Abstract
Anxiolytic drugs are widely used in the elderly, a population particularly sensitive to stress. Stress, aging and anxiolytics all affect low-frequency oscillations in the hippocampus and prefrontal cortex (PFC) independently, but the interactions between these factors remain unclear. Here, we compared the effects of stress (elevated platform, EP) and anxiolytics (diazepam, DZP) on extracellular field potentials (EFP) in the PFC, parietal cortex and hippocampus (dorsal and ventral parts) of adult (8 months) and aged (18 months) Wistar rats. A potential source of confusion in the experimental studies in rodents comes from locomotion-related theta (6–12 Hz) oscillations, which may overshadow the direct effects of anxiety on low-frequency and especially on the high-amplitude oscillations in the Mu range (7–12 Hz), related to arousal. Animals were restrained to avoid any confound and isolate the direct effects of stress from theta oscillations related to stress-induced locomotion. We identified transient, high-amplitude oscillations in the 7–12 Hz range (“Mu-bursts”) in the PFC, parietal cortex and only in the dorsal part of hippocampus. At rest, aged rats displayed more Mu-bursts than adults. Stress acted differently on Mu-bursts depending on age: it increases vs. decreases burst, in adult and aged animals, respectively. In contrast DZP (1 mg/kg) acted the same way in stressed adult and age animal: it decreased the occurrence of Mu-bursts, as well as their co-occurrence. This is consistent with DZP acting as a positive allosteric modulator of GABAA receptors, which globally potentiates inhibition and has anxiolytic effects. Overall, the effect of benzodiazepines on stressed animals was to restore Mu burst activity in adults but to strongly diminish them in aged rats. This work suggests Mu-bursts as a neural marker to study the impact of stress and DZP on age.
Highlights
Stress is a set of physiological responses triggered by an aversive situation (Kim and Diamond, 2002)
Phase-locking was higher during Mu-bursts in one of the two structure than in non-bursting episodes, suggesting synchronization processes between the prefrontal cortex (PFC) and dorsal hippocampus (dHPC) even during ‘‘subthreshold’’ oscillations in the Mu range (Kruskal-Wallis test χ 2 = 23.2 ∗∗∗Prest = 3.661 e-5 and χ 2 = 23.65; ∗∗∗Pstress = 2.961 e-5, Table 2 and Figure 3E, down). These results indicate that Mu-bursts can be generated independently in the PFC and dHPC, while being highly synchronized, and that stress affected the occurrence of Mu-bursts rather than the fine temporal relations between them
While the ventral hippocampus (vHPC) is known to be directly implicated in anxiety-related processes through direct connections with the amygdala and bed nucleus of stria terminalis (Adhikari, 2014; Adhikari et al, 2015; Padilla-Coreano et al, 2016), the dHPC is believed to exert a role in contextual fear learning only (Bannerman et al, 2004; Fanselow and Dong, 2010)
Summary
Stress is a set of physiological responses triggered by an aversive situation (Kim and Diamond, 2002). The neurological consequences of stress and age appear strikingly similar: both are associated with alterations of neuronal plasticity and increased risk of brain disorders (Morrison and Baxter, 2012; Prenderville et al, 2015). These similarities suggest that age itself may act as a stressor factor (Buechel et al, 2014). This link between age and stress is highlighted by an altered brain plasticity in elderly after exposure to new-onset stress (Morrison and Baxter, 2012; Lindenberger, 2014; Prenderville et al, 2015), and that aged individuals often cope with stressful situations (Barrientos et al, 2012; Buechel et al, 2014)
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