Biology subjects

Grissom, N. M.

Publications and source records attributed to Grissom, N. M..

11 recordsLinked to original sources

bioRxiv2025

Synaptic Dysfunction and Compensation After NMDA Receptor Ablation in the Mouse Medial Prefrontal Cortex

N-methyl-D-aspartate receptors (NMDARs) in the prefrontal cortex (PFC) are critical regulators of neuronal excitability, synaptic plasticity, and cognitive function. NMDAR disruptions, including pharmacological blockade and anti-NMDAR encephalitis, can mimic symptoms of schizophrenia. These observations support the glutamate hypothesis of schizophrenia, which posits that symptoms arise from abnormal corticolimbic glutamatergic signaling. Further evidence for this theory includes abnormal expression of NMDARs and decreased dendritic spine density in the PFC of individuals with schizophrenia, as well as altered spine density and synaptic transmission caused by genetic manipulation of NMDARs. However, it is unknown how progressive loss of NMDAR function in the PFC during adolescence - a developmental time period associated with significant synaptic pruning and symptom onset in schizophrenia - affects excitatory synaptic structure and function. In this study, we used in vivo genome editing to ablate expression of the Grin1 gene, which encodes the obligate GluN1 subunit of NMDARs, in medial PFC neurons of female and male adolescent mice. We assessed synaptic density and function in layer V pyramidal neurons at multiple time points using whole-cell patch-clamp electrophysiology, integrated with confocal imaging of dendritic spine architecture in recorded neurons. NMDAR ablation caused an early decrease in basilar dendritic spine density, followed by a rebound in spine density and corresponding increase in AMPAR-mediated synaptic transmission, suggesting that synaptic compensation maintains an allostatic set point. Our findings demonstrate that NMDAR ablation initially disrupts local PFC networks, followed by recovery via compensatory processes that could be impaired in disease states.

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↗

bioRxiv2024

Touchscreen response precision is sensitive to the explore/exploit tradeoff

The explore/exploit tradeoff is a fundamental property of choice selection during reward-guided decision making. In perceptual decision making, higher certainty decisions are more motorically precise, even when the decision does not require motor accuracy. However, while we can parametrically control uncertainty in perceptual tasks, we do not know what variables - if any - shape motor precision and reflect subjective certainty during reward-guided decision making. Touchscreens are increasingly used across species to measure choice, but provide no tactile feedback on whether an action is precise or not, and therefore provide a valuable opportunity to determine whether actions differ in precision due to explore/exploit state, reward, or individual variables. We find all three of these factors exert independent drives towards increased precision. During exploit states, successive touches to the same choice are closer together than those made in an explore state, consistent with exploit states reflecting higher certainty and/or motor stereotypy in responding. However, exploit decisions might be expected to be rewarded more frequently than explore decisions. We find that exploit choice precision is increased independently of a separate increase in precision due to immediate past reward, suggesting multiple mechanisms regulating choice precision. Finally, we see evidence that male mice in general are less precise in their interactions with the touchscreen than females, even when exploiting a choice. These results suggest that as exploit behavior emerges in reward-guided decision making, individuals become more motorically precise reflecting increased certainty, even when decision choice does not require additional motor accuracy, but this is influenced by individual differences and prior reward. These data uncover the hidden potential for touchscreen tasks in any species to uncover the latent neural states that unite cognition and movement.

animal behavior and cognition↗

bioRxiv2024

Sex Differences in Morphine Sensitivity of Neuroligin-3 Knockout Mice

Sex has a strong influence on the prevalence and course of brain conditions, including autism spectrum disorders. The mechanistic basis for these sex differences remains poorly understood, due in part to historical bias in biomedical research favoring analysis of male subjects, and the exclusion of female subjects. For example, studies of male mice carrying autism-associated mutations in neuroligin-3 are over-represented in the literature, including our own prior work showing diminished responses to chronic morphine exposure in male neuroligin-3 knockout mice. We therefore studied how constitutive and conditional genetic knockout of neuroligin-3 affects morphine sensitivity of female mice. In contrast to male mice, female neuroligin-3 knockout mice showed normal psychomotor sensitization after chronic morphine exposure. However, in the absence of neuroligin-3 expression, both female and male mice show a similar change in the topography of locomotor stimulation produced by morphine. Conditional genetic deletion of neuroligin-3 from dopamine neurons increased the locomotor response of female mice to high doses of morphine, contrasting with the decrease in psychomotor sensitization caused by the same manipulation in male mice. Together, our data reveal that knockout of neuroligin-3 has both common and distinct effects on morphine sensitivity in female and male mice. These results also support the notion that female sex can confer resilience against the impact of autism-associated gene variants.

neuroscience↗

bioRxiv2024

Persistent Decision-Making in Mice, Monkeys, and Humans

Humans have the capacity to persist in behavioural policies, even in challenging environments that lack immediate reward. Persistence is the scaffold on which many higher executive functions are built. However, it remains unclear whether humans are uniquely persistent or, instead, if this capacity is widely conserved across species. To address this question, we compared humans with mice and monkeys in harmonised versions of a dynamic decision-making task. The task encouraged all species to strike a balance between persistently exploiting one policy and exploring alternative policies that could become better at any moment. Although all three species had similar strategies, we found that both primate species--humans and monkeys--were able to persist in exploitation for longer than the mice. The similarities in persistence patterns in humans and monkeys, as opposed to mice, may be related to the various ecological, neurobiological, or cognitive factors that differ systematically between these species.

animal behavior and cognition↗

bioRxiv2023

Differential processing of delay versus uncertainty in male but not female 16p11.2 hemideletion mice

Neurodevelopmental disorders are associated with differences in learning and motivation that can influence executive function, including behavioral flexibility and decision making. 16p11.2 hemideletion is a chromosomal copy number variant that is linked to neurodevelopmental disorders. 16p11.2 hemideletion in mice has been previously found to produce male-biased changes in reward learning, but the link between this and altered flexible decision making is poorly understood. We challenged 16p11.2 hemideletion mice with two reward-guided decision making tasks assessing flexible decision making under cost, delay and probability discounting. Both tasks elicited long-term changes in flexible decision making that separated 16p11.2 hemideletion males from wildtype males. In delay discounting,16p11.2 hemideletion males had a stronger, less flexible preference for the large reward at long delays, and this effect was reduced as wildtype males adjusted their preference to match that of the hemideletion males. In probability discounting, 16p11.2 hemideletion males initially had a similar preference for seeking improbable large rewards as did wildtype males, but over time began to prefer certainty to a greater extent than did wildtype males. Female mice discounted similarly for delayed or risky rewards regardless of the presence of the copy number variant. We have previously seen that male 16p11.2 hemideletion mice commit fewer nonreinforced responses than male wildtype mice in an operant setting, which we replicate here in delay discounting, while the introduction of risky rewards eliminates genotype differences in nonreinforced responses. Overall these data suggest that 16p11.2 hemideletion in males leads to differential processing of costs of delay versus inconsistency, with greater aversion to uncertainty than delays, and greater behavioral control by cues that consistently predict an outcome.

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↗

bioRxiv2021

Sequential delay and probability discounting tasks in mice reveal anchoring effects partially attributable to decision noise

Delay discounting and probability discounting decision making tasks in rodent models have high translational potential. However, it is unclear whether the discounted value of the large reward option is the main contributor to variability in animals choices in either task, which may limit translatability to human discounting data. Male and female mice underwent sessions of delay and probability discounting in sequence to assess how choice behavior adapts over experience with each task. To control for "anchoring" (persistent choices based on the initial delay or probability), mice experienced "Worsening" schedules where the large reward was offered under initially favorable delay or probability conditions that became less favorable during testing, followed by "Improving" schedules where the large reward was offered under initially unfavorable conditions that improved over a session. During delay discounting, both male and female mice showed elimination of anchoring effects over training. In probability discounting, both sexes of mice continued to show some anchoring even after months of training. One possibility is that noisy action selection could contribute to these anchoring effects, rather than persistent fluctuations in value discounting. We fit choice behavior in individual animals using models that included both a value-based discounting parameter and a decision noise parameter that captured variability in choices deviating from value maximization. Changes in anchoring behavior over time were tracked by changes in our decision noise parameter, not the value parameter. Thus, changes in discounting behavior in mice can result from changes in exploration of the environment rather than changes in reward valuation.

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↗

bioRxiv2019

Divergent strategies for learning in males and females

A frequent assumption in value-based decision-making tasks is that agents make decisions based on the feature dimension that reward probabilities vary on. However, in complex, multidimensional environments, stimuli can vary on multiple dimensions at once, meaning that the feature deserving the most credit for outcomes is not always obvious. As a result, individuals may vary in the strategies used to sample stimuli across dimensions, and these strategies may have an unrecognized influence on decision-making. Sex is a proxy for multiple genetic and endocrine influences that can influence decision-making strategies, including how environments are sampled. In this study, we examined the strategies adopted by female and male mice as they learned the value of stimuli that varied in both image and location in a visually-cued two-armed bandit, allowing two possible dimensions to learn about. Female mice acquired the correct image-value associations more quickly than male mice, and they used a fundamentally different strategy to do so. Female mice constrained their decision-space early in learning by preferentially sampling one location over which images varied. Conversely, male strategies were inconsistent, changing frequently and strongly influenced by the immediate experience of stochastic rewards. Individual strategies were related to sex-gated changes in neuronal activation in early learning. Together, we find that in mice, sex is linked with divergent strategies for sampling and learning about the world, revealing substantial unrecognized variability in the approaches implemented during value-based decision-making.

animal behavior and cognition↗