Biology subjects

Nagai, Y.

Publications and source records attributed to Nagai, Y..

41 records · Page 3Linked to original sources

bioRxiv2020

Single caudate neurons encode temporally discounted value for formulating motivation for action

The term temporal discounting describes both choice preferences and motivation for delayed rewards. Here we show that neuronal activity in the dorsal part of the primate caudate head (dCDh) signals the temporally discounted value needed to compute the motivation for delayed rewards. Macaque monkeys performed an instrumental task, in which visual cues indicated the forthcoming size and delay duration before reward. Single dCDh neurons represented the temporally discounted value without reflecting changes in the animals physiological state. Bilateral pharmacological or chemogenetic inactivation of dCDh markedly distorted the normal task performance based on the integration of reward size and delay, but did not affect the task performance for different reward sizes without delay. These results suggest that dCDh is involved in encoding the integrated multidimensional information critical for motivation.

neuroscience↗

bioRxiv2020

Genetically targeted reporter imaging of deep neuronal network in the mammalian brain

Positron Emission Tomography (PET) allows biomolecular tracking, while PET monitoring of brain networks has been hampered by the lack of a suitable reporter. Here, we describe in vivo brain imaging that takes advantage of bacterial dihydrofolate reductase, ecDHFR, and its unique antagonist, TMP. In mice, peripheral administration of radiofluorinated and fluorescent TMP analogs enabled PET and intravital microscopy, respectively, of neuronal ecDHFR expressions. This technique is applicable to the visualization of neuronal ensemble activities elicited by chemogenetic manipulation in the mouse hippocampus. Notably, ecDHFR-PET offers mapping of neuronal projections in non-human primate brains, indicating the availability of ecDHFR-based tracking technologies for network monitoring. Finally, we demonstrate the utility of TMP analogs for PET assays of turnover and self-assembly of proteins tagged with ecDHFR mutants. Our findings may facilitate a broad spectrum of PET analyses of a mammalian brain circuit at molecular levels that were not previously applicable for technical reasons.

neuroscience↗

bioRxiv2020

An Anti-amyloidogenic treatment to specifically block the consolidation of traumatic events in mouse

Post-traumatic stress disorder (PTSD) is a mental health disorder triggered by the exposure to a traumatic event that manifests with anguish, intrusive memories and negative mood changes. So far, there is no efficient treatment for PTSD other than symptomatic palliative care. Based on the implication of the functional amyloid cytoplasmic polyadenylation element binding protein-3 (CPEB3) in the consolidation of memory, we propose its active amyloid state as a possible therapeutic target by blocking the consolidation of traumatic memories through polyglutamine binding peptide 1 (QBP1), an inhibitor of the amyloid oligomerization previously investigated in Drosophila. To test this idea in mammals, here we have developed a transgenic mouse that constitutively expresses QBP1 peptide. We first assessed the innocuousness of this peptide for the normal development of the animal, which also showed normal locomotor activity and anxiety. By performing a battery of standard memory paradigms, we then showed that hippocampal-dependent and aversive memories were impaired in the QBP1 mice. Furthermore, protein expression in the hippocampi of experienced mice showed that QBP1 mice do not increase their levels of amyloid oligomerization, evincing the blockade of the CPEB3 protein in its inactive state. The ability of QBP1 to block aversive memories in mice represents the proof of concept of a novel pharmacological approach for prophylaxis and therapy of acute stress and post-traumatic stress disorders.

animal behavior and cognition↗

bioRxiv2019

Deschloroclozapine: a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys

The chemogenetic technology Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) affords remotely reversible control of cellular signaling, neuronal activity and behavior. Although the combination of muscarinic-based DREADDs with clozapine-N-oxide (CNO) has been widely used, sluggish kinetics, metabolic liabilities, and potential off-target effects of CNO represent areas for improvement. Here we provide a new high affinity and selective agonist deschloroclozapine (DCZ) for muscarinic-based DREADDs. Positron emission tomography revealed that DCZ selectively bound to and occupied DREADDs in both mice and monkeys. Systemic delivery of low doses of DCZ (1 or 3 g/kg) enhanced neuronal activity via hM3Dq within minutes in mice and monkeys. Intramuscular injections of DCZ (100 g/kg) reversibly induced spatial working memory deficits in monkeys expressing hM4Di in the prefrontal cortex. DCZ represents the most potent, selective, metabolically stable and fast-acting DREADD agonist reported with utility in both mice and non-human primates for a variety of applications.

neuroscience↗

bioRxiv2018

Signaling incentive and drive in the primate ventral pallidum for motivational control of goal-directed action

Processing incentive and drive is essential for control of goal-directed behavior. The limbic part of the basal ganglia has been emphasized in these processes, yet the exact neuronal mechanism has remained elusive. In this study, we examined the neuronal activity of the ventral pallidum (VP) and its upstream area, the rostromedial caudate (rmCD), while two male macaque monkeys performed an instrumental lever-release task, in which a visual cue indicated the forthcoming reward size. We found that the activity of some neurons in VP and rmCD reflected the expected reward-size transiently following the cue. Reward-size coding appeared earlier and stronger in VP than in rmCD. We also found that the activity in these areas was modulated by the satiation level of monkeys, which also occurred more frequently in VP than in rmCD. The information regarding reward-size and satiation-level was independently signaled in the neuronal populations of these areas. The data thus highlighted the neuronal coding of key variables for goal-directed behavior in VP. Furthermore, pharmacological inactivation of VP induced more severe deficit of goal-directed behavior than inactivation of rmCD, which was indicated by abnormal error repetition and diminished satiation effect on the performance. These results suggest that VP encodes incentive value and internal drive, and plays a pivotal role in the control of motivation to promote goal-directed behavior.\n\nSignificance StatementThe limbic part of the basal ganglia has been emphasized in the motivational control of goal-directed action. Here, we investigated how the ventral pallidum (VP) and the rostromedial caudate (rmCD) encode incentive value and internal drive, and control goal-directed behavior. Neuronal recording and subsequent pharmacological inactivation revealed that VP had stronger coding of reward size and satiation level than rmCD. Reward size and satiation level were independently encoded in the neuronal population of these areas. Furthermore, VP inactivation impaired goal-directed behavior more severely than rmCD inactivation. These results highlighted the central role of VP in the motivational control of goal-directed action.

neuroscience↗