AM ZOOLOCIST, 7:161-169 (1967).

The Neurosecretory Neuron in Neuroendocrine Regulatory Mechanisms

BERTA SCHARRER
Department of Anatomy, Albert Einstein College of Medicine, New York, N.Y.
SYNOPSIS. The widespread occurrence of neurosecretory neurons in the animal
kingdom suggests a functional significance that is basic and special. The explanation of
the need for this unusual cell type lies in the fact that it forms a link between the
nervous and the endocrine systems whose functional interdependence forms the basis for
the effectiveness of regulatory mechanisms in the animal world. These two integrative
systems function in different ways. The neurosecretory cell, with its dual characteristics,

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and this cell alone, seems capable of receiving messages in "neural" language, and of
transmitting this information in modified "endocrine" language to glandular cells.
The neurosecretory neuron occupies a central position in neuroendocrine interactions,
not only because it is geared for communication with the endocrine apparatus, but
because it serves as a singular channel ("final common path," E. Scharrer, 1965) through
which a multitude of afferent stimuli, after being processed, are channeled to a variety
of endocrine way stations and thus exert control over their effector organs.

One of the most fertile concepts in the 1963; Nalbandov, 1963; Bajusz and Jasmin,
progress of endocrine research has been 1964; E. Scharrer, 1966; Weitzman, 1964-
that of the functional interdependence of 1966). Only some of these will be included
organs concerned with regulatory mech- in the following discussion whose central
anisms. Under physiological conditions, in- topic is the elucidation of the phenomenon
dividual glands of internal secretion do not of neurosecretion and its role in neuroen-
function autonomously, but rather as links docrine integration. Even at that, current
in an ever-changing sequence of events. In research contributions in this area are be-
their entirety, these glands constitute the coming so numerous that only a small
endocrine apparatus, one of the two in- selection of representative references can be
tegrative organ systems of higher organisms. given. These contain much of the docu-
Environmental stimuli affecting the en- mentation for the views expressed in the
docrine system reach it by way of the nerv- following pages and should be consulted
ous apparatus, the other of the two sys- for further orientation in this field.
tems of communication. Its makeup of in- If indeed nervous and endocrine com-
numerable links (neuron chains) is too ponents join forces by serving as alternating
well known to require discussion. What has links in chains of regulatory activities, there
not been fully appreciated, however, until must be means of communication between
very recently is the high degree of mutual neurons and endocrine cells, and vice versa.
interdependence that exists between the Are the signals involved the same as, or
nervous and the endocrine systems. And different from, those used between two
yet, the situation could not be otherwise, neurons, or two endocrine cells, respec-
because heterogeneous directives aimed at tively?
a given effector organ simultaneously, in The type of chemical messenger (hor-
order to be "effective" at all, must not mone) by which an endocrine cell com-
contradict each other. municates with either another endocrine or
The manner in which the two integrative a "final target" cell (such as a uterine
systems communicate with each other in muscle fiber) can also serve for conveying
coordinating the body's autonomic adjust- information to a neural recipient. A well
ments, and the outcome of this combined known example is the effect of circulating
activity, constitute Neuroendocrinology. gonadal steroids on special cell groups in
This young, but rapidly expanding dis- the mammalian hypothalamus, called "hor-
cipline encompasses many facets of mutual mone-sensitive neurons." These cells con-
interaction (see Scharrer and Scharrer, vert the information conveyed by such
(161)
162 BERTA SCHARRER

stimuli into appropriate neural activity But after several decades of strife, the con-
and elicit two types of response. One is a cept of neurosecretion is now firmly es-
change in an animal's behavior, as during tablished, and its study has become a most
estrus, the other is an endocrine event and active field in contemporary biological
involves, somewhere in the relay system, research. A brief characterization of the
a step from neuron to endocrine cell. neurosecretory neuron may be in order
Since the recipient cell is one geared to before considering its special task of
communication by chemical messengers, mediating between the two systems of
the switchover from nervous to endocrine integration.
system could well be accomplished by

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neurotransmitter substances (e.g., acetyl- THE NEUROSECRETORY NEURON AND THE
CONCEPT OF NEUROSECRETION
choline or noradrenaline) in a manner
comparable to neurochemical events in- The terms "neurosecretion" and "neuro-
volved in "ordinary" synaptic transmission. secretory cell" were coined to denote the
This would require that axonal terminals existence of a distinct class of neurons that
conveying such information make direct engages in glandular activity to a degree
contact with endocrine cells, since neuro- above and beyond that observed in ordinary
transmitters are known to act in loco and nerve cells. The claim for being singled out
to be destroyed promptly after having in this manner rests primarily on the fact
elicited a response. Only pinpointed signals that neurosecretory cells produce chemical
of very short duration could, therefore, be mediators of hormonal character and are
involved and in this event every single thus capable of dispatching signals to
endocrine cell would have to be "inner- distant non-nervous centers by a vascular
vated." There is no convincing morpho- route.
logical evidence for such an assumption, The existence of neurosecretory activities
even though nerve terminals have now was initially postulated on the basis of
been shown, by means of electron micro- morphological information. Crucial tests of
scopy, to establish close contact with paren- the validity of this concept have been
chymal cells of at least some endocrine provided by correlation of cytological
glands. The organs involved (pars inter- knowledge with physiological and bio-
media of vertebrate pituitary, corpus al- chemical experimentation. Today, morpho-
latum of insects) are, however, exceptional logical research, by its extension to the
in that they represent parts of neurose- ultrastructural level, has again moved into
cretory systems, which provide a special the limelight as an essential prerequisite for
type of innervation (to be discussed below). the solution of a number of problems still
To reach the remainder of the endocrine under dispute.
system, nerve cells have to produce and re- The subject of neurosecretion has been
lease hormones which are better suited for reviewed repeatedly (see Scharrer and
the task at hand. By definition, hormonal Scharrer, 1963, for earlier references; Bern
mediators bridge distances and affect and Hagadorn, 1965; Picard and Stahl,
multiple instead of single target cells over 1966; Turner, 1966). A monumental vol-
a certain (often considerably sustained) ume on neurosecretion (Gabe, 1966) has
period of time. Lacking these important now become available in English trans-
characteristics, neurotransmitters do not lation. The following summary of the
qualify as hormones and should retain their characteristics of neurosecretory neurons
separate status as neurohumors. can, therefore, be brief and focus on those
The postulate that neural elements en- aspects that are pertinent to our topic.
gage in the manufacture of hormones was a The neurosecretory cell is neither an or-
bold departure from long established ideas. dinary neuron nor an endocrine cell, but a
It is not surprising, therefore, that it met combination of both. Its neuronal features
with a large share of persistent opposition. resemble those of ordinary neurons con-
 THE ROLE OF THE NEUROSECRETORY NEURON 163

cerning both structure and function. The charge occurs at the axon terminal. Neuro-
production of a visible secretory material secretory granules reach this site by
marks the neurosecretory neuron as a gland proximo-distal axonal transport. Evidence
cell, and the fact that extractable cellular for the occurrence of this "migration" is
products act in the manner of hormones conclusively provided by the accumulation
places it in the realm of endocrine elements. of material at the proximal stump of the
The glandular products of "classical" surgically interrupted pathway, and by the
neurosecretory cells are polypeptides time sequence in the changing distribution
(bound by a carrier protein, neurophysin) of incorporated labeled precursors as deter-
and thus differ chemically from known mined by autoradiographic techniques

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neurotransmitter substances. Neurosecre- (Flament-Durand, 1966).
tory material may be observed in both A prominent characteristic of neurose-
perikaryon and cellular processes. At the cretory systems among invertebrates as well
level of the light microscope, the demon- as vertebrates is the aggregation of bulbous,
stration of this intracytoplasmic material secretion-filled terminals around vascular
involves its selective stainability by methods channels; they form separate anatomical
such as Gomori's chrome-hematoxylin entities, called "neurohemal organs." The
phloxin and aldehyde fuchsin, Adams and best known examples of these storage
Sloper's alcian blue technique, and depots are the neurohypophysis of verte-
Schiebler and Sterba's pseudoisocyanin- brates, the corpus cardiacum of insects, and
fluorescence method (Sterba, 1965). the sinus gland of crustaceans. Further-
In electron micrographs, neurosecretory more, such neurosecretory systems com-
cells can be recognized by the presence of monly show an intimate relationship be-
membrane-bounded cytoplasmic granules of tween the neurohemal organ and a non-
varying, but generally high, electron den- neural endocrine structure (adenohypophy-
sity and characteristic size ranges (frequent- sis of vertebrates, corpus allatum of insects).
ly of the order of 1000 to 3000 A). However, The compact spatial arrangement of
this characteristic should not by itself be neurosecretory terminals in these neuro-
considered as an absolute criterion. Evi- hemal organs and the large amounts of
dence gathered from both light- and stored material present make them well
electron-microscopic investigation leads to suited for histophysiological experimen-
the conclusion that neurosecretory sub- tation. Appropriate stimulation, such as
stances are produced in the perikaryon. prolonged thirsting in the rat for example,
The ultrastructural "events" involved in leads to a depletion of stored neurosecretory
their elaboration are virtually the same as substance in the posterior pituitary, and
those in other well documented cases of rehydration induces a gradual re-establish-
synthesis of proteinaceous glandular pro- ment of "normal" stores of the physio-
ducts, e.g., the zymogen granules of the logically active material.
exocrine pancreas. The material appears to The neurohormone released into the sys-
be manufactured by the ergastoplasm temic circulation may affect an endocrine
(rough-surfaced endoplasmic reticulum) of gland at some distance from the site of
the perikaryon and then to be "packaged" discharge (as in the control of the pro-
in the Golgi apparatus, where measured thoracic gland of insects), or exercise direct
amounts are pinched off into the cytoplasm. control over an equally distant non-endo-
The neurosecretory granules are stored crine "terminal target" (such as the kidney
in the cytoplasm, apparently for varying cells concerned with water conservation).
periods of time, until their content is re- The latter case is an example of a first-order
leased. This may take place (at least in effect.
principle) at various levels of the neuron, There is, among vertebrates, also a more
e.g., the perikaryon. However, in most of "exclusive" vascular route by which neuro-
the known neurosecretory centers, dis- hormonal stimuli may reach their desti-
164 BERTA SCHARRER

nations. The hypophysial portal system vesicles, a role most likely concerned with
channels "hypothalamic releasing factors" the release mechanism of neurosecretory
to endocrine cells of the anterior pituitary. products, to be discussed shortly.
Here the results are either second- or third- Little is known about a possible fourth
order neuroendocrine events (with one or vehicle for the conveyance of neurosecre-
two endocrine centers interposed). tory material. Various light- and ultrami-
A third possibility for the nervous system croscopic data suggest a release into the
to reach endocrine targets has been cerebrospinal fluid. The functional sig-
mentioned earlier and is exemplified by the nificance of this phenomenon is difficult to
control mechanism over the pars inter- assess. It has been suggested (Fridberg and

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media and the corpus allatum. It is the Nishioka, 1966) that neurohormone ex-
most "directed" among the existing path- truded into the third ventricle or central
ways, and involves close contact between canal may become absorbed by the chorioid
axon terminals and endocrine cells (se- plexus and then reach target organs by vas-
cretomotor junctions). When the gap be- cular transport. There may also be effects
tween axolemma and plasma membrane of of neurosecretory substances distributed by
an endocrine cell at such a junction is the cerebrospinal fluid on nerve centers
sufficiently small (of the order of 200- other than those in which these hormones
300 A), a neurohumoral mode of transmis- originate.
sion is feasible. This certainly applies to There is still much uncertainty as to
cases of innervation of gland cells by non- what constitutes the stimulus for the liber-
neurosecretory fibers (Picard and Stahl,
ation of neurosecretory material from its
1966).
intraneuronal storage site. Are the signals
It is unknown whether or not neuro- for discharge provided by the same neuron,
transmitter substances play a comparable or do they have to come from a separate
role when endocrine cells are affected at neuron with which the neurosecretory fiber
equally close range by neurosecretory fibers is in direct contact? (See, for example,
(see Polenov, et al., 1965). Since their Heller and Ginsburg, 1966; Sloper, 1966.)
terminals, like those of ordinary axons, A closely related and similarly vexing
contain small, clear ("synaptic") vesicles, question concerns the form in which the
a morphological basis for such activity active principles are released into the ex-
exists. However, it seems more likely that tracellular channels. There are indications
the neurosecretory cell makes use of its for several possibilities, but none of them
special chemical endowment for eliciting has been satisfactorily proved. On morpho-
responses from the effector cell, irrespective logical grounds, it seems unlikely that
of the distance involved. Cases in point are membrane-bounded granules enter the cir-
the pituitary of fishes (Knowles and Voll- culation in intact form. Probably the shell
rath, 1966a, b) and probably the prothorac- is left behind when the active polypeptides,
ic gland of insects (B. Scharrer, 1964), or- with or without their carrier protein, are
gans of internal secretion that are "in- liberated from the neurosecretory terminal.
nervated" by neurosecretory fibers. In both Some investigators, therefore, interpret the
instances, extracellular gaps (around 3000- "synaptic vesicles" in these terminals as
4000 A) have been observed exceeding remnants of neurosecretory granules from
those characteristic of synapses. The neuro- which part or all of the content has been
secretory terminals need not, and here evi- discharged. Others hold that their presence
dently do not, approach target cells quite signifies a role of acetylcholine in the liber-
as closely as would be required for ordinary ation of the active polypeptides, presuma-
synaptic contact. Consequently, the small, bly by altering membrane-permeability.
clear vesicles present in neurosecretory ter- Since the neurosecretory neuron is capa-
minals must be interpreted as playing a ble of conducting impulses, the signal for
role different from that of regular synaptic the release of polypeptide hormones could
 T H E ROLE OF THE NEI.'ROSECRETORY NEURON 165

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FIG. I. Electron micrograph o£ corpus cardiacum of insect, Leucophaea maderae, showing
"synaptoid" contact (arrow) between neurosecretory axon with large electron-dense granules and
vesicles (A liber) and another axon containing smaller dense-core granules (B fiber). X 42,400.
(Reprinted from B. Scharrer, 1963, Z. Zellforsch. 60:761-796.)
well be given by the same cell that furnishes "releasing factors" of polypeptide nature,
these substances. But there is also evidence or perhaps by themselves supplying one or
for an alternative solution of this problem. more releasing factors. The latter pos-
Currently, considerable attention is sibility has been explored, for example, by
being given to the interpretation of existing the examination of existing relationships
"synaptoid" contacts between "classical" between changes in the dopamine content
neurosecretory fibers (A fibers of Knowles, of tubero-infundibular B fibers and specific
1965) with polypeptide-containing granules events in the reproductive physiology of
of more than 1000 A and axons with mem- rats (Fuxe, et al., 1966b).
brane-bounded electron-dense granules of B-type fibers seem to belong to a class of
somewhat different appearance and a neurons that are rich in monoamines.
diameter of less than 1000 A (B fibers of Their existence can be demonstrated by a
Knowles; see also B. Scharrer, 1963, and technique utilizing highly specific histo-
Fig. 1). These B fibers may influence the chemical fluorescence (Falck, et al., 1962,
release of peptide neurohormones from ter- 1965). However, there is as yet no certainty
minals of A fibers in neurohemal organs of about the precise intracytoplasmic localiza-
vertebrates and invertebrates. tion of the catecholamines involved. Cur-
It appears that B fibers that terminate at rent views associate them with small vesicles
capillaries of the median eminence (Rinne of the "synaptic" type rather than with the
and Arstila, 1965-66; Monroe, 1966, and small dense-core granules mentioned above.
others) play an essential role in the control Such clear vesicles are numerous not only
of adenohypophysial functions, either by in the axon terminals but also in the
monitoring the discharge of hypothalamic perikaryons of B-type neurons, and their
1G6 Jiv.RTA SUIAKREK

distribution parallels the sites of formation of the nervous apparatus is now firmly
and/or storage of catecholamine as deter- established.
mined by the fluorescence-technique (Fuxe,
THE SPECIAL ROLE OF THE NEUROSECRETORY
et ah, 1966a). •
NEURON IN NEUROENDOCRINE INTERACTIONS
If it can be established that physiologi-
cally active catecholamines released from We may now return to the cardinal
neurons reach target cells by a vascular question, i.e., the reason for the existence
route, such as the hypophysial portal sys- of neurosecretory neurons. Their wide-
tem, these catecholamines would then spread occurrence in the animal kingdom
qualify as neurohormones. In this event, suggests a functional significance that is

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their cells of origin would become es- basic and special. The explanation of the
tablished as another class of neurosecretory need for this unusual cell type lies in the
neurons whose major difference from the fact, already touched upon earlier in this
classical prototype would be the non- text, that the two integrative systems
polypeptide character of their physiologi- function in different ways. In the nervous
cally active secretory products. In short, tissue, we have primarily a point-to-point
chemical considerations in the characteriza- transmission of signals with a duration of
tion and classification of neurosecretory the order of fractions of a second. In the
systems may have to undergo modification.
The existence of more than one class of EXTEROCEPTIVE AND INTEROCEPTIVE

neurosecretory neurons had been detected

earlier, at the light-microscopic level, on \
the basis of different tinctorial affinities.
The well established common variety,
whose secretory products stain with chrome
hematoxylin or aldehyde fuchsin, seems to
correspond to the A fibers observed in
electron micrographs. On the other hand,
neurosecretory neurons with staining pro-
perties different from those of "classical" A
fibers, may turn out to belong to class B
fibers and may fulfill functions of a special
kind, in particular those involving short
term activities.
In summary, the development in recent
years of more sophisticated methods in-
volving high resolution microscopy and
cytotopochemistry has provided answers to
questions for which earlier microscopic
techniques had been inadequate. At the
same time, this deeper penetration into the
phenomenon of neurosecretion has opened
up new problems. The establishment of
valid criteria for neurosecretory neurons
has undergone changes (see Knowles and FIG. 2. Diagram illustrating theoretically possible
Bern, 1966), but some uncertainty remains neuroendocrine interactions. Both nervous and hor-
concerning the precise borderline between monal signals are symbolized by arrows. In any
ordinary and neurosecretory neurons. given case of a function under neuroendocrine con-
trol, in any particular animal, only some of the
Further modulations of our concepts will pathways are actually used. (Reprinted from
undoubtedly occur, but the special status of Scharrer and Scharrer, 1963, Neuroendocrinology,
the neurosecretory neuron within the rest Columbia University Press, New York.)
 THE ROF.F. OF THE NEUROSECRETORY NEURON 167

endocrine system, there occurs a much its dual characteristics, and this cell alone,
slower and much less directed transmission seems capable of receiving messages in
of messages. The neurosecretory cell with "neural language," and of transmitting this

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HYPOTHALAMUS

NEUROSECRETORY CELL

ENDOCRINE /
C ) ADENOHYPOPHYSIS

ORGANS/

TARGET

FIC. 3. Xeurosecretory cells acting as mediators between nervous and endocrine systems. The
diagram illustrates the relationship for the prototype of a neuroendocrine integration center,
the hypothalamus of higher vertebrates. (Reprinted from Scharrer and Scharrer, 1963,
Nituroendocrinology, Columbia University Press, New York.)
168 BERTA SCHARRER

information in modified "endocrine lan- events in the ovary with periodic con-
guage" to a glandular cell (E. Scharrer, sequences in peripheral target organs, es-
1952). pecially the uterus.
Now that this crucial point has been Another example of complex neuroendo-
elucidated, we can present a scheme for crine interaction is the control of insect
all of the theoretically possible interactions development. Growth and metamorphosis
between neural and endocrine factors. A depend on gradual shifts in the relative im-
diagram (Fig. 2) shows how various af- portance of two interacting hormonal cen-
ferent stimuli from the internal and ex- ters, the prothoracic gland and the corpus
ternal milieus enter central circuits that allatum. Here the central nervous system

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link the neural and endocrine components not only governs the cyclic performance of
of the integrative apparatus, and how effer- each individual gland, but apparently also
ent signals from endocrine centers reach serves to coi'relate the simultaneous ac-
"final targets." tivities of both. The integrative center in
The neurosecretory neuron occupies a question is part of the protocerebrum. By
central position in all of these interactions, means of a blood-borne neurosecretory
not only because it is geared for communi- principle, it stimulates the release of the
cation with the endocrine apparatus, but molting hormone, ecdysone, from the
because it serves as a singular channel prothoracic gland, and by direct nerve sup-
("final common path," E. Scharrer 1965, ply (at least part of which is neurosecre-
1966) through which a multitude of af- tory) it regulates the amount of juvenile
ferent stimuli after being processed reach hormone furnished by the corpus allatum.
a variety of endocrine way stations (Fig. 3). Only by coming from the same source can
This common pathway is more constant these neural signals for two chains of com-
than the rest of the possible connections mand guarantee the proper adjustments
diagrammed in Fig. 2. Among the latter, between both parallel endocrine activities
various suitable combinations may be in during each of the consecutive develop-
operation depending on the type of mental steps.
physiological process, or the animal species,
or other variable factors we happen to be SUMMARY
dealing with. A detailed documentation of The functional interdependence of the
this basic scheme may be found in the nervous and endocrine systems forms the
text by Scharrer and Scharrer (1963). Here basis for the effectiveness of regulatory
a brief survey of two representative ex- mechanisms in the animal world. An im-
amples may serve to illustrate the principle. portant link between these two integrative
One concerns mammalian reproduction systems is provided by a class of cellular
where the control mechanism of the cyclic elements with dual capacities, the neurose-
events in the female requires a complex cretory neurons. Through these inter-
combination of signals. Among a variety of mediaries a multiplicity of signals, received
conditioning factors entering the central and processed by the nervous system, are
circuits are extrinsic sensory (olfactory, channeled to endocrine centers to exert
visual, etc.) signals, afferent endocrine control over their intricate functions.
stimuli (including gonadal feedback), and
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