Active (new and reactivated) memories are considered to be labile and sensitive to treatments disrupting the time-dependent consolidation/reconsolidation processes required for their stabilization. Active memories also allow the integration of new information for updating memories. Here, we investigate the possibility that, when active, the internal state provided by amnesic treatments is represented and integrated within the initial memory and that amnesia results from the absence of this state at testing. We showed in rats that the amnesia resulting from systemic, intracerebroventricular and intrahippocampal injections of the protein synthesis inhibitor cycloheximide, administered after inhibitory avoidance training or reactivation, can be reversed by a reminder, including re-administration of the same drug. Similar results were obtained with lithium chloride (LiCl), which does not affect protein synthesis, when delivered systemically after training or reactivation. However, LiCl can induce memory given that a conditioned taste aversion was obtained for a novel taste, presented just before conditioning or reactivation. These results indicate that memories can be established and maintained without de novo protein synthesis and that experimental amnesia may not result from a disruption of memory consolidation/reconsolidation. The findings more likely support the integration hypothesis: posttraining/postreactivation treatments induce an internal state, which becomes encoded with the memory, and should be present at the time of testing to ensure a successful retrieval. This integration concept includes most of the previous explanations of memory recovery after retrograde amnesia and critically challenges the traditional memory consolidation/reconsolidation hypothesis, providing a more dynamic and flexible view of memory.
Although generalization to conditioned stimuli is not a new phenomenon, renewed interest in understanding its biological underpinning has stemmed from its association with a number of anxiety disorders. Generalization as it relates to fear processing is a temporally dynamic process in which animals, including humans, display fear in response to similar yet distinct cues or contexts as the time between training and testing increases. This Review surveys the literature on contextual fear generalization and its relation to several views of memory, including systems consolidation, forgetting, and transformation hypothesis, which differentially implicate roles of the hippocampus and neocortex in memory consolidation and retrieval. We discuss recent evidence on the neurobiological mechanisms contributing to the increase in fear generalization over time and how generalized responding may be modulated by acquisition, consolidation, and retrieval mechanisms. Whereas clinical perspectives of generalization emphasize a lack of fear inhibition to CS cues or fear toward intermediate CS cues, the time-dependent nature of generalization and its relation to traditional views on memory consolidation and retrieval are often overlooked. Understanding the time-dependent increase in fear generalization has important implications not only for understanding how generalization contributes to anxiety disorders but also for understanding basic long-term memory function. © 2016 Wiley Periodicals, Inc.
In previous studies using male rodents, context change disrupted a fear response at a short, but not a long, retention interval. Here, we examined the effects of context changes on fear responses as a function of time in male and female rats. Males displayed context discrimination at all intervals, whereas females exhibited generalization by 5 d. Ovariectomized females with no hormone replacement displayed context discrimination at 5 d, whereas those receiving 17b-estradiol generalized their fear response to a neutral context. These results demonstrate that fear generalization for contextual cues occurs faster in female rats and is mediated, in part, by estrogens.Anxiety disorders are the most prevalent mental disorder in the US ). More specifically, females are 60% more likely than males to be diagnosed with an anxiety disorder (Kessler et al. 1994;Wang et al. 2005) and the exact cause of this sex difference is unknown. For example, post-traumatic stress disorder (PTSD) is one specific anxiety disorder with a higher prevalence rate in females (Kessler et al. 1995;Olff et al. 2007). PTSD is marked by the persistence of fear and anxiety and the tendency to generalize fear to neutral cues and contexts (Grillon and Morgan 1999;Brewin 2001). These symptoms are possibly due to deficits in discriminatory fear learning (Grillon and Morgan 1999;Jovanovic et al. 2009Jovanovic et al. , 2010 or the result of hyperarousal associated with anxiety disorders (Archer 1974;Bartolini et al. 1987;Armstrong and Hille 1998).Studies of fear generalization with animals have demonstrated that a learned fear response is context-dependent; fear responses are significantly attenuated when testing occurs at a short interval (e.g., 1 d after training) in a neutral context (i.e., the context shift effect). However, when rodents are tested at long delays after training (e.g., 14 d after training), the context shift effect is eliminated; rodents freeze equivalently to the training and the neutral context (Riccio et al. 1984;Zhou and Riccio 1996;Biedenkapp and Rudy 2007;Wiltgen and Silva 2007). Over time, rodents generalize their fear response to neutral contexts. For example, Zhou and Riccio (1996) trained male rats in passive avoidance and tested 1 or 14 d after training in the same context as training or a neutral context. At 1 d, rats tested in the neutral context display little or no avoidance, whereas those tested in the same context demonstrate high levels of avoidance (i.e., the context shift effect). However, 14 d after training, the groups tested in a neutral context had performance comparable to the group in the same (training) context (Zhou and Riccio 1996). This effect has been replicated by several labs (for review, see Jasnow et al. 2012).In recent years, several hypotheses have been developed to explain the phenomenon of fear generalization in animal models. Hippocampal-dependent memory, such as memory for context, undergoes a transfer from short-term hippocampal stores to more long-term cortical stores, a process known as syste...
The microdeletion of copy number variant 16p11.2 is one of the most common genetic mutations associated with neurodevelopmental disorders, such as Autism Spectrum Disorders (ASDs). Here, we describe our comprehensive behavioral phenotyping of the 16p11.2 deletion line developed by Alea Mills on a C57BL/6J and 129S1/SvImJ F1 background (Del m). Male and female Del m mice were tested in developmental milestones as preweanlings (PND2-PND12), and were tested in open field activity, elevated zero maze, rotarod, novel object recognition, fear conditioning, social approach, and other measures during post-weaning (PND21), adolescence (PND42), and adulthood (>PND70). Developmentally, Del m mice show distinct weight reduction that persists into adulthood. Del m males also have reduced grasp reflexes and limb strength during development, but no other reflexive deficits whereas Del m females show limb strength deficits and decreased sensitivity to heat. In a modified version of a rotarod task that measures balance and coordinated motor activity, Del m males, but not females, show improved performance at high speeds. Del m males and females also show agespecific reductions in anxiety-like behavior compared with WTs, but neither sex show deficits in a social preference task. When assessing learning and memory, Del m males and females show age-specific impairments in a novel object or spatial object recognition, but no deficits in contextual fear memory. This work extends the understanding of the behavioral phenotypes seen with 16p11.2 deletion by emphasizing age and sex-specific deficits; important variables to consider when studying mouse models for neurodevelopmental disorders.
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