Optogenetic Stimulation of Locus Ceruleus Neurons Augments Inhibitory Transmission to Parasympathetic Cardiac Vagal Neurons via Activation of Brainstem α1 and β1 Receptors

Abstract

Locus ceruleus (LC) noradrenergic neurons are critical in generating alertness. In addition to inducing cortical arousal, the LC also orchestrates changes in accompanying autonomic system function that compliments increased attention, such as during stress, excitation, and/or exposure to averse or novel stimuli. Although the association between arousal and increased heart rate is well accepted, the neurobiological link between the LC and parasympathetic neurons that control heart rate has not been identified. In this study, we test directly whether activation of noradrenergic neurons in the LC influences brainstem parasympathetic cardiac vagal neurons (CVNs). CVNs were identified in transgenic mice that express channel-rhodopsin-2 (ChR2) in LC tyrosine hydroxylase neurons. Photoactivation evoked a rapid depolarization, increased firing, and excitatory inward currents in ChR2-expressing neurons in the LC. Photostimulation of LC neurons did not alter excitatory currents, but increased inhibitory neurotransmission to CVNs. Optogenetic activation of LC neurons increased the frequency of isolated glycinergic IPSCs by 27 Ϯ 8% (p ϭ 0.003, n ϭ 26) and augmented GABAergic IPSCs in CVNs by 21 Ϯ 5% (p ϭ 0.001, n ϭ 26). Inhibiting ␣1, but not ␣2, receptors blocked the evoked responses. Inhibiting ␤1 receptors prevented the increase in glycinergic, but not GABAergic, IPSCs in CVNs. This study demonstrates LC noradrenergic neurons inhibit the brainstem CVNs that generate parasympathetic activity to the heart. This inhibition of CVNs would increase heart rate and risks associated with tachycardia. The receptors activated within this pathway, ␣1 and/or ␤1 receptors, are targets for clinically prescribed antagonists that promote slower, cardioprotective heart rates during heightened vigilant states.

Asphyxia-activated corticocardiac signaling accelerates onset of cardiac arrest

“…The efferent homeostatic control of cardiac physiology is mediated by the sympathetic and parasympathetic nervous systems in the brainstem and the hypothalamus. Stimulation of locus coeruleus noradrenergic neurons leads to activation of GABAergic inhibition of parasympathetic cardiac vagal neurons via the activation of brainstem adrenergic receptors (14). In our studies, extracellular release of GABA and norepinephrine increased more than 20-fold within the first minute of asphyxia in both frontal and occipital lobes.…”

“…Stimulation of locus coeruleus neurons, the site of norepinephrine synthesis critical in generating alertness, leads to activation of GABAergic neurotransmission and inhibition of parasympathetic cardiac vagal neurons via the activation of brainstem adrenergic receptors (14). Overexpression of a serotonin receptor in raphe nuclei results in sporadic autonomic crises including bradycardia (15).…”

Neurotransmission to parasympathetic cardiac vagal neurons in the brain stem is altered with left ventricular hypertrophy-induced heart failure

“…The second major source of inhibitory activity to CVNs originates in the locus coeruleus, a nucleus involved in inducing cortical arousal and orchestrating changes in accompanying autonomic system function that compliments increased attention, such as during stress, excitation, and/or exposure to averse or novel stimuli. Locus coeruleus noradrenergic neurons depress the activity of cardioinhibitory parasympathetic cardiac vagal neurons by polysynaptic activation of inhibitory neurotransmission within this brain stem autonomic and attentiveness circuitry (38). This network interaction is dependent on activation of ␣ 1 -receptors that mediate increases in both GABAergic and glycinergic neurotransmission, whereas ␤ 1 -receptor activation increases glycinergic, but not GABAergic, neurotransmission to CVNs upon locus coeruleus photoactivation (38).…”

“…Locus coeruleus noradrenergic neurons depress the activity of cardioinhibitory parasympathetic cardiac vagal neurons by polysynaptic activation of inhibitory neurotransmission within this brain stem autonomic and attentiveness circuitry (38). This network interaction is dependent on activation of ␣ 1 -receptors that mediate increases in both GABAergic and glycinergic neurotransmission, whereas ␤ 1 -receptor activation increases glycinergic, but not GABAergic, neurotransmission to CVNs upon locus coeruleus photoactivation (38).…”

Synthetic biology of cell signaling

“…Work by Darrow et al (2015) focused on ChR2 application in auditory neuron stimulation within mice resulting in a display of feasibility in vivo though further work is needed to increase channel kinetics to levels akin to that of auditory signals. Wang et al (2014) used transgenic mice expressing ChR2 in locus ceruleus neurons to study the stimulation of noradrenergic neurons on the locus ceruleus and the way by targets ChR2 in those neurons. Optogenetic tools are also being developed to treat retinitis pigmentosa, a degenerative vision defect, via overexpression of the receptor in key cell types in the retina to restore their lightsensing properties (Busskamp et al 2012).…”