Biology subjects

Kumata, K.

Publications and source records attributed to Kumata, K..

3 recordsLinked to original sources

bioRxiv2024

Longitudinal assessment of DREADD expression and efficacy in the monkey brain

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) offer a powerful means for reversible control of neuronal activity through systemic administration of inert actuators. Because chemogenetic control relies on DREADD expression levels, understanding and quantifying the temporal dynamics of their expression is crucial for planning long-term experiments in monkeys. In this study, we longitudinally quantified in vivo DREADD expression in macaque monkeys using positron emission tomography with the DREADD-selective tracer [11C]deschloroclozapine (DCZ), complemented by functional studies. Twenty macaque monkeys were evaluated after being injected with adeno-associated virus vectors expressing the DREADDs hM4Di or hM3Dq, whose expression was quantified as changes in [11C]DCZ binding potential from baseline levels. Expression levels of both hM4Di and hM3Dq peaked around 60 days post-injection, remained stable for about 1.5 years, and declined gradually after two years. Significant chemogenetic control of neural activity and behavior persisted for about two years. The presence of protein tags significantly influenced expression levels, with co-expressed protein tags reducing overall expression levels. These findings provide valuable insights and guidelines for optimizing the use of DREADDs in long-term primate studies and potential therapeutic applications.

neuroscience↗

bioRxiv2023

Reduced serotonergic transmission alters sensitivity to cost and reward via 5-HT1A and 5-HT1B receptors in monkeys

Deficiency of the serotonin (5-HT) system is considered one of the core biological pathologies of depression and other psychiatric disorders whose key symptom is decreased motivation. Yet, the exact role of 5-HT in motivation remains controversial and elusive. Here, we pharmacologically manipulated the 5-HT system and quantified effects on motivation in terms of incentives and costs for goal-directed action in monkeys. Reversible inhibition of 5-HT synthesis increased refusal responses and reaction times in goal-directed task performance, indicating decreased motivation that could be separated into value-dependent and -independent components. To identify the receptor subtypes involved in these components, we systemically administered antagonists specific for four major 5-HT receptor subtypes: 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4. Positron emission tomography visualized the unique distribution of each subtype in limbic brain regions and determined the systemic antagonist dose that achieved approximately 30% occupancy. We found that blockade of 5-HT1A, but not other receptor subtypes, increased sensitivity to future workload and time-delay to reward, and decreased motivation in a value-independent manner. Moreover, blocking only 5-HT1B receptors reduced the impact of incentive value on motivation. These results suggest that two distinct processes, mediated by 5-HT1A and 5-HT1B receptors, lead to reduced motivation in 5-HT system deficiency.

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↗