Differential effects of the stress peptides PACAP and CRF on sleep architecture in mice

Abstract

Stress produces profound effects on behavior, including persistent alterations in sleep patterns. Here we examined the effects of two prototypical stress peptides, pituitary adenylate cyclase-activating polypeptide (PACAP) and corticotropin-releasing factor (CRF), on sleep architecture and other translationally-relevant endpoints. Male and female mice were implanted with subcutaneous transmitters enabling continuous measurement of electroencephalography (EEG) and electromyography (EMG), as well as body temperature and locomotor activity, without tethering that restricts free movement, body posture, or head orientation during sleep. At baseline, females spent more time awake (AW) and less time in slow wave sleep (SWS) than males. Mice then received intracerebral infusions of PACAP or CRF at doses producing equivalent increases in anxiety-like behavior. The effects of PACAP on sleep architecture were similar in both sexes and resembled those reported in male mice after chronic stress exposure. Compared to vehicle infusions, PACAP infusions decreased time in AW, increased time in SWS, and increased rapid eye movement sleep (REM) time and bouts on the day following treatment. In addition, PACAP effects on REM time remained detectable a week after treatment. PACAP infusions also reduced body temperature and locomotor activity. Under the same experimental conditions, CRF infusions had minimal effects on sleep architecture in either sex, causing only transient increases in SWS during the dark phase, with no effects on temperature or activity. These findings suggest that PACAP and CRF have fundamentally different effects on sleep-related metrics, and provide new insights into the mechanisms by which stress disrupts sleep.

Circulating PACAP levels are associated with altered imaging measures of entorhinal cortex neurite density in posttraumatic stress disorder

“…Based on prior evidence that PACAP relates to hyperarousal in PTSD, digital phenotyping metrics of arousal would be worth examination in future studies. Recent work in mice shows that acute administration of PACAP can regulate sleep architecture captured using subcutaneous detectors (Foilb et al, 2024 ), although future work is needed to precisely model the types of long-term changes in PACAP function and sleep that might be seen in people with PTSD. Nonetheless, further research is needed to test the hypothesis that structural changes of the EC may serve as an intermediary factor influencing the relationship between PACAP and lower functional connectivity of the amygdala and hippocampus in PTSD.…”

“…Posttraumatic stress disorder (PTSD) is characterised by intrusion, avoidance, negative emotions, and hyperarousal symptoms after exposure to severe trauma (Ressler et al, 2022 ). Pituitary adenylate cyclase-activating polypeptide (PACAP) is a well-established neuromodulator of stress and arousal (Hammack & May, 2015 ), is involved in the secretion and production of corticotropin-releasing hormone (Agarwal et al, 2005 ; Boucher et al, 2021 ; Stroth & Eiden, 2010 ), stress-related sleep disturbance in mice (Foilb et al, 2024 ), and has been associated with hyperarousal symptoms of PTSD (Ressler et al, 2011 ). Stress-induced morphological alterations of the medial temporal lobe (MTL), including changes in amygdala and hippocampal volume, are implicated in PTSD (Shin et al, 2006 ).…”

The α2 Adrenoceptor Agonist and Sedative/Anaesthetic Dexmedetomidine Excites Diverse Neuronal Types in the Ventrolateral Preoptic Area of Male Mice

“…Boys had longer sleep latency, and worse sleep efficiency than girls on Saturday nights ( Hrozanova et al, 2023 ). In exploring the effects of pituitary adenylate cyclase-activating polypeptide (PACAP) and corticotropin-releasing factor (CRF) on sleep structure, the researchers found that at baseline, male mice spent more time in NREM sleep and less time in wake than female mice ( Foilb et al, 2023 ). Only male mice were used in our experiment.…”

Acute sleep deprivation reduces fear memories in male and female mice

“…In experiments designed specifically to examine how fear conditioning affects sleep patterns, mice were implanted with wireless transmitters (HD-X02; Data Sciences International [DSI], St. Paul, MN) to enable continuous collection of EEG (electroencephalography) and EMG (electromyography) data, as described 31,[46][47][48] . Mice were anesthetized via intraperitoneal (IP) injections of 100 mg/kg ketamine/10 mg/kg xylazine mixed in saline.…”

“…In parallel, we examined the effects of our sleep deprivation regimen on expression of mRNA encoding brain-derived neurotropic factor (BDNF), molecule implicated in neuroplasticity, in brain areas implicated in the development, expression, and extinction of fear-related behaviors 17,25,26 . Given the well-characterized sex differences in baseline sleep parameters [27][28][29][30][31] , interactions between sleep and gonadal hormones 28,30,[32][33][34][35][36] , and the prevalence of trauma-related illnesses such as PTSD [37][38][39][40][41][42][43][44] , we designed the studies to enable qualitative and quantitative comparisons between males and females. Our findings show that delayed sleep deprivation can reduce expression of conditioned fear in both sexes, and raise the possibility that the effects of this regimen are not due to disruption of memory consolidation but instead caused by BDNF-mediated neuroadaptations within the BLA that actively suppress expression of fear.…”