Promoting sleep health during pregnancy for enhancing women's health: a longitudinal randomized controlled trial combining biological, physiological and psychological measures, Maternal Outcome after THERapy for Sleep (MOTHERS).

BACKGROUND: Sleep is vital for maintaining individuals' physical and mental health and is particularly challenged during pregnancy. More than 70% of women during the gestational period report insomnia symptoms. Sleep dysfunction in the peripartum increases the risk for a cascade of negative health outcomes during late pregnancy, birth, and postpartum. While psychological interventions are considered the first line treatment for sleep difficulties, they are still scarcely offered during pregnancy and there is a lack of longitudinal research combining psychological and physiological indices. METHODS: The present protocol outlines a randomized controlled trial aimed at testing the long-term effectiveness of an automatized digitalized psychoeducational intervention for insomnia for expectant mothers complaining insomnia symptoms without comorbidity. Outcomes include physiological, hormonal, and subjective indices of maternal psychopathology, stress, and emotional processes, and sleep and wellbeing of the family system. The trial is part of a longitudinal study evaluating expectant mothers from early pregnancy (within the 15th gestational week) to 6-months postpartum through 6 observational phases: baseline (BSL), 6- and 12-weeks from BSL (FU1-FU2), 2-to-4 weeks after delivery (FU3), and 3- and 6-months after delivery (FU4-5). We plan to recruit 38 women without sleep difficulties (Group A) and 76 women with sleep difficulties (Group B). Group B will be randomly assigned to digital psychological control intervention (B1) or experimental psychoeducational intervention targeting insomnia (B2). At 3 time points, an ecological-momentary-assessment (EMA) design will be used to collect data on sleep and emotions (diaries), sleep-wake parameters (actigraphy) and stress reactivity (salivary cortisol). We will also test the DNA methylation of genes involved in the stress response as biomarkers of prenatal poor sleep. Information on partner's insomnia symptoms and new-borns' sleep will be collected at each stage. DISCUSSION: The proposed protocol aims at testing an easily accessible evidence-based psychoeducational intervention for expectant mothers to help them improving sleep, health, and wellbeing in the peripartum. The results could improve the understanding and management of sleep difficulties and peripartum depression. TRIAL REGISTRATION: The study protocol has been registered on 22 April 2024 with ClinicalTrials.gov Protocol Registration and Results System (PRS), ID: NCT06379074. PROTOCOL VERSION: April 23, 2024.

Trans-generational effects of parental exposure to drugs of abuse on offspring memory functions.

Recent evidence reported that parental-derived phenotypes can be passed on to the next generations. Within the inheritance of epigenetic characteristics allowing the transmission of information related to the ancestral environment to the offspring, the specific case of the trans-generational effects of parental drug addiction has been extensively studied. Drug addiction is a chronic disorder resulting from complex interactions among environmental, genetic, and drug-related factors. Repeated exposures to drugs induce epigenetic changes in the reward circuitry that in turn mediate enduring changes in brain function. Addictive drugs can exert their effects trans-generally and influence the offspring of addicted parents. Although there is growing evidence that shows a wide range of behavioral, physiological, and molecular phenotypes in inter-, multi-, and trans-generational studies, transmitted phenotypes often vary widely even within similar protocols. Given the breadth of literature findings, in the present review, we restricted our investigation to learning and memory performances, as examples of the offspring's complex behavioral outcomes following parental exposure to drugs of abuse, including morphine, cocaine, cannabinoids, nicotine, heroin, and alcohol.

Land/Water Aerobic Activities: Two Sides of the Same Coin. A Comparative Analysis on the Effects in Cognition of Alzheimer's Disease.

 Evidence in the literature indicates that aerobic physical activity may have a protective role in aging pathologies. However, it has not been clarified whether different types of aerobic exercise produce different effects. In particular, these potential differences have not been explored in patients with Alzheimer's disease (AD). The present narrative review has the specific aim of evaluating whether land (walking/running) and water (swimming) aerobic activities exert different effects on cognitive functions and neural correlates in AD patients. In particular, the investigation is carried out by comparing the evidence provided from studies on AD animal models and on patients. On the whole, we ascertained that both human and animal studies documented beneficial effects of land and water aerobic exercise on cognition in AD. Also, the modulation of numerous biological processes is documented in association with structural modifications. Remarkably, we found that aerobic activity appears to improve cognition per se, independently from the specific kind of exercise performed. Aerobic exercise promotes brain functioning through the secretion of molecular factors from skeletal muscles and liver. These molecular factors stimulate neuroplasticity, reduce neuroinflammation, and inhibit neurodegenerative processes leading to amyloid-ß accumulation. Additionally, aerobic exercise improves mitochondrial activity, reducing oxidative stress and enhancing ATP production. Aerobic activities protect against AD, but implementing exercise protocols for patients is challenging. We suggest that health policies and specialized institutions should direct increasing attention on aerobic activity as lifestyle modifiable factor for successful aging and age-related conditions.

Advance in Neurotoxicity Research from Development to Aging.

A substance capable of inducing a consistent pattern of neural dysfunction in the chemistry or structure of the nervous system may be defined as neurotoxic [...].

A systematic review and meta-analysis of the association between young adults' sleep habits and substance use, with a focus on self-medication behaviours.

Young adults (18-30 years) are vulnerable to sleep-wake disturbances and substance use, which are bi-directionally associated. The present work aims to organise the literature that deals with the association between sleep and substance use in young adults, also considering self-medication behaviours. We adopted a framework that accounts for the multidimensionality of sleep and the effect of different substances. We considered sleep disturbances (insomnia symptoms, sleep quality), sleep health dimensions (duration, satisfaction, efficiency, timing, daytime alertness), circadian characteristics (chronotype). Substances were alcohol, caffeine, nicotine, cannabis, others. We included 46 studies. The use of caffeine and nicotine was associated with higher odds of sleep disturbances. No significant effect was detected for sleep duration. In narrative findings, daytime dysfunction was associated with alcohol and caffeine use, and poor sleep satisfaction with nicotine use. Few evidence were available for the other sleep health dimensions. Evening chronotype was associated with alcohol, caffeine, and nicotine use. Few studies focused on cannabis or self-medication. Longitudinal results were inconclusive. We found a distinct pattern of associations between different substances and different sleep outcomes. Further investigation considering the multidimensionality of sleep would create a better understanding of the complex relationship between substance use and sleep health in young adults.

Environmental Enrichment Protects against Neurotoxic Effects of Lipopolysaccharide: A Comprehensive Overview.

Neuroinflammation is a pathophysiological condition associated with damage to the nervous system. Maternal immune activation and early immune activation have adverse effects on the development of the nervous system and cognitive functions. Neuroinflammation during adulthood leads to neurodegenerative diseases. Lipopolysaccharide (LPS) is used in preclinical research to mimic neurotoxic effects leading to systemic inflammation. Environmental enrichment (EE) has been reported to cause a wide range of beneficial changes in the brain. Based on the above, the purpose of the present review is to describe the effects of exposure to EE paradigms in counteracting LPS-induced neuroinflammation throughout the lifespan. Up to October 2022, a methodical search of studies in the literature, using the PubMed and Scopus databases, was performed, focusing on exposure to LPS, as an inflammatory mediator, and to EE paradigms in preclinical murine models. On the basis of the inclusion criteria, 22 articles were considered and analyzed in the present review. EE exerts sex- and age-dependent neuroprotective and therapeutic effects in animals exposed to the neurotoxic action of LPS. EE's beneficial effects are present throughout the various ages of life. A healthy lifestyle and stimulating environments are essential to counteract the damages induced by neurotoxic exposure to LPS.

Dietary Protection against Cognitive Impairment, Neuroinflammation and Oxidative Stress in Alzheimer's Disease Animal Models of Lipopolysaccharide-Induced Inflammation.

Alzheimer's disease (AD) is a rapidly growing epidemic with a heavy social and economic burden. Evidence suggests that systemic inflammation, dysregulation of the immune response and the resulting neuroinflammation and neurodegeneration play a significant role in AD pathogenesis. Currently, given that there is no fully convincing cure for AD, the interest in lifestyle factors (such as diet), which potentially delay onset and reduce the severity of symptoms, is increasing. This review is aimed at summarizing the effects of dietary supplementation on cognitive decline, neuroinflammation and oxidative stress in AD-like animal models with a focus on neuroinflammation induced by lipopolysaccharide (LPS) injection, which mimics systemic inflammation in animals. The compounds reviewed include curcumin, krill oil, chicoric acid, plasmalogens, lycopene, tryptophan-related dipeptides, hesperetin and selenium peptides. Despite the heterogeneity of these compounds, there is a strong consensus on their counteracting action on LPS-induced cognitive deficits and neuroinflammatory responses in rodents by modulating cell-signaling processes, such as the NF-κB pathway. Overall, dietary interventions could represent an important resource to oppose AD due to their influence in neuroprotection and immune regulation.

Walking, Running, Swimming: An Analysis of the Effects of Land and Water Aerobic Exercises on Cognitive Functions and Neural Substrates.

In the brain and cognitive reserves framework, aerobic exercise is considered as a protective lifestyle factor able to induce positive effects on both brain structure and function. However, specific aspects of such a beneficial effect still need to be completely clarified. To this aim, the present narrative review focused on the potential brain/cognitive/neural reserve-construction mechanisms triggered by different aerobic exercise types (land activities; such as walking or running; vs. water activities; such as swimming), by considering human and animal studies on healthy subjects over the entire lifespan. The literature search was conducted in PubMed database. The studies analyzed here indicated that all the considered kinds of activities exert a beneficial effect on cognitive/behavioral functions and on the underlying brain neurobiological processes. In particular, the main effects observed involve the cognitive domains of memory and executive functions. These effects appear related to structural and functional changes mainly involving the fronto-hippocampal axis. The present review supports the requirement of further studies that investigate more specifically and systematically the effects of each type of aerobic activity, as a basis to plan more effective and personalized interventions on individuals as well as prevention and healthy promotion policies for the general population.

Environmental Enrichment Enhances Cerebellar Compensation and Develops Cerebellar Reserve.

The brain is able to change its structure and function in response to environmental stimulations. Several human and animal studies have documented that enhanced stimulations provide individuals with strengthened brain structure and function that allow them to better cope with damage. In this framework, studies based on the exposure of animals to environmental enrichment (EE) have provided indications of the mechanisms involved in such a beneficial action. The cerebellum is a very plastic brain region that responds to every experience with deep structural and functional rearrangement. The present review specifically aims to collect and synthesize the evidence provided by animal models on EE exposure effects on cerebellar structure and function by considering the studies on healthy subjects and on animals exposed to EE both before and after damage involving cerebellar functionality. On the whole, the evidence supports the role of EE in enhancing cerebellar compensation and developing cerebellar reserve. However, since studies addressing this issue are still scarce, large areas of inconsistency and lack of clarity remain. Further studies are required to provide suggestions on possible mechanisms of enhancement of compensatory responses in human patients following cerebellar damage.

n-3 PUFA Improve Emotion and Cognition during Menopause: A Systematic Review.

Women show an increased risk of cognitive impairment and emotional disorders, such as anxiety and depression, when approaching menopause. Data on risk and protection factors have yielded robust evidence on the effects of lifestyle factors, such as diet, in preserving emotional and cognitive functioning. This review focused on the effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) on anxiety, depression, and cognition during the menopausal transition. This systematic review considered all articles published until 31 December 2021, and the search was performed on two databases, PubMed and Scopus. The fields of interest were "menopause", "n-3 PUFA" and "emotional and cognitive aspects". Out of the 361 articles found on PubMed and 283 on Scopus, 17 met inclusion criteria. They encompassed 11 human and 6 animal studies. Most studies reported relieved depressive symptoms in relation to n-3 PUFA intake. While controversial results were found on anxiety and cognition in humans, n-3 PUFA consistently reduced anxiety symptoms and improved cognition in animal studies. Taken together, n-3 PUFA intake shows beneficial effects on emotional and cognitive behaviours during menopause transition. However, further investigations could increase knowledge about the effectiveness of n-3 PUFA on psychological well-being in this delicate period of feminine life.

Multigenerational effects of paternal spatial training are lasting in the F1 and F2 male offspring.

Recent studies on intergenerational transmission of learning and memory performances demonstrated that parental spatial training before fertilization could facilitate learning and memory in the offspring, but many questions remain unclarified. Essential issues regarding whether and how long the effects of parental training in a task can last in several generations, and whether learning a task repeated in the successive generations can enhance a load of multigenerational effects. In the present study, the spatial performances of F1 and F2 generations of male offspring of fathers or grandfathers spatially trained in the Morris Water Maze were evaluated and compared with the performance of a control sample matched for age and sex. Further, to investigate the memory process in F1 and F2 male offspring, brain-derived neurotrophic factor (BDNF), p-ERK1/2 and acetylated histone 3 lysine 14 (H3K14) expression levels in the hippocampus were analyzed. The findings showed that paternal training reduced escape latencies and increased time spent in the target quadrant by F1 and F2 male offspring. Besides, paternal spatial training repeated in two generations did not enhance the beneficial effects on offspring's spatial performances. These findings were supported by neurobiologic data showing that paternal training increased BDNF and p-ERK1/2 in the hippocampus of F1 and F2 male offspring. Furthermore, the hippocampal level of acetylated H3K14 increased in the offspring of spatially trained fathers, reinforcing the hypothesis that the augmented histone acetylation might play an essential role in the inheritance of spatial competence.

Environmental Enrichment Effects on the Brain-Derived Neurotrophic Factor Expression in Healthy Condition, Alzheimer's Disease, and Other Neurodegenerative Disorders.

Brain-derived neurotrophic factor (BDNF), a protein belonging to the neurotrophin family, is known to be heavily involved in synaptic plasticity processes that support brain development, post-lesion regeneration, and cognitive performances, such as learning and memory. Evidence indicates that BDNF expression can be epigenetically regulated by environmental stimuli and thus can mediate the experience-dependent brain plasticity. Environmental enrichment (EE), an experimental paradigm based on the exposure to complex stimulations, constitutes an efficient means to investigate the effects of high-level experience on behavior, cognitive processes, and neurobiological correlates, as the BDNF expression. In fact, BDNF exerts a key role in mediating and promoting EE-induced plastic changes and functional improvements in healthy and pathological conditions. This review is specifically aimed at providing an updated framework of the available evidence on the EE effects on brain and serum BDNF levels, by taking into account both changes in protein expression and regulation of gene expression. A further purpose of the present review is analyzing the potential of BDNF regulation in coping with neurodegenerative processes characterizing Alzheimer's disease (AD), given BDNF expression alterations are described in AD patients. Moreover, attention is also paid to EE effects on BDNF expression in other neurodegenerative disease. To investigate such a topic, evidence provided by experimental studies is considered. A deeper understanding of environmental ability in modulating BDNF expression in the brain may be fundamental in designing more tuned and effective applications of complex environmental stimulations as managing approaches to AD.

New prospects on cerebellar reserve: Remarks on neuroprotective effects of experience in animals and humans.

The ability of the brain to change structure and function in response to experience accounts for its ability to successfully adapt to the environment in both learning processes and unique phases, such as during development and repair. On this basis, the occurrence of the brain, cognitive, and neural reserves has been advanced to explain the discrepancies between the extent of neurological damage and the severity of clinical manifestations described in patients with different life span experiences. Research on this topic highlighted the neuroprotective role of complex stimulations, allowing the brain to better cope with the damage. This framework was initially developed by observing patients with Alzheimer's disease, and it has since been progressively expanded to multifarious pathological states. The cerebellum is known to be particularly responsive to experience through extensive plastic rearrangements. The neuroprotective value exerted by reserve mechanisms appears to be suitable for basic neuronal plasticity in the cerebellum. Thus, it is of primary interest to deepen our understanding of how life experiences modify individuals' cerebellar morphology and functionality. The present study is aimed at analyzing the evidence provided on this topic by animal and human studies. For animals, we considered the studies in which subjects were submitted to enhanced stimulations before the damage occurred. For humans, we considered studies in which previous lifelong high-level experiences were associated with superior cerebellar abilities to cope with injury. Detailed indications of the processes underlying cerebellar reserves may be important in proposing effective interventions for patients suffering from pathologies that directly or indirectly damage cerebellar functionality.

Maternal spatial training before fertilization improves the spatial learning process in female offspring.

Recent results of our team showed that parental spatial training before fertilization improves the offspring's spatial memory. However, the process of spatial learning (short-term/working and long-term memories, mnesic consolidation and procedures) in the offspring has not been fully clarified yet. Therefore, this study aimed at specifically analyzing whether maternal learning of a spatial task before fertilization can impact on the process of spatial learning in the female offspring. In the present study, 8-week-old female Wistar rats that had been spatially trained (or not) in the Morris Water Maze (MWM) were mated with conspecific standard-reared male rats, and their 4-week-old female offspring were spatially tested in the same MWM to evaluate their learning and memory processes. Results showed that the female offspring of trained mothers significantly displayed lower escape latencies, higher swimming speed, shorter total distance swum, longer percentage of time spent in the target quadrant and better localization memory in comparison to the female offspring of not trained mothers. Further, MWM performances of mothers trained and their female offspring significantly correlated. These findings indicate that the maternal spatial training before fertilization improves the spatial learning and memory consolidation process of the female offspring.

Does Experience Enhance Cognitive Flexibility? An Overview of the Evidence Provided by the Environmental Enrichment Studies.

Neuroplasticity accounts for the ability of the brain to change in both structure and function in consequence of life experiences. An enhanced stimulation provided by the environment is able to create a form of brain, neural, and cognitive reserve, which allows an individual to cope better with the environmental demands, also in case of neural damage leading to cognitive decline. With its complex manipulation of several stimuli, the animal experimental paradigm of environmental enrichment (EE) appears particularly effective in modulating the ability to successfully respond to the ever-changing characteristics of the environment. According to this point, it could be very relevant to analyze the specific effects of EE on cognitive flexibility (CF). CF could be defined as the ability to effectively change behavior in response to the environmental condition changing. This review article is specifically aimed to summarize and focus on the available evidence in relation to the effects of EE on CF. To this aim, findings obtained in behavioral tasks specifically structured to investigate animal CF, such as reversal learning and attentional set-shifting tests (tasks based on the request of responding to a rewarding rule that changes, within one or multiple perceptual dimensions), are reviewed. Data provided on the structural and biochemical correlates of these findings are also enumerated. Studies realized in healthy animals and also in pathological models are considered. On the whole, the summarized evidence clearly supports the specific beneficial effects of EE on CF. However, further studies on this key topic are strictly required to gain a comprehensive and detailed framework on the mechanisms by which an enhanced stimulation could improve CF.

Effects of pre-reproductive maternal enrichment on maternal care, offspring's play behavior and oxytocinergic neurons.

Potentiating social, cognitive, and sensorimotor stimulations the Environmental Enrichment (EE) increases levels of novelty and complexity experienced by individuals. Growing evidence demonstrates that parental EE experience, even occurring in the pre-reproductive phase, affects behavioral and neural developmental trajectories of the offspring. To discover how the accumulation of early maternal complex experiences may inform and shape the social behavior of the following generation, we examined the effects of pre-reproductive enrichment of dams (post-natal days 21-72) on the play performances of their male and female adolescent offspring. Furthermore, we examined the effects of pre-reproductive enrichment on maternal behavior (during post-partum days 1-10) and male intruder aggression (on post-partum day 11). Since oxytocin modulates maternal care, social bonding, and agonistic behavior, the number of oxytocinergic neurons of the paraventricular (PVN) and supraoptic (SON) nuclei was examined in both dams and offspring. Results revealed that enriched females exhibited higher levels of pup-oriented behaviors, especially Crouching, and initiated pup-retrieval more quickly than standard females after the maternal aggression test. Such behavioral peculiarities were accompanied by increased levels of oxytocinergic neurons in PVN and SON. Moreover, pre-reproductive maternal EE cross-generationally influenced the offspring according to sex. Indeed, male pups born to enriched females exhibited a reduced play fighting associated with a higher number of oxytocinergic neurons in SON in comparison to male pups born to standard-housed females. In conclusion, pre-reproductive EE to the mothers affects their maternal care and has a cross-generational impact on the social behavior of their offspring that do not directly experiences EE. This article is part of the Special Issue entitled "Neurobiology of Environmental Enrichment".

Pre-reproductive Parental Enriching Experiences Influence Progeny's Developmental Trajectories.

While the positive effects of environmental enrichment (EE) applied after weaning, in adulthood, during aging, or even in the presence of brain damage have been widely described, the transgenerational effects of pre-reproductive EE have been less examined. And yet, this issue is remarkable given that parental environmental experience may imprint offspring's phenotype over generations through many epigenetic processes. Interactions between individual and environment take place lifelong even before conception. In fact, the environment pre-reproductively experienced by the mother and/or the father exerts a substantial impact on neural development and motor and cognitive performances of the offspring, even if not directly exposed to social, cognitive, physical and/or motor enrichment. Furthermore, pre-reproductive parental enrichment exerts a transgenerational impact on coping response to stress as well as on the social behavior of the offspring. Among the effects of pre-reproductive parental EE, a potentiation of the maternal care and a decrease in global methylation levels in the frontal cortex and hippocampus of the progeny have been described. Finally, pre-reproductive EE modifies different pathways of neuromodulation in the brain of the offspring (involving brain-derived neurotrophic factor, oxytocin and glucocorticoid receptors). The present review highlights the importance of pre-reproductive parental enrichment in altering the performances not only of animals directly experiencing it, but also of their progeny, thus opening the way to new hypotheses on the inheritance mechanisms of behavioral traits.

Rethinking the Reserve with a Translational Approach: Novel Ideas on the Construct and the Interventions.

The concept of brain, cognitive, and neural reserves has been introduced to account for the apparent discrepancies between neurological damage and clinical manifestations. However, these ideas are yet theoretical suggestions that are not completely assimilated in the clinical routine. The mechanisms of the reserves have been extensively studied in neurodegenerative pathologies, in particular in Alzheimer's disease. Both human and animal studies addressed this topic by following two parallel pathways. The specific aim of the present review is to attempt to combine the suggestions derived from the two different research fields to deepen the knowledge about reserves. In fact, the achievement of a comprehensive theoretical framework on reserve mechanisms is an essential step to propose well-timed interventions tailored to the clinical characteristics of patients. The present review highlights the importance of addressing three main aspects: the definition of reserve proxy measures, the interaction between reserve level and therapeutic interventions, and the specific time-window of reserve efficacy.