Biology subjects

Golden, C. E. M.

Publications and source records attributed to Golden, C. E. M..

4 recordsLinked to original sources

bioRxiv2024

Acetylcholine demixes heterogeneous dopamine signals for learning and moving

Midbrain dopamine neurons promote both reinforcement learning and movement vigour1-12. A major outstanding question is how dopamine-recipient neurons in the striatum parse these heterogeneous signals. Previous work suggests that cholinergic striatal interneurons may play a role, perhaps by gating dopamine-dependent plasticity13-16, but this has not been tested in behaving animals. Here we studied rats performing a decision-making task with reward- and movement-related events at distinct time points. Optical measurement of dopamine and acetylcholine release in the dorsomedial striatum (DMS) revealed distinct dynamics at task events. Reward cues evoked cholinergic pauses with different phase relationships relative to dopamine. When dopamine slightly lagged cholinergic dips, dopamine predicted future behaviour, and DMS firing rates on subsequent trials. In contrast, when dopamine slightly preceded cholinergic dips, there was no observable relationship between dopamine and learning. Finally, when dopamine was coincident with cholinergic bursts, it preceded and predicted the vigour of upcoming contralateral orienting movements. Our findings suggest that the precise phase relationship between dopamine and acetylcholine allows dopamine to be used for either movement or learning depending on instantaneous behavioural context.

neuroscience↗

bioRxiv2024

Mesolimbic dopamine encodes reward prediction errors independent of learning rates

Biological accounts of reinforcement learning posit that dopamine encodes reward prediction errors (RPEs), which are multiplied by a learning rate to update state or action values. These values are thought to be represented in synaptic weights in the striatum, and updated by dopamine-dependent plasticity, suggesting that dopamine release might reflect the product of the learning rate and RPE. Here, we leveraged the fact that animals learn faster in volatile environments to characterize dopamine encoding of learning rates in the nucleus accumbens core (NAcc). We trained rats on a task with semi-observable states offering different rewards, and rats adjusted how quickly they initiated trials across states using RPEs. Computational modeling and behavioral analyses showed that learning rates were higher following state transitions, and scaled with trial-by-trial changes in beliefs about hidden states, approximating normative Bayesian strategies. Notably, dopamine release in the NAcc encoded RPEs independent of learning rates, suggesting that dopamine-independent mechanisms instantiate dynamic learning rates.

neuroscience↗

bioRxiv2023

Estrogenic control of reward prediction errors and reinforcement learning

Gonadal hormones act throughout the brain1, and neuropsychiatric disorders vary in symptom severity over the reproductive cycle, pregnancy, and perimenopause2-4. Yet how hormones influence cognitive processes is unclear. Exogenous 17{beta}-estradiol modulates dopamine signaling in the nucleus accumbens core (NAcc)5,6, which instantiates reward prediction errors (RPEs) for reinforcement learning7-16. Here we show that endogenous 17{beta}-estradiol enhances RPEs and sensitivity to previous rewards by reducing dopamine reuptake proteins in the NAcc. Rats performed a task with different reward states; they adjusted how quickly they initiated trials across states, balancing effort against expected rewards. NAcc dopamine reflected RPEs that predicted and causally influenced initiation times. Elevated endogenous 17{beta}-estradiol increased sensitivity to reward states by enhancing dopaminergic RPEs in the NAcc. Proteomics revealed reduced dopamine transporter expression. Finally, knockdown of midbrain estrogen receptors suppressed reinforcement learning. 17{beta}-estradiol therefore controls RPEs via dopamine reuptake, mechanistically revealing how hormones influence neural dynamics for motivation and learning.

neuroscience↗

bioRxiv2018

Disruption of the KH1 domain of Fmr1 leads to transcriptional alterations and attentional deficits in rats

Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the FMR1 gene. FXS is a leading monogenic cause of autism spectrum disorder (ASD) and inherited intellectual disability (ID). In most cases, the mutation is an expansion of a microsatellite (CGG triplet), which leads to suppressed expression of the fragile X mental retardation protein (FMRP), an RNA-binding protein involved in multiple aspects of mRNA metabolism. Interestingly, we found that the previously published Fmr1 knockout rat model of FXS expresses a transcript with an in-frame deletion of a K-homology (KH) domain, KH1. KH domains are RNA-binding domains of FMR1 and several of the few, known point mutations associated with FXS are found within them. We observed that this deletion leads to medial prefrontal cortex (mPFC)-dependent attention deficits, similar to those observed in FXS, and to alterations in transcriptional profiles within the mPFC, which mapped to two weighted gene coexpression network analysis modules. We demonstrated that these modules are conserved in human frontal cortex, are enriched for known FMRP targets and for genes involved in neuronal and synaptic processes, and that one is enriched for genes that are implicated in ASD, ID, and schizophrenia. Hub genes in these conserved modules represent potential targets for FXS. These findings provide support for a prefrontal deficit in FXS, indicate that attentional testing might be a reliable cross-species tool for investigating the pathophysiology of FXS and a potential readout for pharmacotherapy testing, and identify dysregulated gene expression modules in a relevant brain region.\n\nSignificance StatementThe significance of the current study lies in two key domains. First, this study demonstrates that deletion of the Fmrp-KH1 domain is sufficient to cause major mPFC-dependent attention deficits in both males and females, like those observed in both individuals with FXS and in knockout mouse models for FXS. Second, the study shows that deletion of the KH1 domain leads to alterations in the transcriptional profiles within the medial prefrontal cortex (mPFC), which are of potential translational value for subjects with FXS. These findings indicate that attentional testing might be a reliable cross-species tool for investigating the pathophysiology of FXS and a potential readout for pharmacotherapy testing and also highlight hub genes for follow up.

neuroscience↗