Too Little and Too Much: Balanced Hippocampal, But Not Medial Prefrontal, Neural Activity Is Required for Intact...

Impaired GABAergic inhibition, so-called neural disinhibition, in the prefrontal cortex and hippocampus has been linked to cognitive deficits. The novel object recognition (NOR) task has been used widely to study cognitive deficits in rodents. However, the contribution of prefrontal cortical and hippocampal GABAergic inhibition to NOR task performance has not been established. Here, we investigated NOR task performance in male Lister hooded rats following regional neural disinhibition or functional inhibition, using intracerebral microinfusion of the GABA_A receptor antagonist picrotoxin or agonist muscimol, respectively. Our infusion targets were the medial prefrontal cortex (mPFC), dorsal hippocampus (DH), and ventral hippocampus (VH). Using a within-subject design, we compared NOR task performance (1 min retention delay) following bilateral regional saline, picrotoxin, or muscimol infusions made before the acquisition phase. In mPFC, neither functional inhibition nor neural disinhibition affected object recognition memory. However, in both the DH and VH, neural disinhibition impaired NOR relative to saline control, mainly by reducing novel object exploration time. In addition, functional inhibition of the DH impaired NOR, whereas VH functional inhibition tended to reduce novel object exploration at the highest dose used (alongside substantial nonspecific behavioral effects). Overall, our data suggest that hippocampal, but not prefrontal, GABAergic inhibition contributes to NOR at a 1 min retention delay. Moreover, such NOR performance likely requires balanced neural activity in the DH, with both too little and too much DH activity impairing NOR memory. Our findings support that the NOR task can be used to investigate hippocampal GABAergic dysfunction in rodent models.