動物の適応行動における手綱核研究の最前線 Role of the habenula in regulation of the adaptive behaviors
S1-1-1-1 攻撃行動における自信の蓄積における手綱核の関与 The roles of the habenula in gain of self-confidence in aggressive behavior ○岡本　仁 ○Okamoto Hitoshi 理化学研究所 脳科学総合研究センター RIKEN, Brain Science Institute The habenula (Hb) is an evolutionarily conserved diencephalic structure. The dorsal and ventral Hb (dHb and vHb) of zebrafish correspond respectively to the medial and lateral habenula (MHb and LHb) of mammals. The functions of the MHb in mammals have long remained ambiguous. Recently, we demonstrated in zebrafish that the lateral subnuclei of the dorsal habenula (dHbL) are asymmetrically connected with the dorsal and intermediate parts of the interpeduncular nucleus (d/iIPN). Specific silencing of the dHbL-d/iIPN pathway rendered animals extraordinarily prone to freeze in response to conditioned fear stimuli, while the control fish showed only flight behaviors, implicating this pathway in experience-dependent reevaluation of danger during the fear conditioning trials. We wondered whether the same capacity of this pathway is utilized in case of fighting between two males which have become territorial after isolation, because constant reevaluation of the opponent's strength is necessary during fight until the dominant winner and subordinate loser is ultimately determined. In wild-type zebrafish, it is reported that previous winning experience remarkably increases the probability of winning a subsequent contest. However, this experience-dependent behavior was not found in dHbL-silenced fish. Most of the dHbL-silenced winners of the first interaction lost the second interaction against a naive dHbL-silenced fish, suggesting the role of the dHbL-d/iIPN pathway in accumulation of confidence upon victory in fight.	S1-1-1-2 うつ病における外側手綱核の役割 Role of the lateral habenula in pathophysiology of major depression ○相澤秀紀 ○Aizawa Hidenori 東京医科歯科大学　難治疾患研究所 Tokyo Medical and Dental University, Medical Research Institute Monoamines such as serotonin play central roles in the pathophysiology of the major depression. It remains, however, unclear how the monoaminergic systems are dysregulated in depression. Lateral habenula (LHb) is a nucleus regulating the monoaminergic activity, since it is activated in response to the aversive stimuli. Recent study reported increased blood flow in the habenula of the patients with depression and facilitation of the excitatory postsynaptic potential in the habenula of rat helpless model for depression. These facts prompted us to hypothesize that the increased activity in the mouse LHb leads to the deterioration of the depressive behaviors such as despair. Glutamate mediates the excitatory synaptic transmission in LHb, and glutamate transporters in the astrocyte play critical role in clearance of glutamate in the synaptic cleft. To examine the depressive behaviors in the animals with hyperactivated LHb, we injected the dihydrokainic acid (DHK), a specific inhibitor of the major glutamate transporter GLT-1, to LHb. With bilateral activation of LHb, a large number of c-Fos-positive cells were observed specifically in LHb. Tail suspension test after DHK injection revealed that immobility time were significantly longer in the DHK-injected mice than control suggesting that increase of glutamatergic transmission in LHb exacerbated the behavioral despair induced by acute stress. Examining the effects of long-lasting LHb activation by genetic manipulation during the chronic defeat stress may clarify the role of LHb in the pathophysiology of depression. Finally, I would like to discuss a role of LHb in REM sleep disturbance, since we recently found that LHb regulate the maintenance of REM sleep whose latency at the sleep onset was reported to be shortened in depression patients. Examination of the endophenotype such as REM sleep defects in the mouse model of depression may clarify the missing link between sleep disturbance and despair behavior in depression.
S1-1-1-3 Lateral habenula signals for seeking information and other rewards ○Ethan S. Bromberg-Martin National Eye Institute, USA The lateral habenula (LHb) is in an ideal position to control motivation, since it receives input signals about rewards and punishments and has powerful control over neuromodulators. This makes it critical to understand the motivational signals that the LHb generates and the neural codes it uses to transmit them. I will present evidence that single LHb neurons signal multiple forms of reward, including simple rewards like water and abstract rewards like the value of getting advance information about future events. LHb neurons transmit these reward signals using two neural codes: phasic, transient "reward prediction error" signals, and tonic, sustained signals that can anticipate upcoming events. Finally, I will present evidence about the input pathways that send these signals to the LHb, how the LHb uses these signals to control downstream brain structures such as midbrain dopamine neurons, and their implications for motivational networks in the brain.	S1-1-1-4 Inputs and outputs of the lateral habenula: physiological and behavioral studies ○Roberto Malinow University of California, San Diego The lateral habenula (LHb) has recently been identifiedas a key regulator of the reward system by drivinginhibition onto dopaminergic neurons. However, thenature and potential modulation of the major inputto the LHb originating from the basal ganglia arepoorly understood. Although the output of the basalganglia is thought to be primarily inhibitory, here weshow that transmission from the basal ganglia tothe LHb is excitatory, glutamatergic, and suppressedby serotonin. Behaviorally, activation of this pathwayis aversive, consistent with its role as an ''antireward''signal. Our demonstration of an excit<br>atory projectionfrom the basal ganglia to the LHb explains howLHb-projecting basal ganglia neurons can havesimilar encoding properties as LHb neurons themselves.Our results also provide a link betweenantireward excitatory synaps<br>es and serotonin, aneuromodulator implicated in depression.
S1-1-1-5 注意欠陥・多動性障害と手綱核との関係 Habenula in the pathogenesis of ADHD ○後藤幸織1, 李英娥2, 瀧田正寿3 ○Yukiori Goto1, Young-A Lee2, Masatoshi Takita3 京都大学霊長類研究所1, 富山大・和漢研2, 産総研3 The Primate Research Institute (PRI)1, Inst Natural Med, Univ Toyama, Toyama2, AIST, Tsukuba3 The habenula is an important brain structure that regulates the monoamine systems such as dopamine and serotonin, and therefore, its dysfunction has been implicated in a number of psychiatric disorders such as depression and schizophrenia. Attention deficit/hyperactivity disorder (ADHD) is a childhood onset psychiatric condition, which is thought to involve monoamine deficit. Nevertheless, whether any alteration in habenula function is associated with ADHD has not been known. I am going to address the possibility of habenula deficit during early brain development in the pathogenesis of ADHD, based on our recent study with neonatal habenula lesion in rodents, along with other supporting evidence from studies such as those reporting genes associated with ADHD could also regulate development of the habenua-monoamine network.	S1-1-1-6 The lateral habenula is differentially coupled to prefrontal and hippocampal networks ○Lucas Lecourtier1, Romain Goutagny1, Michael Loureiro1 Laboratoire d'Imagerie et de Neurosciences Cognitive Université de Strasbourg1, Laboratoire de Neurosciences Cognitives et Adaptatives2, Laboratoire de Neurosciences Cognitives et Adaptatives3 The lateral habenula (LHb) has been postulated to play a role in hippocampo-cortical dependent processing of contextual informations and spatial memory. To test this hypothesis, we simultaneously recorded local field potentials (LFP) within the LHb, the dorsal hippocampus (dHPC) and the medial prefrontal cortex (mPFC) in freely-moving rats, during a 24-hour session as well as during spatial recognition test in an open field.During the 24-hour session, we found that LHb local activity was modulated according to brain states, with prominent theta rhythm during wake and REM sleep. During these states, LHb theta oscillations were significantly coherent with both dHPC and mPFC. To test if the LHb can genuinely generate theta oscillations, we performed single-cell recordings in urethane anaesthetized rats and found LHb cells firing selectively during episods of cortical theta oscillations.To further test whether these coherent theta oscillations might have a functional role in a HPC/mPFC-dependant task, we performed LFP recordings during a spatial recognition test designed to evaluate habituation and subsequent reactions to changes in the spatial layout of three objects within an open field (OF). Following three consecutive sessions during which the objects remained in the same location (habituation sessions), in a subsequent test session, one object was left in place (undisplaced), one object was placed at the former location of the remaining one (substituted), the latter being moved to a location previously free of any object (new location). During the test session, rats preferentially explored the new location object, showing a memory for the previous layout of the context. This preference was correlated to a specific and significant increase in theta power within the LHb. In conclusion, we have shown that the LHb is functionally connected with the hippocampo-cortical system and that it plays a role in the processing of contextual informations and spatial memory.

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