The genetic basis of inter-individual variation in recovery from traumatic brain injury.

Traumatic brain injury (TBI) is one of the leading causes of death among young people, and is increasingly prevalent in the aging population. Survivors of TBI face a spectrum of outcomes from short-term non-incapacitating injuries to long-lasting serious and deteriorating sequelae. TBI is a highly complex condition to treat; many variables can account for the observed heterogeneity in patient outcome. The limited success of neuroprotection strategies in the clinic has led to a new emphasis on neurorestorative approaches. In TBI, it is well recognized clinically that patients with similar lesions, age, and health status often display differences in recovery of function after injury. Despite this heterogeneity of outcomes in TBI, restorative treatment has remained generic. There is now a new emphasis on developing a personalized medicine approach in TBI, and this will require an improved understanding of how genetics impacts on long-term outcomes. Studies in animal model systems indicate clearly that the genetic background plays a role in determining the extent of recovery following an insult. A candidate gene approach in human studies has led to the identification of factors that can influence recovery. Here we review studies of the genetic basis for individual differences in functional recovery in the CNS in animals and man. The application of in vitro modeling with human cells and organoid cultures, along with whole-organism studies, will help to identify genes and networks that account for individual variation in recovery from brain injury, and will point the way towards the development of new therapeutic approaches

Early-life adversity and neurological disease: age-old questions and novel answers.

Neurological illnesses, including cognitive impairment, memory decline and dementia, affect over 50 million people worldwide, imposing a substantial burden on individuals and society. These disorders arise from a combination of genetic, environmental and experiential factors, with the latter two factors having the greatest impact during sensitive periods in development. In this Review, we focus on the contribution of adverse early-life experiences to aberrant brain maturation, which might underlie vulnerability to cognitive brain disorders. Specifically, we draw on recent robust discoveries from diverse disciplines, encompassing human studies and experimental models. These discoveries suggest that early-life adversity, especially in the perinatal period, influences the maturation of brain circuits involved in cognition. Importantly, new findings suggest that fragmented and unpredictable environmental and parental signals comprise a novel potent type of adversity, which contributes to subsequent vulnerabilities to cognitive illnesses via mechanisms involving disordered maturation of brain 'wiring'

Effects of Adolescent THC Exposure on the Prefrontal GABAergic System: Implications for Schizophrenia-Related Psychopathology.

Marijuana is the most commonly used drug of abuse among adolescents. Considerable clinical evidence supports the hypothesis that adolescent neurodevelopmental exposure to high levels of the principal psychoactive component in marijuana, -delta-9-tetrahydrocanabinol (THC), is associated with a high risk of developing psychiatric diseases, such as schizophrenia later in life. This marijuana-associated risk is believed to be related to increasing levels of THC found within commonly used marijuana strains. Adolescence is a highly vulnerable period for the development of the brain, where the inhibitory GABAergic system plays a pivotal role in the maturation of regulatory control mechanisms in the central nervous system (CNS). Specifically, adolescent neurodevelopment represents a critical period wherein regulatory connectivity between higher-order cortical regions and sub-cortical emotional processing circuits such as the mesolimbic dopamine (DA) system is established. Emerging preclinical evidence demonstrates that adolescent exposure to THC selectively targets schizophrenia-related molecular and neuropharmacological signaling pathways in both cortical and sub-cortical regions, including the prefrontal cortex (PFC) and mesolimbic DA pathway, comprising the ventral tegmental area (VTA) and nucleus accumbens (NAc). Prefrontal cortical GABAergic hypofunction is a key feature of schizophrenia-like neuropsychopathology. This GABAergic hypofunction may lead to the loss of control of the PFC to regulate proper sub-cortical DA neurotransmission, thereby leading to schizophrenia-like symptoms. This review summarizes preclinical evidence demonstrating that reduced prefrontal cortical GABAergic neurotransmission has a critical role in the sub-cortical DAergic dysregulation and schizophrenia-like behaviors observed following adolescent THC exposure

Prenatal exposure to environmental insults and enhanced risk of developing Schizophrenia and Autism Spectrum Disorder : focus on biological pathways and epigenetic mechanisms

When considering neurodevelopmental disorders (NDDs), Schizophrenia (SZ) and Autism Spectrum Disorder (ASD) are considered to be among the most severe in term of prevalence, morbidity and impact on the society. Similar features and overlapping symptoms have been observed at multiple levels, suggesting common pathophysiological bases. Indeed, recent genome-wide association studies (GWAS) and epidemiological data report shared vulnerability genes and environmental triggers across the two disorders. In this review, we will discuss the possible biological mechanisms, including glutamatergic and GABAergic neurotransmissions, inflammatory signals and oxidative stress related systems, which are targeted by adverse environmental exposures and that have been associated with the development of SZ and ASD. We will also discuss the emerging role of the gut microbiome as possible interplay between environment, immune system and brain development. Finally, we will describe the involvement of epigenetic mechanisms in the maintenance of long-lasting effects of adverse environments early in life. This will allow us to better understand the pathophysiology of these NDDs, and also to identify novel targets for future treatment strategies

GSK3β:a plausible mechanism of cognitive and hippocampal changes induced by erythropoietin treatment in mood disorders?

Abstract Mood disorders are associated with significant psychosocial and occupational disability. It is estimated that major depressive disorder (MDD) will become the second leading cause of disability worldwide by 2020. Existing pharmacological and psychological treatments are limited for targeting cognitive dysfunctions in mood disorders. However, growing evidence from human and animal studies has shown that treatment with erythropoietin (EPO) can improve cognitive function. A recent study involving EPO-treated patients with mood disorders showed that the neural basis for their cognitive improvements appeared to involve an increase in hippocampal volume. Molecular mechanisms underlying hippocampal changes have been proposed, including the activation of anti-apoptotic, antioxidant, pro-survival and anti-inflammatory signalling pathways. The aim of this review is to describe the potential importance of glycogen synthase kinase 3-beta (GSK3β) as a multi-potent molecular mechanism of EPO-induced hippocampal volume change in mood disorder patients. We first examine published associations between EPO administration, mood disorders, cognition and hippocampal volume. We then highlight evidence suggesting that GSK3β influences hippocampal volume in MDD patients, and how this could assist with targeting more precise treatments particularly for cognitive deficits in patients with mood disorders. We conclude by suggesting how this developing area of research can be further advanced, such as using pharmacogenetic studies of EPO treatment in patients with mood disorders

New insights on the interplay between psychopharmacology and neuroplasticity in psychiatric disorders

Tese de Doutoramento em Ciências da SaúdeIt is now clear that various forms of structural plasticity, including the generation of new neurons and glial cells, may modify pathophysiological processes in neuropsychiatric disorders, namely in depression. In fact, several studies have shown decreased hippocampal neurogenesis in depressed patients, while treatment with different antidepressant drugs in animal models increases neurogenesis in this region, allowing the recovery from emotional and cognitive changes. However, these effects have not been described for all the available classes of antidepressant drugs. Furthermore, the neuroplastic effects of antidepressants in other neurogenic regions such as the hypothalamus have yet to be determined. Despite the importance of these drugs in the recovery from depression, a significant proportion of depressed patients reveal incomplete remission and develop treatment-resistant forms of the disorder. The use of atypical antipsychotics in these cases has been widely used in the clinical setting. However, the neuroplastic effects of these drugs in depression and schizophrenia are still largely unknown. Taking this into consideration we aimed to explore new perspectives on the interplay between psychopharmacology and neuroplasticity in these psychiatric disorders. To explore the neuroplastic effects of the antidepressant Pirlindole, a MAO-A (monoamine oxidase, type A) inhibitor, we used the unpredictable chronic mild stress (uCMS) animal model of depression. Our results indicate that Pirlindole is able to reverse the behavioural effects of stress exposure, potentiating hippocampal adult neurogenesis and rescuing the stress-induced dendritic atrophy of granule neurons in the dentate gyrus of the hippocampus. These results further reinforce the notion that the modulation of monoaminergic neurotransmission is involved in the neuroplastic effects of currently available antidepressant drugs. To dissect the potential actions of antidepressants in adult neurogenesis in the hypothalamus we treated animals exposed to uCMS with two different classes of antidepressants: fluoxetine (a selective serotonin reuptake inhibitor) and imipramine (a tricyclic antidepressant). Our results demonstrate that chronic stress and antidepressant treatment can modulate hypothalamic neurogenesis. Moreover, we proved that different classes of antidepressants, with an opposite action on appetite and body weight gain, differentially modulate hypothalamic neurogenesis. This data indicates that in addition to the neuroplastic effects on the hippocampus, stress and antidepressant drugs also modulate hypothalamic adult neurogenesis.Furthermore, we explored the role of neuroplasticity in the therapeutic actions of atypical antipsychotics in depression. To achieve this, we treated animals exposed to uCMS with a classical (haloperidol) and an atypical (clozapine) antipsychotic. Our data demonstrates that the atypical antipsychotic clozapine improved measures of depressive-like behavior while haloperidol had no beneficial effect, aggravating learned helplessness in the forced swimming test and behavior flexibility in a cognitive task. Importantly, an upregulation of adult neurogenesis and neuronal survival was observed in animals treated with clozapine while haloperidol promoted a downregulation of these processes. These results demonstrate that the atypical antipsychotic is able to reverse the behavioral effects of chronic stress by improving adult neurogenesis, cell survival and neuronal reorganization. Finally, to understand the impact of different classes of antipsychotics in the negative and cognitive symptoms of schizophrenia, we used a neurodevelopmental model of schizophrenia. Animals expose prenatally to the cytostatic agent methylazoxymethanol (MAM) presented specific cognitive deficits and social impairments. The classical antipsychotic haloperidol presented no beneficial effects in these behavioral dimensions. The atypical antipsychotic clozapine and risperidone revealed a positive effect on both dimensions while aripiprazole presented a significant effect in the social measure. Adult gliogenesis is affected in animals exposed to MAM, being modulated by the atypical antipsychotics used. Neurogenesis is not altered in MAM animals, with haloperidol negatively affecting this phenomenon. In this work, we proved that classical and atypical antipsychotics differentially modulate hippocampal cell genesis possibly contributing to different behavioural actions in hippocampal dependent functions. Together, these findings contribute to expand our knowledge on the role of psychopharmacological agents (including antidepressants and antipsychotics) on the modulation of different neuroplastic events, including cell genesis and neuronal remodelling. In the future, this knowledge may help to pave the way for new therapeutic interventions both in depression and schizophrenia.É actualmente sabido que várias formas de plasticidade estrutural, incluindo a formação de novos neurónios e células da glia, podem modificar o processo patofisiológico em algumas doenças neuropsiquiátricas, nomeadamente a depressão. De facto, vários estudos têm demonstrado uma redução da neurogénese hipocampal em pacientes com depressão. Para além disso, o tratamento com diferentes fármacos, nomeadamente os antidepressivos, revelou em modelos animais, aumentar a neurogénese nesta região cerebral, permitindo uma recuperação na componente emocional e cognitiva. Contudo, estes efeitos não estão descritos para todas as classes de antidepressivos disponíveis. Além disso, os efeitos dos antidepressivos na neuroplasticidade em outras regiões neurogénicas como o hipotálamo ainda não foram determinados. Apesar da importância destes fármacos na recuperação da depressão, uma proporção significativa de pacientes revela remissão incompleta bem como formas resistentes ao tratamento da doença. Nestes casos, o uso de antipsicóticos atípicos tem sido amplamente utilizado no contexto clínico. No entanto, os efeitos destes fármacos na neuroplasticidade na depressão e esquizofrenia são ainda amplamente desconhecidos. Tendo isto em consideração, propusemos explorar novas perspectivas na inter-relação entre a psicofarmacologia e a neuroplasticidade nestas doenças psiquiátricas. Para determinar os efeitos do antidepressivo inibidor da MAO-A (monoamina oxidase, tipo A) Pirlindol na neuroplasticidade, utilizamos o modelo animal de exposição a stress crónico moderado e imprevisível (uCMS). Os nossos resultados indicam que o Pirlindol é capaz de reverter os efeitos comportamentais de exposição ao stress, potenciando o aumento na neurogénese no hipocampo adulto e recuperando igualmente a atrofia dendrítica induzida pelo stress em neurónios granulares no giro dentado do hipocampo. Estes resultados reforçam a ideia de que a modulação da neurotransmissão monoaminérgica está envolvida nos efeitos neuroplasticos promovida pelos antidepressivos. Para dissecar, as acções dos antidepressivos na neurogénese hipotalâmica, utilizamos o modelo animal de depressão uCMS e tratamento com diferentes classes de antidepressivos: fluoxetina (um inibidor selectivo da reabsorção de serotonina) e imipramina (um antidepressivo tricíclico). Os nossos resultados demonstram que o stress crónico e o tratamento com antidepressivos modulam a neurogénese no hipotálamo. Além disso, provou-se que diferentes classes de antidepressivos, com uma acção contrária no apetite e no ganho de peso corporal, modulam a neurogénese no hipotálamo de uma forma diferencial. Estes resultados, indicam que, para além do hipocampo, o stress e os antidepressivos também modulam a neurogénese no hipotálamo adulto. Em seguida, exploramos o papel da neuroplasticidade nas acções terapêuticas dos antipsicóticos atípicos na depressão. Para isso, utilizou-se o modelo animal de depressão uCMS e tratamento com o antipsicótico clássico (haloperidol) e o atípico (clozapina). Os nossos dados demonstram que, o antipsicótico atípico clozapina melhorou o comportamento depressivo. Por outro lado, o haloperidol não teve qualquer efeito benéfico, agravando o desalento aprendido no teste de natação forçada e a flexibilidade comportamental numa tarefa cognitiva. Simultaneamente observou-se um aumento da neurogénese adulta e da sobrevivência neuronal em animais tratados com clozapina, enquanto que o haloperidol promoveu uma redução nestes processos. Estes resultados, demonstram que o antipsicótico atípico é capaz de reverter os efeitos comportamentais do stress crónico através da melhoria na neurogénese adulta, da sobrevivência celular e da reorganização neuronal. Por último, para compreender o impacto das diferentes classes de antipsicóticos nos sintomas negativos e cognitivos da esquizofrenia, utilizamos um modelo de neurodesenvolvimento desta mesma patologia. Os animais expostos no período pré-natal ao agente acetato de metilazoximetanol (MAM) apresentaram défices cognitivos e sociais. O antipsicótico clássico haloperidol não apresentou efeitos benéficos nestas dimensões de comportamento. Por outro lado, os antipsicóticos atípicos, clozapina e risperidona, apresentaram um efeito positivo em ambas as dimensões com o aripiprazol apresentando apenas um efeito estatístico na dimensão social. A gliogénese adulta esta afectada nos animais MAM, sendo esta modulada pelos antipsicóticos atípicos usados. A neurogénese não se encontra alterada neste modelo, sendo, no entanto, negativamente afectada pelo haloperidol. Neste trabalho, provamos que os antipsicóticos clássicos e atípicos modulam diferencialmente a formação de novas células no hipocampo, contribuindo possivelmente para diferentes acções comportamentais, em funções dependentes do hipocampo. Em suma, estes resultados contribuem para expandir o nosso conhecimento sobre o papel de agentes psicofarmacológicos (incluindo antidepressivos e antipsicóticos) na modulação de diferentes eventos neuroplásticos, incluindo a formação de novas células e a remodelação neuronal. No futuro, este conhecimento poderá ajudar na implementação de novas intervenções terapêuticas tanto na depressão como na esquizofrenia.The work presented in this thesis was performed in the Life and Health Sciences Research Institute (ICVS), University of Minho. Financial support was provided by a PhD grant (SFRH/BD/88825/2012) from the FCT - Foundation for Science and Technology -, by FEDER funds through the Operational Programme Competitiveness Factors - COMPETE and National Funds through FCT under the project POCI-01-0145-FEDER-007038; and by the project NORTE-01-0145-FEDER-000013, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF)

Zebrafish: A Model Deciphering the Impact of Flavonoids on Neurodegenerative Disorders

Over the past century, advances in biotechnology, biochemistry, and pharmacognosy have spotlighted flavonoids, polyphenolic secondary metabolites that have the ability to modulate many pathways involved in various biological mechanisms, including those involved in neuronal plasticity, learning, and memory. Moreover, flavonoids are known to impact the biological processes involved in developing neurodegenerative diseases, namely oxidative stress, neuroinflammation, and mitochondrial dysfunction. Thus, several flavonoids could be used as adjuvants to prevent and counteract neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Zebrafish is an interesting model organism that can offer new opportunities to study the beneficial effects of flavonoids on neurodegenerative diseases. Indeed, the high genome homology of 70% to humans, the brain organization largely similar to the human brain as well as the similar neuroanatomical and neurochemical processes, and the high neurogenic activity maintained in the adult brain makes zebrafish a valuable model for the study of human neurodegenerative diseases and deciphering the impact of flavonoids on those disorders

Narrative Review of the Complex Interaction between Pain and Trauma in Children: A Focus on Biological Memory, Preclinical Data, and Epigenetic Processes

The incidence and collective impact of early adverse experiences, trauma, and pain continue to increase. This underscores the urgent need for translational efforts between clinical and preclinical research to better understand the underlying mechanisms and develop effective therapeutic approaches. As our understanding of these issues improves from studies in children and adolescents, we can create more precise preclinical models and ultimately translate our findings back to clinical practice. A multidisciplinary approach is essential for addressing the complex and wide-ranging effects of these experiences on individuals and society. This narrative review aims to (1) define pain and trauma experiences in childhood and adolescents, (2) discuss the relationship between pain and trauma, (3) consider the role of biological memory, (4) decipher the relationship between pain and trauma using preclinical data, and (5) examine the role of the environment by introducing the importance of epigenetic processes. The ultimate scope is to better understand the wide-ranging effects of trauma, abuse, and chronic pain on children and adolescents, how they occur, and how to prevent or mitigate their effects and develop effective treatment strategies that address both the underlying causes and the associated physiological and psychological effects

A Potential Role For Sap97 In Psychiatric Disorders

The goal of this dissertation is to further understand the genetic architecture of neuropsychiatric disorders, such as autism spectrum disorder (ASD) and schizophrenia (SCZ). We attempt to understand the functional significance of the gene synapse associated protein of 97KDa (SAP97) and identify a novel role for SAP97 in the etiology of neuropsychiatric disorders. SAP97 belongs to a family of scaffolding proteins, the membrane-associated guanylate kinases (MAGUKs), that are highly enriched in the postsynaptic density of synapses and play an important role in organizing protein complexes necessary for synaptic development and plasticity. Large-scale genetic studies have implicated MAGUKs in neuropsychiatric disorders such as intellectual disability, ASD, and SCZ, but knock-out mice have been impossible to study because the Sap97 null mice die soon after birth due to a craniofacial defect. In Chapter 2, we studied the transcriptomic and behavioral consequences of a viable, brain-specific conditional knockout of Sap97 (SAP97-cKO). RNA sequencing (RNAseq) from hippocampi from control and SAP97-cKO male animals identified 67 differentially expressed transcripts, which were specifically enriched for SCZ-related genes. Subjecting SAP97-cKO mice to a battery of behavioral tests revealed a subtle anxiety-like phenotype present in both male and female SAP97-cKO animals, as well as a mild male-specific cognitive deficit and female-specific motor learning deficit. Collectively, this work suggests that loss of Sap97 alters behavior, and may contribute to some of the endophenotypes present in SCZ. In Chapter 3, we discuss how the SAP97-cKO mouse may serve as a novel model system for interrogating aspects of the cellular and molecular defects underlying SCZ and other related neuropsychiatric disorders

Characterizing neuroanatomical changes in parvalbumin and perineuronal nets in a rat DISC-1 knock out model

BACKGROUND: Schizophrenia is a debilitating disorder that has a profound impact on quality of life due to the presence of both cognitive deficits and psychotic symptoms. Despite having significant global economic and social costs and a worldwide prevalence of 1%, schizophrenia is still not well understood. Research has been making strides in uncovering the pathophysiology and the etiology that drive this disease, ranging from genetic abnormalities, disrupted circuitry, changes in microarchitecture, to impaired synaptic connectivity. Evidence suggests that disrupted-in-schizophrenia-1 (DISC1) driven genetic disturbances in fast-spiking parvalbumin (PV) neurons and their surrounding perineuronal nets (PNNs) likely contribute to schizophrenia etiology as they are part of the microcircuits required for working memory, a cognitive function that has been consistently impaired in schizophrenic patients. OBJECTIVE: To identify the neuroanatomical changes in PV neurons and surrounding PNNs in the superficial and deep layers of the prelimbic and infralimbic prefrontal cortex of a rat DISC-1 knockout model. METHODS: 19 DISC1-KO male rats and 15 wildtype rats were treated with saline or MK-801. They were sacrificed between P268-269 and brains were extracted and separated at the corpus callosum. After fixing and preserving, the brains were sliced then stained to visualize parvalbumin and perineuronal nets with immunohistochemistry. Slices were imaged and analyzed for PV, PNN, and PV+PNN counts in the superficial and deep regions of the prelimbic and infralimbic cortices. Averages counts within each group were taken and analyzed via 2-way ANOVAs for each brain region and dependent variable. RESULTS: DISC1-KO rats displayed the following trending changes: decreased PV cells in deep layers of infralimbic and decreased PNNs throughout the prelimbic cortex. MK-801 appears to increase the number of unsheathed PV cells in the superficial layers of prelimbic and infralimbic cortex. It decreased the number of PNNs in the prelimbic of wildtype animals but not in the DISC1-KO cohort. MK-801 moderately increased PV counts in DISC1-KO. CONCLUSIONS: This DISC1-KO model is a promising model of schizophrenia as we see the same directionality of decreases in PV and PNN as post mortem human studies. Furthermore, MK-801 is seen to have an increasing trend effect on PV cells, which should be considered when interpreting findings in future studies that look at these markers