Melamine disrupts spatial reversal learning and learning strategy via inhibiting hippocampal BDNF-mediated neural activity

Abstract

Although several studies showed adverse neurotoxic effects of melamine on hippocampus (HPC)-dependent learning and reversal learning, the evidence for this mechanism is still unknown. We recently demonstrated that intra-hippocampal melamine injection affected the induction of long-term depression, which is associated with novelty acquisition and memory consolidation. Here, we infused melamine into the HPC of rats, and employed behavioral tests, immunoblotting, immunocytochemistry and electrophysiological methods to sought evidence for its effects on cognitive flexibility. Rats with intra-hippocampal infusion of melamine displayed dose-dependent increase in trials to the criterion in reversal learning, with no locomotion or motivation defect. Compared with controls, melamine-treated rats avoided HPC-dependent place strategy. Meanwhile, the learning-induced BDNF level in the HPC neurons was significantly reduced. Importantly, bilateral intra-hippocampal BDNF infusion could effectively mitigate the suppressive effects of melamine on neural correlate with reversal performance, and rescue the strategy bias and reversal learning deficits. Our findings provide first evidence for the effect of melamine on cognitive flexibility and suggest that the reversal learning deficit is due to the inability to use place strategy. Furthermore, the suppressive effects of melamine on BDNF-mediated neural activity could be the mechanism, thus advancing the understanding of compulsive behavior in melamine-induced and other neuropsychiatric disorders.

Ensemble remodeling supports memory-updating

“…Reversal learning is a common paradigm for measuring memory flexibility 20 where the subject must inhibit previously learned behavioral responses and adopt new ones. Although many reversal learning tasks focus on striatal, orbitofrontal, and prefrontal cortical contributions [20][21][22] , the hippocampus has also been shown to be important for memory flexibility during spatial reversal 6,23,24 . For example, long-term depression (LTD) in the hippocampus is critical for reversal learning of a spatial memory on the Morris water maze [25][26][27] .…”

Aluminium oxide nanoparticles compromise spatial memory performance and proBDNF-mediated neuronal function in the hippocampus of rats

“…As described previously [ 56 , 57 ], the open field consisted of a square plastic-made arena (91.5 cm × 91.5 cm × 61 cm). The field was divided into a peripheral region (within 15.25 cm of the walls) and central region (61 cm × 61 cm) of approximately equal area.…”

“…One week before behavioral training, electrode implantation was conducted using previously reported procedures [ 56 , 67 , 68 ]. Briefly, rats were anesthetized with isoflurane and prepared for surgery.…”

Prelimbic proBDNF facilitates memory destabilization by regulation of neuronal function in juveniles

“…According to the previous principle (Sun et al , 2021c; Sun et al , 2021d), prelimbic cortex were dissected and homogenized in lysis buffer (pH 7.4) containing a cocktail of protein phosphatase and proteinase inhibitors (Sigma). The samples were centrifuged at 14,000 r.p.m.…”