Transcriptomic analysis of the human habenula in schizophrenia.

Importance: Habenula (Hb) pathophysiology is involved in many neuropsychiatric disorders, including schizophrenia. Deep brain stimulation and pharmacological targeting of the Hb are emerging as promising therapeutic treatments. However, little is known about the cell type-specific transcriptomic organization of the human Hb or how it is altered in schizophrenia. Objective: To define the molecular neuroanatomy of the human habenula and identify transcriptomic changes in individuals with schizophrenia compared to neurotypical controls. Design Setting and Participants: This study utilized Hb-enriched postmortem human brain tissue. Single nucleus RNA-sequencing (snRNA-seq) and single molecule fluorescent in situ hybridization (smFISH) experiments were conducted to identify molecularly defined Hb cell types and map their spatial location (n=3-7 donors). Bulk RNA-sequencing and cell type deconvolution were used to investigate transcriptomic changes in Hb-enriched tissue from 35 individuals with schizophrenia and 33 neurotypical controls. Gene expression changes associated with schizophrenia in the Hb were compared to those previously identified in the dorsolateral prefrontal cortex (DLPFC), hippocampus, and caudate. Main Outcomes and Measures: Semi-supervised snRNA-seq cell type clustering. Transcript visualization and quantification of smFISH probes. Bulk RNA-seq cell type deconvolution using reference snRNA-seq data. Schizophrenia-associated gene differential expression analysis adjusting for Hb and thalamus fractions, RNA degradation-associated quality surrogate variables, and other covariates. Cross-brain region schizophrenia-associated gene expression comparison. Results: snRNA-seq identified 17 cell type clusters across 16,437 nuclei, including 3 medial and 7 lateral Hb populations. Cell types were conserved with those identified in a rodent model. smFISH for cell type marker genes validated snRNA-seq Hb cell types and depicted the spatial organization of subpopulations. Bulk RNA-seq analyses yielded 45 schizophrenia-associated differentially expressed genes (FDR < 0.05), with 32 (71%) unique to Hb-enriched tissue. Conclusions: These results identify topographically organized cell types with distinct molecular signatures in the human Hb. They further demonstrate unique transcriptomic changes in the epithalamus associated with schizophrenia, thereby providing molecular insights into the role of Hb in neuropsychiatric disorders.

Call for a more balanced approach to understanding orbital frontal cortex function.

Orbital frontal cortex (OFC) research has historically emphasized the function of this associative cortical area within top-down theoretical frameworks. This approach has largely focused on mapping OFC activity onto human-defined psychological or cognitive constructs and has often led to OFC circuitry bearing the weight of entire theoretical frameworks. New techniques and tools developed in the last decade have made it possible to revisit long-standing basic science questions in neuroscience and answer them with increasing sophistication. We can now study and specify the genetic, molecular, cellular, and circuit architecture of a brain region in much greater detail, which allows us to piece together how they contribute to emergent circuit functions. For instance, adopting such systematic and unbiased bottom-up approaches to elucidating the function of the visual system has paved the way to building a greater understanding of the spectrum of its computational capabilities. In the same vein, we argue that OFC research would benefit from a more balanced approach that also places focus on novel bottom-up investigations into OFC's computational capabilities. Furthermore, we believe that the knowledge gained by employing a more bottom-up approach to investigating OFC function will ultimately allow us to look at OFC's dysfunction in disease through a more nuanced biological lens. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

A Push For Examining Subjective Experience in Value-Based Decision-Making.

Subjective experience is a powerful contributor to value-based decision-making. Not every decision is the same, nor made in isolation. Rather, decision-making relies on historical information and internal states for adaptive control. Hence, it is inherently continuous with respect to time - one decision or action evolves into the next. However, forays into the neurobiological underpinnings of decision-making have too frequently ignored the contribution of such continuous subjective experience, instead tying circuit activity and brain area involvement to discrete averaged behaviors and task parameters. While much information has been gained through these investigations, recent works have demonstrated the potential for a greater understanding of neural mechanisms when the continuous, experiential nature of behavior is integrated into the investigation. Such integration has important implications for disease states with disordered decision-making such as addiction, where subjective experience is a large contributor to the disorder.

Mechanism for differential recruitment of orbitostriatal transmission during actions and outcomes following chronic alcohol exposure.

Psychiatric disease often produces symptoms that have divergent effects on neural activity. For example, in drug dependence, dysfunctional value-based decision-making and compulsive-like actions have been linked to hypo- and hyperactivity of orbital frontal cortex (OFC)-basal ganglia circuits, respectively; however, the underlying mechanisms are unknown. Here we show that alcohol-exposed mice have enhanced activity in OFC terminals in dorsal striatum (OFC-DS) associated with actions, but reduced activity of the same terminals during periods of outcome retrieval, corresponding with a loss of outcome control over decision-making. Disrupted OFC-DS terminal activity was due to a dysfunction of dopamine-type 1 receptors on spiny projection neurons (D1R SPNs) that resulted in increased retrograde endocannabinoid signaling at OFC-D1R SPN synapses reducing OFC-DS transmission. Blocking CB1 receptors restored OFC-DS activity in vivo and rescued outcome-based control over decision-making. These findings demonstrate a circuit-, synapse-, and computation-specific mechanism gating OFC activity in alcohol-exposed mice.

Orbital frontal cortex updates state-induced value change for decision-making.

Recent hypotheses have posited that orbital frontal cortex (OFC) is important for using inferred consequences to guide behavior. Less clear is OFC's contribution to goal-directed or model-based behavior, where the decision to act is controlled by previous experience with the consequence or outcome. Investigating OFC's role in learning about changed outcomes separate from decision-making is not trivial and often the two are confounded. Here we adapted an incentive learning task to mice, where we investigated processes controlling experience-based outcome updating independent from inferred action control. We found chemogenetic OFC attenuation did not alter the ability to perceive motivational state-induced changes in outcome value but did prevent the experience-based updating of this change. Optogenetic inhibition of OFC excitatory neuron activity selectively when experiencing an outcome change disrupted the ability to update, leaving mice unable to infer the appropriate behavior. Our findings support a role for OFC in learning that controls decision-making.