1,721,002 research outputs found
MicroRNAs and psychiatric disorders : from aetiology to treatment
No full textThe emergence of psychiatric disorders relies on the interaction between genetic vulnerability and environmental adversities. Several studies have demonstrated a crucial role for epigenetics (e.g. DNA methylation, post-translational histone modifications and microRNA-mediated post-transcriptional regulation) in the translation of environmental cues into adult behavioural outcome, which can prove to be harmful thus increasing the risk to develop psychopathology. Within this frame, non-coding RNAs, especially microRNAs, came to light as pivotal regulators of many biological processes occurring in the Central Nervous System, both during the neuronal development as well as in the regulation of adult function, including learning, memory and neuronal plasticity. On these basis, in recent years it has been hypothesised a central role for microRNA modulation and expression regulation in many brain disorders, including neurodegenerative disorders and mental illnesses. Indeed, the aim of the present review is to present the most recent state of the art regarding microRNA involvement in psychiatric disorders. We will first describe the mechanisms that regulate microRNA biogenesis and we will report evidences of microRNA dysregulation in peripheral body fluids, in postmortem brain tissues from patients suffering from psychopathology as well as in animal models. Last, we will discuss the potential to consider microRNAs as putative target for pharmacological intervention, using common psychotropic drugs or more specific tools, with the aim to normalize functions that are disrupted in different psychiatric conditions
BEHAVIORAL, MOLECULAR AND EPIGENETIC CONSEQUENCES OF EARLY LIFE STRESS EXPOSURE AND THEIR IMPACT ON ADULT PSYCHOPATHOLOGY
Full text linkThere is now consistent evidence that psychiatric diseases may often represent the consequence of exposure to adverse events early in life, which may disrupt the correct program of brain maturation thus leading to long-lasting changes in brain function.
Accordingly, exposure to stress during gestation in rats has a strong impact on brain development and can cause long-term abnormalities in adult behavior (Fumagalli et al., 2007; Seckl, 1998). In this context, the study of environmental manipulations in animal models offers the possibility to investigate the mechanisms that may be responsible for functional deterioration, with the advantage of keeping the influence of various factors such as the timing and intensity of the adverse condition, the growth environment and the genetic background under control.
Given all these premises, in this study we first set up and employed a paradigm of prenatal stress in rodents in order to reproduce early life adversities that may encompass pregnancy and early postnatal life. Indeed, gestational stress has long-lasting effects on the hypothalamic-pituitary-adrenal (HPA) axis and on the behavior of the dams, suggesting that alterations in maternal behavior following exposure to prenatal stress could also contribute to the long-term effects (Maccari et al., 2003; Maccari and Morley-Fletcher, 2007) of this environmental stressor. In particular, the paradigm we employed consisted in restraining the dams during the last week of gestation for 45 minutes three times a day under bright light, from gestation day 14 until delivery. We next sacrificed the pups, both males and females, at different postnatal time points, in order to create a time profile of the modifications under investigation.
First, we tested the cognitive functionality of adult animals with the object recognition test, since cognitive disabilities are one of the common symptoms that characterize different psychiatric conditions (Disner et al., 2011; Lapiz-Bluhm et al., 2008; Lesh et al., 2011; Lewis et al., 2012).
Next, we performed a detailed analysis of two candidate systems whose deterioration could contribute to the development of the diseased phenotype, namely the glucocorticoid receptor (GR) and the neurotrophin brain-derived neurotrophic factor (BDNF), through basal and functional analyses at gene and protein levels. These two systems have emerged as the most vulnerable elements of exposure to stress during development and can be considered markers of the dysfunctions associated with psychiatric disorders. The HPA axis is involved in the response to stressful events (Maccari et al., 2003), whereas neuronal plasticity represents an array of mechanisms involved in the adaptive capacity to environmental changes (Calabrese et al., 2009; Duman and Monteggia, 2006).
We performed the analyses at various stages of development, trying to establish how early the molecular alterations become manifest and their persistence in time. Notably this bears the possibility to evaluate the potential of early pharmacological interventions that may prove effective in preventing the molecular and functional alterations set in motion by prenatal stress exposure, leading to long-term beneficial effects on the brain function.
Several animal models and human studies suggest that the effect of exposure to stress early in life on lifelong phenotypes is mediated by epigenetic regulation of gene expression involving changes in DNA methylation (McGowan and Szyf, 2010; Weaver, 2007). A further aspect of this experimental work was thus to determine the methylome profile of the hippocampus and the prefrontal cortex of adult rats exposed to prenatal stress. In order to do this, we combined methylated DNA immunoprecipitation (MeDIP) followed by the hybridization on a custom designed high-density oligonucleotide arrays, in order to identify, with an unbiased approach, the genes that are persistently affected by gestational exposure to stress at expression level through changes in the methylation of their promoters.
Last, we aimed at identifying novel candidate markers in a translational approach, by comparing the methylome results obtained in the rat model with a non-human primate model based on different rearing condition, and with a human model of maternal adversities. The identification of genes that show a similar response to early adversities in the brain and in peripheral tissues, in three different species and across the lifespan, is critical for the development of novel diagnostic tools and for therapeutic interventions
Anatomical specificity in the modulation of activity-regulated genes after acute or chronic lurasidone treatment
No full textLurasidone is a novel second generation antipsychotic drug characterized by a multi-receptor profile. Besides the high affinity for 5-HT2A and D2 receptors, it is also characterized by potent 5-HT7 receptor antagonism, which may be beneficial for mood and cognition. Considering that dose-dependent changes in receptor occupancy may differentially impact gene transcription, we aimed at investigating the effects of acute and chronic treatments with different doses of lurasidone (1, 3 and 10mg/kg) in rats on the expression of the activity-regulated genes Arc, Zif268 and Npas4, which are markers of neuronal activation and are also associated with neuroadaptive mechanisms. Our results show dose-dependent and anatomically-selective differences after acute and chronic lurasidone treatment. Indeed, the effects produced by acute treatment seem to reflect the modulatory activity of lurasidone at selected neurotransmitter receptors. In fact, low doses of the drug acted in the hippocampus, while high doses acted in the striatum, reflecting the high predominance of D2 receptor expression in this brain region. On the contrary, chronic treatment with lurasidone revealed a different profile of IEGs modulation, possibly reflecting neuroadaptive changes set in motion in response to repetitive drug exposure. In summary, the multi-receptor profile of lurasidone leads to the recruitment of different brain structures in a dose-related manner and this may be important for its therapeutic properties, particularly with respect to antidepressant activity and cognition
Acute mania and psychotic symptoms in bipolar patients: The efficacy of treatment with risperidone and olanzapine
No full textWhile a controversy has endured as to whether schizophrenia evidences the geographical variations in rate that characterise essentially all medical conditions, even less is known of such fundamental aspects of the epidemiology of schizoaffective and bipolar disorder. Within an ethnically and socioeconomically homogeneous region of rural Ireland, population 29,542, several methodological refinements were adopted to seek an epidemiologically complete population of 'all' cases of these disorders, with each potential case interviewed and diagnosed. Prevalence and morbid risk were calculated over the region as a whole and for each of the 39 constituent District Electoral Divisions [DEDs], by place at birth and by place at onset. Using multiple sources of information, 115 cases of schizophrenia, 33 of schizoaffective disorder and 77 of bipolar disorder were identified. Unremarkable overall prevalence and morbid risk values obscured marked variation between District Electoral Divisions for schizophrenia. No such variation was observed for bipolar disorder. These data indicate, using improved methodology, that what is often interpreted as an invariant overall rate of schizophrenia across countries and cultures may not apply to spatial microstructure; macroscopic rates can obscure small area variations when ethnic and socioeconomic diversity are minimised and effects of urbanicity are absent. Under these conditions, small area variations in bipolar disorder may be limited
Chronic lurasidone treatment normalizes GABAergic marker alterations in the dorsal hippocampus of mice exposed to prenatal immune activation
Full text linkPrenatal maternal infection represents a risk factor for the development of psychopathologic conditions later in life. Clinical evidence is also supported by animal models in which the vulnerability to develop a schizophrenic-like phenotype likely originates from inflammatory processes as early as in the womb. Prenatal immune challenge, for example, induces a variety of long-term behavioral alterations in mice, such as deficits in recognition and spatial working memory, perseverative behaviors and social impairments, which are relevant to different symptom clusters of schizophrenia. Here, we investigated the modulation of GABAergic markers in the dorsal and ventral hippocampus of adult mice exposed to late prenatal immune challenge with the viral mimetic Poly(I:C) (polyriboinosinic-polyribocytidilic-acid) at gestational day 17, and we evaluated the ability of chronic treatment with the multi-receptor antipsychotic lurasidone to modulate the alterations produced by maternal infection. Poly(I:C) mice show a significant reduction of key GABAergic markers, such as GAD67 and parvalbumin, specifically in the dorsal hippocampus, which were normalized by chronic lurasidone administration. Moreover, chronic drug administration increases the expression of the pool of brain derived neurotrophic factor (BDNF) transcripts with the long 3’-UTR as well as the levels of mature BDNF protein in the synaptosomal compartment, selectively in dorsal hippocampus. All in all, our findings demonstrate that lurasidone is effective in ameliorating molecular abnormalities observed in Poly(I:C) mice, providing further support to the neuroplastic properties of this multi-receptor antipsychotic drug
Repeated aripiprazole treatment regulates Bdnf, Arc and Npas4 expression under basal condition as well as after an acute swim stress in the rat brain
No full textDespite the rapid control of schizophrenic symptoms is due to the ability of antipsychotic drugs (APDs) to block D2 receptors in the mesolimbic pathway, it is now well-established that the therapeutic effects rely on adaptive mechanisms set in motion by their long-term administration. Such neuroplastic mechanisms depend on the pharmacological profile of the drug employed, with marked differences existing between first and second generation APDs. On these bases, the major accomplishment of this work was to investigate neuroadaptive changes set in motion by repeated treatment with aripiprazole, a novel APD that is unique for being a partial agonist at dopamine D2 receptors. Moreover, given that stress plays a critical role in the exacerbation of disease symptoms, we also investigated whether aripiprazole could influence the dynamic response of the brain to an acute challenge. We found that repeated aripiprazole treatment in rats regulates the expression of different markers of neuroplasticity such as Bdnf, Arc and Npas4 in a brain-region specific fashion; more importantly, the expression of these molecules was significantly up-regulated by an acute swim stress only in aripiprazole-treated animals, which is suggestive of increased ability to cope with the adverse event. We indeed found an overall facilitation of Bdnf expression, an effect that is mainly evident in the prefrontal cortex on the pool of transcripts undergoing dendritic localization. Overall, our results provide novel information regarding the mechanisms through which aripiprazole may regulate brain function and could contribute to improve neuroplastic defects that are associated with schizophrenia symptomatology
The long-term impact of early adversities on psychiatric disorders : focus on neuronal plasticity
No full textThe impact of early physical and social environments on life-long pathological phenotypes is well known and there is now compelling evidence that stressful experiences during gestation or early in life can lead to enhanced susceptibility to mental illness. Here, we discuss the data from preclinical studies aimed at investigating the molecular consequences of the exposure to stressful events during prenatal or early postnatal life that might contribute to later psychopathology. Particularly, we will discuss the existence of age windows of vulnerability to environmental conditions during brain maturation using as examples several studies performed with different animal models. Specifically, major deviations from normative neurobehavioural trajectories have been reported in animal models obtained following exposure to severe stress (maternal separation) ea rly in infancy or with rodent models of difficult and/or stressful pregnancies, including obstetric complications (e.g. prenatal restrain stress) and gestational exposure to infection (e.g prenatal immune challenge). These models have been associated with profound long-lasting deficits in the offspring's emotional and social behaviour, and with molecular changes associated with neuroplasticity
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