Functionally Antagonistic Transcription Factors IRF1 and IRF2 Regulate the Transcription of the Dopamine Receptor D2 Gene Associated with Aggressive Behavior of Weaned Pigs

Aggressive behavior has negative effects on animal welfare and growth performance in pigs. The dopamine receptor D2 (DRD2) has a critical neuromodulator role in the dopamine signal pathway within the brain to control behavior. A functional single-nucleotide polymorphism (SNP), rs1110730503, in the promoter region of the porcine DRD2 gene was identified, which affects aggressive behavior in pigs. A chromatin immunoprecipitation (ChIP) assay was used to identify the interactions between interferon regulatory factor 1 (IRF1) and IRF2 with the DRD2 gene. The overexpression or knockdown of these two transcription factors in porcine kidney-15 (PK15) and porcine neuronal cells (PNCs) indicate that the binding of IRF1 to DRD2 promotes the transcription of the DRD2 gene, but the binding of IRF2 to the DRD2 gene inhibits its transcription. Furthermore, IRF1 and IRF2 are functionally antagonistic to each other. The downregulation of DRD2 or upregulation of IRF2 increased the apoptosis rate of porcine neuroglial cells. Taken together, we found that transcriptional factors IRF1 and IRF2 have vital roles in regulating the transcription of the DRD2 gene, and rs1110730503 (−915A/T) is a functional SNP that influences IRF2 binding to the promoter of the DRD2 gene. These findings will provide further insight towards controlling aggressive behavior in pigs.

"Learning in reverse: Dopamine errors drive excitatory and inhibitory components of backward conditioning in an outcome-specific manner".

For over two decades, midbrain dopamine was considered synonymous with the prediction error in temporal-difference reinforcement learning. Central to this proposal is the notion that reward-predictive stimuli become endowed with the scalar value of predicted rewards. When these cues are subsequently encountered, their predictive value is compared to the value of the actual reward received allowing for the calculation of prediction errors. Phasic firing of dopamine neurons was proposed to reflect this computation, facilitating the backpropagation of value from the predicted reward to the reward-predictive stimulus, thus reducing future prediction errors. There are two critical assumptions of this proposal: 1) that dopamine errors can only facilitate learning about scalar value and not more complex features of predicted rewards, and 2) that the dopamine signal can only be involved in anticipatory learning in which cues or actions precede rewards. Recent work has challenged the first assumption, demonstrating that phasic dopamine signals across species are involved in learning about more complex features of the predicted outcomes, in a manner that transcends this value computation. Here, we tested the validity of the second assumption. Specifically, we examined whether phasic midbrain dopamine activity would be necessary for backward conditioning- when a neutral cue reliably follows a rewarding outcome. Using a specific Pavlovian-to-Instrumental Transfer (PIT) procedure, we show rats learn both excitatory and inhibitory components of a backward association, and that this association entails knowledge of the specific identity of the reward and cue. We demonstrate that brief optogenetic inhibition of ventral tegmental area dopamine (VTA DA) neurons timed to the transition between the reward and cue, reduces both of these components of backward conditioning. These findings suggest VTA DA neurons are capable of facilitating associations between contiguously occurring events, regardless of the content of those events. We conclude that these data are in line with suggestions that the VTA DA error acts as a universal teaching signal. This may provide insight into why dopamine function has been implicated in a myriad of psychological disorders that are characterized by very distinct reinforcement-learning deficits.

Pivotal role of PDE10A in the integration of dopamine signals in mice striatal D1 and D2 medium-sized spiny neurones

Dopamine in the striatum plays a crucial role in reward processes and action selection. Dopamine signals are transduced by D1 and D2 dopamine receptors which trigger mirror effects through the cAMP/PKA signalling cascade in D1 and D2 medium-sized spiny neurones (MSNs). Phosphodiesterases (PDEs), which determine the profile of cAMP signals, are highly expressed in MSNs, but their respective roles in dopamine signal integration remain poorly understood. We used genetically-encoded FRET biosensors to monitor at the single cell level the functional contribution of PDE2A, PDE4 and PDE10A in the changes of the cAMP/PKA response to transient and continuous dopamine in mouse striatal brain slices. We found that PDE2A, PDE4 and PDE10A operate on the moderate to high cAMP levels elicited by D1 or A2A receptor stimulation. In contrast, only PDE10A is able to reduce cAMP down to baseline in both type of neurones, leading to the dephosphorylation of PKA substrates. PDE10A is therefore critically required for dopamine signal integration in both D1 and D2 MSNs.

Distinct temporal difference error signals in dopamine axons in three regions of the striatum in a decision-making task

SUMMARYDifferent regions of the striatum regulate different types of behavior. However, how dopamine signals differ across striatal regions and how dopamine regulates different behaviors remain unclear. Here, we compared dopamine axon activity in the ventral, dorsomedial, and dorsolateral striatum, while mice performed in a perceptual and value-based decision task. Surprisingly, dopamine axon activity was similar across all three areas. At a glance, the activity multiplexed different variables such as stimulus-associated values, confidence and reward feedback at different phases of the task. Our modeling demonstrates, however, that these modulations can be inclusively explained by moment-by-moment changes in the expected reward, i.e. the temporal difference error. A major difference between these areas was the overall activity level of reward responses: reward responses in dorsolateral striatum (DLS) were positively shifted, lacking inhibitory responses to negative prediction error. Tenets of habit and skill can be explained by this positively biased dopamine signal in DLS.

Dopamine Signaling in the Dorsomedial Striatum Promotes Compulsive Behavior

SUMMARYHabits and compulsions are two aspects of behavior that often develop in parallel and together lead to inflexible responding. Both habits and compulsions are hypothesized to be involved in psychiatric disorders such as drug addiction and obsessive-compulsive disorder (OCD), but they are distinct behaviors that may rely on different brain circuitries. We developed an experimental paradigm to track the development of both habits and compulsions in individual animals while recording neural activity. We performed fiber photometry measurements of dopamine axon activity while mice engaged in reinforcement learning on a random interval (RI60) schedule and found that the emergence of compulsion was predicted by the dopamine signal in the dorsomedial striatum (DMS). By amplifying this DMS dopamine signal throughout training using optogenetics, we accelerated animals’ transitions to compulsion, irrespective of habit formation. These results establish DMS dopamine signaling as a key controller of compulsions.

Ramping and State Uncertainty in the Dopamine Signal

Reinforcement learning models of the basal ganglia map the phasic dopamine signal to reward prediction errors (RPEs). Conventional models assert that, when a stimulus reliably predicts a reward with fixed delay, dopamine activity during the delay period and at reward time should converge to baseline through learning. However, recent studies have found that dopamine exhibits a gradual ramp before reward in certain conditions even after extensive learning, such as when animals are trained to run to obtain the reward, thus challenging the conventional RPE models. In this work, we begin with the limitation of temporal uncertainty (animals cannot perfectly estimate time to reward), and show that sensory feedback, which reduces this uncertainty, will cause an unbiased learner to produce RPE ramps. On the other hand, in the absence of feedback, RPEs will be flat after learning. These results reconcile the seemingly conflicting data on dopamine behaviors under the RPE hypothesis.

Dopamine neurons drive fear extinction learning by signaling the omission of expected aversive outcomes

Extinction of fear responses is critical for adaptive behavior and deficits in this form of safety learning are hallmark of anxiety disorders. However, the neuronal mechanisms that initiate extinction learning are largely unknown. Here we show, using single-unit electrophysiology and cell-type specific fiber photometry, that dopamine neurons in the ventral tegmental area (VTA) are activated by the omission of the aversive unconditioned stimulus (US) during fear extinction. This dopamine signal occurred specifically during the beginning of extinction when the US omission is unexpected, and correlated strongly with extinction learning. Furthermore, temporally-specific optogenetic inhibition or excitation of dopamine neurons at the time of the US omission revealed that this dopamine signal is both necessary for, and sufficient to accelerate, normal fear extinction learning. These results identify a prediction error-like neuronal signal that is necessary to initiate fear extinction and reveal a crucial role of DA neurons in this form of safety learning.