Brief Optogenetic Inhibition of the Basolateral Amygdala (BLA) in Mice Alters Effects of Stressful Experiences on Rapid Eye Movement Sleep (REM)

Abstract

Study Objectives: Stressful events can directly produce significant alterations in subsequent sleep, in particular rapid eye movement sleep (REM); however, the neural mechanisms underlying the process are not fully known. Here, we investigated the role of the basolateral nuclei of the amygdala (BLA) in regulating the effects of stressful experience on sleep. Methods: We used optogenetics to briefly inhibit glutamatergic cells in BLA during the presentation of inescapable footshock (IS) and assessed effects on sleep, the acute stress response, and fear memory. c-Fos expression was also assessed in the amygdala and the medial prefrontal cortex (mPFC), both regions involved in coping with stress, and in brain stem regions implicated in the regulation of REM. Results: Compared to control mice, peri-shock inhibition of BLA attenuated an immediate reduction in REM after IS and produced a significant overall increase in REM. Moreover, upon exposure to the shock context alone, mice receiving peri-shock inhibition of BLA during training showed increased REM without altered freezing (an index of fear memory) or stress-induced hyperthermia (an index of acute stress response). Inhibition of BLA during REM under freely sleeping conditions enhanced REM only when body temperature was high, suggesting the effect was influenced by stress. Peri-shock inhibition of BLA also led to elevated c-Fos expression in the central nucleus of the amygdala and mPFC and differentially altered c-Fos activity in the selected brain stem regions. Conclusions: Glutamatergic cells in BLA can modulate the effects of stress on REM and can mediate effects of fear memory on sleep that can be independent of behavioral fear.

The Basolateral Amygdala Mediates the Role of Rapid Eye Movement Sleep in Integrating Fear Memory Responses

“…However, we have found that BLA also plays an important role in fear-associated changes in sleep after fearful experiences and the recall of fearful memories. Rapid eye movement sleep (REM), in particular, can be fear conditioned, and several studies in mice [16] and rats [17,18] have demonstrated that REM can be altered by both shock training (ST) and fearful memories alone, and that fear-induced alterations in REM are regulated by BLA [19][20][21]. Recently, we demonstrated that brief optogenetic inhibition of BLA glutamatergic neurons (BLA Glu ), specifically for 10 sec around the time of shock presentation, could attenuate ST-induced reductions in REM without altering subsequent fear memory-induced freezing [16].…”

“…Rapid eye movement sleep (REM), in particular, can be fear conditioned, and several studies in mice [16] and rats [17,18] have demonstrated that REM can be altered by both shock training (ST) and fearful memories alone, and that fear-induced alterations in REM are regulated by BLA [19][20][21]. Recently, we demonstrated that brief optogenetic inhibition of BLA glutamatergic neurons (BLA Glu ), specifically for 10 sec around the time of shock presentation, could attenuate ST-induced reductions in REM without altering subsequent fear memory-induced freezing [16]. We further found that, under baseline conditions, optogenetic inhibition of BLA Glu during naturally occurring REM enhances REM-associated-theta (θ) activity in the EEG (REM-θ), increases attempts at transitioning into REM, and thus can increase REM amount under some circumstances [16].…”

Optogenetics: Solving the Enigma of Sleep

“…REM sleep is often affected by mood, stress and fear, but their relationships are complex [54]. It has been hypothesized that REM sleep plays a role in the emotional management of traumatic experiences [54,55].…”

“…REM sleep is often affected by mood, stress and fear, but their relationships are complex [54]. It has been hypothesized that REM sleep plays a role in the emotional management of traumatic experiences [54,55]. Machida et al [54] demonstrated that stress-induced reduction of REM sleep was attenuated by inhibiting glutamatergic neurons of the basolateral nuclei of the amygdala (BLA).…”

“…It has been hypothesized that REM sleep plays a role in the emotional management of traumatic experiences [54,55]. Machida et al [54] demonstrated that stress-induced reduction of REM sleep was attenuated by inhibiting glutamatergic neurons of the basolateral nuclei of the amygdala (BLA). This finding suggests that glutamatergic neurons in BLA may interfere the normal physiology of REM sleep generation in response to acute stress.…”