Perceptual learning deficits mediated by somatostatin releasing inhibitory interneurons of olfactory bulb in an early life stress mouse model

Abstract Early life adversity (ELA) causes aberrant functioning of neural circuits affecting the health of an individual. While ELA-induced behavioural disorders resulting from sensory and cognitive disabilities can be assessed clinically, the neural mechanisms need to be probed using animal models by employing multi-pronged experimental methods. As ELA can alter perception, we investigated the effect of early weaning on murine olfaction. By implementing go/no-go odour discrimination paradigm, we observed olfactory learning and memory impairments in early life stressed (ELS) male mice. As olfactory bulb (OB) circuitry plays a critical role in odour learning, we studied the plausible changes in the OB of ELS mice. Lowered c-Fos activity in the external plexiform layer and a reduction in the number of dendritic processes of somatostatin-releasing, GABAergic interneurons (SOM-INs) in the ELS mice led us to hypothesize the underlying circuit. We recorded reduced synaptic inhibitory feedback on mitral/tufted (M/T) cells, in the OB slices from ELS mice, explaining the learning deficiency caused by compromised refinement of OB output. The role of SOM-INs was revealed by learning-dependent refinement of Ca2+ dynamics quantified by GCaMP6f signals. Further, the causal role of SOM-INs involving circuitry was investigated by optogenetic bi-directional modulation during odour discrimination learning. Photo-activating these neurons rescued ELA-induced learning deficits. Conversely, photo-inhibition caused learning deficiency in control animals, while it completely abolished the learning in ELS mice, confirming the adverse effects mediated by SOM-INs. Our results thus establish the role of specific inhibitory circuit in pre-cortical sensory area in orchestrating ELAdependent changes.