Dopamine signals as temporal difference errors: recent advances.

November 10, 2020

In the brain, dopamine is thought to drive reward-based learning by signaling temporal difference reward prediction errors (TD errors), a 'teaching signal' used to train computers. Recent studies using optogenetic manipulations have provided multiple pieces of evidence supporting that phasic dopamine signals function as TD errors. Furthermore, novel experimental results have indicated that when the current state of the environment is uncertain, dopamine neurons compute TD errors using 'belief states' or a probability distribution over potential states. It remains unclear how belief states are computed but emerging evidence suggests involvement of the prefrontal cortex and the hippocampus. These results refine our understanding of the role of dopamine in learning and the algorithms by which dopamine functions in the brain.

Increase in Seizure Susceptibility After Repetitive Concussion Results from Oxidative Stress, Parvalbumin-Positive Interneuron Dysfunction and Biphasic Increases in Glutamate/GABA Ratio

November 3, 2020

Chronic symptoms indicating excess cortical excitability follow mild traumatic brain injury, particularly repetitive mild traumatic brain injury (rmTBI). Yet mechanisms underlying post-traumatic excitation/inhibition (E/I) ratio abnormalities may differ between the early and late post-traumatic phases. We therefore measured seizure threshold and cortical gamma-aminobutyric acid (GABA) and glutamate (Glu) concentrations, 1 and 6 weeks after rmTBI in mice. We also analyzed the structure of parvalbumin-positive interneurons (PVIs), their perineuronal nets (PNNs), and their electroencephalography (EEG) signature (gamma frequency band power). For mechanistic insight, we measured cortical oxidative stress, reflected in the reduced/oxidized glutathione (GSH/GSSG) ratio. We found that seizure susceptibility increased both early and late after rmTBI. However, whereas increased Glu dominated the E/I 1 week after rmTBI, Glu concentration normalized and the E/I was instead characterized by depressed GABA, reduced per-PVI parvalbumin expression, and reduced gamma EEG power at the 6-week post-rmTBI time point. Oxidative stress was increased early after rmTBI, where transient PNN degradation was noted, and progressed throughout the monitoring period. We conclude that GSH depletion, perhaps triggered by early Glu-mediated excitotoxicity, leads to late post-rmTBI loss of PVI-dependent cortical inhibitory tone. We thus propose dampening of Glu signaling, maintenance of redox state, and preservation of PVI inhibitory capacity as therapeutic targets for post-rmTBI treatment.

An evolutionarily acquired microRNA shapes development of mammalian cortical projections

November 2, 2020

The corticospinal tract is unique to mammals and the corpus callosum is unique to placental mammals (eutherians). The emergence of these structures is thought to underpin the evolutionary acquisition of complex motor and cognitive skills. Corticospinal motor neurons (CSMN) and callosal projection neurons (CPN) are the archetypal projection neurons of the corticospinal tract and corpus callosum, respectively. Although a number of conserved transcriptional regulators of CSMN and CPN development have been identified in vertebrates, none are unique to mammals and most are coexpressed across multiple projection neuron subtypes. Here, we discover 17 CSMN-enriched microRNAs (miRNAs), 15 of which map to a single genomic cluster that is exclusive to eutherians. One of these, miR-409-3p, promotes CSMN subtype identity in part via repression of LMO4, a key transcriptional regulator of CPN development. In vivo, miR-409-3p is sufficient to convert deep-layer CPN into CSMN. This is a demonstration of an evolutionarily acquired miRNA in eutherians that refines cortical projection neuron subtype development. Our findings implicate miRNAs in the eutherians' increase in neuronal subtype and projection diversity, the anatomic underpinnings of their complex behavior.

Global regulatory features of alternative splicing across tissues and within the nervous system of C. elegans

October 30, 2020

Alternative splicing plays a major role in shaping tissue-specific transcriptomes. Among the broad tissue types present in metazoans, the central nervous system contains some of the highest levels of alternative splicing. Although many documented examples of splicing differences between broad tissue types exist, there remains much to be understood about the splicing factors and the cis sequence elements controlling tissue and neuron subtype-specific splicing patterns. By using translating ribosome affinity purification coupled with deep-sequencing (TRAP-seq) in Caenorhabditis elegans, we have obtained high coverage profiles of ribosome-associated mRNA for three broad tissue classes (nervous system, muscle, and intestine) and two neuronal subtypes (dopaminergic and serotonergic neurons). We have identified hundreds of splice junctions that exhibit distinct splicing patterns between tissue types or within the nervous system. Alternative splicing events differentially regulated between tissues are more often frame-preserving, are more highly conserved across Caenorhabditis species, and are enriched in specific cis regulatory motifs, when compared with other types of exons. By using this information, we have identified a likely mechanism of splicing repression by the RNA-binding protein UNC-75/CELF via interactions with cis elements that overlap a 5' splice site. Alternatively spliced exons also overlap more frequently with intrinsically disordered peptide regions than constitutive exons. Moreover, regulated exons are often shorter than constitutive exons but are flanked by longer intron sequences. Among these tissue-regulated exons are several highly conserved microexons <27 nt in length. Collectively, our results indicate a rich layer of tissue-specific gene regulation at the level of alternative splicing in C. elegans that parallels the evolutionary forces and constraints observed across metazoa.

The rational use of causal inference to guide reinforcement learning strengthens with age

October 27, 2020

Beliefs about the controllability of positive or negative events in the environment can shape learning throughout the lifespan. Previous research has shown that adults' learning is modulated by beliefs about the causal structure of the environment such that they update their value estimates to a lesser extent when the outcomes can be attributed to hidden causes. This study examined whether external causes similarly influenced outcome attributions and learning across development. Ninety participants, ages 7 to 25 years, completed a reinforcement learning task in which they chose between two options with fixed reward probabilities. Choices were made in three distinct environments in which different hidden agents occasionally intervened to generate positive, negative, or random outcomes. Participants' beliefs about hidden-agent intervention aligned with the true probabilities of the positive, negative, or random outcome manipulation in each of the three environments. Computational modeling of the learning data revealed that while the choices made by both adults (ages 18-25) and adolescents (ages 13-17) were best fit by Bayesian reinforcement learning models that incorporate beliefs about hidden-agent intervention, those of children (ages 7-12) were best fit by a one learning rate model that updates value estimates based on choice outcomes alone. Together, these results suggest that while children demonstrate explicit awareness of the causal structure of the task environment, they do not implicitly use beliefs about the causal structure of the environment to guide reinforcement learning in the same manner as adolescents and adults.