TrkB-BDNF Signalling and Arc/Arg3.1 Immediate Early Genes in the Anterior Cingulate Cortex and Hippocampus: Insights into Novel Memory Milestones Through Behavioural Tagging

In recent years, there has been a surge in interest in investigating the mechanisms underlying memory consolidation. However, our understanding of the behavioural tagging (BT) model and its establishment in diverse brain regions remains limited. This study elucidates the contributions of the anterior cingulate cortex (ACC) and hippocampus in the formation of long-term memory (LTM) employing behaviour tagging as a model for studying the underlying mechanism of LTM formation in rats. Existing knowledge highlights a protein synthesis–dependent phase as imperative for LTM. Brain-derived neurotrophic factor (BDNF) stands as a pivotal plasticity-related protein (PRP) in mediating molecular alterations crucial for long-term synaptic plasticity and memory consolidation. Our study offers evidence suggesting that tropomyosin receptor kinase B (TrkB), the receptor of BDNF, may act as a combined “behavioural tag/PRP”. Interfering with the expression of these molecules resulted in impaired LTM after 24 h. Furthermore, augmenting BDNF expression led to an elevation in Arc protein levels in both the ACC and hippocampus regions. Introducing novelty around weak inhibitory avoidance (IA) training resulted in heightened step-down latencies and expression of these molecules, respectively. We also demonstrate that the increase in Arc expression relies on BDNF synthesis, which is vital for the memory consolidation process. Additionally, inhibiting BDNF using an anti-BDNF function-blocking antibody impacted Arc expression in both the ACC and hippocampus regions, disrupting the transformations from labile to robust memory. These findings mark the initial identification of a “behavioural tag/PRP” combination and underscore the involvement of the TrkB-BDNF-Arc cascade in the behavioural tagging model of learning and memory. Synaptic plasticity induced by behavioural tagging phenomenon: Schematic representation orchestrating cellular level changes in synaptic plasticity induced by behavioural level transitions via behavioural tagging (BT) phenomenon. BT was achieved by incorporating open-field (OF) exploration with novel object recognition (NOR) and inhibitory avoidance test (IAT) paradigm. Exposing the animals to weak events through the NOR and IAT paradigms could only result in transient form of learning (short-term memory) by forming learning tags, whereas exposing the animals to a novel environment through OF resulted in a more stable form of memory (long-term memory) by capturing plasticity-related proteins in a restricted critical time window only. After a weak training, novelty exposure to OF works as a stimulant of pre-synaptic terminal and promotes the escape of stored glutamate into the synaptic cleft which is taken up by postsynaptic terminal’s glutamatergic receptors α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) and N-methyl-d-aspartate (NMDA) receptors causing AMPA receptors to open and allowing Na+ ion influx into the postsynaptic neuron causing positive change in the membrane potential leading to a shift in electrical charge called depolarisation. The elevated build-up of influxed Na+ ions unplugs the Mg2+ ions from the pockets of NMDAR, making way for even more Na+ ion influx, facilitating Ca2+ ion influx into the postsynaptic neuron, which leads to a secondary signalling cascade and activation of kinase proteins, resulting in plasticity changes that strengthen the synapse. This cascade eventually upregulates BDNF transcription, which activates TrkB receptors present on postsynaptic neuron, further enhancing expression of another PRP Arc protein in the novelty-exposed group of animals. Thus, this figure underscores the effect of behavioural tagging on the intricate interplay between cellular level changes involving TrkB, BDNF and Arc in maintaining long-term memory in the hippocampus and anterior cingulate cortex region.