Memory retrieval of inhibitory avoidance requires histamine H1 receptor activation in the hippocampus

Abstract

Retrieval represents a dynamic process that may require neuromodulatory signaling. Here, we report that the integrity of the brain histaminergic system is necessary for retrieval of inhibitory avoidance (IA) memory, because rats depleted of histamine through lateral ventricle injections of α-fluoromethylhistidine (a-FMHis), a suicide inhibitor of histidine decarboxylase, displayed impaired IA memory when tested 2 d after training. a-FMHis was administered 24 h after training, when IA memory trace was already formed. Infusion of histamine in hippocampal CA1 of brain histamine-depleted rats (hence, amnesic) 10 min before the retention test restored IA memory but was ineffective when given in the basolateral amygdala (BLA) or the ventral medial prefrontal cortex (vmPFC). Intra-CA1 injections of selective H1 and H2 receptor agonists showed that histamine exerted its effect by activating the H1 receptor. Noteworthy, the H1 receptor antagonist pyrilamine disrupted IA memory retrieval in rats, thus strongly supporting an active involvement of endogenous histamine; 90 min after the retention test, c-Fos-positive neurons were significantly fewer in the CA1s of a-FMHis-treated rats that displayed amnesia compared with in the control group. We also found reduced levels of phosphorylated cAMP-responsive element binding protein (pCREB) in the CA1s of a-FMHis-treated animals compared with in controls. Increases in pCREB levels are associated with retrieval of associated memories. Targeting the histaminergic system may modify the retrieval of emotional memory; hence, histaminergic ligands might reduce dysfunctional aversive memories and improve the efficacy of exposure psychotherapies.

Keywords: H1 receptor; histamine; inhibitory avoidance; memory; retrieval.

Fig. 1.

Effect of histamine acute depletion through a-FMHis administration on IA task. The schematic drawing shows the sequence of behavior procedures and treatments. Rats were implanted with an infusion cannula in the LV and distributed to three groups: one group received saline (SAL) 24 h before and after IA training (control), a second group received a-FMHis 24 h before IA training and SAL 24 h after training, and the third group received SAL 24 h before IA training and a-FMHis 24 h after training. Data are expressed as means ± SEMs of 10–12 animals for each group. ****P < 0.0001 vs. control (one-way ANOVA and Bonferroni’s MCT).

Fig. 2.

Effect of histamine infusion into the BLA, vmPFC, or CA1 on a-FMHis– or anisomycin-induced amnesia. The schematic drawings show the sequence of behavior procedures and treatments. Rats were implanted with infusion cannula in the LV to administer a-FMHis or saline (SAL) and a second cannula bilaterally in the (A) BLA, (B) vmPFC, or (C and D) CA1. Data are expressed as means ± SEMs of 10–12 animals for each group. ****P < 0.0001 vs. respective controls (one-way ANOVA and Bonferroni’s MCT). ANI, anisomycin; HA, histamine.

Fig. 3.

Effect of histamine receptor ligands infusion into CA1 on a-FMHis–induced amnesia. The schematic drawings show the sequence of procedures and treatments. Rats were implanted with infusion cannulas in the (A) LV and (B) CA1 bilaterally. Data are expressed as means ± SEMs of 8–12 animals for each group. PYR, pyrilamine; SAL, saline. *P < 0.05 vs. controls (unpaired t test); ***P < 0.001 vs. controls (one-way ANOVA and Bonferroni’s MCT).

Fig. 4.

c-Fos expression in the CA1 of rats trained and tested for IA memory is blunted in a-FMHis–treated rats. The schematic drawing shows the sequence of procedures and treatment. Brain coronal sections show the effect of exposure to retention test on c-Fos protein expression in the (A) BLA, (B) vmPFC, and (C) CA1 of rats given intra-LV infusions of saline (SAL) or a-FMHis 24 h after IA training. Data are expressed as means ± SEM of three to four rats for each group. (Scale bars: A, 100 μm; B, 500 µm; C, Upper, 100 µm; C, Lower, 500 µm.) ****P < 0.0001 (unpaired t test).

Fig. 5.

Effect of histamine depletion on levels of CREB phosphorylation in the BLA, vmPFC, and CA1 of rats trained and tested for IA memory. The schematic drawing displays the sequence of procedures and treatments. Rats were implanted with an infusion cannula in the LV. Representative immunoblots and densitometric quantification are shown. Data are expressed as means ± SEMs of four rats. **P < 0.01 vs. respective saline (SAL; one-way ANOVA and Bonferroni’s MCT).