Neuropeptides and neurotransmitters that modulate thalamo-cortical pathways relevant to migraine headache

Abstract

Dynamic thalamic regulation of sensory signals allows the cortex to adjust better to rapidly changing behavioral, physiological and environmental demands. To fulfill this role, thalamic neurons must themselves be subjected to constantly changing modulatory inputs that originate in multiple neurochemical pathways involved in autonomic, affective and cognitive functions. This review defines a chemical framework for thinking about the complexity of factors that modulate the response properties of relay trigeminovascular thalamic neurons. Following the presentation of scientific evidence for monosynaptic connections between thalamic trigeminovascular neurons and axons containing glutamate, GABA, dopamine, noradrenaline, serotonin, histamine, orexin and melanin-concentrating hormone, this review synthesizes a large body of data to propose that the transmission of headache-related nociceptive signals from the thalamus to the cortex is modulated by potentially opposing forces and that the so-called ‘decision’ of which system (neuropeptide/neurotransmitter) will dominate the firing of a trigeminovascular thalamic neuron at any given time is determined by the constantly changing physiological (sleep, wakefulness, food intake, body temperature, heart rate, blood pressure), behavioral (addiction, isolation), cognitive (attention, learning, memory use) and affective (stress, anxiety, depression, anger) adjustment needed to keep homeostasis.

Historically, the thalamus was viewed as a simple relay station for sensory information from the periphery to the cortex. This view has been replaced by the concept that instead of ‘just’ transferring sensory signals from subcortical nuclei to the cortex, thalamic neurons play central role in the selection, amplification, and prioritization process that determines which type of information should be made available to the cortex at any given time^{1, 2}. Being the so-called ‘gate-keeper’ of the cortex, thalamic neurons regulate the flow of rapidly-changing sensory signals, thus allowing the cortex to adjust to the constantly evolving behavioral and environmental demands¹.

To regulate the amount of sensory signals that reach the cortex, thalamic neurons must themselves be subjected to a variety of modulatory inputs that originate in cortical, hypothalamic, brainstem, spinal and intrathalamic nuclei^{1, 3–6}. In the context of somatosensory and nociceptive information, the more extensively studied networks that drive and/or modulate the activity of relay thalamic neurons are the excitatory glutamatergic input originating in corticothalamic, spinothalamic and medial lemniscus tract neurons, and the inhibitory GABAergic input involving the reticular thalamic nucleus (Kaneko and Mizuno, 1988; McCormick and von Krosigk, 1992; Jones, 2007). The excitatory glutamate input, acting through metabotropic mGluRs, is capable of producing sustained neuronal firing whereas the inhibitory GABA input, acting through the GABAb receptor is capable of switching off the sustained neuronal activity⁷.

Far less is known about the regulation of relay thalamic neurons by other neurotransmitters and neuropeptides³ from various brain regions. Candidates include those from the brainstem and hypothalamus. Brainstem inputs include serotonergic projections from raphe nuclei^{8, 9}, noradrenergic projections from locus coeruleus and the A5 catecholamine group in the pons^8–10, and dopaminergic projections from periaqueductal gray, and the lateral parabrachial nucleus^11–15. Hypothalamic inputs include additional dopaminergic projections from A11/A13^11–15, histaminergic projections from the tuberomammillary nucleus^{16, 17}, orexinergic projections from the perifornical, dorsomedial and lateral hypothalamus^{18, 19}, and melanin-concentrating hormone (MCH) projections from the lateral hypothalamus^20–22.

The potential release of these neurotransmitters/neuropeptides on relay thalamic nuclei suggests that the modulation of individual neurons is rather complex, likely subjected to opposing forces driven by a variety of changing external and internal conditions that require constant behavioral, physiological, and affective adjustments. To understand how ‘a decision’ is made on whether or not a relay thalamic neuron fires, for how long, and at what frequency, it is necessary to determine which neuropeptides/neurotransmitters are in a position to govern the activity of individual thalamic neurons that share a common function. In the current review we describe an array of neuropeptides/neurotransmitters that may modulate individual, physiologically-identified thalamic trigeminovascular neurons believed to play a role in the generation of headache perception during migraine.

The discharge mode of relay thalamocortical neurons is either burst or tonic^{1, 23}. The burst discharge is commonly associated with lower excitability, drowsiness, and in the context of headache, responses to acute pain, whereas the tonic discharge has been associated with higher excitability, wakefulness, and chronic pain state^{4, 24–26}. In principle, each of the neurotransmitters/neuropeptides discussed below have close apposition with thalamic trigeminovascular neurons and as such, can potentially shift their firing mode from burst to tonic if it is excitatory, and from tonic to burst if it is inhibitory. As in other systems, the action of each neuropeptide/neurotransmitter on individual thalamic neuron depends on the type of release and reuptake, the type of receptor activated, and most likely the location of the neuron and its projection targets in the cortex. Since this information is not available for thalamic trigeminovascular neurons, which are the subject of this review, speculation on possible roles of the identified neuropeptides/neurotransmitters in setting thalamic transmission, as it may be related to migraine headache, is based on their known action in other systems.

A. Glutamatergic innervation

Axons immunoreactive to VGluT2, thus containing the excitatory neurotransmitter glutamate, are present at high density in all thalamic nuclei known to contain trigeminovascular neurons including VPM, Po, LP and LD (Fig. 1A). When examined in sections containing the trigeminovascular neuron(s), dense VGluT2 immunopositive vesicles are seen in close apposition to the cell body, proximal and distal dendrites (Fig. 1B).

Figure 1.

Glutamatergic innervation of thalamic trigeminovascular neurons. (A) Left: Immunopositive VGluT2 synaptic vesicles (green) surrounding a thalamic dura-sensitive neuron (red) labeled with TMR–dextran. Arrowheads indicate close apposition of VGluT2 positive axons and the cell body and dendrites of the labeled neuron. Upper right: Location of the dura-sensitive neuron (red star) shown at left. Number in red indicates distance from bregma (mm). Lower right: Fluorescent images showing VGluT2 axonal labeling in thalamic Po and VPM nuclei. Scale bars = 100 mm. (B) Close apposition between VGluT2 immunopositive vesicles and thalamic trigeminovascular neurons. The three views in the x-y, y-z and x-z planes provide evidence that VGluT2 immunopositive vesicles (green) may contact cell bodies, proximal and distal dendrites of trigeminovascular neurons in LP (red). Arrowheads indicate probable contact point on each view. Note that some green-labeled vesicles and red-labeled soma or dendrites are in the same focal plane (yellow). Scale bar = 50 μm. Adapted from Noseda et al., 2014²⁷

Vesicular glutamate transporters (VGluTs) are responsible for glutamate trafficking and for the subsequent regulated release of glutamate at the synapse. Glutamate excites relay thalamocortical neurons through NMDA receptors, if the sensory stimulus is prolong, and through non-NMDA receptors if the sensory stimulus is brief^{28, 29}. Of the three isoforms of VGluT, we opted to study VGluT2 because it is expressed most densely in relay thalamic nuclei^30–34 and in ascending trigeminal sensory neurons that project to VPM and Po^{35, 36}. Since VGluT1 axons originate in corticothalamic neurons, we interpreted the presence of VGluT2 on thalamic trigeminovascular neurons as constituting the main drive for activation of these neurons by glutamatergic input they receive from ascending trigeminothalamic (possibly dura-sensitive) neurons in SpV.

B. Dopaminergic innervation

Axons immunoreactive to Tyrosine Hydroxylase (TH), thus containing the catecholamine neurotransmitter dopamine, are present at moderate density in all thalamic nuclei known to contain trigeminovascular neurons (Fig. 2A). When examined in sections containing the trigeminovascular neuron(s), moderate density of TH immunopositive axons and varicosities are seen in close apposition to proximal and distal dendrites (Fig. 2B). We interpreted some of the TH-positive axons as dopaminergic based on a recent retrograde tracing study where we showed that the dopaminergic cells group A11/A13 project to the same Po and LP areas in which trigeminovascular neurons are found³⁷.

Figure 2.

Dopaminergic innervation of thalamic trigeminovascular neurons. (A) Left: Immunopositive Tyrosine Hydroxylase axons (green) surrounding a thalamic dura-sensitive neuron (red) labeled with TMR–dextran. Nuclear counterstaining was performed with DAPI (blue). Arrowheads indicate close apposition of TH positive axons and the cell body and dendrites of the labeled neuron. Because TH is present in noradrenergic and dopaminergic cells, the interpretation of its labeling must take into consideration these two neurotransmitters. Upper right: Location of the dura-sensitive neuron (red star) shown at left. Number in red indicates distance from bregma (mm). Lower right: Fluorescent image showing TH labeling of cell bodies in the hypothalamic A11 nucleus. Scale bars = 100 mm. (B) Close apposition between TH immunopositive axons and thalamic trigeminovascular neurons. The three views in the x-y, y-z and x-z planes provide evidence that TH immunopositive fibers (green) may contact proximal and distal dendrites of trigeminovascular neurons in Po (red). Arrowheads indicate probable contact point on each view. Note that some green-labeled axons and red-labeled dendrites are in the same focal plane (yellow). Scale bar = 50 μm. Adapted from Noseda et al., 2014²⁷

In the context of migraine, dopamine has been considered for its role in promoting hypothalamic-mediated symptoms/prodromes such as yawning and nausea³⁸, and more recently, modulation of dorsal horn trigeminovascular neurons³⁹. Further supporting this hypothalamic connection is the finding that the A11 dopaminergic cell group in the medial hypothalamus innervates trigeminovascular neurons in both, the medullary dorsal horn^{40, 41} and the thalamic relay nuclei³⁷. The rich innervation of thalamic trigeminovascular neurons by dopaminergic fibers suggests that modulation of transmission of nociceptive trigeminovascular signals by dopamine may also occur at the thalamus. When conceptualizing dopamine role in migraine, a consideration should be given to the activation of thalamic D₁ and D₂ receptors which facilitate membrane depolarization and increase spike discharge in somatosensory VPL/VPM thalamic neurons⁴², and to the selective uptake of cocaine by dopaminergic nerve terminals in the thalamus as these findings define the possibility that thalamic dopamine pathways may be critically involved in drug-addiction, impulse control, affect, attention and decision making^43–49. Translating these into clinical implications, thalamic dopamine may thus be considered as a possible contributor to behaviors that lead to medication-overuse headache and exacerbation of headache by negative emotions, effort to control anger and irritability, cognitive tasks that require attention and the need to make mundane decisions.

C. Serotoninergic innervation

Serotoninergic innervation was determined using Serotonin Transporter – SERT (Fig. 3A), a stable marker of serotoninergic fibers in the brain⁵⁰. Axons immunoreactive to SERT, thus containing the monoamine neurotransmitter serotonin, were present at high density in all thalamic nuclei known to contain trigeminovascular neurons (Fig. 3B). When examined in sections containing the trigeminovascular neuron(s), dense SERT immunopositive axons and varicosities were seen in close apposition to the cell body, proximal and distal dendrites.

Figure 3.

Serotoninergic innervation of thalamic trigeminovascular neurons. (A) Left: Immunopositive Serotonin Transporter axons (green) surrounding a thalamic dura-sensitive neuron (red) labeled with TMR–dextran. Nuclear counterstaining was performed with DAPI (blue). Arrowheads indicate close apposition of SERT positive axons and the cell body and dendrites of the labeled neuron. Upper right: Location of the dura-sensitive neuron (red star) shown at left. Number in red indicates distance from bregma (mm). Scale bars = 100 mm. Since SERT does not stain cell somas, it was not possible to use this marker to identify the serotoninergic neurons in the raphe nuclei that project to the thalamic nuclei containing trigeminovascular neurons. (B) Close apposition between Serotoninergic axons and thalamic trigeminovascular neurons. Images from the original z-stack (obtained every 1 μm) were used to create orthogonal views in the y-z and x-z planes. The three views provide evidence that SERT immunopositive fibers (green) may contact cell bodies, proximal and distal dendrites of trigeminovascular neurons in Po (red). Note that some green-labeled axons and red-labeled soma or dendrites are in the same focal plane (yellow). Scale bar = 50 μm. Adapted from Noseda et al., 2014²⁷

Relevant to this study is that serotonin has long been implicated in migraine pathophysiology^{51, 52}, that this implication has lead to the development of 5HT_1B/1D receptor agonists (i.e., triptans) for acute treatment of migraine, that serotonergic innervation of VPM and Po originating mainly in the rostral raphe^{8, 53–56}, and that depending on the amount of serotonin release in the thalamus, it could be facilitatory (at low concentration) or inhibitory (at high concentration) to relay neurons in VPM and Po⁵⁷. In principle, a high concentration of serotonin is inhibitory whereas a low concentration is excitatory. Accordingly, the very dense innervation of thalamic trigeminovasular neurons observed in the figure above can provide an anatomical substrate for a predominantly inhibitory effect of serotonin on transmission of trigeminovascular information between the thalamus and the cortex, as well as the inhibition of trigeminovascular thalamic neurons by local administration of 5HT₁ agonists⁵⁸. Given the latter, we were surprized by the total absence of 5HT_1D receptors in the thalamus. This finding suggests that the inhibition of thalamic trigeminovascular neurons response to dural stimulation occur at an earlier synapse along the trigeminovasculat pathway⁵⁹, rather than in the thalamus. On a more global view, serotonin, through its involvement in stress⁶⁰, anxiety⁶¹, depression⁶², sleep⁶³, apetite⁶⁴, and learning⁶¹ may help facilitate the reciprocal relationship between these affective and physiological states and migraine.

D. Noradrenergic innervation

Axons immunoreactive to Dopamine β-Hydroxylase (DBH), thus containing the catecholamine neurotransmitter noradrenaline, are present at moderate-to-high density in all thalamic nuclei known to contain trigeminovascular neurons (Fig. 4A). When examined in sections containing the trigeminovascular neuron(s), moderate-to-high density of DBH immunopositive axons and varicosities are seen in close apposition to the cell body, proximal and distal dendrites (Fig. 4B). These DBH axons originate in the locus coeruleus, the main producer of noradrenalin in the brain.

Figure 4.

Noradrenergic innervation of thalamic trigeminovascular neurons. (A) Left: Immunopositive Dopamine β-Hydroxylase axons (green) surrounding a thalamic dura-sensitive neuron (red) labeled with TMR–dextran. Nuclear counterstaining was performed with DAPI (blue). Arrowheads indicate close apposition of DBH positive axons and the cell body and dendrites of the labeled neuron. Upper right: Location of the dura-sensitive neuron (red star) shown at left. Number in red indicates distance from bregma (mm). Lower right: Fluorescent image showing DBH labeling of cell bodies in the LC of the brainstem. Scale bars = 100 mm. (B) Close apposition between DBH immunopositive axons and thalamic trigeminovascular neurons. The three views in the x-y, y-z and x-z planes provide evidence that DBH immunopositive fibers (green) may contact cell bodies, proximal and distal dendrites of trigeminovascular neurons in Po (red). Arrowheads indicate probable contact point on each view. Note that some green-labeled axons and red-labeled soma or dendrites are in the same focal plane (yellow). Scale bar = 50 μm. Adapted from Noseda et al., 2014²⁷

Because of the wide distribution of noradrenergic fibers in the brain it is difficult to assign to this neurotransmitter a specific role in certain function. Rather, it is thought to improve signal-to-noise ratio in the firing of neurons that respond to sensory stimuli^{10, 65–67} when conditions involve anticipation, reward, and changing cognitive and emotional circumstances⁶⁸. To be in a position to modulate thalamic neurons, noradrenergic fibers project heavily to all thalamic sensory nuclei^{69, 70} and act on both α and β adrenoceptors, which together modulate firing rate, set a pacemaker current, determine membrane resting potential, and synaptic strength^71–74. In the context of migraine, noradrenaline, which usually prolongs the activation of thalamic neurons^75–78, may be involved in setting abnormal excitability level in trigeminovascular neurons, centrally, and the magnitude of arterial hypertension, peripherally. This view is supported by the finding that β₁ adrenoceptor blockers, which are among the very few drugs approved as migraine prophylactics⁷⁹, inhibit the activity of thalamic trigeminovascular neurons⁸⁰. The observed relationship between noradrenergic fibers and thalamic trigeminovascular neurons provide a direct anatomical substrate for the central action of β1 adrenoceptor blockers in migraine. Given that activation of β₁ adrenoceptor enhances the hyperpolarization-activated cation current (Ih) responsible for setting the so-called pacemaker activity level and the resting membrane potential in those relay thalamic neurons that exhibit such current^{71, 73, 74}, it is reasonable to speculate that thalamic trigeminovascular neurons exhibit the hyperpolarization-activated cation current – a current that may render them likely to exhibit a prolonged firing mode.

E. Histaminergic innervation

Axons immunoreactive to histamine neurotransmitter were present at moderate density in LP and LD, and at low density in VPM and Po (Fig. 5A). When examined in sections containing the trigeminovascular neuron(s), moderate density of histaminergic immunopositive axons and varicosities are seen in close apposition to the cell body, proximal and distal dendrites (Fig. 5B). This histaminergic innervation originates in the dorsal and ventral tuberomammillary nuclei of the hypothalamus, the sole producers of histamine in the brain.

Figure 5.

Histaminergic innervation of thalamic trigeminovascular neurons. (A) Left: Immunopositive Histamine axons (green) surrounding a thalamic dura-sensitive neuron (red) labeled with TMR–dextran. Nuclear counterstaining was performed with DAPI (blue). Arrowheads indicate close apposition of Histamine positive axons and the cell body and dendrites of the labeled neuron. Upper right: Location of the dura-sensitive neuron (red star) shown at left. Number in red indicates distance from bregma (mm). Lower right: Fluorescent image showing Histamine labeling of cell bodies in the hypothalamic DTM and VTM nuclei. Scale bars = 100 mm. (B) Close apposition between Histamine immunopositive axons and thalamic trigeminovascular neurons. The three views in the x-y, y-z and x-z planes provide evidence that Histamine immunopositive fibers (green) may contact cell bodies, proximal and distal dendrites of trigeminovascular neurons in LP (red). Arrowheads indicate probable contact point on each view. Note that some green-labeled axons and red-labeled soma or dendrites are in the same focal plane (yellow). Scale bar = 50 μm. Adapted from Noseda et al., 2014²⁷

In the context of migraine, histamine has been considered for its role in causing H₁ receptor mediated arterial dilatation and the consequential induction of delayed headache⁸¹. The findings that histaminergic nerve terminals converge on thalamic trigeminovascular neurons suggest that histamine role in migraine may also include modulation of thalamic trigeminovascular neurons through excitatory H₁ receptors whose action enhances slow depolarization current capable of switching neuronal discharge mode from burst to tonic⁸². In the CNS, histamine originates exclusively from neurons of the tuberomammillary hypothalamic nucleus^{16, 17}. Given that these neurons are active during the wake-state and quiescent during the sleep state^83–85 and that histamine switches the firing mode of relay thalamic neurons from burst to tonic^{3, 82}, it is tempting to speculate that the modulation of thalamic trigeminovascular neurons by the histaminergic pathway may play a role in the partial, or even complete, headache relief provided by sleep.

F. Melanin-concentrating hormone innervation

Axons immunoreactive to MCH are present at low density in all thalamic nuclei known to contain trigeminovascular neurons (Fig. 6A). When examined in sections containing the trigeminovascular neuron(s), low density of MCH immunopositive axons and varicosities are seen in close apposition to the proximal and distal dendrites, but not the cell body (Fig. 6B). These MCH axons originate mainly in the lateral hypothalamus.

Figure 6.

MCH innervation of thalamic trigeminovascular neurons. (A) Left: Immunopositive Melanin Concentrating Hormone axons (green) surrounding a thalamic dura-sensitive neuron (red) labeled with TMR–dextran. Nuclear counterstaining was performed with DAPI (blue). Arrowheads indicate close apposition of MCH positive axons and the cell body and dendrites of the labeled neuron. Upper right: Location of the dura-sensitive neuron (red star) shown at left. Number in red indicates distance from bregma (mm). Lower right: Fluorescent image showing MCH labeling of cell bodies in the lateral hypothalamus. Scale bars = 100 mm. (B) Close apposition between MCH immunopositive axons and thalamic trigeminovascular neurons. The three views in the x-y, y-z and x-z planes provide evidence that MCH immunopositive fibers (green) may contact distal dendrites of trigeminovascular neurons in VPM (red). Arrowheads indicate probable contact point on each view. Note that some green-labeled axons and red-labeled dendrites are in the same focal plane (yellow). Scale bar = 50 μm. Adapted from Noseda et al., 2014²⁷

The MCH system, which originates in the hypothalamus and contain GABA⁸⁶ is thought to play a modulatory/inhibitory role in the regulation of energy expenditure, arousal, locomotion, sexual behavior and a variety of autonomic functions^87–91. Being excited by increased glucose level after a meal, MCH neurons are thought to promote sleep and energy expenditure (i.e., cessation of food intake) by releasing GABA at multiple cortical, subcortical, brainstem and spinal areas they project to. To date, this system has not been considered in the pathophysiology of migraine or other headaches. The findings that hypothalamic MCH neurons issue axons that terminate on thalamic trigeminovascular neurons define a novel anatomo-functional substrate for hypothesizing about possible interactions between food intake, drowsiness and migraine. It is tempting to propose that the mechanism by which eating may make patients ‘feel better’ during migraine involves increased level of glucose, activation of hypothalamic MCH neurons⁹², and the consequential inhibition of relay thalamic trigeminovascular neurons. Conversely, this anatomo-functional substrate may also explain a part of the reasons for why migraine is promoted by skipping a meal. Skipping a meal inhibits MCH neurons (as glucose level goes down) that, when inactive, may release far less GABA around thalamic trigeminovascular neurons. Reduced GABA input might then enhance neuronal excitability, rendering them more likely to respond to subthreshold input they receive from ascending dura-sensitive neurons in the spinal trigeminal nucleus.

G. Orexinergic innervation

Axons immunoreactive to orexin A were present at low density in LP, LD and most medial part of Po, and at very low density in VPM and most lateral part of Po (Fig. 7A). When examined in sections containing the trigeminovascular neuron(s), low density of orexinergic immunopositive axons and varicosities were seen in close apposition to the proximal and distal dendrites, but not the cell body (Fig. 7B). These orexinergic axons originate mainly in the perifornical hypothalamic area.

Figure 7.

Orexinergic innervation of thalamic trigeminovascular neurons. (A) Left: Immunopositive Orexin A axons (green) surrounding a thalamic dura-sensitive neuron (red) labeled with TMR–dextran. Nuclear counterstaining was performed with DAPI (blue). Arrowheads indicate close apposition of OrA positive axons and the cell body and dendrites of the labeled neuron. Upper right: Location of the dura-sensitive neuron (red star) shown at left. Number in red indicates distance from bregma (mm). Lower right: Fluorescent image showing OrA labeling of cell bodies in the hypothalamic perifornical area (PeF). Scale bars = 100 mm. (B) Close apposition between Orexin A immunopositive axons and thalamic trigeminovascular neurons. The three views in the x-y, y-z and x-z planes provide evidence that Orexin A immunopositive fibers (green) may contact proximal and distal dendrites of trigeminovascular neurons in LD (red). Arrowheads indicate probable contact point on each view. Note that some green-labeled axons and red-labeled dendrites are in the same focal plane (yellow). Scale bar = 50 μm. Adapted from Noseda et al., 2014²⁷

The orexin system originates in the LH and projects to the cortex, thalamus, brainstem, spinal cord and other hypothalamic nuclei^{19, 93–96}. It consists of 2 neuropeptides (orexin A, orexin B) that are synthesized by the same gene⁹⁷ and act on 2 classes of receptors, the selective orexin receptor 1 (orexin A) and the non-selective orexin receptor 2 (orexin A and B). The wide distribution of orexin fibers in the brain support a role in regulating food intake, arousal, wakefulness and sympathetically-mediated increase in body temperature, heart rate and blood pressure⁹⁸. Opposite to the function of the MCH system, orexin neurons are excited by falling glucose levels, and their activation promotes food intake and wakefulness^99–101. Of potential relevance to the pathophysiology of migraine are orexinergic axons in nociceptive laminae of the medullary dorsal horn and in close apposition to thalamic trigeminovascular neurons. Although no information is available regarding the direction in which orexin modulates thalamic trigeminovascular neurons, in vitro slice recording of thalamic neurons suggests that both orexin B and, for a lesser extent, orexin A are capable of depolarizing these neurons sufficently to switch their firing from the sleep-associated burst mode to the wakefulness-associated tonic mode¹⁰². In the context of migraine, it is thus reasonable to hypothesize that the mechanism by which eating may reduce headache intensity involves not only local release of GABA from activated MCH neurons but also inhibition of facilitatory orexin input to thalamic trigeminovascular neurons induced by increased glucose level (orexin neurons are inhibited by glucose). And conversely, fasting-induced fall in glucose activates the orexinergic neurons which in turn facilitate excitability through local release of orexin B and orexin A.

The relative innervation density of each of the neuropeptides and neurotransmitters described above is shown in Figure 8. As a rule, when the density is higher, more opportunities are created for a chemical pathway to modulate the activity of the targeted neuron. Accordingly, it is concluded that the activity of thalamic trigeminovascular neurons is modulated mainly by glutamate, GABA, dopamine and serotonin, to a lesser extent by noradrenaline and histamine, and least by MCH and orexin.

Figure 8.

Density maps of thalamic innervation by neurotransmitters and neuropeptides. Photomicrographs showing immunofluorescence staining of each biomarker in thalamic areas where juxtacellularly labeled trigeminovascular neurons were recorded (for anatomical reference, see figures 1–7). Adjacent to each fluorescent image, binary heat maps showing all pixels (in red) containing positive immunostaining are shown as a quantitative measurement of innervation density. Numbers in white reflect the percent of pixels with staining. Scale bar = 100 μm.

Summary

The thalamus is intricately connected with multiple cortical, subcortical and brainstem regions. It is viewed as an important subcortical hub with respect to functional brain networks¹⁰³ involved in processes that are altered in certain disease states^{104, 105}. In the migraine brain, changes in modulation of thalamic neurons by various inputs may have significant effects on thalamic functional connectivity during both the interictal and the ictal state. The diverse neurochemical pathways that converge on thalamic trigeminovascular neurons (Fig. 9A–B) and the probability that many of them modulate neuronal activity in the same direction under certain conditions (e.g., sleep deprivation) and in opposite directions under other conditions (e.g., when satiated or scared) define a sophisticated neuroanatomical network that may help us conceptualize how sensory, physiological, cognitive and affective conditions trigger, worsen or improve migraine headache.

Figure 9.

(A) Schematic illustration of the neurotransmitter and neuropeptidergic systems innervating thalamic trigeminovascular neurons in VPM, Po and LP. The peripheral (meningeal nociceptors) and central (trigemino-thalamic) components of the trigeminovascular pathway are shown in red. The neurotransmitter and neuropeptidergic systems are color coded as follow: (a) Glutamate from SpVC/C1-2 in red; (b) GABA from Rt in yellow; (c) Noradrenalin from LC in blue; (d) Serotonin from RMg and DR in green; (e) Histamine from DTM and VTM in orange; (f) Melanin Concentrating Hormone from LH in purple; (g) Orexin from PeF in black; (h) Dopamine from A11 in brown. (B) The diverse neurochemical pathways that converge on thalamic trigeminovascular neurons and the probability that many of them modulate neuronal activity in the same direction under certain conditions (e.g., sleep deprivation, wakefulness, food withhold, stress, anxiety) and in opposite directions under other conditions (e.g., food intake, sleep) define a sophisticated neuroanatomical network that may help us conceptualize how sensory, physiological, cognitive and affective conditions trigger, worsen or improve migraine headache. Adapted from Noseda et al., 2014²⁷