Home > Conscious > Chapter 7 > 7.5. Alpha Waves and HCN Channels



Figure 7-8a. The thalamic nuclei. The lateral geniculate nucleus may regulate consciousness by modulating oscillation frequencies between the alpha band and slower theta and delta bands via HCN channels. [Source: Wikipedia]

Alpha rhythms in the posterior regions (occipital, temporal and parietal lobes) may originate from the thalamus (Schreckenberger et al., 2004), specifically the lateral geniculate nucleus (LGN) (Hughes et al., 2004; Figure 5-7) and pulvinar (Saalmann et al., 2012). In the ascending arousal system, the pedunculopontine tegmental nucleus (PPN or PPT) projects to the thalamus, including LGN and pulvinar (Strumpf et al., 2016). During relaxed wakefulness, the EEG exhibits prominent alpha rhythms, but in early sleep the alpha power decreases, especially in the posterior regions. By contrast, the theta rhythms increase during early sleep and the delta band (1 - 4 Hz) emerges in deeper sleep. Incidentally, the LGN neurons also oscillate at the alpha band during wakefulness and decelerate to theta frequencies in early sleep (Hughes et al., 2004). According to the Alpha hypothesis, consciousness arises from globally synchronized α oscillations. Therefore, LGN may regulate consciousness by shifting oscillation frequencies between the alpha band and slower theta and delta bands.

LGN expresses abundant HCN channels (Kanyshkova et al., 2009), which play a crucial role in the modulation of intrinsic firing frequencies (Lüthi and McCormick, 1998). The full name of HCN channels is "hyperpolarization-activated cyclic nucleotide-gated channels". As the name implies, they are regulated by cyclic adenosine monophosphate (cAMP). Increased cAMP concentration will facilitate channel opening. When the HCN channel is open, Na+ ions will flow inward, resulting in depolarization (Biel et al., 2009). Normally, depolarization should increase neuronal excitability, but in many cases, the opening of HCN channels was found to reduce excitability. This puzzling observation has now been resolved. It turns out that the depolarization induced by HCN channels can open M-type potassium channels, which have inhibitory effects (George et al., 2009). As a result, before the membrane potential depolarized by HCN channels reaches the threshold, it could be hyperpolarized by the M-type potassium channels. Consequently, the opening of HCN channels attenuates excitability, unless the threshold is low.

In the LGN, the neurons that oscillate at the α band have a high threshold (Lorincz et al., 2009). Hence, the opening of HCN channels should have inhibitory effects on neuronal firing. A number of neurotransmitters can regulate HCN channels through cAMP, such as the acetylcholine (ACh) discussed in Section 5.4. ACh has five mAChRs, designated as M1-M5. Activation of M2 or M4 reduces cAMP concentration (Foster et al., 2014) (Figure 7-8). ACh may act on M2 or M4 to attenuate the cAMP production and HCN opening, thereby increasing excitability. Furthermore, HCN channels also modulate firing frequencies. Depending on unknown factors, the opening of HCN channels may increase or decrease spiking rates (Deng et al., 2015; Chen et al., 2015).

In the LGN, it seems that HCN activation may reduce spiking rates. Therefore, at deep sleep, with reduced synaptic inputs, the LGN neurons may hyperpolarize to activate HCN channels, which then interact with the low threshold (T type) Ca2+ channels to produce the delta oscillation (Lüthi and McCormick, 1998). During arousal, the ACh released from PPN may suppress HCN currents, resulting in neuronal firing at higher frequencies, i.e, the α band.


Figure 7-8. (A) Activation of dopamine's D1 receptors stimulates the conversion from ATP to cAMP by adenylyl cyclase (AC), thus increasing cAMP production. (B) Activation of acetylcholine's M2 or M4 receptors inhibits AC activity, leading to the reduction of cAMP. [Adapted from: Wikipedia]

While ACh is crucial for the α wave originating from the thalamus, orexin may play important roles in the α wave originating from anterior cingulate cortex (ACC). Orexin neurons in the lateral hypothalamus project to the medial prefrontal cortex, including ACC (Jin et al., 2016). The released orexin can act on its OX2 receptor to inhibit cAMP production (Urbańska et al., 2012), and suppress HCN currents (Li et al., 2010).

Another important HCN regulator is dopamine, through its D1 receptor. Activation of D1 increases cAMP production (Figure 7-8), consistent with the finding that infusion of D1 agonist into medial frontal cortex attenuates α activity (Parker et al., 2015). The α wave plays a key role in attention (Klimesch, 2012). This may explain why D1 is implicated in attention deficit/hyperactivity disorder (ADHD) (Misener et al., 2004) and schizophrenia (Abi-Dargham et al., 2012). D1 also plays an important role in slow wave sleep, possibly because the slow wave sleep is facilitated by "early firing cells" that oscillate at the α frequency (see next section).