神経疾患・損傷研究モデルとしての霊長類における神経科学的研究
Neuroscience Researches on non-human primates as a model system to study the neural disease and damage
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Using eye movements to probe brain function and dysfunction across the lifespan
○Douglas P. Munoz1
Centre for Neuroscience Studies, Queen's University1

There is an urgent need to identify key biomarkers of normal and abnormal development and aging to optimize human health. The MUNOZ lab uses the saccadic eye movement system to probe sensory, motor and cognitive function in normal and abnormal development and aging. Anatomical, physiological, clinical, and imaging studies have contributed to our extensive knowledge of the neural circuit that controls saccadic eye movements (Munoz and Everling 2004; Munoz and Coe 2011), spanning specific regions of parietal and frontal cortices, basal ganglia, thalamus, superior colliculus, cerebellum, and brainstem reticular formation. Many of these areas of the brain are known to change in structure and function during normal and abnormal aging. Eye movement tasks, in which visual stimuli are presented on a computer screen and eye movements are recorded with a video-based eye tracker, can be designed to probe specific aspects of sensory, motor, and cognitive function that are known to change across the lifespan. This can be combined with functional brain imaging to investigate the neural substrate controlling the behaviour. Detailed quantitative assessment of eye movement behaviour can reveal functional markers for abnormal development or aging. In this talk I will show how translational work with humans and non-human primates can be used to gain understanding into neural circuitry and disease processes.
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Neural mechanisms underlying negative emotion regulation: Insights from the study of genetic polymorphisms and behavioural traits in marmosets
○Angela C. Roberts1
Dept of Physiology, Development and Neuroscience, University of Cambridge, UK1

Dysregulated emotions are a core feature of many neuropsychiatric disorders and are often associated with altered activity in limbic emotional circuitry that includes the amygdala, hippocampus and prefrontal cortex (PFC). Altered activity in serotoninergic forebrain systems has also been implicated and currently, the front-line treatment of these disorders includes drugs that target the serotonin system. However, our understanding of the interaction between these brain structures, and their modulation by serotonin, in the control and regulation of emotion is only in its infancy. Much insight has been gained recently into the role of the medial PFC in the regulation of the amygdala-dependent freezing response to a fear conditioned stimulus, primarily from studies in rodents. However, the neuroimaging of patients with mood and anxiety disorders have revealed structural and activity changes not only in the medial but also the ventral PFC, including orbitofrontal and ventrolateral PFC. These regions are at their most highly developed in primates and thus, to further our understanding of the regulation of amygdala-dependent emotional learning and expression by the ventral PFC we have developed models of positive and negative emotional learning and expression in a new world primate, the common marmoset. Since emotional responses are composed of both physiological and behavioural components we use an automated telemetry system to allow the simultaneous measurement of behavioural and autonomic e.g. heart rate and blood pressure, emotional responses in freely moving marmosets. This also helps bridge the gap between current human and rodent studies in which the primary measures of emotional expression are autonomic activity and behaviour, respectively. So far we have identified the critical role of the orbitofrontal cortex in the regulation of both positive (Reekie et al, 2008) and negative (Agustin-Pavon et al, 2012) emotional responses, responses that we have already shown to be dependent upon the amygdala. Lesions of the OFC not only disrupt the contextual regulation of autonomic and behavioural emotional responses as contingencies in the environment change but also lead to their uncoupling, an effect that could have a major impact on overall levels of emotionality. A separate contribution is also made by the ventrolateral PFC. In addition, we have identified the critical role of serotonin in modulating the processing of positive and negative feedback within the amygdala and ventral PFC, dissociating it's role from that of dopamine. More recently, we have begun to explore prefronto-amygdala circuits in the context of individual differences in both genes and behavioural traits. It has been hypothesised that high trait anxiety and 5-HT transporter polymorphisms may act as vulnerability factors for developing neuropsychiatric disorders and so, using structural MRI, microPET and microdialysis we have begun to identify alterations in the prefronto-amygdala network in marmosets that are related to these individual differences.
Refs
Reekie Y. L., Braesicke K., Man M., Roberts A.C. (2008) Uncoupling of behavioral and autonomic responses following lesions of the primate orbitofrontal cortex. Proceedings of the National Academy of Sciences. 105:9787-92.
Agustín-Pavón C., Braesicke K., Shiba Y., Santangelo A.M., Mikheenko Y., Cockroft G., Asma F., Clarke H., Man M., Roberts A.C. (2012) Lesions of ventrolateral prefrontal or anterior orbitofrontal cortex in primates heighten negative emotion. Biological Psychiatry, 72:266-272.
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霊長類脳における遺伝子操作法の開発
How to control gene expression in the primate brain

○山森哲雄1
○Tetsuo Yamamori1
自然科学研究機構基礎生物学研究所1
National Institute for Basic Biology1

We have been studying the genes selectively expressed in primate neocortex, which can be grouped into the primary visual area selectively expressed and the association areas selectively expressed genes (Yamamori, T, 2011). Our study with Dr. Hiromichi Sato's group, Osaka University, using specific agonists and antagonists demonstrated the function of 5HT1B and 5HT2A as controlling signal to noise (S/N) ratio and the gain of responses in the neurons of the primary visual cortex, respectively (Watakabe et al., 2009). However, since selective inhibitors and stimulants are not usually available for other area-selective genes, it is essential to establish a general strategy to control the gene expression in primates. We have been working to control and visualize the gene expression in marmosets as a primate model system. Our approach has been to use Sh(short hairpin)-RNA to knock down a target gene in a region selective manner with AAV (adeno-associated virus) vectors. In this presentation, I will first present our recent results in targeting D1 and D2 receptors in the marmoset striatum and then would like to discuss how to use this approach to identify the functions of area-selectively expressed genes in primates. References1. Yamamori, T. Selective gene expression in regions of primate neocortex: Implications for cortical specialization. Progress in Neurobiology 94, 201-222, 2011.2. Watakabe et al., Enriched expression of serotonin 1B and 2A receptor genes in macaque visual cortex and their bidirectional modulatory effects on neuronal responses. Cereb. Cortex 19, 1915-1928, 2009.
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運動機能回復に対する腹側線条体の役割
Role of the ventral striatum for the functional recovery after spinal cord injury

○西村幸男1,2,3
○Yukio Nishimura1,2,3
自然科学研究機構生理学研究所1, 総合研究大学院大学 生理科学2, 科学技術振興機構 さきがけ3
National Institute for Physiological Sciences1, The Graduated Univ. for Advanced Sci., Hayama, Japan2, JST PRESTO, Tokyo, Japan3

It is believed that depression impedes and motivation enhances functional recovery after neuronal damage such as spinal-cord injury and stroke. However, the neuronal substrate underlying such psychological effects on functional recovery remains unclear. A longitudinal study of brain activation in the non-human primate model of partial spinal-cord injury using positron emission tomography revealed a contribution of the primary motor cortex to the recovery of finger dexterity through the rehabilitative training. Here, we show that activity of the ventral striatum, including the nucleus accumbens, which plays a critical role in processing of motivation, increased and its functional connectivity with M1 emerged and was progressively strengthened during the recovery. In addition, functional connectivities among M1, the ventral striatum and other structures belonging to neural circuits for processing motivation, such as the orbitofrontal cortex, anterior cingulate cortex and pedunculopontine tegmental nucleus were also strengthened during the recovery. To clarify the causal relationship between functional recovery and activity of ventral striatum, we performed reversible pharmacological blockade of ventral striatum throughout at various stages and observed its effect on the finger dexterity. The inactivation of striatum significantly impaired finger dexterity throughout all the recovery stages, though preoperative inactivation showed only minor effect. In addition to the impairment of finger dexterity, the inactivation induced somnolent state for retrieval as well. On the other hand, the inactivation did not affect the movements of the ipsilateral side. These results suggest that the ventral striatum plays an important role in maintenance of the functional recovery and motivational regulation of motor learning required for functional recovery after spinal-cord injury.
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