A biophysically-based neuromorphic model of spike rate- and timing-dependent plasticity.

Current advances in neuromorphic engineering have made it possible to emulate complex neuronal ion channel and intracellular ionic dynamics in real time using highly compact and power-efficient complementary metal-oxide-semiconductor (CMOS) analog very-large-scale-integrated circuit technology. Recently, there has been growing interest in the neuromorphic emulation of the spike-timing-dependent plasticity (STDP) Hebbian learning rule by phenomenological modeling using CMOS, memristor or other analog devices. Here, we propose a CMOS circuit implementation of a biophysically grounded neuromorphic (iono-neuromorphic) model of synaptic plasticity that is capable of capturing both the spike rate-dependent plasticity (SRDP, of the Bienenstock-Cooper-Munro or BCM type) and STDP rules. The iono-neuromorphic model reproduces bidirectional synaptic changes with NMDA receptor-dependent and intracellular calcium-mediated long-term potentiation or long-term depression assuming retrograde endocannabinoid signaling as a second coincidence detector. Changes in excitatory or inhibitory synaptic weights are registered and stored in a nonvolatile and compact digital format analogous to the discrete insertion and removal of AMPA or GABA receptor channels. The versatile Hebbian synapse device is applicable to a variety of neuroprosthesis, brain-machine interface, neurorobotics, neuromimetic computation, machine learning, and neural-inspired adaptive control problems.

Stream-based Hebbian eigenfilter for real-time neuronal spike discrimination.

BACKGROUND: Principal component analysis (PCA) has been widely employed for automatic neuronal spike sorting. Calculating principal components (PCs) is computationally expensive, and requires complex numerical operations and large memory resources. Substantial hardware resources are therefore needed for hardware implementations of PCA. General Hebbian algorithm (GHA) has been proposed for calculating PCs of neuronal spikes in our previous work, which eliminates the needs of computationally expensive covariance analysis and eigenvalue decomposition in conventional PCA algorithms. However, large memory resources are still inherently required for storing a large volume of aligned spikes for training PCs. The large size memory will consume large hardware resources and contribute significant power dissipation, which make GHA difficult to be implemented in portable or implantable multi-channel recording micro-systems. METHOD: In this paper, we present a new algorithm for PCA-based spike sorting based on GHA, namely stream-based Hebbian eigenfilter, which eliminates the inherent memory requirements of GHA while keeping the accuracy of spike sorting by utilizing the pseudo-stationarity of neuronal spikes. Because of the reduction of large hardware storage requirements, the proposed algorithm can lead to ultra-low hardware resources and power consumption of hardware implementations, which is critical for the future multi-channel micro-systems. Both clinical and synthetic neural recording data sets were employed for evaluating the accuracy of the stream-based Hebbian eigenfilter. The performance of spike sorting using stream-based eigenfilter and the computational complexity of the eigenfilter were rigorously evaluated and compared with conventional PCA algorithms. Field programmable logic arrays (FPGAs) were employed to implement the proposed algorithm, evaluate the hardware implementations and demonstrate the reduction in both power consumption and hardware memories achieved by the streaming computing RESULTS AND DISCUSSION: Results demonstrate that the stream-based eigenfilter can achieve the same accuracy and is 10 times more computationally efficient when compared with conventional PCA algorithms. Hardware evaluations show that 90.3% logic resources, 95.1% power consumption and 86.8% computing latency can be reduced by the stream-based eigenfilter when compared with PCA hardware. By utilizing the streaming method, 92% memory resources and 67% power consumption can be saved when compared with the direct implementation of GHA. CONCLUSION: Stream-based Hebbian eigenfilter presents a novel approach to enable real-time spike sorting with reduced computational complexity and hardware costs. This new design can be further utilized for multi-channel neuro-physiological experiments or chronic implants.

Effects of maturation and acidosis on the chaos-like complexity of the neural respiratory output in the isolated brainstem of the tadpole, Rana esculenta.

Human ventilation at rest exhibits mathematical chaos-like complexity that can be described as long-term unpredictability mediated (in whole or in part) by some low-dimensional nonlinear deterministic process. Although various physiological and pathological situations can affect respiratory complexity, the underlying mechanisms remain incompletely elucidated. If such chaos-like complexity is an intrinsic property of central respiratory generators, it should appear or increase when these structures mature or are stimulated. To test this hypothesis, we employed the isolated tadpole brainstem model [Rana (Pelophylax) esculenta] and recorded the neural respiratory output (buccal and lung rhythms) of pre- (n = 8) and postmetamorphic tadpoles (n = 8), at physiologic (7.8) and acidic pH (7.4). We analyzed the root mean square of the cranial nerve V or VII neurograms. Development and acidosis had no effect on buccal period. Lung frequency increased with development (P < 0.0001). It also increased with acidosis, but in postmetamorphic tadpoles only (P < 0.05). The noise-titration technique evidenced low-dimensional nonlinearities in all the postmetamorphic brainstems, at both pH. Chaos-like complexity, assessed through the noise limit, increased from pH 7.8 to pH 7.4 (P < 0.01). In contrast, linear models best fitted the ventilatory rhythm in all but one of the premetamorphic preparations at pH 7.8 (P < 0.005 vs. postmetamorphic) and in four at pH 7.4 (not significant vs. postmetamorphic). Therefore, in a lower vertebrate model, the brainstem respiratory central rhythm generator accounts for ventilatory chaos-like complexity, especially in the postmetamorphic stage and at low pH. According to the ventilatory generators homology theory, this may also be the case in mammals.

Pacemakers handshake synchronization mechanism of mammalian respiratory rhythmogenesis.

Inspiratory and expiratory rhythms in mammals are thought to be generated by pacemaker-like neurons in 2 discrete brainstem regions: pre-Bötzinger complex (preBötC) and parafacial respiratory group (pFRG). How these putative pacemakers or pacemaker networks may interact to set the overall respiratory rhythm in synchrony remains unclear. Here, we show that a pacemakers 2-way "handshake" process comprising pFRG excitation of the preBötC, followed by reverse inhibition and postinhibitory rebound (PIR) excitation of the pFRG and postinspiratory feedback inhibition of the preBötC, can provide a phase-locked mechanism that sequentially resets and, hence, synchronizes the inspiratory and expiratory rhythms in neonates. The order of this handshake sequence and its progression vary depending on the relative excitabilities of the preBötC vs. the pFRG and resultant modulations of the PIR in various excited and depressed states, leading to complex inspiratory and expiratory phase-resetting behaviors in neonates and adults. This parsimonious model of pacemakers synchronization and mutual entrainment replicates key experimental data in vitro and in vivo that delineate the developmental changes in respiratory rhythm from neonates to maturity, elucidating their underlying mechanisms and suggesting hypotheses for further experimental testing. Such a pacemakers handshake process with conjugate excitation-inhibition and PIR provides a reinforcing and evolutionarily advantageous fail-safe mechanism for respiratory rhythmogenesis in mammals.

A picoampere A/D converter for biosensor applications.

Detection and analysis of biological and biochemical signals via compact sensor systems require low-power and compact analog-to-digital converter (ADC) systems. Here we present a highly sensitive flash current-mode ADC (IADC) design with resolution down to 15pA. The IADC's small-size and low-power capabilities allow integration for stand-alone biological or chemical microsensor applications.

Homeostatic competition: evidence of a serotonin-gated spinoparabrachial pathway for respiratory and thermoregulatory interaction.

Control of breathing and thermoregulation are vital physiological functions for the maintenance of arterial blood gas and pH homeostasis and body temperature homeostasis, respectively. It is widely believed that these homeostatic regulation functions act independently of one another via certain set point or feedfoward/feedback control mechanisms that are specific to each system. Here, the notion of "homeostatic competition" is introduced to depict the interaction of the respiratory and thermal controllers in negotiating a minimum-work ventilatory pattern that is optimal for survival in the face of conflicting homeostatic objectives during thermal stress. It is proposed that such competitive respiratory-thermoregulatory interaction may be mediated by the lateral parabrachial nucleus in dorsolateral pons, a critical site which receives cutaneous thermoafferent information via a serotonin-gated spinoparabrachial pathway and has been shown to modulate both chemoreflex and thermoreflex responses.

Bilateral lesions of pontine Kölliker-Fuse nuclei provoke apnea instead of apneusis in anesthetized adult rats.

The Kölliker-Fuse nucleus (KF) has been traditionally dubbed the "pneumotaxic center". Here, we report that lesions of KF nuclei of bilateral pons caused apnea (complete cessation of phrenic discharge) instead of apneusis in urethane-anesthetized, vagotomized, paralyzed and ventilated adult rats. After bilateral lesions of KF nuclei with the neuroexcitotoxin kainic acid, phrenic discharge disappeared and no spontaneous recovery of phrenic discharge was observed for up to 3 hours. During the apnea, hypoxia or hypercapnia provoked transient rhythmic phrenic discharge. The present finding showed that the KF nucleus not only directly participates in inspiratory to expiratory phase switching, but also provides a vital excitatory drive that is requisite for the generation of inspiratory activity.

Paradoxical potentiation of exercise hyperpnea in congestive heart failure contradicts Sherrington chemoreflex model and supports a respiratory optimization model.

Congestive heart failure (CHF) patients suffer decreased exercise tolerance, yet they demonstrate an augmented ventilatory response to exercise such that P(aCO2) remains normal (isocapnic) from rest to maximal exercise in the face of increased pulmonary dead space (Fig. 1). On the other hand, the effect of a large external dead space is hypercapnic instead of isocapnic. This discrepancy suggests that external dead space and pulmonary dead space may exert distinct influences on control of breathing. These paradoxical clinical phenomena are at variance with the conventional chemoreflex model (Johnson 2001), but appear to be consistent with the predictions of the optimization model (Poon 2001; Poon, Tin et al. 2007).

Intrinsic and synaptic long-term depression of NTS relay of nociceptin- and capsaicin-sensitive cardiopulmonary afferents hyperactivity.

The nucleus tractus solitarius (NTS) in the caudal medulla is a gateway for a variety of cardiopulmonary afferents important for homeostatic regulation and defense against airway and cardiovascular insults and is a key central target potentially mediating the response habituation to these inputs. Here, whole-cell and field population action potential recordings and infrared imaging in rat brainstem slices in vitro revealed a compartmental pain-pathway-like organization of capsaicin-facilitated vs. nocistatin-facilitated/nociceptin-suppressed neuronal clusters in an NTS region, which receives cardiopulmonary A- and C-fiber afferents with differing capsaicin sensitivities. All capsaicin-sensitive neurons and a fraction of nociceptin-sensitive neurons expressed N-methyl-D: -aspartate (NMDA) receptor-dependent synaptic long-term depression (LTD) following afferent stimulation. All neurons also expressed activity-dependent decrease of excitability (intrinsic LTD), which converted to NMDA receptor-dependent intrinsic long-term potentiation after GABA(A) receptor blockade. Thus, distinct intrinsic and synaptic LTD mechanisms in the NTS specific to the relay of A- or C-fiber afferents may underlie the response habituation to persistent afferents hyperactivity that are associated with varying physiologic challenges and cardiopulmonary derangements-including hypertension, chronic cough, asthmatic bronchoconstriction, sustained elevated lung volume in chronic obstructive pulmonary disease or in continuous positive-airway-pressure therapy for sleep apnea, metabolic acidosis, and prolonged exposure to hypoxia at high altitude.

A kinetic model unifying presynaptic short-term facilitation and depression.

Short-term facilitation and depression refer to the increase and decrease of synaptic strength under repetitive stimuli within a timescale of milliseconds to seconds. This phenomenon has been attributed to primarily presynaptic mechanisms such as calcium-dependent transmitter release and presynaptic vesicle depletion. Previous modeling studies that aimed to integrate the complex short-term facilitation and short-term depression data derived from varying synapses have relied on computer simulation or abstract mathematical approaches. Here, we propose a unified theory of synaptic short-term plasticity based on realistic yet tractable and testable model descriptions of the underlying intracellular biochemical processes. Analysis of the model equations leads to a closed-form solution of the resonance frequency, a function of several critical biophysical parameters, as the single key indicator of the propensity for synaptic facilitation or depression under repetitive stimuli. This integrative model is supported by a broad range of transient and frequency response experimental data including those from facilitating, depressing or mixed-mode synapses. Specifically, the theory predicts that high calcium initial concentration and large gain of calcium action result in low resonance frequency and hence depressing behavior. In contrast, for synapses that are less sensitive to calcium or have higher recovery rate, resonance frequency becomes higher and thus facilitation prevails. The notion of resonance frequency therefore allows valuable quantitative parametric assessment of the contributions of various presynaptic mechanisms to the directionality of synaptic short-term plasticity. Thus, the model provides the reasons behind the switching behavior between facilitation and depression observed in experiments. New experiments are also suggested to control the short-term synaptic signal processing through adjusting the resonance frequency and bandwidth.

Use-dependent learning and memory of the Hering-Breuer inflation reflex in rats.

The classic Hering-Breuer inflation reflex (HBIR) is a widely held tenet for understanding the lung volume-related vagal control of respiratory rhythm. Recent evidence, however, has revealed that the fictive HBIR elicited by electrical vagal stimulation in rats is not static but may be attenuated centrally by two forms of non-associative learning (habituation and desensitization) that continually mitigate the reflex effects with exponential adaptations like a differentiator or high-pass filter. Desensitization is analogous to habituation but exhibits an explicit short-term memory (STM) in the form of a rebound response with exponential decay during recovery from stimulation. To investigate whether such learning and memory effects are lung volume related and use-dependent (practice makes perfect), we compared the time-dependent changes in inspiratory and expiratory durations (t(I) and t(E)) during and after 1 or 8 min unilateral lung inflation or high-frequency, low-intensity vagal stimulation in anaesthetized, uni- or bi-vagotomized rats. Unilateral lung inflation and vagal stimulation both elicited abrupt shortening of t(I) and lengthening of t(E) (HBIR effects) and gradual habituation and desensitization throughout the 1 or 8 min test period, followed by rebound responses in t(I) and t(E) with exponential recovery (STM effects) in the post-test period. In both cases, the STM time constants for t(I) and t(E) were significantly longer with the 8 min test than with the 1 min test (17-45 versus 4-11 s, P < 0.01). We conclude that the HBIR and its central habituation and desensitization are mediated peripherally by lung volume-related vagal afferents, and that the STM of desensitization is use-dependent. The translational implications of these findings are discussed.

Lateral parabrachial nucleus mediates shortening of expiration and increase of inspiratory drive during hypercapnia.

We have previously shown that unilateral or bilateral lesions of the lateral parabrachial nucleus (LPBN) in anesthetized, vagotomized rats markedly and selectively attenuate the shortening of expiratory duration (T(E)) during hypoxia without appreciably affecting all other hypoxic response components. Here, we report that unilateral LPBN lesion by kainic acid in the same group of animals not only abolished normal T(E)-shortening during central chemoreceptors activation by hyperoxic hypercapnia, but led to paradoxical T(E)-prolongation and corresponding decrease of respiratory frequency. Furthermore, LPBN lesion significantly attenuated the increase in phrenic activity during hyperoxic hypercapnia, without appreciably affecting the corresponding shortening of inspiratory duration (T(I)). These findings provide the first evidence indicating that central chemoafferent inputs are organized in parallel and segregated pathways that separately modulate inspiratory drive, T(I), and T(E) in conjunction with similar parallel and segregated central processing of peripheral chemoafferent inputs reported previously [Young, D.L., Eldridge, F.L., Poon, C.S., 2003. Integration-differentiation and gating of carotid afferent traffic that shapes the respiratory pattern. J. Appl. Physiol. 94, 1213-1229].

Lateral parabrachial nucleus mediates shortening of expiration during hypoxia.

Acute hypoxia elicits complex time-dependent responses including rapid augmentation of inspiratory drive, shortening of inspiratory and expiratory durations (T(I), T(E)), and short-term potentiation and depression. The central pathways mediating these varied effects are largely unknown. Here, we show that the lateral parabrachial nucleus (LPBN) of the dorsolateral pons specifically mediates T(E)-shortening during hypoxia and not other hypoxic response components. Twelve urethane-anesthetized and vagotomized adult Sprague-Dawley rats were exposed to 1-min poikilocapnic hypoxia before and after unilateral kainic acid or bilateral electrolytic lesioning of the LPBN. Bilateral lesions resulted in a significant increase in baseline T(E) under hyperoxia. After unilateral or bilateral lesions, the decrease in T(E) during hypoxia was markedly attenuated without appreciable changes in all other hypoxic response components. These findings add to the mounting evidence that the central processing of peripheral chemoafferent inputs is segregated into parallel integrator and differentiator (low-pass and high-pass filter) pathways that separately modulate inspiratory drive, T(I), T(E) and resultant short-term potentiation and depression.

Effects of inspiratory loading on the chaotic dynamics of ventilatory flow in humans.

Human ventilation at rest exhibits complexity and chaos. The aim of this study was to determine whether suprapontine interferences with the automatic breathing control could contribute to ventilatory chaos. We conducted a post hoc analysis of a previous study performed in awake volunteers exhibiting cortical pre-motor potentials during inspiratory loading. In eight subjects, flow was recorded at rest, while breathing against inspiratory threshold loads (median 21.5 cm H(2)O) and resistive loads (50 cm H(2)Ol(-1)s(-1)) loads, and while inhaling 7% CO(2)-93% O(2). Chaos was identified through noise titration (noise limit, NL) and the sensitivity to initial conditions was assessed through the largest Lyapunov exponent (LLE). Breath-by-breath variability was evaluated using the coefficient of variation of several ventilatory variables. Chaos was consistently present in ventilatory flow recordings, but mechanical loading did not alter NL, LLE, or variability. In contrast, CO(2) altered chaos and reduced variability. In conclusion, inspiratory loading - and any resultant respiratory-related cortical activity - were not associated with changes in ventilatory chaos in this study, arguing against suprapontine contributions to ventilatory complexity.

Modulation of Hering-Breuer reflex by ventrolateral pons.

The vagally-mediated Hering-Breuer reflex (HBR) is known to be modulated by the classic pneumotaxic center in the dorsolateral pons. In this work, we investigated whether the HBR was also modulated by the ventrolateral pons (vl-pons). Experiments were performed on urethane anesthetized adult rats. The HBR was elicited by electrical stimulation of the vagus nerve and its strength was compared before and after electrical stimulation or microinjection of MK-801 (non-competitive NMDA receptor antagonist) at the vl-pons. We found that the inspiratory inhibition and expiratory prolongation effects of the HBR were strengthened after electrical stimulation at the vl-pons but were weakened after microinjecting MK-801. Results suggested that the vl-pons could influence the respiratory rhythm by modulating the strength of HBR via NMDA receptor-mediated neurotransmission.

Placebo-controlled crossover assessment of mecasermin for the treatment of Rett syndrome.

Objective: To measure the efficacy of mecasermin (recombinant human insulin-like growth factor 1, rhIGF-1), for treating symptoms of Rett syndrome (RTT) in a pediatric population using a double-blind crossover study design. Methods: Thirty girls with classic RTT in postregression stage were randomly assigned to placebo or rhIGF-1 in treatment period 1 and crossed over to the opposite assignment for period 2 (both 20 weeks), separated by a 28-week washout period. The primary endpoints were as follows: Anxiety Depression and Mood Scale (ADAMS) Social Avoidance subscale, Rett Syndrome Behaviour Questionnaire (RSBQ) Fear/Anxiety subscale, Parent Target Symptom Visual Analog Scale (PTSVAS) top three concerns, Clinical Global Impression (CGI), Parent Global Impression (PGI), and the Kerr severity scale. Cardiorespiratory- and electroencephalography (EEG)-based biomarkers were also analyzed. Results: There were no significant differences between randomization groups. The majority of AEs were mild to moderate, although 12 episodes of serious AEs occurred. The Kerr severity scale, ADAMS Depressed Mood subscale, Visual Analog Scale Hyperventilation, and delta average power change scores significantly increased, implying worsening of symptoms. Electroencephalography (EEG) parameters also deteriorated. A secondary analysis of subjects who were not involved in a placebo recall confirmed most of these findings. However, it also revealed improvements on a measure of stereotypic behavior and another of social communication. Interpretation: As in the phase 1 trial, rhIGF-1 was safe; however, the drug did not reveal significant improvement, and some parameters worsened.

Cytoarchitecture of pneumotaxic integration of respiratory and nonrespiratory information in the rat.

The "pneumotaxic center" in the Kölliker-Fuse and medial parabrachial nuclei of dorsolateral pons (dl-pons) plays an important role in respiratory phase switching, modulation of respiratory reflex, and rhythmogenesis. Recent electrophysiological and neural tracing data implicate additional pneumotaxic nuclei in (and a broader role for) the dl-pons in integrating respiratory and nonrespiratory information. Here, we examined the cytoarchitecture of the greater pneumotaxic center and its integrating function by using combined extracellular recording and juxtacellular labeling of unit respiratory rhythmic neurons in dl-pons in urethane-anesthetized, vagotomized, paralyzed, and servo-ventilated adult Sprague Dawley rats. Perievent histogram analysis identified four major types of neuronal discharge patterns: inspiratory, expiratory (with three subdivisions), inspiratory-expiratory, and expiratory-inspiratory phase spanning, sometimes with mild tonic background activity. Most recorded neurons were localized in the Kölliker-Fuse and medial parabrachial nuclei, but some were also found in lateral parabrachial nucleus, intertrigeminal nucleus, principal trigeminal sensory nucleus, and supratrigeminal nucleus. The majority of labeled neurons had large and spatially extended dendritic trees that spanned several of these dl-pons subnuclei, often with terminal dendrites ending in the ventral spinocerebellar tract. The distal sections of the primary and higher-order dendrites exhibited rich varicosities, sometimes with dendritic spines. Axons of some labeled neurons were traced all the way to the ventrolateral pons (vl-pons). These findings extend and generalize the classical definition of the pneumotaxic center to include extensive somatic-axonal-dendritic integration of complex descending and ascending respiratory information as well as nociceptive and possibly musculoskeletal and trigeminal information in multiple dl-pons and vl-pons structures in the rat.

Homeostasis of exercise hyperpnea and optimal sensorimotor integration: the internal model paradigm.

Homeostasis is a basic tenet of biomedicine and an open problem for many physiological control systems. Among them, none has been more extensively studied and intensely debated than the dilemma of exercise hyperpnea - a paradoxical homeostatic increase of respiratory ventilation that is geared to metabolic demands instead of the normal chemoreflex mechanism. Classical control theory has led to a plethora of "feedback/feedforward control" or "set point" hypotheses for homeostatic regulation, yet so far none of them has proved satisfactory in explaining exercise hyperpnea and its interactions with other respiratory inputs. Instead, the available evidence points to a far more sophisticated respiratory controller capable of integrating multiple afferent and efferent signals in adapting the ventilatory pattern toward optimality relative to conflicting homeostatic, energetic and other objectives. This optimality principle parsimoniously mimics exercise hyperpnea, chemoreflex and a host of characteristic respiratory responses to abnormal gas exchange or mechanical loading/unloading in health and in cardiopulmonary diseases - all without resorting to a feedforward "exercise stimulus". Rather, an emergent controller signal encoding the projected metabolic level is predicted by the principle as an exercise-induced 'mental percept' or 'internal model', presumably engendered by associative learning (operant conditioning or classical conditioning) which achieves optimality through continuous identification of, and adaptation to, the causal relationship between respiratory motor output and resultant chemical-mechanical afferent feedbacks. This internal model self-tuning adaptive control paradigm opens a new challenge and exciting opportunity for experimental and theoretical elucidations of the mechanisms of respiratory control - and of homeostatic regulation and sensorimotor integration in general.

Phrenic long-term facilitation is robust to hypercapnia and hypocapnia but not hyperventilatory hypotension under PEEP.

Phrenic long-term facilitation (LTF) has been extensively studied in anesthetized animals under well-defined physiological conditions but the factors underlying its possible manifestation under clinically relevant conditions are not well understood. Here, we examine the stability of LTF in the face of hypercapnic or hypocapnic challenges in anesthetized, paralyzed and mechanically ventilated rats. Sixty minutes after induction of phrenic LTF by intermittent hypoxia the animal was exposed to one of four conditions for 5 min with or without positive end-expiratory pressure (PEEP, 3-4 cmH(2)O): hypocapnic apnea, hypocapnia (5 Torr below resting level), 5% CO(2) and 10% CO(2). LTF at 60 min post-intermittent hypoxia was approximately 39% above baseline. Following the above CO(2) tests, LTF almost invariably returned to the corresponding pre-test level after recovery for 20 min. The only exception was the combination of hypocapnic apnea and PEEP, which resulted in a marked decrease in mean arterial pressure (to 38-55mmHg) during test and a subsequent paradoxical sustained attenuation of LTF (to approximately 8% above baseline) even after mean arterial pressure had fully recovered. The results suggest that LTF, once developed, is highly robust to changes in CO(2) levels and is attenuated only after severe hypotension secondary to excessive hyperventilation under PEEP.

α2-Adrenergic blockade rescues hypoglossal motor defense against obstructive sleep apnea.

Decreased noradrenergic excitation of hypoglossal motoneurons during sleep causing hypotonia of pharyngeal dilator muscles is a major contributor to the pathogenesis of obstructive sleep apnea (OSA), a widespread disease for which treatment options are limited. Previous OSA drug candidates targeting various excitatory/inhibitory receptors on hypoglossal motoneurons have proved unviable in reactivating these neurons, particularly during rapid-eye-movement (REM) sleep. To identify a viable drug target, we show that the repurposed α2-adrenergic antagonist yohimbine potently reversed the depressant effect of REM sleep on baseline hypoglossal motoneuron activity (a first-line motor defense against OSA) in rats. Remarkably, yohimbine also restored the obstructive apnea-induced long-term facilitation of hypoglossal motoneuron activity (hLTF), a much-neglected form of noradrenergic-dependent neuroplasticity that could provide a second-line motor defense against OSA but was also depressed during REM sleep. Corroborating immunohistologic, optogenetic, and pharmacologic evidence confirmed that yohimbine's beneficial effects on baseline hypoglossal motoneuron activity and hLTF were mediated mainly through activation of pontine A7 and A5 noradrenergic neurons. Our results suggest a 2-tier (impaired first- and second-line motor defense) mechanism of noradrenergic-dependent pathogenesis of OSA and a promising pharmacotherapy for rescuing both these intrinsic defenses against OSA through disinhibition of A7 and A5 neurons by α2-adrenergic blockade.