Howard P. Roffwarg: sleep pioneer, legend, and ontogenetic hypothesis author.

Narrated in this article are accounts of the many contributions Howard P. Roffwarg, MD, made to the field of sleep research and sleep medicine across his entire professional career as a student, a mentor, a leader in the Sleep Research Society, a sleep medicine clinician, and a scientist who performed experimental investigations in humans and animals. Dr Roffwarg was the originator of what is known as the "Ontogenetic Hypothesis" of sleep.

Inhibitory and excitatory amino acid neurotransmitters are utilized by the projection from the dorsal deep mesencephalic nucleus to the sublaterodorsal nucleus REM sleep induction zone.

The sublaterodorsal nucleus (SLD) in the pons of the rat is a locus supporting short-latency induction of a REM sleep-like state following local application of a GABAA receptor antagonist or kainate, glutamate receptor agonist. One putatively relevant source of these neurotransmitters is from the region of the deep mesencephalic nucleus (DpMe) just ventrolateral to the periaquiductal gray, termed the dorsal DpMe (dDpMe). Here, the amino acid neurotransmitter innervation of SLD from dDpMe was studied utilizing anterograde tract-tracing with biotinylated dextranamine (BDA) and fluorescence immunohistochemistry visualized with laser scanning confocal microscopy.

GABAA receptors are located in cholinergic terminals in the nucleus pontis oralis of the rat: implications for REM sleep control.

The oral pontine reticular formation (PnO) of rat is one region identified in the brainstem as a rapid eye movement (REM) sleep induction zone. Microinjection of GABA(A) receptor antagonists into PnO induces a long lasting increase in REM sleep, which is similar to that produced by cholinergic agonists. We previously showed that this REM sleep-induction can be completely blocked by a muscarinic antagonist, indicating that the REM sleep-inducing effect of GABA(A) receptor antagonism is dependent upon the local cholinergic system.

GABA(A) receptors implicated in REM sleep control express a benzodiazepine binding site.

It has been reported that non-subtype-selective GABAA receptor antagonists injected into the nucleus pontis oralis (PnO) of rats induced long-lasting increases in REM sleep. Characteristics of these REM sleep increases were identical to those resulting from injection of muscarinic cholinergic agonists. Both actions were blocked by the muscarinic antagonist, atropine.

A novel GABAergic afferent input to the pontine reticular formation: the mesopontine GABAergic column.

Pharmacological manipulations of gamma-aminobutyric acid (GABA) neurotransmission in the nucleus pontis oralis (PnO) of the rat brainstem produce alterations in sleep/wake behavior. Local applications of GABA(A) receptor antagonists and agonists increase REM sleep and wake, respectively. These findings support a role for GABAergic mechanisms of the PnO in the control of arousal state.

Ablation of Kv3.1 and Kv3.3 potassium channels disrupts thalamocortical oscillations in vitro and in vivo.

The genes Kcnc1 and Kcnc3 encode the subunits for the fast-activating/fast-deactivating, voltage-gated potassium channels Kv3.1 and Kv3.3, which are expressed in several brain regions known to be involved in the regulation of the sleep-wake cycle.

Carbachol induction of REM sleep in the rat is more effective at lights-out than lights-on.

Long-lasting increases in REM sleep are induced in the rat following injection of small amounts of muscarinic receptor agonists into the caudal oral pontine reticular formation. By injecting carbachol at the beginning of the light period or beginning of the dark period, we sought to determine whether the muscarinic, REM sleep induction is influenced by the time of day it is initiated. We found that carbachol is more effective at increasing REM sleep when administered at the beginning of the dark in 87% of the cases.

Kv3 potassium channels control the duration of different arousal states by distinct stochastic and clock-like mechanisms.

Sleep-wake behavior is tightly controlled in many animal species, suggesting genetically encoded, homeostatic control mechanisms that determine arousal-state dynamics. We reported that two voltage-gated potassium channels, Kv3.1 and Kv3.

Adenosine A1 receptors mediate inhibition of cAMP formation in vitro in the pontine, REM sleep induction zone.

Microinjection of adenosine A1 receptor agonist or an inhibitor of adenylyl cyclase into the caudal, oral pontine reticular formation (PnOc) of the rat induces a long-lasting increase in REM sleep. Here, we report significant inhibition of forskolin-stimulated cAMP in dissected pontine tissue slices containing the PnOc incubated with the A1 receptor agonist, cyclohexaladenosine (10(-8) M). These data are consistent with adenosine A1 receptor agonist actions on REM sleep mediated through inhibition of cAMP.