Correlative studies have strongly linked phasic changes in dopamine activity with reward prediction error signaling. But causal evidence that these brief changes in firing actually serve as error signals to drive associative learning is more tenuous. While there is direct evidence that brief increases can substitute for positive prediction errors, there is no comparable evidence that similarly brief pauses can substitute for negative prediction errors. Lacking such evidence, the effect of increases in firing could reflect novelty or salience, variables also correlated with dopamine activity. Here we provide such evidence, showing in a modified Pavlovian over-expectation task that brief pauses in the firing of dopamine neurons in rat ventral tegmental area at the time of reward are sufficient to mimic the effects of endogenous negative prediction errors. These results support the proposal that brief changes in the firing of dopamine neurons serve as full-fledged bidirectional prediction error signals.

Summary The hippocampus and orbitofrontal cortex (OFC) both make important contributions to decision making and other cognitive processes. However, despite anatomical links between the two, few studies have tested the importance of hippocampal–OFC interactions. Here, we recorded OFC neurons in rats performing a decision making task while suppressing activity in a key hippocampal output region, the ventral subiculum. OFC neurons encoded information about expected outcomes and rats’ responses. With hippocampal output suppressed, rats were slower to adapt to changes in reward contingency, and OFC encoding of response information was strongly attenuated. In addition, ventral subiculum inactivation prevented OFC neurons from integrating information about features of outcomes to form holistic representations of the outcomes available in specific trial blocks. These data suggest that the hippocampus contributes to OFC encoding of both concrete, low-level features of expected outcomes, and abstract, inferred properties of the structure of the world, such as task state.

The parabrachial nuclei of the pons (PbN) receive almost direct input from taste buds on the tongue and control basic taste-driven behaviors. Thus it is reasonable to hypothesize that PbN neurons might respond to tastes in a manner similar to that of peripheral receptors, i.e., that these responses might be narrow and relatively "dynamics free." On the other hand, the majority of the input to PbN descends from forebrain regions such as gustatory cortex (GC), which processes tastes with "temporal codes" in which firing reflects first the presence, then the identity, and finally the desirability of the stimulus. Therefore a reasonable alternative hypothesis is that PbN responses might be dominated by dynamics similar to those observed in GC. Here we examined simultaneously recorded single-neuron PbN (and GC) responses in awake rats receiving exposure to basic taste stimuli. We found that pontine taste responses were almost entirely confined to canonically identified taste-PbN (t-PbN). Taste-specificity was found, furthermore, to be time varying in a larger percentage of these t-PbN responses than in responses recorded from the tissue around PbN (including non-taste-PbN). Finally, these time-varying properties were a good match for those observed in simultaneously recorded GC neurons-taste-specificity appeared after an initial nonspecific burst of action potentials, and palatability emerged several hundred milliseconds later. These results suggest that the pontine taste relay is closely allied with the dynamic taste processing performed in forebrain.

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27Conditioned taste aversion (CTA) is a form of one-trial learning dependent on basolateral 28 amygdala projection neurons (BLApn). Its underlying cellular and molecular mechanisms 29 are poorly understood, however. We used RNAseq from BLApn to identify learning-30 related changes in Stk11, a kinase with well-studied roles in growth, metabolism and 31 development, but not previously implicated in learning. Deletion of Stk11 restricted to 32 BLApn completely blocks memory when occurring prior to training, but not following it, 33 despite altering neither BLApn-dependent encoding of taste palatability in gustatory 34 cortex, nor transcriptional activation of BLApn during training. Deletion of Stk11 in BLApn 35 also increases their intrinsic excitability. Conversely, BLApn activated by CTA to express 36 the immediate early gene Fos had reduced excitability. BLApn knockout of Fos also 37 increased excitability and impaired learning. These data suggest that Stk11 and Fos 38 expression play key roles in CTA long-term memory formation, perhaps by modulating 39 the intrinsic excitability of BLApn. (149 words) 40 41 103 104 Results 105CTA long-term memory requires BLA transcription 106 In order to determine whether CTA requires new RNA transcription within the BLA, we 107 inhibited transcription by injecting Actinomycin-D (1 µl, 50 ng, bilaterally, Figure 1), a 108 widely used RNA polymerase 2 inhibitor (Alberini, 2009), into the BLA 20 min prior to CTA 109 training, and tested memory 48 hours later. As a control, a separate group of mice 110 received vehicle injection (1 µl of PBS, bilaterally). CTA training consisted of 30 min of 111 access to 0.5% saccharin followed by an intraperitoneal injection of 0.15M LiCl, 2% body 112 weight; (Figure 1-figure supplement 1). A two-way ANOVA comparing vehicle and 113 actinomycin-D injected mice before and after training revealed significant training and 114 129 analysis revealed significant reduction in the consumption of saccharin (CTA vs. Test) for 130 the vehicle group, indicating impairment of learning for the actinomycin-D treated group 131 compared to control mice. As a convergent measure, we also assessed the strength of 132 CTA memory by calculating the relative consumption of saccharin during the test day to 133 that consumed on the training day (Neseliler et al., 2011). The differences between the 134 groups were large (23% in the vehicle group vs. 80 % for the actinomycin D group) and 135 significant. Meanwhile, actinomycin-treated mice were neither impaired in their ability to 136 detect the palatability of saccharin, nor in their drinking behavior-consumption of 137 saccharin during CTA training was similar for the two groups, as was consumption of 138 water 8 hours after the test ( Figure 1E), suggesting that these nonspecific effects cannot 139 account for the memory impairment. Thus, BLA transcription is essential for CTA memory 140 formation. These results extend prior work showing the importance of BLA protein 141 synthesis for CTA memory (Josselyn et al., 2...