Balancing risk-return decisions by manipulating the mesofrontal circuits in primates

リスクと報酬の意思決定バランスを光で調節 --精神神経疾患などの病態解明に期待--. 京都大学プレスリリース. 2024-01-05.Lighting the Circuits to Risky Decision-Making. 京都大学プレスリリース. 2024-01-05.Decision-making is always coupled with some level of risk, with more pathological forms of risk-taking decisions manifesting as gambling disorders. In macaque monkeys trained in a high risk–high return (HH) versus low risk–low return (LL) choice task, we found that the reversible pharmacological inactivation of ventral Brodmann area 6 (area 6V) impaired the risk dependency of decision-making. Selective optogenetic activation of the mesofrontal pathway from the ventral tegmental area (VTA) to the ventral aspect of 6V resulted in stronger preference for HH, whereas activation of the pathway from the VTA to the dorsal aspect of 6V led to LL preference. Finally, computational decoding captured the modulations of behavioral preference. Our results suggest that VTA inputs to area 6V determine the decision balance between HH and LL

Investigating the Influence of GABA Neurons on Dopamine Neurons in the Ventral Tegmental Area Using Optogenetic Techniques

Dopamine (DA) is the key regulator of reward behavior. The DA neurons in the ventral tegmental area (VTA) and their projection areas, which include the prefrontal cortex (PFC), nucleus accumbens (NAc), and amygdala, play a primary role in the process of reward-driven behavior induced by the drugs of addiction, including nicotine and alcohol. In our previous study, we developed a novel platform consisting of micro-LED array devices to stimulate a large area of the brain of rats and monkeys with photo-stimulation and a microdialysis probe to estimate the DA release in the PFC. Our results suggested that the platform was able to detect the increased level of dopamine in the PFC in response to the photo-stimulation of both the PFC and VTA. In this study, we used this platform to photo-stimulate the VTA neurons in both ChrimsonR-expressing (non-specific) wild and dopamine transporter (DAT)-Cre (dopamine specific) mice, and measured the dopamine release in the nucleus accumbens shell (NAcShell). We measured the DA release in the NAcShell in response to optogenetic stimulation of the VTA neurons and investigated the effect of GABAergic neurons on dopaminergic neurons by histochemical studies. Comparing the photo-stimulation frequency of 2 Hz with that of 20 Hz, the change in DA concentration at the NAcShell was greater at 20 Hz in both cases. When ChrimsonR was expressed specifically for DA, the release of DA at the NAcShell increased in response to photo-stimulation of the VTA. In contrast, when ChrimsonR was expressed non-specifically, the amount of DA released was almost unchanged upon photo-stimulation. However, for nonspecifically expressed ChrimsonR, intraperitoneal injection of bicuculline, a competitive antagonist at the GABA-binding site of the GABAA receptor, also significantly increased the release of DA at the NAcShell in response to photo-stimulation of the VTA. The results of immunochemical staining confirm that GABAergic neurons in the VTA suppress DA activation, and also indicate that alterations in GABAergic neurons may have serious downstream effects on DA activity, NAcShell release, and neural adaptation of the VTA. This study also confirms that optogenetics technology is crucial to study the relationship between the mesolimbic dopaminergic and GABAergic neurons in a neural-specific manner

Monitoring Neural Activities in the VTA in Response to Nicotine Intake Using a Novel Implantable Microimaging Device

Measurements of the deep brain area of rodents has been one of the most important methods to study deep brain activities, in part due to limited access of this region. In order to address this problem, we have designed and fabricated an implantable microimaging device for fluorescence imaging in the deep brain of rodents. In this study, we established a new fabrication method of a flat and uniformed fluorescence filter for an implantable microimaging device which obtained higher quality images, and aimed to show the performance of the device in the ventral tegmental area (VTA) of rats. We introduced GCaMP6s in the VTA of rats by adeno-associated viral (AAV) injection. The change in the fluorescence intensity was associated with nicotine administration and was observed by using our custom implantable microimaging device. We showed that nicotine administration significantly affected the excitation of DA neurons in different sub-regions of the VTA, reaching a maximum activation between 6-10 minutes following nicotine exposure, followed by a decrease after 31-35 minutes. Therefore, we believe our implantable microimaging device can potentially be used to monitor the neural activation within the sub-regions of the VTA in response to acute nicotine exposure by using GCaMP

Wide field-of-view lensless fluorescence imaging device with hybrid bandpass emission filter

We demonstrate a highly sensitive lensless fluorescence imaging device with a wide field-of-view by using a hybrid bandpass filter composed of interference filters, an absorption filter, and a fiber optic plate. The hybrid filter shows high excitation light rejection characteristics even in a lensless setup. In this study, we fabricated a hybrid bandpass filter and improved fluorescence observation performance for a target with auto-fluorescence. The filter was combined with a large image sensor with an imaging area of 67 mm2. As a demonstration, a brain slice from a green fluorescent protein transgenic mouse was observed and fluorescent cell bodies were detected with the lensless imaging device

Investigating the Modulation of the VTA Neurons in Nicotine-Exposed Pups during Early Maturation Using Optogenetics

Advancing the understanding of the relationship between perinatal nicotine addiction and the reward mechanism of the brain is crucial for uncovering and implementing new treatments for addiction control and prevention. The mesolimbic pathway of the brain, also known as the reward pathway, consists of two main areas that regulate dopamine (DA) and addiction-related behaviors. The ventral tegmental area (VTA) releases DA when stimulated, causing the propagation of neuronal firing along the pathway. This ends in the release of DA into the extracellular space of the nucleus accumbens (NAc), which is directly modulated by the uptake of DA. Much research has been conducted on the effects of nicotine addiction, but little research has been conducted concerning nicotine addiction and the mesolimbic pathway regarding maturation due to the small brain size. In this study, we apply our novel microstimulation experimental system to rat pups that have been perinatally exposed to nicotine. By using our self-fabricated photo-stimulation (PS) device, we can stimulate the VTA and collect dialysate, which is then used to estimate DA released into the NAc. The proposed platform has demonstrated the potential to monitor neural pathways as the pups mature

Investigating the Modulation of the VTA Neurons in Nicotine-Exposed Pups during Early Maturation Using Optogenetics

Advancing the understanding of the relationship between perinatal nicotine addiction and the reward mechanism of the brain is crucial for uncovering and implementing new treatments for addiction control and prevention. The mesolimbic pathway of the brain, also known as the reward pathway, consists of two main areas that regulate dopamine (DA) and addiction-related behaviors. The ventral tegmental area (VTA) releases DA when stimulated, causing the propagation of neuronal firing along the pathway. This ends in the release of DA into the extracellular space of the nucleus accumbens (NAc), which is directly modulated by the uptake of DA. Much research has been conducted on the effects of nicotine addiction, but little research has been conducted concerning nicotine addiction and the mesolimbic pathway regarding maturation due to the small brain size. In this study, we apply our novel microstimulation experimental system to rat pups that have been perinatally exposed to nicotine. By using our self-fabricated photo-stimulation (PS) device, we can stimulate the VTA and collect dialysate, which is then used to estimate DA released into the NAc. The proposed platform has demonstrated the potential to monitor neural pathways as the pups mature