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Catecholaminergic Brain Stem Regulatory Systems

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Abstract

The sections in this article are:

1 Catecholaminergic Cell Groups
1.1 Noradrenergic Cell Groups
1.2 Dopaminergic Cell Groups
2 Phylogenetic Perspective
2.1 Comparative Aspects of Brain Stem Catecholaminergic Cell Groups
2.2 Catecholaminergic Projections to Forebrain
3 Catecholaminergic Fiber Tracts
3.1 Dorsal Tegmental Bundle
3.2 Central Tegmental Tract
3.3 Periventricular System
3.4 Nigrostriatal Pathway
3.5 Medial Forebrain Bundle
4 Dopaminergic Projection Systems
4.1 Mesotelencephalic System
4.2 Diencephalic Projections of Mesencephalic Dopaminergic Cell Groups
4.3 Descending Projections From Mesencephalic Dopaminergic Cell Groups
4.4 Projections of Diencephalic Cell Groups
5 Mesotelencephalic Dopaminergic Neurons and Organization of Striatal and Limbic Forebrain Circuitry
5.1 General Organizational Features
5.2 Transmitter Characteristics
6 Functional Aspects of Mesotelencephalic Dopamine System
6.1 Dopamine‐Deficiency Syndrome
6.2 Simplified Scheme for Dopaminergic Regulation of Striatal Output Functions
6.3 Dopaminergic Modulation of Neurotransmission in Substantia Nigra Through Dendrites of Nigral Neurons
7 Noradrenergic Projection Systems
7.1 Locus Coeruleus System
7.2 Lateral Tegmental and Dorsal Medullary Systems
8 Noradrenergic Systems Viewed as Components of Brain Stem Reticular Formation
9 Functional Aspects of Brain Stem Noradrenergic Systems
9.1 Neuromodulatory Actions
9.2 Arousal and Attention
9.3 Descending Effects on Locomotion
9.4 Blood Flow, Stress, and Epileptic Seizures
10 Regenerative Responses and Functional Recovery After Brain Injury
10.1 Regeneration After Axotomy
10.2 Collateral Sprouting After Deafferentation
10.3 Compensatory Hyperactivity
10.4 Reinnervation and Recovery of Function by Grafted Catecholaminergic Neurons
11 Summary
11.1 Catecholamine Neurons Can Operate in Both Synaptic and Neurohumoral Manners
11.2 Catecholamines Function at Both Axonal and Dendritic Terminals
11.3 Catecholamine Release Depends on Neuronal Activity and Local Transmitter Interactions
Figure 1. Figure 1.

Distribution of catecholamine (CA)‐containing cell bodies in rat brain (coronal sections). ar, Arcuate nucleus; CC, crus cerebri; CSC, commissure of superior colliculus; DLF, dorsal longitudinal fasciculus; dm, dorsomedial hypothalamic n.; drn, dorsal raphe n.; F, fornix; FLM, f. longitudinalis medialis; FMT, f. mammillothalamicus; FR, f. retroflexus; G VII, genu of facial nerve; gp, globus pallidus; H1 and H2, tegmental fields of Forel; ha, anterior hypothalamic area; hl, lateral hypothalamic area; hp, posterior hypothalamic area; IC, internal capsule; ioc, inferior olivary complex; ip, interpeduncular n.; lc, locus coeruleus; LM, lemniscus medialis; MCP, middle cerebellar peduncle; me V, mesencephalic trigeminal n.; MFB, medial forebrain bundle; MLF, medial longitudinal f.; N III, oculomotor nerve; N VII, facial nerve; n V, principal trigeminal n.; n VII, facial n.; n X, dorsal motor n. of vagus; n XII, hypoglossal n.; ns V, spinal trigeminal n.; nst, n. of solitary tract; nvm, medial vestibular n.; nvp, posterior vestibular n.; OC, optic chiasm; OT, optic tract or olfactory tubercle; P, pyramidal tract; PC, posterior commissure; pm, posterior mammillary n.; pv, periventricular hypothalamic n.; r, n. ruber; rl, lateral reticular n.; sc, suprachiasmatic n.; SCP, superior cerebellar peduncle; SM, stria medullaris; snc, substantia nigra, pars compacta; snr, substantia nigra, pars reticulata; soc, superior olivary complex; TS V, spinal tract of trigeminal nerve; V, trigeminal nerve; V III, 3rd ventricle; V IV, 4th ventricle; vm, ventromedial n.; vta, ventral tegmental area; vtn, ventral tegmental or ventral thalamic n.; and ZI, zona incerta.

Adapted from Björklund and Nobin 46, Dahlström and Fuxe 102, Palkovits and Jacobowitz 403, and Swanson and Hartman 507
Figure 2. Figure 2.

Distribution of noradrenergic neurons (•) in locus coeruleus of rat; sections are transverse to longitudinal axis of brain stem. Level 1 is most rostral and level 6 most caudal. dtn, Dorsal tegmental n.; and Vm, mesencephalic trigeminal n.

Adapted from Grzanna and Molliver 201
Figure 3. Figure 3.

Distribution of dopaminergic neurons in A10 cell group and medial substantia nigra, as revealed by tyrosine hydroxylase immunohistochemistry. A is most rostral and H most caudal. AOB, basal n. of accessory optic tract; bp, brachium pontis; CL, central linear n.; cp, cerebral peduncle; dbc, decussation of brachium conjunctivum; EW, Edinger‐Westphal n.; fr, f. retroflexus; IF, interfascicular n.; IPC, central interpeduncular n.; IPF, interpeduncular fossa; IPI, posterior interpeduncular n., inner division; IPO, posterior interpeduncular n., outer division; IPP, paramedian interpeduncular n.; ml, medial lemniscus; mlf, medial longitudinal f.; MM, medial mammillary n.; mp, mammillary peduncle; mt, mammillothalamic tract; PHA, posterior hypothalamic area; PVp, posterior periventricular n.; RL, rostral linear n.; RN, red n.; RR, retrorubral n.; SNc, substantia nigra, pars compacta; SNr, substantia nigra, pars reticulata; SUMl, supramammillary region, pars lateralis; SUMm, supra‐mammillary region, pars medialis; TM, tuberomammillary n.; VTA, ventral tegmental area; vtd, ventral tegmental decussation; ZI, zona incerta; III, oculomotor n.; IIIn, oculomotor nerve; and IIIr, oculomotor root fibers.

From Swanson 502
Figure 4. Figure 4.

Relative development of pontine, mesencephalic, and diencephalic CA neuron systems in 7 vertebrate classes. Values are crude estimates of number of cell bodies, as extracted from various studies, a, Ref. 521; b, ref. 520; c, ref. 501; d, ref. 341; e, ref. 22; f, ref. 502; g, ref. 537; i, ref. 414; j, ref. 418; k, refs. 60,410. NA, norephinephrine; DA, dopamine; and A, epinephrine.

Figure 5. Figure 5.

Major CA projection systems in 5 classes of vertebrates (A, fish; B, amphibian; C, turtle; D, chicken; E, rat). ACC, anterior cingulate cortex; AS, n. accumbens septi; CER, cerebellum; DC, dorsal cortex; LPO, paraolfactory lobe; LS, lateral septal n.; NPT, n. posterior tuberis; PA, Palleo‐striatum augmentatum; PFC, prefrontal cortex; PVO, paraventricular organ; S, septum; STR, striatum; TECT, tectum.

Adaped from Parent et al. 414, Parent 413,681, Dubé and Parent 127, and Lindvall and Björklund 297
Figure 6. Figure 6.

Ascending CA fiber system of dorsal tegmental bundle (DTB), originating in locus coeruleus (LC), and its projections in diencephalon. Medial part of MFB and cells in medial part of pars compacta of substantia nigra (SNC) are also included. Figure is composite of slightly different sagittal planes. am, Anteromedial n.; av, anteroventral n.; DPS, dorsal periventricular system; DSCP, decussation of superior cerebellar peduncles; G VII, genu of facial nerve; lh, lateral habenular n.; MB, medullary CA bundle; ML, medial lemniscus; ret, reticular n.; SOD, supraoptic decussations; and TR, tegmental CA radiations.

From Lindvall and Björklund 297
Figure 7. Figure 7.

Ascending and descending CA fiber systems in central tegmental tract (CTT) and its caudal extension, the medullary CA bundle (MB). Rostrally, part of nigrostriatal pathway is represented in its extension through internal capsule (CI) and globus pallidus. Figure is composite of different sagittal planes. Note that mesencephalic and pontine parts of drawing illustrate plane situated ∼0.5 mm more medial than rest. AC, anterior commissure; CC, crus cerebri; G VII, genu of facial nerve; ML, medial lemniscus; NCP, n. caudatus‐putamen; NSP, nigrostriatal pathway; OT, optic tract; SC, n. subcoeruleus; SNC, substantia nigra, pars compacta; so, supraoptic n.; SOD, supraoptic decussations; ST, stria terminalis; and TUB, olfactory tubercle.

From Lindvall and Björklund 297
Figure 8. Figure 8.

Periventricular CA fiber system rostral to locus coeruleus. Figure is composite of somewhat different paramedian sagittal planes. dmh, Dorsomedial hypothalamic n.; DPB, dorsal periventricular bundle; DTB, dorsal tegmental bundle; mh, medial habenular n.; MP, mammillary peduncle; pf, parafascicular n.; pvh, paraventricular hypothalamic n.; pvt, paraventricular thalamic n.; rh, rhomboidal n.; and VPS, ventral periventricular system.

From Lindvall and Björklund 297
Figure 9. Figure 9.

Horizontal section through dorsal part of MFB system, ventral part of nigrostriatal pathway (NSP), and ansa lenticularis (AL). Compare with sagittal drawings in Figs. 6 and 7. Figure is composite of slightly different horizontal planes. AC, anterior commissure; ACC, n. accumbens; can, central amygdaloid n.; CTT, central tegmental tract; dmh, dorsomedial hypothalamic n.; and st, interstitial n. of stria terminalis.

From Lindvall and Björklund 297
Figure 10. Figure 10.

Mesostriatal (A) and mesolimbocortical (B) dopamine (DA) projection systems. Stippling indicates innervated areas. a, N. accumbens; ACC, anterior cingulate cortex; AN, amygdaloid nuclei; CE, entorhinal cortex; cp, n. caudatus‐putamen; MCG, mesencephalic DA cell groups; OB, olfactory bulb; PFC, prefrontal cortex; pi, piriform cortex; sl, lateral septal n.; and tu, tuberculum olfactorium.

Figure 11. Figure 11.

Twenty‐four frontal planes showing distribution and density of DA terminals in CNS of rat. Terminal densities: very dense (4+), dense (3+), medium dense (2+), least dense (1+). Terminal distribution of incertohypothalamic and tuberohypophysial DA systems is not shown. AA, area amygdaloidea anterior; ab, n. amygdaloideus basalis; abl, n. amygdaloideus basalis, pars lateralis; abm, n. amygdaloideus basalis, pars medialis; ac, n. amygdaloideus centralis; aco, n. amygdaloideus corticalis; al, n. amygdaloideus lateralis; ala, n. amygdaloideus lateralis, pars anterior; alp, n. amygdaloideus lateralis, pars posterior; AM, anteromedial system; am, n. amygdaloideus medialis; CA, commissura anterior; CAI, capsula interna; CCA, corpus callosum; CFV, commissura fornicis ventralis; cgm, corpus geniculatum mediale; cl, claustrum; CO, chiasma opticum; CP, commissura posterior; dcgl, n. dorsalis corporis geniculati lateralis; ep, n. entopeduncularis; FH, fimbria hippocampi; FMI, forceps minor; GCC, genu corporis callosi; gp, globus pallidus; HI, hippocampus; HIA, hippocampus anterior; hl, n. habenulae lateralis; hm, n. habenulae medialis; hpv, n. paraventricularis hypothalami; ic, insulae Calleja; iCM, insula Calleja magna; mi, massae intercalatae; mml, n. mamillaris medialis, pars lateralis; mmm, n. mamillaris medialis, pars medialis; na, n. arcuatus; ncs, n. centralis superior; ndm, n. dorsomedialis; nha, n. hypothalamicus anterior; nhp, n. hypothalamicus posterior; nist, n. interstitialis striae terminalis; nistd, n. interstitialis striae terminalis, pars dorsalis; nistv, n. interstitialis striae terminalis, pars ventralis; npl, n. prelateralis mamillaris; nsc, n. suprachiasmaticus; nso, n. supraopticus; nvm, n. ventromedialis; oam, n. olfactorius anterior, pars medialis; oap, n. olfactorius anterior, pars posterior; ol, n. tractus olfactorii lateralis; P, tractus corticospinalis; p, n. pretectalis; PCS, pedunculus cerebellaris superior; pf, n. parafascicularis; pol, n. preopticus lateralis; pom, n. preopticus medialis; pv, n. paraventricularis thalami; S, subiculum; sf, n. fimbrialis septi; SG, supragenual system; sl, n. lateralis septi; SM, stria medullaris thalami; sm, n. medialis septi; snc, substantia nigra, pars compacta; snr, substantia nigra, pars reticulata; SR, sulcus rhinalis; SRH, suprarhinal system; ST, stria terminalis; sut, n. subthalamicus; tam, n. anterior medialis thalami; TD, tractus diagonalis Broca; td, n. tractus diagonalis Broca; tl, n. lateralis thalami; tlp, n. lateralis posterior thalami; tml, n. medialis thalami, pars lateralis; tmm, n. medialis thalami, pars medialis; TO, tractus opticus; TOI, tractus olfactorius intermedius; TOL, tractus olfactorius lateralis; tol, n. tractus optici, pars lateralis; tom, n. tractus optici, pars medialis; tr, n. reticularis thalami; tv, n. ventralis thalami; and vcgl, n. ventralis corporis geniculati lateralis.

Data from refs. 34,63,143,145,148,169,172,226,228,229,295,297,300,302,303,305,660,349,354,482,483,525
Figure 12. Figure 12.

Topographical organization of mesostriatal DA projections, as viewed in frontal (A, B) or horizontal (C) planes. Compare with Figs. 1, 3, and 11. acc, N. accumbens; ncp, n. caudatus‐putamen; ot, olfactory tubercle; and rrn, retrorubral n. (A8).

Figure 13. Figure 13.

Topographical organization of mesolimbocortical DA projections to some limbic and allocortical (A) and neocortical (B) areas. Compare with Figs. 1, 3, and 11. AM, anteromedial system; C, corpus callosum; CC, crus cerebri; CPF, piriform cortex; DG, dentate gyrus; EC, external capsule; ERC, entorhinal cortex; H, hippocampus; ic, internal capsule; ip, interpeduncular n.; LS, lateral septal n.; SG, supragenual system; and SR, suprarhinal system.

Figure 14. Figure 14.

A: diencephalic DA projection systems, including incertohypothalamic, tuberohypophysial, periventricular, and diencephalospinal systems. H, hypothalamus; ME, median eminence; P, pituitary gland; PO, preoptic area; S, septal area; SP, spinal cord; and T, thalamus. B: proposed arrangement of diencephalospinal DA system.

Figure 15. Figure 15.

Distribution of incertohypothalamic fiber system at 6 representative frontal levels (a‐f). Locations of CA‐containing cell groups (A11, A13, A14) are also indicated. ah, Anterior hypothalamic n.; dh, dorsal hypothalamic area; dm, dorsomedial hypothalamic n.; MT, mammillothalamic tract; OC, optic chiasm; ph, posterior hypothalamic n.; pom, medial preoptic n.; PPN, periventricular preoptic nuclei; pv, periventricular hypothalamic n.; st, interstitial n. of stria terminalis; and vm, ventromedial hypothalamic n.

From Björklund et al. 44
Figure 16. Figure 16.

Arrangement of tuberohypophysial DA system in rat. A: distribution of CA‐containing terminals in median eminence, neural lobe (NL), pars intermedia (PI), and pars distalis (PD). VIII, 3rd ventricle. B and C: projection patterns from paraventricular (HPV) and arcuate (AR) nuclei to median eminence and pituitary.

From Björklund et al. 42
Figure 17. Figure 17.

Anatomical relationships between cerebral cortex, striatal complex, thalamus, and ventral mesencephalon. Left‐tilted hatching, areas innervated by substantia nigra; right‐tilted hatching, areas innervated by DA neurons of A10 cell group. ACC, n. accumbens; CP, n. caudatus‐putamen; DP, dorsal pallidum; HL, lateral habenular n.; MD, mediodorsal thalamic n.; OT, olfactory tubercle; ST, bed n. of stria terminalis; VL + VA, ventrolateral and ventral anterior thalamic nuclei; and VP, ventral pallidum.

Figure 18. Figure 18.

Comparison of areas within striatal complex receiving afferents from nigral and DA neurons of A10 cell group (left) and from different parts of cortical mantle and amygdala (right).

Figure 19. Figure 19.

Some major pathways and transmitter characteristics related to nigral DA projection to dorsal part of striatal complex (i.e., n. caudatus‐putamen). ENK, enkephalin; SP, substance P; and nc. entoped., n. entopenduncularis.

Figure 20. Figure 20.

Some major pathways and transmitter characteristics related to DA projection from VTA and medial substantia nigra to ventral part of striatal complex and to limbic cortex. MD, mediodorsal thalamic nucleus; and BNST, bed n. of stria terminalis.

Figure 21. Figure 21.

Proposed model for action of mesostriatal DA system. Behavioral response (R) evoked by an activating sensory input (I) is modulated by DA system via inhibitory control mechanism. Dopaminergic denervation (bottom) results in inhibition of behavioral response.

Figure 22. Figure 22.

Simplified scheme illustrating some possible interactions between systems containing DA, GABA, glutamate (GLU), and acetylcholine (ACh) in basal ganglia. A: level‐setting action; B: gating action. r, Reticulata; and c, compacta.

Figure 23. Figure 23.

Possible modes of action of DA released from dendrites in substantia nigra. 1, Autoinhibition of dopaminergic neurons; 2, lateral inhibition; 3, modulation of GABA release from striatonigral afferents and GABAergic interneurons; 4, direct activation of reticulata neurons; and 5, attenuation of inhibitory action of GABA at afferent synapses.

Figure 24. Figure 24.

Pontine NE projection systems, with cell bodies in locus coeruleus‐subcoeruleus complex, as well as A5 and A7 cell groups. APL, amygdala‐piriform lobe; CC, cerebral cortex; CER, cerebellum; H, hypothalamus; HI, hippocampus; OB, olfactory bulb; S, septal area; SP, spinal cord; T, thalamus; and TE, tectum.

Figure 25. Figure 25.

Retrograde labeling of cells in locus coeruleus after horseradish peroxidase injections into various forebrain areas. VLC, ventral locus coeruleus; ALC, anterior locus coeruleus; MV, mesencephalic n. of trigeminal nerve; and 4, 4th ventricle. A, C, and D are coronal sections at mid, anterior, and posterior levels of nucleus; B is parasagittal section.

From McNaughton and Mason 348
Figure 26. Figure 26.

Terminal distribution of locus coeruleus NE afferents to rat hippocampus, in 7 equally spaced coronal levels through hippocampal formation.

From Björklund et al. 47
Figure 27. Figure 27.

Various routes for locus coeruleus axons to hippocampus, with their percent contribution to total noradrenergic innervation of hippocampal formation. CB, cingulum bundle; DTB, dorsal tegmental bundle; FF, fimbria‐fornix; LC, locus coeruleus; and VP, ventral path.

Adapted from Gage et al. 619
Figure 28. Figure 28.

Proposed arrangement of noradrenergic fiber trajectories to neocortex. Medial cortex is mainly innervated by fibers that ascend through septum (s), curve over genu of corpus callosum (CC), and then run caudally in supracallosal stria. Dorsolateral cortex is innervated by axons from MFB that reach the frontal pole, turn dorsally over forceps minor (FMI), and continue caudally within deep layers of frontal and dorsolateral cortex, ncp, N. caudatus‐putamen.

Adapted from Morrison et al. 364
Figure 29. Figure 29.

Proposed arrangement of coeruleospinal (A) and tegmentospinal (B) noradrenergic systems.

Figure 30. Figure 30.

Medullary noradrenergic projection systems, with cell bodies in A1 and A2 cell groups. AM, amygdala; H, hypothalamus; PO, preoptic area; S, septal area; and T, thalamus.

Figure 31. Figure 31.

Relationship of pontine and medullary noradrenergic projection systems to some major functional systems in brain and spinal cord. A: neuromodulator action; increased signal‐to‐noise ratio. Left, blockade of background activity; right, potentiation of phasic excitation. B: level‐setting action; disinhibition or gain control. Left, lateral geniculate nucleus; right, olfactory bulb. G, granule cells; +, excitation; and −, inhibition.

Figure 32. Figure 32.

Proposed models for neuromodulatory and level‐setting actions of noradrenergic system, d, Dorsal; v, ventral.

Data from Woodward et al. 558, Nakai and Takaori 374, and Jahr and Nicoll 241
Figure 33. Figure 33.

Command‐driving function of mesencephalic locomotor region (MLR) in regulation of spinal locomotion generator. Pontine noradrenergic neurons may participate in this control.

Adapted from Grillner 191
Figure 34. Figure 34.

A: normal CA innervation pattern in retrochiasmatic region of rat. B: extent of denervation and axotomy acutely (1 wk) after intraventricular injection of 5,7‐dihydroxytryptamine (150 μg). C and D: subsequent sprouting and regrowth of lesioned CA axons (C, 3 wk; D, 3–6 mo). Illustrations are drawn from vibratome sections treated according to glyoxylic acid fluorescence method. AH, anterior hypothalamic area; PN, periventricular hypothalamic n.; PVN, paraventricular hypothalamic n.

From Björklund and Lindvall 585
Figure 35. Figure 35.

Compensatory collateral sprouting of locus coeruleus NE afferents to hippocampal formation after lesion of supracallosal pathway [running in cingulum (CC) bundle, top] and after lesion of supracallosal plus fimbria‐fornix (FF) pathways (bottom). In each case extent of spared NE innervation and its subsequent expansion over time is indicated by crosshatching. Compare with Figs. 26 and 27.

From Gage et al. 620


Figure 1.

Distribution of catecholamine (CA)‐containing cell bodies in rat brain (coronal sections). ar, Arcuate nucleus; CC, crus cerebri; CSC, commissure of superior colliculus; DLF, dorsal longitudinal fasciculus; dm, dorsomedial hypothalamic n.; drn, dorsal raphe n.; F, fornix; FLM, f. longitudinalis medialis; FMT, f. mammillothalamicus; FR, f. retroflexus; G VII, genu of facial nerve; gp, globus pallidus; H1 and H2, tegmental fields of Forel; ha, anterior hypothalamic area; hl, lateral hypothalamic area; hp, posterior hypothalamic area; IC, internal capsule; ioc, inferior olivary complex; ip, interpeduncular n.; lc, locus coeruleus; LM, lemniscus medialis; MCP, middle cerebellar peduncle; me V, mesencephalic trigeminal n.; MFB, medial forebrain bundle; MLF, medial longitudinal f.; N III, oculomotor nerve; N VII, facial nerve; n V, principal trigeminal n.; n VII, facial n.; n X, dorsal motor n. of vagus; n XII, hypoglossal n.; ns V, spinal trigeminal n.; nst, n. of solitary tract; nvm, medial vestibular n.; nvp, posterior vestibular n.; OC, optic chiasm; OT, optic tract or olfactory tubercle; P, pyramidal tract; PC, posterior commissure; pm, posterior mammillary n.; pv, periventricular hypothalamic n.; r, n. ruber; rl, lateral reticular n.; sc, suprachiasmatic n.; SCP, superior cerebellar peduncle; SM, stria medullaris; snc, substantia nigra, pars compacta; snr, substantia nigra, pars reticulata; soc, superior olivary complex; TS V, spinal tract of trigeminal nerve; V, trigeminal nerve; V III, 3rd ventricle; V IV, 4th ventricle; vm, ventromedial n.; vta, ventral tegmental area; vtn, ventral tegmental or ventral thalamic n.; and ZI, zona incerta.

Adapted from Björklund and Nobin 46, Dahlström and Fuxe 102, Palkovits and Jacobowitz 403, and Swanson and Hartman 507


Figure 2.

Distribution of noradrenergic neurons (•) in locus coeruleus of rat; sections are transverse to longitudinal axis of brain stem. Level 1 is most rostral and level 6 most caudal. dtn, Dorsal tegmental n.; and Vm, mesencephalic trigeminal n.

Adapted from Grzanna and Molliver 201


Figure 3.

Distribution of dopaminergic neurons in A10 cell group and medial substantia nigra, as revealed by tyrosine hydroxylase immunohistochemistry. A is most rostral and H most caudal. AOB, basal n. of accessory optic tract; bp, brachium pontis; CL, central linear n.; cp, cerebral peduncle; dbc, decussation of brachium conjunctivum; EW, Edinger‐Westphal n.; fr, f. retroflexus; IF, interfascicular n.; IPC, central interpeduncular n.; IPF, interpeduncular fossa; IPI, posterior interpeduncular n., inner division; IPO, posterior interpeduncular n., outer division; IPP, paramedian interpeduncular n.; ml, medial lemniscus; mlf, medial longitudinal f.; MM, medial mammillary n.; mp, mammillary peduncle; mt, mammillothalamic tract; PHA, posterior hypothalamic area; PVp, posterior periventricular n.; RL, rostral linear n.; RN, red n.; RR, retrorubral n.; SNc, substantia nigra, pars compacta; SNr, substantia nigra, pars reticulata; SUMl, supramammillary region, pars lateralis; SUMm, supra‐mammillary region, pars medialis; TM, tuberomammillary n.; VTA, ventral tegmental area; vtd, ventral tegmental decussation; ZI, zona incerta; III, oculomotor n.; IIIn, oculomotor nerve; and IIIr, oculomotor root fibers.

From Swanson 502


Figure 4.

Relative development of pontine, mesencephalic, and diencephalic CA neuron systems in 7 vertebrate classes. Values are crude estimates of number of cell bodies, as extracted from various studies, a, Ref. 521; b, ref. 520; c, ref. 501; d, ref. 341; e, ref. 22; f, ref. 502; g, ref. 537; i, ref. 414; j, ref. 418; k, refs. 60,410. NA, norephinephrine; DA, dopamine; and A, epinephrine.



Figure 5.

Major CA projection systems in 5 classes of vertebrates (A, fish; B, amphibian; C, turtle; D, chicken; E, rat). ACC, anterior cingulate cortex; AS, n. accumbens septi; CER, cerebellum; DC, dorsal cortex; LPO, paraolfactory lobe; LS, lateral septal n.; NPT, n. posterior tuberis; PA, Palleo‐striatum augmentatum; PFC, prefrontal cortex; PVO, paraventricular organ; S, septum; STR, striatum; TECT, tectum.

Adaped from Parent et al. 414, Parent 413,681, Dubé and Parent 127, and Lindvall and Björklund 297


Figure 6.

Ascending CA fiber system of dorsal tegmental bundle (DTB), originating in locus coeruleus (LC), and its projections in diencephalon. Medial part of MFB and cells in medial part of pars compacta of substantia nigra (SNC) are also included. Figure is composite of slightly different sagittal planes. am, Anteromedial n.; av, anteroventral n.; DPS, dorsal periventricular system; DSCP, decussation of superior cerebellar peduncles; G VII, genu of facial nerve; lh, lateral habenular n.; MB, medullary CA bundle; ML, medial lemniscus; ret, reticular n.; SOD, supraoptic decussations; and TR, tegmental CA radiations.

From Lindvall and Björklund 297


Figure 7.

Ascending and descending CA fiber systems in central tegmental tract (CTT) and its caudal extension, the medullary CA bundle (MB). Rostrally, part of nigrostriatal pathway is represented in its extension through internal capsule (CI) and globus pallidus. Figure is composite of different sagittal planes. Note that mesencephalic and pontine parts of drawing illustrate plane situated ∼0.5 mm more medial than rest. AC, anterior commissure; CC, crus cerebri; G VII, genu of facial nerve; ML, medial lemniscus; NCP, n. caudatus‐putamen; NSP, nigrostriatal pathway; OT, optic tract; SC, n. subcoeruleus; SNC, substantia nigra, pars compacta; so, supraoptic n.; SOD, supraoptic decussations; ST, stria terminalis; and TUB, olfactory tubercle.

From Lindvall and Björklund 297


Figure 8.

Periventricular CA fiber system rostral to locus coeruleus. Figure is composite of somewhat different paramedian sagittal planes. dmh, Dorsomedial hypothalamic n.; DPB, dorsal periventricular bundle; DTB, dorsal tegmental bundle; mh, medial habenular n.; MP, mammillary peduncle; pf, parafascicular n.; pvh, paraventricular hypothalamic n.; pvt, paraventricular thalamic n.; rh, rhomboidal n.; and VPS, ventral periventricular system.

From Lindvall and Björklund 297


Figure 9.

Horizontal section through dorsal part of MFB system, ventral part of nigrostriatal pathway (NSP), and ansa lenticularis (AL). Compare with sagittal drawings in Figs. 6 and 7. Figure is composite of slightly different horizontal planes. AC, anterior commissure; ACC, n. accumbens; can, central amygdaloid n.; CTT, central tegmental tract; dmh, dorsomedial hypothalamic n.; and st, interstitial n. of stria terminalis.

From Lindvall and Björklund 297


Figure 10.

Mesostriatal (A) and mesolimbocortical (B) dopamine (DA) projection systems. Stippling indicates innervated areas. a, N. accumbens; ACC, anterior cingulate cortex; AN, amygdaloid nuclei; CE, entorhinal cortex; cp, n. caudatus‐putamen; MCG, mesencephalic DA cell groups; OB, olfactory bulb; PFC, prefrontal cortex; pi, piriform cortex; sl, lateral septal n.; and tu, tuberculum olfactorium.



Figure 11.

Twenty‐four frontal planes showing distribution and density of DA terminals in CNS of rat. Terminal densities: very dense (4+), dense (3+), medium dense (2+), least dense (1+). Terminal distribution of incertohypothalamic and tuberohypophysial DA systems is not shown. AA, area amygdaloidea anterior; ab, n. amygdaloideus basalis; abl, n. amygdaloideus basalis, pars lateralis; abm, n. amygdaloideus basalis, pars medialis; ac, n. amygdaloideus centralis; aco, n. amygdaloideus corticalis; al, n. amygdaloideus lateralis; ala, n. amygdaloideus lateralis, pars anterior; alp, n. amygdaloideus lateralis, pars posterior; AM, anteromedial system; am, n. amygdaloideus medialis; CA, commissura anterior; CAI, capsula interna; CCA, corpus callosum; CFV, commissura fornicis ventralis; cgm, corpus geniculatum mediale; cl, claustrum; CO, chiasma opticum; CP, commissura posterior; dcgl, n. dorsalis corporis geniculati lateralis; ep, n. entopeduncularis; FH, fimbria hippocampi; FMI, forceps minor; GCC, genu corporis callosi; gp, globus pallidus; HI, hippocampus; HIA, hippocampus anterior; hl, n. habenulae lateralis; hm, n. habenulae medialis; hpv, n. paraventricularis hypothalami; ic, insulae Calleja; iCM, insula Calleja magna; mi, massae intercalatae; mml, n. mamillaris medialis, pars lateralis; mmm, n. mamillaris medialis, pars medialis; na, n. arcuatus; ncs, n. centralis superior; ndm, n. dorsomedialis; nha, n. hypothalamicus anterior; nhp, n. hypothalamicus posterior; nist, n. interstitialis striae terminalis; nistd, n. interstitialis striae terminalis, pars dorsalis; nistv, n. interstitialis striae terminalis, pars ventralis; npl, n. prelateralis mamillaris; nsc, n. suprachiasmaticus; nso, n. supraopticus; nvm, n. ventromedialis; oam, n. olfactorius anterior, pars medialis; oap, n. olfactorius anterior, pars posterior; ol, n. tractus olfactorii lateralis; P, tractus corticospinalis; p, n. pretectalis; PCS, pedunculus cerebellaris superior; pf, n. parafascicularis; pol, n. preopticus lateralis; pom, n. preopticus medialis; pv, n. paraventricularis thalami; S, subiculum; sf, n. fimbrialis septi; SG, supragenual system; sl, n. lateralis septi; SM, stria medullaris thalami; sm, n. medialis septi; snc, substantia nigra, pars compacta; snr, substantia nigra, pars reticulata; SR, sulcus rhinalis; SRH, suprarhinal system; ST, stria terminalis; sut, n. subthalamicus; tam, n. anterior medialis thalami; TD, tractus diagonalis Broca; td, n. tractus diagonalis Broca; tl, n. lateralis thalami; tlp, n. lateralis posterior thalami; tml, n. medialis thalami, pars lateralis; tmm, n. medialis thalami, pars medialis; TO, tractus opticus; TOI, tractus olfactorius intermedius; TOL, tractus olfactorius lateralis; tol, n. tractus optici, pars lateralis; tom, n. tractus optici, pars medialis; tr, n. reticularis thalami; tv, n. ventralis thalami; and vcgl, n. ventralis corporis geniculati lateralis.

Data from refs. 34,63,143,145,148,169,172,226,228,229,295,297,300,302,303,305,660,349,354,482,483,525


Figure 12.

Topographical organization of mesostriatal DA projections, as viewed in frontal (A, B) or horizontal (C) planes. Compare with Figs. 1, 3, and 11. acc, N. accumbens; ncp, n. caudatus‐putamen; ot, olfactory tubercle; and rrn, retrorubral n. (A8).



Figure 13.

Topographical organization of mesolimbocortical DA projections to some limbic and allocortical (A) and neocortical (B) areas. Compare with Figs. 1, 3, and 11. AM, anteromedial system; C, corpus callosum; CC, crus cerebri; CPF, piriform cortex; DG, dentate gyrus; EC, external capsule; ERC, entorhinal cortex; H, hippocampus; ic, internal capsule; ip, interpeduncular n.; LS, lateral septal n.; SG, supragenual system; and SR, suprarhinal system.



Figure 14.

A: diencephalic DA projection systems, including incertohypothalamic, tuberohypophysial, periventricular, and diencephalospinal systems. H, hypothalamus; ME, median eminence; P, pituitary gland; PO, preoptic area; S, septal area; SP, spinal cord; and T, thalamus. B: proposed arrangement of diencephalospinal DA system.



Figure 15.

Distribution of incertohypothalamic fiber system at 6 representative frontal levels (a‐f). Locations of CA‐containing cell groups (A11, A13, A14) are also indicated. ah, Anterior hypothalamic n.; dh, dorsal hypothalamic area; dm, dorsomedial hypothalamic n.; MT, mammillothalamic tract; OC, optic chiasm; ph, posterior hypothalamic n.; pom, medial preoptic n.; PPN, periventricular preoptic nuclei; pv, periventricular hypothalamic n.; st, interstitial n. of stria terminalis; and vm, ventromedial hypothalamic n.

From Björklund et al. 44


Figure 16.

Arrangement of tuberohypophysial DA system in rat. A: distribution of CA‐containing terminals in median eminence, neural lobe (NL), pars intermedia (PI), and pars distalis (PD). VIII, 3rd ventricle. B and C: projection patterns from paraventricular (HPV) and arcuate (AR) nuclei to median eminence and pituitary.

From Björklund et al. 42


Figure 17.

Anatomical relationships between cerebral cortex, striatal complex, thalamus, and ventral mesencephalon. Left‐tilted hatching, areas innervated by substantia nigra; right‐tilted hatching, areas innervated by DA neurons of A10 cell group. ACC, n. accumbens; CP, n. caudatus‐putamen; DP, dorsal pallidum; HL, lateral habenular n.; MD, mediodorsal thalamic n.; OT, olfactory tubercle; ST, bed n. of stria terminalis; VL + VA, ventrolateral and ventral anterior thalamic nuclei; and VP, ventral pallidum.



Figure 18.

Comparison of areas within striatal complex receiving afferents from nigral and DA neurons of A10 cell group (left) and from different parts of cortical mantle and amygdala (right).



Figure 19.

Some major pathways and transmitter characteristics related to nigral DA projection to dorsal part of striatal complex (i.e., n. caudatus‐putamen). ENK, enkephalin; SP, substance P; and nc. entoped., n. entopenduncularis.



Figure 20.

Some major pathways and transmitter characteristics related to DA projection from VTA and medial substantia nigra to ventral part of striatal complex and to limbic cortex. MD, mediodorsal thalamic nucleus; and BNST, bed n. of stria terminalis.



Figure 21.

Proposed model for action of mesostriatal DA system. Behavioral response (R) evoked by an activating sensory input (I) is modulated by DA system via inhibitory control mechanism. Dopaminergic denervation (bottom) results in inhibition of behavioral response.



Figure 22.

Simplified scheme illustrating some possible interactions between systems containing DA, GABA, glutamate (GLU), and acetylcholine (ACh) in basal ganglia. A: level‐setting action; B: gating action. r, Reticulata; and c, compacta.



Figure 23.

Possible modes of action of DA released from dendrites in substantia nigra. 1, Autoinhibition of dopaminergic neurons; 2, lateral inhibition; 3, modulation of GABA release from striatonigral afferents and GABAergic interneurons; 4, direct activation of reticulata neurons; and 5, attenuation of inhibitory action of GABA at afferent synapses.



Figure 24.

Pontine NE projection systems, with cell bodies in locus coeruleus‐subcoeruleus complex, as well as A5 and A7 cell groups. APL, amygdala‐piriform lobe; CC, cerebral cortex; CER, cerebellum; H, hypothalamus; HI, hippocampus; OB, olfactory bulb; S, septal area; SP, spinal cord; T, thalamus; and TE, tectum.



Figure 25.

Retrograde labeling of cells in locus coeruleus after horseradish peroxidase injections into various forebrain areas. VLC, ventral locus coeruleus; ALC, anterior locus coeruleus; MV, mesencephalic n. of trigeminal nerve; and 4, 4th ventricle. A, C, and D are coronal sections at mid, anterior, and posterior levels of nucleus; B is parasagittal section.

From McNaughton and Mason 348


Figure 26.

Terminal distribution of locus coeruleus NE afferents to rat hippocampus, in 7 equally spaced coronal levels through hippocampal formation.

From Björklund et al. 47


Figure 27.

Various routes for locus coeruleus axons to hippocampus, with their percent contribution to total noradrenergic innervation of hippocampal formation. CB, cingulum bundle; DTB, dorsal tegmental bundle; FF, fimbria‐fornix; LC, locus coeruleus; and VP, ventral path.

Adapted from Gage et al. 619


Figure 28.

Proposed arrangement of noradrenergic fiber trajectories to neocortex. Medial cortex is mainly innervated by fibers that ascend through septum (s), curve over genu of corpus callosum (CC), and then run caudally in supracallosal stria. Dorsolateral cortex is innervated by axons from MFB that reach the frontal pole, turn dorsally over forceps minor (FMI), and continue caudally within deep layers of frontal and dorsolateral cortex, ncp, N. caudatus‐putamen.

Adapted from Morrison et al. 364


Figure 29.

Proposed arrangement of coeruleospinal (A) and tegmentospinal (B) noradrenergic systems.



Figure 30.

Medullary noradrenergic projection systems, with cell bodies in A1 and A2 cell groups. AM, amygdala; H, hypothalamus; PO, preoptic area; S, septal area; and T, thalamus.



Figure 31.

Relationship of pontine and medullary noradrenergic projection systems to some major functional systems in brain and spinal cord. A: neuromodulator action; increased signal‐to‐noise ratio. Left, blockade of background activity; right, potentiation of phasic excitation. B: level‐setting action; disinhibition or gain control. Left, lateral geniculate nucleus; right, olfactory bulb. G, granule cells; +, excitation; and −, inhibition.



Figure 32.

Proposed models for neuromodulatory and level‐setting actions of noradrenergic system, d, Dorsal; v, ventral.

Data from Woodward et al. 558, Nakai and Takaori 374, and Jahr and Nicoll 241


Figure 33.

Command‐driving function of mesencephalic locomotor region (MLR) in regulation of spinal locomotion generator. Pontine noradrenergic neurons may participate in this control.

Adapted from Grillner 191


Figure 34.

A: normal CA innervation pattern in retrochiasmatic region of rat. B: extent of denervation and axotomy acutely (1 wk) after intraventricular injection of 5,7‐dihydroxytryptamine (150 μg). C and D: subsequent sprouting and regrowth of lesioned CA axons (C, 3 wk; D, 3–6 mo). Illustrations are drawn from vibratome sections treated according to glyoxylic acid fluorescence method. AH, anterior hypothalamic area; PN, periventricular hypothalamic n.; PVN, paraventricular hypothalamic n.

From Björklund and Lindvall 585


Figure 35.

Compensatory collateral sprouting of locus coeruleus NE afferents to hippocampal formation after lesion of supracallosal pathway [running in cingulum (CC) bundle, top] and after lesion of supracallosal plus fimbria‐fornix (FF) pathways (bottom). In each case extent of spared NE innervation and its subsequent expansion over time is indicated by crosshatching. Compare with Figs. 26 and 27.

From Gage et al. 620
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Anders Björklund, Olle Lindvall. Catecholaminergic Brain Stem Regulatory Systems. Compr Physiol 2011, Supplement 4: Handbook of Physiology, The Nervous System, Intrinsic Regulatory Systems of the Brain: 155-235. First published in print 1986. doi: 10.1002/cphy.cp010403