Fear-potentiated acoustic startle paradigms have been used to investigate phasic and sustained components of conditioned fear in rats and humans. This study describes a novel training protocol to assess phasic and sustained fear in freely behaving C57BL/6J mice, using freezing and/or fear-potentiated startle as measures of fear, thereby, if needed, allowing in vivo application of various techniques, such as optogenetics, electrophysiology and pharmacological intervention, in freely behaving animals. An auditory Pavlovian fear conditioning paradigm, with pseudo-randomized conditioned-unconditioned stimulus presentations at various durations, is combined with repetitive brief auditory white noise burst presentations during fear memory retrieval 24 h after fear conditioning. Major findings are that (1) a motion sensitive platform built on mechano-electrical transducers enables measurement of startle responses in freely behaving mice, (2) absence or presence of startle stimuli during retrieval as well as unpredictability of a given threat determine phasic and sustained fear response profiles and (3) both freezing and startle responses indicate phasic and sustained components of behavioral fear, with sustained freezing reflecting unpredictability of conditioned stimulus (CS)/unconditioned stimulus (US) pairings. This paradigm and available genetically modified mouse lines will pave the way for investigation of the molecular and neural mechanisms relating to the transition from phasic to sustained fear.Keywords: Anxiety, behavior, conditioning, fear, freely moving, learning, mouse, predictability, retrieval, unpredictability In such a conditioned fear paradigm, a neutral stimulus (e.g. tone or light) is paired with an aversive stimulus (e.g. electric footshock) to evaluate short-term as well as long-term conditioned fear responses to the predictable conditioned threat. Thus, after Pavlovian fear conditioning, presentation of the conditioned stimulus (CS) alone has the ability to generate a variety of behavioral expressions, such as freezing and/or fear-potentiated startle responses, indicating states of fear and anxiety. Fear is a generally adaptive state of apprehension that develops rapidly and declines quickly once the threatening stimulus is absent; a physiological situation reflecting a phasic fear state, which can be measured after training to short and discrete cues that are predictably paired with aversive events (e.g. footshock) Davis et al. 2010;de Jongh et al. 2003;Miles et al. 2011). In contrast to that, situations in patients suffering from anxiety disorders are characterized by a more long-lasting state of fear. It is, therefore, assumed that clinical symptoms of several anxiety disorders can be modeled more precisely with paradigms aiming on these long-lasting and sustained, rather than phasic fear states. To account for that, experimental studies have begun to focus on more long-lasting states of fear, that are elicited by less predictable threats using fear-potentiated startle as behavioral readout in...
Behavioral profiles are strongly shaped by an individual's whole life experience. The accumulation of negative experiences over lifetime is thought to promote anxiety-like behavior in adulthood (“allostatic load hypothesis”). In contrast, the “mismatch hypothesis” of psychiatric disease suggests that high levels of anxiety-like behavior are the result of a discrepancy between early and late environment. The aim of the present study was to investigate how different life histories shape the expression of anxiety-like behavior and modulate fear memory. In addition, we aimed to clarify which of the two hypotheses can better explain the modulation of anxiety and fear. For this purpose, male mice grew up under either adverse or beneficial conditions during early phase of life. In adulthood they were further subdivided in groups that either matched or mismatched the condition experienced before, resulting in four different life histories. The main results were: (i) Early life benefit followed by late life adversity caused decreased levels of anxiety-like behavior. (ii) Accumulation of adversity throughout life history led to impaired fear extinction learning. Late life adversity as compared to late life benefit mainly affected extinction training, while early life adversity as compared to early life benefit interfered with extinction recall. Concerning anxiety-like behavior, the results do neither support the allostatic load nor the mismatch hypothesis, but rather indicate an anxiolytic effect of a mismatched early beneficial and later adverse life history. In contrast, fear memory was strongly affected by the accumulation of adverse experiences over the lifetime, therefore supporting allostatic load hypothesis. In summary, this study highlights that anxiety-like behavior and fear memory are differently affected by specific combinations of adverse or beneficial events experienced throughout life.
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