Biology subjects

Keiflin, R.

Publications and source records attributed to Keiflin, R..

6 recordsLinked to original sources

bioRxiv2026

Reward Memories Bias Instrumental Rule Selection via the Orbitofrontal-to-Secondary Motor cortex Pathway

Reward-predictive cues can influence decision-making and promote the pursuit of specific outcomes. This influence is classically studied using specific Pavlovian-to-instrumental transfer (sPIT), in which Pavlovian cues bias action selection and promote the instrumental action (often a left or right lever press) directed toward the cued outcome. However, naturalistic reward pursuit often extends beyond selecting discrete actions and requires selecting abstract rules that organize multiple actions into goal-directed sequences. The influence of cued reward memories on such rule selection has received less attention, and the neural circuits mediating this effect remains largely unknown. Here, we developed the specific Pavlovian-to-Rules-to-Instrumental Transfer (sPRInT) task, an adaptation of sPIT designed to examine how Pavlovian reward cues bias instrumental rule selection. We then used pathway-specific chemogenetic silencing to test the contribution of orbitofrontal cortex projections to secondary motor cortex (OFC[->]M2) to this effect. Rats expressing hM4Di or mCherry in OFC[->]M2 neurons learned a three-step instrumental sequence (sample lever [->] nosepoke [->] choice lever). In alternating blocks, rats used either a delayed non-match-to-sample rule or a visually guided rule to select the final action in the sequence and earn distinct outcomes (dNMTS-O1; VIS-O2). In a second phase, two distinct auditory cues were established as Pavlovian predictors of the two outcomes (S1-O1; S2-O2). Finally, in nonrewarded probe tests preceded by DCZ injections, we examined how presentation of these Pavlovian cues biased instrumental choices by promoting the use of an abstract rule. In control (mCherry) rats, Pavlovian cues promoted the adoption of the rule corresponding to the cued outcome (S1 promoted dNMTS; S2 promoted the VIS rule). In hM4Di rats, DCZ-mediated inactivation of OFC[->]M2 projection neurons diminished this effect. In contrast, OFC[->]M2 inhibition spared conventional sPIT, in which reward-predictive cues directly biased action selection without requiring abstract rules or extended action sequences. These findings demonstrate that cued reward memories can govern abstract rule selection and identify OFC[->]M2 as a critical circuit for translating those memories into goal-appropriate behavioral strategies.

neuroscience↗

bioRxiv2026

Orbitofrontal circuits for context-gated reward predictions

The orbitofrontal cortex (OFC) is essential for the contextual regulation of reward predictions, yet the circuit mechanisms underlying this function remain unclear. Here, we dissected the roles of two major OFC efferent pathways --projections to the central dorsal striatum (CDS) and the mediodorsal thalamus (MDT)-- in contextual regulation. Male and female rats performed a context-dependent discrimination task in which the reward-predictive status of two auditory target cues (X and Y) was determined by a visual contextual cue (A). Using temporally precise optogenetic inhibition of OFC terminals, we found that silencing OFC[->]CDS profoundly disrupted contextual gating, virtually abolishing the negatively gated component (A:Y- / Y+) while producing modest effects on the positively gated component (A:X+ / X-). In contrast, OFC[->]MDT inhibition produced modest and qualitatively distinct effects, characterized by a generalized increase in responding in context A and a decrease in context noA. These effects were reproduced in a connectionist model in which context influenced predictions either additively (via elemental representations) or by acting as a gatekeeper (via configural cue/context representations). Disrupting the configural pathway mimicked OFC[->]CDS silencing, whereas amplifying additive contextual inputs replicated OFC[->]MDT inhibition. Together, these findings reveal complementary circuit mechanisms through which the OFC shapes context-appropriate reward seeking.

neuroscience↗

bioRxiv2024

Partially dissociable roles of the Orbitofrontal cortex and dorsal Hippocampus in context-dependent (hierarchical) reward predictions and contextual inference in learning

Reward cues are often ambiguous; what is good in one context is not necessarily good in another context. To solve this ambiguity, animals form hierarchical associations in which the context acts as a gatekeeper in the retrieval of the appropriate cue-evoked memory, ensuring context-appropriate behavior. These hierarchical associative structures also influence future learning by promoting the formation of new context-dependent associations (leading to the inference of context-dependency for new associations). The orbitofrontal cortex (OFC) and the dorsal hippocampus (DH) are both proposed to encode a "cognitive map" that includes the representation of hierarchical, context-dependent, associations. However the causal role of the OFC and DH in the different functional properties of hierarchical associations remains controversial. Here we used chemogenetic inactivations, in rats, to examine the role of OFC and DH in 1) the contextual regulation of performance, and 2) the contextual learning bias conferred by hierarchical associations. We show that OFC is required for both manifestations of hierarchical associations. In contrast, DH contribution appears limited to the contextual learning bias. This study provides novel insight into the different functional properties of context-dependent hierarchical associations, and establishes the OFC as a critical orchestrator of these different contextual effects.

neuroscience↗

bioRxiv2023

Sex differences in discrimination behavior and orbitofrontal engagement during context-gated reward prediction

Animals, including humans, rely on contextual information to interpret ambiguous stimuli. Impaired context processing is a hallmark of several neuropsychiatric disorders, including schizophrenia, autism spectrum disorders, post-traumatic stress disorder, and addiction. While sex differences in the prevalence and manifestations of these disorders are well established, potential sex differences in context processing remain uncertain. Here we examined sex differences in the contextual control over cue-evoked reward seeking and its neural correlates, in rats. Male and female rats were trained in a bidirectional occasion-setting preparation in which the validity of two auditory reward-predictive cues was informed by the presence, or absence, of a visual contextual feature (LIGHT: X+ / DARK: X- / LIGHT: Y- / DARK: Y+). Females were significantly slower to acquire contextual control over cue-evoked reward seeking. However, once established, the contextual control over behavior was more robust in female rats; it showed less within-session variability (less influence of prior reward) and greater resistance to acute stress. This superior contextual control achieved by females was accompanied by an increased activation of the orbitofrontal cortex compared to males. Critically, these behavioral and neural sex differences were specific to the contextual modulation process and not observed in simple, context-independent, reward prediction tasks. These results indicate a sex-biased trade-off between the speed of acquisition and the robustness of performance in the contextual modulation of cued reward seeking. The different distribution of sexes along the fast learning {leftrightarrow} steady performance continuum might reflect different levels of engagement of the orbitofrontal cortex, and might have implications for our understanding of sex differences in psychiatric disorders.

neuroscience↗

bioRxiv2022

From Prediction to Action: Dissociable Roles of Ventral Tegmental Area and Substantia Nigra Dopamine Neurons in Instrumental Reinforcement

Reward-seeking requires the coordination of motor programs to achieve goals. Midbrain dopamine neurons are critical for reinforcement and their activation is sufficient for learning about cues, actions, and outcomes. Here we examine in detail the mechanisms underlying the ability of ventral tegmental area (VTA) and substantia nigra (SNc) dopamine neurons to support instrumental learning. By exploiting numerous behavioral tasks in combination with time-limited optogenetic manipulations, we reveal that VTA and SNc dopamine neurons generate reinforcement through separable psychological processes. VTA dopamine neurons imbue actions and their associated cues with motivational value that allows flexible and persistent pursuit whereas SNc dopamine neurons support time-limited, precise, action-specific learning that is non-scalable and inflexible. This architecture is reminiscent of actor-critic reinforcement learning models with VTA and SNc instructing the critic and actor, respectively. Our findings indicate that heterogeneous dopamine systems support unique forms of instrumental learning that ultimately result in disparate reward-seeking strategies.

neuroscience↗

bioRxiv2017

Phasic Activation of Ventral Tegmental, but not Substantia Nigra, Dopamine Neurons Promotes Model-Based Pavlovian Reward Learning

Dopamine (DA) neurons in the ventral tegmental area (VTA) and substantia nigra (SNc) encode reward prediction errors (RPEs) and are proposed to mediate error-driven learning. However the learning strategy engaged by DA-RPEs remains controversial. Model-free associations imbue cue/actions with pure value, independently of representations of their associated outcome. In contrast, model-based associations support detailed representation of anticipated outcomes. Here we show that although both VTA and SNc DA neuron activation reinforces instrumental responding, only VTA DA neuron activation during consumption of expected sucrose reward restores error-driven learning and promotes formation of a new cue[->]sucrose association. Critically, expression of VTA DA-dependent Pavlovian associations is abolished following sucrose devaluation, a signature of model-based learning. These findings reveal that activation of VTA-or SNc-DA neurons engages largely dissociable learning processes with VTA-DA neurons capable of participating in model-based predictive learning, while the role of SNc-DA neurons appears limited to reinforcement of instrumental responses.

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