Summary Spatial working memory, the caching of behaviorally relevant spatial cues on a timescale of seconds, is a fundamental constituent of cognition. While the prefrontal cortex and hippocampus are known to jointly contribute to successful spatial working memory, the anatomical pathway and temporal window for interaction of these structures critical to spatial working memory has not yet been established. Here, we find that direct hippocampal-prefrontal afferents are critical for encoding, but not for maintenance or retrieval, of spatial cues. These cues are represented by the activity of individual prefrontal units in a manner that is dependent on hippocampal input only during the cue-encoding phase of a spatial working memory task. Successful encoding of these cues appears to be mediated by gamma-frequency synchrony between the two structures. These findings indicate a critical role for the direct hippocampal-prefrontal afferent pathway in the continuous updating of task-related spatial information during spatial working memory.

The mediodorsal thalamus (MD) shares reciprocal connectivity with the prefrontal cortex (PFC) and decreased MD-PFC connectivity is observed in schizophrenia patients. Patients also display cognitive deficits including impairments in working memory, but a mechanistic link between thalamo-prefrontal circuit function and working memory is missing. Here, using pathway-specific inhibition we found directional interactions between MD and medial PFC (mPFC), with MD-to-mPFC supporting working memory maintenance and mPFC-to-MD supporting subsequent choice. We further identify mPFC neurons that display elevated spiking during the delay, a feature that was absent on error trials and required MD inputs for sustained maintenance. Strikingly, delay-tuned neurons had minimal overlap with spatially-tuned neurons and each mPFC population exhibited mutually exclusive dependence on MD and hippocampal inputs. These findings indicate a role for the MD in sustaining prefrontal activity during working memory maintenance. Consistent with this idea we found that enhancing MD excitability was sufficient to enhance task performance.

The ventral hippocampus (vHPC), medial prefrontal cortex (mPFC), and basolateral amygdala (BLA) are each required for the expression of anxiety-like behavior. Yet the role of each individual element of the circuit is unclear. The projection from the vHPC to the mPFC has been implicated in anxiety-related neural synchrony and spatial representations of aversion. The role of this projection was examined using multi-site neural recordings combined with optogenetic terminal inhibition. Inhibition of vHPC input to the mPFC disrupted anxiety and mPFC representations of aversion, and reduced theta synchrony in a pathway-, frequency- and task-specific manner. Moreover, bilateral, but not unilateral inhibition altered physiological correlates of anxiety in the BLA, mimicking a safety-like state. These results reveal a specific role for the vHPC-mPFC projection in anxiety-related behavior and the spatial representation of aversive information within the mPFC.

Although cortico-striato-thalamo-cortical (CSTC) circuit dysregulation is correlated with obsessive compulsive disorder (OCD), causation cannot be tested in humans. We used optogenetics in mice to simulate CSTC hyperactivation observed in OCD patients. Whereas acute orbitofrontal cortex (OFC)–ventromedial striatum (VMS) stimulation did not produce repetitive behaviors, repeated hyperactivation over multiple days generated a progressive increase in grooming, a mouse behavior related to OCD. Increased grooming persisted for 2 weeks after stimulation cessation. The grooming increase was temporally coupled with a progressive increase in light-evoked firing of postsynaptic VMS cells. Both increased grooming and evoked firing were reversed by chronic fluoxetine, a first-line OCD treatment. Brief but repeated episodes of abnormal circuit activity may thus set the stage for the development of persistent psychopathology.