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Ascending projections from spinal cord and brainstem to periaqueductal gray and thalamusKlop, Esther Marije

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GENERAL DISCUSSION

In the present thesis new fi ndings on the afferent pathways of the PAG, key structure in the emotional motor system, have been described. It was found that a specifi c part of the tegmental fi eld, the NRA, has specifi c projections to the PAG. Furthermore, two brainstem areas, the nucleus prepositus hypoglossi and the periparabigeminal area, both involved in oculomotor regulation, have been demonstrated to project to the dorsolateral PAG. These results were noteworthy, since projections from pons and medulla were believed not to reach the dorsolateral PAG. Furthermore, these fi ndings place the dorsolateral PAG in the oculomotor system, which might have important implications for how we view the function of the dorsolateral PAG.In addition to projections from the brainstem to the PAG, projections from the spinal cord to the thalamus were studied. Remarkably, no comprehensive study on the cells contributing to the spinothalamic tract existed in cat. Such a study was needed to allow for careful comparison of the spinal input to the PAG with the spinal input to the thalamus, the best known receiver of spinal afferents. To provide a detailed map of the spinothalamic tract, thalamus projecting cells in every lamina in every spinal segment were plotted and counted. It was found that the majority of spinothalamic neurons is not located in lamina I. Also, for the fi rst time the existence of at least fi ve clusters of spinothalamic cells was demonstrated. The fact that differences were found in the location of spinal neurons that project to thalamus and PAG provides new evidence for the idea of an ‘emotional sensori-motor system’ that receives specifi c sensory input. The main conclusions and implications of the studies performed for the present thesis are being discussed in further detail below.

BRAINSTEM AFFERENTS TO THE PAGAfferents from the nucleus retroambiguus to the PAGIn chapter 2 projections from the NRA to the PAG were described. A remarkable fi nding was that the termination pattern in the PAG from fi bers originating in the NRA is very specifi c. Projections from the NRA reach only the most central regions in the lateral PAG at caudal-intermediate levels. This is signifi cant, since our and other studies have shown that after injections in other parts of the lateral tegmental fi eld, a very general projection pattern can be found in the PAG, involving the lateral, dorsomedial and, to a lesser extent, the ventrolateral columns. Projections in the other direction, from PAG to NRA, had been described by Holstege (1989), who hypothesized that the PAG-NRA-motoneuron pathway is the fi nal common pathway for vocalization. Later it was found that the NRA also projects to motoneurons in the lumbosacral spinal cord (VanderHorst and Holstege, 1995; VanderHorst et al., 2000b), probably for the coordination of lordosis posture for mating. The projections from the NRA to the PAG terminate in the same region as projections

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from the sacral cord (Blok et al., 1995; VanderHorst et al., 1996), which points to a role for the NRA-PAG projection in the feedback on mating behavior.

Projections from prepositus hypoglossi nucleus and the periparabigeminal area to the dorsolateral PAG suggest a role for this column in the oculomotor systemIn chapter 3 of this thesis it was shown that from pons and medulla the nucleus prepositus hypoglossi (PPH) projects specifi cally to the dorsolateral column of the PAG. This is a remarkable fi nd, since projections from the lower brainstem were assumed not to target the dorsolateral PAG. The PPH is involved in oculomotor control, which led to the hypothesis that the dorsolateral PAG also plays a role in this system. In search for other brainstem regions involved in oculomotor control that project to the dorsolateral PAG, it was found that the periparabigeminal area (PPBGA) in the midbrain projects to this area (chapter 4). From the literature it is known that other oculomotor related areas, such as the frontal eye fi elds (Stanton et al., 1988; Leichnetz and Gonzalo-Ruiz, 1996), and substantia nigra pars reticulata (Harting and Van Lieshout, 1991) also project to the dorsolateral PAG. Furthermore, cells in the dorsolateral PAG in monkey have been shown to stop fi ring just before the onset of, and during, saccades (Kase et al., 1986). However, these indications that the dorsolateral PAG receives information about eye movements had not received much attention before. Additionally, the studies on PPH and PPBGA projections to the dorsolateral PAG revealed that the dorsolateral PAG consists of at least two subdivisions. In our studies it was found that different parts of the PPH project to different parts of the dorsolateral column (fi g. 1). The caudal PPH and PPBGA were found to project to only a small patch on the dorsolateral edge of the PAG. The supragenual PPH and the tegmental fi eld medial from PPBGA project to the dorsolateral column, but not to the small patch on the dorsolateral edge. Again, although evidence for these two divisions can be found in the literature, no attention had been given to this fact before.

caudal nucleus prepositus hypoglossi

periparabigeminal area

supragenual nucleus prepositus hypoglossi

mesencephalic tegmental fieldmedial from periparabigeminal area

Figure 1. Schematic representation of the projections from different parts of nucleus prepositus hypoglossi and mesencephalic tegmental fi eld to different parts of the dorsolateral periaque-ductal gray.

147

General Discussion

SPINAL AFFERENTS TO THE THALAMUSTotal number of spinothalamic neuronsIn chapter 5 it was described that after large thalamic injections using WGA-HRP 4584 to 6082 neurons in the entire spinal cord were labeled in a 1:4 series of sections. Taking into account the spread to non-thalamic areas in some cases and applying the correction factor of Abercrombie (1946), it was estimated that 12,000 cells make up the spinothalamic tract in cats. This number was higher than earlier estimations in cat, that were not based on countings of neurons in all spinal cord segments. Comprehensive studies on the cells of origin of the spinothalamic tract already existed in rat and monkey, which makes it possible to compare between species. In rat, it has been estimated that a total of 9000 spinothalamic neurons exists (Burstein et al., 1990b), while in monkey this was 18,000 (Apkarian and Hodge, 1989a). For the estimation in monkey, however, no correction factor was used, and it is therefore probably an overestimation.

Comparison of the number of spinothalamic neurons with the number of spino-PAG and spinohypothalamic neuronsConcerning the numbers of neurons in other ascending pathways, the number of spino-PAG neurons in cat was estimated to be 15,000 (Mouton and Holstege, 2000). No study ever gave a precise estimate of the spinohypothalamic tract in cat, but interpolation of the data of the study of Katter et al. (1991) and application of the same correction factor as used in our study, would lead to an estimate of 1000 cells in the feline spinohypothalamic tract. This means that the ratio of the numbers of spinothalamic, spino-PAG and spinohypothalamic cells in cat is 1 : 1.25 : 0.1. Apparently, in cat more cells contribute to the spino-PAG pathway than to the spinothalamic tract, and relatively very few cells make up the spinohypothalamic tract. Lack of data on numbers of cells on the major ascending spinal tract in rat and monkey, makes it diffi cult to compare between species. It is not known in rat how many cells are involved in the spino-PAG pathway. Concerning the other two pathways, it was estimated that in rat more than 9500 spinothalamic neurons (Burstein et al. 1990a), and 9000 spinohypothalamic neurons exist (Burstein et al., 1990b). These two pathways are almost equally as strong in rats, while in cats the spinothalamic tract is ten times stronger than the spinohypothalamic tract. Also, it is an intriguing fi nding that in terms of absolute numbers, the spinohypothalamic tract in rats contains nine times more neurons than in cats. The number of spinohypothalamic neurons in monkey is unknown. The number of spinothalamic cells was estimated to be approximately 18,000 (Apkarian and Hodge, 1989a), and of spino-PAG cells approximately 10,000 (Wiberg et al., 1987) in this species. However, the number of spinothalamic neurons is probably an overestimation, because no correction factor was used to calculate it. Of the number of spino-PAG cells it is unclear how the authors calculated this number from their data. Surprisingly, still no clear concept exists about the numbers of spinal neurons contributing to the major ascending tracts in the most commonly used laboratory animals.

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T7T2

L5T12

C4 C7

L2 Coc 2S1

C1

C1 C2 C3

originates in lamina I throughout the length of the spinal cordprojects to thalamus, PAG, parabrachial nucleipossible function relay of nociceptive, mechanical and visceral information

originates in ventrolateral part of laminae VI-VII and lamina VIII of C1-C3projects to thalamus, PAG, n. Darkschewitsch, hypothalamuspossible function unknown

T7

T2

L5T12

C4 C7

L2 Coc 2S1

C1

originates in lamina V throughout the length of the spinal cordprojects to thalamus, PAG, parabrachial nucleipossible function relay of nociceptive, mechanical and visceral information

Figure 2. Schematic overview of ascending systems from the spinal cord.

149

General Discussion

T5 L4T9 L2T13T1

L4S1 S3L6 Coc 2

L7S1

S2 S3L6

originates in lamina X of the thoracic and upper lumbar cordprojects to PAG, hypothalamus, parabrachial nucleipossible function unknown

originates in medial part of laminae VI-VII and VIII of L4-Coc2projects to thalamus, PAG, n. Darkschewitsch, deep tectal layerspossible function unknown

originates in lateral part of lamina I of L6-S2 and in laminae V-VIIand X of S1-S3

projects to PAG, parabrachial nucleipossible function relay of information concerning micturition and mating behavior

C1 C2

originates in lamina VI of C1 and C2projects to thalamus, deep tectal layers, dorsal column nucleipossible function unknown

Figure 2 (continued). Schematic overview of ascending systems from the spinal cord.

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Lamina I projections to the thalamus provide only a minor portion of all spinal projections to the thalamusProjections from lamina I to the thalamus have received much attention, probably because the lamina I-thalamic projection is thought to play an important role in pain, a signifi cant clinical problem. Most likely, this unbalanced attention has led to the common believe that lamina I neurons provide the major part of the spinothalamic tract. However, when all segments of the cat spinal cord are studied, it appears that only 15% of all spinothalamic neurons are located in lamina I. If such fi gures also exist in humans, these fi ndings could have important implications for intervention in the functioning of the spinothalamic tract in patients, for example with cordotomy for pain relief. Lesioning ‘the’ spinothalamic tract probably not only affects lamina I projections, but also, and especially, non-lamina I projections, which are probably involved in other functions than pain. It has been shown that in monkey axons of lamina I cells travel somewhat more dorsally in the white matter than axons of neurons in deeper laminae (Apkarian and Hodge,1989b). It needs to be investigated how these fi ndings translate to the situation in human, but it might point to the benefi t and necessity of more precise surgery.

At least fi ve groups of neurons project from the spinal cord to the thalamus.In our study on the cells of origin of the spinothalamic tract, for the fi rst time all spinal segments were studied in cat, which led to an overview of the segmental and laminar distribution of all spinothalamic cells. It was found that at least fi ve separate clusters of spinothalamic neurons exist (fi g. 2). These different clusters have specifi c rostrocaudal locations and are not restricted by laminar boundaries. Although spinothalamic cells had been described at similar locations in rats, cats and monkeys, these clusters had not been identifi ed before. The function of most of these clusters remains unknown.

COMPARISON OF SPINO-PAG AND SPINOTHALAMIC PATHWAYSComparison of the spinothalamic clusters with the spino-PAG clusters (Mouton and Holstege, 2000) reveals remarkable similarities, and also differences. Spinothalamic clusters in lamina I (A), in lamina V (B), in the ventrolateral upper cervical cord (C), and in the medial lumbosacral cord (E) have been found on a similar location as cells in the spino-PAG clusters I, II and IV (fi g. 2). Double labeling or physiological studies are necessary to fi nd out whether one individual neuron in one of these areas projects the PAG, the thalamus or to both structures. No cells project to the PAG from the location of spinothalamic cluster D in lamina VI of C1-C2. Conversely, no cells project to the thalamus from the location of spino-PAG clusters III in the lamina X of the thoraco-lumbar cord, and spino-PAG cluster V in the lateral sacral cord. Besides thalamus and PAG, other supraspinal structures such as hypothalamus and the nucleus of Darkschewitsch receive input from neurons located at the same location as some, but not all, spinothalamic clusters. Figure 2 shows the projections from different spinal cord regions to different supraspinal structures. It can be concluded that different afferent systems in the spinal cord project to different brain structures,

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General Discussion

probably refl ecting the differences in function of the different spinal clusters. Three studies were specifi cally performed to compare the spinothalamic and spino-PAG clusters in detail. These are discussed below.

More lamina I cells project to PBN and PAG than to the thalamusIn neuroanatomical textbooks the spinothalamic tract receives most attention regarding pain pathways. However, in chapter 8 it was shown that in cat many more cells project to brainstem structures, such as PBN and PAG, than to thalamus. In fact, in cat four times as many lamina I neurons project to the PBN and two times as many to the PAG, as to the thalamus. On the other hand, it has to be kept in mind that many neurons from other laminae than lamina I project to the thalamus (see chapter 6 of this thesis), PAG (Mouton et al., 2001) and PBN (Panneton and Burton, 1985). As in studies on the spinothalamic tract, of all spinal projections to the PAG, lamina I projections have been emphasized, since it was found that stimulation of the PAG can elicit strong analgesia. Similar to the spinothalamic projections, only a minor portion (approximately 25%) of spino-PAG projections originates in lamina I (Mouton et al., 2001).

Large numbers of neurons project from the upper cervical cord to thalamus and PAGIn chapter 9 it was shown that large numbers of neurons project from the upper cervical cord to thalamus and PAG. Almost half of both the spino-PAG and spinothalamic neurons in C1-C3 was located in the ventrolateral part of the ventral horn. The rostrocaudal distribution of the spino-PAG and spinothalamic neurons was also very similar: the greatest density of labeled neurons was found in the middle part of C1. This implies that the large groups of spino-PAG and spinothalamic neurons in the upper cervical cord are not just a caudal extension of the large group of neurons projecting to PAG or thalamus from the reticular formation of the brainstem. The qualitative and quantitative similarities between the spino-PAG and spinothalamic neurons in C1-C3 suggests that neurons in the upper cervical cord might have collaterals to both PAG and thalamus. Double tracer studies with fl uorescent tracers or physiological studies can be used to resolve this issue.

Specifi c input from the sacral cord reaches the PAG, but not the thalamusA specifi c group of neurons in the lateral sacral cord has been described to project to the PAG (VanderHorst et al., 1996; Mouton and Holstege, 2000). These cells are believed to transmit information from genitals and bladder, important for micturition and mating behavior. Work in the present thesis shows that this group of neurons does not project to the thalamus (chapter 10), the main gateway to the cortex, indicating that information relayed by this group of sacral neurons might not reach consciousness.

Comparing spinal input to the PAG with spinal input to the thalamus, brings to light similarities, but also important differences. Neurons in lamina VI of the upper cervical

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spinal cord project to the thalamus and not to the PAG. Conversely, neurons in specifi c areas of the spinal cord (lamina X of the thoracolumbar cord, and the lateral sacral cord), probably involved in relaying visceral information, project directly to the PAG, but not to the thalamus. Furthermore, many more lamina I cells project to the PAG than to the thalamus. These fi ndings implicate that the PAG, key structure in the emotional motor system, directly receives particular kinds of information that the thalamus does not, and vice versa. The present results provide new evidence for the statement that one should not speak of the ‘emotional motor system’, but of the ‘emotional sensori-motor system’ (Mouton, 1999), because the emotional motor system receives specifi c sensory input. Moreover, these fi ndings have implications for how we view the somatic sensory system. Neuroanatomical textbooks often describe ‘the’ somatic sensory system as consisting of the pathways from the dorsal columns and the spinal cord to the thalamus. Projections to brainstem centers are often depicted as collaterals of these ascending thalamic pathways. Results from the studies presented in this thesis show that this view is neither complete nor accurate.

EpilogueIn the present thesis anatomical studies using neural tracing methods were described. These, and other, tracing studies provide hypotheses about the functions of the neural pathways, and they thereby give direction to future physiological, behavioral, pharmacological and molecular biological studies on these functions. Furthermore, knowledge of the anatomy of the pathways of the brain is essential for the interpretation of results obtained by modern neuroimaging methods, such as PET and fMRI. The colorful ‘blobs’ in brain scans represent brain areas involved in complicated networks. Until now, neuroimaging techniques are not sophisticated enough to show how these areas function within a particular network. Neuroanatomical work, using the animal brain as a model for the human brain, is necessary to shed light on the architecture and functioning of these patways.Neuroanatomy, therefore, is an important discipline, but it is sometimes pushed aside by those that use techniques that are more ‘hip and happening’. It must be kept in mind that in case of the brain ‘function follows form’. It is not enough to know which brain areas are active during a certain behavior or which neurotransmitters are being released. Without knowledge of the underlying pathways, it will remain impossible to adequately, effi ciently and specifi cally intervene in processes of the brain, or even begin to understand them.

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