Nucleus Accumbens Dopamine D1-Receptor-Expressing Neurons Control the Acquisition of Sign-Tracking to Conditioned Cues in Mice

Following repeated pairings, the reinforcing and motivational properties (incentive salience) of a reward can be transferred onto an environmental stimulus which can then elicit conditioned responses, including Pavlovian approach behavior to the stimulus (a sign-tracking response). In rodents, acquisition of sign-tracking in autoshaping paradigms is sensitive to lesions and dopamine D1 receptor antagonism of the nucleus accumbens (NAc) of the ventral striatum. However, currently, the possible roles of dorsal striatal subregions, as well as of the two major striatal neuron types, dopamine D1-/D2-expressing medium spiny neurons (MSNs), in controlling the development of conditioned responses is still unclear and warrants further study. Here, for the first time, we used a transgenic mouse line combined with striatal subregion-specific AAV virus injections to separately express tetanus toxin in D1-/D2- MSNs in the NAc, dorsomedial striatum, and dorsolateral striatum, to permanently block neurotransmission in these neurons during acquisition of an autoshaping task. Neurotransmission blocking of NAc D1-MSNs inhibited the acquisition of sign-tracking responses when the initial conditioned response for each conditioned stimulus presentation was examined, confirming our initial hypothesis. These findings suggest that activity in NAc D1-MSNs contributes to the attribution of incentive salience to conditioned stimuli

Natural and Artificial Intelligence: A brief introduction to the interplay between AI and neuroscience research

Neuroscience and artificial intelligence (AI) share a long history of collaboration. Advances in neuroscience, alongside huge leaps in computer processing power over the last few decades, have given rise to a new generation of in silico neural networks inspired by the architecture of the brain. These AI systems are now capable of many of the advanced perceptual and cognitive abilities of biological systems, including object recognition and decision making. Moreover, AI is now increasingly being employed as a tool for neuroscience research and is transforming our understanding of brain functions. In particular, deep learning has been used to model how convolutional layers and recurrent connections in the brain’s cerebral cortex control important functions, including visual processing, memory, and motor control. Excitingly, the use of neuroscience-inspired AI also holds great promise for understanding how changes in brain networks result in psychopathologies, and could even be utilized in treatment regimes. Here we discuss recent advancements in four areas in which the relationship between neuroscience and AI has led to major advancements in the field; (1) AI models of working memory, (2) AI visual processing, (3) AI analysis of big neuroscience datasets, and (4) computational psychiatry

Cellular senescence in white matter microglia is induced during ageing in mice and exacerbates the neuroinflammatory phenotype

Cellular senescence, a state of irreversible cell-cycle arrest caused by a variety of cellular stresses, is critically involved in age-related tissue dysfunction in various organs. However, the features of cells in the central nervous system that undergo senescence and their role in neural impairment are not well understood as yet. Here, through comprehensive investigations utilising single-cell transcriptome analysis and various mouse models, we show that microglia, particularly in the white matter, undergo cellular senescence in the brain and spinal cord during ageing and in disease models involving demyelination. Microglial senescence is predominantly detected in disease-associated microglia, which appear in ageing and neurodegenerative diseases. We also find that commensal bacteria promote the accumulation of senescent microglia and disease-associated microglia during ageing. Furthermore, knockout of p16 INK4a, a key senescence inducer, ameliorates the neuroinflammatory phenotype in damaged spinal cords in mice. These results advance our understanding of the role of cellular senescence in the central nervous system and open up possibilities for the treatment of age-related neural disorders.Matsudaira T., Nakano S., Konishi Y., et al. Cellular senescence in white matter microglia is induced during ageing in mice and exacerbates the neuroinflammatory phenotype. Communications Biology 6, 665 (2023); https://doi.org/10.1038/s42003-023-05027-2

Opposing Roles of Dopamine Receptor D1- and D2-Expressing Neurons in the Anteromedial Olfactory Tubercle in Acquisition of Place Preference in Mice

Olfaction induces adaptive motivated behaviors. Odors associated with food induce attractive behavior, whereas those associated with dangers induce aversive behavior. We previously reported that learned odor-induced attractive and aversive behaviors accompany activation of the olfactory tubercle (OT) in a domain- and cell type-specific manner. Odor cues associated with a sugar reward induced attractive behavior and c-fos expression in the dopamine receptor D1-expressing neurons (D1 neurons) in the anteromedial OT. In contrast, odor cues associated with electrical shock induced aversive behavior and c-fos expression in the pamine receptor D2-expressing neurons (D2 neurons) in the anteromedial OT, as well as the D1 neurons in the lateral OT. Here, we investigated whether the D1 and D2 neurons in the anteromedial OT play distinct roles in attractive or aversive behaviors, using optogenetic stimulation and real-time place preference (RTPP) tests. Mice expressing ChETA (ChR2/E123T)-enhanced yellow fluorescent protein (EYFP) in the D1 neurons in the anteromedial OT spent a longer time in the photo-stimulation side of the place preference chamber than the control mice expressing EYFP. On the other hand, upon optogenetic stimulation of the D2 neurons in the anteromedial OT, the mice spent a shorter time in the photo-stimulation side than the control mice. Local neural activation in the anteromedial OT during the RTPP tests was confirmed by c-fos mRNA expression. These results suggest that the D1 and D2 neurons in the anteromedial OT play opposing roles in attractive and aversive behaviors, respectively

Nuclear-translocated Glyceraldehyde-3-phosphate Dehydrogenase Promotes Poly(ADP-ribose) Polymerase-1 Activation during Oxidative/Nitrosative Stress in Stroke

peer reviewedIn addition to its role in DNA repair, nuclear poly(ADP-ribose) polymerase-1 (PARP-1) mediates brain damage when it is over-activated by oxidative/nitrosative stress. Nonetheless, it remains unclear how PARP-1 is activated in neuropathological contexts. Here we report that PARP-1 interacts with a pool of glyceradehyde-3-phosphate dehydrogenase (GAPDH) that translocates into the nucleus under oxidative/nitrosative stress both in vitro and in vivo. A well conserved amino acid at the N terminus of GAPDH determines its protein binding with PARP-1. Wild-type (WT) but not mutant GAPDH, that lacks the ability to bind PARP-1, can promote PARP-1 activation. Importantly, disrupting this interaction significantly diminishes PARP-1 overactivation and protects against both brain damage and neurological deficits induced by middle cerebral artery occlusion/reperfusion in a rat stroke model. Together, these findings suggest that nuclear GAPDH is a key regulator of PARP-1 activity, and its signaling underlies the pathology of oxidative/nitrosative stress-induced brain damage including stroke

ソクザカク コリン サドウセイ シンケイ サイボウ ノ ジョキョ ニ ヨル コカイン エ ノ カンジュセイ ノ ゾウダイ

京都大学0048新制・課程博士博士(医学)甲第9430号医博第2443号新制||医||790(附属図書館)UT51-2002-G188京都大学大学院医学研究科生理系専攻(主査)教授 大森 治紀, 教授 柴崎 浩, 教授 中西 重忠学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA

ソクザカク コリン サドウセイ シンケイ サイボウ ノ ジョキョ ニ ヨル コカイン エ ノ カンジュセイ ノ ゾウダイ

京都大学0048新制・課程博士博士(医学)甲第9430号医博第2443号新制||医||790(附属図書館)UT51-2002-G188京都大学大学院医学研究科生理系専攻(主査)教授 大森 治紀, 教授 柴崎 浩, 教授 中西 重忠学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA

Nucleus Accumbens Dopamine D1-Receptor-Expressing Neurons Control the Acquisition of Sign-Tracking to Conditioned Cues in Mice

Following repeated pairings, the reinforcing and motivational properties (incentive salience) of a reward can be transferred onto an environmental stimulus which can then elicit conditioned responses, including Pavlovian approach behavior to the stimulus (a sign-tracking response). In rodents, acquisition of sign-tracking in autoshaping paradigms is sensitive to lesions and dopamine D1 receptor antagonism of the nucleus accumbens (NAc) of the ventral striatum. However, currently, the possible roles of dorsal striatal subregions, as well as of the two major striatal neuron types, dopamine D1-/D2-expressing medium spiny neurons (MSNs), in controlling the development of conditioned responses is still unclear and warrants further study. Here, for the first time, we used a transgenic mouse line combined with striatal subregion-specific AAV virus injections to separately express tetanus toxin in D1-/D2- MSNs in the NAc, dorsomedial striatum, and dorsolateral striatum, to permanently block neurotransmission in these neurons during acquisition of an autoshaping task. Neurotransmission blocking of NAc D1-MSNs inhibited the acquisition of sign-tracking responses when the initial conditioned response for each conditioned stimulus presentation was examined, confirming our initial hypothesis. These findings suggest that activity in NAc D1-MSNs contributes to the attribution of incentive salience to conditioned stimuli