Homeostatic Factors Research Articles

Brain-Wide Synaptic Inputs to Aromatase-Expressing Neurons in the Medial Amygdala Suggest Complex Circuitry for Modulating Social Behavior.

Here, we reveal an unbiased view of the brain regions that provide specific inputs to aromatase-expressing cells in the medial amygdala, neurons that play an outsized role in the production of sex-specific social behaviors, using rabies tracing and light sheet microscopy. While the downstream projections from these cells are known, the specific inputs to the aromatase-expressing cells in the medial amygdala remained unknown. We observed established connections to the medial amygdala (e.g., bed nucleus of the stria terminalis and accessory olfactory bulb) indicating that aromatase neurons are a major target cell type for efferent input including from regions associated with parenting and aggression. We also identified novel and unexpected inputs from areas involved in metabolism, fear and anxiety, and memory and cognition. These results confirm the central role of the medial amygdala in sex-specific social recognition and social behavior, and point to an expanded role for its aromatase-expressing neurons in the integration of multiple sensory and homeostatic factors, which are likely used to modulate many other social behaviors.

Stroke: What's Sleep Got to Do With It?

Ischemic strokes most often occur between 6 am and 12 am after awakening from sleep but up to 30% occur during sleep. Wake-up strokes (WUS) are new focal neurological deficit(s) persisting for ≥ 24 hours attributable to an ischemic event present on patient awakening. Obstructive sleep apnea (OSA) is a major risk factor for WUS because it compounds the instability of the morning environment and increases the likelihood of cardiovascular events, including hypertension, atrial fibrillation, right-to-left shunts, and stroke. Circadian-driven alterations in structural, homeostatic, and serological factors also predispose to WUS. Also, WUS patients are often not considered candidates for time-dependent intravenous thrombolysis therapy because of an uncertain onset time. However, using the tissue clock (positive diffusion weighted imaging-negative fluid-attenuated inversion recovery mismatch) dates the WUS as 3 to 4.5 hours old and permits consideration for intravenous thrombolysis and if needed mechanical thrombectomy. Given the high prevalence of moderate/severe OSA in stroke patients and its impact on stroke outcomes, screening with overnight pulse oximetry and home sleep apnea test is needed. Treating OSA poststroke remains challenging. Polysomnographic changes in sleep architecture following acute/subacute stroke may also impact upon stroke outcome.

Impact of SARS-CoV-2 on Sleep / Wake Cycle and Melatonin

The world has come to a halt as a result of the SARS-CoV-2 pandemic, which has forced most countries to implement lockdown for the maintenance of the spread of infection. This commentary highlights the important role of sleep as a public health problem, especially in stressful life stages such as the COVID-19 pandemic, and is evidence-based and practical for managing sleep disorders during this crisis. People’s routine has changed due to lockdown, including physical activities, eating habits, electronic usage, and sleeping habits. This has caused disruption between the external and internal zeitgebers and have the greatest impact on melatonin hormone. Melatonin is a key regulator of sleep-in body and controls other hormone cycles as endogenous synchroniser. Sleep is influenced by both circadian and homeostatic factors and sleep problems have a wide range of impacts on the body, effecting different physiological system. So, we should maintain a sleep / wake cycle which will benefit the overall health.

LIGHT controls distinct homeostatic and inflammatory gene expression profiles in esophageal fibroblasts via differential HVEM and LT\u03b2R-mediated mechanisms

Fibroblasts mediate tissue remodeling in eosinophilic esophagitis (EoE), a chronic allergen-driven inflammatory pathology. Diverse fibroblast subtypes with homeostasis-regulating or inflammatory profiles have been recognized in various tissues, but which mediators induce these alternate differentiation states remain largely unknown. We recently identified that TNFSF14/LIGHT promotes an inflammatory esophageal fibroblast in vitro. Herein we used esophageal biopsies and primary fibroblasts to investigate the role of the LIGHT receptors, herpes virus entry mediator (HVEM) and lymphotoxin-beta receptor (LTβR), and their downstream activated pathways, in EoE. In addition to promoting inflammatory gene expression, LIGHT down-regulated homeostatic factors including WNTs, BMPs and type 3 semaphorins. In vivo, WNT2B+ fibroblasts were decreased while ICAM-1+ and IL-34+ fibroblasts were expanded in EoE, suggesting that a LIGHT-driven gene signature was imprinted in EoE versus normal esophageal fibroblasts. HVEM and LTβR overexpression and deficiency experiments demonstrated that HVEM regulates a limited subset of LIGHT targets, whereas LTβR controls all transcriptional effects. Pharmacologic blockade of the non-canonical NIK/p100/p52-mediated NF-κB pathway potently silenced LIGHT’s transcriptional effects, with a lesser role found for p65 canonical NF-κB. Collectively, our results show that LIGHT promotes differentiation of esophageal fibroblasts toward an inflammatory phenotype and represses homeostatic gene expression via a LTβR-NIK-p52 NF-κB dominant pathway.

Induced Pluripotent Stem Cell-Derived Gamma Delta CAR-T Cells for Cancer Immunotherapy

Induced Pluripotent Stem Cell-Derived Gamma Delta CAR-T Cells for Cancer Immunotherapy

Establishment, maintenance, and recall of inflammatory memory.

Known for nearly a century but through mechanisms that remain elusive, cells retain a memory of inflammation that equips them to react quickly and broadly to diverse secondary stimuli. Using murine epidermal stem cells as a model, we elucidate how cells establish, maintain, and recall inflammatory memory. Specifically, we landscape and functionally interrogate temporal, dynamic changes to chromatin accessibility, histone modifications, and transcription factor binding that occur during inflammation, post-resolution, and in memory recall following injury. We unearth an essential, unifying role for the general stress-responsive transcription factor FOS, which partners with JUN and cooperates with stimulus-specific STAT3 to establish memory; JUN then remains with other homeostatic factors on memory domains, facilitating rapid FOS re-recruitment and gene re-activation upon diverse secondary challenges. Extending our findings, we offer a comprehensive, potentially universal mechanism behind inflammatory memory and less discriminate recall phenomena with profound implications for tissue fitness in health and disease.

Desynchrony and synchronisation underpinning sleep–wake cycles

This paper studies mechanisms of synchronisation and loss of synchrony among the three key oscillatory processes controlling sleep–wake cycles in the human brain: the 24-h circadian oscillator, the homeostatic sleep drive, and the environmental light–dark cycle. Synchronisation of these three rhythms promotes sleep and brain clearance and is critical for human health. Their desynchrony, on the other hand, is associated with impaired performance and disease development, including cancer, cardiovascular disease, and mental disorders. A biophysical model of arousal dynamics simulating sleep–wake cycles and circadian rhythms is used as the study system. It is based on established neurobiological mechanisms controlling sleep–wake transitions and incorporates the three oscillatory processes. Nonlinear dynamics methods and synchronisation theory are used to numerically investigate model dynamics under conditions that are not easily achievable in experiments. The role of homeostatic brain clearance rate in synchronisation is investigated, and selective turning on and off of coupling strengths between the oscillators allows us to determine their role in oscillators’ dynamics. We find that, in the absence of coupling between the circadian and homeostatic oscillators, the default state of the model corresponds to the endogenous homeostatic period that is far from $$\sim $$ 24-h rhythm of the circadian and light–dark cycles. Combined action of light and circadian oscillator on the homeostatic rhythm is required to achieve the typical sleep–wake pattern that is observed in young healthy people. Under 12-/12-h light–dark conditions with light at 80 lux, change of homeostatic clearance rate is found to induce two types of desynchronisation: (i) fast clearance rates $$\tau _H<58.1$$ h desynchronise the homeostatic oscillator from the circadian, while the circadian rhythm remains entrained to the light–dark cycle, and (ii) slow clearance rates $$\tau _H>69$$ h maintain synchronisation between the homeostatic and circadian oscillators, but the period of both is different from that of the light–dark cycle. Between these regimes, all three rhythms are synchronised under the studied conditions. The model predicts that the system is highly sensitive to external inputs to the neuronal populations of the sleep–wake switch, which affect the endogenous period of the homeostatic oscillator and can lead to complete loss of sleep. Model dynamics show that loss of synchronisation, which is traditionally ascribed solely to impairment of the circadian oscillator, can be caused by changes in the homeostatic clearance rate of the brain or external input to the neuronal populations of the sleep–wake switch. Thus, changes in circadian, homeostatic, and external factors (combined or specific) may be responsible for conditions of desynchronisation. This has significant implications for understanding individual variability in sleep–wake patterns and in mechanisms of sleep and circadian disorders, indicating that both the homeostatic and circadian mechanisms can be responsible for the same clinical or behavioural presentation of a disease.

Roles of Fibroblast Growth Factors and Their Therapeutic Potential in Treatment of Ischemic Stroke.

Stroke is the leading cause of death worldwide, and its treatment remains a challenge. Complex pathological processes are involved in stroke, which causes a reduction in the supply of oxygen and energy to the brain that triggers subsequent cascade events, such as oxidative stress, inflammatory responses and apoptosis, resulting in brain injury. Stroke is a devastating disease for which there are few treatments, but physical rehabilitation can help improve stroke recovery. Although there are very few treatments for stroke patients, the discovery of fibroblast growth factors (FGFs) in mammals has led to the finding that FGFs can effectively treat stroke in animal models. As presented in this review, FGFs play essential roles by functioning as homeostatic factors and controlling cells and hormones involved in metabolism. They could be used as effective therapeutic agents for stroke. In this review, we will discuss the pharmacological actions of FGFs on multiple targets, including their ability to directly promote neuron survival, enhance angiogenesis, protect against blood-brain barrier (BBB) disruption, and regulate microglial modulation, in the treatment of ischemic stroke and their theoretical mechanisms and actions, as well as the therapeutic potential and limitations of FGFs for the clinical treatment of stroke.

The daily rhythms of working memory and their methodological constraints: a critical overview

ABSTRACT Working memory (WM) performance is not constant throughout the 24-hour cycle. Daily oscillations in WM performance are modulated by interactions between circadian and homeostatic factors. However, investigations that ascertained the circadian rhythm(s) of WM found contradictory results regarding the moments in which the lowest and highest peaks of WM performance occur across the light-dark cycle. This review analyses the findings and methodological approaches of past studies that assessed the circadian cycle(s) of WM and explores the main methodological constraints that may explain their mixed findings. Such differences may be explained by (1) the use of diverse experimental protocols; (2) the employment of different degrees of control of confounding exogenous variables; (3) the application of different types of WM paradigms; (4) the use of different conceptualizations and operationalizations to assess the daily rhythm(s) of WM. Some investigations that evaluated the daily pattern of WM performance considered this cognitive function as a single unit and used general/single measures of WM capacity to estimate the parameters of its circadian cycle, while others tried to disentangle the daily rhythms of the subcomponents of WM. Findings of structural and neurobehavioral studies suggest that the subcomponents of WM present independent circadian rhythms.

Diverse innate stimuli activate basophils through pathways involving Syk and IκB kinases

Mature basophils play critical inflammatory roles during helminthic, autoimmune, and allergic diseases through their secretion of histamine and the type 2 cytokines interleukin 4 (IL-4) and IL-13. Basophils are activated typically by allergen-mediated IgE cross-linking but also by endogenous "innate" factors. The aim of this study was to identify the innate stimuli (cytokines, chemokines, growth factors, hormones, neuropeptides, metabolites, and bacterial products) and signaling pathways inducing primary basophil activation. Basophils from naïve mice or helminth-infected mice were cultured with up to 96 distinct stimuli and their influence on basophil survival, activation, degranulation, and IL-4 or IL-13 expression were investigated. Activated basophils show a heterogeneous phenotype and segregate into distinct subsets expressing IL-4, IL-13, activation, or degranulation markers. We find that several innate stimuli including epithelial derived inflammatory cytokines (IL-33, IL-18, TSLP, and GM-CSF), growth factors (IL-3, IL-7, TGFβ, and VEGF), eicosanoids, metabolites, TLR ligands, and type I IFN exert significant direct effects on basophils. Basophil activation mediated by distinct upstream signaling pathways is always sensitive to Syk and IκB kinases-specific inhibitors but not necessarily to NFAT, STAT5, adenylate cyclase, or c-fos/AP-1 inhibitors. Thus, basophils are activated by very diverse mediators, but their activation seem controlled by a core checkpoint involving Syk and IκB kinases.

Investigation on Neurobiological Mechanisms of Dreaming in the New Decade.

Dream research has advanced significantly over the last twenty years, thanks to the new applications of neuroimaging and electrophysiological techniques. Many findings pointed out that mental activity during sleep and wakefulness shared similar neural bases. On the other side, recent studies have highlighted that dream experience is promoted by significant brain activation, characterized by reduced low frequencies and increased rapid frequencies. Additionally, several studies confirmed that the posterior parietal area and prefrontal cortex are responsible for dream experience. Further, early results revealed that dreaming might be manipulated by sensory stimulations that would provoke the incorporation of specific cues into the dream scenario. Recently, transcranial stimulation techniques have been applied to modulate the level of consciousness during sleep, supporting previous findings and adding new information about neural correlates of dream recall. Overall, although multiple studies suggest that both the continuity and activation hypotheses provide a growing understanding of neural processes underlying dreaming, several issues are still unsolved. The impact of state-/trait-like variables, the influence of circadian and homeostatic factors, and the examination of parasomnia-like events to access dream contents are all opened issues deserving further deepening in future research.

Christianity and Subjective Wellbeing: A Study of Hong Kong

This paper examined the relationship between Christianity and subjective wellbeing by embedding in a revised homeostatic model of subjective wellbeing (SWB) which integrates the affective (homeostatically protected mood: content, happy and excited), cognitive (self-esteem, optimism and perceived control: primary control and secondary control) and experiential factors relating to SWB. In Christianity, God is the creator and lord of life and its doctrine advocates self-abnegation and committing to God; hence, three hypotheses were tested as: First, compared with those without religious belief, the Christians would be higher in SWB, secondary control and optimism, but lower in primary control and self-esteem. Second, for the Christians, each of the cognitive factors of secondary control and optimism would predict more significant SWB variance beyond the other homeostatic model factors than that of primary control and self-esteem. Third, compared with those without religious belief, each of the cognitive factors of secondary control and optimism for Christians would predict more significant SWB variance beyond the other homeostatic model factors, while that of primary control and self-esteem would predict less significant SWB variance. Four hundred and eighteen Chinese respondents were recruited in Hong Kong (178 Christians and 240 without religious belief) to complete a questionnaire. The results revealed that no significant intergroup difference was found on SWB and all cognitive factors. Besides, while Christians’ optimism predicted more significant SWB variance than primary control (3%) and self-esteem (1%), their secondary control failed to make any independent contribution. Additionally, compared with those without religious belief, Christians’ primary control (2%) and self-esteem (3%) explained lesser significant SWB variance. However, while Christians’ optimism predicted more significant variance (3%) than those without religious belief, secondary control for each of the groups failed to make any independent contribution. The results were discussed in terms of inappropriateness and non-specificity of the scale used in measuring secondary control, and a newly proposed construct of religious self-esteem.

Healthy Sleepers Can Worsen Their Sleep by Wanting to Do so: The Effects of Intention on Objective and Subjective Sleep Parameters.

PurposeSleep is regulated by homeostatic and circadian factors. In addition, psychological factors have a strong modulatory impact on our sleep, but the exact underlying mechanisms are still largely unknown. Here, we examined the role of intentions on subjective and objective sleep parameters. Young healthy sleepers were instructed to voluntarily either worsen or improve their sleep. We predicted that participants would be capable of worsening, but not improving, their sleep compared to a regular sleep condition. In addition, we predicted that the instruction to alter sleep would lead to a higher discrepancy between subjective and objective sleep variables.Participants and MethodsTwenty-two healthy students participated in one adaptation and three experimental nights. Polysomnography and subjective sleep parameters were measured during all four nights. Participants were instructed to sleep regularly (“neutral”), better (“good”) or worse (“bad”) than normal, in a counterbalanced order.ResultsThe instruction to sleep “bad” increased objective sleep onset latency and the number of awakings during the night. The effects were stronger on subjective sleep variables, resulting in a higher sleep misperception in the “bad” condition as compared to the other two conditions. The instruction to sleep “good” did not improve sleep nor did it affect sleep misperception.ConclusionWe conclude that intention is sufficient to impair (but not improve) subjective and objective sleep quality and to increase sleep misperception in healthy young sleepers. Our results have important implications for the understanding of the impact of psychological factors on our sleep.

Electrophysiological Correlates of Dream Recall During REM Sleep: Evidence from Multiple Awakenings and Within-Subjects Design.

PurposeIn the current study, we aimed to investigate the EEG correlates of dream recall (DR) monitoring both the homeostatic and state-trait like factors. We assessed the influence of the time of night on the EEG correlates of DR from REM sleep. Specifically, we tested the continuity-hypothesis (on the theta EEG band) and the activation-hypothesis (on the delta and beta bands).MethodsTwenty-seven subjects underwent polysomnography with multiple provoked awakenings during REM sleep. Only the subjects showing combinations of dream recall (REC) and non-REC (NREC) conditions in both first (1st–2nd sleep cycle) and second (3rd–4th sleep cycle) part of the night were included in the analyses. The final sample was composed of 10 subjects (mean age 24±0.70). EEG power spectra of the 5-min of REM sleep preceding each awakening were computed by a fast Fourier transform. The following frequency bands were considered: delta (0.50–4.75 Hz), theta (5.00–7.75 Hz), and beta (16.00–24.75 Hz). We also calculated the delta/beta power ratio as an integrated EEG index of activation.ResultsThe 2×2 within-subjects ANOVA recall × time revealed: a) no significant effect for time and no interaction; b) significant differences over the occipital area in the beta band; c) significant differences over the parietal area for the activation index values. Overall, the results indicated that DR is associated with higher activation regardless of homeostatic pressure across the night of sleep.ConclusionIn line with recent findings, we have shown that DR is predicted by desynchronized EEG activity during REM sleep, providing clear evidence in favor of the activation-hypothesis. We have also confirmed that the EEG pattern of DR can be ascribed to state-like factors. Further studies should assess whether homeostatic modulation may interact with some dream features and the related EEG predictors.

Fatigability and Cardiorespiratory Impairments in Parkinson's Disease: Potential Non-Motor Barriers to Activity Performance.

Parkinson’s disease (PD) is the second most common neurodegenerative condition after Alzheimer’s disease, affecting an estimated 160 per 100,000 people 65 years of age or older. Fatigue is a debilitating non-motor symptom frequently reported in PD, often manifesting prior to disease diagnosis, persisting over time, and negatively affecting quality of life. Fatigability, on the other hand, is distinct from fatigue and describes the magnitude or rate of change over time in the performance of activity (i.e., performance fatigability) and sensations regulating the integrity of the performer (i.e., perceived fatigability). While fatigability has been relatively understudied in PD as compared to fatigue, it has been hypothesized that the presence of elevated levels of fatigability in PD results from the interactions of homeostatic, psychological, and central factors. Evidence from exercise studies supports the premise that greater disturbances in metabolic homeostasis may underly elevated levels of fatigability in people with PD when engaging in physical activity. Cardiorespiratory impairments constraining oxygen delivery and utilization may contribute to the metabolic alterations and excessive fatigability experienced in individuals with PD. Cardiorespiratory fitness is often reduced in people with PD, likely due to the combined effects of biological aging and impairments specific to the disease. Decreases in oxygen delivery (e.g., reduced cardiac output and impaired blood pressure responses) and oxygen utilization (e.g., reduced skeletal muscle oxidative capacity) compromise skeletal muscle respiration, forcing increased reliance on anaerobic metabolism. Thus, the assessment of fatigability in people with PD may provide valuable information regarding the functional status of people with PD not obtained with measures of fatigue. Moreover, interventions that target cardiorespiratory fitness may improve fatigability, movement performance, and health outcomes in this patient population.

Edograms: recording the microstructure of meal intake in humans-a window on appetite mechanisms.

Early attempts at the objective measurement of food intake in humans followed many heuristic pioneer studies in laboratory animals, which revealed how homeostatic and hedonic factors interact to shape the daily eating patterns. Early studies in humans examined the characteristics of intake responses at discrete ingestive events. Described for the first time in 1969, the edogram consisted of a parallel recording of chewing and swallowing responses during standardized lunches, allowing parameters of the "microstructure of meals" to be quantified under varying conditions of deprivation or sensory stimulation, in parallel with overall meal size, meal duration, and eating rate. Edographic studies showed consistent changes in the microstructure of meals in response to palatability level (increased eating rate, decreased chewing time and number of chews per food unit, shorter intrameal pauses, and increased prandial drinking under improved palatability). Longer premeal deprivation affected the eating responses at the beginning of meals (decreased chewing time and number of chews per food unit) but not at the end. Eating rate decelerated during the course of meals in normal-weight participants but not in participants with obesity. These observations largely agreed with contemporary works using other objective measurement methods. They were confirmed and expanded in later studies, notably in the investigation of satiation mechanisms affecting weight control. Importantly, research has demonstrated that the parameters of the microstructure of meals not only reflect the influence of stimulatory/inhibitory factors but can, per se, exert a causal role in satiation and satiety. The early edographic recording instruments were improved over the years and taken out of laboratory settings in order to address the measurement of spontaneous intake responses in free-living individuals. Much remains to be done to make these instruments entirely reliable under the immense variety of situations where food consumption occurs.

Assessing the Management of Excessive Daytime Sleepiness by Napping Benefits

Demanding lifestyle characterized by extended working hours, shift work schedules as well as excessive use of mobile gadgets leads to the disruption of the circadian and homeostatic factors affecting the sleep quality of individuals. As consequence, subjects complain of suffering several sleep disorders some of them characterized by inducing excessive daytime sleepiness (EDS). Currently, the therapeutic approaches for managing EDS include medication, promotion of sleep hygiene, cognitive and behavioral therapy or using of continuous positive airway pressure machine. In this review, we propose the posology of the personalized sleep medicine by the prescription of naps for treating EDS. This review included the online search in PubMed and manual review of articles (basic and clinical trials) of a range of personalized medicine potentially associated to factors of dosage in areas such as nutrition, sports and sleep. Articles in English were identified and subsequently analyzed for consideration for this review. Current evidence has demonstrated that naps exert positive outcomes for individuals complaining with EDS. The dosage of naps might follow similar procedures as reported for personalized interventions in diets or exercise programs (by taking the right dose, at the proper time, with a recommended frequency) which have demonstrated successfully results. The management of EDS may include the personalized sleep medicine considering the prescription of dosage of naps.

ВЛИЯНИЕ IL-7 И IL-15 НА T-РЕГУЛЯТОРНЫЕ КЛЕТКИ ЗДОРОВЫХ ДОНОРОВ И ПАЦИЕНТОВ С РЕВМАТОИДНЫМ АРТРИТОМ IN VITRO

The aim of this study was to assess the infl uence of homeostatic factors IL-7 and IL-15, that induced homeostatic proliferation (HP), on the phenotypic characteristics of T-regulatory cells (Treg) from healthy donors and patients with rheumatoid arthritis (RA) in vitro. Analysis of Treg phenotype was performed by fl ow cytometry, using Foxp3, CD127, CD4 and CD25. Isolated from the blood cells were cultured with and without stimulation during 7 days. IL-7, IL-15 and anti-CD3 antibodies supplemented IL-2 were chosen as activators. Purifi ed Treg cells were labeled with CFSE dye to assess proliferation. We estimated that HP factors eff ectively maintain the number and phenotype (CD25 + FoxP3 + ) of Treg in vitro. Also, in patients group we showed an increasing of CD4 + CD25 + FoxP3 + cells under all stimulation condition that may indicate the induction of Treg from conventional T cells. Herewith under IL-7 and IL-15 Treg cells from RA patients had a low proliferative activity than Treg from donors. The reduced proliferative activity of Treg in the group of RA-patients under IL-7 and IL-15 perhaps make a signifi - cant contribution to the development of the disease due to the delay of Treg pool reconstitution in the lymphopenia conditions on the initial stage. Furthermore, increased induction of CD4 + CD25 + FoxP3 + cells in PBMC cultures in patients group associated with pathogenesis of RA, since induced Treg have transient and unstable expression of FoxP3.

Food anticipatory circadian rhythms in mice entrained to long or short day photoperiods

Food anticipatory activity (FAA) rhythms that emerge in nocturnal rodents fed once daily are mediated by food-entrainable circadian oscillators (FEOs) located outside of the suprachiasmatic nucleus (SCN), the site of a circadian pacemaker required for entrainment to daily light-dark (LD) cycles. Specification of the neural and molecular substrates of FEOs driving FAA is complicated by homeostatic, hedonic and environmental factors that can modulate expression of activity independent of circadian timing. Here, we examined the effect of photoperiod (duration of the daily light period) on FAA in mice fed during the last 4 h or middle 4 h of the light period for at least 5 weeks. Long photoperiods decrease SCN pacemaker amplitude, which may favor expression of FAA during the day, when the SCN normally opposes activity in nocturnal rodents. To test this prediction, in Experiment 1, mice housed with or without running discs were entrained to 24 h LD cycles with 8 h (L8) or 16 h (L16) photoperiods. When food was restricted to the last 4 h of the light period (late-day), mice housed with running discs showed more FAA in L16, whereas mice without running discs showed more FAA in L8. In Experiment 2, mice were entrained to L8 or L16 photoperiods, and the 4 h daily meal was centered in the light period (mid-day). FAA was decreased relative to late-day fed mice, but did not vary by photoperiod. In Experiment 3, mice with or without running discs were entrained to L12 or L18 photoperiods, with mealtime centered in the light period. FAA again did not differ between photoperiods. In constant dark (DD) prior to food restriction, the period (τ) of free-running rhythms was shorter in mice entrained to long days. This known after-effect of photoperiod on τ was absent in DD immediately following restricted feeding. The phase of LD entrainment, unmasked on the first day of DD with food ad-libitum, was significantly advanced in mice from the late-day feeding schedule, compared to mice from the mid-day schedules. These results indicate that FAA in mice does not vary systematically with photoperiod, possibly because daytime feeding schedules attenuate the effect of photoperiod on the mouse SCN pacemaker. FAA in the present study was more strongly influenced by running disc availability and by meal time within the light period, possibly due to effects on LD entrainment, which was phase advanced by late-day but not midday feeding.

Inhibition of formyl peptide receptors improves the outcome in a mouse model of Alzheimer disease

BackgroundAn important hallmark of Alzheimer’s disease (AD) is the increase of Aβ1-42 burden and its accumulation to senile plaques, leading the reactive gliosis and neurodegeneration. The modulation of glia cell function represents an attractive therapeutic strategy, but is currently limited by an incomplete understanding of its relevance for AD. The chemotactic G-protein coupled formyl peptide receptor (FPR), which is known to modulate Aβ1-42 uptake and signal transduction, might be one candidate molecule regulating glia function in AD. Here, we investigate whether the modulation of FPR exerts beneficial effects in an AD preclinical model.MethodsTo address this question, APP/PS1 double-transgenic AD mice were treated for 20 weeks with either the pro-inflammatory FPR agonist fMLF, the FPR1/2 antagonist Boc2 or the anti-inflammatory FPR2 agonist Ac2-26. Spatial learning and memory were evaluated using a Morris water maze test. Immunohistological staining, gene expression studies, and flow cytometry analyses were performed to study neuronal loss, gliosis, and Aß-load in the hippocampus and cortex, respectively.ResultsFPR antagonism by Boc2-treatment significantly improved spatial memory performance, reduced neuronal pathology, induced the expression of homeostatic growth factors, and ameliorated microglia, but not astrocyte, reactivity. Furthermore, the elevated levels of amyloid plaques in the hippocampus were reduced by Boc2-treatment, presumably by an induction of amyloid degradation.ConclusionsWe suggest that the modulation of FPR signaling cascades might be considered as a promising therapeutic approach for alleviating the cognitive deficits associated with early AD. Additional studies are now needed to address the downstream effectors as well as the safety profile of Boc2.