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 [...].

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.

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.

Cerebellar BDNF Promotes Exploration and Seeking for Novelty.

Background: Approach system considered a motivational system that activates reward-seeking behavior is associated with exploration/impulsivity, whereas avoidance system considered an attentional system that promotes inhibition of appetitive responses is associated with active overt withdrawal. Approach and avoidance dispositions are modulated by distinct neurochemical profiles and synaptic patterns. However, the precise working of neurons and trafficking of molecules in the brain activity predisposing to approach and avoidance are yet unclear. Methods: In 3 phenotypes of inbred mice, avoiding, balancing, and approaching mice, selected by using the Approach/Avoidance Y-maze, we analyzed endogenous brain levels of brain derived neurotrophic factor, one of the main secretory proteins with pleiotropic action. To verify the effects of the acute increase of brain derived neurotrophic factor, balancing and avoiding mice were bilaterally brain derived neurotrophic factor-infused in the cortical cerebellar regions. Results: Approaching animals showed high levels of explorative behavior and response to novelty and exhibited higher brain derived neurotrophic factor levels in the cerebellar structures in comparison to the other 2 phenotypes of mice. Interestingly, brain derived neurotrophic factor-infused balancing and avoiding mice significantly increased their explorative behavior and response to novelty. Conclusions: Cerebellar brain derived neurotrophic factor may play a role in explorative and novelty-seeking responses that sustain the approach predisposition.

Environmental Factors Promoting Neural Plasticity: Insights from Animal and Human Studies.

We do not all grow older in the same way. Some individuals have a cognitive decline earlier and faster than others who are older in years but cerebrally younger. This is particularly easy to verify in people who have maintained regular physical activity and healthy and cognitively stimulating lifestyle and even in the clinical field. There are patients with advanced neurodegeneration, such as Alzheimer's disease (AD), that, despite this, have mild cognitive impairment. What determines this interindividual difference? Certainly, it cannot be the result of only genetic factors. We are made in a certain manner and what we do acts on our brain. In fact, our genetic basis can be modulated, modified, and changed by our experiences such as education and life events; daily, by sleep schedules and habits; or also by dietary elements. And this can be seen as true even if our experiences are indirectly driven by our genetic basis. In this paper, we will review some current scientific research on how our experiences are able to modulate the structural organization of the brain and how a healthy lifestyle (regular physical activity, correct sleep hygiene, and healthy diet) appears to positively affect cognitive reserve.

The effects of motor rehabilitation training on clinical symptoms and serum BDNF levels in Parkinson's disease subjects.

Increasing evidence suggests that motor rehabilitation may delay Parkinson's disease (PD) progression. Moreover, parallel treatments in animals up-regulate brain-derived neurotrophic factor (BDNF). Thus, we investigated the effect of a motor rehabilitation protocol on PD symptoms and BDNF serum levels. Motor rehabilitation training consisted of a cycle of 20 days/month of physiotherapy divided in 3 daily sessions. Clinical data were collected at the beginning, at the end, and at 90 days follow-up. BDNF serum levels were detected by ELISA at 0, 7, 14, 21, 30, and 90 days. The follow-up period had a duration of 60 days (T30-T90). The results showed that at the end of the treatment (day 30), an improvement in extrapyramidal signs (UPDRS III; UPDRS III - Gait and Balance items), motor (6 Minute Walking Test), and daily living activities (UPDRS II; PDQ-39) was observed. BDNF levels were increased at day 7 as compared with baseline. After that, no changes in BDNF were observed during the treatment and in the successive follow-up. This study demonstrates that motor rehabilitation training is able to ameliorate PD symptoms and to increase temporarily BDNF serum levels. The latter effect may potentially contribute to the therapeutic action.

BDNF serum levels in subjects developing or not post-traumatic stress disorder after trauma exposure.

Post-traumatic stress disorder (PTSD) is a syndrome resulting from exposure to a severe traumatic event that poses threatened death or injury and produces intense fear and helplessness. The neural structures implicated in PTSD development belong to the limbic system, an important region for emotional processing. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that serves as survival factor for selected populations of central nervous system (CNS) neurons and plays a role in the limbic system by regulating synaptic plasticity, memory processes and behavior. Impaired BDNF production in the brain can lead to a variety of CNS dysfunctions including symptoms associated with PTSD. However, so far fewer studies have investigated this neurotrophin in patients with PTSD. Furthermore, given the multiple role of BDNF in various CNS disorders, it cannot be excluded that traumatic events per se may influence neurotrophin levels, without a direct association to the PTSD syndrome. To elucidate these issues, in this study we analyzed BDNF serum levels in two groups of subjects: patients with trauma exposure who developed PTSD, and subjects with trauma exposure who did not develop PTSD. We found that BDNF serum levels were lower in PTSD patients as compared to related control subjects. Thus, these data suggest that BDNF might be involved in pathophysiology of PTSD and consequently therapeutic approaches aimed at restoring BDNF serum levels may be beneficial to this pathology.

The effect of neuropeptide Y on cell survival and neurotrophin expression in in-vitro models of Alzheimer's disease.

Alzheimer's disease (AD) is a disorder characterized by the accumulation of abnormally folded protein fragments in neurons, i.e., ß-amyloid (Aß) and tau protein, leading to cell death. Several neuropeptides present in the central nervous system (CNS) are believed to be involved in the pathophysiology of AD. Among them, neuropeptide Y (NPY), a small peptide widely distributed throughout the brain, has generated interest because of its role in neuroprotection against excitotoxicity in animal models of AD. In addition, it has been shown that NPY modulates neurogenesis. Interestingly, these latter effects are similar to those elicited by neurotrophins, which are critical molecules for the function and survival of neurons that degenerate during the course of AD. In this review we summarize the evidence for the involvement of NPY and neurotrophins in AD pathogenesis, and the similarity between them in CNS neurons. Finally, we recapitulate our recent in-vitro evidence for the involvement of neurotrophin nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in the neuroprotective effect elicited by NPY in AD neuron-like models (neuroblastoma cells or primary cultures exposed to toxic concentrations of Aß's pathogenic fragment 25-35), and propose a putative mechanism based on NPY-induced inhibition of voltage-dependent Ca(2+) influx in pre- and post-synaptic neurons.

The Complex Relationship between Sleep and Cognitive Reserve: A Narrative Review Based on Human Studies.

Sleep and brain/cognitive/neural reserve significantly impact well-being and cognition throughout life. This review aims to explore the intricate relationship between such factors, with reference to their effects on human cognitive functions. The specific goal is to understand the bidirectional influence that sleep and reserve exert on each other. Up to 6 February 2024, a methodical search of the literature was conducted using the PubMed database with terms related to brain, cognitive or neural reserve, and healthy or disturbed sleep. Based on the inclusion criteria, 11 articles were selected and analyzed for this review. The articles focus almost exclusively on cognitive reserve, with no explicit connection between sleep and brain or neural reserve. The results evidence sleep's role as a builder of cognitive reserve and cognitive reserve's role as a moderator in the effects of physiological and pathological sleep on cognitive functions. In conclusion, the findings of the present review support the notion that both sleep and cognitive reserve are critical factors in cognitive functioning. Deepening comprehension of the interactions between them is essential for devising strategies to enhance brain health and resilience against age- and pathology-related conditions.

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.

A Comprehensive Assessment of Bedtime Routines and Strategies to Aid Sleep Onset in College Students: A Web-Based Survey.

College students often experience sleep-wake alterations. Different factors can contribute to insomnia symptoms in this population. The present study aims at investigating pre-sleep behaviours and strategies used to aid sleep onset in young college students and their association with insomnia symptoms. A total of 548 Italian college students (mean age = 23.48 years, range = 19-30 years, 80.5% female) completed a web-based survey on pre-sleep behaviours and sleep-onset facilitators, insomnia symptoms and sleep hygiene, anxiety and depression, and coping strategies. The use of electronic devices at bedtime and as a sleep-onset facilitator was predominant. Students using specific behaviours as sleep-onset facilitators were characterised by more psychological difficulties and poorer sleep. In multivariable linear regression analysis, the frequency of using medications and melatonin, regardless of motivations, was associated with higher insomnia symptoms. The use of specific sleep-onset facilitators positively correlated with the severity of insomnia symptoms. Many students engage in behaviours that are considered sleep-interfering and that are often employed in an attempt to facilitate sleep onset without benefits. Overall, the motivational factors behind pre-sleep behaviours need to be addressed in preventive programs targeting young college students.

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.

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.

Cortical metabolic deficits in a rat model of cholinergic basal forebrain degeneration.

Evidence indicates that the degeneration of basal forebrain cholinergic neurons may represent an important factor underlying the progressive cognitive decline characterizing Alzheimer's disease (AD). However, the nature of the relationship between cholinergic depletion and AD is not fully elucidated. This study aimed at clarifying some aspects of the relation existing between deficits in cerebral energy metabolism and degeneration of cholinergic system in AD, by investigating the neuronal metabolic activity of several cortical areas after depletion of basal forebrain cholinergic neurons. In cholinergically depleted rats, we evaluated the neuronal metabolic activity by assaying cytochrome oxidase (CO) activity in frontal, parietal and posterior parietal cortices at four different time-points after unilateral injection of 192 IgG-saporin in the nucleus basalis magnocellularis. Unilateral depletion of cholinergic cells in the basal forebrain induced a bilateral decrease of metabolic activity in all the analyzed areas. Frontal and parietal cortices showed decreased metabolic activity even 3 days after the lesion, when the cholinergic degeneration was still incomplete. In posterior parietal cortex metabolic activity decreased only 7 days after the lesion. The possible molecular mechanisms underlying these findings were also investigated. Real-time PCR showed an increase of CO mRNA levels at 3, 7 and 15 days after the lesion both in frontal and parietal cortices, followed by normalization at 30 days. Western Blot analysis did not show any change in CO protein levels at any time-point after the lesion. Our findings support a link between metabolic deficit and cholinergic hypofunctionality characterizing AD pathology. The present model of cholinergic hypofunctionality provides a useful means to study the complex mechanisms linking two fundamental and interrelated phenomena characterizing AD from the early stages.

NPY modulates miR-30a-5p and BDNF in opposite direction in an in vitro model of Alzheimer disease: a possible role in neuroprotection?

Using in vitro models of Alzheimer's disease (AD), we found that the toxic effects of amyloid beta 25-35 (Aß(25-35)) on the neurotrophin brain-derived neurotrophic factor (BDNF) were counteracted by pre-incubation with neuropeptide Y (NPY), a neuropeptide expressed within the central nervous system. Nonetheless, the mechanism of action of NPY on BDNF neuronal production in the presence of Aß is not known. BDNF expression might be directly regulated by microRNA (miRs), small non-coding DNA fragments that regulate the expression of target genes. Thus, there is the possibility that miRs alterations are present in AD-affected neurons and that NPY influences miR expression. To test this hypothesis, we exposed NPY-pretreated primary rat cortical neurons to Aß(25-35) and measured miR-30a-5p (a member of the miR-30a family involved in BDNF tuning expression) and BDNF mRNA and protein expression after 24 and 48 h. Our results demonstrated that pre-treatment with NPY decreased miR-30a-5p expression and increased BDNF mRNA and protein expression at 24 and 48 h of incubation with Aß. Therefore, this study demonstrates that NPY modulates BDNF and its regulating microRNA miR-30a-5p in opposite direction with a mechanism that possibly contributes to the neuroprotective effect of NPY in rat cortical neurons exposed to Aß.

Enhanced BDNF serum levels in patients with severe pathological gambling.

Although the pathophysiology of gambling is unknown, an involvement of midbrain dopaminergic pathway has been hypothesized. In this study, the association between brain-derived neurotrophic factor (BDNF) and pathological gambling was investigated. We measured BDNF serum levels in (1) video players (n=10); (2) card players (n=9); (3) mixed players (n=21; both video and card players) and (4) age-matched controls (n=18). Mixed players had increased BDNF serum levels as compared to controls and higher South Oaks Gambling Screen score as compared to card or video players. Thus, the data demonstrate that patients affected by severe pathological gambling show enhanced BDNF serum levels.

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.

A single intraperitoneal injection of endotoxin in rats induces long-lasting modifications in behavior and brain protein levels of TNF-α and IL-18.

BACKGROUND: Systemic inflammation might cause neuronal damage and sustain neurodegenerative diseases and behavior impairment, with the participation of pro-inflammatory cytokines, like tumor necrosis factor (TNF)-α and interleukin (IL)-18. However, the potential contribution of these cytokines to behavioral impairment in the long-term period has not been fully investigated. METHODS: Wistar rats were treated with a single intraperitoneal injection of LPS (5 mg/kg) or vehicle. After 7 days and 10 months, the animal behavior was evaluated by testing specific cognitive functions, as mnesic, discriminative, and attentional functions, as well as anxiety levels. Contextually, TNF-α and IL-18 protein levels were measured by ELISA in defined brain regions (that is, frontal cortex, hippocampus, striatum, cerebellum, and hypothalamus). RESULTS: Behavioral testing demonstrated a specific and persistent cognitive impairment characterized by marked deficits in reacting to environment modifications, possibly linked to reduced motivational or attentional deficits. Concomitantly, LPS induced a TNF-α increase in the hippocampus and frontal cortex (from 7 days onward) and cerebellum (only at 10 months). Interestingly, LPS treatment enhanced IL-18 expression in these same areas only at 10 months after injection. CONCLUSIONS: Overall, these results indicate that the chronic neuroinflammatory network elicited by systemic inflammation involves a persistent participation of TNF-α accompanied by a differently regulated contribution of IL-18. This leads to speculation that, though with still unclear mechanisms, both cytokines might take part in long-lasting modifications of brain functions, including behavioral alteration.

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.