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INTRODUCTION: Natural rewards and addictive substances both act on the brain’s reward system, however it remains unclear whether they reinforce actions through the same mechanisms. AIM(S): Our goal was to compare the strategy employed by mice when choosing between two actions with variable chance to access alcohol or sweetened solution. METHOD(S): We have developed a novel method to assess behavioral strategy employed by mice when selecting between options associated with different probabilities of receiving a reward. A group of animals is implanted with radiofrequency chips and introduced to an IntelliCage, where their activity in cage corners is continuously recorded. After a period of adaptation, mice are offered accessto saccharin or alcohol solution in two opposite corners, with free access to water in the remaining corners. Initially, upon entering a rewarded cornerthere is a 90%chance that accessto saccharine or alcohol solution will be granted after 2 seconds. As the procedure progresses, the probability changes periodically between 90% and 30% and cycles through all possible combinations between the two rewarded corners. RESULTS: We tested choice between solutions 0.1% (w/v) saccharin, 4% (v/v) ethanol or a combination of them. In case of the sweetened water reward, the main factor affecting choice was time elapsed from last decision. The effect of the outcome of the previous choice was also significant, but overall smaller. In case of the alcohol solution, the effects of time and previous outcome were weaker, animals were more likely to repeat previous choice. We also observed that irrespective of strategy choices follow a specific time pattern, with majority occurring at discrete intervals. CONCLUSIONS: The type of reward strongly affected animals’ behavioral strategy. Probabilistic access to sweetened water was associated with high probability of switching between choices, while access to alcohol solution led to frequent repeating of the same choice. FINANCIAL SUPPORT: NCN Sonata Bis UMO-2012/07/E/ NZ3/01785 .
BACKGROUND AND AIMS: The immediacy or delay of a reward affect its perceived value. Here we present a new model of assessing delay discounting in group housed mice. METHODS: A group of animals was implanted subcutaneously with radiofrequency identification chips and placed in a cage equipped with sensors for automatic tracking (IntelliCage Plus). Each of the cage’s corners had 2 drinking bottles accessed through a small compartment that allows only one mouse inside. The effect of the delay was assessed by first allowing mice with free access to water or 0.1% saccharin and then progressively increasing the delay till gate blocking the saccharin bottle raised. RESULTS: In line with expectations, while mice initially showed a 95.4% preference for saccharine it decreased to 50% at 17 s delay and finally to 12% at 55 s delay. In the delay discounting model with 3 types of rewards (saccharin 0.01% or 0.1% and water), initial preference of 0.1% saccharine was 92.4%, an increase in delay to 55 s of access decreased preference to 7.8% and caused an increase of preference of the 0.01% saccharine solution from 3.2% to 64.7%. We tested the effects of tranylcypromine, a monoamine oxygenase inhibitor (3 mg/kg, 3 injections in 48 h intervals), cloccinamox, an opioid receptor antagonist (10 mg/kg, single injection) and ketamine, an NMDA receptor partial antagonist (20 mg/kg, single injection) on delay discounting. Treatment with tranylcypromine led to increase in discounting of the delay, at 17 s the saccharin preference was 51% in the control group but only 4% in drug-treated mice. A similar trend towards increased discounting was observed in case of ketamine, while clocinnamox had no effect. CONCLUSIONS: The main advantages of the new model are the ability to test behaviour in the home cage, during natural activity cycles, no interaction with the experimenter and without food deprivation. Further development of the model may permit testing of social effects on discounting.
INTRODUCTION: Reinforcement learning causes an action that produced a satisfying effect in a particular situation to become more likely to occur again in that situation. The process is essential in adaptive behavior; however, actual choices often appear to diverge from what could be inferred from simple reinforcement learning. AIM(S): Here we investigate how the time intervals between actions affect the choices made. METHOD(S): Groups of C57BL6/J mice were housed in IntelliCages with access to water and chow ad libitum and were able to access bottles with a reward in the form of a saccharin solution (0.1% w/v), alcohol (4% w/v), or a mixture of the two. The probability of receiving a reward in two of the cage corners changed to 0.9 or 0.3 every 48 h over a period of ~33 days. RESULTS: We observed that, in most animals, the odds of repeating the choice of a corner were increased if that choice was previously rewarded. Interestingly, the time elapsed from the previous choice also increased the probability of repeating the choice, irrespective of the previous outcome. Behavioral data were fitted with a series of reinforcement learning models based on Q‑learning. We found that introducing an interval‑dependent adjustment allowed for better description of the observed behavior, and the size of the time effect differed depending on the type of reward offered. CONCLUSIONS: We find that, at longer time intervals, repeating the previous choice becomes more probable, irrespective of the previous outcome. Thus, at least in this specific case, time may make a past mistake more likely to be repeated.
Dopamine plays a key role in the control of behaviour and motor functions. The amount of neurotransmitterreleased into a synapse depends on the firing pattern of dopaminergic neurons, which occurs as a continuum be‑ tween regular and bursting modes of activity. The latter mode results in a phasic increase of dopamine release, whereas a basal level of neurotransmitter is maintained by non-bursting (tonic or irregular) firing of dopaminergic neurons. While functional NMDA receptors are considered crucial for evoking dopaminergic neurons’ bursts of ac‑ tion potentials, it remains an open question whether other neurotransmitters also evoke this type of activity. There‑ fore, the aim of our research was to determine the effect of cholinergic receptor stimulation on the activity of dopa‑ mine neurons lacking functional NMDA receptor. We used a genetically modified strain of mice (NR1DATCreERT2), which allowed us to induce a deletion of the NR1 NMDA receptor subunit selectively on dopaminergic neurons of adult animals. Experiments were performed on urethane anaesthetised animals. We used multi-barrel glass micro‑ pipettes (five barrels), allowing us to combine single unit extracellular recordings of midbrain dopaminergic neu‑ rons’ activity and iontophoresis, local application of drugs (a nonspecific agonist of cholinergic receptors – carbachol; muscarinic and nicotinic receptor antagonists – scopol‑ amine and mecamylamine, respectively; and NMDA). Loss of NMDA receptors on dopaminergic neurons decreased their basal firing rate, attenuated bursting, and abolished responsivity to NMDA compared to wild-type animals. Af‑ ter application of carbachol, the vast majority of dopami‑ nergic neurons increased their firing rate. Interestingly, some of the recorded cells, both in control and NR1DAT‑ CreERT2 mice, developed slow oscillatory changes in firing rate, which transformed into robust complex bursts of ac‑ tion potentials. These results show that agonists of cholin‑ ergic receptors can modulate rate as well as pattern of fir‑ ing of the midbrain dopaminergic neurons. Furthermore, our observations suggest that activation of cholinergic re‑ ceptors alone, i.e. without the involvement of NMDA recep‑ tors, can switch a subpopulation of dopaminergic neurons to a burst firing mode. Funding: NCN, Poland, PRELUDIUM 2015/19/N/NZ4/00960.
BACKGROUND AND AIMS: Reinforcement-based learning drives behavior towards actions with highest perceived outcome value. It’s essential features are the ability to associate actions or stimuli with rewards, discounting of the delay or probability of the rewards and balance between exploitation of known rewarded actions against exploration of new possibilities. Here we investigate how disrupting NMDA receptor-dependent signaling in the brain’s dopamine systems affects reinforcement learning. METHODS: Genetically modified mice with selective inactivation of NMDA receptors on dopaminergic or dopaminoceptive neurons were generated using the CreERT2/loxP system. Behavior of control and mutant mice was assessed in tasks involving instrumental or Pavlovian learning as well as discounting of reward probability and delay. RESULTS: Inactivation of NMDA receptors on dopaminergic neurons impaired the acquisition of conditioned reinforcement, even though it had no general effect on associative learning. Conversely, in mice with inactivation of NMDA receptors in dopaminoceptive neurons, an opposite phenotype was observed: deficits in associative learning but normal conditioned reinforcement. Interestingly, the effects of the mutations on performance in probabilistic reversal or discounting was limited. CONCLUSIONS: These results show discrete functions of dopamine signaling in control of reinforcement learning. Mutations in either dopaminergic or dopaminoceptive neurons selectively affected conditioned reinforcement or associative learning, respectively.
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