Kenneth M McCullough1, Galen Missig1, Mykel A Robble1, Allison R Foilb1, Audrey M Wells1, Jakob Hartmann1, Kasey J Anderson1, Rachael L Neve2, Eric J Nestler3, Kerry J Ressler1, William A Carlezon4. 1. Basic Neuroscience Division, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts. 2. Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts. 3. Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York. 4. Basic Neuroscience Division, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts. Electronic address: bcarlezon@mclean.harvard.edu.
Abstract
BACKGROUND: Stress is implicated in the pathophysiology of major depression and posttraumatic stress disorder. These conditions share core features, including motivational deficits, heighted anxiety, and sleep dysregulation. Chronic stress produces these same features in rodents, with some individuals being susceptible or resilient, as seen in humans. While stress-induced neuroadaptations within the nucleus accumbens are implicated in susceptibility-related dysregulation of motivational and emotional behaviors, their effects on sleep are unclear. METHODS: We used chemogenetics (DREADDs [designer receptors exclusively activated by designer drugs]) to examine the effects of selective alterations in activity of nucleus accumbens medium spiny neurons expressing dopamine D1 receptors (D1-MSNs) or dopamine D2 receptors (D2-MSNs) on sleep-related end points. Mice were implanted with wireless transmitters enabling continuous collection of data to quantify vigilance states over a 20-day test period. Parallel cohorts were examined in behavioral tests assessing stress susceptibility. RESULTS: D1- and D2-MSNs play dissociable roles in sleep regulation. Stimulation of inhibitory or excitatory DREADDs expressed in D1-MSNs exclusively affects rapid eye movement sleep, whereas targeting D2-MSNs affects slow wave sleep. The combined effects of D1-MSN inhibition and D2-MSN activation on sleep resemble those of chronic social defeat stress. Alterations in D1-MSN function also affect stress susceptibility in social behavior tests. Elevation of CREB (cAMP response element-binding protein) within D1-MSNs is sufficient to produce stress-like effects on rapid eye movement sleep. CONCLUSIONS: In addition to regulation of motivational and emotional behaviors, the nucleus accumbens also influences sleep, an end point with high translational relevance. These findings provide a neural basis for comorbidity in key features of stress-related illness.
BACKGROUND: Stress is implicated in the pathophysiology of major depression and posttraumatic stress disorder. These conditions share core features, including motivational deficits, heighted anxiety, and sleep dysregulation. Chronic stress produces these same features in rodents, with some individuals being susceptible or resilient, as seen in humans. While stress-induced neuroadaptations within the nucleus accumbens are implicated in susceptibility-related dysregulation of motivational and emotional behaviors, their effects on sleep are unclear. METHODS: We used chemogenetics (DREADDs [designer receptors exclusively activated by designer drugs]) to examine the effects of selective alterations in activity of nucleus accumbens medium spiny neurons expressing dopamine D1 receptors (D1-MSNs) or dopamine D2 receptors (D2-MSNs) on sleep-related end points. Mice were implanted with wireless transmitters enabling continuous collection of data to quantify vigilance states over a 20-day test period. Parallel cohorts were examined in behavioral tests assessing stress susceptibility. RESULTS: D1- and D2-MSNs play dissociable roles in sleep regulation. Stimulation of inhibitory or excitatory DREADDs expressed in D1-MSNs exclusively affects rapid eye movement sleep, whereas targeting D2-MSNs affects slow wave sleep. The combined effects of D1-MSN inhibition and D2-MSN activation on sleep resemble those of chronic social defeat stress. Alterations in D1-MSN function also affect stress susceptibility in social behavior tests. Elevation of CREB (cAMP response element-binding protein) within D1-MSNs is sufficient to produce stress-like effects on rapid eye movement sleep. CONCLUSIONS: In addition to regulation of motivational and emotional behaviors, the nucleus accumbens also influences sleep, an end point with high translational relevance. These findings provide a neural basis for comorbidity in key features of stress-related illness.
Authors: Justin T Baker; Laura T Germine; Kerry J Ressler; Scott L Rauch; William A Carlezon Journal: Neuropsychopharmacology Date: 2018-08-02 Impact factor: 7.853
Authors: John W Muschamp; Ashlee Van't Veer; Aram Parsegian; Miranda S Gallo; Melissa Chen; Rachael L Neve; Edward G Meloni; William A Carlezon Journal: J Neurosci Date: 2011-02-23 Impact factor: 6.167
Authors: E Souêtre; E Salvati; J L Belugou; D Pringuey; M Candito; B Krebs; J L Ardisson; G Darcourt Journal: Psychiatry Res Date: 1989-06 Impact factor: 3.222
Authors: Diego A Pizzagalli; Moria Smoski; Yuen-Siang Ang; Alexis E Whitton; Gerard Sanacora; Sanjay J Mathew; John Nurnberger; Sarah H Lisanby; Dan V Iosifescu; James W Murrough; Hongqiu Yang; Richard D Weiner; Joseph R Calabrese; Wayne Goodman; William Z Potter; Andrew D Krystal Journal: Neuropsychopharmacology Date: 2020-06-16 Impact factor: 7.853
Authors: Andrew D Krystal; Diego A Pizzagalli; Moria Smoski; Sanjay J Mathew; John Nurnberger; Sarah H Lisanby; Dan Iosifescu; James W Murrough; Hongqiu Yang; Richard D Weiner; Joseph R Calabrese; Gerard Sanacora; Gretchen Hermes; Richard S E Keefe; Allen Song; Wayne Goodman; Steven T Szabo; Alexis E Whitton; Keming Gao; William Z Potter Journal: Nat Med Date: 2020-03-30 Impact factor: 53.440
Authors: Rong Guo; Dylan Thomas Vaughan; Ana Lourdes Almeida Rojo; Yanhua H Huang Journal: Neuropsychopharmacology Date: 2022-06-16 Impact factor: 7.853
Authors: Kerry J Ressler; Sabina Berretta; Vadim Y Bolshakov; Isabelle M Rosso; Edward G Meloni; Scott L Rauch; William A Carlezon Journal: Nat Rev Neurol Date: 2022-03-29 Impact factor: 44.711