RESUMO
Over the last few decades, there has been a progressive transition from a categorical to a dimensional approach to psychiatric disorders. Especially in the case of substance use disorders, interest in the individual vulnerability to transition from controlled to compulsive drug taking warrants the development of novel dimension-based objective stratification tools. Here we drew on a multidimensional preclinical model of addiction, namely the 3-criteria model, previously developed to identify the neurobehavioural basis of the individual's vulnerability to switch from controlled to compulsive drug taking, to test a machine-learning assisted classifier objectively to identify individual subjects as vulnerable/resistant to addiction. Datasets from our previous studies on addiction-like behaviour for cocaine or alcohol were fed into a variety of machine-learning algorithms to develop a classifier that identifies resilient and vulnerable rats with high precision and reproducibility irrespective of the cohort to which they belong. A classifier based on K-median or K-mean-clustering (for cocaine or alcohol, respectively) followed by artificial neural networks emerged as a highly reliable and accurate tool to predict if a single rat is vulnerable/resilient to addiction. Thus, each rat previously characterized as displaying 0-criterion (i.e., resilient) or 3-criteria (i.e., vulnerable) in individual cohorts was correctly labelled by this classifier. The present machine-learning-based classifier objectively labels single individuals as resilient or vulnerable to developing addiction-like behaviour in a multisymptomatic preclinical model of addiction-like behaviour in rats. This novel dimension-based classifier increases the heuristic value of these preclinical models while providing proof of principle to deploy similar tools for the future of diagnosis of psychiatric disorders.
Assuntos
Comportamento Aditivo , Transtornos Relacionados ao Uso de Cocaína , Cocaína , Transtornos Relacionados ao Uso de Substâncias , Animais , Ratos , Reprodutibilidade dos Testes , Comportamento Aditivo/diagnóstico , Comportamento Aditivo/psicologia , Aprendizado de Máquina , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Transtornos Relacionados ao Uso de Cocaína/psicologiaRESUMO
The identification of neural substrates underlying the long lasting debilitating impact of drug cues is critical for developing novel therapeutic tools. Metabolic coupling has long been considered a key mechanism through which astrocytes and neurons actively interact in response of neuronal activity, but recent findings suggested that disrupting metabolic coupling may represent an innovative approach to prevent memory formation, in particular drug-related memories. Here, we review converging evidence illustrating how memory and addiction share neural circuitry and molecular mechanisms implicating lactate-mediated metabolic coupling between astrocytes and neurons. With several aspects of addiction depending on mnemonic processes elicited by drug experience, disrupting lactate transport involved in the formation of a pathological learning, linking the incentive, and motivational effects of drugs with drug-conditioned stimuli represent a promising approach to encourage abstinence.
Assuntos
Astrócitos/fisiologia , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Ácido Láctico/metabolismo , Memória , Neurônios/fisiologia , Animais , Astrócitos/metabolismo , Transtornos Relacionados ao Uso de Cocaína/psicologia , Condicionamento Psicológico , Humanos , MotivaçãoRESUMO
Fragile X syndrome (FXS) is characterized by intellectual disability and autistic traits, and results from the silencing of the FMR1 gene coding for a protein implicated in the regulation of protein synthesis at synapses. The lack of functional Fragile X mental retardation protein has been proposed to result in an excessive signaling of synaptic metabotropic glutamate receptors, leading to alterations of synapse maturation and plasticity. It remains, however, unclear how mechanisms of activity-dependent spine dynamics are affected in Fmr knockout (Fmr1-KO) mice and whether they can be reversed. Here we used a repetitive imaging approach in hippocampal slice cultures to investigate properties of structural plasticity and their modulation by signaling pathways. We found that basal spine turnover was significantly reduced in Fmr1-KO mice, but markedly enhanced by activity. Additionally, activity-mediated spine stabilization was lost in Fmr1-KO mice. Application of the metabotropic glutamate receptor antagonist α-Methyl-4-carboxyphenylglycine (MCPG) enhanced basal turnover, improved spine stability, but failed to reinstate activity-mediated spine stabilization. In contrast, enhancing phosphoinositide-3 kinase (PI3K) signaling, a pathway implicated in various aspects of synaptic plasticity, reversed both basal turnover and activity-mediated spine stabilization. It also restored defective long-term potentiation mechanisms in slices and improved reversal learning in Fmr1-KO mice. These results suggest that modulation of PI3K signaling could contribute to improve the cognitive deficits associated with FXS.
Assuntos
Cognição , Espinhas Dendríticas/patologia , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Síndrome do Cromossomo X Frágil/fisiopatologia , Potenciação de Longa Duração , Animais , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/patologia , Região CA1 Hipocampal/fisiopatologia , Células Cultivadas , Espinhas Dendríticas/metabolismo , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/metabolismo , Receptores de Glutamato Metabotrópico/antagonistas & inibidoresRESUMO
Absence of statistical significance (i.e., p > 0.05) in the results of a frequentist test comparing two samples is often used as evidence of absence of difference, or absence of effect of a treatment, on the measured variable. Such conclusions are often wrong because absence of significance may merely result from a sample size that is too small to reveal an effect. To conclude that there is no meaningful effect of a treatment/condition, it is necessary to use an appropriate statistical approach. For frequentist statistics, a simple tool for this goal is the 'two one-sided t-test,' a form of equivalence test that relies on the a priori definition of a minimal difference considered to be relevant. In other words, the smallest effect size of interest should be established in advance. We present the principles of this test and give examples where it allows correct interpretation of the results of a classical t-test assuming absence of difference. Equivalence tests are also very useful in probing whether certain significant results are also biologically meaningful, because when comparing large samples it is possible to find significant results in both an equivalence test and in a two-sample t-test, assuming no difference as the null hypothesis.
RESUMO
The ability to adapt one's behavior in response to changing circumstances, or cognitive flexibility, is often altered in neuropsychiatric and neurodevelopmental conditions. In rodents, cognitive flexibility is frequently assessed using associative learning paradigms with a reversal component. The majority of existing protocols rely on unrestrictive exploration with no discouragement of wrong responses and are often influenced by spatial cues, at least during the test's learning phase. Here, we present a rewarded contingency discrimination learning test that minimizes the task's spatial component and contains an element that actively discourages pure exploratory responses. The method described herein is a manual version that can be performed using home-made equipment, but the test setup is amenable to automatization and can be adapted to address more complex cognitive demands, including conditional associative learning, attentional set formation, and attention shifting.
RESUMO
Oxytocin (OT) orchestrates social and emotional behaviors through modulation of neural circuits. In the central amygdala, the release of OT modulates inhibitory circuits and, thereby, suppresses fear responses and decreases anxiety levels. Using astrocyte-specific gain and loss of function and pharmacological approaches, we demonstrate that a morphologically distinct subpopulation of astrocytes expresses OT receptors and mediates anxiolytic and positive reinforcement effects of OT in the central amygdala of mice and rats. The involvement of astrocytes in OT signaling challenges the long-held dogma that OT acts exclusively on neurons and highlights astrocytes as essential components for modulation of emotional states under normal and chronic pain conditions.
Assuntos
Astrócitos/metabolismo , Núcleo Central da Amígdala/metabolismo , Emoções/fisiologia , Neurônios/metabolismo , Ocitocina/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Núcleo Central da Amígdala/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ocitocina/farmacologia , Ratos , Ratos Wistar , Receptores de Ocitocina/metabolismoRESUMO
The adipocyte plasma membrane-associated protein APMAP is expressed in the brain where it associates with γ-secretase, a protease responsible for the generation of the amyloid-ß peptides (Aß) implicated in the pathogenesis of Alzheimer's disease (AD). In this study, behavioral investigations revealed spatial learning and memory deficiencies in our newly generated mouse line lacking the protein APMAP. In a mouse model of AD, the constitutive deletion of APMAP worsened the spatial memory phenotype and led to increased Aß production and deposition into senile plaques. To investigate at the molecular level the neurobiological functions of APMAP (memory and Aß formation) and a possible link with the pathological hallmarks of AD (memory impairment and Aß pathology), we next developed a procedure for the high-grade purification of cellular APMAP protein complexes. The biochemical characterization of these complexes revealed a series of new APMAP interactomers. Among these, the heat shock protein HSPA1A and the cation-dependent mannose-6-phosphate receptor (CD-M6PR) negatively regulated APP processing and Aß production, while clusterin, calnexin, arginase-1, PTGFRN and the cation-independent mannose-6-phosphate receptor (CI-M6PR/IGF2R) positively regulated APP and Aß production. Several of the newly identified APMAP interactomers contribute to the autophagy-lysosome system, further supporting an emergent agreement that this pathway can modulate APP metabolism and Aß generation. Importantly, we have also demonstrated increased alternative splicing of APMAP and lowered levels of the Aß controllers HSPA1A and CD-M6PR in human brains from neuropathologically verified AD cases.