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The cost of data movement has always been an important concern in high performance computing (HPC) systems. It has now become the dominant factor in terms of both energy consumption and performance. Support for expression of data locality has been explored in the past, but those efforts have had only modest success in being adopted in HPC applications for various reasons. them However, with the increasing complexity of the memory hierarchy and higher parallelism in emerging HPC systems, locality management has acquired a new urgency. Developers can no longer limit themselves to low-level solutions and ignore the potential for productivity and performance portability obtained by using locality abstractions. Fortunately, the trend emerging in recent literature on the topic alleviates many of the concerns that got in the way of their adoption by application developers. Data locality abstractions are available in the forms of libraries, data structures, languages and runtime systems; a common theme is increasing productivity without sacrificing performance. This paper examines these trends and identifies commonalities that can combine various locality concepts to develop a comprehensive approach to expressing and managing data locality on future large-scale high-performance computing systems.

Obsessive-Compulsive Disorder (OCD) is a debilitating illness consisting of obsessions and compulsions. OCD severity and treatment response are correlated with avoidant behaviors thought be performed to alleviate obsession-related anxiety. However, little is known about either the role of avoidance in the development of OCD or the interplay between anxiety states and avoidance behaviors. We have developed an instrumental negative reinforcement (i.e. active avoidance) paradigm in which mice must lever-press to avoid upcoming foot shocks. We show that mice (both sexes) can learn this task with high acquisition rates (75%) and that this behavior is largely stable when introducing uncertainty and modifying task structure. Furthermore, mice continue to perform avoidance responses on trials where lever pressing is not reinforced and increase response rates as they are maintained on this paradigm. With this paradigm, we did not find a relationship between negative reinforcement history and anxiety-related behaviors in well-established anxiety assays. Finally, we performed exploratory analyses to identify candidate regions involved in well-trained negative reinforcement using expression of the immediate early gene c-Fos. We detected correlated c-Fos expression in 1) cortico-striatal regions which regulate active avoidance in other paradigms and 2) amygdala circuits known to regulate conditioned defensive behaviors. Significance Statement Studies in patients with OCD suggest that compulsions are performed to avoid perceived threats and modulate anxiety tied to obsessions and/or compulsions. The negative reinforcement of avoidance and alleviated anxiety could therefore be a key driver of compulsive behaviors. However, there are still outstanding questions concerning the relationship between these two behaviors and the neural circuits involved in mediating negative reinforcement. We have developed an operant negative reinforcement paradigm in mice with discrete avoid and escape behaviors that can be learned without prior reward training with high throughput (75% acquisition) with responding that persists during nonreinforced trials. However, no differences were observed between negative reinforcement vs. unshocked and inescapably shocked controls, suggesting that continued negative reinforcement did not impact anxiety., (Copyright © 2024 the authors.)

Compulsive behaviors are a hallmark symptom of obsessive compulsive disorder (OCD). Striatal hyperactivity has been linked to compulsive behavior generation in correlative studies in humans and causal studies in rodents. However, the contribution of the two distinct striatal output populations to the generation and treatment of compulsive behavior is unknown. These populations of direct and indirect pathway-projecting spiny projection neurons (SPNs) have classically been thought to promote or suppress actions, respectively, leading to a long-held hypothesis that increased output of direct relative to indirect pathway promotes compulsive behavior. Contrary to this hypothesis, here we find that indirect pathway hyperactivity is associated with compulsive grooming in the Sapap3-knockout mouse model of OCD-relevant behavior. Furthermore, we show that suppression of indirect pathway activity using optogenetics or treatment with the first-line OCD pharmacotherapy fluoxetine is associated with reduced grooming in Sapap3-knockouts. Together, these findings highlight the striatal indirect pathway as a potential treatment target for compulsive behavior., (© 2024. The Author(s).)

Obsessive-compulsive disorder (OCD) is a chronic and severe psychiatric disorder for which effective treatment options are limited. Structural and functional neuroimaging studies have consistently implicated the orbitofrontal cortex (OFC) and striatum in the pathophysiology of the disorder. Recent genetic evidence points to involvement of components of the excitatory synapse in the etiology of OCD. However, the transcriptional alterations that could link genetic risk to known structural and functional abnormalities remain mostly unknown. To assess potential transcriptional changes in the OFC and two striatal regions (caudate nucleus and nucleus accumbens) of OCD subjects relative to unaffected comparison subjects, we sequenced messenger RNA transcripts from these brain regions. In a joint analysis of all three regions, 904 transcripts were differentially expressed between 7 OCD versus 8 unaffected comparison subjects. Region-specific analyses highlighted a smaller number of differences, which concentrated in caudate and nucleus accumbens. Pathway analyses of the 904 differentially expressed transcripts showed enrichment for genes involved in synaptic signaling, with these synapse-associated genes displaying lower expression in OCD subjects relative to unaffected comparison subjects. Finally, we estimated that cell type fractions of medium spiny neurons were lower whereas vascular cells and astrocyte fractions were higher in tissue of OCD subjects. Together, these data provide the first unbiased examination of differentially expressed transcripts in both OFC and striatum of OCD subjects. These transcripts encoded synaptic proteins more often than expected by chance, and thus implicate the synapse as a vulnerable molecular compartment for OCD.

Obsessive compulsive disorder (OCD) is a severe illness that affects 2-3% of people worldwide. OCD neuroimaging studies have consistently shown abnormal activity in brain regions involved in decision-making (orbitofrontal cortex [OFC]) and action selection (striatum). However, little is known regarding molecular changes that may contribute to abnormal function. We therefore examined expression of synaptic genes in post-mortem human brain samples of these regions from eight pairs of unaffected comparison and OCD subjects. Total grey matter tissue samples were obtained from medial OFC (BA11), lateral OFC (BA47), head of caudate, and nucleus accumbens (NAc). Quantitative polymerase chain reaction (qPCR) was then performed on a panel of transcripts encoding proteins related to excitatory synaptic structure, excitatory synaptic receptors/transporters, and GABA synapses. Relative to unaffected comparison subjects, OCD subjects had significantly lower levels of several transcripts related to excitatory signaling in both cortical and striatal regions. However, a majority of transcripts encoding excitatory synaptic proteins were lower in OFC but not significantly different in striatum of OCD subjects. Composite transcript level measures supported these findings by revealing that reductions in transcripts encoding excitatory synaptic structure proteins and excitatory synaptic receptors/transporters occurred primarily in OFC of OCD subjects. In contrast, transcripts associated with inhibitory synaptic neurotransmission showed minor differences between groups. The observed lower levels of multiple glutamatergic transcripts across both medial and lateral OFC may suggest an upstream causal event. Together, these data provide the first evidence of molecular abnormalities in brain regions consistently implicated in OCD human imaging studies.

OCD has lagged behind other psychiatric illnesses in the identification of molecular treatment targets, due in part to a lack of significant findings in genome-wide association studies. However, while progress in this area is being made, OCD's symptoms of obsessions, compulsions, and anxiety can be deconstructed into distinct neural functions that can be dissected in animal models. Studies in rodents and non-human primates have highlighted the importance of cortico-basal ganglia-thalamic circuits in OCD pathophysiology, and emerging studies in human post-mortem brain tissue point to glutamatergic synapse abnormalities as a potential cellular substrate for observed dysfunctional behaviors. In addition, accumulated evidence points to a potential role for neuromodulators including serotonin and dopamine in both OCD pathology and treatment. Here, we review current efforts to use animal models for the identification of molecules, cell types, and circuits relevant to OCD pathophysiology. We start by describing features of OCD that can be modeled in animals, including circuit abnormalities and genetic findings. We then review different strategies that have been used to study OCD using animal model systems, including transgenic models, circuit manipulations, and dissection of OCD-relevant neural constructs. Finally, we discuss how these findings may ultimately help to develop new treatment strategies for OCD and other related disorders., (© 2021. Springer Nature Switzerland AG.)