MacPherson P, McGaffigan R, Wahlsten D, Nguyen PV. Impaired fear memory, altered object memory and modified hippocampal synaptic plasticity in split-brain mice. Brain Res 1210: 179-188

University of Alberta School of Medicine, Department of Physiology, Edmonton, Alberta, Canada T6G 2H7.
Brain Research (Impact Factor: 2.84). 06/2008; 1210:179-88. DOI: 10.1016/j.brainres.2008.03.008
Source: PubMed


The hippocampus is critical for memory formation. However, the contributions of the hippocampal commissure (HC) and the corpus callosum (CC) are less clear. To elucidate the role of the forebrain commissures in learning and memory, we performed a behavioural and electrophysiological characterization of an inbred mouse strain that displays agenesis of the CC and congenitally reduced HC (BTBR T+ tf/J; 'BTBR'). Compared to a control strain, BTBR mice have severely impaired contextual fear memory, with normal object recognition memory. Interestingly, continuous environmental "enrichment" significantly increased object recognition in BTBR, but not in control C57BL/6 ('BL/6') mice. In area CA1 of hippocampal slices, BTBR displayed intact expression of long-term potentiation (LTP), paired-pulse facilitation (PPF) and basal synaptic transmission, compared to BL/6 mice. However, BTBR hippocampal slices show an increased susceptibility to depotentiation (DPT), an activity-induced reversal of LTP. We conclude that the HC and CC are critical for some forms of hippocampal memory and for synaptic resistance to DPT. Agenesis of the CC and HC may unmask some latent ability to encode, store or retrieve certain forms of recognition memory. We suggest that the increased susceptibility to DPT in BTBR may underlie the memory phenotype reported here.

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    • "In mice 40 days post-injury, we found elevated levels of activated microglia in the corpus callosum as assessed by Iba1 immunoreactivity. The corpus callosum carries interhemispheric connections that are important for the processing of social and emotional information in humans [38,39], and loss of the corpus callosum in mice impacts emotional memory more than object memory [40]. Iba1 positive cells were elevated in the corpus callosum of rcTBI injured animals compared to shams, regardless of their shock stress status. "
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    ABSTRACT: The debilitating effects of repetitive concussive traumatic brain injury (rcTBI) have been increasingly recognized in both military and civilian populations. rcTBI may result in significant neurological, cognitive, and affective sequelae, and is often followed by physical and/or psychological post-injury stressors that may exacerbate the effects of the injury and prolong the recovery period for injured patients. However, the consequences of post-injury stressors and their subsequent effects on social and emotional behavior in the context of rcTBI have been relatively little studied in animal models. Here, we use a mouse model of rcTBI with two closed-skull blunt impacts 24 hours apart and social and emotional behavior testing to examine the consequences of a stressor (foot shock fear conditioning) following brain injury (rcTBI). rcTBI alone did not affect cued or contextual fear conditioning or extinction compared to uninjured sham animals. In the sucrose preference test, rcTBI animals had decreased preference for sucrose, an anhedonia-like behavior, regardless of whether they experienced foot shock stress or were non-shocked controls. However, rcTBI and post-injury foot shock stress had synergistic effects in tests of social recognition and depression-like behavior. In the social recognition test, animals with both injury and shock were more impaired than either non-shocked injured mice or shocked but uninjured mice. In the tail suspension test, injured mice had increased depression-like behavior compared with uninjured mice, and shock stress worsened the depression-like behavior only in the injured mice with no effect in the uninjured mice. These results provide a model of subtle emotional behavioral deficits after combined concussive brain injury and stress, and may provide a platform for testing treatment and prevention strategies for social behavior deficits and mood disorders that are tailored to patients with traumatic brain injury.
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    • "Deficits in fear conditioning have been consistently noted in several rodent models of autism, including the vasoactive intestinal peptide knockout mice [10], prenatal exposure to valproic acid mouse model [21], and the BTBR inbred strain[20] [41]. However, there are two conflicting reports of Pavlovian eyeblink conditioning humans with ASD in the normal IQ range, either no differences were discovered [1] or there were differences in the amplitude and timing of the conditioned response [33]. "
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    • "Reversal learning deficits also feature in human patients with schizophrenia [58] as well as in mouse models for autism and schizophrenia [41], [59], [60], [61], [62], [63], [64], [65]. Similarly, contextual and cue fear conditioning deficits in GluD1 knockout mice also occur in mice models implicated in ASDs and schizophrenia [61], [62], [66], [67], [68] and may represent impaired conditioned association in schizophrenic and ASD individuals [69], [70], [71], [72]. Interestingly, GluD1 knockout mouse manifested an enhanced working memory. "
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