Basal ganglia circuitry that interlinks sleep, insomnia and anxiety

Poor sleep and anxiety affect many people worldwide. One hypothesis is that good sleep reduces the impact of stress, and that poor sleep may itself trigger serious depression. Rapid Eye Movement (REM) sleep may be particularly important in promoting emotional resilience and guarding against depression. We have discovered new circuitry in the hypothalamus and basal ganglia that contributes to generating REM sleep, and this circuitry overlaps with circuitry that regulates stress, depression and motor movements. Can this circuitry be exploited to learn about the function of REM sleep, and ultimately improve mental health by lowering stress and anxiety levels? Three of the brain regions we have found to regulate sleep-wake states (the lateral habenula, the entopeduncular nucleus, and the subthalamic nucleus) are already used clinically to treat Parkinson's disease via deep brain stimulation, to alleviate major depression or motor symptoms. Some patients report that deep brain stimulation at the three sites we mention above also improves their sleep. On the other hand, deep-brain stimulation in these regions can also trigger depression/anxiety. Therefore, we plan to understand more about the parallel wiring in this complex system, and isolate the specific sleep-inducing components. It may be possible, for example, to selectively enhance REM sleep. Currently our work is at a "blue skies" phase. But understanding more about how sleep could boost emotional resilience and feelings of well-being could ultimately improve human health, both in patients living with severe depression and posttraumatic stress disorder and those living with neurodegenerative disease.

Although REM sleep was discovered some 70 years ago, researchers are still puzzled about its function. REM sleep has been hypothesized to promote emotional health or resilience, for example, by enabling contextual memory and/or forgetting about emotionally- salient stimuli, and diverse low-level chronic stressors, substantially increases the amount of REM sleep. In these situations, more REM sleep could be an adaptation to deal with stress or processing adverse emotional memories. Similarly, people living with severe depression or post-traumatic-stress disorder have elevated REM sleep, a potentially restorative mechanism. An alternative interpretation is that more REM sleep in these conditions could be an abnormality contributing further to pathology. Indeed, monoamine reuptake blockers, taken for depression, markedly decrease or even eliminate REM. These apparent discrepancies as to whether changes in REM sleep are beneficial or harmful remain unresolved. In this work we will investigate if REM is beneficial for dealing with stress.
Our lab has discovered two new features that generate REM sleep in the forebrain: a basal ganglia pathway incorporating the entopeduncular (EP) nucleus, and a REM theta power generator in the lateral preoptic hypothalamus (LPO) hypothalamus. These two pathways may be linked together. Overall, combining all our recent published work, we have shown a new strand of sleep-inducing circuitry extends from the EP (cells co-release somatostatin, glutamate and GABA) to the lateral habenula (LHb, cells release glutamate) to GABA cells in the VTA, which in turn project to cells in the lateral hypothalamus to induce NREM and REM sleep. This EP-LHb-VTA-LH sleep circuitry itself may be partially heterogeneous. We will investigate this new type of extended sleep circuit to determine how REM sleep is generated and what its functional consequences may be for regulating stress and anxiety levels.