Comprehensive Physiology Wiley Online Library

Organization of Mammalian Neuroendocrine System

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Abstract

The sections in this article are:

1 Regulation of Pituitary Gland
2 Anatomy of Pituitary Gland and Circumventricular Organs
3 Anatomy of Hypothalamus
3.1 Pathway‐Tracing Methods
4 Pathways Containing Hormones of Magnocellular Neurosecretory System
4.1 Projections to Pituitary
4.2 Projection to Median Eminence
4.3 Projections to Limbic Region and Choroid Plexus
4.4 Projections to Brain Stem and Spinal Cord
4.5 Suprachiasmatic Nucleus
5 Pathways Containing Hormones of Parvocellular Neurosecretory System
5.1 Thyrotropin‐Releasing Hormone
5.2 Gonadotropin‐Releasing Hormone
5.3 Somatostatin
5.4 Growth Hormone‐Releasing Hormone
5.5 Corticotropin‐Releasing Hormone
6 Summary
6.1 Location of Neurosecretory Cell Bodies
6.2 Extrahypophysial Pathways
6.3 Afferent Control of Peptidergic Neurons
7 Conclusion
Figure 1. Figure 1.

Schematic midsagittal view of embryonic human brain at 7‐mm stage. Hypothalamus (H) develops in basal plate, ventral to sulcus limitans (SL) and caudal to the groove that separates medial striatal ridge (M) from preoptic region (P). Arrow points to evagination that will form stalk and posterior lobe of pituitary gland. DR, diencephalic roof plate; H, presumptive hippocampus; L, lateral striatal ridge; LT, lamina terminalis; oc, presumptive optic chiasm; r, rhinal fissure; S, presumptive septal region; T, thalamus; TR, telencephalic roof plate.

Data from Bailey 10, Christ 72, and Hines 145
Figure 2. Figure 2.

Schematic midsaggital view of adult rat brain to show location of specialized structures associated with 3rd ventricle (V3), including median eminence (ME) and stalk of pituitary (S), vascular organ of lamina terminalis (OV), and subfornical organ (SF). A, anterior lobe (pituitary); ac, anterior commissure; AQ, cerebral aqueduct; cc, corpus callosum; I, intermediate lobe (pituitary); M, mammillary body; MI, massa intermedia (thalamus); P, posterior lobe (pituitary); PG, pineal gland; R, diencephalic roof plate.

Figure 3. Figure 3.

General organization of hypothalamic cell groups as seen in schematic horizontal view of right side of rat brain. Thin oval structure to left represents 3rd ventricle (V3), which lies in the midline; anterior is at top. Note that hypothalamus can be divided into 3 longitudinal zones. Thin periventricular zone lies next to 3rd ventricle, medial zone consists of a series of discrete cell groups arranged from anterior to posterior, and lateral zone consists of lateral preoptic (LPO) and lateral hypothalamic (LHA) areas. Hypothalamus can be further divided into 4 transverse regions more or less defined by nuclei in medial zone: preoptic region, which is coextensive with medial preoptic nucleus (MP); anterior region, which is coextensive with anterior hypothalamic nucleus (AH); tuberal region, which is coextensive with ventromedial (VM) and dorsomedial nuclei; and mammillary region, which is coextensive with premammillary, medial and lateral mammillary (MAM), and supramammillary (SUM) nuclei. A, amygdala; ARH, arcuate nucleus; B, bed nucleus of stria terminalis; DB, nucleus of diagonal band; GP, globus pallidus; H, hippocampus; ic, internal capsule; LS, lateral septal nucleus; MePO, median preoptic nucleus; ot, optic tract; OVLT, vascular organ of lamina terminalis; PAG, periaqueductal gray; PHA, posterior hypothalamic area; PVH, paraventricular nucleus; PVp, posterior periventricular nucleus; SCh, suprachiasmatic nucleus; SI, substantia innominata; SN, substantia nigra; STR, striatum; TN, anteroventral periventricular nucleus; VL, lateral ventricle; VT, ventral tegmental area. For discussion of cytoarchitectonic features here and in Fig. 4, see refs. 259,313,347,366,370.

Figure 4. Figure 4.

Photomicrographs of frontal sections through each of the 4 major regions of hypothalamus illustrated in Fig. 3. A: preoptic; B: anterior; C: tuberal; and, D: mammillary. Unlabeled region in D, medial to lateral mammillary nucleus, is medial mammillary nucleus; supramammillary nucleus lies just dorsal to these 2 nuclei. A, anterior lobe (pituitary); AA, anterior amygdalar area; AH, anterior hypothalamic area; am, anterior magnocellular part of paraventricular nucleus (PV); ap, anterior parvocellular part of PV; AR, arcuate nucleus; BST, bed nucleus of stria terminalis; cp, cerebral peduncle; DG, dentate gyrus; DM, dorsomedial nucleus; f, fornix; GP, gobus pallidus; I, intermediate lobe of pituitary; ic, internal capsule; LHA, lateral hypothalamic area; LM, lateral mammillary nucleus; LPO, lateral preoptic area; m, mammillothalamic tract; MA, medial nucleus (amygdala); mc, medial corticohypothalamic tract; ME, median eminence; MP, medial preoptic nucleus; MR, mammillary recess; ot, optic tract; P, posterior lobe of pituitary; PH, posterior hypothalamic area; Pp, preoptic periventricular nucleus; PVp, posterior periventricular nucleus; RC, retrochiasmatic area; RE, nucleus reuniens; RT, reticular nucleus (thalamus); sc, supramammillary commissure; SC, suprachiasmatic nucleus; SI, substantia innominata; sm, stria medullaris; SO, supraoptic nucleus; SOr, supraoptic nucleus, retrochiasmatic part; st, stria terminalis; ti, tubero‐infundibular tract; TM, tuberomammillary nucleus; VM, ventromedial nucleus; ZI, zona incerta. Celloidin sections of rat, 40 μm thick; thionine stain. × 40.

Figure 5. Figure 5.

Part of a hypothetical neural circuit illustrating use of neuroanatomical pathway tracing methods. Two neurons that synthesize different transmitters (open and filled circles) are located at a, and send axons to terminal fields at A, B, and C. Note that lesion or tracer injection at A may inadvertently affect preterminal axons that end in site B. Two different retrograde tracers, r1 and r2, can be injected to determine whether individual cells in a give rise to divergent collaterals, while an anterograde tracer can be injected to determine total output of cells in a. Immunohistochemical methods may be used to identify cell types in a.

Figure 6. Figure 6.

Hypothalamoneurohypophysial system as seen in frontal section through rat diencephalon, stained with antiserum to neurophysin that labels both vasopressin and oxytocin neurons. Paraventricular nuclei are triangular structures on either side of 3rd ventricle (in midline); supraoptic nuclei lie on lateral edges of optic tracts. Fibers from paraventricular nuclei arch laterally and then ventrally to dorsal surface of optic tracts, where they are joined by fibers from supraoptic nuclei. Together these fibers continue medially to median eminence (ventral to 3rd ventricle). Most of the fibers pass through internal lamina of median eminence to posterior pituitary, although some end in neurohemal zone of external lamina. Some fibers can also be seen coursing toward stria terminalis (dorsolateral corners of micrograph) and up midline to the paraventricular nuclei of thalamus, which lie just medial to stria medullaris (light fiber tract on either side of midline, at top of micrograph). Dark‐field photomicrograph of biotin‐avidin‐stained section, 30 μm thick. × 20.

Figure 7. Figure 7.

Distribution of neurons (dots) that project to posterior pituitary, as determined by retrograde transport studies in rat. A: dark region in midline, just above optic chiasm (oc) represents vascular organ of lamina terminalis; it does not contain retrogradely labeled cells. A‐G (arrangement of frontal sections from rostral to caudal): a, anterior magnocellular part of paraventricular nucleus; ac, anterior commissure; AH, anterior hypothalamic nucleus; AR, arcuate nucleus; BS, bed nucleus of stria terminalis; c, nucleus circularis; d, dorsal parvocellular part of paraventricular nucleus; DB, nucleus of diagonal band; DM, dorsomedial nucleus; f, fornix; G, globus pallidus; ic, internal capsule; LH, lateral hypothalamic area; LP, lateral preoptic area; m, posterior magnocellular part of paraventricular nucleus; Me, median preoptic nucleus; ME, median eminence; MP, medial preoptic area; MS, medial septal nucleus; oc, optic chiasm; ot, optic tract; p, perifornical accessory magnocellular group; PT, parataenial nucleus; PV, periventricular preoptic nucleus; Re, nucleus reuniens; RT, reticular nucleus of thalamus; S, supraoptic nucleus; SI, substantia innominata; sm, stria medullaris; st, stria terminalis; VM, ventromedial nucleus; V3, 3rd ventricle; ZI, zona incerta.

Adapted from Kelly and Swanson 184
Figure 8. Figure 8.

Eight photomicrographs of frontal sections through approximately same part of paraventricular nucleus in different rats. Third ventricle can be seen at left in each micrograph. VAS: vasopressinergic neurons centered in posterior magnocellular part of nucleus. OXY: oxytocinergic neurons form a ring around vasopressinergic (V) zone in posterior magnocellular part of nucleus. CRH: corticotropin‐releasing hormone‐stained neurons form dense cluster in dorsal medial parvocellular part of nucleus, just medial to vasopressin (V) cell group, and ventral to dorsal parvocellular part, which projects to spinal cord (SC). ENK: enkephalin‐stained neurons are also centered in dorsal medial parvocellular part, where they are colocalized with CRH, as well as in a region just lateral to paraventricular nucleus. SS: somatostatin‐stained neurons centered in periventricular part of nucleus. TRH: thyrotropin‐releasing hormone‐immunoreactive cells are found in medial zone of medial parvocellular part of nucleus, just lateral to somatostatinergic neurons, and ventral to CRH neurons. A cluster of such neurons is also seen just lateral to nucleus, in region that also contains enkephalin‐immunoreactive neurons. DVC: distribution of retrogradely labeled neurons in ventral medial parvocellular part of nucleus, after injection of true blue in dorsal vagal complex in medulla. SC: retrogradely labeled neurons in ventral medial and dorsal parvocellular parts of nucleus after injection of true blue in upper thoracic levels of spinal cord, including sympathetic intermediolateral column. Note that dorsal parvocellular part projects almost exclusively to spinal cord. All photomicrographs × 80.

Photomicrographs by Drs. L. W. Swanson, P. E. Sawchenko, and R. W. Lind
Figure 9. Figure 9.

Summary diagram of known direct neural inputs to magnocellular vasopressinergic (vas) neurons in paraventricular (and supraoptic) nuclei of rat. A1, noradrenergic cell group in ventrolateral medulla; MePO, median preoptic nucleus; ne, norepinephrine; NTS, nucleus of solitary tract; PVH, paraventricular nucleus; SFO, subfornical organ; IX, glossopharyngeal nerve; X, vagus nerve.

Figure 10. Figure 10.

Summary diagram of known direct neural inputs to magnocellular oxytocinergic (oxy) neurons in paraventricular (and supraoptic) nuclei of rat. ARH, arcuate nucleus; BST, bed nucleus of stria terminalis; DMH, dorsomedial nucleus; DR, dorsal raphe nucleus; DRG, thoracic dorsal root ganglion; MePO, median preoptic nucleus; MR, median raphe nucleus; PVH, paraventricular nucleus; SFO, subfornical organ.

Figure 11. Figure 11.

Photomicrograph to show distribution of oxytocin‐immunoreactive fibers from paraventricular nucleus in vicinity of caudal part of dorsal motor nucleus of vagus nerve. Vagal motoneurons have been retrogradely labeled with true blue injected into cervical parts of vagus nerve. Central canal is dark oval in midline, at bottom of micrograph. Viewed in microscope, cells were labeled blue and fibers were labeled green (indirect immunofluorescence, with fluorescein). × 150.

Courtesy of Dr. P. E. Sawchenko
Figure 12. Figure 12.

Double retrograde transport experiments indicate that paraventricular nucleus (PVH) contains essentially 3 different types of vasopressinergic (and oxytocinergic) neurons. 1) Magnocellular neurons project to posterior pituitary (PP). 2) Parvocellular neurons project to external lamina (neurohemal zone) of the median eminence (ME). 3) Mediocellular neurons project through medial fore‐brain bundle (mfb) to midbrain, pons, medulla, and spinal cord. CG, central gray; DMX, dorsal motor nucleus of vagus nerve; EW, Edinger‐Westphal nucleus; IML, intermediolateral column (spinal cord); LC, locus coeruleus; MZ, marginal zone (spinal cord); NTS, nucleus of the solitary tract; PB, parabrachial nucleus; PPN, pedunculopontine nucleus.

Figure 13. Figure 13.

Schematic horizontal view of major subdivisions of paraventricular nucleus in rat. am, Anterior magnocellular; ap, anterior parvocellular; dp, dorsal parvocellular; lp, lateral parvocellular; mm, medial magnocellular; mp, medial parvocellular; pm, posterior magnocellular; pv, periventricular.

From Swanson et al. 387
Figure 14. Figure 14.

Summary diagram of direct neural inputs to parts (dorsal and ventral medial parvocellular) of paraventricular nucleus that project directly to autonomic cell groups in brain stem and spinal cord in rat. A1, noradrenergic cell group in ventrolateral medulla; BST, bed nucleus of stria terminalis; HYP, hypothalamic cell groups; NTS, A2 noradrenergic cell group in nucleus of solitary tract; PB, parabrachial nucleus; R, serotonergic raphe nuclei of midbrain; SFO, subfornical organ; ZI, zona incerta; IX, glossopharyngeal nerve; X, vagus nerve.

Figure 15. Figure 15.

Paraventricular nucleus of rat can be roughly divided into 3 major zones: one that projects to median eminence (ME), one to posterior pituitary (PP), and one to autonomic cell groups in brain stem and spinal cord (ANS). Also see Fig. 8. dp, Dorsal parvocellular part; lp, lateral parvocellular part; mpd and mpv, dorsal and ventral medial parvocellular parts; pml and pmm, lateral (vasopressinergic) and medial (oxytocinergic) posterior magnocellular parts; pv, periventricular part.

From Swanson and Sawchenko 386
Figure 16. Figure 16.

Summary diagram of organization of noradrenergic fibers (*) to 3 zones of paraventricular nucleus illustrated in Fig. 15. Projections arise from 3 cell groups in brain stem: A2 group in nucleus of solitary tract (NTS), A1 group in ventrolateral medulla, and locus coeruleus (LC). Each of these cell groups appears to receive visceral sensory information, either directly or indirectly, from glossopharyngeal (IX) or vagus (X) nerves. ANS, autonomic cell groups; ME, neurohemal zone of median eminence; PP, posterior pituitary.

Figure 17. Figure 17.

Distribution of neurons (dots) that project to neurohemal zone of median eminence in rat, as determined by retrograde transport methods. A‐F: arrangement of frontal sections from rostral to caudal. ac, Anterior commissure; AD, anterodorsal preoptic nucleus; AH, anterior hypothalamic nucleus; ap, anterior parvocellular part of paraventricular nucleus; AR, arcuate nucleus; AV, antero‐ventral periventricular nucleus; BS, bed nucleus of stria terminalis; d, dorsal periventricular part of paraventricular nucleus; DB, nucleus of diagonal band; DM, dorsomedial nucleus; f, fornix; LH, lateral hypothalamic area; LP, lateral preoptic area; LS, lateral septal nucleus; LSv, ventral part of LS; m, posterior magnocellular part of paraventricular nucleus; Me, median preoptic nucleus; MN, medial preoptic nucleus; mp, medial parvocellular part of paraventricular nucleus; MP, medial preoptic area; MS, medial septal nucleus; oc, optic chiasm; ot, optic tract; PH, posterior hypothalamic area; PMv, ventral premammillary nucleus; Pp, preoptic periventricular nucleus; PT, paraventricular nucleus of thalamus; pv, periventricular part of paraventricular nucleus; PVa, anterior periventricular nucleus; PVH, paraventricular nucleus of hypothalamus; PVp, posterior periventricular nucleus; RC, retrochiasmatic nucleus; sm, stria medullaris; SC, suprachiasmatic nucleus; SO, supraoptic nucleus; VL, lateral ventricle; VM, ventromedial nucleus; ZI, zona incerta.

Data from refs. 216,389, and 438
Figure 18. Figure 18.

Distribution of thyrotropin‐releasing hormone‐immunoreactive cell bodies (dots) in hypothalamus of rat. A–F: arrangement of frontal sections from rostral to caudal. Many neurons in bed nucleus of stria terminalis (BS), dorsomedial nucleus (DM), and lateral hypothalamic area (LH) do not appear to send fibers to median eminence (see Fig. 17). For other abbreviations see legend to Fig. 17.

Data from P. E. Sawchenko and L. W. Swanson, unpublished observations, and ref. 214
Figure 19. Figure 19.

Distribution of gonadotropin‐releasing hormone‐immunoreactive neurons (dots) in and around hypothalamus of rat. For abbreviations see legend to Fig. 17.

Data from refs. 30,180,429
Figure 20. Figure 20.

Distribution of gonadotropin‐releasing hormone‐immunoreactive cells and fibers in baboon hypothalamus. AC, anterior commissure; CC, corpus callosum; CF, columns of fornix; CN, caudate nucleus; CP, cerebral peduncle; FM, fasciculus retroflexus; FX, fornix; GP, globus pallidus; HDBB, horizontal limb of nucleus of diagonal band; ic, internal capsule; LSN, lateral septal nucleus; LV, lateral ventricle; MB, mammillary body; ME, median eminence; MPO, medial preoptic area; MSN, medial septal nucleus; oc, optic chiasm; OT, optic tract; PVN, paraventricular nucleus; SMT, stria medullaris; SON, supraoptic nucleus; TC, tuber cinereum.

From Marshall and Goldsmith 231
Figure 21. Figure 21.

Distribution of somatostatin‐immunoreactive neurons (dots) in periventricular zone of hypothalamus of rat. For abbreviations see legend to Fig. 17.

Data from refs. 31,95,110,181,317
Figure 22. Figure 22.

Distribution of growth hormone‐releasing hormone‐immunoreactive cell bodies in rat. For abbreviations see legend to Fig. 17.

Data from Sawchenko et al. 436
Figure 23. Figure 23.

Photomicrograph of growth hormone‐releasing hormone‐immunoreactive fibers in median eminence and pituitary stalk of rat. A few immunoreactive cell bodies can also be seen in arcuate nucleus, just lateral to ventral tip of 3rd ventricle (in middle, at top). Immunofluorescence. × 350.

From Sawchenko et al. 436
Figure 24. Figure 24.

Distribution of corticotropin‐releasing hormone‐immunoreactive cell bodies (dots) in and around paraventricular nucleus (PVH) of rat. AHA, anterior hypothalamic nucleus; am, anterior magnocellular part of PVH; ap, anterior parvocellular part of PVH; BST, bed nucleus of stria terminalis; BSTp, bed nucleus of stria terminalis (preoptic part); dp, dorsal parvocellular part of PVH; fx, fornix; lp, lateral parvocellular part of PVH; mct, medial corticohypothalamic tract; mp, medial parvocellular part of PVH; pm, posterior magnocellular part of PVH; PT, parataenial nucleus; pv, periventricular part of PVH; PVT, paraventricular nucleus (thalamus); ZI, zona incerta.

From Swanson et al. 388
Figure 25. Figure 25.

Summary diagram of direct neural pathways to region of corticotropin‐releasing hormone (crh) cell bodies in dorsal medial parvocellular part of paraventricular nucleus (see Fig. 24) in rat. A1, noradrenergic cell group in ventral medulla; BST, bed nucleus of stria terminalis; HYP, hypothalamic cell groups; ME, neurohemal zone of median eminence; NTS, nucleus of solitary tract (A2 noradrenergic cell group); PB, parabrachial nucleus; SFO, subfornical organ.

Figure 26. Figure 26.

Summary diagram of major cell groups (dots) and fiber tracts that cross‐react with antisera to corticotropin‐releasing hormone in rat. ac, Anterior commissure; A1, A5, noradrenergic cell groups; BST, bed nucleus of stria terminalis; cc, corpus callosum; CeA, central nucleus of amygdala; CG, central gray; DR, dorsal raphe nucleus; DVC, dorsal vagal complex; HIP, hippocampus; LDT, laterodorsal tegmental nucleus; LHA, lateral hypothalamic area; LC, locus coeruleus; ME, median eminence (neurohemal zone); mfb, medial forebrain bundle; MID THAL, midline thalamic nuclei; MPO, medial preoptic area; MR, median raphe nucleus; MVN, medial vestibular nucleus; PB, parabrachial nucleus; POR, perioculomotor raphe nucleus; PP, posterior pituitary; PVH, paraventricular nucleus of hypothalamus; SEPT, septal region; SI, substantia innominata; st, stria terminalis.

From Swanson et al. 388
Figure 27. Figure 27.

Summary diagram of location of cell bodies that synthesize known hypophysiotropic hormones and project to neuro‐hemal zone of median eminence, projected on midsagittal view of rat brain (see Fig. 2 for identification of other structures). Outlined areas, major concentrations of cell types, although some of the zones would clearly overlap when viewed from this perspective (see Figs. 18, 19, 21, 22, 24). CRH, corticotropin‐releasing hormone; DA, dopamine; GnRH, gonadotropin‐releasing hormone; GRH, growth hormone‐releasing hormone; MI, massa intermedia (interthalamic adhesion); S, septal region; SS, somatostatin.

Figure 28. Figure 28.

Diagrammatic representation of topographic relation of major cell types in paraventricular nucleus of rat. Frontal view, with 3rd ventricle at left, approximately at level shown in Fig. 8. CRH, corticotropin‐releasing hormone (parvocellular); DA, dopamine (parvocellular); DVC, dorsal vagal complex (parasympathetic); IML, intermediolateral column (sympathetic); OXY, oxytocin (magnocellular); SS, somatostatin (parvocellular); TRH, thyrotropin‐releasing hormone (parvocellular); VAS, vasopressin (magnocellular).



Figure 1.

Schematic midsagittal view of embryonic human brain at 7‐mm stage. Hypothalamus (H) develops in basal plate, ventral to sulcus limitans (SL) and caudal to the groove that separates medial striatal ridge (M) from preoptic region (P). Arrow points to evagination that will form stalk and posterior lobe of pituitary gland. DR, diencephalic roof plate; H, presumptive hippocampus; L, lateral striatal ridge; LT, lamina terminalis; oc, presumptive optic chiasm; r, rhinal fissure; S, presumptive septal region; T, thalamus; TR, telencephalic roof plate.

Data from Bailey 10, Christ 72, and Hines 145


Figure 2.

Schematic midsaggital view of adult rat brain to show location of specialized structures associated with 3rd ventricle (V3), including median eminence (ME) and stalk of pituitary (S), vascular organ of lamina terminalis (OV), and subfornical organ (SF). A, anterior lobe (pituitary); ac, anterior commissure; AQ, cerebral aqueduct; cc, corpus callosum; I, intermediate lobe (pituitary); M, mammillary body; MI, massa intermedia (thalamus); P, posterior lobe (pituitary); PG, pineal gland; R, diencephalic roof plate.



Figure 3.

General organization of hypothalamic cell groups as seen in schematic horizontal view of right side of rat brain. Thin oval structure to left represents 3rd ventricle (V3), which lies in the midline; anterior is at top. Note that hypothalamus can be divided into 3 longitudinal zones. Thin periventricular zone lies next to 3rd ventricle, medial zone consists of a series of discrete cell groups arranged from anterior to posterior, and lateral zone consists of lateral preoptic (LPO) and lateral hypothalamic (LHA) areas. Hypothalamus can be further divided into 4 transverse regions more or less defined by nuclei in medial zone: preoptic region, which is coextensive with medial preoptic nucleus (MP); anterior region, which is coextensive with anterior hypothalamic nucleus (AH); tuberal region, which is coextensive with ventromedial (VM) and dorsomedial nuclei; and mammillary region, which is coextensive with premammillary, medial and lateral mammillary (MAM), and supramammillary (SUM) nuclei. A, amygdala; ARH, arcuate nucleus; B, bed nucleus of stria terminalis; DB, nucleus of diagonal band; GP, globus pallidus; H, hippocampus; ic, internal capsule; LS, lateral septal nucleus; MePO, median preoptic nucleus; ot, optic tract; OVLT, vascular organ of lamina terminalis; PAG, periaqueductal gray; PHA, posterior hypothalamic area; PVH, paraventricular nucleus; PVp, posterior periventricular nucleus; SCh, suprachiasmatic nucleus; SI, substantia innominata; SN, substantia nigra; STR, striatum; TN, anteroventral periventricular nucleus; VL, lateral ventricle; VT, ventral tegmental area. For discussion of cytoarchitectonic features here and in Fig. 4, see refs. 259,313,347,366,370.



Figure 4.

Photomicrographs of frontal sections through each of the 4 major regions of hypothalamus illustrated in Fig. 3. A: preoptic; B: anterior; C: tuberal; and, D: mammillary. Unlabeled region in D, medial to lateral mammillary nucleus, is medial mammillary nucleus; supramammillary nucleus lies just dorsal to these 2 nuclei. A, anterior lobe (pituitary); AA, anterior amygdalar area; AH, anterior hypothalamic area; am, anterior magnocellular part of paraventricular nucleus (PV); ap, anterior parvocellular part of PV; AR, arcuate nucleus; BST, bed nucleus of stria terminalis; cp, cerebral peduncle; DG, dentate gyrus; DM, dorsomedial nucleus; f, fornix; GP, gobus pallidus; I, intermediate lobe of pituitary; ic, internal capsule; LHA, lateral hypothalamic area; LM, lateral mammillary nucleus; LPO, lateral preoptic area; m, mammillothalamic tract; MA, medial nucleus (amygdala); mc, medial corticohypothalamic tract; ME, median eminence; MP, medial preoptic nucleus; MR, mammillary recess; ot, optic tract; P, posterior lobe of pituitary; PH, posterior hypothalamic area; Pp, preoptic periventricular nucleus; PVp, posterior periventricular nucleus; RC, retrochiasmatic area; RE, nucleus reuniens; RT, reticular nucleus (thalamus); sc, supramammillary commissure; SC, suprachiasmatic nucleus; SI, substantia innominata; sm, stria medullaris; SO, supraoptic nucleus; SOr, supraoptic nucleus, retrochiasmatic part; st, stria terminalis; ti, tubero‐infundibular tract; TM, tuberomammillary nucleus; VM, ventromedial nucleus; ZI, zona incerta. Celloidin sections of rat, 40 μm thick; thionine stain. × 40.



Figure 5.

Part of a hypothetical neural circuit illustrating use of neuroanatomical pathway tracing methods. Two neurons that synthesize different transmitters (open and filled circles) are located at a, and send axons to terminal fields at A, B, and C. Note that lesion or tracer injection at A may inadvertently affect preterminal axons that end in site B. Two different retrograde tracers, r1 and r2, can be injected to determine whether individual cells in a give rise to divergent collaterals, while an anterograde tracer can be injected to determine total output of cells in a. Immunohistochemical methods may be used to identify cell types in a.



Figure 6.

Hypothalamoneurohypophysial system as seen in frontal section through rat diencephalon, stained with antiserum to neurophysin that labels both vasopressin and oxytocin neurons. Paraventricular nuclei are triangular structures on either side of 3rd ventricle (in midline); supraoptic nuclei lie on lateral edges of optic tracts. Fibers from paraventricular nuclei arch laterally and then ventrally to dorsal surface of optic tracts, where they are joined by fibers from supraoptic nuclei. Together these fibers continue medially to median eminence (ventral to 3rd ventricle). Most of the fibers pass through internal lamina of median eminence to posterior pituitary, although some end in neurohemal zone of external lamina. Some fibers can also be seen coursing toward stria terminalis (dorsolateral corners of micrograph) and up midline to the paraventricular nuclei of thalamus, which lie just medial to stria medullaris (light fiber tract on either side of midline, at top of micrograph). Dark‐field photomicrograph of biotin‐avidin‐stained section, 30 μm thick. × 20.



Figure 7.

Distribution of neurons (dots) that project to posterior pituitary, as determined by retrograde transport studies in rat. A: dark region in midline, just above optic chiasm (oc) represents vascular organ of lamina terminalis; it does not contain retrogradely labeled cells. A‐G (arrangement of frontal sections from rostral to caudal): a, anterior magnocellular part of paraventricular nucleus; ac, anterior commissure; AH, anterior hypothalamic nucleus; AR, arcuate nucleus; BS, bed nucleus of stria terminalis; c, nucleus circularis; d, dorsal parvocellular part of paraventricular nucleus; DB, nucleus of diagonal band; DM, dorsomedial nucleus; f, fornix; G, globus pallidus; ic, internal capsule; LH, lateral hypothalamic area; LP, lateral preoptic area; m, posterior magnocellular part of paraventricular nucleus; Me, median preoptic nucleus; ME, median eminence; MP, medial preoptic area; MS, medial septal nucleus; oc, optic chiasm; ot, optic tract; p, perifornical accessory magnocellular group; PT, parataenial nucleus; PV, periventricular preoptic nucleus; Re, nucleus reuniens; RT, reticular nucleus of thalamus; S, supraoptic nucleus; SI, substantia innominata; sm, stria medullaris; st, stria terminalis; VM, ventromedial nucleus; V3, 3rd ventricle; ZI, zona incerta.

Adapted from Kelly and Swanson 184


Figure 8.

Eight photomicrographs of frontal sections through approximately same part of paraventricular nucleus in different rats. Third ventricle can be seen at left in each micrograph. VAS: vasopressinergic neurons centered in posterior magnocellular part of nucleus. OXY: oxytocinergic neurons form a ring around vasopressinergic (V) zone in posterior magnocellular part of nucleus. CRH: corticotropin‐releasing hormone‐stained neurons form dense cluster in dorsal medial parvocellular part of nucleus, just medial to vasopressin (V) cell group, and ventral to dorsal parvocellular part, which projects to spinal cord (SC). ENK: enkephalin‐stained neurons are also centered in dorsal medial parvocellular part, where they are colocalized with CRH, as well as in a region just lateral to paraventricular nucleus. SS: somatostatin‐stained neurons centered in periventricular part of nucleus. TRH: thyrotropin‐releasing hormone‐immunoreactive cells are found in medial zone of medial parvocellular part of nucleus, just lateral to somatostatinergic neurons, and ventral to CRH neurons. A cluster of such neurons is also seen just lateral to nucleus, in region that also contains enkephalin‐immunoreactive neurons. DVC: distribution of retrogradely labeled neurons in ventral medial parvocellular part of nucleus, after injection of true blue in dorsal vagal complex in medulla. SC: retrogradely labeled neurons in ventral medial and dorsal parvocellular parts of nucleus after injection of true blue in upper thoracic levels of spinal cord, including sympathetic intermediolateral column. Note that dorsal parvocellular part projects almost exclusively to spinal cord. All photomicrographs × 80.

Photomicrographs by Drs. L. W. Swanson, P. E. Sawchenko, and R. W. Lind


Figure 9.

Summary diagram of known direct neural inputs to magnocellular vasopressinergic (vas) neurons in paraventricular (and supraoptic) nuclei of rat. A1, noradrenergic cell group in ventrolateral medulla; MePO, median preoptic nucleus; ne, norepinephrine; NTS, nucleus of solitary tract; PVH, paraventricular nucleus; SFO, subfornical organ; IX, glossopharyngeal nerve; X, vagus nerve.



Figure 10.

Summary diagram of known direct neural inputs to magnocellular oxytocinergic (oxy) neurons in paraventricular (and supraoptic) nuclei of rat. ARH, arcuate nucleus; BST, bed nucleus of stria terminalis; DMH, dorsomedial nucleus; DR, dorsal raphe nucleus; DRG, thoracic dorsal root ganglion; MePO, median preoptic nucleus; MR, median raphe nucleus; PVH, paraventricular nucleus; SFO, subfornical organ.



Figure 11.

Photomicrograph to show distribution of oxytocin‐immunoreactive fibers from paraventricular nucleus in vicinity of caudal part of dorsal motor nucleus of vagus nerve. Vagal motoneurons have been retrogradely labeled with true blue injected into cervical parts of vagus nerve. Central canal is dark oval in midline, at bottom of micrograph. Viewed in microscope, cells were labeled blue and fibers were labeled green (indirect immunofluorescence, with fluorescein). × 150.

Courtesy of Dr. P. E. Sawchenko


Figure 12.

Double retrograde transport experiments indicate that paraventricular nucleus (PVH) contains essentially 3 different types of vasopressinergic (and oxytocinergic) neurons. 1) Magnocellular neurons project to posterior pituitary (PP). 2) Parvocellular neurons project to external lamina (neurohemal zone) of the median eminence (ME). 3) Mediocellular neurons project through medial fore‐brain bundle (mfb) to midbrain, pons, medulla, and spinal cord. CG, central gray; DMX, dorsal motor nucleus of vagus nerve; EW, Edinger‐Westphal nucleus; IML, intermediolateral column (spinal cord); LC, locus coeruleus; MZ, marginal zone (spinal cord); NTS, nucleus of the solitary tract; PB, parabrachial nucleus; PPN, pedunculopontine nucleus.



Figure 13.

Schematic horizontal view of major subdivisions of paraventricular nucleus in rat. am, Anterior magnocellular; ap, anterior parvocellular; dp, dorsal parvocellular; lp, lateral parvocellular; mm, medial magnocellular; mp, medial parvocellular; pm, posterior magnocellular; pv, periventricular.

From Swanson et al. 387


Figure 14.

Summary diagram of direct neural inputs to parts (dorsal and ventral medial parvocellular) of paraventricular nucleus that project directly to autonomic cell groups in brain stem and spinal cord in rat. A1, noradrenergic cell group in ventrolateral medulla; BST, bed nucleus of stria terminalis; HYP, hypothalamic cell groups; NTS, A2 noradrenergic cell group in nucleus of solitary tract; PB, parabrachial nucleus; R, serotonergic raphe nuclei of midbrain; SFO, subfornical organ; ZI, zona incerta; IX, glossopharyngeal nerve; X, vagus nerve.



Figure 15.

Paraventricular nucleus of rat can be roughly divided into 3 major zones: one that projects to median eminence (ME), one to posterior pituitary (PP), and one to autonomic cell groups in brain stem and spinal cord (ANS). Also see Fig. 8. dp, Dorsal parvocellular part; lp, lateral parvocellular part; mpd and mpv, dorsal and ventral medial parvocellular parts; pml and pmm, lateral (vasopressinergic) and medial (oxytocinergic) posterior magnocellular parts; pv, periventricular part.

From Swanson and Sawchenko 386


Figure 16.

Summary diagram of organization of noradrenergic fibers (*) to 3 zones of paraventricular nucleus illustrated in Fig. 15. Projections arise from 3 cell groups in brain stem: A2 group in nucleus of solitary tract (NTS), A1 group in ventrolateral medulla, and locus coeruleus (LC). Each of these cell groups appears to receive visceral sensory information, either directly or indirectly, from glossopharyngeal (IX) or vagus (X) nerves. ANS, autonomic cell groups; ME, neurohemal zone of median eminence; PP, posterior pituitary.



Figure 17.

Distribution of neurons (dots) that project to neurohemal zone of median eminence in rat, as determined by retrograde transport methods. A‐F: arrangement of frontal sections from rostral to caudal. ac, Anterior commissure; AD, anterodorsal preoptic nucleus; AH, anterior hypothalamic nucleus; ap, anterior parvocellular part of paraventricular nucleus; AR, arcuate nucleus; AV, antero‐ventral periventricular nucleus; BS, bed nucleus of stria terminalis; d, dorsal periventricular part of paraventricular nucleus; DB, nucleus of diagonal band; DM, dorsomedial nucleus; f, fornix; LH, lateral hypothalamic area; LP, lateral preoptic area; LS, lateral septal nucleus; LSv, ventral part of LS; m, posterior magnocellular part of paraventricular nucleus; Me, median preoptic nucleus; MN, medial preoptic nucleus; mp, medial parvocellular part of paraventricular nucleus; MP, medial preoptic area; MS, medial septal nucleus; oc, optic chiasm; ot, optic tract; PH, posterior hypothalamic area; PMv, ventral premammillary nucleus; Pp, preoptic periventricular nucleus; PT, paraventricular nucleus of thalamus; pv, periventricular part of paraventricular nucleus; PVa, anterior periventricular nucleus; PVH, paraventricular nucleus of hypothalamus; PVp, posterior periventricular nucleus; RC, retrochiasmatic nucleus; sm, stria medullaris; SC, suprachiasmatic nucleus; SO, supraoptic nucleus; VL, lateral ventricle; VM, ventromedial nucleus; ZI, zona incerta.

Data from refs. 216,389, and 438


Figure 18.

Distribution of thyrotropin‐releasing hormone‐immunoreactive cell bodies (dots) in hypothalamus of rat. A–F: arrangement of frontal sections from rostral to caudal. Many neurons in bed nucleus of stria terminalis (BS), dorsomedial nucleus (DM), and lateral hypothalamic area (LH) do not appear to send fibers to median eminence (see Fig. 17). For other abbreviations see legend to Fig. 17.

Data from P. E. Sawchenko and L. W. Swanson, unpublished observations, and ref. 214


Figure 19.

Distribution of gonadotropin‐releasing hormone‐immunoreactive neurons (dots) in and around hypothalamus of rat. For abbreviations see legend to Fig. 17.

Data from refs. 30,180,429


Figure 20.

Distribution of gonadotropin‐releasing hormone‐immunoreactive cells and fibers in baboon hypothalamus. AC, anterior commissure; CC, corpus callosum; CF, columns of fornix; CN, caudate nucleus; CP, cerebral peduncle; FM, fasciculus retroflexus; FX, fornix; GP, globus pallidus; HDBB, horizontal limb of nucleus of diagonal band; ic, internal capsule; LSN, lateral septal nucleus; LV, lateral ventricle; MB, mammillary body; ME, median eminence; MPO, medial preoptic area; MSN, medial septal nucleus; oc, optic chiasm; OT, optic tract; PVN, paraventricular nucleus; SMT, stria medullaris; SON, supraoptic nucleus; TC, tuber cinereum.

From Marshall and Goldsmith 231


Figure 21.

Distribution of somatostatin‐immunoreactive neurons (dots) in periventricular zone of hypothalamus of rat. For abbreviations see legend to Fig. 17.

Data from refs. 31,95,110,181,317


Figure 22.

Distribution of growth hormone‐releasing hormone‐immunoreactive cell bodies in rat. For abbreviations see legend to Fig. 17.

Data from Sawchenko et al. 436


Figure 23.

Photomicrograph of growth hormone‐releasing hormone‐immunoreactive fibers in median eminence and pituitary stalk of rat. A few immunoreactive cell bodies can also be seen in arcuate nucleus, just lateral to ventral tip of 3rd ventricle (in middle, at top). Immunofluorescence. × 350.

From Sawchenko et al. 436


Figure 24.

Distribution of corticotropin‐releasing hormone‐immunoreactive cell bodies (dots) in and around paraventricular nucleus (PVH) of rat. AHA, anterior hypothalamic nucleus; am, anterior magnocellular part of PVH; ap, anterior parvocellular part of PVH; BST, bed nucleus of stria terminalis; BSTp, bed nucleus of stria terminalis (preoptic part); dp, dorsal parvocellular part of PVH; fx, fornix; lp, lateral parvocellular part of PVH; mct, medial corticohypothalamic tract; mp, medial parvocellular part of PVH; pm, posterior magnocellular part of PVH; PT, parataenial nucleus; pv, periventricular part of PVH; PVT, paraventricular nucleus (thalamus); ZI, zona incerta.

From Swanson et al. 388


Figure 25.

Summary diagram of direct neural pathways to region of corticotropin‐releasing hormone (crh) cell bodies in dorsal medial parvocellular part of paraventricular nucleus (see Fig. 24) in rat. A1, noradrenergic cell group in ventral medulla; BST, bed nucleus of stria terminalis; HYP, hypothalamic cell groups; ME, neurohemal zone of median eminence; NTS, nucleus of solitary tract (A2 noradrenergic cell group); PB, parabrachial nucleus; SFO, subfornical organ.



Figure 26.

Summary diagram of major cell groups (dots) and fiber tracts that cross‐react with antisera to corticotropin‐releasing hormone in rat. ac, Anterior commissure; A1, A5, noradrenergic cell groups; BST, bed nucleus of stria terminalis; cc, corpus callosum; CeA, central nucleus of amygdala; CG, central gray; DR, dorsal raphe nucleus; DVC, dorsal vagal complex; HIP, hippocampus; LDT, laterodorsal tegmental nucleus; LHA, lateral hypothalamic area; LC, locus coeruleus; ME, median eminence (neurohemal zone); mfb, medial forebrain bundle; MID THAL, midline thalamic nuclei; MPO, medial preoptic area; MR, median raphe nucleus; MVN, medial vestibular nucleus; PB, parabrachial nucleus; POR, perioculomotor raphe nucleus; PP, posterior pituitary; PVH, paraventricular nucleus of hypothalamus; SEPT, septal region; SI, substantia innominata; st, stria terminalis.

From Swanson et al. 388


Figure 27.

Summary diagram of location of cell bodies that synthesize known hypophysiotropic hormones and project to neuro‐hemal zone of median eminence, projected on midsagittal view of rat brain (see Fig. 2 for identification of other structures). Outlined areas, major concentrations of cell types, although some of the zones would clearly overlap when viewed from this perspective (see Figs. 18, 19, 21, 22, 24). CRH, corticotropin‐releasing hormone; DA, dopamine; GnRH, gonadotropin‐releasing hormone; GRH, growth hormone‐releasing hormone; MI, massa intermedia (interthalamic adhesion); S, septal region; SS, somatostatin.



Figure 28.

Diagrammatic representation of topographic relation of major cell types in paraventricular nucleus of rat. Frontal view, with 3rd ventricle at left, approximately at level shown in Fig. 8. CRH, corticotropin‐releasing hormone (parvocellular); DA, dopamine (parvocellular); DVC, dorsal vagal complex (parasympathetic); IML, intermediolateral column (sympathetic); OXY, oxytocin (magnocellular); SS, somatostatin (parvocellular); TRH, thyrotropin‐releasing hormone (parvocellular); VAS, vasopressin (magnocellular).

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L. W. Swanson. Organization of Mammalian Neuroendocrine System. Compr Physiol 2011, Supplement 4: Handbook of Physiology, The Nervous System, Intrinsic Regulatory Systems of the Brain: 317-363. First published in print 1986. doi: 10.1002/cphy.cp010406