Histamine in the basolateral amygdala promotes inhibitory avoidance learning independently of hippocampus

Significance Integrity of the brain histaminergic system is necessary for long-term memory (LTM) but not short-term memory of step-down inhibitory avoidance (IA). Histamine depletion in hippocampus or basolateral amygdala (BLA) impairs LTM of that task. Histamine infusion into either structure restores LTM in histamine-depleted rats. The restoring effect in BLA occurs even when hippocampal activity was impaired. Cyclic adenosine monophosphate (cAMP) responsive-element-binding protein phosphorylation correlates anatomically and temporally with histamine-induced memory recall. Thus, histaminergic neurotransmission appears critical to provide the brain with the plasticity necessary for IA through recruitment of alternative circuits. Our findings indicate that the histaminergic system comprises parallel, coordinated pathways that provide compensatory plasticity when one brain structure is compromised. Recent discoveries demonstrated that recruitment of alternative brain circuits permits compensation of memory impairments following damage to brain regions specialized in integrating and/or storing specific memories, including both dorsal hippocampus and basolateral amygdala (BLA). Here, we first report that the integrity of the brain histaminergic system is necessary for long-term, but not for short-term memory of step-down inhibitory avoidance (IA). Second, we found that phosphorylation of cyclic adenosine monophosphate (cAMP) responsive-element-binding protein, a crucial mediator in long-term memory formation, correlated anatomically and temporally with histamine-induced memory retrieval, showing the active involvement of histamine function in CA1 and BLA in different phases of memory consolidation. Third, we found that exogenous application of histamine in either hippocampal CA1 or BLA of brain histamine-depleted rats, hence amnesic, restored long-term memory; however, the time frame of memory rescue was different for the two brain structures, short lived (immediately posttraining) for BLA, long lasting (up to 6 h) for the CA1. Moreover, long-term memory was formed immediately after training restoring of histamine transmission only in the BLA. These findings reveal the essential role of histaminergic neurotransmission to provide the brain with the plasticity necessary to ensure memorization of emotionally salient events, through recruitment of alternative circuits. Hence, our findings indicate that the histaminergic system comprises parallel, coordinated path