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Deficits in hippocampus‐dependent memory processes are common across psychiatric and neurodegenerative disorders such as depression, anxiety and Alzheimer's disease. Moreover, stress is a major environmental risk factor for these pathologies and it exerts detrimental effects on hippocampal functioning via the activation of hypothalamic–pituitary–adrenal (HPA) axis. The medial septum cholinergic neurons extensively innervate the hippocampus. Although, the cholinergic septohippocampal pathway (SHP) has long been implicated in learning and memory, its involvement in mediating the adaptive and maladaptive impact of stress on mnemonic processes remains less clear. Here, we discuss current research highlighting the contributions of cholinergic SHP in modulating memory encoding, consolidation and retrieval. Then, we present evidence supporting the view that neurobiological interactions between HPA axis stress response and cholinergic signalling impact hippocampal computations. Finally, we critically discuss potential challenges and opportunities to target cholinergic SHP as a therapeutic strategy to improve cognitive impairments in stress‐related disorders. We argue that such efforts should consider recent conceptualisations on the dynamic nature of cholinergic signalling in modulating distinct subcomponents of memory and its interactions with cellular substrates that regulate the adaptive stress response.

Experiencing some early life adversity can have an “inoculating” effect that promotes resilience in adulthood. However, the mechanisms underlying stress inoculation are unknown, and animal models are lacking. Here we used the limited bedding and nesting (LBN) model of adversity to evaluate stress inoculation of addiction-related phenotypes. In LBN, pups from postnatal days 2 to 9 and their dams were exposed to a low-resource environment. In adulthood, they were tested for addiction-like phenotypes and compared to rats raised in standard housing conditions. High levels of impulsivity are associated with substance abuse, but in males, LBN reduced impulsive choice compared to controls. LBN males also self-administered less morphine and had a lower breakpoint on a progressive ratio reinforcement schedule than controls. These effects of LBN on addiction-related behaviors were not found in females. Because the nucleus accumbens (NAc) mediates these behaviors, we tested whether LBN altered NAc physiology in drug-naïve and morphine-exposed rats. LBN reduced the frequency of spontaneous excitatory postsynaptic currents in males, but a similar effect was not observed in females. Only in males did LBN prevent a morphine-induced increase in the AMPA/NMDA ratio. RNA sequencing was performed to delineate the molecular signature in the NAc associated with LBN-derived phenotypes. LBN produced sex-specific changes in transcription, including in genes related to glutamate transmission. Collectively, these studies reveal that LBN causes a male-specific stress inoculation effect against addiction-related phenotypes. Identifying factors that promote resilience to addiction may reveal novel treatment options for patients.