El presente artículo, gratuito en Science, investiga en un modelo en rata, las rutas neuronales por las que se extinguen los recuerdos negativos. Tal vez si se desentraña la función de la amígdala en dichos experimentos, revierta en el tratamiento de fenómenos como el conocido como estrés postraumático. Es importante identificar las formas en que se "digieren" experiencias dolorosas. Estudios como el que aquí se reseña da una idea de que sin entender el funcionamiento básico del cerebro es imposible abordar sus patologías.
Prefrontal inputs to the amygdala instruct fear extinction memory formation
Abstract
Persistent anxiety after a psychological trauma is a hallmark of many anxiety disorders. However, the neural circuits mediating the extinction of traumatic fear memories remain incompletely understood. We show that selective, in vivo stimulation of the ventromedial prefrontal cortex (vmPFC)–amygdala pathway facilitated extinction memory formation, but not retrieval. Conversely, silencing the vmPFC-amygdala pathway impaired extinction formation and reduced extinction-induced amygdala activity. Our data demonstrate a critical instructional role for the vmPFC-amygdala circuit in the formation of extinction memories. These findings advance our understanding of the neural basis of persistent fear, with implications for posttraumatic stress disorder and other anxiety disorders.
Keywords
- optogenetics
- prefrontal cortex
- amygdala
- fear extinction,memory retrieval,anxiety
- post-traumatic stress disorder
INTRODUCTION
Anxiety disorders, trauma and stress-related disorders, and phobias (1) are highly prevalent psychiatric conditions that are still inadequately treated. Recent years have seen rapid advances in the understanding of the neural basis of pathological anxiety and the learning processes that underlie anxiety responses associated with a traumatic event, such as fear conditioning and extinction (2–6). However, there remain outstanding questions regarding the critical functional brain circuits that regulate the formation and extinction of fear memories.
Previous studies have shown that successful fear extinction in rodents is associated with robust activity in the ventromedial prefrontal cortex (vmPFC) (notably, the infralimbic cortex), the medial intercalated cell nuclei of the amygdala (mICNs), and a subpopulation of basolateral amygdala (BL) “extinction” neurons, whereas deficient extinction corresponds to sustained activity in the prelimbic cortex (PL) and a subset of BL (“fear”) neurons (2, 4–8). Furthermore, electrically or pharmacologically stimulating the vmPFC is found to strengthen extinction in parallel with changes in the excitability and plasticity of BL and mICN neurons, whereas vmPFC lesions or inactivation disrupts extinction and attenuates BL-to-ICN-driven inhibition of central medial amygdala (CeM) output (9–15).
Collectively, these prior findings propose a model whereby inputs from the vmPFC to the amygdala support the formation of extinction memories and/or gate the expression of these memories. However, previous experimental manipulations either lack precise temporal control over the circuit or affect vmPFC projections not only to the amygdala but also to other target regions implicated in fear, such as the hippocampus, striatum, and midbrain
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