12 research outputs found
Microtubule and microtubule associated protein anomalies in psychiatric disease
No full textAnomalies in neuronal cell architecture, in particular dendritic complexity and synaptic density changes, are widely observed in the brains of subjects with schizophrenia or mood disorders. The concept that a disturbed microtubule cytoskeleton underlies these abnormalities and disrupts synaptic connectivity is supported by evidence from clinical studies and animal models. Prominent changes in tubulin expression levels are commonly found in disease specific regions such as the hippocampus and prefrontal cortex of psychiatric patients. Genetic linkage studies associate tubulin-binding proteins such as the dihydropyrimidinase family with an increased risk to develop schizophrenia and bipolar disorder. For many years, altered immunoreactivity of microtubule associated protein-2 has been a hallmark found in the brains of individuals with schizophrenia. In this review, we present a growing body of evidence that connects a dysfunctional microtubule cytoskeleton with neuropsychiatric illnesses. Findings from animal models are discussed together with clinical data with a particular focus on tubulin post-translational modifications and on microtubule-binding proteins
JNK regulation of depression and anxiety
No full textDepression and anxiety are the most common mood disorders affecting 300 million sufferers worldwide. Maladaptive changes in the neuroendocrine stress response is cited as the most common underlying cause, though how the circuits underlying this response are controlled at the molecular level, remains largely unknown. Approximately 40% of patients do not respond to current treatments, indicating that untapped mechanisms exist. Here we review recent evidence implicating JNK in the control of anxiety and depressive-like behavior with a particular focus on its action in immature granule cells of the hippocampal neurogenic niche and the potential for therapeutic targeting for affective disorders
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No full textRas-ERK signalling in the brain plays a central role in drug addiction. However, to date, no clinically relevant inhibitor of this cascade has been tested in experimental models of addiction, a necessary step toward clinical trials. We designed two new cell-penetrating peptides - RB1 and RB3 - that penetrate the brain and, in the micromolar range, inhibit phosphorylation of ERK, histone H3 and S6 ribosomal protein in striatal slices. Furthermore, a screening of small therapeutics currently in clinical trials for cancer therapy revealed PD325901 as a brain-penetrating drug that blocks ERK signalling in the nanomolar range. All three compounds have an inhibitory effect on cocaine-induced ERK activation and reward in mice. In particular, PD325901 persistently blocks cocaine-induced place preference and accelerates extinction following cocaine self- administration. Thus, clinically relevant, systemically administered drugs that attenuate Ras-ERK signalling in the brain may be valuable tools for the treatment of cocaine addiction
c-Jun N-terminal Kinase (JNK) Regulation of Neuroplastic Changes in Brain Associated with Anxiety- and Depressive-like Behavior
No full textAnxiety disorders and clinical depression are leading causes of disability worldwide and affect more than 300 million people of all ages, more prominently women (World Health Organization, 2017). Comorbid depression and anxiety disorders appear in up to 75% of patients, and to further complicate the picture, higher severity and chronicity of illness, reduced quality of life, treatment resistance and poor therapeutic effects are expected when comorbidity of anxiety with depression is diagnosed.
Current therapies stimulate neuroplastic changes in the brain, as a basis for their therapeutic action. In particular, it has been shown that several classes of antidepressants stimulate adult neurogenesis in the hippocampal formation, which is one brain region mostly affected by these two conditions. Nevertheless, current pharmacotherapy conveys a number of drawbacks, including delayed onset of clinical effects and debilitating side effects. Such inefficiency is most likely due to a lack of knowledge of the neuroanatomical and physiological changes occurring during the disease state. Thereby, unravelling the etiology and the pathophysiological mechanisms leading to the aberrant cerebral activity caused by the illnesses might ultimately overcome the downsides of current therapies.
Most recently, the Mitogen Activated Protein kinases (MAPs) have been linked to the development of mood disorders. In particular, the c-Jun N-terminal kinase (JNK) subfamily of MAPKs are activated by different external stressors, such as DNA damage, oxidative stress, cytoskeletal changes, infection or inflammation, and the JNK signaling has been found to be fundamental in brain developmental processes. Moreover, JNK activity modulates brain structures and neuronal morphology. Thus, generation of JNK inhibitors has been progressing as a new attractive avenue for more targeted therapies with less adverse side effects.
The work presented in this thesis tackles the role of JNK signaling in regulation of adult hippocampal neurogenesis and in the control of anxiety-like and depressivelike behavior in mice. By using Jnk1 knockout mice and pharmacological inhibition of JNK pathway, the kinase activity was found linked to adult neurogenesis and emotional behavior in mice. More specifically, Jnk1-/- mice exhibited low anxiety-like and depressive-like phenotype in a battery of behavioral tests. Remarkably, genetic and pharmacological inhibition of JNK heightened proliferation, maturation and survival of the newly born neurons of the hippocampus and facilitated dendrite arborization of newborn neurons, suggesting promotion of integration of the adult born cells into the pre-existing circuitry of the hippocampus. Specific retroviral targeting of JNK in the adult born granule cells of the hippocampus produced low anxiety-like phenotype after four weeks of viral expression and decreased depressivelike phenotype eight-week post-injection. The last part of this thesis aimed to investigate synaptic changes of the adult born granule cells of the hippocampus upon JNK kinase inhibition. Using a calcium indicator downstream of JNK inhibition, we recorded the activity of newly born neurons in awake mice. Our preliminary data indicate that JNK inhibition appears to increase adult born granule cells synaptic activity at four weeks of age in mice undergoing social interaction, and at six weeks of age in response to open field and enriched environment exposure. Altogether, the data presented in this thesis provide evidence on JNK modulation of the neurogenic niche of the hippocampus and of the dentate gyrus synaptic activity. Furthermore, these findings highlight the JNK pathway as a putative novel drug target against anxiety and mood disorders.ei tietoa saavutettavuudest
Chronic treatment with the antipsychotic drug blonanserin modulates the responsiveness to acute stress with anatomical selectivity
No full textRationale Patients diagnosed with schizophrenia typically receive life-long treatments with antipsychotic drugs (APDs). However, the impact of chronic APDs treatment on neuroplastic mechanisms in the brain remains largely elusive. Objective Here, we focused on blonanserin, a second-generation antipsychotic (SGA) that acts as an antagonist at dopamine D2, D3, and serotonin 5-HT2A receptors, and represents an important tool for the treatment of schizophrenia. Methods We used rats to investigate the ability of chronic treatment blonanserin to modulate the activity of brain structures relevant for schizophrenia, under baseline conditions or in response to an acute forced swim session (FSS). We measured the expression of different immediate early genes (IEGs), including c-Fos, Arc/Arg 3.1, Zif268 and Npas4. Results Blonanserin per se produced limited changes in the expression of these genes under basal conditions, while, as expected, FSS produced a significant elevation of IEGs transcription in different brain regions. The response of blonanserin-treated rats to FSS show anatomical and gene-selective differences. Indeed, the upregulation of IEGs was greatly reduced in the striatum, a brain structure enriched in dopamine receptors, whereas the upregulation of some genes (Zif268, Npas4) was largely preserved in other regions, such as the prefrontal cortex and the ventral hippocampus. Conclusions Taken together, our findings show that chronic exposure to blonanserin modulates selective IEGs with a specific anatomical profile. Moreover, the differential activation of specific brain regions under challenging conditions may contribute to specific clinical features of the drug
Long-lasting effects of prenatal stress on HPA axis and inflammation : a systematic review and multilevel meta-analysis in rodent studies
No full textExposure to prenatal stress (PNS) can lead to long-lasting neurobiological and behavioral consequences for the offspring, which may enhance the susceptibility for mental disorders. The hypothalamus-pituitary-adrenal (HPA) axis and the immune system are two major factors involved in the stress response. Here, we performed a systematic review and meta-analysis of rodent studies that investigated the effects of PNS exposure on the HPA axis and inflammatory cytokines in adult offspring. Our analysis shows that animals exposed to PNS display a consistent increase in peripheral corticosterone (CORT) levels and central corticotrophin-releasing hormone (CRH), while decreased levels of its receptor 2 (CRHR2). Meta-regression revealed that sex and duration of PNS protocol are covariates that moderate these results. There was no significant effect of PNS in glucocorticoid receptor (GR), CRH receptor 1 (CRHR1), pro- and anti-inflammatory cytokines. Our findings suggest that PNS exposure elicits long-lasting effects on the HPA axis function, providing an important tool to investigate in preclinical settings key pathological aspects related to early-life stress exposure. Furthermore, researchers should be aware of the mixed outcomes of PNS on inflammatory markers in the adult brain
Behavioral and molecular effects of the antipsychotic drug blonanserin in the chronic mild stress model
No full textPsychiatric disorders represent a critical challenge to our society, given their high global prevalence, complex symptomatology, elusive etiology and the variable effectiveness of pharmacological therapies. Recently, there has been a shift in investigating and redefining these diseases by integrating behavioral observations and multilevel neurobiological measures. Accordingly, endophenotype-oriented studies are needed to develop new therapeutic strategies, with the idea of targeting shared symptoms instead of one defined disease. With these premises, here we investigated the therapeutic properties of chronic treatment with the second-generation antipsychotic blonanserin in counteracting the alterations caused by 7 weeks of Chronic Mild Stress (CMS) in the rat. CMS is a well-established preclinical model able to induce depressive and anxiety-like alterations, which are shared by different psychiatric disorders. Our results demonstrated that the antipsychotic treatment normalizes the CMS-induced emotionality deficits, an effect that may be due to its ability in modulating, within the prefrontal cortex, redox mechanisms, a molecular dysfunction associated with several psychiatric disorders. These evidences provide new insights in the therapeutic properties and potential use of blonanserin as well as in its mechanisms of action and provide further support for the role of oxidative stress in the pathophysiology of psychiatric disorders
Seismic assessment of existing three-dimensional RC beam-column joints and retrofit with fully fastened haunches
No full textDOTTORATOSopralluoghi post-sisma sovente hanno riportato danni ai nodi trave-pilastro, in edifici a telaio in cemento armato (c.a.). Le fessure si mostrano prevalentemente diagonali suggerendo uno stato di sforzo per taglio. La Tesi affronta il comportamento di nodi tridimensionali (3D) in c.a., sotto azione sismica, rinforzati mediante angolari metallici. Questa ultima condizione, nel contesto della attuale letteratura tecnica, è stata studiata sperimentalmente per i soli casi di nodi due-dimensionali (2D). La estensione a geometrie 3D ha carattere innovativo. L'interesse è limitato a nodi ad una via con trave trasversale, e nodi d'angolo entrambe che presentino (i) soletta piena, (ii) assenza di staffatura. Il comportamento meccanico è stato studiato attraverso una indagine sperimentale, analitica e numerica. Presupposta la natura dello stato di sforzo tipo taglio che si instaura nella zona nodale, la discussione dei risultati privilegia uno approccio basato sullo equilibrio a discapito della congruenza delle deformazioni. La presenza della soletta influisce nella sollecitazione di taglio. La resistenza a taglio del nodo aumenta per effetto del confinamento indotto dalla trave trasversale. Resta incognito quale sia il detrimento della resistenza nella condizione bi-assiale. Si raccomanda la applicazione del metodo "tirante-puntone" come strumento di analisi strutturale per nodi trave-colonna (3D e 2D) rinforzati con angolari metallici.Post-earthquake surveys reported that severe shear damage localizes in the beam-column joint volume for seismic deficient Reinforced Concrete (RC) structures, especially in absence of horizontal reinforcement. This Thesis addresses the problem of three-dimensional (3D) RC joints under seismic conditions. The interest is limited to exterior joints with slab and transverse beam and corner joints with slab, both un-reinforced. Feasibility of haunch retrofit solution is investigated. The Author is aware that, he is neither the first nor the only one working along these lines. However, up to now experimental studies addressed the problem of 2D joints in the majority of the cases as it emerges from a wide systematic review of the literature. The description of the 3D sub-assemblage behavior under seismic conditions is achieved throughout analytical, numerical and experimental methods. Given the shear nature of the beam-column joint stress field, which almost precludes the use of compatibility, results of the experiments are discussed privileging a force-based approach. Influence of slab participation on joint shear demand and resistance is proved. Influence of bi-axial conditions for joint shear demand and strength remains un-solved apart from improved understanding and a new meta-analysis. Application of strut-and-tie model is recommended as a simple tool for the design of haunch retrofit solution both in the case of 2D and 3D beam-column joints.DIPARTIMENTO DI INGEGNERIA CIVILE E AMBIENTALE33CORONELLI, DARIO ANGELO MARIAMARIANI, STEFAN
JNK Regulation of Depression and Anxiety
No full textDepression
and anxiety are the most common mood disorders affecting 300 million
sufferers worldwide. Maladaptive changes in the neuroendocrine stress
response is cited as the most common underlying cause, though how the
circuits underlying this response are controlled at the molecular level,
remains largely unknown. Approximately 40% of patients do not respond
to current treatments, indicating that untapped mechanisms exist. Here
we review recent evidence implicating JNK in the control of anxiety and
depressive-like behavior with a particular focus on its action in
immature granule cells of the hippocampal neurogenic niche and the
potential for therapeutic targeting for affective disorders.Anxiety and depression are among the largest causes of disability worldwide [1].
They have complex and varied etiologies with genetic, epigenetic and
environmental factors contributing to disease susceptibility.
Maladaptative changes in normal stress responses leading to long lasting
physical changes at the level of synapses and circuits are believed to
be among the underlying causes. Antidepressant drugs have targeted the
same core mechanisms for several decades, yet treatment-resistant
depression is still a major problem, indicating the need for a paradigm
shift [2].
Many theories of depression have been proposed, including dysregulation
of monoaminergic neurotransmission, neurotrophic factors and
hippocampal neurogenesis [3, 4].
However, the signalling molecules that govern mood and its underlying
circuitry are largely unknown and identifying these will be essential
for a comprehensive understanding of mood disorders and development of
new treatments.</p
Derangement of Ras-Guanine Nucleotide-Releasing Factor 1 (Ras-GRF1) and Extracellular Signal-Regulated Kinase (ERK) Dependent Striatal Plasticity in L-DOPA-Induced Dyskinesia
No full textBACKGROUND: Bidirectional long-term plasticity at the corticostriatal synapse has been proposed as a central cellular mechanism governing dopamine-mediated behavioral adaptations in the basal ganglia system. Balanced activity of medium spiny neurons (MSNs) in the direct and the indirect pathways is essential for normal striatal function. This balance is disrupted in Parkinson's disease and in L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID), a common motor complication of current pharmacotherapy of Parkinson's disease.
METHODS: Electrophysiological recordings were performed in mouse cortico-striatal slice preparation. Synaptic plasticity, such as long-term potentiation (LTP) and depotentiation, was investigated. Specific pharmacological inhibitors or genetic manipulations were used to modulate the Ras-extracellular signal-regulated kinase (Ras-ERK) pathway, a signal transduction cascade implicated in behavioral plasticity, and synaptic activity in different subpopulations of striatal neurons was measured.
RESULTS: We found that the Ras-ERK pathway, is not only essential for long-term potentiation induced with a high frequency stimulation protocol (HFS-LTP) in the dorsal striatum, but also for its reversal, synaptic depotentiation. Ablation of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1), a neuronal activator of Ras proteins, causes a specific loss of HFS-LTP in the medium spiny neurons in the direct pathway without affecting LTP in the indirect pathway. Analysis of LTP in animals with unilateral 6-hydroxydopamine lesions (6-OHDA) rendered dyskinetic with chronic L-DOPA treatment reveals a complex, Ras-GRF1 and pathway-independent, apparently stochastic involvement of ERK.
CONCLUSIONS: These data not only demonstrate a central role for Ras-ERK signaling in striatal LTP, depotentiation, and LTP restored after L-DOPA treatment but also disclose multifaceted synaptic adaptations occurring in response to dopaminergic denervation and pulsatile administration of L-DOPA
