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Neuronal Circuits of NREM Sleep Control in the Basal Forebrain and Midbrain


Sleep is a fundamental behavior in the animal kingdom. It is essential for optimal cognition,

general health, immune function and neuronal plasticity. Irregular or insufficient sleep may

cause emotional disturbances, abnormal homeostasis of physiological functions. About 30%

adults in the US suffered from insomnia. Therefore, understanding of the sleep‐wake circuit will

contribute to the cure of not only sleep disorders, but also other psychiatric diseases. A crucial

step in understanding the neural circuits controlling sleep is to identify the sleep neurons. In my

thesis, I used transgenic Cre mouse lines, virus‐mediated circuit tracing, and optogenetic

manipulation to identify the sleep‐promoting neurons and dissect the neural circuits for

controlling sleep and arousal.

In chapter 2: The basal forebrain (BF) contains a spatially intermingled diverse population of

neurons that play key roles in multiple brain functions, including sleep‐wake regulation,

attention, and learning/memory. For sleep‐wake regulation, the cholinergic, glutamatergic, and

parvalbumin‐expressing (PV) GABAergic neurons have been shown to promote wakefulness,

whereas the somatostatin‐expressing (SOM) GABAergic neurons promote NREM sleep. To

understand how these cell types in the same area have different functions in sleep‐wake

regulation, we used rabies virus ‐mediated monosynaptic retrograde tracing to label the inputs

and adeno‐associated virus to trace axonal projections. We identified numerous brain areas

connected to the BF. These results reveal the long‐range wiring diagram of the BF circuit with

highly convergent inputs and divergent outputs and point to both functional commonality and

specialization of different BF cell types.

In chapter3: We identified the neurotensin (NTS) neurons in the preoptic area, posterior

thalamus (pTh), and ventrolateral periaqueductal gray (vlPAG) as NREM sleep‐promoting

neurons based on optogenetic manipulation. Using rabies virus‐mediated monosynaptic

retrograde tracing combined with fluorescent in situ hybridization (FISH) experiment, we also

showed that cholecystokinin (CCK) and calcitonin gene‐related peptide alpha (Calca) neurons in

the EW (CCKEW), and NTS neurons in the vlPAG (NTSvlPAG) form reciprocal connections to each

other. These cell types may cooperate to promote NREM sleep.

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