Biology subjects

Knep, E.

Publications and source records attributed to Knep, E..

5 recordsLinked to original sources

bioRxiv2025

NMDA receptor ablation in medial prefrontal cortex disrupts value updating and reward history integration

Schizophrenia, a serious mental illness, is associated with evidence of NMDA receptor (NMDAR) dysfunction and characterized by cognitive impairments that reflect impaired value updating and feedback-driven control; however the cellular and circuit-level mechanisms underlying these disruptions remain unclear. Here we test how NMDA receptor (NMDAR) signaling in the medial prefrontal cortex (mPFC) contributes to adaptive decision-making by combining targeted genetic ablation in mice and systemic pharmacology. Using a CRISPR-Cas9 approach to eliminate the obligate GluN1 subunit, we induced spatially confined NMDAR hypofunction in mPFC and compared its effects to systemic pharmacological blockade with the NMDAR antagonist MK-801 during performance of a touchscreen-based restless bandit task. Prefrontal NMDAR ablation impaired value discrimination, weakened the use of negative feedback, and reduced mutual information between recent outcomes and current choices, indicating disrupted reward-history integration. Reinforcement-learning models incorporating a choice-kernel term best captured behavior and revealed that NMDAR ablation selectively dampened learning and choice-history parameters governing flexible updating. Systemic MK-801 produced broad impairments in control animals, reducing accuracy, mutual information, and outcome sensitivity, yet exerted only modest additional effects after NMDAR ablation, suggesting that prefrontal NMDAR loss occluded much of the pharmacological disruption. Simulations using fitted RLCK parameters reproduced these patterns, showing convergent flattening of choice dynamics under MK-801 and persistent deficits in GluN1 ablated animals. Together, these findings demonstrate that prefrontal NMDAR signaling is necessary for effective value updating and feedback-driven learning, and that its loss recapitulates core features of systemic NMDAR hypofunction. This work establishes a mechanistic bridge between localized cortical glutamatergic dysfunction and the reinforcement-learning disturbances characteristic of schizophrenia.

neuroscience↗

bioRxiv2025

16p11.2 duplication shows early male-biased impacts on reward learning, but NMDA receptor antagonism reduces optimal choice selection in both wildtypes and 16p11.2 duplication

Rationale16p11.2 duplication is associated with numerous neuropsychiatric conditions at a genome-wide level, including psychosis. Mice modeling 16p11.2 duplication may provide important insights into cognitive risk factors, in particular in reward-guided decision making. NMDAR function has also been implicated in psychosis phenotypes, but whether these phenotypes differ by genetic risk factor is unknown. ObjectivesWe aimed to: 1) identify sex and genotype differences in early operant training and two-arm spatial restless bandit task performance; 2) examine the effects of an NMDAR antagonist on task performance and strategy across genotypes. Methods16p11.2 duplication and wildtype mice completed a series of training schedules of escalating difficulty followed by bandit tasks. MK-801 and saline were administered in alternating sessions prior to later bandit task performance. ResultsLarge sex differences in early operant training revealed some male-biased impacts of 16p11.2 duplication, contingent on training schedule difficulty. Once on the two-arm spatial restless bandit task, 16p11.2 duplication was no longer a strong contributor to decision making. However, MK-801 decreased the tendency to stay with a rewarded choice, lowered the probability of selecting the highest rewarded option, and decreased the influence of prior outcomes on choice. ConclusionsThe male-biased vulnerability in early operant training suggests that strategies for learning early schemas or in novel environments may be impacted by 16p11.2 duplication in males. In contrast, NMDAR are influential in the ability to flexibly switch between choices, and disrupting this function significantly impairs decision making in all animals.

animal behavior and cognition↗

bioRxiv2025

Sex-biased computations underlying differential set shift performance in mice

Cognitive flexibility can be defined as the ability to adaptively shift between choices or strategies based on environmental feedback and it is disrupted in numerous neuropsychiatric conditions. Individual differences in the computations supporting cognitive flexibility are poised to reveal mechanisms of neuropsychiatric risk and resilience. One critical variable well known to influence individual differences in neuropsychiatric risk is sex. While previous research has identified sex differences in value based decision making in mice, whether sex reflects a major source of variation in cognitive flexibility remains unknown. To directly assess sex-biased individual differences in cognitive flexibility, we developed a novel touchscreen Set Shift task that permits robust and continuous testing in mice. Using this task, we discovered that female mice completed significantly more rule shifts with fewer errors than males. We next employed a suite of computational models that revealed sex-biased individual differences in the computations underlying cognitive flexibility. Overall, our results suggest that following rule shifts, female mice learn the new rule faster and commit to exploiting rule choices sooner compared to males - sometimes because they commit to multiple rules simultaneously. This suggests that increased choice stability in female rodents enhances commitment to a strategy during periods of uncertainty and directly contributes to increased rule shifting. This supports the counterintuitive conclusion that a high degree of stable choice is a strong requirement for enhanced cognitive flexibility in the Set Shift task, one of the gold standard cognitive flexibility tasks.

animal behavior and cognition↗

bioRxiv2023

Dopamine and norepinephrine differentially mediate the exploration-exploitation tradeoff

The catecholamines dopamine (DA) and norepinephrine (NE) have been implicated in neuropsychiatric vulnerability, in part via their roles in mediating the decision making processes. Although the two neuromodulators share a synthesis pathway and are co-activated, they engage in distinct circuits and roles in modulating neural activity across the brain. However, in the computational neuroscience literature, they have been assigned similar roles in modulating the exploration-exploitation tradeoff. Revealing how each neuromodulator contributes to this explore-exploit process is important in guiding mechanistic hypotheses emerging from computational psychiatric approaches. To understand the differences and overlaps of the roles of dopamine and norepinephrine in mediating exploration, a direct comparison using the same dynamic decision making task is needed. Here, we ran mice in a restless bandit task, which encourages both exploration and exploitation. We systemically administered a nonselective DA antagonist (flupenthixol), a nonselective DA agonist (apomorphine), a NE beta-receptor antagonist (propranolol), and a NE beta-receptor agonist (isoproterenol), and examined changes in exploration within subjects across sessions. We found a bidirectional modulatory effect of dopamine receptor activity on exploration - increasing dopamine activity decreased exploration and decreasing dopamine activity increased exploration. The modulation of exploration via beta-noradrenergic activity was mediated by sex. Computational model parameters revealed that dopamine modulation affected exploration via decision noise and norepinephrine modulation via outcome sensitivity. Together, these findings suggested that the mechanisms that govern the transition between exploration and exploitation are sensitive to changes in both catecholamine functions and revealed differential roles for NE and DA in mediating exploration. Significance StatementBoth dopamine (DA) and norepinephrine (NE) has been implicated in the decision making process. Although these two catecholamines have shared aspects of their biosynthetic pathways and projection targets, they are thought to exert many core functions via distinct neural targets and receptor subtypes. However, the computational neuroscience literature often ascribes similar roles to these catecholamines, despite the above evidence. Resolving this discrepancy is important in guiding mechanistic hypotheses emerging from computational psychiatric approaches. This study examines the role of dopamine and norepinephrine on the explore-exploit tradeoff. By testing mice, we were able to compare multiple pharmacological agents within subjects, and examine source of individual differences, allowing direct comparison between the effects of these two catecholamines in modulating decision making.

animal behavior and cognition↗

bioRxiv2020

Sex differences in learning from exploration

Sex-based modulation of cognitive processes could set the stage for individual differences in vulnerability to neuropsychiatric disorders. While value-based decision making processes in particular have been proposed to be influenced by sex differences, the overall correct performance in decision making tasks often show variable or minimal differences across sexes. Computational tools allow us to uncover latent variables that define different decision making approaches, even in animals with similar correct performance. Here, we quantify sex differences in mice in the latent variables underlying behavior in a classic value-based decision making task: a restless 2-armed bandit. While male and female mice had similar accuracy, they achieved this performance via different patterns of exploration. Male mice tended to make more exploratory choices overall, largely because they appeared to get "stuck" in exploration once they had started. Female mice tended to explore less, but learned more quickly during exploration. Together, these results suggest that sex exerts stronger influences on decision making during periods of learning and exploration than during stable choices. Exploration during decision making is altered in people diagnosed addictions, depression, and neurodevelopmental disabilities, pinpointing the neural mechanisms of exploration as a highly translational avenue for conferring sex-modulated vulnerability to neuropsychiatric diagnoses.

animal behavior and cognition↗