Biology subjects

Fetcho, R. N.

Publications and source records attributed to Fetcho, R. N..

5 recordsLinked to original sources

bioRxiv2026

Cell-type-specific encoding of effort-based decision-making in the dorsal raphe nucleus

Effort-based decision-making, the process of weighing reward benefits against effort costs, is essential for adaptive behavior. Although the dorsal raphe nucleus (DRN) contributes to reward processing and effort-related behaviors, how specific DRN neuronal subtypes contribute to effort-based decision-making remains poorly understood. Using fiber photometry to record DRN serotonergic and GABAergic neurons during an effort-based decision-making task, we found that tonic fluctuations in DRN serotonergic activity were selectively associated with persistent selection of the high-value option. Furthermore, we found that while neither neuronal population was sensitive to relative reward magnitude, effort expenditure selectively enhanced decision- and reward-related signals carried by serotonergic and GABAergic neurons, respectively. Together, these findings support a cell type-specific model in which serotonergic activity provides a signal linking persistent motivational states to effortful choice, whereas GABAergic activity may contribute to evaluating or updating reward outcomes after effort expenditure. SIGNIFICANCE STATEMENTChoosing whether a reward is worth the effort required to obtain it is essential for adaptive behavior, yet the neural mechanisms underlying this process remain incompletely understood. Here, we identify distinct contributions of serotonin- and GABAergic neurons in the dorsal raphe nucleus, a major source of brain serotonin, to effort-based decision-making. Serotonergic neurons were preferentially engaged in sustained motivational state and action selection, and GABAergic neurons in the processing of reward outcomes following costly actions. Our findings reveal a cell type-specific organization of effort-based reward seeking in the dorsal raphe nucleus and provide a framework for understanding how motivational states, decisions, and reward outcomes are coordinated.

neuroscience↗

bioRxiv2026

Cellular and molecular coding of habit-driven behavior in the dorsal raphe nucleus

Chronic stress has potent effects on reward-seeking behavior, reducing hedonic drive but also biasing individuals toward habitual responding at the expense of goal-directed action. While prior studies have implicated corticostriatal circuits in these shifts, the contribution of the dorsal raphe nucleus (DRN) - a central neuromodulatory hub that regulates motivational states - remains poorly understood. Here, we identify a key role for DRN neurons in mediating stress-induced transitions from goal-directed to habit-driven behavior. Using two-photon calcium imaging in awake behaving mice, we show that DRN neurons encode representations of both effort expenditures and reward acquisition that are integrated at the single-neuron level. Chronic stress selectively enhances reward-related responses in habit-driven individuals, and deficits in reward-related activity in DRN neurons predict future habit formation after chronic stress. Single-nucleus transcriptional profiling revealed that chronic stress drives habit-related gene expression changes in GABAergic DRN neurons, including upregulation of genes implicated in synapse function and inhibitory signaling, and identified potential pharmacological treatment targets. Optogenetic inhibition of DRN GABA neurons rescued stress effects on habit formation, driving stable shifts in operant responding that persisted for days. Together, these findings establish the DRN as a critical modulator of stress-induced behavioral inflexibility, and identify a new role for DRN GABAergic neurons in determining stress susceptibility and driving stable and persistent switches in operant responding during recovery from chronic stress.

neuroscience↗

bioRxiv2025

Striatal pathways oppositely shift cortical activity along the decision axis

The cortex and basal ganglia are organized into multiple parallel loops that serve motor, limbic, and cognitive functions. The classic model of cortico-basal ganglia interactions posits that within each loop, the direct pathway of the basal ganglia activates the cortex and the indirect pathway inhibits it1-3. While this model has found support in the motor domain4,5, whether opponent control by the two pathways extends to the cognitive domain remains unknown. Here, we record from anterior cingulate cortex (ACC) and dorsomedial striatum (DMS) while inhibiting direct or indirect pathway neurons in DMS, as mice perform an accumulation-of-evidence task6-10. Inconsistent with the classic model, the manipulations do not produce opponent changes in overall ACC activity. Instead, the pathways exert opponent influence over a subpopulation of ACC neurons that encode accumulated sensory evidence, the task-relevant decision variable. The direction of the modulation depends on a neurons tuning to ipsilateral versus contralateral evidence, such that the two pathways generate opponent shifts in coding specifically along the decision axis. Thus, our results uncover unexpected specificity in the effects of basal ganglia pathways on the cortex, with the two pathways of the DMS exerting opponent control not on overall activity but on coding of the relevant task variable. This functional specificity may extend to other basal ganglia loops to support different aspects of adaptive behavior, with the pathways serving a general role in selecting and shifting cortical representations to subserve circuit-specific functions.

neuroscience↗

bioRxiv2023

A neural mechanism for learning from delayed postingestive feedback

Animals learn the value of foods based on their postingestive effects and thereby develop aversions to foods that are toxic1-6 and preferences to those that are nutritious7-14. However, it remains unclear how the brain is able to assign credit to flavors experienced during a meal with postingestive feedback signals that can arise after a substantial delay. Here, we reveal an unexpected role for postingestive reactivation of neural flavor representations in this temporal credit assignment process. To begin, we leverage the fact that mice learn to associate novel15-18, but not familiar, flavors with delayed gastric malaise signals to investigate how the brain represents flavors that support aversive postingestive learning. Surveying cellular resolution brainwide activation patterns reveals that a network of amygdala regions is unique in being preferentially activated by novel flavors across every stage of the learning process: the initial meal, delayed malaise, and memory retrieval. By combining high-density recordings in the amygdala with optogenetic stimulation of genetically defined hindbrain malaise cells, we find that postingestive malaise signals potently and specifically reactivate amygdalar novel flavor representations from a recent meal. The degree of malaise-driven reactivation of individual neurons predicts strengthening of flavor responses upon memory retrieval, leading to stabilization of the population-level representation of the recently consumed flavor. In contrast, meals without postingestive consequences degrade neural flavor representations as flavors become familiar and safe. Thus, our findings demonstrate that interoceptive reactivation of amygdalar flavor representations provides a neural mechanism to resolve the temporal credit assignment problem inherent to postingestive learning.

neuroscience↗

bioRxiv2019

Epigenetically bistable regions across neuron-specific genes govern neuron eligibility to a coding ensemble in the hippocampus

Episodic memories are stored in distributed neurons but how eligibility of individual neurons to coding ensembles is determined remains elusive. We identified thousands of predominantly bistable (CpG methylated or unmethylated) regions within neuronal gene bodies, established during the development of the mouse hippocampal dentate gyrus. Reducing DNA methylation and the proportion of the methylated epialleles at bistable regions compromised novel context-induced neuronal activation and spatial memory. Conversely, increasing methylation and the frequency of the methylated epialleles at bistable regions enhanced intrinsic excitability and spatial memory but impaired spatial working memory, indicating that the developmentally established methylated-unmethylated epiallelic balance at bistable regions is essential for proper neuronal excitability and hippocampal cognitive functions. Single-nucleus profiling revealed the enrichment of specific epialleles from a subset of bistable regions, primarily exonic, in encoding neurons. We propose a model in which epigenetically bistable regions create neuron heterogeneity, and specific constellations of exonic epialleles dictate, via modulating neuronal excitability, eligibility to a coding ensemble.

neuroscience↗