REM sleep disruption, substance use and affective disorders, and regulation by a specialized subtype of brain serotonergic neuron

Disturbances in sleep architecture are major risk factors for, and often endophenotypes of, substance use disorder (SUD) and affective disorders. Neurobiological links between sleep dysfunction and SUD and major depressive disorder (MDD) that might explain the comorbidity are just beginning to be delineated. Clear, though, is that sleep features and their restoration have significant diagnostic, prognostic, and therapeutic value. REM pressure – rapid eye movement (REM) sleep pressure – is an especially relevant parameter. Humans cycle through REM and non-REM (NREM) stages during sleep. REM pressure considers the percentage of REM sleep duration (REM%), the frequency of rapid eye movements (REM density, REMr) during REM sleep periods, and latency to the first REM bout. Elevated REM pressure indicates greater REM% and/or REMr and/or shorter latency, and often tracks SUD and MDD and accompanies improvement of manic symptoms in bipolar disorder (BD). A helpful schema portrays a spectrum of REM pressure with extremes associated with SUD and major affective disorders: for example, low levels linked to SUD and manic BD episodes, elevation has been documented as accompanying improvement of manic symptoms, and high levels have been found associated with depressive symptoms, even predictive of future risk and illness progression. While the association between altered REM pressure and SUD and major affective disorders is well documented, little is known about the neural circuits that dynamically set REM pressure and their relationship to circuitry underlying drug reward, addiction, relapse, and affective state. In this exploratory, foundational R21 grant, we seek to delineate the function and brain circuitry involving a specialized subtype of dual serotonergic- glutamatergic neuron that has the potential to link sleep architecture, notably the proportion of NREM and REM sleep, with alterations in neurocognitive and neurobehavioral constructs relevant to SUD and affective disorders. Discoveries may also include a new example of individual neurons segregating different neurotransmitters to axon collaterals innervating different brain regions, resulting in multilevel differential control of brain functions depending on state and environmental input. Given the high conservation of brainstem raphe circuits in mice and humans, strong translational potential is expected: Research outcomes of potential significance to public health include the discovery of neurological and molecular substrates that might inform therapeutic leads with the potential for bettering the quality of life for individuals suffering from sleep, mood, and substance use disorders.