Lateral entorhinal cortex supports the development of prefrontal network activity that bridges temporally discontiguous stimuli.

The lateral entorhinal cortex (LEC) is an essential component of the brain circuitry supporting long-term memory by serving as an interface between the hippocampus and neocortex. Dysfunction of the LEC affects sensory coding in the hippocampus, leading to a view that the LEC provides the hippocampus with highly processed sensory information. It remains unclear, however, how the LEC modulates neural processing in the neocortical regions. To address this point, we pharmacologically inactivated the LEC of male rats during a temporal associative learning task and examined its impact on local network activity in one of the LEC's efferent targets, the prelimbic region of the medial prefrontal cortex (mPFC). Rats were exposed to two neutral stimuli, one of which was paired with an aversive eyelid shock over a short temporal delay. The LEC inhibition reduced the expression of anticipatory blinking responses to the reinforced stimuli without increasing responses to nonreinforced stimuli. In control rats, both the reinforced and nonreinforced stimuli evoked a short-lived, wide-band increase in the prelimbic network activity. With learning, the initial increase of gamma-band activity started to extend into the interval between the reinforced neutral stimulus and the eyelid shock. LEC inhibition attenuated the learning-induced sustained activity, without affecting the initial transient activity. These results suggest that the integrity of LEC is necessary for the formation of temporal stimulus associations and its neural correlates in the mPFC. Given the minimal effects on the innate network responses to sensory stimuli, the LEC appears not to be the main source of sensory inputs to the mPFC; rather it may provide a framework that shapes the mPFC network response to behaviorally relevant cues.