Essential role of p21Waf1/Cip1 in the modulation of post-traumatic hippocampal Neural Stem Cells response.

BACKGROUND: Traumatic Brain Injury (TBI) represents one of the main causes of brain damage in young people and the elderly population with a very high rate of psycho-physical disability and death. TBI is characterized by extensive cell death, tissue damage and neuro-inflammation with a symptomatology that varies depending on the severity of the trauma from memory loss to a state of irreversible coma and death. Recently, preclinical studies on mouse models have demonstrated that the post-traumatic adult Neural Stem/Progenitor cells response could represent an excellent model to shed light on the neuro-reparative role of adult neurogenesis following damage. The cyclin-dependent kinase inhibitor p21Waf1/Cip1 plays a pivotal role in modulating the quiescence/activation balance of adult Neural Stem Cells (aNSCs) and in restraining the proliferation progression of progenitor cells. Based on these considerations, the aim of this work is to evaluate how the conditional ablation of p21Waf1/Cip1 in the aNSCS can alter the adult hippocampal neurogenesis in physiological and post-traumatic conditions. METHODS: We designed a novel conditional p21Waf1/Cip1 knock-out mouse model, in which the deletion of p21Waf1/Cip1 (referred as p21) is temporally controlled and occurs in Nestin-positive aNSCs, following administration of Tamoxifen. This mouse model (referred as p21 cKO mice) was subjected to Controlled Cortical Impact to analyze how the deletion of p21 could influence the post-traumatic neurogenic response within the hippocampal niche. RESULTS: The data demonstrates that the conditional deletion of p21 in the aNSCs induces a strong increase in activation of aNSCs as well as proliferation and differentiation of neural progenitors in the adult dentate gyrus of the hippocampus, resulting in an enhancement of neurogenesis and the hippocampal-dependent working memory. However, following traumatic brain injury, the increased neurogenic response of aNSCs in p21 cKO mice leads to a fast depletion of the aNSCs pool, followed by declined neurogenesis and impaired hippocampal functionality. CONCLUSIONS: These data demonstrate for the first time a fundamental role of p21 in modulating the post-traumatic hippocampal neurogenic response, by the regulation of the proliferative and differentiative steps of aNSCs/progenitor populations after brain damage.

The role of glial cells in mental illness: a systematic review on astroglia and microglia as potential players in schizophrenia and its cognitive and emotional aspects.

Schizophrenia is a complex and severe mental disorder that affects approximately 1% of the global population. It is characterized by a wide range of symptoms, including delusions, hallucinations, disorganized speech and behavior, and cognitive impairment. Recent research has suggested that the immune system dysregulation may play a significant role in the pathogenesis of schizophrenia, and glial cells, such as astroglia and microglia known to be involved in neuroinflammation and immune regulation, have emerged as potential players in this process. The aim of this systematic review is to summarize the glial hallmarks of schizophrenia, choosing as cellular candidate the astroglia and microglia, and focusing also on disease-associated psychological (cognitive and emotional) changes. We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched PubMed, Scopus, and Web of Science for articles that investigated the differences in astroglia and microglia in patients with schizophrenia, published in the last 5 years. The present systematic review indicates that changes in the density, morphology, and functioning of astroglia and microglia may be involved in the development of schizophrenia. The glial alterations may contribute to the pathogenesis of schizophrenia by dysregulating neurotransmission and immune responses, worsening cognitive capabilities. The complex interplay of astroglial and microglial activation, genetic/epigenetic variations, and cognitive assessments underscores the intricate relationship between biological mechanisms, symptomatology, and cognitive functioning in schizophrenia.

Physical Exercise as Disease-Modifying Alternative against Alzheimer's Disease: A Gut-Muscle-Brain Partnership.

Alzheimer's disease (AD) is a common cause of dementia characterized by neurodegenerative dysregulations, cognitive impairments, and neuropsychiatric symptoms. Physical exercise (PE) has emerged as a powerful tool for reducing chronic inflammation, improving overall health, and preventing cognitive decline. The connection between the immune system, gut microbiota (GM), and neuroinflammation highlights the role of the gut-brain axis in maintaining brain health and preventing neurodegenerative diseases. Neglected so far, PE has beneficial effects on microbial composition and diversity, thus providing the potential to alleviate neurological symptoms. There is bidirectional communication between the gut and muscle, with GM diversity modulation and short-chain fatty acid (SCFA) production affecting muscle metabolism and preservation, and muscle activity/exercise in turn inducing significant changes in GM composition, functionality, diversity, and SCFA production. This gut-muscle and muscle-gut interplay can then modulate cognition. For instance, irisin, an exercise-induced myokine, promotes neuroplasticity and cognitive function through BDNF signaling. Irisin and muscle-generated BDNF may mediate the positive effects of physical activity against some aspects of AD pathophysiology through the interaction of exercise with the gut microbial ecosystem, neural plasticity, anti-inflammatory signaling pathways, and neurogenesis. Understanding gut-muscle-brain interconnections hold promise for developing strategies to promote brain health, fight age-associated cognitive decline, and improve muscle health and longevity.

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.

Alzheimer's disease and depression in the elderly: A trajectory linking gut microbiota and serotonin signaling.

The occurrence of neuropsychiatric symptoms in the elderly is viewed as an early sign of subsequent cognitive deterioration and conversion from mild cognitive impairment to Alzheimer's disease. The prognosis in terms of both the severity and progression of clinical dementia is generally aggravated by the comorbidity of neuropsychiatric symptoms and decline in cognitive function. Undeniably, aging and in particular unhealthy aging, is a silent "engine of neuropathology" over which multiple changes take place, including drastic alterations of the gut microbial ecosystem. This narrative review evaluates the role of gut microbiota changes as a possible unifying concept through which the comorbidity of neuropsychiatric symptoms and Alzheimer's disease can be considered. However, since the heterogeneity of neuropsychiatric symptoms, it is improbable to describe the same type of alterations in the bacteria population observed in patients with Alzheimer's disease, as well as it is improbable that the variety of drugs used to treat neuropsychiatric symptoms might produce changes in gut bacterial diversity similar to that observed in the pathophysiology of Alzheimer's disease. Depression seems to be another very intriguing exception, as it is one of the most frequent neuropsychiatric symptoms in dementia and a mood disorder frequently associated with brain aging. Antidepressants (i.e., serotonin reuptake inhibitors) or tryptophan dietary supplementation have been shown to reduce Amyloid ß-loading, reinstate microbial diversity and reduce the abundance of bacterial taxa dominant in depression and Alzheimer's disease. This review briefly examines this trajectory by discussing the dysfunction of gut microbiota composition, selected bacterial taxa, and alteration of tryptophan and serotonin metabolism/neurotransmission as overlapping in-common mechanisms involved with depression, Alzheimer's disease, and unhealthy aging.

The Cerebellum as an Embodying Machine.

Whereas emotion theorists often keep their distance from the embodied approach, theorists of embodiment tend to treat emotion as a mainly physiologic process. However, intimate links between emotions and the body suggest that emotions are privileged phenomena to attempt to reintegrate mind and body and that the body helps the mind in shaping emotional responses. To date, research has favored the cerebrum over other parts of the brain as a substrate of embodied emotions. However, given the widely demonstrated contribution of the cerebellum to emotional processing, research in affective neuroscience should consider embodiment theory as a useful approach for evaluating the cerebellar role in emotion and affect. The aim of this review is to insert the cerebellum among the structures needed to embody emotions, providing illustrative examples of cerebellar involvement in embodied emotions (as occurring in empathic abilities) and in impaired identification and expression of embodied emotions (as occurring in alexithymia).

Only Words Count; the Rest Is Mere Chattering: A Cross-Disciplinary Approach to the Verbal Expression of Emotional Experience.

The analysis of sequences of words and prosody, meter, and rhythm provided in an interview addressing the capacity to identify and describe emotions represents a powerful tool to reveal emotional processing. The ability to express and identify emotions was analyzed by means of the Toronto Structured Interview for Alexithymia (TSIA), and TSIA transcripts were analyzed by Natural Language Processing to shed light on verbal features. The brain correlates of the capacity to translate emotional experience into words were determined through cortical thickness measures. A machine learning methodology proved that individuals with deficits in identifying and describing emotions (n = 7) produced language distortions, frequently used the present tense of auxiliary verbs, and few possessive determiners, as well as scarcely connected the speech, in comparison to individuals without deficits (n = 7). Interestingly, they showed high cortical thickness at left temporal pole and low at isthmus of the right cingulate cortex. Overall, we identified the neuro-linguistic pattern of the expression of emotional experience.

Correction: Cutuli et al. Neuroprotective Role of Dietary Supplementation with Omega-3 Fatty Acids in the Presence of Basal Forebrain Cholinergic Neurons Degeneration in Aged Mice. Int. J. Mol. Sci. 2020, 21, 1741.

The authors wish to make the following corrections to this paper [...].

Cerebellum, Embodied Emotions, and Psychological Traits.

This chapter addresses how the embodiment approach may represent a unifying perspective for examining the cerebellar role in emotional behavior and psychological traits. It is not intended to be exhaustive, but rather it can be a good starting point for advancing the cerebellar neural mechanism underlying embodiment. Our goal is to provide illustrative examples of embodied emotions and psychological traits in the emerging field of emotional and cognitive cerebellum. We illustrate how the cerebellum could be an important hub in the embodiment processes, associated with empathic abilities, impaired emotional identification and expression (as occurring for example in the presence of alexithymia), and specific psychological constructs (i.e., hypnotizability).

BDNF and its Role in the Alcohol Abuse Initiated During Early Adolescence: Evidence from Preclinical and Clinical Studies.

Brain-derived neurotrophic factor (BDNF) is a crucial brain signaling protein that is integral to many signaling pathways. This neurotrophin has shown to be highly involved in brain plastic processes such as neurogenesis, synaptic plasticity, axonal growth, and neurotransmission, among others. In the first part of this review, we revise the role of BDNF in different neuroplastic processes within the central nervous system. On the other hand, its deficiency in key neural circuits is associated with the development of psychiatric disorders, including alcohol abuse disorder. Many people begin to drink alcohol during adolescence, and it seems that changes in BDNF are evident after the adolescent regularly consumes alcohol. Therefore, the second part of this manuscript addresses the involvement of BDNF during adolescent brain maturation and how this process can be negatively affected by alcohol abuse. Finally, we propose different BNDF enhancers, both behavioral and pharmacological, which should be considered in the treatment of problematic alcohol consumption initiated during the adolescence.

Effects of Palmitoylethanolamide on Neurodegenerative Diseases: A Review from Rodents to Humans.

Palmitoylethanolamide (PEA) stands out among endogenous lipid mediators for its neuroprotective, anti-inflammatory, and analgesic functions. PEA belonging to the N-acetylanolamine class of phospholipids was first isolated from soy lecithin, egg yolk, and peanut flour. It is currently used for the treatment of different types of neuropathic pain, such as fibromyalgia, osteoarthritis, carpal tunnel syndrome, and many other conditions. The properties of PEA, especially of its micronized or ultra-micronized forms maximizing bioavailability and efficacy, have sparked a series of innovative research to evaluate its possible application as therapeutic agent for neurodegenerative diseases. Neurodegenerative diseases are widespread throughout the world, and although they are numerous and different, they share common patterns of conditions that result from progressive damage to the brain areas involved in mobility, muscle coordination and strength, mood, and cognition. The present review is aimed at illustrating in vitro and in vivo research, as well as human studies, using PEA treatment, alone or in combination with other compounds, in the presence of neurodegeneration. Namely, attention has been paid to the effects of PEA in counteracting neuroinflammatory conditions and in slowing down the progression of diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Frontotemporal dementia, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis. Literature research demonstrated the efficacy of PEA in addressing the damage typical of major neurodegenerative diseases.

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.

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.

Macro- and micro-structural cerebellar and cortical characteristics of cognitive empathy towards fictional characters in healthy individuals.

Few investigations have analyzed the neuroanatomical substrate of empathic capacities in healthy subjects, and most of them have neglected the potential involvement of cerebellar structures. The main aim of the present study was to investigate the associations between bilateral cerebellar macro- and micro-structural measures and levels of cognitive and affective trait empathy (measured by Interpersonal Reactivity Index, IRI) in a sample of 70 healthy subjects of both sexes. We also estimated morphometric variations of cerebral Gray Matter structures, to ascertain whether the potential empathy-related peculiarities in cerebellar areas were accompanied by structural differences in other cerebral regions. At macro-structural level, the volumetric differences were analyzed by Voxel-Based Morphometry (VBM)- and Region of Interest (ROI)-based approaches, and at a micro-structural level, we analyzed Diffusion Tensor Imaging (DTI) data, focusing in particular on Mean Diffusivity and Fractional Anisotropy. Fantasy IRI-subscale was found to be positively associated with volumes in right cerebellar Crus 2 and pars triangularis of inferior frontal gyrus. The here described morphological variations of cerebellar Crus 2 and pars triangularis allow to extend the traditional cortico-centric view of cognitive empathy to the cerebellar regions and indicate that in empathizing with fictional characters the cerebellar and frontal areas are co-recruited.

Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer's Disease.

What happens precociously to the brain destined to develop Alzheimer's Disease (AD) still remains to be elucidated and this is one reason why effective AD treatments are missing. Recent experimental and clinical studies indicate that the degeneration of the dopaminergic (DA) neurons in the Ventral Tegmental Area (VTA) could be one of the first events occurring in AD. However, the causes of the increased vulnerability of DA neurons in AD are missing. Here, we deeply investigate the physiology of DA neurons in the VTA before, at the onset, and after onset of VTA neurodegeneration. We use the Tg2576 mouse model of AD, overexpressing a mutated form of the human APP, to identify molecular targets that can be manipulated pharmacologically. We show that in Tg2576 mice, DA neurons of the VTA at the onset of degeneration undergo slight but functionally relevant changes in their electrophysiological properties and cell morphology. Importantly, these changes are associated with accumulation of autophagosomes, suggestive of a dysfunctional autophagy, and with enhanced activation of c-Abl, a tyrosine kinase previously implicated in the pathogenesis of neurodegenerative diseases. Chronic treatment of Tg2576 mice with Nilotinib, a validated c-Abl inhibitor, reduces c-Abl phosphorylation, improves autophagy, reduces Aß levels and - more importantly - prevents degeneration as well as functional and morphological alterations in DA neurons of the VTA. Interestingly, the drug prevents the reduction of DA outflow to the hippocampus and ameliorates hippocampal-related cognitive functions. Our results strive to identify early pathological brain changes in AD, to provide a rational basis for new therapeutic interventions able to slow down the disease progression.

Optogenetic Stimulation of Prelimbic Pyramidal Neurons Maintains Fear Memories and Modulates Amygdala Pyramidal Neuron Transcriptome.

Fear extinction requires coordinated neural activity within the amygdala and medial prefrontal cortex (mPFC). Any behavior has a transcriptomic signature that is modified by environmental experiences, and specific genes are involved in functional plasticity and synaptic wiring during fear extinction. Here, we investigated the effects of optogenetic manipulations of prelimbic (PrL) pyramidal neurons and amygdala gene expression to analyze the specific transcriptional pathways associated to adaptive and maladaptive fear extinction. To this aim, transgenic mice were (or not) fear-conditioned and during the extinction phase they received optogenetic (or sham) stimulations over photo-activable PrL pyramidal neurons. At the end of behavioral testing, electrophysiological (neural cellular excitability and Excitatory Post-Synaptic Currents) and morphological (spinogenesis) correlates were evaluated in the PrL pyramidal neurons. Furthermore, transcriptomic cell-specific RNA-analyses (differential gene expression profiling and functional enrichment analyses) were performed in amygdala pyramidal neurons. Our results show that the optogenetic activation of PrL pyramidal neurons in fear-conditioned mice induces fear extinction deficits, reflected in an increase of cellular excitability, excitatory neurotransmission, and spinogenesis of PrL pyramidal neurons, and associated to strong modifications of the transcriptome of amygdala pyramidal neurons. Understanding the electrophysiological, morphological, and transcriptomic architecture of fear extinction may facilitate the comprehension of fear-related disorders.