空間・恐怖記憶回路の生物学的基盤 The Circuits of Space and Fear
S2-1-2-1 PERK-eIF2α signaling in synaptic plasticity, cognition, and brain disorders ○Eric Klann1 The Center for Neural Science, New York University1 The proper regulation of translation is required for the formation of long-lasting synaptic plasticity and long-term memory. A major site of translational control involves the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) by PKR-like endoplasmic reticulum (ER) kinase (PERK). To study the role of PERK-eIF2α signaling in synaptic plasticity and cognition, we used the Cre-lox expression system to selectively disrupt PERK expression in the adult mouse forebrain. We found that PERK conditional knockout (cKO) mice displayed abnormal synaptic plasticity and cognitive dysfunction, consistent with a role for PERK-eIF2α signaling in these processes. Interestingly, it has been reported that eIF2α phosphorylation is elevated in the brains of Alzheimer's disease (AD) patients and mouse models of AD. Therefore, we crossed PERK cKO mice with APP/PS1 mutant mice to determine whether reducing eIF2α phosphorylation could correct synaptic and cognitive deficits displayed by these AD model mice. We found that decreasing eIF2α phosphorylation via genetic reduction of PERK corrected impairments in synaptic plasticity and spatial memory deficits displayed by the APP/PS1 mutant mice. Our findings are consistent with the notion that eIF2α phosphorylation is a key site for the control of synaptic plasticity and memory in physiological and pathophysiological conditions.	S2-1-2-2 Role of NMDA receptor in an autistic mouse model ○Bong-Kiun Kaang1 Departments of Biological Sciences and Brain and Cognitive Sciences, Seoul National University1 Altered synaptic structure and function are implicated in the molecular pathogenesis of autism as in other synaptopathies. Detailed functions of the synaptic proteins in these synaptopathies are, however, not clearly understood. Shank proteins or ProSAPs are core scaffolding synaptic proteins of the postsynaptic density containing multi-domain structures that provide multiple protein-protein interaction sites to link glutamate receptors, cytoskeletons and other scaffolding proteins. Recently, de novo SHANK2 microdeletions were found in ASD patients. One of these mutations results in loss of exons 6 and 7 and a frameshift. To understand how this microdeletion is related to the autistic behaviors, we examined synaptic properties in the hippocampal SC to CA1 synapses of KO mice carrying a mutation identical to the human microdeletion. We found that basal synaptic transmission at CA1 synapses was not changed in Shank2 KO mice relative to WT animals. NMDA receptor dependent LTP and LTD at CA1 synapses were impaired in Shank2 KO mice. Furthermore, the NMDA/AMPA ratio was reduced by 40% relative to WT synapses, suggesting that reduced NMDA receptor function may contribute to ASD-like behaviors in Shank2 KO mice. To test this hypothesis and to restore NMDA receptor function, we used D-cycloserine, a partial agonist at the glycine-binding site of NMDA receptors, and CDPPB, a membrane-permeable positive allosteric modulator of mGluR5, which increases the responsiveness of mGluR5 to glutamate and enhances NMDA receptor function. We found that both D-cycloserine and CDPPB fully recovered the NMDA/AMPA ratio in hippocampal KO slices. Moreover, CDPPB restored the impaired LTP and LTD in Shank2 KO brain slices.
S2-1-2-3 Context novelty modulates hippocampal circuit interactions ○Thomas J. McHugh1 RIKEN Brain Science Institute1 Contextual learning involves associating cues with a particular environment and relating them to past experiences. The hippocampus processes and stores contextual information, however questions remain about the interactions between its multiple circuits during memory recall and how unique circuits influence behavior. To address this we examined the commonalities of context encoding across the CA3/CA2/CA1 axis. While we found largely coherent responses in control mice, we employed conditional genetics to demonstrate that a loss of synaptic plasticity in DG or CA3 revealed distinct functions of each CA field in context processing. We compared mice exposed sequentially to a familiar context or to a familiar then a novel context to reveal that the active ensemble of neurons in each CA field predicted a unique aspect of behavior. Further, our data suggest that the poorly understood region CA2 can act as a comparator of current and past experience.	S2-1-2-4 Optogenetic activation of presynaptic inputs in lateral amygdala forms fear memory ○Jin-Hee Han1 Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST)1 The lateral amygdala (LA) has been proposed as a critical site for fear memory storage and, long-term potentiation (LTP) at LA synapses induced by fear conditioning has been thought to be the cellular mechanism underlying fear memory formation. However, similar synaptic changes are also observed in upstream areas, such as the medial geniculate nucleus (MGN) and auditory cortex (AC), raising the critical question of where the fear memory is actually formed and stored. Here we used optogenetic approach to determine if direct stimulation of the presynaptic auditory projections in the LA can serve as a conditioned stimulus (CS) that, when paired with a foot shock unconditioned stimulus (US), can drive fear conditioning. Mice were injected with AAV-ChR2 in the two main auditory pathways to LA, MGN and AC, sending auditory information into the LA during auditory fear conditioning. Optical photostimulation was used to activate ChR2-expressing presynaptic axons in the LA as a CS for fear conditioning. 24 hours later, the same optogenetic CS produced robust freezing responses while control mice injected with AAV-GFP did not. In parallel, we also examined LTP induction in LA slices with ChR2 expression in MGN and AC projections to LA neurons. Whole-cell patch recording showed that pairing photo-stimulation (3 Hz) of auditory projections in LA with postsynaptic current injection produced strong LTP at LA synapses. The in vivo measurement of EFP (evoked field potential) also revealed that the fear conditioning induced LTP at LA synapses. Our data provide compelling evidence that fear memory can be formed in the LA synapses independent of the activity of upstream areas delivering auditory information and LTP at the LA synapses may underlie fear memory formation.
S2-1-2-5 Neuronal encoding of the transition from specific to generalized fear in the amygdala ○Sumantra Chattarji1, Supriya Ghosh1 Neurobiology, National Centre for Biological Sciences1 One of the most powerful model systems for elucidating the neural basis of learning is Pavlovian fear conditioning, in which subjects rapidly learn to associate a previously neutral tone (CS, conditioned stimulus) with a coincident aversive stimulus (US, unconditioned stimulus), e.g. a footshock. Re-exposure to the CS alone elicits a conditioned response ?“freezing”, which provides a measure for the learned association. The early stages of fear memory formation involve strengthening of sensory afferents from the thalamus to the lateral amygdala (LA). As useful as this simple behavioral model has been in studying basic cellular mechanisms of associative learning, it does not capture some of the essential features of learning in the “real world”, where learned associations are rarely invariant over time and need to be generalized appropriately to novel settings. There are costs associated with both too little and too much generalization. Understanding these processes is also critical for gaining insights into affective disorders such as post-traumatic stress disorder (PTSD), which may be viewed as an instance of overgeneralization. Hence, we use in vivo unit recordings in awake, behaving rats to examine the neuronal encoding of fear generalization. Rats, chronically implanted with a microdrive containing multiple movable electrode bundles, were trained to associate one of two conditioned stimuli in a differential fear conditioning paradigm with either a weak or strong US. Single isolated neurons were classified based on their changes in differential responses to CS+ (paired with US) and CS- (not paired with US), following learning. Rats were first conditioned with weak US, and then reconditioned 24 h later with strong US. After weak-US conditioning, rats exhibited significantly higher freezing to CS+ than CS-. Correspondingly, a significantly greater proportion of recorded tone responsive LA cells showed cue-specificity by showing enhanced response to CS+, while a smaller number failed to discriminate between CS+ and CS-. In contrast, after strong-US, a much larger proportion of cells failed to discriminate between CS+ over CS-. Thus, a more aversive US elicited a significant shift towards cells showing loss in cue-specificity. Strikingly, same neurons that were initially able to differentiate CS+ from CS-, failed to do so after re-conditioning with higher US. This shift was paralleled by greater fear generalization at the behavioral level. These neural mechanisms may provide insights into the transition of emotional states from normal fear to pathological anxiety exhibited in stress disorders.	S2-1-2-6 恐怖記憶形成により誘導される扁桃体中心核シナプス増強 Synaptic Potentiation in the Nociceptive Amygdala Following Fear Learning in Mice ○渡部文子1, 加藤総夫1,2 ○Ayako M. Watabe1, Fusao Kato1,2 慈恵医大・医・神経生理1, 名古屋大2 Dept Neurosci, Jikei Univ Schl of Med1, Nagoya Univ2 Pavlovian fear conditioning is a classical form of associative learning, which depends on associative synaptic plasticity in the amygdala. Recent findings suggest that the central amygdala (CeA) plays an active role in the acquisition of fear learning. However, little is known about the synaptic properties of the CeA in fear learning. The capsular part of the central amygdala (CeC) receives direct nociceptive information from the external part of the lateral parabrachial nucleus (lPB), as well as highly processed polymodal signals from the basolateral nucleus of the amygdala (BLA). Therefore, we focused on CeC as a convergence point for polymodal BLA signals and nociceptive lPB signals, and explored the synaptic regulation of these pathways in fear conditioning. Here we show that fear conditioning results in synaptic potentiation in both BLA-CeC and lPB-CeC synapses. This potentiation is dependent on associative fear learning rather than on nociceptive or sensory experience, or fear retrieval. We also found that the synaptic weight of the lPB-CeC and BLA-CeC pathways was correlated in fear-conditioned mice, suggesting that fear learning may induced activity-dependent heterosynaptic interactions between these two pathways. This synaptic potentiation is associated with both postsynaptic and presynaptic changes in the lPB-CeC and BLA-CeC pathways. These results indicate that the CeC may provide an important locus of Pavlovian association, integrating direct nociceptive signals with polymodal sensory signals. In addition to the well-established plasticity of the lateral amygdala, the multi-step nature of this association system contributes to the highly orchestrated tuning of fear learning.

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