Persistence Of Fear Memory Research Articles

Behavioral characteristics of rats predisposed to learned helplessness: Reduced reward sensitivity, increased novelty seeking, and persistent fear memories

The congenitally helpless rat strain, which was selectively bred for increased susceptibility to learned helplessness, may model the predisposition to affective disorders, including depression and post-traumatic stress disorder. Other than the selected trait, the behavior of this strain is not well characterized. In this study, we assessed congenitally helpless rats on several behavioral tests. First, we assessed reward sensitivity by measuring their consumption of a 5% sucrose solution. Next, we assessed exploratory behavior and fearfulness in both a novel and familiar open field, and in a light–dark test. Finally, we assessed fear conditioning by exposing the animals to 4 tone-shock pairs on 1 day (acquisition) and then presenting 60 tones over the next 2 days (extinction). Compared to normal Sprague–Dawley controls, congenitally helpless rats showed less consumption of the sucrose solution and more exploratory behavior in the novel, but not the familiar, open fields. They also showed less fearfulness in the light–dark test, but more conditioned freezing to the tone predicting shock. Moreover, this freezing was resistant to extinction; congenitally helpless rats not only failed to show a fear decrement during extinction, but actually showed increased fear, a phenomenon termed “paradoxical enhancement.” Thus, congenitally helpless rats appear to have a behavioral phenotype characterized by reduced sensitivity to reward, increased drive to explore novel environments, and increased propensity to form and maintain fear-associated memories. This behavioral phenotype is discussed as resembling the personality of humans vulnerable to post-traumatic stress disorder.

Altered Behavioral Responses to Noxious Stimuli and Fear in Glutamate Receptor 5 (GluR5)- or GluR6-Deficient Mice

Different kainate receptor (KAR) subtypes contribute to the regulation of both excitatory and inhibitory transmission. However, no study has reported a role for KAR subtypes in behavioral responses to persistent pain and fear memory. Here we show that responses to capsaicin or inflammatory pain were significantly reduced in mice lacking glutamate receptor 5 (GluR5) but not GluR6 subunits. In classic fear-memory tests, mice lacking GluR6 but not GluR5 showed a significant reduction in fear memory when measured 3, 7, or 14 d after training. Additionally, synaptic potentiation was significantly reduced in the lateral amygdala of GluR6 but not GluR5 knock-out mice. Our findings provide evidence that distinct KAR subtypes contribute to chemical/inflammatory pain and fear memory. Selectively targeting different KAR subtypes may provide a useful strategy for treating persistent pain and fear-related mental disorders.

Identification of a Signaling Network in Lateral Nucleus of Amygdala Important for Inhibiting Memory Specifically Related to Learned Fear

We identified the Grp gene, encoding gastrin-releasing peptide, as being highly expressed both in the lateral nucleus of the amygdala, the nucleus where associations for Pavlovian learned fear are formed, and in the regions that convey fearful auditory information to the lateral nucleus. Moreover, we found that GRP receptor (GRPR) is expressed in GABAergic interneurons of the lateral nucleus. GRP excites these interneurons and increases their inhibition of principal neurons. GRPR-deficient mice showed decreased inhibition of principal neurons by the interneurons, enhanced long-term potentiation (LTP), and greater and more persistent long-term fear memory. By contrast, these mice performed normally in hippocampus-dependent Morris maze. These experiments provide genetic evidence that GRP and its neural circuitry operate as a negative feedback regulating fear and establish a causal relationship between Grpr gene expression, LTP, and amygdala-dependent memory for fear.

Key word index

Over the past decades, behaviour and cognitive psychology have produced fruitful and mutually converging theories from which hypotheses could be derived on the nature and origin of fear and anxiety disorders. Notwithstanding the emergence of effective treatments, there are still many questions that remain to be answered. Here, I will argue that the burgeoning field of behavioural neuroscience may advance our understanding of fear, anxiety disorders and its treatments. Decades of fear-conditioning research across species have begun to elucidate the neurobiological mechanisms underlying associative fear learning and memory. The fear-conditioning paradigm provides a well-controlled and fine-grained research platform to examine these processes. Although the traditional fear conditioning paradigm was originally designed to unveil general principles of fear (un)learning, it is well-suited to understand the transition from normal fear to pathological fear and the mechanisms of change. This paper presents 1) a selection of fear conditioning studies on the generalization and persistence of associative fear memory as intermediate phenotypes of fear and anxiety disorders, and 2) insights from neuroscience on the malleability of fear memory with the potential to provide a long-term cure for anxiety and related disorders.