Does phasic dopamine release cause policy updates?

Phasic dopamine activity is believed to both encode reward-prediction errors (RPEs) and to cause the adaptations that these errors engender. If so, a rat working for optogenetic stimulation of dopamine neurons will repeatedly update its policy and/or action values, thus iteratively increasing its work rate. Here, we challenge this view by demonstrating stable, non-maximal work rates in the face of repeated optogenetic stimulation of midbrain dopamine neurons. Furthermore, we show that rats learn to discriminate between world states distinguished only by their history of dopamine activation. Comparison of these results to reinforcement learning simulations suggests that the induced dopamine transients acted more as rewards than RPEs. However, pursuit of dopaminergic stimulation drifted upwards over a time scale of days and weeks, despite its stability within trials. To reconcile the results with prior findings, we consider multiple roles for dopamine signalling.

Bmal1 in the striatum influences alcohol intake in a sexually dimorphic manner.

Alcohol consumption has been strongly associated with circadian clock gene expression in mammals. Analysis of clock genes revealed a potential role of Bmal1 in the control of alcohol drinking behavior. However, a causal role of Bmal1 and neural pathways through which it may influence alcohol intake have not yet been established. Here we show that selective ablation of Bmal1 (Cre/loxP system) from medium spiny neurons of the striatum induces sexual dimorphic alterations in alcohol consumption in mice, resulting in augmentation of voluntary alcohol intake in males and repression of intake in females. Per2mRNA expression, quantified by qPCR, decreases in the striatum after the deletion of Bmal1. To address the possibility that the effect of striatal Bmal1 deletion on alcohol intake and preference involves changes in the local expression of Per2, voluntary alcohol intake (two-bottle, free-choice paradigm) was studied in mice with a selective ablation of Per2 from medium spiny neurons of the striatum. Striatal ablation of Per2 increases voluntary alcohol intake in males but has no effect in females. Striatal Bmal1 and Per2 expression thus may contribute to the propensity to consume alcohol in a sex -specific manner in mice.

Dopamine neurons do not constitute an obligatory stage in the final common path for the evaluation and pursuit of brain stimulation reward.

The neurobiological study of reward was launched by the discovery of intracranial self-stimulation (ICSS). Subsequent investigation of this phenomenon provided the initial link between reward-seeking behavior and dopaminergic neurotransmission. We re-evaluated this relationship by psychophysical, pharmacological, optogenetic, and computational means. In rats working for direct, optical activation of midbrain dopamine neurons, we varied the strength and opportunity cost of the stimulation and measured time allocation, the proportion of trial time devoted to reward pursuit. We found that the dependence of time allocation on the strength and cost of stimulation was similar formally to that observed when electrical stimulation of the medial forebrain bundle served as the reward. When the stimulation is strong and cheap, the rats devote almost all their time to reward pursuit; time allocation falls off as stimulation strength is decreased and/or its opportunity cost is increased. A 3D plot of time allocation versus stimulation strength and cost produces a surface resembling the corner of a plateau (the "reward mountain"). We show that dopamine-transporter blockade shifts the mountain along both the strength and cost axes in rats working for optical activation of midbrain dopamine neurons. In contrast, the same drug shifted the mountain uniquely along the opportunity-cost axis when rats worked for electrical MFB stimulation in a prior study. Dopamine neurons are an obligatory stage in the dominant model of ICSS, which positions them at a key nexus in the final common path for reward seeking. This model fails to provide a cogent account for the differential effect of dopamine transporter blockade on the reward mountain. Instead, we propose that midbrain dopamine neurons and neurons with non-dopaminergic, MFB axons constitute parallel limbs of brain-reward circuitry that ultimately converge on the final-common path for the evaluation and pursuit of rewards.

Exploring the role of locomotor sensitization in the circadian food entrainment pathway.

Food entrainment is the internal mechanism whereby the phase and period of circadian clock genes comes under the control of daily scheduled food availability. Food entrainment allows the body to efficiently realign the internal timing of behavioral and physiological functions such that they anticipate food intake. Food entrainment can occur with or without caloric restriction, as seen with daily schedules of restricted feeding (RF) or restricted treat (RT) that restrict food or treat intake to a single feeding time. However, the extent of clock gene control is more pronounced with caloric restriction, highlighting the role of energy balance in regulating clock genes. Recent studies have implicated dopamine (DA) to be involved in food entrainment and caloric restriction is known to affect dopaminergic pathways to enhance locomotor activity. Since food entrainment results in the development of a distinct behavioral component, called food anticipatory activity (FAA), we examined the role of locomotor sensitization (LS) in food entrainment by 1) observing whether amphetamine (AMPH) sensitization results in enhanced locomotor output of FAA and 2) measuring LS of circadian and non-circadian feeding paradigms to an acute injection of AMPH (AMPH cross-sensitization). Unexpectedly, AMPH sensitization did not show enhancement of FAA. On the contrary, LS did develop with sufficient exposure to RF. LS was present after 2 weeks of RF, but not after 1, 3 or 7 days into RF. When food was returned and rats regain their original body weight at 10-15 days post-RF, LS remained present. LS did not develop to RT, nor to feedings of a non-circadian schedule, e.g. variable restricted feeding (VRF) or variable RT (VRT). Further, when RF was timed to the dark period, LS was observed only when tested at night; RF timed to the light period resulted in LS that was present during day and night. Taken together our results show that LS develops with food entrainment to RF, an effect that is dependent on the chronicity and circadian phase of RF but independent of body weight. Given that LS involves reorganization of DA-regulated motor circuitry, our work provides indirect support for the role of DA in the food entrainment pathway of RF. The findings also suggest differences in neuronal pathways involved in LS from AMPH sensitization and LS from RF.

Rotavirus infection activates dendritic cells from Peyer's patches in adult mice.

This study used an in vivo mouse model to analyze the response of dendritic cells (DCs) in Peyer's patches (PPs) within the first 48 h of infection with the wild-type murine rotavirus EDIM (EDIM(wt)). After the infection, the absolute number of DCs was increased by 2-fold in the PPs without a modification of their relative percentage of the total cell number. Also, the DCs from PPs of infected mice showed a time-dependent migration to the subepithelial dome (SED) and an increase of the surface activation markers CD40, CD80, and CD86. This response was more evident at 48 h postinfection (p.i.) and depended on viral replication, since DCs from PPs of mice inoculated with UV-treated virus did not show this phenotype. As a result of the activation, the DCs showed an increase in the expression of mRNA for the proinflammatory cytokines interleukin-12/23p40 (IL-12/23p40), tumor necrosis factor alpha (TNF-alpha), and beta interferon (IFN-beta), as well as for the regulatory cytokine IL-10. These results suggest that, a short time after rotavirus infection, the DCs from PPs play a critical role in controlling the infection and, at the same time, avoiding an excessive inflammatory immune response.

A selective blocker of Kv1.2 and Kv1.3 potassium channels from the venom of the scorpion Centruroides suffusus suffusus.

A novel potassium channel blocker peptide was purified from the venom of the scorpion Centruroides suffusus suffusus by high-performance liquid chromatography and its amino acid sequence was completed by Edman degradation and mass spectrometry analysis. It contains 38 amino acid residues with a molecular weight of 4000.3Da, tightly folded by three disulfide bridges. This peptide, named Css20, was shown to block preferentially the currents of the voltage-dependent K+-channels Kv1.2 and Kv1.3. It did not affect several other ion channels tested at 10 nM concentration. Concentration-response curves of Css20 yielded an IC50 of 1.3 and 7.2 nM for Kv1.2- and Kv1.3-channels, respectively. Interestingly, despite the similar affinities for the two channels the association and dissociation rates of the toxin were much slower for Kv1.2, implying that different interactions may be involved in binding to the two channel types; an implication further supported by in silico docking analyses. Based on the primary structure of Css20, the systematic nomenclature proposed for this toxin is alpha-KTx 2.13.