Knockout of NMDARs in CA1 and dentate gyrus fails to impair temporal control of conditioned behavior in mice.

The hippocampus has been implicated in temporal learning. Plasticity within the hippocampus requires NMDA receptor-dependent glutamatergic neurotransmission. We tested the prediction that hippocampal NMDA receptors are required for learning about time by testing mice that lack postembryonal NMDARs in the CA1 and dentate gyrus (DG) hippocampal subfields on three different appetitive temporal learning procedures. The conditional knockout mice (Grin1ΔDCA1 ) showed normal sensitivity to cue duration, responding at a higher level to a short duration cue than compared to a long duration cue. Knockout mice also showed normal precision and accuracy of response timing in the peak procedure in which reinforcement occurred after 10 s delay within a 30 s cue presentation. Mice were tested on the matching of response rates to reinforcement rates on instrumental conditioning with two levers reinforced on a concurrent variable interval schedule. Pressing on one lever was reinforced at a higher rate than the other lever. Grin1ΔDGCA1 mice showed normal sensitivity to the relative reinforcement rates of the levers. In contrast to the lack of effect of hippocampal NMDAR deletion on measures of temporal sensitivity, Grin1ΔDGCA1 mice showed increased baseline measures of magazine activity and lever pressing. Furthermore, reversal learning was enhanced when the reward contingencies were switched in the lever pressing task, but this was true only for mice trained with a large difference between relative reinforcement rates between the levers. The results failed to demonstrate a role for NMDARs in excitatory CA1 and DG neurons in learning about temporal information.

Brainstem networks construct threat probability and prediction error from neuronal building blocks.

When faced with potential threat we must estimate its probability, respond advantageously, and leverage experience to update future estimates. Threat estimation is the proposed domain of the forebrain, while behaviour is elicited by the brainstem. Yet, the brainstem is also a source of prediction error, a learning signal to acquire and update threat estimates. Neuropixels probes allowed us to record single-unit activity across a 21-region brainstem axis in rats receiving probabilistic fear discrimination with foot shock outcome. Against a backdrop of diffuse behaviour signaling, a brainstem network with a dorsal hub signaled threat probability. Neuronal function remapping during the outcome period gave rise to brainstem networks signaling prediction error and shock on multiple timescales. The results reveal brainstem networks construct threat probability, behaviour, and prediction error signals from neuronal building blocks.

The GluA1 AMPAR subunit is necessary for hedonic responding but not hedonic value in female mice.

The GluA1 subunit of the AMPA receptor has been implicated in anhedonia. Mice that lack GluA1 (Gria1 knockout mice) show reduced lick cluster size, a measure of palatability in feeding behaviour. This deficit may reflect a role for GluA1 in encoding the hedonic value of palatable substances or instead a role for GluA1 in the behavioural expression of hedonic value. We tested the role of GluA1 in hedonic value by assessing sensitivity to changes in the rewarding property of sucrose as a consequence of negative/positive contrast effects in female mice. During training, on half of the days consumption of a flavour (CS+) mixed with 4% sucrose was preceded by consumption of 1% sucrose (positive contrast). On the other half of days consumption of a different flavour (CS-) mixed with 4% sucrose was preceded by consumption of 16% sucrose (negative contrast). In the test session both wild-type, controls and Gria1 knockout mice consumed more of the CS+ flavour than the CS- flavour. While Gria1 knockout mice showed reduced lick cluster sizes, both genotypes made larger lick clusters for the CS+ flavour than the CS- flavour suggesting that the CS+ was more palatable than the CS-. A follow up experiment in normal mice demonstrated that the negative contrast procedure resulted in a conditioned reduction of palatability of the CS- in comparison to an associatively neutral, novel flavour. The results failed to demonstrate a role for GluA1 in hedonic value suggesting that, instead, GluA1 is necessary for hedonic responding.

A biphasic reduction in a measure of palatability following sucrose consumption in mice.

Consumption of foods results in a transient reduction in hedonic value that influences the extent and nature of feeding behavior. The time course of this effect, however, is poorly specified. In an initial experiment, using an analysis of the microstructure of licking in mice we found that consumption of sucrose led to a rapid reduction in lick cluster size, a measure of palatability, which recovered after 10 min, but reemerged 60min after initial consumption. We then replicated the finding that lick cluster size is reduced after 60min, but not 10min, under conditions in which a number of potential behavioural confounds were removed. In Experiment 2 the effect was replicated using a between-subjects design that ruled out the possibility that the effect was a specific consequence of the within-subjects procedures used in the first experiment, in which mice may have come to expect sucrose at different time points within the feeding session. While Experiments 1 and 2 confounded the time between periods of access to sucrose with time since the start of the feeding session, this confound was removed in Experiment 3, and, similar to the previous experiments, it was found that a second reduction in palatability occurred after 60min. Therefore, the effect was dependent only on the time since the previous exposure to sucrose, demonstrating that sucrose consumption initiates a biphasic reduction in palatability. The reduction in lick cluster size after 60min was not typically accompanied by a reduction in consumption suggesting that the more slowly developing reduction in the palatability measure was not simply a consequence of post-ingestive satiety. The cause of the biphasic change is not yet clear, and may reflect independent processes or the consequence of a single process that initiates multiple changes in palatability over time.

Memory-dependent effects on palatability in mice.

While palatability depends on the properties of particular foods, it is also determined by prior experience, suggesting that memory affects the hedonic value of a substance. Here, we report two procedures that affect palatability in mice: negative contrast and flavour habituation. A microstructure analysis of licking behaviour was employed, with the lick cluster size (the number of licks made in quick succession before a pause) used as a measure of palatability. It was first confirmed that lick cluster size increased monotonically as a function of sucrose concentration, whereas consumption followed an inverted U-shaped function. In a successive negative contrast procedure it was found that when shifted from a high sucrose concentration (32%) to a low sucrose concentration (4%), mice made smaller lick clusters than a group that only received the low concentration. Mice exposed to flavours (cherry or grape Kool Aid) mixed with sucrose (16%) made larger lick clusters for familiar flavours compared to novel flavours. This habituation effect was evident after short (5min) and long (24h) test intervals. Both successive negative contrast and flavour habituation failed to affect levels of consumption. Collectively, the results show that prior experience can have effects on lick cluster size that are equivalent to increasing or decreasing the sweetness of a solution. Thus, palatability is not a fixed property of a substance but is dependent on expectation or familiarity that occurs as a result of memory.