Tag: sleep

Essay 29: Sleep and Basal Ganglia

On March 29, 2024

The original impetus for this sleep essay was the idea that the basal ganglia could best be understood as a sleep and wake circuit [Kazmierczak and Nicola 2022]. After reviewing the rest of the brainstem sleep circuitry, it’s time to tackle the original problem.

Snr as a sleep/wake gate

Snr (substantia nigra pars reticulata) is the output node of the basal ganglia. It’s a set of GABA neurons that tonically suppress the majority of all brainstem motor areas including MLR (midbrain locomotor region), OT (optic tectum), and R.rs (hindbrain reticulospinal motor command) with corollary discharge to the thalamus. Snr can inhibit initiation of eating and motion [Rossi et al 2016], but don’t disrupt ongoing actions [Liu et al 2018]. Disruption of Snr can cause hyperactivity and insomnia [Geraschenko et al 2006]. The caudal Snr derives from hindbrain r1 (rhombomere r1 near the midbrain-hindbrain boundary) [Achim et al 2012], [Lahti et al 2015], [Partanen and Achim 2022], suggesting it may be evolutionarily old, possibly older than other basal ganglia regions.

*Sleep as gating motive from action or sleep from action. Wake as disinhibiting sleep. Snr (substantia nigra pars reticulata).*

As described in part 1 this essay, sleep suppresses senses, motivation and action. To implement this suppression, sleep could disconnect senses and motivation neurons from action neurons. In the above diagram, the gate is conceptual. The circuit could also inhibit the sense or action nodes directly instead of requiring specific gating neurons. This gating architecture has the advantage of simplicity because the sleep circuit can be localized in the gate, while the senses and actions can be mostly free of sleep circuitry.

As a preview, sleep neurotransmitters and peptides in BG (basal ganglia) include AD (adenosine), enk (enkephalin), MOR (μ-opioid receptor), and wake neurotransmitters include DA (dopamine), tac1 (tachykinin 1 aka neurokinin 1 aka substance P), dyn (dynorphin), and DOR (δ-opioid receptor).

If the vertebrate brain follows this architecture, Snr is well-placed to control that gate. Snr.m (medial Snr) projections have many collaterals to distinct motor areas and suppressing the wake-promoting areas covered earlier in this essay, which suggests widespread suppression as opposed to fine-grained control.

Snr.m gad2 connectivity. 60% of Snr.m inputs are from motor, motivation and wake areas. H.l (lateral habenula), H.stn (subthalamic nucleus), H.zi (zona incerta), M.pag (periaqueductal gray), OT.m (medial optic tectum), P.ge (external global pallidus), Ppt (pedunculopontine nucleus), R.rs (reticulospinal motor command), S.d (dorsal striatum), Snr.m (medial substantia nigra pars reticulata).

As the above diagram illustrates, despite its description as basal ganglia output, 60% of the gad2 (genetic marker), Snr.m inputs are outside of the basal ganglia, particularly from the midbrain (30%) and hypothalamus (10%) [Liu et al 2020]. Snr.m has two independent neuron types marked by gad2 and pv (parvalbumin), which are topographically organized with gad2 in Snr.m and pv in Snr.l (lateral Snr). While Snr.l.pv seems to be strictly motor related, Snr.m.gad2 are sleep related [Liu et al 2020]. However, [Lai et al 2021] reports Snr.l as sleep related.

*Functional sleep and action requirements. Any ongoing action should suppress sleep, and sleep should suppress all actions.*

Snr’s widespread motor and motivation connectivity suggests a possible primitive role in sleep. Sleep needs to suppress all actions, but any ongoing action needs to suppress sleep, because an animal shouldn’t fall asleep while eating or moving. It seems plausible that a primitive proto-vertebrate could have used Snr for sleep regulation without needing the rest of the basal ganglia.

Because astrocytes can integrate inputs spatially and temporally and are associated with sleep, it’s plausible that Snr astrocyte would be involved in this circuit. Interestingly Snr astrocytes are sensitive to dopamine and become hyperactive in the absence of dopamine [Bosson et al 2015] and are sensitive to glutamate from H.stn [Barat et al 2015].

Dopamine D2.i sleep / wake circuit

Although the independent Snr circuit is a functional sleep / wake gating circuit, it tonically inhibits the sense to action circuit, adding noise. An improvement to the circuit enables the gate when a signal is available, using the striatum to selectively open the gate. This circuit uses dopamine to open and close the gate. High dopamine is a wake signal and low dopamine is a sleep signal.

In the above diagram, Snr and S.d2 (D2.i associated striatum projection neurons) are sleep-promoting regions and S.d1 (D1.s associated striatum projection neurons) is a wake-promoting region. D2.i (inhibitory Gi-protein dopamine receptor) disconnects inputs, as opposed to inhibiting a neuron directly. When DA is available, S.d2 is disconnected, and S.d1 inhibits Snr, opening the gate. When DA is low, S.d2 is active, which inhibits S.d1, disinhibiting Snr, closing the gate and producing sleep. The D2i between S.d2 and S.d1 is from [Dobbs et al 2016].

The idea of the circuit is that the sense signal disinhibits itself during wake, but sleep prevents sense from disinhibiting itself. The minimal system only requires D2i circuits [Oishi et al 2017]. Wake enables the gate, and sleep disables the gate. Although I’ll cover D1s later, D2i is more fundamental because disabling D1s can be reversed by sufficient arousal, but disabling D2i can’t [Kazmierczak and Nicola 2022].

Note the diagram is somewhat incorrect, because direct S.d2 to S.d1 connection is weak [Tepper 2008]. Instead, S.d2 GABA inhibits S.d1 input at distal dendrites as opposed to inhibiting the neuron soma itself.

P.v ventral pallidum and S.core

While S.d2 neurons in model above suppresses motor for sleep, S.d2 in S.core (ventral striatum core aka nucleus accumbens) can produce sleep pressure by inhibiting the wake supporting P.v (ventral pallidum) [Oishi et al 2017]. P.v is a tonically active, wake-promoting nucleus, primarily inhibiting sleep areas or disinhibiting wake areas.

Sleep/wake control adding P.v as a tonic wake producing node. DA (dopamine), D2i (inhibitory Gi-coupled dopamine receptor), H.l (lateral hypothalamus), Hb.l (lateral habenula), M.pag (periaqueductal gray), Ppt (pedunculopontine nucleus – ACh), P.v (ventral pallidum), S.d1 (D1-associated striatum projection neuron), S.d2 (D2-associated striatum projection neuron), Snr (substantia nigra pars reticulata), V.mr (median raphe – serotonin), Vta (ventral tegmental area – dopamine).

P.v fill a similar wake-promoting role as S.d1, but unlike S.d1 it’s tonically active and affects the motivation loop of H.l, Hb.l, and Vta instead of gating sense from action. Where P.v supports general wake, S.d1 supports specific wake for an action. Like the previous basal ganglia sub-circuit, this sub-circuit only requires D2i receptors.

P.v promotes wake by inhibiting Hb.l sleep-producing system [Li et al 2023]. It also promotes wake through Vta by disinhibiting GABA interneurons [Li et al 2021]. (It could also disinhibit H.l orexin but I don’t have a reference).

In the model above, stimulating S.d2 inhibits wake-producing P.v, which disinhibits sleep-producing areas like Hb.l and inhibits wake-producing areas like H.l and Vta through GABA interneurons. Conversely, stimulating the D2i receptor by high DA inhibits S.d2, which disinhibits Pv, allowing it so promote wake. Disabling the D2i receptor activates S.d2, promoting sleep even with high dopamine [Qu et al 2010].

Note that S.d1 also connects to P.v and can produce wake [Zhang et al 2023]. P.v has multiple sub-populations with opposing functions. For example, it has both a hedonic hot spot for liked food and a cold spot for disliked food [Castro et al 2015]. For the sake of simplicity the diagram only shows a sleep-promoting path through S.d2, but there may be a wake-promoting path through S.d2 to an opposing P.v subpopulation.

D1s – stimulator dopamine receptors

Although using only D2i as a mode switch to the sleep path is functional, it can be improved by also enhancing the wake path with D1s (stimulatory Gs-coupled dopamine receptor).

D1s as enhancing the basal ganglia wake path. DA (dopamine), D1s (stimulatory Gs-coupled dopamine receptor), D2i (inhibitory Gi-coupled dopamine receptor), S.d1 (D1-associated striatum projection neuron), S.d2 (D2-associated striatum projection neuron), Snc (substantia nigra pars compacta – dopamine), Snr (substantia nigra pars reticulata).

The improved circuit works exactly like the D2i-only circuit but enhances the wake path when DA is available. Dopamine boosts both the signals from the sense to S.d1 and the signal from S.d1 to Snr [Salvatore 2024], [Kliem 2007], [Rice and Patel 2015]. When dopamine is available, it boots the sense to S.d1 signal with D1s, which more strongly disinhibits the gate by inhibiting Snr, which is also boosted by D1s.

The D1s in Snr and dopamine may be more important for motor suppression than dopamine in the striatum [Salvatore 2024]. In Parkinson’s disease and also normal aging, bradykinesia (slow movement) correlates with dopamine in Snr more closely than dopamine in the striatum. Motor symptoms in Parkinson’s disease don’t generally occur until striatal dopamine is reduced by 80%, but the effect on Snr is more immediate with only a small drop of dopamine.

Note that the Snc (substantia nigra pars compacta) to Snr dopamine comes from somatodendritic broadcast, not from an axon synapse. Snc dendrites in Snr produce dopamine to enhance the S.d1 to Snr connection.

Although the previous diagrams show the basic logic of the circuit, the basal ganglia use adenosine as a sleep-producing neurotransmitter, competing with dopamine.

Adenosine in striatum sleep

Adenosine is a product of the energy molecule ATP and is produced by neural activity, and also as a astrocyte transmission molecule. Although adenosine can accumulate in a circadian manner, particularly in P.bf (basal forebrain), it’s typically a shorter term sleep pressure. Caffeine is wake promoting by suppressing adenosine receptors.

Dopamine and adenosine are paired, opposing neurotransmitters in the basal ganglia: dopamine produces wake and adenosine promotes sleep. As an opposing signal to dopamine, the adenosine circuit is a flip version of the dopamine circuit.

Parallel adenosine sleep circuit in the basal ganglia. AD (adenosine), A1i (inhibitory Gi-coupled adenosine receptor), A2a.s (stimulatory Gs-coupled adenosine receptor), S.d1 (D1-associated striatum projection neuron), S.d2 (D2-associated striatum projection neuron), Snr (substantia nigra pars reticulata).

When adenosine is active in the above circuit, it cuts off S.d1 input and output and enhances S.d2’s suppression of S.d1. With S.d2 fully suppressed, Snr is free to suppress the gate and therefore suppress sleeping action.

Since adenosine is low in the morning, sleep is suppressed, which is enhanced by high ultradian morning dopamine. If A2a.s (stimulating Gs-coupled adenosine receptor) are stimulated in the striatum, the animal is more likely to sleep even in the morning [Yuan et al 2017], specifically in S.core not S.sh (ventral striatum shell aka nucleus accumbens) [Oishi et al 2017].

The dual signal system allows for interesting combinations at the boundary between sleep and wake. If adenosine is high with sleep pressing, then a large amount of dopamine motivation is required to continue wake. In fact, sleep deprivation down regulates D2i receptors, moving from the neuron membrane to the interior [Volkow et al 2012], which tips the balance toward sleep by diminishing the D2i-mediated wake signal. Caffeine inhibits both the A1i (inhibitory Gi-coupled adenosine receptor) and A2a.s receptors, tipping the balance to dopamine wake.

Dorsal striatum indirect path

The full S.d (dorsal striatum) path includes an indirect path, but this path may be more related to pure motor control, not sleep. As mentioned above, Snr divides into two populations Snr.l with pv neurons and Snr.m with gad2 neurons, and the Snr.l neurons are motor related, not sleep related [Liu et al 2020]. Similarly, the indirect path including P.ge (external globus pallidus) and H.stn (sub thalamic nucleus) may not be sleep related. Nevertheless, I’ll include it here, in case it is sleep related.

S.d model with indirect path included. DA (dopamine), D1s (stimulatory Gs-coupled dopamine receptor), D2i (inhibitory Gi-coupled dopamine receptor), H.stn (subthalamic nucleus), P.ge (external globus pallidus), S.d1 (D1-associated striatum projection neuron), S.d2 (D2-associated striatum projection neuron), Snc (substantia nigra pars compacta), Snr (substantia nigra pars reticulata).

Note that both P.ge and H.stn are tonically active, and they oscillate together at beta frequencies (roughly 10hz), which suppresses action. An excessive beta oscillation in this P.ge and H.stn circuit is a Parkinson’s disease symptom that suppresses motion and can also interrupt sleep. D2i receptors in H.stn mean that dopamine suppresses H.stn output [Shen et al 2012].

One significant experiment showed that lesioning P.ge increased wake by 40%, particularly eliminating normal circadian night-time sleep, replacing it with day-time like napping [Qiu et al 2016], which would suggest that P.ge is a major sleep center like Po.vl (ventrolateral preoptic area) [Vetrivelan et al 2010]. Note that this analysis would suggest that my basal ganglia sleep diagram is entirely wrong, because P.ge as a sleep center is basically incompatible with its position in the circuit.

P.ge – external globus pallidus

Lesioning P.ge increases wake by 40%, almost entirely eliminating circadian sleep [Qiu et al 2016]. However, this produces hyperactive chewing, weight loss, abnormal motor behavior and death in 3-4 weeks [Vetrivelan et al 2010]. Other manipulations of P.ge produce hyperactivity, abnormal movement, and odd stereotypical behavior [Gittis et al 2014]. So, it’s unclear to me that P.ge is a sleep center, but removing P.ge produces excessive action which then suppresses sleep.

In addition, P.ge is a heterogenous area with at least three major cell types with distinct projections and roles. Arkypallidal neurons project strongly and exclusively to the striatum. Lhx6 neurons project strongly to Snc and to some areas of H.stn, excluding the center. Pv neurons project to all of H.stn and also to T.pf (parafascical thalamus) [Gittis et al 2014].

Distinct projection neuron types of P.ge. H.stn (subthalamic nucleus), P.ge (external globus pallidus), Snc (substantia nigra pars compacta), Snr (substantia nigra pars reticulata), Spn (striatal projection neuron), Spv (pv marked striatum interneuron), T.pf (parafascicular thalamus).

With three projection types, it’s possible that they have entirely separate functions. For example, the lhx6 projections are functionally compatible with a sleep promoting role, and lhx6 neurons in H.zi (zona incerta) are sleep promoting [Liu et al 2017].

References

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Essay 29: sleep circuits

By ferg

On March 27, 2024

In Uncategorized

The first two parts of this essay were a general overview of the necessity of sleep and some of the properties. Here I’m going over some of the brainstem circuits that control sleep.

Wake ignition

Waking requires intrinsic motivation because sleeping places the animal away from distraction, to an extreme in hibernation. A short nap, as is more typical in the waking period, needs to end without needing external stimulus or an internal one like hunger. What’s needed is an internal ignition source to drive wake and motivation.

In rodents, if the area around R.pb (parabrachial nucleus in r1) is lesioned, the animal remains in a coma [Fuller et al 2011]. For humans, a study of coma showed a pattern of the same area as consistently being destroyed [Grady et al 2022]. However, the exact cells aren’t known, and other studies that lesion R.pb for conditioned taste studies don’t produce coma. Still, this site seems a likely ignition area.

Possible wake ignition subcircuit. R.pb is the main ignition source and wakes motivational areas like H.l. H.l (lateral hypothalamus), N5 (trigeminal nerve), N10 (vagus nerve), Nsp (spinal cord), R.pb (parabrachial nucleus), R.pz (parafacial zone).

The above diagram shows a possible wake ignition circuit. The area around R.pb is the main wake ignition node. R.pb produces wake by stimulating motivational areas like H.l (and others).

It’s not known if the R.pb area is self-igniting or if astrocytes in the area are critical, or if it uses peripheral wake signals such as N5 (trigeminal nerve), N10 (vagus nerve), or N.sp (spinal cord or other periphery) [Grady et al 2022]. In the fruit fly Drosophila specialized peripheral leg neurons can promote daytime sleep [Jones et al 2023]. These specialized neurons are distinct from sensor or motor neurons. In addition peripheral neurons from Drosophila PPM area are wake promoting [Satterfield et al 2022]. So, it seems plausible that peripheral nerves such as N5, N10, or N.sp could have similar wake-producing neurons, although this is entirely speculative.

If R.pb is a wake-ignition system, then sleep needs to suppress it, whether by internal clock regulation, or external suppression. In the hindbrain, R.pz (parafacial zone near N7 and r5 / r6) suppresses R.pb to create sleep [Anaclet et al 2014]. Disabling R.pz decreases NREM sleep by 30% [Erikson et al 2019].

Hindbrain (rhombomere) sleep

R.rs (reticulospinal) neurons in the caudal hindbrain (medulla, r6-r8) have both wake and sleep effects. Because R.rs are motor control neurons, they need to suppress sleep while they’re active, but the same area also contains sleep promoting areas. So, when experimenters stimulate the area, the animal remains awake, but immediately following the end of stimulation the animal sleeps, because the sleep-inhibition is removed. [Teng et al 2022]. These R.rs neurons (ventrolateral medulla) send collaterals to Po.vl (ventrolateral preoptic area), which is a forebrain sleep / wake area.

Midbrain sleep

A specific nucleus near N3 (oculomotor nerve) and associated motor areas (Edinger-Westphal) is a sleep promoting area. Stimulating it increases NREM [Zhang et al 2019]. (I’m just noting this for reference. I don’t understand how this area connects with other sleep areas.)

Ventral preoptic area

Although wake-maintaining areas are widely distributed, and much of sleep-circuitry is postponing sleep for ongoing actions, sleep-promoting area are more rare. One sleep-promoting area is Po.vl (ventrolateral preoptic area) and Po.mn (median preoptic area), which are adjacent area. Po.vl is inhibitory GABA and inhibits neurotransmitter wake areas like V.lc (locus coeruleous – norepinephrine), Vta (dopamine), V.dr (serotonin), M.pag.v (which is V.dr but refers to a dopamine area), and Ppt (pedunculopontine nucleus – acetylcholine) and P.ldt (laterodorsal tegmental nucleus – also acetylcholine).

In the diagram above, Po.vl promotes sleep by inhibiting wake-promoting areas, here represented by H.l and V, where V includes the neurotransmitter wake areas. This Po.vl function is one pole of the flip-flop analogy [Saper et al 2001], driving sleep transitions faster and supporting continuous sleep, avoiding fragmentation.

Lateral Hypothalamus

H.l is a sleep wake hub [Gazea 2021] with both wake-promoting peptide orexin, and GABA neurons promoting wake. The orexin peptide is wake-related, because if it’s missing, people and animals develop narcolepsy and cataplexy. H.l orexin neurons project to other wake-promoting areas like V.lc, Ppt, V.dr, Vta, and is believed to sustain wakefulness.

Stimulating orexin neurons does produce wake after sleep, but only after 10-20 seconds, so these aren’t directly wake producing, but more wake facilitating. In contrast, V.lc norepinephrine neurons produce wake in 2 seconds [Yamaguchi et al 2018].

In addition, a study suggested that human orexin is low at dawn, a time when people are active and twos to peak at dusk [Mogavero et al 2023]. So orexin’s role is something more complicated than simply a wake-promoting peptide. (Note: this study seemed somewhat unreliable. I’d like to see a more detailed orexin over time study for rodents, where measurements can be more precise).

Other sleep and wake neurons exist in H.l without the orexin [Heiss et al 2018]. For example, some Vta GABA neurons that express SST (somatostatin) store sleep requirements for up to 5 hours, and signal the extra sleep need to H.l [Yu et al 2019].

*Lateral hypothalamus and value neurotransmitters as a wake hub. Hb (habenula), H.l (lateral hypothalamus), pineal (pineal gland), R.pb (parabrachial nucleus), V (wake-promoting neuropeptides)*

The above diagram shows two complementary roles for H.l. First, H.l can suppress Hb.l circadian sleep-promoting path with H.l orexin projections to Hb that inhibit anaesthesia [Zhou et al 2023] and promote aggressive arousal [Flanigan et al 2020].

The positive feedback loop from H.l to Hb (habenula) to V and back to H.l sustains wake. The gain for positive feedback could vary in circadian cycles. A high gain in the morning could produce full wake even with little activity. A low gain at night would make it harder to sustain wake.

Misc notes: Sleep preparation is a distinct, complicated pre-sleep behavior. One trigger seems to be from F.pl (pre limbic frontal cortex) SST neurons to H.l [Tossell et al 2023]. Astrocytes also seem to be involved with H.l wake, are active when waking and promoting wakefulness [Cai et al 2022]. H.pv is also sleep promoting and if it’s knocked out, significant daytime sleep increases, particularly in the morning [Chen et al 2021]. In contrast, the posterior hypothalamus has astrocytes that increase sleep at night [Pelluru et al 2016].

Vta sleep/wake glutamate and GABA

For the moment, let’s ignore Vta (ventral tegmental area) dopamine. Vta includes glutamate and GABA neurons that derive from r1 (hindbrain rhombomere 1) [Lahti et al 2016] that enhance wake with glutamate [Yu et al 2019] and enhance sleep with GABA [Chowdury et al 2019]. The tail of Vta, RMTg (rostromedial tegmental are in r2 / r3) is essential for NREM sleep [Yang et al 2018].

Vta glutamate, GABA, and DA all control sleep using H.l and S.msh (medial shell of the ventral stratum aka nucleus accumbens). As noted above, H.l is a coordinator of sleep and wake with not only orexin but also GABA and glutamate. Inhibiting Vta GABA bypasses sleep homeostasis, producing a mania state during circadian wake times [Yu et al 2021], [Yu et al 2022].

Vta glutamate stimulation promotes continuous wake independent of DA [Yu et al 2019], via projections to H.l, S.sh, and P.v (ventral pallidum), particularly the NOS1 cells.

Vta.g (GABA neurons of Vta) stimulation encourages NREM sleep. If Vta.g are inhibited, the animal remains 100% awake for hours, during the normal wake period, not the normal sleep period [Yu et al 2022]. The Hb.l projection to Vta.g is required for the anesthetic propofol to work [Gelegen et al 2018].

Interestingly, a specific SST (somatostatin) subset of Vta GABA retains a future sleep requirement from social defeat, where social defeat produces extra sleep. When the rodent loses a conflict, these Vta SST neurons have elevated calcium for up to five hours, and then the animal sleeps, these neurons fire to H.l, extending sleep duration [Yu et al 2019]. Speculating here, this multi-hour memory suggests a possible astrocyte involvement.

Returning the dopamine. Vta dopamine produces wake, while Vta dopamine inhibition produces sleep with nesting behavior [Eban-Rothschild et al 2016], as opposed to immediate collapse like narcolepsy. Low dopamine in a behaviorist experiment produces long decays, difficulty in locomotion and sleepiness [Nicola 2007]. However, other studies argue that dopamine itself is not wake promoting [Takata et al 2018].

Habenula

As mentioned in a previous post, Hb (habenula) is a sleep-promoting area as a motor-inhibiting area driven by the pineal gland and extending melatonin’s role [Hikosaka 2012]. This sleep promoting area is in a positive feedback loop with the wake-promoting neurotransmitters and peptides.

This above diagram is a different perspective on the prior H.l diagram, where I’ve merged H.l into V and made the motor and motivation suppression explicit. Here the wake-promoting neurotransmitters gate motivation and motor, extending the role of melatonin, which suppresses action.

Active actions promote wake and suppress sleep, like the R.rs wake efferent copies [Teng et al 2022], by stimulating the value neurons. In turn, the value neurons suppress the habenula such as Vta to Hb.l [Webster et al 2021] and serotonin inhibiting Hb.l [Tchenio 2016], H.l orexin and GABA also inhibit Hb.l [Flanigan 2020], [Gazea 2021]. As mentioned above, these positive feedback loops sustain wake despite sleep pressure.

Summary circuit

Putting these components of the sleep/wake circuit together produces something like the following, where I’ve emphasized the habenula to show how that subsystem fit into the whole circuit.

Sleep/wake circuit emphasizing the pineal, melatonin habenula path. Hb (habenula), H.l (lateral hypothalamus), S/P (basal ganglia), Po.v (ventrolateral and median preoptic areas), R.pb (parabrachial nucleus), R.pz (parafacial zone).

As before, the circadian sleep drive from the pineal gland drives the habenula, which inhibits wake neurotransmitters, which inhibits motivation and action using the basal ganglia as a gate. Ongoing action sustains wake against habenula-driven sleep pressure.

*Sleep/wake summary circuit. Hb (habenula), H.l (lateral hypothalamus), S/P (basal ganglia), Po.vl (ventrolateral preoptic area), R.pb (parabrachial nucleus), R.pz (parafacial zone).*

The full diagram includes the wake-ignition circuit from R.pb, the sleep-sustain circuit in Po.v (Po.vl and Po.mn), and the wake-sustain circuit in H.l and V. As a reminder, this model is highly simplified and really only serves as a skeleton to organize the various brainstem sleep systems.

Cortical slow wave sleep

Although I’m trying to avoid the cortex as long as possible, studies use cortical slow waves as a sleep marker, so it’s inescapable. Cortical slow waves are globally synchronized neuron firing between around 0.5Hz to 4Hz. The slow wave firing has no information content, but the oscillations may help clear the cortex of metabolic toxins.

During wake, neurons expend to fill the intercellular space because of the neuron’s ion gradients. Filling the intercellular space means the CSF (cerebral-spinal fluid) can’t clear metabolic toxins [Xie et al 2013]. Slow wave sleep shrinks the neurons allowing fluid to fill the intercellular space, and the oscillations may even help with fluid circulation [Fultz et al 2019].

Cortical sleep appears strongly coupled to astrocytes. Astrocyte calcium precedes slow waves in the cortex [Poskanzer and Yuste 2016]. Astrocytes may even organized SWS waves across the cortex, using electrical gap junctions to connect to astrocyte neighbors [Vaidyanathan et al 2021].

*Wake signals driving cortical wake. C (cortex), H.l (lateral hypothalamus), Hb (habenula), P.bf (basal forebrain), V (wake neuropeptides)*

The above diagram shows a simplified cortical wake circuit, although the cortex is also affected by wake neurotransmitters norepinephrine, serotonin and dopamine. In this model the cortex is mostly an appendage of the brainstem sleep circuit, waking when the brainstem wakes.

P.bf (basal forebrain) is a set of GABA and ACh nuclei that activate the cortex, hippocampus, and olfactory bulb. Although P.bf is identified by its ACh neurons, the GABA projections seem to be more important for wake.

Notes: Local cortical sleep pressure is signaled with GABA [Alfonsa et al 2023]. Parts of the cortex can sleep independently [Krueger et al 2013].

Ppt and P.ldt ACh and wake

Although I’ve lumped Ppt (pedunculopontine nucleus) and P.ldt (laterodorsal tegmental nucleus) with the “V” wake promoting areas, they deserve a special mention because of their connection and similarity with P.bf. Ppt and P.ldt are ACh ganglia near the isthmus midbrain-hindbrain boundary. Ppt is part of the MLR, showing the tight connection between locomotion and wake. Ppt feeds into P.bf, the striatum, and other locomotive regions like H.stn.

Interestingly, all Ppt neurons self-generate gamma oscillations through intrinsic channels [Garcia-Rill et al 2015]. So it could be an ignition source of gamma activation in the striatum and cortex.

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Essay 29: Sleep – circadian

By ferg

On March 22, 2024

In Uncategorized

As mentioned in the previous post, sleep is often divided into circadian sleep and homeostatic sleep, although this model is an oversimplification in part because of the metabolic cycles [Borbély et al 2016]. Despite the caveats, I think starting from circadian circuits is a good start.

Also as mentioned previously, circadian cycles may have started as an oxidation-reduction cycle to project from oxygen’s toxicity after the Great Oxidation Event [Edgar et al 2012]. One of the early solutions is melatonin, a powerful natural antioxidant [Tosches et al 2014].

Melatonin

Melatonin exists in almost all animals except sponges. Along with its antioxidant properties, it signals for the zooplankton diel vertical migration, swimming toward the light at dusk and sinking at night [Tosches et al 2014].

In the migrating zooplankton, melatonin triggers ACh (acetylcholine) neurons, which rhythmically spike and these spikes disrupt the cilia, disorganizing them and allowing the plankton to sink.

Reptile and mammal complications

As a complication to understanding the vertebrate circuits, both reptiles and mammals have sleep requirements at odds with aquatic vertebrates. Because land temperatures change more than water temperatures, and reptiles are cold-blooded, their sleep and wake is necessarily strongly tied to temperature as well as the common light/dark connection [Rial et al 2022]. So, sleep and temperature are highly correlated, which makes the Poa (preoptic area) combination of temperature and sleep functions more reasonable than a seemingly random combination.

Mammals have the additional complication of the evolutionary nocturnal bottleneck [Rial et al 2022], meaning the simple heuristic of nighttime melatonin for sleep isn’t sufficient. The pineal melatonin is still at night for nocturnal animals [cite], and the light signaling needs to flip. Although diurnal mammals are no longer nocturnal, their clock circuitry retains the heritage of a nocturnal flip.

As a specific example, all non-mammalian vertebrates use the pineal gland as a circadian oscillator, not H.scn (subthalamic nucleus) [Vatine et al 2011].

Pineal gland and habenula

The pineal gland in the midbrain is the vertebrate’s main source of melatonin. Evolutionarily, the pineal gland is derived from photosensitive cells that directly convert light and dark into melatonin. In non-mammals, the pineal gland is still photosensitive. In the zebrafish, the pineal photoreceptor is still effect and entrains circadian cycles [Vatine et al 2011], and an analogous region in the non-vertebrate chordate Amphioxus provides a similar function, showing the pineal gland’s conserved function in vertebrates [Lacalli 2022].

Hb.m and Hb.l (medial and lateral habenula) derive from the pineal complex, and may have originally been effectors of the pineal gland, serving a nervous function analogous to melatonin [Hikosaka 2010]. Hb.l in particular is well-suited to control neurotransmitters associated with wake, such as dopamine from Vta (ventral tegmental area), serotonin from V.dr and V.mr (dorsal and medial raphe), and norepinephrine from V.lc (locus coeruleus). Note that melatoninAs explored in essay 20, Hb.m is involved in primitive phototaxis and chemotaxis and is well-placed to inhibit those actions during sleep.

*Habenula control of sleep by gating motive from action. Hb (habenula), pineal (pineal gland).*

In the above diagram, a primitive habenula function is to suppress sensation, motivation and action for sleep by suppression wake-supporting neurotransmitters. Although the diagram illustrates the habenula as disconnecting motive from action, it could also disconnect sense from action, as in phototaxis or chemotaxis in Hb.m.

Hb.m includes an internal entrainable circadian clock, unlike Hb.l. The Hb.m clock is necessary for ultradian foraging. The foraging ultradian is around four hours, generally on waking. Both dopamine and NE (norepinephrine) are elevated [Wang et al 2023] and reciprocally the circadian clock is set by dopamine and NE [Salaberry and Mendoza 2022].

Some misc notes: Hb.l is required for some anesthesia (propofol) and stimulating Hb.l strongly induces NREM, and suppresses motor [Gelengen et al 2018]. Hb.l stimulus produces NREM [Goldstein 1983]. Hb.l is more active mid and late day and early night [Aizawa et al 2013] (possibly producing morning ultradian activity). Hb.l manipulation produces wake fragmentation in the wake period and sleep fragmentation in the sleep period via orexin in H.l [Gelengen et al 2018].

Cell clocks

As mentioned in the introduction, the oxidation-reduction protection may have led to the development of cellular clocks. Essentially all cells have circadian cycle in protein expression, including metabolic and detoxification cells in the liver, heart, kidneys and digestion [Dibner et al 2010], even including gut bioflora. The clocks are synchronized by multiple signals, including feeding patterns, but most studied by light.

For example, dopamine is under clock control and is modulated by melatonin [Ashton and Jagannath 2020]. In S.v (ventrial striatum aka nucleus accumbens) dopamine is at a daily low at night. DAT (dopamine transporter), affected by cocaine, is regulated by clock genes [Alsonso et al 2021], possibly under control of astrocytes. Dopamine is particularly tonically high in early morning before eating with an ultradian cycle of about four hours. Two four-ish hour dopamine cycles are known: the FEO (food entrainable oscillator), which produces pre-feeding activity [Dibner et al 2010], and MASCO (methamphetamine-sensitive circadian oscillatory) [Tataroglu et al 2006], which may be the same system.

The retina itself is under circadian control, modulated by dopamine and D2i (inhibitory Gi-coupled dopamine receptor) [Yujinovsky et al 2006], including in frogs [Cahill and Besharse 1991].

And astrocytes in S.v are under circadian cell clock control [Becker-Krail et al 2022]. Astrocytes are well-placed to manage sleep because they have widespread connections to many synapses and are connected to other astrocytes with gap junctions, allowing for integration over time and space and widespread broadcast signaling.

H.scn circadian entrainment

The circadian system has three distinct components that can either work on their own or work together:

Cell clocks
Light / dark photoreceptors or feeding signals and behavior
Entraining the cell clock to the signal (zeitgeber)

If the eye area of the mollusk sea hare is lesioned, circadian entrainment is eliminated, but because of other photoreceptors, the animal still follows light and dark cycles as long as the light changes. The deficit is only exposed when the lesioned mollusks are placed under continual dark [Vorster et al 2014], [Newcomb et al 2014]. Similarly, in zebrafish many cells are photoreceptive without entraining the cellular clocks.

Mammals use H.scn (suprachiasmatic nucleus) to coordinate circadian cellular clocks. The H.scn name is important, but it’s located above the optic crossing (suprachiasmatic) and developmentally the retina develops from the hypothalamus adjacent to H.scn.

Abstract representation of the mammalian brain highlighting the proximity of the retina and H.scn. arc (H.arc – arcuate nucleus), C (cortex), CB (cerebellum), H.l (lateral hypothalamus), ip (R.ip interpeduncular nucleus), mb (H.mb mammillary bodies), MHB (midbrain-hindbrain boundary), P (pallidum), S (striatum), scn (suprachiasmatic nucleus), sum (supramammillary nucleus), Vta (ventral tegmental area), r1 (rhombomere 1), ZLI (zona-limitans intrathalamica)

The diagram above shows the rough location of the retina development area and H.scn, which both develop from the hypothalamus. A primitive eye with only a few photoreceptors would have been part of the hypothalamus, and like the mollusk the photoreceptor would be near the clock entrainment circuit that became H.scn.

The H.scn clock signal is somewhat indirect, with an interim projection to H.scz to H.dm (dorsomedial hypothalamus) and finally to H.l (lateral hypothalamus) for wake and Po.vl (ventrolateral preoptic area) for sleep. H.scn uses dopamine from Vta as part of its synchronization [Grippo et al 2017].

Ultradian DA – morning foraging

The sleep / wake cycle has an additional boost during normal foraging times such as immediately after waking. In the subjective morning (dark for rodents), wake is encouraged, homeostatic sleep is suppressed, and dopamine levels are higher. After the foraging boost ends, but still in the wake period, tonic dopamine levels drop and the animals take more frequent naps. This hut radian boost of about four hours affects learning and behavior as well as modulating drug abuse [Ruby et al 2013].

*Sleep / wake cycle showing morning boost. ZT (zeitgeber time).*

Because this ultradian foraging boots wake and suppresses sleep significantly, studies that stimulate or inhibit sleep and wake can specifically affect the ultradian boost without affecting other sleep / wake periods. So it’s very important to look at the hourly effects because the experimental modulation might reduce the foraging boost specifically, but a summary might show a general sleep increase.

H.scn circadian entrainment uses dopamine. DA from either Vta [Grippo et al 2017], [Tang et al 2022] and/or H.sum (supramammillary nucleus) [Luo et al 2018] can entrain food circadian cycles. Note that since the dopamine “A10” area extends beyond the Vta to include H.sum and M.pag.v on opposite ends of the Vta, these studies may be reporting the same area.

As mentioned above, there are also the food entrained oscillator [Liu et al 2012], [Gallardo et al 2014], [Pendergast and Yamazaki 2019], [Ashton and Jagannath 2020], and the meth-sensitive oscillator [Tataroglu et al 2006], which are also dopamine related and may be part of the same system.

Neurotransmitters and peptides

The inhibitory neurotransmitter GABA is associated with sleep, and many sleep drugs are GABA stimulants. GABA neurons in Snr (substantia nigra pars reticulata), H.zi (zona incerta), Vta, and Po.vl are all associated with sleep. As mentioned above GABA from mitochondria and in Hydra are used as a sleep promoting neurotransmitter.

While GABA is associated with sleep, other major neurotransmitters like NE, DA, 5HT (serotonin), ACh (acetylcholine) and histamine are associated with wake maintenance of the execution of wakefulness. As discussed in the previous post, ongoing actions need to suppress sleep. NE, DA, and 5HT are all maintain wake while the animal is active and drop when the animal is winding down activity to sleep. Cortical wake requires activity in ACh-rich area in Ppt (pedunculopontine nucleus), P.ldt (laterodorsal tegmental nucleus), and P.bf (basal forebrain).

Produced by H.l, orexin (aka hypocretin) appears to be a wake-maintenance peptide since removal of orexin produces narcolepsy. H.l orexin projects to essentially all of the other wake-maintaining neurotransmitters, including NE, DA, 5HT and ACh. Orexin is slow, waking after tens of seconds, while stimulating V.lc NE is around two seconds [Yamaguchi et al 2018]. On counterargument is that orexin can ramp later in the day [Grady et al 2006], [Mogavero et al 2023], which would suggest that it’s not part of the ultradian foraging system, although it’s also highly tied to foraging. (Suggesting I need to read more articles to see if the contradiction has been resolved.)

Although orexin is the most dramatic of H.l wake, H.l also includes wake and sleep producing GABA and glutamate neurons that may be even more important for wake, independent of the orexin function. Unfortunately, H.l is complex enough that the different functions haven’t been fully pulled apart.

Adenosine is a sleep-promoting molecule derived from the energy molecule ATP, and has extensive receptor throughout the brain, notable in the striatum. Because it’s a product of ATP, it measures local neural activity and possibly sleep need. Its measurement of global brain activity for homeostatic sleep seems more questionable, but adenosine does accumulate throughout the wake period in P.bf [Porkka-Heiskanan et al 2000].

Inflammation peptides like IL-1β are also sleep-promoting [Imeri and Opp 2009]. In addition to their inflammation-related sleep, they seem to be part of normal homeostatic sleep signaling. In Drosophila sleep-need astrocytes produce IL-1β as a signaling peptide [Blum et al 2021]. In zebrafish, sleep deprivation correlates with immune signaling [Williams et al 2007].

Next: ignition and maintenance circuits

After this general discussion on sleep wake, the next post will cover some of the specific sleep and wake circuits, particularly those associated with wake ignition, wake maintenance and sleep maintenance.

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Essay 29: sleep – oxidation [1/3]

By ferg

On March 21, 2024

In Uncategorized

Because sleep is a global state that suppresses senses and actions, its control circuitry affects essentially all neural systems. For example, an article on dopamine and S.v (ventral striatum aka nucleus accumbens) suggested that dopamine acts more like a wake signal than an abstract reward signal [Kazmierczak and Nicola 2022]. If that explanation is accurate, then understanding the sleep system is a prerequisite for understanding the whole system.

From the study, low dopamine caused the rodents to either fall asleep normally or collapse in cataplexy, depending on whether D1s (stimulating Gs-coupled dopamine receptor) or D2i (inhibitory Gi-coupled dopamine receptor) were disabled. Many studies omit qualitative behavior like animals falling asleep, reporting only statistical summaries of success or failure.

The Great Oxidation Event

Sleep exists for essentially all animals including primitive animals like hydra and even single celled eukaryotes. Beyond sleep, oxidation-reduction cycles exist even for bacteria. 2.5 billion years ago in the Great Oxidation Event when photosynthesis created the toxin oxygen, most life died except for like that developed defenses against oxidation and ROS (reductive oxygen species). One of these cellular defenses was an oxidation-reduction cycle to spend time repairing oxygen damage. Cellular clocks developed around these primitive, conserved oxidation-reduction cycles [Edgar et al 2012].

Mitochondria in eukaryotes produce additional toxic oxygen ROS. One general sleep theory proposes that mitochondria force sleep on their hosts to allow for repair [Hartman and Kempf 2023]. In essentially all cells the cell clock and the mitochondrial clock are in sync [Scrima et al 2016]. In this model, sleep repairs oxidation damage in a quiet, low energy mode. Mitochondria produce GABA to signal to the host cell for its sleep need [Adams and O’Brien 2023]. GABA is the main inhibitory neurotransmitter, possibly directly inhibiting the containing neuron.

In the cortex a more sophisticated system passes damaged mitochondria from neurons to astrocytes, when then modulate sleep [Haydon 2017]. Astrocytes strong coupling between sleep and neural activity is important in many brain areas. In particular, astrocytes emit sleep transmitters adenosine and GABA, and connect to neighboring astrocytes with gap junctions to integrate sleep pressure spatially and temporally. Astrocyte can emit adenosine and GABA, both sleep signals. So, sleep can’t be treated as a straight neural circuit without considering the actions of astrocytes.

Beyond the brain, metabolic cells such as the liver and even gut microflora have circadian cycles and these metabolic cycles work best when synchronized with sleep [Borbély et al 2016].

Sleep basics

While sleep in mammals can be detected by slow waves in the cortex, a more general criteria is necessary to cover insects like Drosophila and worms like C. elegans. The following properties are generally used to identify sleep:

Behavioral quiescence
Sensory inhibition
Sleep position

From an implementation perspective, sleep has a global coordination problem because all processes need to sleep simultaneously. In contrast, waking processes such as foraging only needs to activate task-relevant areas, and other areas can rest outside of a general sleep state. Columns in the cortex, for example, can fall into a slow wave state while the animal is awake. Although no lesion of the brain produces a wake-only state [Krueger et al 2013], so there is no single sleep center, sleep requires global coordination.

Inhibit the link from stimulus to response
Inhibit intrinsic motivation
Inhibit cognitive processes

Two process model of sleep

The two process model of sleep considers circadian and homeostatic as two separate processes driving sleep. In addition, the animal’s activity can postpone sleep [Yamagata et al 2021]. Circadian sleep handles the major daily sleep need while homeostatic sleep covers local sleep needs.

Criticisms of this model point out metabolic anabolic and catabolic cycles are more related to feeding cycles than light cycles [Borbély et al 2016]. The presence of cell clocks in most cells suggests that circadian isn’t a global requirement. In addition, ultradian (4h) feeding cycles cause food anticipatory activity [Dibner et al 2010].

As a specific counterexample, the snail sleep can be model well by simple stochastic oscillator between wake and quiescence [Stephenson 2011]. In contrast zooplankton follow a clear circadian migration between light and dark [Tosches et al 2014].

From a circuit perspective, the two process model has value because some areas like Hb (habenula), Po.vl (ventrolateral preoptic area), and H.scn (suprachiasmatic nucleus) are more easily understandable from a circadian perspective.

Bistable sleep and wake

Although it might sound obvious that sleep and wake are distinct states, implementing this bistable system requires coordination. Violations of this bistability are unusual, like sleepwalking. As in essay 27, where the state transition between seeking food and eating required a circuit using H.stn (subthalamic nucleus) and Snr (substantia nigra pars reticulata), the sleep and wake circuits need circuits to manage their distinction and transition.

*The sleep/wake transition needs to have high gain to avoid metastability.*

Clear state transitions try to avoid metastability, a transitional non-state between the target states. Metastability always exists, but can be minimized by increasing the feedback gain between the states. A high gain, tight transition minimizes the probability of a metastable state. In the mammalian brain, positive feedback and lateral inhibition in Po.vl (ventrolateral preoptic area) and H.l.ox (orexin area of lateral hypothalamus) help make the switch tighter. [Saper et al 2001] calls this a flip-flop with the similarity to bistable electrical latches, where a high gain to avoid metastability is also very important to maintain binary values with a continuous voltage.

While high gain and lateral inhibition is important for sleep, an additional concept called hysteresis is also important to create long continuous sleep bouts and avoid sleep fragmentation.

Hysteresis: sticky switches

In a naive implementation of homeostatic sleep, the animal sleeps when sleep pressure rises past a threshold, and wakes when the pressure drops. Unfortunately, this system could quickly oscillate, where a short nap of a few seconds crosses the threshold and wakes the animal, which quickly tires and takes a new nap. To avoid this fragmented sleep, the threshold needs to be sticky: it’s harder to wake when the animal sleeps, and harder to sleep when the animal wakes.

This kind of sticky switch is called hysteresis. The threshold for switching states depends on the current state.

Since sleep inhibits sensory input, noises that would keep an animal awake are ignored. Since sleep inhibits actions, the animal is unlikely to run into a situation that requires action. On the other side, any ongoing action will maintain wake. The transition to sleep needs to be slow to ensure that all actions have completed. In addition, long lasting peptides like orexin from H.l can maintain wake for minutes, ensuring a minimum wake bout length.

Note that circadian sleep process is another solution to the sleep oscillation problem. Because time is inexorable, circadian sleep time also shifts the sleep threshold, making it increasingly difficult to sustain wake.

Sleep and wake asymmetry

Sleep and wake are asymmetrical, unlike a symmetrical flip-flop. Any ongoing action needs to maintain wake, and falling asleep is a slow, decaying process, but waking needs to be fast when responding to an alarm. This asymmetrical slow drop to sleep and quick rise to wake is reflected in neurotransmitter levels like dopamine [Zhang et al 2023].

In terms of circuitry, an area around R.pb (parabrachial nucleus) is required for wake. If that area is lesioned, the animal remains in a coma [Fuller et al 2011]. There is no equivalent sleep area that produces a wake-only state when lesioned [Krueger et al 2013].

Next: circadian

After the general discussion of sleep, I think exploring the circadian aspect of sleep is a good direct. Circadian sleep is an ancient system, existing in zooplankton and preexisting more complicated sleep systems.

References

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