Controllable and Uncontrollable Stress Differentially Impact Fear Conditioned Alterations in Sleep and Neuroimmune Signaling in Mice

Abstract

Stress induces neuroinflammation and disrupts sleep, which together can promote a number of stress-related disorders. Fear memories associated with stress can resurface and reproduce symptoms. Our previous studies have demonstrated sleep outcomes can be modified by stressor controllability following stress and fear memory recall. However, it is unknown how stressor controllability alters neuroinflammatory signaling and its association with sleep following fear memory recall. Mice were implanted with telemetry transmitters and experienced escapable or inescapable footshock and then were re-exposed to the shuttlebox context one week later. Gene expression was assessed with Nanostring® panels using RNA extracted from the basolateral amygdala and hippocampus. Freezing and temperature were examined as behavioral measures of fear. Increased sleep after escapable stress was associated with a down-regulation in neuro-inflammatory and neuro-degenerative related genes, while decreased sleep after inescapable stress was associated with an up-regulation in these genes. Behavioral measures of fear were virtually identical. Sleep and neuroimmune responses appear to be integrated during fear conditioning and reproduced by fear memory recall. The established roles of disrupted sleep and neuroinflammation in stress-related disorders indicate that these differences may serve as informative indices of how fear memory can lead to psychopathology.

Differential Impact of Social Isolation and Space Radiation on Behavior and Motor Learning in Rats

“…Social interaction appears to be linked to learning and is evolutionarily conserved across taxonomic classes. The hippocampus is a key region for both memory and sleep [ 32 , 33 ], and stress and/or stress-induced changes in sleep, can both alter the processing of new information [ 34 ] and the retrieval of previously acquired memories [ 35 ]. This evidence supports our observed learning impairment in the SI animals during the beginning of the BB task, and it is plausible that the increased stress sensitivity of the SI vulnerable animals led to a greater learning impairment, as stress can alter hippocampal morphology and induce synapse loss within the hippocampus [ 36 , 37 ].…”

Modeling integrated stress, sleep, fear and neuroimmune responses: Relevance for understanding trauma and stress-related disorders

“…In a study using NanoString® panels that assessed multiple immune pathways, we found that contextual fear memories associated with ES resulted in a down-regulation in HPC of many genes associated with neuroinflammation and an up-regulation of genes associated with neuroprotection ( Adkins et al, 2022 ) (see Fig. 4 ).…”

“…IS showed up-regulation of genes involved in cytokine signaling (Tnfrsf25, p = 0.013); activation of the innate immune response (Lcn2, p = 0.0132); recruitment of neutrophils (Lcn2, p = 0.0132 and Ncf1, p = 0.0149); and the Arc gene. Adapted from Adkins et al, (2022) . …”

Barrier–environment interactions along the gut–brain axis and their influence on cognition and behaviour throughout the lifespan

“…In fact, controllable events might even promote control over unpredictable events 153 and produce differential HPA activation or immune profiles. 154 , 155 Interestingly, voluntary exercise can be seen as a controllable event that produces several changes to the BBB and GB ( Figure 3 ). A better understanding of the impact of physical exercise on these barriers could help its promotion in the context of mental health or other conditions.…”