経験・学習依存的な情動変化の神経回路基盤とその破綻 Neural circuits of experience dependent emotional change
S2-3-3-1 恐怖条件づけ学習を担うニューロン集団の変化 Reorganization of neuronal populations contributes to fear conditioning ○野村洋1, 松木則夫1 ○Hiroshi Nomura1, Norio Matsuki1 東京大学大学院薬学系研究科薬品作用学教室1 Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, The University of Tokyo1 Fear conditioning is a learning paradigm in which animals and humans learn an association between conditioned (e.g. context, tone) and unconditioned (e.g. electrical shock) stimuli. When a mouse receives footshocks in a context, the mouse's behavioral response to the context is changed to freezing. What is the neuronal activity and synaptic mechanisms underlying the behavioral change? Individual fear memories are encoded in specific neuronal subpopulations within the amygdala. However, the activity and synaptic change in specific neuronal subpopulations remain unclear. In this study, we investigated alteration of neuronal population response to conditioning context and synaptic alteration in memory-related neuronal populations. Neuronal activities in the basolateral amygdala (BLA) were measured during context presentation before, during and after conditioning by mapping of immediate early gene transcripts. Fear conditioning reorganized population response to the context. The change of neuronal activity depended on their activity during conditioning and correlated with freezing time. Next, the synaptic transmission of BLA neurons active and inactive during context presentation following fear conditioning was examined. BLA neurons active during context presentation were identified by using Arc-dVenus transgenic mice in which destabilized fluorescent protein dVenus is driven under the Arc gene promoter. We found that fear conditioning induces presynaptic potentiation and that the potentiation is localized in active neurons. Taken together, we have demonstrated that fear conditioning reorganized neuronal population engaged in the conditioning context with presynaptic potentiation.	S2-3-3-2 ショウジョウバエin vivoイメージングを用いた加齢依存的記憶低下の解析 Age-dependent memory impairment analyzed through functional imaging in Drosophila ○殿城亜矢子1,2 ○Ayako Tonoki1,2, Ronald L. Davis2 千葉大学大学院薬学研究院生化学1, スクリプス研究所フロリダ神経科学2 Dept Biochemistry, Grad School of Pharmaceutical, Chiba University1, Department of Neuroscience, The Scripps Research Institute Florida, FL, USA2 Memory impairment is one of the common complaints of the elderly. However, the biological basis for memory impairment with aging remains obscure. To reveal the cellular memory processes that are disrupted with aging, we have used functional cellular imaging, which has recently been applied in Drosophila for discovering and visualizing memory traces, which are defined as the neurophysiologic changes that occur in neurons due to learning. Functional imaging of neural activity in the processes of the dorsal paired medial (DPM) and mushroom body (MB) neurons revealed that the capacity to form an intermediate-term memory (ITM) trace in the DPM neurons after learning is lost with age, while the capacity to form a short-term memory trace in the α´/β´ MB neurons remains unaffected by age. Stimulation of the DPM neurons by activation of a temperature-sensitive cation channel between acquisition and retrieval enhanced ITM in aged but not young flies. These data indicate that the functional state of the DPM neurons is selectively altered with age to cause an age-related impairment of ITM, and demonstrate that altering the excitability of DPM neurons can restore age-related memory impairments.
S2-3-3-3 長期記憶形成におけるアストロサイトの役割 The role of astrocytes in hippocampal-dependent long-term memory formation ○鈴木章円1 ○Akinobu Suzuki1, Sarah A Stern2,3, Virginia Gao2,3, Michael G Garelick3, Pierre J Magistretti4, Cristina M Alberini2,3 富山大学大学院 医学薬学研究部1 Graduate School of Pharmaceutical Sciences, University of Toyama1, Friedman Brain Institute, Graduate School of Biological Science, Mount Sinai School of Medicine, New York, NY2, Center for Neural Science, New York University, New York, NY3, Mind Inst., Swiss Federal Inst. of Technol. Lausanne, Lausanne, Switzerland4 The role of astrocytes and their functional crosstalk with neurons in cognitive functions is poorly understood. Astrocytes and neurons might actually be linked through the coupling of energy metabolism. Glycogen, which is primarily stored in astrocytes, contributes to neuronal function by being broken down into lactate. Here, we investigated the role of glycogenolysis and lactate transport in a hippocampal-dependent memory task. We found that blocking glycogenolysis with the glycogen phosphorylase inhibitor, 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) bilaterally into the hippocampus before inhibitory avoidance (IA) training significantly blocked long-term memory. Furthermore, blocking the lactate transport from astrocytes to neurons with antisense-mediated disruption of the astrocytic lactate transporter monocarboxylate transporter 1 (MCT1) or MCT4 and the neuronal lactate transporter MCT2 blocked long-term memory. We also found that IA learning leads to a significant increase in extracellular lactate levels in the rat hippocampus that derives from astrocytic glycogenolysis and that exogenous administration of L-lactate into hippocampus rescued the memory impairment produced by DAB. L-lactate rescued the memory impairment produced by MCT1 or MCT4 disruption, but did not affect the amnesia produced by MCT2 knock-down. Finally, molecular mechanisms underlying memory formation and related synaptic modifications, including induction of Arc, pCREB and pcofilin were blocked by DAB and rescued by L-lactate. We conclude that astrocytic glycogenolysis and astrocyte-neuron lactate transport play an essential role in the hippocampus during long-term memory formation.	S2-3-3-4 Assembling a behavioral state: distinct neural outputs orchestrate independent features of anxiety ○Sung-Yon Kim1, Avishek Adhikari1, Soo Y. Lee1, James H. Marshel1, Christina K. Kim1, Caitlin S. Mallory1, Maisie Lo1, Sally Pak1, Joanna Mattis1, Byung K. Lim2, Robert Malenka2, Rachel Neve33, Kay M. Tye3, Melissa R. Warden1, Karl Deisseroth1 Department of Bioengineering, Stanford University, CA, U.S.A1, Department of Psychiatry and Behavioral Sciences, Stanford University, CA, U.S.A.2, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology3 Behavioral states in mammals, such as the anxious state, consist of multiple features, including behavioral preferences, physiological changes and subjective valence. Here, we aimed to address this question focusing on anxiety, which is a tractable behavioral state, as several of its features are readily quantifiable. We identified a surprising new role for the bed nucleus of the stria terminalis (BNST) in orchestrating the coordinated reduction of diverse features of anxiety-related phenotypes through distinct output projections. We first demonstrate that two BNST subregions exert opposite effects in anxiety: oval/ovBNST-activity was anxiogenic while anterodorsal/adBNST-associated activity was anxiolytic (decreasing both physiological and behavioral measures of anxiety). Also, we establish that three independent adBNST subpopulations projecting to the lateral hypothalamus, parabrachial nucleus and ventral tegmental area modulate risk-avoidance, respiratory rate and subjective preference, respectively. Our data supports the idea that these largely non-overlapping subpopulations may be recruited by recurrent excitation upon stimulation, leading to anxiolysis. Lastly, supporting the physiological relevance of these findings, in vivo recordings from behaving mice showed that spiking patterns in adBNST neurons specifically differentiated safe and anxiogenic environments. These results demonstrate that distinct BNST subregions exert opposite effects in anxiety, establish separable anxiolytic roles for different adBNST projections, and illustrate processes underlying the coordinated real-time selection of features for the assembly of the anxious state.
S2-3-3-5 恐怖抑制の新しい方法としての社会的ストレス緩衝作用 Social buffering as a novel way to suppress fear responses ○清川泰志1 ○Yasushi Kiyokawa1 東京大院・農・獣医動物行動1 Lab Vet Etho, Univ of Tokyo1 In social buffering, a phenomenon known in various species, stress responses are less distinct when an animal is exposed to a stressor with one or more conspecific animals. We have found that the presence of an unfamiliar conspecific could block fear responses including freezing in response to an auditory or contextual conditioned stimulus in male rats. The intensity of this social buffering is affected by a stress status of and familiarity with the conspecific. For example, the presence of a fearful or unfamiliar conspecific was less effective in social buffering as compared to a non-fearful or familiar conspecific. These results suggest the existence of additional systems that modify the intensity of social buffering. We further analyzed the signals mediating social buffering of conditioned fear responses. We found that the subjects with lesion of the main olfactory epithelium showed fear responses to the conditioned stimulus even if a conspecific was present. In addition, we could induce social buffering by presenting olfactory signals that were derived from a conspecific. These results suggest that the olfactory signals that are perceived at the main olfactory epithelium mediate social buffering of conditioned fear responses. Concurrent researches on this experimental model could propose a hypothetical neural pathway underlying social buffering. After being received at the main olfactory epithelium, olfactory signals are transmitted to the main olfactory bulb and subsequently to the posteromedial region of the olfactory peduncle. The olfactory peduncle then suppresses ipsilateral lateral and central amygdala activation thorough indirect projection and, as a result, blocks fear responses in response to the conditioned stimulus. Because it does not require any pre-training to suppress behavioral and neural responses to the conditioned stimulus like extinction procedure, we propose that social buffering can be a novel way to suppress fear responses in animals.	S2-3-3-6 扁桃体GABA作動性介在細胞集団を介した恐怖消去学習機構 The mechanisms of fear extinction mediating GABAergic interalated neuron in the amygdala ○天野大樹1 ○Taiju Amano1, Denis Pare2 理化学研究所脳科学総合研究センター1, ラトガース大学2 RIKEN BSI1, CMBN, Rutgers Univ, Newark, NJ, USA2 Accumulating data suggest that the amygdala plays a critical role in the acquisition and expression of conditioned fear responses. The lateral nucleus (LA) is the input station of the amygdala for information about conditioned stimuli (CS), whereas the medial sector of the central nucleus (CeM) is the main output region that projects to brainstem fear effectors. However, there are no direct projections from LA to CeM. We hypothesized that the basal nuclei of the amygdala (including BA; basolateral; BL and basomedial; BM) bridge the gap between LA and CeM. We examined the effects of local BL and/or BM inactivations with muscimol 15 min prior to testing fear recall. Independent inactivation of either BL or BM did not reduce conditioned freezing even though an extinction recall deficit was seen the next day. In contrast, combined BL-BM inactivation blocked fear expression. These results suggest that BL and BM nuclei are both involved in fear expression but that there is functional redundancy between them. Furthermore, the extinction deficit caused by BL and/or BM inactivation suggests that these nuclei normally drive extinction related plasticity in one or more of their targets. Likely candidates include infralimbic and GABAergic intercalated (ITC) neurons. We tested the BL-mediated responses of CeM and ITC neurons by whole-cell patch-clamp recording. We observed that extinction training causes a potentiation of BL inputs to ITC neurons, an effect that required infralimbic activity during or shortly after extinction training and caused increased feed-forward inhibition in CeM. Enhancement of BL inputs to ITC neurons involved an altered expression profile of ionotropic glutamate receptors. Therefore, we propose that the expression of conditioned fear responses is determined by the balance between excitatory BA inputs and feed-forward inhibition mediated by ITC neurons in CeM fear output neurons.

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