice, their social sniffing phenotype is not expressed and their social contact phenotype is reduced. Our findings highlight the presence of a social phenotype in the early stages of AD and indicate a role for social environment variation in the expression of social behavior of WT and J20 mice.

Cofilin overactivation improves hippocampus-dependent short-term memory.

Many living organisms of the animal kingdom have the fundamental ability to form and retrieve memories. Most information is initially stored as short-term memory, which is then converted to a more stable long-term memory through a process called memory consolidation. At the neuronal level, synaptic plasticity is crucial for memory storage. It includes the formation of new spines, as well as the modification of existing spines, thereby tuning and shaping synaptic efficacy. Cofilin critically contributes to memory processes as upon activation, it regulates the shape of dendritic spines by targeting actin filaments. We previously found that prolonged activation of cofilin in hippocampal neurons attenuated the formation of long-term object-location memories. Because the modification of spine shape and structure is also essential for short-term memory formation, we determined whether overactivation of hippocampal cofilin also influences the formation of short-term memories. To this end, mice were either injected with an adeno-associated virus expressing catalytically active cofilin, or an eGFP control, in the hippocampus. We show for the first time that cofilin overactivation improves short-term memory formation in the object-location memory task, without affecting anxiety-like behavior. Surprisingly, we found no effect of cofilin overactivation on AMPA receptor expression levels. Altogether, while cofilin overactivation might negatively impact the formation of long-lasting memories, it may benefit short-term plasticity.

Short-term effects of side-alternating Whole-Body Vibration on cognitive function of young adults.

Recent research in rodents and humans revealed that Whole-Body Vibration (WBV) is beneficial for cognitive functions. However, the optimal WBV conditions are not established: contrary to vertical WBV, side-alternating WBV was not investigated before. The present study investigated the short-term effects of side-alternating WBV in standing and sitting posture on specific cognitive function of young adults. We used a balanced cross-over design. Sixty healthy young adults (mean age 21.7 ± 2.0 years, 72% female) participated. They were exposed to three bouts of two-minute side-alternating WBV (frequency 27 Hz) and three control conditions in two different sessions. In one session a sitting posture was used and in the other session a standing (semi-squat) posture. After each condition selective attention and inhibition was measured with the incongruent condition of the Stroop Color-Word Interference Test. WBV significantly (p = 0.026) improved selective attention and inhibition in the sitting posture, but not in the standing posture. The sitting posture was perceived as more comfortable, joyous and less exhaustive as compared to the standing posture. This study demonstrated that side-alternating WBV in sitting posture improves selective attention and inhibition in healthy young adults. This indicates that posture moderates the cognitive effect of WBV, although the effects are still small. Future studies should focus on the working mechanisms and further optimization of settings, especially in individuals who are unable to perform active exercise.