The effect of US signalling and the US-CS interval in backward conditioning was assessed in mice. For one group of mice the presentation of food was signalled by a tone and for another group, food was unsignalled. For half of the mice, within each group, the presentation of food preceded a visual cue by 10 s. For the other half, food was presented at the start of the visual cue (0-s US-CS interval), resulting in simultaneous pairings of these events. A summation test and a subsequent retardation test were used to assess the inhibitory effects of backward conditioning in comparison to training with a non-reinforced visual cue that controlled for the possible effects of latent inhibition and conditioned inhibition caused as a consequence of differential conditioning. In the summation test unsignalled presentations of the US resulted in inhibition when the US-CS interval was 10 s, but not 0 s. Signalled presentations of the US resulted in inhibition, independent of the US-CS interval. In the retardation test, independent of US signalling, a US-CS interval of 10 s failed to result in inhibition, but an interval of 0 s resulted in greater conditioned responding to the backward CS than the control CS. A generalisation decrement account of the effect of signalling the US with a 0-s US-CS interval, which resulted in reduced responding in the summation test and faster acquisition in the retardation test, is discussed.

Lesion and electrophysiological studies in rodents have identified the amygdala and hippocampus (HPC) as key structures for Pavlovian fear conditioning, but human functional neuroimaging studies have not consistently found activation of these structures. This could be because hemodynamic responses cannot detect the sparse neuronal activity proposed to underlie conditioned fear. Alternatively, differences in experimental design or fear levels could account for the discrepant findings between rodents and humans. To help distinguish between these alternatives, we used tissue oxygen amperometry to record hemodynamic responses from the basolateral amygdala (BLA), dorsal HPC (dHPC) and ventral HPC (vHPC) in freely-moving rats during the acquisition and extinction of conditioned fear. To enable specific comparison with human studies we used a discriminative paradigm, with one auditory cue [conditioned stimulus (CS)+] that was always followed by footshock, and another auditory cue (CS-) that was never followed by footshock. BLA tissue oxygen signals were significantly higher during CS+ than CS- trials during training and early extinction. In contrast, they were lower during CS+ than CS- trials by the end of extinction. dHPC and vHPC tissue oxygen signals were significantly lower during CS+ than CS- trials throughout extinction. Thus, hemodynamic signals in the amygdala and HPC can detect the different patterns of neuronal activity evoked by threatening vs. neutral stimuli during fear conditioning. Discrepant neuroimaging findings may be due to differences in experimental design and/or fear levels evoked in participants. Our methodology offers a way to improve translation between rodent models and human neuroimaging.

Genetic variation in the human serotonin transporter (5-HTT) has been linked to altered fear learning but the data are inconsistent and the mechanism is unclear. The present study investigated conditioned aversive learning in 5-HTT knockout (KO) mice while simultaneously recording neural network activity (theta oscillations) and hemodynamic responses (tissue oxygen delivery) from the amygdala, a brain region necessary for forming fearful memories. Conditioned aversive learning was measured using a discrimination learning task in which one auditory cue was paired with foot-shock, whereas a second auditory cue was not. Compared with wild-type mice, 5-HTTKO mice exhibited faster discrimination learning. This effect was associated with stronger theta frequency oscillations and greater hemodynamic changes in the amygdala in response to both the emotionally relevant cues and the unconditioned foot-shock stimulus. Furthermore, hemodynamic responses to the unconditioned stimulus predicted behavioral discrimination performance the following day. Acute pharmacological 5-HTT blockade in wild-type mice produced a similar effect, to the extent that administration of citalopram during the fear conditioning sessions enhanced fear memory recall. Collectively, our data argue that loss of 5-HTT function enhances amygdala responsivity to aversive events and facilitates learning for emotionally relevant cues.

Abrupt cessation of therapy with a selective serotonin reuptake inhibitor (SSRI) is associated with a discontinuation syndrome, typified by numerous disabling symptoms, including anxiety. Surprisingly, little is known of the behavioural effect of SSRI discontinuation in animals.

The GluA1 AMPAR subunit (encoded by the Gria1 gene) has been implicated in schizophrenia. Gria1 knockout in mice results in recently experienced stimuli acquiring aberrantly high salience. This suggests that GluA1 may be important for learning that is sensitive to the temporal contiguity between events. To test this, mice were trained on a Pavlovian trace conditioning procedure in which the presentation of an auditory cue and food were separated by a temporal interval. Wild-type mice initially learnt, but with prolonged training came to withhold responding during the trace-conditioned cue, responding less than for another cue that was nonreinforced. Gria1 knockout mice, in contrast, showed sustained performance over training, responding more to the trace-conditioned cue than the nonreinforced cue. Therefore, the trace-conditioned cue acquired inhibitory properties (signalling the absence of food) in wild-type mice, but Gria1 deletion impaired the acquisition of inhibition, thus maintaining the stimulus as an excitatory predictor of food. Furthermore, when there was no trace both groups showed successful learning. These results suggest that cognitive abnormalities in disorders like schizophrenia in which gluatamatergic signalling is implicated may be caused by aberrant salience leading to a change in the nature of the information that is encoded.

Every day we make decisions critical for adaptation and survival. We repeat actions with known consequences. But we also draw on loosely related events to infer and imagine the outcome of entirely novel choices. These inferential decisions are thought to engage a number of brain regions; however, the underlying neuronal computation remains unknown. Here, we use a multi-day cross-species approach in humans and mice to report the functional anatomy and neuronal computation underlying inferential decisions. We show that during successful inference, the mammalian brain uses a hippocampal prospective code to forecast temporally structured learned associations. Moreover, during resting behavior, coactivation of hippocampal cells in sharp-wave/ripples represent inferred relationships that include reward, thereby "joining-the-dots" between events that have not been observed together but lead to profitable outcomes. Computing mnemonic links in this manner may provide an important mechanism to build a cognitive map that stretches beyond direct experience, thus supporting flexible behavior.

The 5-hydroxytryptamine (5-HT) transporter (5-HTT) is believed to play a key role in both normal and pathological psychological states. Much previous data suggest that the s allele of the polymorphic regulatory region of the 5-HTT gene promoter is associated with reduced 5-HTT expression and vulnerability to psychiatric disorders, including anxiety and depression. In comparison, the l allele, which increases 5-HTT expression, is generally considered protective. However, recent data link this allele to both abnormal 5-HT signalling and psychopathic traits. Here, we studied the processing of aversive and rewarding cues in transgenic mice that over-express the 5-HTT (5-HTTOE mice). Compared with wild-type mice, 5-HTTOE mice froze less in response to both a tone that had previously been paired with footshock, and the conditioning context. In addition, on a decision-making T-maze task, 5-HTTOE mice displayed reduced preference for a larger, delayed reward and increased preference for a smaller, immediate reward, suggesting increased impulsiveness compared with wild-type mice. However, further inspection of the data revealed that 5-HTTOE mice displayed a relative insensitivity to reward magnitude, irrespective of delay. In contrast, 5-HTTOE mice appeared normal on tests of spatial working and reference memory, which required an absolute choice between options associated with either reward or no reward. Overall, the present findings suggest that 5-HTT over-expression results in a reduced sensitivity to both positive and negative reinforcers. Thus, these data show that increased 5-HTT expression has some maladaptive effects, supporting recent suggestions that l allele homozygosity may be a potential risk factor for disabling psychiatric traits.