No abstract

Aversive associative memories formed by the association between a neutral conditioned stimulus (CS+) and an aversive unconditioned stimulus (US+) are progressively made permanent by a process of consolidation 1 . However upon retrieval, intervention by amnestic agents [2][3][4][5][6][7] , either prior to or immediately after retrieval, results in disruption of the previously consolidated fear memory. This suggests that a consolidated memory returns to a transient destabilized state shortly after reactivation necessitating a dynamic time-dependent process of reconsolidation in order to persist further. During this reconstruction, a memory is vulnerable to experimental intervention [8][9][10] leading to amnesia, but can also be enhanced [11][12][13] or modified on the long-term [14][15][16] , thereby updating the previous memory with new information [14][15][16][17] . In clinical terms, the bidirectional and adaptive nature of reconsolidation is ideally placed to mediate both the modification of memory strength 12 , as well as memory content 16,18 , rendering this process a promising therapeutical target to counteract the hyper-responsive fear system. In order to fully exploit reconsolidation-based therapies that adapt the content of fear memories, leading to a loss of fear response on the long term, it is crucial to elucidate the molecular underpinnings of reconsolidation, which to this date remain obscure.3 Long-lasting changes in synaptic efficacy brought about by gene transcription, protein synthesis and changes in strength of hippocampal glutamatergic synapses via AMPA receptor trafficking are believed to be the cellular substrates of learning and memory [19][20][21] . Although reconsolidation is not merely a recapitulation of the initial consolidation process 22 , it has been shown that transcription, de novo protein synthesis and synaptic protein degradation in the hippocampus are also necessary for memory remodeling after retrieval 4,7,17,[23][24][25] . Here, we investigated whether the temporal profile of reconsolidation that is hypothesized to be limited to a 6 h time window 5,8 actuates a sequential profile of defined dorsohippocampal AMPA receptor synaptic plasticity that is crucial to the synaptic remodeling that underlies subsequent fear expression (changes in memory strength) and reinterpretation of fear memory after retrieval (changes in memory content). Results Memory recall induces acute hippocampal AMPAR-endocytosisIn order to analyze whether glutamate receptors are regulated during reconsolidation in animals receiving the US+ and retrieval (US-R), we dissected the dorsal hippocampus at 1 and 4 h post-retrieval, and analyzed the synaptic membrane fraction, including membrane-bound proteins and associated proteins 26,27 , by immunoblotting for subunits of AMPA receptors. A no-shock group experiencing retrieval (NS-R) was used to control for the specificity of an aversive-associative memory (Supplementary Fig. S1). These two time points were chosen as they fall within the 6-h time window after ret...

No abstract

Hippocampal and amygdaloid neuroplasticity are important substrates for Pavlovian fear conditioning. The hippocampus has been implicated in trace fear conditioning. However, a systematic investigation of the significance of the trace interval has not yet been performed. Therefore, this study analyzed the time-dependent involvement of N-methyl-D-aspartate (NMDA) receptors in the dorsal hippocampus in one-trial auditory trace fear conditioning in C57BL/6J mice. The NMDA receptor antagonist APV was injected bilaterally into the dorsal hippocampus 15 min before training. Mice were exposed to tone (conditioned stimulus [CS]) and footshock (unconditioned stimulus [US]) in the conditioning context without delay (0 s) or with CS-US (trace) intervals of 1-45 s. Conditioned auditory fear was determined 24 h after training by the assessment of freezing and computerized evaluation of inactivity in a new context; 2 h later, context-dependent memory was tested in the conditioning context. NMDA receptor blockade by APV markedly impaired conditioned auditory fear at trace intervals of 15 s and 30 s, but not at shorter trace intervals. A 45-s trace interval prevented the formation of conditioned tone-dependent fear. Context-dependent memory was always impaired by APV treatment independent of the trace interval. The results indicate that the dorsal hippocampus and its NMDA receptors play an important role in auditory trace fear conditioning at trace intervals of 15-30-s length. In contrast, NMDA receptors in the dorsal hippocampus are unequivocally involved in contextual fear conditioning independent of the trace interval. The results point at a time-dependent role of the dorsal hippocampus in encoding of noncontingent explicit stimuli. Preprocessing of long CS-US contingencies in the hippocampus appears to be important for the final information processing and execution of fear memories through amygdala circuits.