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Microglia, the brain’s resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival 1 . Here we show that microglia are also critical modulators of neuronal activity and associated behavioural responses in mice. Microglia respond to neuronal activation by suppressing neuronal activity, and ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. Suppression of neuronal activation by microglia occurs in a highly region-specific fashion and depends on the ability of microglia to sense and catabolize extracellular ATP, which is released upon neuronal activation by neurons and astrocytes. ATP triggers the recruitment of microglial protrusions and is converted by the microglial ATP/ADP hydrolysing ectoenzyme CD39 into AMP; AMP is then converted into adenosine by CD73, which is expressed on microglia as well as other brain cells. Microglial sensing of ATP, the ensuing microglia-dependent production of adenosine, and the adenosine-mediated suppression of neuronal responses via the adenosine receptor A 1 R are essential for the regulation of neuronal activity and animal behaviour. Our findings suggest that this microglia-driven negative feedback mechanism operates similarly to inhibitory neurons and is essential for protecting the brain from excessive activation in health and disease. Microglia, the brain’s immune cells, suppress neuronal activity in response to synaptic ATP release and alter behavioural responses in mice.

Cystathionine γ-lyase, which is responsible for the production of cysteine, is decreased in the striatum and cortex of mouse models of Huntington’s disease and in patients with Huntington’s disease, and cysteine supplementation in diet and drinking water partly rescues the phenotype and the diminished longevity of the mouse model. Cysteine link in Huntington's disease Huntington's disease is associated with polyglutamine expansion in the gene encoding huntingtin. Mutant huntingtin is expressed throughout the brain and rest of the body, but the striatum is the most affected brain region. Here it is shown that the enzyme cystathionine γ-lyase (CSE), responsible for cysteine biosynthesis, is decreased in the striatum and cortex of both mouse models and Huntington's disease patients. Mutant huntingtin inhibits the transcriptional activator Sp1, resulting in decreased CSE transcription. Cysteine supplementation in diet and drinking water partially rescues the phenotype and the diminished longevity in the mouse model, suggesting that cysteine supplementation might be beneficial for Huntington's disease patients. Huntington’s disease is an autosomal dominant disease associated with a mutation in the gene encoding huntingtin (Htt) leading to expanded polyglutamine repeats of mutant Htt (mHtt) that elicit oxidative stress, neurotoxicity, and motor and behavioural changes 1 . Huntington’s disease is characterized by highly selective and profound damage to the corpus striatum, which regulates motor function. Striatal selectivity of Huntington’s disease may reflect the striatally selective small G protein Rhes binding to mHtt and enhancing its neurotoxicity 2 . Specific molecular mechanisms by which mHtt elicits neurodegeneration have been hard to determine. Here we show a major depletion of cystathionine γ-lyase (CSE), the biosynthetic enzyme for cysteine, in Huntington’s disease tissues, which may mediate Huntington’s disease pathophysiology. The defect occurs at the transcriptional level and seems to reflect influences of mHtt on specificity protein 1, a transcriptional activator for CSE. Consistent with the notion of loss of CSE as a pathogenic mechanism, supplementation with cysteine reverses abnormalities in cultures of Huntington’s disease tissues and in intact mouse models of Huntington’s disease, suggesting therapeutic potential.

Bioluminescence imaging is a tremendous asset to medical research, providing a way to monitor living cells noninvasively within their natural environments. Advances in imaging methods allow researchers to measure tumor growth, visualize developmental processes, and track cell-cell interactions. Yet technical limitations exist, and it is difficult to image deep tissues or detect low cell numbers in vivo. Iwano et al. designed a bioluminescence imaging system that produces brighter emission by up to a factor of 1000 compared with conventional technology (see the Perspective by Nasu and Campbell). Individual tumor cells were successfully visualized in the lungs of mice. Small numbers of striatal neurons were detected in the brains of naturally behaving marmosets. The ability of the substrate to cross the blood-brain barrier should provide important opportunities for neuroscience research. Science , this issue p. 935 ; see also p. 868 A bioengineered light source allows in vivo imaging of individual cells. Bioluminescence is a natural light source based on luciferase catalysis of its substrate luciferin. We performed directed evolution on firefly luciferase using a red-shifted and highly deliverable luciferin analog to establish AkaBLI, an all-engineered bioluminescence in vivo imaging system. AkaBLI produced emissions in vivo that were brighter by a factor of 100 to 1000 than conventional systems, allowing noninvasive visualization of single cells deep inside freely moving animals. Single tumorigenic cells trapped in the mouse lung vasculature could be visualized. In the mouse brain, genetic labeling with neural activity sensors allowed tracking of small clusters of hippocampal neurons activated by novel environments. In a marmoset, we recorded video-rate bioluminescence from neurons in the striatum, a deep brain area, for more than 1 year. AkaBLI is therefore a bioengineered light source to spur unprecedented scientific, medical, and industrial applications.

Decades of neuroimaging studies have shown modest differences in brain structure and connectivity in depression, hindering mechanistic insights or the identification of risk factors for disease onset 1 . Furthermore, whereas depression is episodic, few longitudinal neuroimaging studies exist, limiting understanding of mechanisms that drive mood-state transitions. The emerging field of precision functional mapping has used densely sampled longitudinal neuroimaging data to show behaviourally meaningful differences in brain network topography and connectivity between and in healthy individuals 2 – 4 , but this approach has not been applied in depression. Here, using precision functional mapping and several samples of deeply sampled individuals, we found that the frontostriatal salience network is expanded nearly twofold in the cortex of most individuals with depression. This effect was replicable in several samples and caused primarily by network border shifts, with three distinct modes of encroachment occurring in different individuals. Salience network expansion was stable over time, unaffected by mood state and detectable in children before the onset of depression later in adolescence. Longitudinal analyses of individuals scanned up to 62 times over 1.5 years identified connectivity changes in frontostriatal circuits that tracked fluctuations in specific symptoms and predicted future anhedonia symptoms. Together, these findings identify a trait-like brain network topology that may confer risk for depression and mood-state-dependent connectivity changes in frontostriatal circuits that predict the emergence and remission of depressive symptoms over time. Precision functional mapping shows that the frontostriatal salience network occupies nearly twice as much of the cortex in people with depression, and this was unaffected by mood changes and detected in children before onset of symptoms.

The cortex projects to the dorsal striatum topographically 1 , 2 to regulate behaviour 3 – 5 , but spiking activity in the two structures has previously been reported to have markedly different relations to sensorimotor events 6 – 9 . Here we show that the relationship between activity in the cortex and striatum is spatiotemporally precise, topographic, causal and invariant to behaviour. We simultaneously recorded activity across large regions of the cortex and across the width of the dorsal striatum in mice that performed a visually guided task. Striatal activity followed a mediolateral gradient in which behavioural correlates progressed from visual cue to response movement to reward licking. The summed activity in each part of the striatum closely and specifically mirrored activity in topographically associated cortical regions, regardless of task engagement. This relationship held for medium spiny neurons and fast-spiking interneurons, whereas the activity of tonically active neurons differed from cortical activity with stereotypical responses to sensory or reward events. Inactivation of the visual cortex abolished striatal responses to visual stimuli, supporting a causal role of cortical inputs in driving the striatum. Striatal visual responses were larger in trained mice than untrained mice, with no corresponding change in overall activity in the visual cortex. Striatal activity therefore reflects a consistent, causal and scalable topographical mapping of cortical activity. Simultaneous mapping of activity across the cortex and dorsal striatum in mice shows that activity in each part of the striatum precisely mirrors that in topographically associated cortical regions, consistently across behavioural contexts.

Mounting evidence suggests that function and connectivity of the striatum is disrupted in schizophrenia 1 – 5 . We have developed a new hypothesis-driven neuroimaging biomarker for schizophrenia identification, prognosis and subtyping based on functional striatal abnormalities (FSA). FSA scores provide a personalized index of striatal dysfunction, ranging from normal to highly pathological. Using inter-site cross-validation on functional magnetic resonance images acquired from seven independent scanners ( n  = 1,100), FSA distinguished individuals with schizophrenia from healthy controls with an accuracy exceeding 80% (sensitivity, 79.3%; specificity, 81.5%). In two longitudinal cohorts, inter-individual variation in baseline FSA scores was significantly associated with antipsychotic treatment response. FSA revealed a spectrum of severity in striatal dysfunction across neuropsychiatric disorders, where dysfunction was most severe in schizophrenia, milder in bipolar disorder, and indistinguishable from healthy individuals in depression, obsessive-compulsive disorder and attention-deficit hyperactivity disorder. Loci of striatal hyperactivity recapitulated the spatial distribution of dopaminergic function and the expression profiles of polygenic risk for schizophrenia. In conclusion, we have developed a new biomarker to index striatal dysfunction and established its utility in predicting antipsychotic treatment response, clinical stratification and elucidating striatal dysfunction in neuropsychiatric disorders. A new cross-validated neuroimaging biomarker that reflects striatal dysfunctioning can be used to distinguish patients with schizophrenia from healthy controls, and is associated with treatment response to antipsychotics.

Which brain regions are causally involved in reward-related behavior? Ferenczi et al. combined focal, cell type-specific, optogenetic manipulations with brain imaging, behavioral testing, and in vivo electrophysiology (see the Perspective by Robbins). Stimulation of midbrain dopamine neurons increased activity in a brain region called the striatum and was correlated with reward-seeking across individual animals. However, elevated excitability of an area called the medial prefrontal cortex reduced both striatal responses to the stimulation of dopamine neurons and the behavioral drive to seek the stimulation of dopamine neurons. Finally, modulating the excitability of medial prefrontal cortex pyramidal neurons drove changes in neural circuit synchrony, as well as corresponding anhedonic behavior. These observations resemble imaging and clinical phenotypes observed in human depression, addiction, and schizophrenia. Science , this issue p. 10.1126/science.aac9698 ; see also p. 10.1126/science.aad9698 Optogenetic and brain imaging approaches reveal a causal brainwide dynamical mechanism for the hedonic-anhedonic transition. [Also see Perspective by Robbins ] Motivation for reward drives adaptive behaviors, whereas impairment of reward perception and experience (anhedonia) can contribute to psychiatric diseases, including depression and schizophrenia. We sought to test the hypothesis that the medial prefrontal cortex (mPFC) controls interactions among specific subcortical regions that govern hedonic responses. By using optogenetic functional magnetic resonance imaging to locally manipulate but globally visualize neural activity in rats, we found that dopamine neuron stimulation drives striatal activity, whereas locally increased mPFC excitability reduces this striatal response and inhibits the behavioral drive for dopaminergic stimulation. This chronic mPFC overactivity also stably suppresses natural reward-motivated behaviors and induces specific new brainwide functional interactions, which predict the degree of anhedonia in individuals. These findings describe a mechanism by which mPFC modulates expression of reward-seeking behavior, by regulating the dynamical interactions between specific distant subcortical regions.

Neuroleptic-induced dystonia is a source of great concern in clinical practice because of its iatrogenic nature which can potentially lead to life-threatening conditions. Since all neuroleptics (antipsychotics) share the ability to block the dopamine D2-type receptors (D2Rs) that are highly enriched in the striatum, this drug-induced dystonia is thought to be caused by decreased striatal D2R activity. However, how associations of striatal D2R inactivation with dystonia are formed remains elusive.A growing body of evidence suggests that imbalanced activities between D1R-expressing medium spiny neurons and D2R-expressing medium spiny neurons (D1-MSNs and D2-MSNs) in the striatal striosome-matrix system underlie the pathophysiology of various basal ganglia disorders including dystonia. Given the specificity of the striatal dopamine D1 system in ‘humans’, this article highlights the striatal striosome hypothesis in causing ‘repetitive’ and ‘stereotyped’ motor symptoms which are key clinical features of dystonia. It is suggested that exposure to neuroleptics may reduce striosomal D1-MSN activity and thereby cause dystonia symptoms. This may occur through an increase in the striatal cholinergic activity and the collateral inhibitory action of D2-MSNs onto neighbouring D1-MSNs within the striosome subfields. The article proposes a functional pathology of the striosome-matrix dopamine system for neuroleptic-induced acute dystonia or neuroleptic-withdrawal dystonia. A rationale for the effectiveness of dopaminergic or cholinergic pharmacotherapy is also provided for treating dystonias. This narrative review covers various aspects of the relevant field and provides a detailed discussion of the mechanisms of neuroleptic-induced dystonia.

Dopamine has long been thought to contribute to neurodegeneration in Parkinson's disease. The authors show that dopamine-induced neuron death in the substantia nigra is dependent on α-synuclein and coincides with increased levels of α-synuclein oligomers. The results suggest a synergistic interaction between dopamine and α-synuclein that underlies neuronal vulnerability in disease. Parkinson's disease (PD) is defined by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy body inclusions containing aggregated α-synuclein. Efforts to explain dopamine neuron vulnerability are hindered by the lack of dopaminergic cell death in α-synuclein transgenic mice. To address this, we manipulated both dopamine levels and α-synuclein expression. Nigrally targeted expression of mutant tyrosine hydroxylase with enhanced catalytic activity increased dopamine levels without damaging neurons in non-transgenic mice. In contrast, raising dopamine levels in mice expressing human A53T mutant α-synuclein induced progressive nigrostriatal degeneration and reduced locomotion. Dopamine elevation in A53T mice increased levels of potentially toxic α-synuclein oligomers, resulting in conformationally and functionally modified species. Moreover, in genetically tractable Caenorhabditis elegans models, expression of α-synuclein mutated at the site of interaction with dopamine prevented dopamine-induced toxicity. These data suggest that a unique mechanism links two cardinal features of PD: dopaminergic cell death and α-synuclein aggregation.

STXBP1 and SCN2A gene mutations are observed in patients with epilepsies, although the circuit basis remains elusive. Here, we show that mice with haplodeficiency for these genes exhibit absence seizures with spike-and-wave discharges (SWDs) initiated by reduced cortical excitatory transmission into the striatum. Mice deficient for Stxbp1 or Scn2a in cortico-striatal but not cortico-thalamic neurons reproduce SWDs. In Stxbp1 haplodeficient mice, there is a reduction in excitatory transmission from the neocortex to striatal fast-spiking interneurons (FSIs). FSI activity transiently decreases at SWD onset, and pharmacological potentiation of AMPA receptors in the striatum but not in the thalamus suppresses SWDs. Furthermore, in wild-type mice, pharmacological inhibition of cortico-striatal FSI excitatory transmission triggers absence and convulsive seizures in a dose-dependent manner. These findings suggest that impaired cortico-striatal excitatory transmission is a plausible mechanism that triggers epilepsy in Stxbp1 and Scn2a haplodeficient mice. Spike and wave discharge (SWD) activity is seen during absence seizures and is thought to be thalamocortical in origin. Here, the authors show that SWDs are initiated through the impaired corticostriatal excitatory transmissions onto striatal fast spiking interneurons.