Biology subjects

Inoue, K.-i.

Publications and source records attributed to Inoue, K.-i..

29 records · Page 2Linked to original sources

bioRxiv2022

Primate dopamine neurons activated in rewarding environment by tonic disinhibition from amygdala

Seeking out good and avoiding bad objects is critical for survival. In practice, objects are rarely good every time or everywhere, but only at the right time or place. Whereas the basal ganglia (BG) are known to mediate goal-directed behavior, for example, saccades to rewarding objects, it remains unclear how such simple behaviors are rendered contingent on higher-order factors, including environmental context. Here we show that amygdala neurons are sensitive to environments and regulate dopamine (DA) neurons via an inhibitory projection to substantia nigra pars reticulata (SNr) neurons. We combined optogenetics and multi-channel recording to demonstrate that rewarding environments induce tonic firing changes in DA neurons. These tonic responses are mediated by disinhibition via GABAergic projection onto DA neurons from SNr, which in turn are suppressed by inhibitory projection from the amygdala. Thus, the amygdala provides an additional source of learning to BG circuits, namely contingencies imposed by the environment.

neuroscience↗

bioRxiv2021

Conservation of the direct and indirect pathways dichotomy in mouse caudal striatum with uneven distribution of dopamine receptor D1- and D2-expressing neurons

The striatum is one of the key nuclei for adequate control of voluntary behaviors and reinforcement learning. Two striatal projection neuron types, expressing either dopamine receptor D1 (D1R) or dopamine receptor D2 (D2R) constitute two independent output routes: the direct or indirect pathways, respectively. These pathways co-work in balance to achieve coordinated behavior. Two projection neuron types are equivalently intermingled in most striatal space. However, recent studies revealed two atypical zones in the caudal striatum: the zone in which D1R-neurons are the minor population (D1R-poor zone) and that in which D2R-neurons are the minority (D2R-poor zone). It remains obscure as to whether these imbalanced zones have similar properties on axonal projections and electrophysiology compared to other striatal regions. Based on morphological experiments in mice using immunofluorescence, in situ hybridization, and neural tracing, here, we revealed that the poor zones densely projected to the globus pallidus and substantia nigra pars lateralis, with a few collaterals in substantia nigra pars reticulata and compacta. Similar to that in other striatal regions, D1R-neurons were the direct pathway neurons. We also showed membrane properties of projection neurons in the poor zones were largely similar to those in the conventional striatum using in vitro electrophysiological recording. In addition, the poor zones existed irrespective of the age or sex of mice. We also identified the poor zones in the common marmoset as well as other rodents. These results suggest that the poor zones in the caudal striatum follow the conventional projection patterns irrespective of imbalanced distribution of projection neurons. The poor zones could be an innate structure and common in mammals. The unique striatal zones possessing highly restricted projections could relate to functions different from those of motor-related striatum.

neuroscience↗

bioRxiv2021

Chronic behavioral manipulation via orally delivered chemogenetic actuator in macaques

The chemogenetic technology referred to as designer receptors exclusively activated by designer drugs (DREADDs) offers reversible means to control neuronal activity for investigating its functional correlation with behavioral action. Deschloroclozapine (DCZ), a recently-developed highly potent and selective DREADDs actuator, displays a capacity to expand the utility of DREADDs for chronic manipulation without side-effects in nonhuman primates, which has not yet been validated. Here we investigated the pharmacokinetics and behavioral effects of orally administered DCZ in macaque monkeys. Pharmacokinetic analysis and positron emission tomography (PET) occupancy examination demonstrated that oral administration of DCZ yielded slower and prolonged kinetics, and that its bioavailability was 10-20% of that in the case of systemic injection. Oral DCZ (300-1000 g/kg) induced significant working memory impairments for at least 4 h in monkeys with hM4Di expressed in the prefrontal cortex. Repeated daily oral doses of DCZ consistently caused similar impairments over two weeks without discernible desensitization. Our results indicate that orally delivered DCZ affords a less invasive strategy for chronic but reversible chemogenetic manipulation of neuronal activity in nonhuman primates, and this has potential for clinical application.

neuroscience↗

bioRxiv2021

A mosaic adeno-associated virus vector as a versatile tool that exhibits high levels of transgene expression and neuron specificity in primate brain

Recent emphasis has been placed on gene transduction mediated through recombinant adeno-associated virus (AAV) vector to manipulate activity of neurons and their circuitry in the primate brain. In the present study, we created a novel AAV vector of which capsid was composed of capsid proteins derived from the serotypes 1 and 2 (AAV1 and AAV2). Following the injection into the frontal cortex of macaque monkeys, this mosaic vector, termed AAV2.1 vector, was found to exhibit the excellence in transgene expression (for the AAV1 vector) and neuron specificity (for the AAV2 vector) simultaneously. To explore its applicability to chemogenetic manipulation and in vivo calcium imaging, the AAV2.1 vector expressing excitatory DREADDs or GCaMP was injected into the striatum or the visual cortex of macaque monkeys, respectively. Our results have defined that such vectors secure intense and stable expression of the target proteins and yield conspicuous modulation and imaging of neuronal activity.

neuroscience↗

bioRxiv2021

Chemogenetic dissection of the primate prefronto-subcortical pathways for working memory and decision-making

The primate prefrontal cortex (PFC) is situated at the core of higher brain functions by linking and cooperating with the caudate nucleus (CD) and mediodorsal thalamus (MD) via neural circuits. However, the distinctive roles of these prefronto-subcortical pathways remain elusive. Combining in vivo neuronal projection mapping with chemogenetic synaptic silencing, we reversibly dissected key pathways from PFC to the CD and MD individually in single monkeys. We found that silencing the bilateral PFC-MD projections, but not the PFC-CD projections, impaired performance in a spatial working memory task. Conversely, silencing the unilateral PFC-CD projection, but not the PFC-MD projection, altered preference in a free-choice task. These results revealed dissociable roles of the prefronto-subcortical pathways in working memory and decision-making, representing the technical advantage of imaging-guided pathway-selective chemogenetic manipulation for dissecting neural circuits underlying cognitive functions in primates.

neuroscience↗

bioRxiv2021

Chemogenetic activation of nigrostriatal dopamine neurons in freely moving common marmosets

To interrogate particular neuronal pathways in non-human primates under natural and stress-free conditions, we applied designer receptors exclusively activated by designer drugs (DREADDs) technology to common marmosets. We injected adeno-associated virus vectors expressing the excitatory DREADD hM3Dq into the unilateral substantia nigra in three marmosets. Using multi-tracer positron emission tomography imaging, we detected DREADD expression in vivo, which was confirmed in nigrostriatal dopamine neurons by immunohisto-chemistry, and assessed activation of the substantia nigra and dopamine release following agonist administration. The marmosets rotated in a contralateral direction relative to the activated side 30-90 min after consuming food containing the highly potent DREADD agonist deschloroclozapine (DCZ), but not on the following days without DCZ. These results indicate that non-invasive and reversible DREADD manipulation will extend the utility of marmoset as a primate model for linking neuronal activity and natural behavior in various contexts.

neuroscience↗

bioRxiv2021

Multiple Monkey Pose Estimation Using OpenPose

This paper proposes a system for pose estimation on monkeys, in diverse and challenging scenarios, and under complex social interactions by using OpenPose. In comparison to most animals used for research, Monkeys present additional difficulties for pose estimation. Multiple degrees of freedom, unique complex postures, intricated social interactions, among others. Our monkey OpenPose trained model is robust against these difficulties. It achieves similar performance as in human pose estimation models, and it can run in Realtime.

neuroscience↗

bioRxiv2020

MacaquePose: A novel 'in the wild' macaque monkey pose dataset for markerless motion capture

Video-based markerless motion capture permits quantification of an animals pose and motion, with a high spatiotemporal resolution in a naturalistic context, and is a powerful tool for analyzing the relationship between the animals behaviors and its brain functions. Macaque monkeys are excellent non-human primate models, especially for studying neuroscience. Due to the lack of a dataset allowing training of a deep neural network for the macaques markerless motion capture in the naturalistic context, it has been challenging to apply this technology for macaques-based studies. In this study, we created MacaquePose, a novel open dataset with manually labeled body part positions for macaques in naturalistic scenes, consisting of >13,000 images, refined by researchers. We show that the pose estimation performance of an artificial neural network trained with the dataset is close to that of a human-level. The MacaquePose will provide a platform for innovative behavior analysis for non-human primate.

neuroscience↗

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↗

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↗

bioRxiv2019

Amygdala controls saccade and gaze physically, motivationally, and socially

The amygdala is uniquely sensitive to emotional events. However, it is not understood whether and how the amygdala uses such emotional signals to control behavior, especially eye movements. We therefore injected muscimol (GABAA agonist) into the central nucleus of amygdala (CeA) in monkeys. This unilateral temporary inactivation suppressed saccades to contralateral but not ipsilateral targets, resulting in longer latencies, hypometric amplitudes, and slower velocity. During free viewing of movies, gaze was distributed mostly in the ipsilateral hemifield. Moreover, CeA inactivation disrupted the tendency of gaze toward social interaction images, which were normally focused on continuously. Conversely, optogenetic stimulation of CeA facilitated saccades to the contralateral side. These findings suggest that CeA controls spatially selective gaze and attention in emotional contexts, and provide a new framework for understanding psychiatric disorders related to amygdala dysfunction.\n\nHighlightsO_LICentral amygdala facilitates contralateral saccades selectively.\nC_LIO_LISaccade facilitation is related to motivational goals and social interaction.\nC_LIO_LIThe amygdala thus controls goal-directed behavior based on emotional contexts.\nC_LI

neuroscience↗