Although evidence suggests that the basolateral amygdala (BLA) and dorsal hippocampus (DH) work together to influence the consolidation of spatial/contextual learning, the circuit mechanism by which the BLA selectively modulates spatial/contextual memory consolidation is not clear. The medial entorhinal cortex (mEC) is a critical region in the hippocampus-based system for processing spatial information. As an efferent target of the BLA, the mEC is a candidate by which the BLA influences the consolidation of such learning. To address several questions regarding this issue, male Sprague Dawley rats received optogenetic manipulations of different BLA afferents immediately after training in different learning tasks. Optogenetic stimulation of the BLA-mEC pathway using ChR2(E123A) after spatial and cued-response Barnes maze training enhanced and impaired retention, respectively, whereas optical inhibition of the pathway using eNpHR3.0 produced trends in the opposite direction. Similar stimulation of the BLA-posterior dorsal striatum pathway had no effect. BLA-mEC stimulation also selectively enhanced retention for the contextual, but not foot shock, component of a modified contextual fear-conditioning procedure. In both sets of experiments, only stimulation using bursts of 8 Hz light pulses significantly enhanced retention, suggesting the importance of driving activity in this frequency range. An 8 Hz stimulation of the BLA-mEC pathway increased local field potential power in the same frequency range in the mEC and in the DH. Together, the present findings suggest that the BLA modulates the consolidation of spatial/contextual memory via projections to the mEC and that activity within the 8 Hz range is critical for this modulation. The mechanism by which the basolateral amygdala (BLA) influences the consolidation of spatial/contextual memory is unknown. Using an optogenetic approach with multiple behavioral procedures, we found that immediate posttraining 8 Hz stimulation of BLA projections to the medial entorhinal cortex (mEC) enhanced retention for spatial/contextual memory, impaired retention for cued-response memory, and had no effect on foot shock learning for contextual fear conditioning. Electrophysiological recordings confirmed that 8 Hz stimulation of this pathway increased activity in the 8 Hz range in the mEC and in the dorsal hippocampus, a region critical for spatial memory consolidation. This suggests that coordinated BLA activity with downstream regions in the 8 Hz activity range immediately after training is important for consolidation of multiple memory forms.

Post-traumatic stress disorder (PTSD) is associated with decreased activity in the prefrontal cortex. PTSD-like pathophysiology and behaviors have been observed in rodents exposed to a single prolonged stress (SPS) procedure. When animals are left alone for 7 days after SPS treatment, they show increased anxiety-like behavior and impaired extinction of conditioned fear, and reduced activity in the prefrontal cortex. Here, we tested the hypothesis that daily optogenetic stimulation of the infralimbic region (IL) of the medial prefrontal cortex (mPFC) during the 7 days after SPS would reverse SPS effects on anxiety and fear extinction. Male Sprague-Dawley rats underwent SPS and then received daily optogenetic stimulation (20 Hz, 2 s trains, every 10 s for 15 min/day) of glutamatergic neurons of the left or right IL for seven days. After this incubation period, rats were tested in the elevated plus-maze (EPM). Twenty-four hours after the EPM test, rats underwent auditory fear conditioning (AFC), extinction training and a retention test. SPS increased anxiety-like behavior in the EPM task and produced a profound impairment in extinction of AFC. Optogenetic stimulation of the left IL, but not right, during the 7-day incubation period reversed the extinction impairment. Optogenetic stimulation did not reverse the increased anxiety-like behavior, suggesting that the extinction effects are not due to a treatment-induced reduction in anxiety. Results indicate that increased activity of the left IL after traumatic experiences can prevent development of extinction impairments. These findings suggest that non-invasive brain stimulation may be a useful tool for preventing maladaptive responses to trauma.

The authors thank John Wemmie, Rong Fan, and Joshua Weiner for their excellent technical assistance and for allowing us to utilize their laboratory facilities for the experiments involving Western blotting.

Previous work from our laboratory suggests that projections from the basolateral amygdala (BLA) to the medial entorhinal cortex (mEC) are a critical pathway by which the BLA modulates the consolidation of spatial learning. Posttraining optogenetic stimulation of this pathway enhances retention of spatial memories. Evidence also indicates that intra-BLA administration of memory-enhancing drugs increases protein levels of activity-regulated cytoskeletal-associated protein (ARC) in the dorsal hippocampus (DH) and that blocking ARC in the DH impairs spatial memory consolidation. Yet, whether optical manipulations of the BLA-mEC pathway after spatial training also alter ARC in the DH is unknown. To address this question, male and female Sprague-Dawley rats received optogenetic stimulation of the BLA-mEC pathway immediately after spatial training using a Barnes maze and, 45 min later, were sacrificed for ARC analysis. Initial experiments found that spatial training increased ARC levels in the DH of rats above those observed in control rats and rats that underwent a cued-response version of the task. Optogenetic stimulation of the BLA-mEC pathway following spatial training, using parameters effective at enhancing spatial memory consolidation, enhanced ARC protein levels in the DH of male rats without affecting ARC levels in the dorsolateral striatum (DLS) or somatosensory cortex. In contrast, similar optical stimulation decreased ARC protein levels in the DLS of female rats without altering ARC in the DH or somatosensory cortex. Together, the present findings suggest a mechanism by which BLA-mEC stimulation enhances spatial memory consolidation in rats and reveals a possible sex-difference in this mechanism.

No abstract