RESUMEN
Selective inhibition of kappa opioid receptors (KORs) is highly anticipated as a pharmacotherapeutic intervention for substance use disorders and depression. The accepted explanation for KOR antagonist-induced amelioration of aberrant behaviors posits that KORs globally function as a negative valence system; antagonism thereby blunts the behavioral influence of negative internal states such as anhedonia and negative affect. While effects of systemic KOR manipulations have been widely reproduced, explicit evaluation of negative valence as an explanatory construct is lacking. Here, we tested a series of falsifiable hypotheses generated a priori based on the negative valence model by pairing reinforcement learning tasks with systemic pharmacological KOR blockade in male C57BL/6J mice. The negative valence model failed to predict multiple experimental outcomes: KOR blockade accelerated contingency learning during both positive and negative reinforcement without altering innate responses to appetitive or aversive stimuli. We next proposed novelty processing, which influences learning independent of valence, as an alternative explanatory construct. Hypotheses based on novelty processing predicted subsequent observations: KOR blockade increased exploration of a novel, but not habituated, environment and augmented the reinforcing efficacy of novel visual stimuli in a sensory reinforcement task. Together, these results revise and extend long-standing theories of KOR system function.
Asunto(s)
Receptores Opioides kappa , Refuerzo en Psicología , Ratones , Masculino , Animales , Ratones Endogámicos C57BL , Aprendizaje , Condicionamiento Clásico , Antagonistas de Narcóticos/farmacologíaRESUMEN
There is inherent tension between methodologies developed to address basic research questions in model species and those intended for preclinical to clinical translation: basic investigations require flexibility of experimental design as hypotheses are rapidly tested and revised, whereas preclinical models emphasize standardized protocols and specific outcome measures. This dichotomy is particularly relevant in alcohol research, which spans a diverse range of basic sciences in addition to intensive efforts towards understanding the pathophysiology of alcohol use disorder (AUD). To advance these goals there is a great need for approaches that facilitate synergy across basic and translational areas of nonhuman alcohol research. In male and female mice, we establish a modular alcohol reinforcement paradigm: Structured Tracking of Alcohol Reinforcement (STAR). STAR provides a robust platform for quantitative assessment of AUD-relevant behavioral domains within a flexible framework that allows direct crosstalk between translational and mechanistically oriented studies. To achieve cross-study integration, despite disparate task parameters, a straightforward multivariate phenotyping analysis is used to classify subjects based on propensity for heightened alcohol consumption and insensitivity to punishment. Combining STAR with extant preclinical alcohol models, we delineate longitudinal phenotype dynamics and reveal putative neuro-biomarkers of heightened alcohol use vulnerability via neurochemical profiling of cortical and brainstem tissues. Together, STAR allows quantification of time-resolved biobehavioral processes essential for basic research questions simultaneous with longitudinal phenotyping of clinically relevant outcomes, thereby providing a framework to facilitate cohesion and translation in alcohol research.
Asunto(s)
Alcoholismo , Etanol , Masculino , Femenino , Ratones , Animales , Consumo de Bebidas Alcohólicas , Refuerzo en Psicología , Proyectos de InvestigaciónRESUMEN
Inhibitory interneurons orchestrate prefrontal cortex (PFC) activity, but we have a limited understanding of the molecular and experience-dependent mechanisms that regulate synaptic plasticity across PFC microcircuits. We discovered that mGlu5 receptor activation facilitates long-term potentiation at synapses from the basolateral amygdala (BLA) onto somatostatin-expressing interneurons (SST-INs) in mice. This plasticity appeared to be recruited during acute restraint stress, which induced intracellular calcium mobilization within SST-INs and rapidly potentiated postsynaptic strength onto SST-INs. Restraint stress and mGlu5 receptor activation each augmented BLA recruitment of SST-IN phasic feedforward inhibition, shunting information from other excitatory inputs, including the mediodorsal thalamus. Finally, studies using cell-type-specific mGlu5 receptor knockout mice revealed that mGlu5 receptor function in SST-expressing cells is necessary for restraint stress-induced changes to PFC physiology and related behaviors. These findings provide new insights into interneuron-specific synaptic plasticity mechanisms and suggest that SST-IN microcircuits may be promising targets for treating stress-induced psychiatric diseases.
Asunto(s)
Interneuronas , Somatostatina , Animales , Interneuronas/fisiología , Potenciación a Largo Plazo , Ratones , Plasticidad Neuronal/fisiología , Corteza Prefrontal/fisiología , Somatostatina/metabolismo , Sinapsis/fisiologíaRESUMEN
In two commentaries, Kostromina and Grishina (2018) and Mironenko (2018) offered constructive thoughts and questions in response to an article by Giordano (2018, Culture & Psychology, 23, 502-518) on the merits of an approach to understanding individual personality that focuses on the processes rather than structures of personality. In this reply, the authors seek to clarify some of the points made in the original article. The authors also describe a personality process-structure duality, whereby personality is conceptualized in terms of processes or structures based on the methods used to study it. If the goal is to understand the dynamic and emergent properties of individual personality, the authors continue to argue for the merits of a process-centric approach and the avoidance of structural thinking.