A mutant mouse with a highly specific contextual fear-conditioning deficit found in an N-ethyl-N-nitrosourea (ENU) mutagenesis screen (original) (raw)
Related papers
Behavioural Brain Research, 1998
Fear conditioning with electric shock (unconditioned stimulus, US) paired with tone cue (conditioned stimulus, CS) has been extensively applied in recent molecular neurobiological analysis of hippocampal dysfunction in mice because the context-dependent test phase of this learning paradigm is claimed to detect hippocampal impairment in a specific manner, whereas the cue-dependent test serves as a control situation independent of hippocampal function. These claims are based on hippocampal lesion studies performed with rats and have not been conclusively confirmed with mice with specific hippocampal lesion. Therefore, I investigated how hippocampal ibotenic acid lesion affects conditioned fear in mice. I confirm that extensive lesions localized to the hippocampus impair context-dependent learning but also show that, unlike in the original rat studies, the behavioral impairment is only partial. Furthermore, studying two inbred strains of mice (C57BL/6 and DBA/2) with highly different hippocampal function, I show that the presence or absence of CS during training may influence the mouse's ability to learn complex multiple contextual stimuli in a genotype-dependent manner. I conclude that performance at the 'context' test may be based on complex configural (hippocampal) learning but it can also be based on a more simple elemental (non-hippocampal) learning thus leading to potentially false-negative findings in the analysis of hippocampal dysfunction.
Generalisation of conditioned fear and its behavioural expression in mice
Behavioural Brain Research, 2003
Mice are favourite subjects in molecular and genetic memory research and frequently studied with classical fear conditioning paradigms that use an auditory cue (conditioned stimulus, CS +) to predict an aversive, unconditioned stimulus (US). Yet the conditions that control fear memory specificity and generalisation and their behavioural expression in such conditioned mice have not been analysed systematically. In the current study we addressed these issues in the most widely used mouse strain of behavioural genetics, C57Bl/6. In keeping with findings in other species we demonstrate the dependence of fear memory generalisation on training intensity (i.e. both US intensity and the number of CS + and US applied) after both excitatory (explicitly paired presentation of CS + and US) and inhibitory training (explicitly unpaired presentation of CS + and US). Furthermore, inhibitory overtraining was associated with changes of uncued anxiety-like behaviour in a light/dark exploration test, indicative of an emotional sensitisation reaction as consequence of a lack of US predictability. Together our results describe the qualitatively and quantitatively different increases of defensive behaviour in response to conditioned stimuli of different salience and identify training conditions that lead to fear memory generalisation and emotional sensitisation in C57Bl/6 inbred mice.
Genetic background differences and nonassociative effects in mouse trace fear conditioning
Learning & Memory, 2007
Fear conditioning, including variants such as delay and trace conditioning that depend on different neural systems, is widely used to behaviorally characterize genetically altered mice. We present data from three strains of mice, C57/BL6 (C57), 129/SvlmJ (129), and a hybrid strain of the two (F 1 hybrids), trained on various versions of a trace fear-conditioning protocol. The initial version was taken from the literature but included unpaired control groups to assess nonassociative effects on test performance. We observed high levels of nonassociative freezing in both contextual and cued test conditions. In particular, nonassociative freezing in unpaired control groups was equivalent to freezing shown by paired groups in the tests for trace conditioning. A number of pilot studies resulted in a new protocol that yielded strong context conditioning and low levels of nonassociative freezing in all mouse strains. During the trace-CS test in this protocol, freezing in unpaired controls remained low in all strains, and both the C57s and F 1 hybrids showed reliable associative trace fear conditioning. Trace conditioning, however, was not obtained in the 129 mice. Our findings indicate that caution is warranted in interpreting mouse fear-conditioning studies that lack control conditions to address nonassociative effects. They also reveal a final set of parameters that are important for minimizing such nonassociative effects and demonstrate strain differences across performance in mouse contextual and trace fear conditioning.
Trace Fear Conditioning: Procedure for Assessing Complex Hippocampal Function in Mice
Bio-protocol, 2018
The trace fear conditioning protocol is designed to measure hippocampal function in mice. The protocol includes a neutral conditioned stimulus (tone) and an aversive unconditioned stimulus (shock), separated in time by a trace interval. The trace interval between the tone and the shock critically involves the hippocampus and could be used to evaluate hippocampal-dependent learning and memory. In this protocol, we presented mice with five pairings of tone and shock separated by a 20 sec trace interval. Freezing was measured 24 h after conditioning to evaluate contextual memory by placing mice in the conditioned chamber. In addition, 48 h after conditioning, freezing was measured in a dark chamber, which served as a different context. This method enables precise detection of hippocampal-dependent learning and memory following pharmacological and genetic manipulations that impair or enhance hippocampal function.
Neurobiology of Learning and Memory, 2011
N-methyl-D-aspartate (NMDA) receptors play an important role in excitatory neurotransmission and mediate synaptic plasticity associated with learning and memory. NMDA receptors are composed of two NR1 and two NR2 subunits and the identity of the NR2 subunit confers unique electrophysiologic and pharmacologic properties to the receptor. The precise role of NR2Ccontaining receptors in vivo is poorly understood. We have performed a battery of behavioral tests on NR2C knockout/nβ-galactosidase knock-in mice and found no difference in spontaneous activity, basal anxiety, forced-swim immobility, novel object recognition, pain sensitivity and reference memory in comparison to wildtype counterparts. However, NR2C knockout mice were found to exhibit deficits in fear acquisition and working memory compared to wildtype mice. Deficit in fear acquisition correlated with lack of fear conditioning-induced plasticity at the thalamo-amygdala synapse. These findings suggest a unique role of NR2C-containing receptors in associative and executive learning representing a novel therapeutic target for cognitive deficits and mental disorders such as post-traumatic stress disorder.
Impaired Extinction of Learned Contextual Fear Memory in Early Growth Response 1 Knockout Mice
Molecules and Cells, 2014
Inductive expression of early growth response 1 (Egr-1) in neurons is associated with many forms of neuronal activity. However, only a few Egr-1 target genes are known in the brain. The results of this study demonstrate that Egr-1 knockout (KO) mice display impaired contextual extinction learning and normal fear acquisition relative to wild-type (WT) control animals. Genome-wide microarray experiments revealed 368 differentially expressed genes in the hippocampus of Egr-1 WT exposed to different phases of a fear conditioning paradigm compared to gene expression profiles in the hippocampus of KO mice. Some of genes, such as serotonin receptor 2C (Htr2c), neuropeptide B (Npb), neuronal PAS domain protein 4 (Npas4), NPY receptor Y1 (Npy1r), fatty acid binding protein 7 (Fabp7), and neuropeptide Y (Npy) are known to regulate processing of fearful memories, and promoter analyses demonstrated that several of these genes contained Egr-1 binding sites. This study provides a useful list of potential Egr-1 target genes which may be regulated during fear memory processing.
Stimulus generalization and return of fear in C57BL/6J mice
Frontiers in Behavioral Neuroscience, 2012
Return of fear following successful exposure therapy is a common problem. More insight into the characteristics of extinction learning is crucial in enhancing the efficiency of therapeutic interventions. In particular, understanding the mechanisms that underlie the generalization of extinction learning to other discrete stimuli is indispensable. Presently, little is known about the molecular and genetic mechanisms underlying this phenomenon. In this study, we attempt to develop a new conditioning protocol to study return of fear, caused by a stimulus change after extinction, in the most commonly used mouse strain of behavioral genetics, C57BL/6J. Perceptual changes to an auditory fear conditioned stimulus led to return of fear after initially successful fear-reduction, relative to appropriate control treatment. We argue that this protocol will be a useful tool to unravel the neurobiological underpinnings that regulate generalization of extinction and return of fear. Key questions for future research include the identification of crucial brain structures, neurotransmitters and signaling pathways that underly this behavioral phenomenon. Arguably, such research will open up new perspectives for neurobiological therapy augmentation.
Modulation of Gene Expression in Contextual Fear Conditioning in the Rat
PLoS ONE, 2013
In contextual fear conditioning (CFC) a single training leads to long-term memory of context-aversive electrical foot-shocks association. Mid-temporal regions of the brain of trained and naive rats were obtained 2 days after conditioning and screened by two-directional suppression subtractive hybridization. A pool of differentially expressed genes was identified and some of them were randomly selected and confirmed with qRT-PCR assay. These transcripts showed high homology for rat gene sequences coding for proteins involved in different cellular processes. The expression of the selected transcripts was also tested in rats which had freely explored the experimental apparatus (exploration) and in rats to which the same number of aversive shocks had been administered in the same apparatus, but temporally compressed so as to make the association between painful stimuli and the apparatus difficult (shock-only). Some genes resulted differentially expressed only in the rats subjected to CFC, others only in exploration or shock-only rats, whereas the gene coding for translocase of outer mitochondrial membrane 20 protein and nardilysin were differentially expressed in both CFC and exploration rats. For example, the expression of stathmin 1 whose transcripts resulted up regulated was also tested to evaluate the transduction and protein localization after conditioning.
Environmental Variables that Ameliorate Extinction Learning Deficits in the 129S1/SvlmJ Mouse Strain
Genes, Brain and Behavior
Fear conditioning is an associative learning process by which organisms learn to avoid environmental stimuli that are predictive of aversive outcomes. Fear extinction learning is a process by which avoidance of fear-conditioned stimuli is attenuated when the environmental stimuli is no longer predictive of the aversive outcome. Aberrant fear conditioning and extinction learning are key elements in the development of several anxiety disorders. The 129S1 inbred strain of mice is used as an animal model for maladaptive fear learning because this strain has been shown to generalize fear to other nonaversive stimuli and is less capable of extinguishing fear responses relative to other mouse strains, such as the C57BL/6. Here we report new environmental manipulations that enhance fear and extinction learning, including the ability to discriminate between an aversively paired tone and a neutral tone, in both the 129S1 and C57BL/6 strains of mice. Specifically, we show that discontinuous ("pipped") tone stimuli significantly enhance within-session extinction learning and the discrimination between neutral and aversively paired stimuli in both strains. Furthermore, we find that extinction training in novel contexts significantly enhances the consolidation and recall of extinction learning for both strains. Cumulatively, these results underscore how environmental changes can be leveraged to ameliorate maladaptive learning in animal models and may advance cognitive and behavioral therapeutic strategies.