Neural circuit mechanisms of early life stress induced olfactory perceptual deficits in mice

Abstract

Early life conditions can shape the brain by introducing changes at multiple levels of an animal’s physiology. Adversity in early life can be damaging to an individual, and depends on the nature, duration and severity of the experience. It can result in long-term maladaptive consequences making the individuals susceptible to depressive disorders during adulthood. Apart from the emotional and cognitive disturbances that can be caused, Early Life Stress (ELS) can also generate changes in sensory perception. Olfactory impairments emerge as one of the early symptoms in patients suffering from major depressive disorders. For investigating the causal link between the altered neural circuits and the behavioral deficits, the well-mapped mouse olfactory system offered an ideal experimental model. We assessed the effect of ELS on the olfactory capabilities of mice. Our findings revealed that the early-weaned mice exhibit slower olfactory perceptual learning when investigated for an array of simple and complex odor pairs using a go/no-go olfactory discrimination paradigm. Poor olfactory learning and memory changes were accompanied with exacerbated anxiety-like responses. The anxious responses were measured using behavioral measures on the well-known open field and elevated plus maze tests. Odor investigation and olfactory detection thresholds, nonetheless, was normal, indicating occurrence of a specific learning and memory deficit in ELS mice. To evaluate if the impairments can be ameliorated, we improved the conditions of early life environment of early weaned mice by implementing the approach of environmental enriched housing. We found out that such a rearing ameliorated their anxiety responses and improved the olfactory perceptual learning. Finally, to unravel the neural underpinnings of ELS dependent olfactory learning changes, we carried out bi-directional optogenetic modulation of a specific sub-population of bulbar GABAergic interneurons releasing somatostatin neuropeptide. Somatostatin neuropeptide has been shown to have anxiolytic effects, however, it’s function in pre-cortical brain regions remains unknown. Using ex-vivo olfactory bulb slices stimulation, we confirmed the release of the neuropeptide on carrying out optogenetic activation of channelrhodopsin-2 (ChR2). Upon photoactivating these interneurons in vivo, early weaned mice displayed improved complex odor discrimination learning. Photo- inhibiting these neurons using Archaerhodopsin (Arch) in normally weaned mice resulted in the learning deficit observed in ELS mice (Pardasani et al., in preparation) (1). Mice use olfaction to locate scent marks for socio-sexual communication as well. We were interested in exploring if ELS influences socio-sexual behaviors. To this end, we firstly developed a novel paradigm to evaluate the multimodal learning and memory of female mice. Our paradigm involved probing the effect of pheromone priming on the chemosensory as well as whisker-mediated investigatory behavior and long-term memory formation in female mice. Whisker intact female mice retained the memory of pheromonal location while whisker deprivation impeded the acquisition of memory. Further, we explored the activation pattern of immediate early gene, Activity regulated cytoskeleton (Arc) in olfactory bulb, somatosensory cortex and hippocampus of female mice during learning and memorizing the pheromone cues. Enhanced activation of the protein was found out in the whisker intact mice which correlated with the intact memory (2). Furthermore, in case of early weaned female mice, multimodal memory was not established and the Arc expression indicated significantly lesser activity in the corresponding brain regions. References: 1. Pardasani M., Srikanth P., Kantroo M., Mahajan S., McGowan E., Abraham, N. M.. Effect of Early life stress on olfactory perceptual learning deficits. (Manuscript under preparation). 2. Pardasani, M., Marathe, S. D., Purnapatre, M. M., Dalvi, U. & Abraham, N. M. Multimodal learning of pheromone locations. The FASEB Journal 35, e21836 (2021).