シンポジウム（Symposium）

Symposium Molecular and circuit mechanisms in physiological and pathological decision-making behavior シンポジウム意思決定行動とその変容の分子・回路機構

7月25日（木）14:40～15:10　第3会場（朱鷺メッセ　2F　メインホールB） 1S03a-1 A role for nucleus accumbens D1-/D2-neuron pathways in controlling learning impaired in psychiatric disorders Tom Macpherson（Macpherson Tom），Takatoshi Hikida（Hikida Takatoshi） Osaka University Institute for Protein Research The nucleus accumbens (NAc) forms a critical component of basal ganglia networks controlling decision-making and action selection, and its dysfunction is thought to contribute to impairments in reward, aversive, and cognitive learning associated with several psychiatric disorders. Within the NAc, medium spiny neurons (MSNs) can largely be divided into two subtypes, dopamine D1 and D2 receptor-expressing MSNs; however, the role of D1- and D2-MSNs in controlling various forms of learning is still unclear. Here we used a reversible neurotransmission blocking (RNB) technique to separately inhibit the activity of NAc D1- and D2-MSNs during appetitive (Autoshaping), aversive (Inhibitory Avoidance), and cognitive (Visual Discrimination) tasks. RNB of NAc D1-MSNs was revealed to impair sign-tracking behavior to a reward-conditioned cue in the autoshaping task, while RNB of NAc D2-MSNs impaired performance in inhibitory avoidance and visual discrimination tasks. We next investigated whether a similar phenotype was observed in a mouse model of psychiatric disorders, and found that similar to RNB of D2-MSNs, this mouse model demonstrated impairments in the aversive and cognitive learning tasks, but not in the reward learning task. Finally, we investigated whether chemicogenetic stimulation of NAc D2-MSNs with DREADD receptors was sufficient to restore normal function in this mouse model. Activation of hM3Dq receptors expressed on NAc D2-MSNs was able to restore performance in inhibitory avoidance and visual discrimination tasks to the level of wildtype controls. These findings elucidate the roles of NAc MSN subtypes in controlling various forms of learning, and suggest NAc D2-MSNs as a possible therapeutic target for the treatment of impaired learning associated with psychiatric disorders.		7月25日（木）15:10～15:40　第3会場（朱鷺メッセ　2F　メインホールB） 1S03a-2 Mesostriatal gating of cue-triggered motivation Benjamin Saunders（Saunders Benjamin） University of Minnesota Environmental cues, through Pavlovian learning, become conditioned stimuli that guide animals toward the acquisition of rewards (for example, food) that are necessary for survival. We tested the fundamental role of midbrain dopamine neurons in conferring predictive and motivational properties to cues, independent of external rewards. We found that brief phasic optogenetic excitation of dopamine neurons in either the ventral tegmental area of substantia nigra, when presented in temporal association with discrete sensory cues, was sufficient to instantiate those cues as conditioned stimuli. These conditioned cues were able to evoke dopamine neuron activity on their own, and to elicit cue-locked conditioned behavior sequences. Notably, we identified highly parcellated functions for dopamine neuron subpopulations projecting to different regions of striatum, revealing dissociable dopamine systems for the generation of incentive value (accumbens core, but not shell) and conditioned movement invigoration (dorsal striatum). Our results indicate that dopamine neurons orchestrate Pavlovian conditioning via functionally heterogeneous, circuit-specific motivational signals to create, gate, and shape cue-controlled behaviors. In ongoing work, we are using deep learning methods for detailed behavior tracking to quantify the physical structure of conditioned cue-evoked movement sequences, and how they may differ across reward modalities (e.g., optogenetic dopamine, sucrose, and cocaine).

7月25日（木）15:40～16:10　第3会場（朱鷺メッセ　2F　メインホールB） 1S03a-3 Manipulating GABA_A receptors: Cocaine potentiation of conditioned responding Sarah L King（King Sarah L）¹，Marsha M Sindarto（Sindarto Marsha M）¹，Jonathan Robertson（Robertson Jonathan）¹，Tom Macpherson（Macpherson Tom）^1,2，Dai N Stephens（Stephens Dai N）¹ ¹School of Psychology, University of Sussex, Brighton, BN1 9QG, United Kingdom ²Laboratory for Advanced Brain Functions, Institute for Protein Research, Osaka University, Japan Neurons of the nucleus accumbens are predominantly GABAergic: all the projection neurons (medium spiny neurons, MSNs) and a majority of the interneurons. Thus GABA transmission is a major contributor to accumbens function and consequent behaviour. We have used genetic tools to dissect out the roles of accumbal synaptic (α2 subunit-containing) and extrasynaptic (α4 subunit-containing) GABA_A receptors (Rs) in conditioned behaviours and the actions of cocaine. Using a combination of techniques we have demonstrated distinct and differing role for α2- and α4-GABA_ARs in cocaine and food conditioned behaviours, and been able to establish the cellular specificity of their involvement. We have used AAV-mediated RNAi to downregulate α2-GABA_ARS specifically in the nucleus accumbens and shown this receptor subtype is necessary for cocaine potentiation of food-conditioned reinforcement behaviour. More recent experiments have displayed the necessity of these receptors on both D1- and D2-containing accumbal neurons for normal cocaine potentiation of responding. To establish the role of α4-GABA_ARs we have used conditional knockout mice, with the knockout localized to D1- and D2-receptor containing neurons respectively. These studies have revealed differing roles for α4-GABA_ARs on D1- and D2-neurons. The absence of α4-GABA_ARs from D1 neurons enhances both cocaine-conditioned place preference, and the acute locomotor activating effects of cocaine. Whereas the absence of α4-GABA_ARs from D2-neurons enhances responding for a cue associated with food reward in the conditioned reinforcement paradigm. In this talk I will discuss how the different properties of α2- and α4-GABA_ARs impact accumbal function to learn about and act upon reward related stimuli.		7月25日（木）16:10～16:40　第3会場（朱鷺メッセ　2F　メインホールB） 1S03a-4 依存症における意思決定の神経回路：島皮質と線条体 Hiroyuki Mizoguchi（溝口博之）¹，Kiyofumi Yamada（山田清文）² ¹名古屋大環境医次世代創薬研究センタ― ²名古屋大院医医療薬学・附属病院薬剤部 Methamphetamine is a widely abused psychostimulant. Repeated intake of methamphetamine leads to drug addiction, a chronically relapsing disorder characterized by compulsive drug taking, inability to limit intake, and intense drug cravings. Accumulating evidence also indicates that patients addicted to methamphetamine exhibit impaired cognitive functions such as executive function, attention, social cognition, flexibility, and working memory. Furthermore, decision-making is altered in patients with drug addiction, including methamphetamine abusers. Altered decision-making in methamphetamine abusers may contribute to the high rate of relapse even after long-term withdrawal with psychosocial support. Thus, a better understanding of the mechanisms underlying impaired decision-making would provide insights into novel and successful treatments for drug addiction. Previously, we demonstrated that insular cortex is a critical region related to risky decision-making in methamphetamine-treated rats. Because the insular cortex is connected to the amygdala and striatum, it constructs the frontostriatal and limbic loops related to decision-making. Thus, addicts may have dysfunction in the insular-striatal pathway, which is associated with increased risk-taking. In fact, recent reports introduced a possible role for a cell-specific neuronal pathway from the insular cortex in reward-based, goal-directed actions. In this symposium, we will discuss about the role of insular-striatal pathway in altered decision-making in methamphetamine-treated animal based on our results.