回路の形成と可塑性の統合的理解へのフロントライン
Toward comprehensive understanding of circuit formation and plasticity
S3-3-1-1
Patterning the binocular projection: molecular control of axon guidance at the optic chiasm midline
○Takaaki Kuwajima1, Yutaka Yoshida4, Thomas Jessell2,5, Takeshi Sakurai6, Veronique Lefebvre7, Carol Mason1,2,3
Dept Path & Cel Bio, Columbia Univ, NY, USA1, Dept Neurosci, Columbia Univ, NY, USA2, Dept Opthal, Columbia Univ, NY, USA3, Div Dev Bio, Cinci Child's Hosp Med Cent, OH, USA4, Dept Bioche&Mol Biophy, HHMI, Columbia Univ, NY, USA5, Medi Innov Cent, Kyoto Univ Grad Sch of Med, Kyoto, Japan6, Dept Cel Bio, Ortho&Rheumato Res Cent, Cleve Clin Lern Res Inst, OH, USA7

During development of neural circuits, axons are guided by molecular cues along their path. The expression of receptors to these cues is tightly regulated by specific transcriptional mechanisms thereby establish a molecular program for axon guidance and cell subtype identity. Retinal axon divergence at the optic chiasm midline is key to establishing binocular visual circuits in higher vertebrates. In mice, retinal ganglion cell (RGC) axons from the ventrotemporal (VT, uncrossed) or non-VT (crossed) retina project to the same (ipsilateral) or opposite side of brain (contralateral), respectively. Our lab has shown that EphB1-expressing axons are repelled by ephrinB2 by glial cells of the chiasm midline and that the transcription factor Zic2 directs the ipsilateral projection through controlling EphB1 expression in uncrossed RGCs (Petros et al., 2008). Recently we characterized a guidance mechanism for contralateral projection: a trio of guidance molecules, NrCAM and Semaphorin6D, and PlexinA1 at the optic chiasm interact with NrCAM and PlexinA1 on crossed RGCs, leading to establishment of the contralateral projection (Kuwajima et al., 2012). The transcription factors controlling the contralateral guidance program are not well understood. We have found that the SoxC transcription factors (Sox4, 11 and 12) are expressed in crossed RGCs,and SoxCs can directly regulate transcriptional activities of PlexinA1 and NrCAM genes. Further, using a SoxCs conditional mutant mouse, we observed that SoxCs regulate RGC differentiation and axon outgrowth of crossed RGCs on chiasm cells in vitro. These programs are essential to understand how axons navigate and form circuits during embryogenesis, and to inform approaches to recapitulate axon growth in damaged nervous systems for neural repair.
S3-3-1-2
高等哺乳動物を用いた脳神経系の遺伝学的解析
Genetic analyses of the central nervous system using higher mammals

○河崎洋志1
○Hiroshi Kawasaki1
金沢大・医・脳細胞遺伝1
Grad Sch of Med, Kanazawa Univ1

Although the parallel visual pathways are a fundamental basis of visual processing and are especially prominent in higher mammals, our knowledge of their molecular properties is still limited. Recently we uncovered a parvocellular-specific molecule in the dorsal lateral geniculate nucleus (dLGN) of higher mammals. Our results suggested a homology between X cells in the ferret dLGN and parvocellular cells in the monkey dLGN. Next, to investigate the roles of these molecules in higher mammals, we successfully developed and validated a rapid and efficient technique that enables genetic manipulations in the brain of carnivore ferrets using in utero electroporation. GFP expression was detectable in the embryo and was observed at least 2 months after birth in ferrets. Our results should help in gaining a fundamental understanding of the development, evolution, function and pathophysiology of the brain structures which are unique to higher mammals.
S3-3-1-3
大脳皮質視覚野の微小神経回路網と機能の経験依存的発達
Experience-dependent maturation of visual cortical circuits and functions

○吉村由美子1,2
○Yumiko Yoshimura1,2
生理学研究所1, 総合研究大学院大学2
National Institute for Physiological Sciences1, The Graduate University for Advanced Studies, Okazaki2

In visual cortex, it is assumed that visual response selectivity emerges from selective connectivity in cortical circuits. We previously reported that pairs of simultaneously recorded layer 2/3 pyramidal cells frequently shared common inputs from nearby excitatory cells in layer 2/3 and 4, only when they were monosynaptically connected, demonstrating the presence of fine-scale networks in visual cortex. To examine the effect of visual deprivation on the maturation of the fine-scale networks, we prepared slices from rats reared in darkness from birth and in a normal visual environment with binocular lid suture from the day of eyelid opening. We performed whole-cell recordings from layer 2/3 pyramidal cells, and analyzed excitatory postsynaptic currents evoked by laser-scanning photostimulation of other nearby cortical cells using caged glutamate. We found that fine-scale networks failed to emerge in both dark-reared and lid-sutured rats. To reveal the functional role of the fine-scale networks, we analyzed visual responses of visual cortical cells in anesthetized rats, in which the networks failed to mature due to either type of deprivation. Compared with normal rats, the optimal spatial frequency of visual stimuli was distributed only in a lower frequency range, and orientation selectivity index was mostly in a range of smaller values in dark-reared and lid-sutured rats, suggesting that the development of diversity in visual responsiveness requires normal visual experience. Cross-correlation analysis of simultaneous recorded cells demonstrated that highly correlated spike activity was found only in pairs of cells with similar selectivity for visual stimuli in normal rats, whereas the cross-correlation value was usually not so high and independent of similarity of visual responsiveness in cell pairs obtained from lid-sutured rats. Thus, fine-scale networks are likely the basis of correlated activity in a local population of cells coding common visual information.
S3-3-1-4
視覚野における方位選択性形成のメカニズム:氏か育ちか
Development of orientation selectivity in visual cortex: Nature or nurture

○大木研一1,2
○Kenichi Ohki1,2
九州大学大学院医学研究院分子生理学1
Dept Mol Physiol, Kyushu Univ1, JST-CREST2

I will discuss how prenatal development and postnatal neuronal activity shape neuronal circuitry and determine orientation selectivity in visual cortex.
S3-3-1-5
Unmasking Molecular and Circuit Mechanisms of Adult Cortical Plasticity
Unmasking Molecular and Circuit Mechanisms of Adult Cortical Plasticity

○森下博文1
○Hirofumi Morishita1
マウントサイナイ医科大学・精神科1
Mount Sinai School of Medicine1

Our adult behavior reflects neural circuits sculpted by experience during early critical periods. Such heightened plasticity declines beyond critical periods, often limiting recovery of function in the adult. On the other hand, the adult brain also needs stability. Failed stabilization can allow circuit disruption by irrelevant information. How does the brain solve this stability-plasticity dilemma? Our study aims to identify key neural mechanisms that regulate a balance between plasticity and stability in the adult brain. Using mouse visual system as a model, we recently identified a novel molecular brake called Lynx1 which increases in adulthood to actively limit brain plasticity. Strikingly, removal of this brake was sufficient to restore visual function in adult animals, implying that the adult brain may have hidden mechanisms of plasticity. Here we aimed to uncover molecular and circuit mechanisms of the adult plasticity normally masked by Lynx1. Uniquely, Lynx1 modulates brain-wide cholinergic systems by directly inhibiting nicotinic acetylcholine receptors. We tested the hypothesis that Lynx1 regulates distributed cholinergic circuits to limit juvenile form of permissive molecular cascades in the adult visual cortex. The identified mechanisms will provide novel insight beyond visual system into how our brain functions and behaviors are optimized across the lifespan.
S3-3-1-6
Finding safety: How amygdala activity is shaped by prefrontal and hippocampal inputs
○Ekaterina Likhtik1, Joseph. M Stujenske1, Mihir. A Topiwala1
Columbia University1

Discriminating between aversive and safe cues is a necessary skill for survival. Fear generalization negatively impacts the ability to compete for resources in animals and is associated with a range of anxiety disorders in humans. The basolateral complex of the amygdala (BLA), medial prefrontal cortex (mPFC) and ventral hippocampus (vHPC) are known to be important areas in anxiety processing, leaving open the question how they function as a network to differentiate anxiogenic and safe states. To address this issue, neural activity was recorded from each area in this network while animals underwent differential fear conditioning and were exposed to the open field. Increased theta-frequency (4-12 Hz) power and synchrony in the mPFC - BLA circuit was found to enhance discrimination between aversive and safe cues in learned fear and aversive versus safe areas in the open field. Furthermore, cell firing in the BLA was entrained to theta inputs from the mPFC only in animals that discriminated between aversive and safe stimuli and only during presentations of stimuli that were recognized as safe. BLA activity in animals with generalized fear responses across aversive and safe stimuli was not tuned to mPFC theta inputs. Notably, the same relationship of BLA tuning to mPFC inputs was seen in the innate anxiety task, where BLA activity was entrained to mPFC theta only in the relative safety of the periphery in the open field. Thus, a shift in amygdala firing to theta coded input from the mPFC is a key factor for discriminative fear learning and anxiolytic state. At the same time the vHPC, an area previously shown to be modulated by theta oscillations in innate anxiety, entrains BLA firing during anxiogenic states, such as when an animal is in the aversive center of the open field. How these findings enrich our current understanding of the prefrontal-amygdala-hippocampal network and its impact on amygdala microcircuits in anxiety and fear will be discussed.
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