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Copyright © 1984 by Annual Reviews Inc. All rights reserved
INTRACEREBRALNEURAL
IMPLANTS:Neuronal
Replacementand Reconstruction
of Damaged
Circuitries
Anders BjOrklund and Ulf Stenevi
Departmentof Histology, University of Lund, S-22362Lund,Sweden
INTRODUCTION
Neural grafting has emerged over the last decade as a viable approach to
studying the developmentand regeneration of neuronal connections in the CNS
of mammals.
In this review we focus on one particular aspect of this technique:
the use of intracerebral neural implants for the reestablishment of severed
connections, the substitution of lost pathways,and the replacementof tissue
defects in the adult mammalianCNS.A survey of the literature showsthat
grafting of neuronal tissue to the mammalian
CNShas been frequently attempted since the end of the last century, but that the results of these earlier studies
were generally very poor. Thompson(1890) and Saltykow(1905) were possibly the first to report results from grafts of adult CNStissue, and Del Conte
(1907) the first to try grafts of embryonictissues to the brains of mammals.
Their results were generally unsuccessful and no clear-cut evidence of good
long-term survival was obtained. Del Conte, in particular, concludedthat the
brain was an unfavorable transplantation site. Similar negative results were
subsequentlypublished, e.g. by Altobelli (1914), Willis (1935), Glees (1955),
Wenzel & B~lehner (1969), and Frotscher et al (1970). Someof the early
investigators were, however, moresuccessful. Ranson(1914) and Tidd (1932)
obtained partial survival of grafted sensory ganglia in the cerebral cortex of
developing rats, and Dunn(1917) reported survival of four out of 44 grafts
of neonatal cerebral cortex, implanted into the cortex of nine to ten day-old
279
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280
BJORKLUND
& STENEVI
rats of the samelitter. Themostinteresting study in the earlier literature is that
of LeGrosClark in 1940. He described excellent survival and differentiation in
a case of embryonicneocortexgrafted to the cortex of a six-weekold rabbit. It
is remarkablethat this paper s~eemedto havepassed relatively unnoticed.In his
autobiography, LeGrosClark (1968) does not even mentionthis study and the
findings were never followed up.
During the last decade these earlier positive findings have been greatly
substantiated and we knowtoday that all parts of the neuraxis can be transplanted with excellent survival, not only to the CNSof developinganimals, as
shownby the early workers, but also to the brain and spinal cord of adult or
evenagedrecipients. Technically,the principal restriction is that grafts of CNS
tissue have to be taken from developing(embryonicor neonatal) donors. In the
most primitive vertebrates, such as urodeles (salamanders and newts) and
fishes, transplantation, reimplantation, or transposition of CNStissue is also
possible in adult individuals (see below). Thereason for this appears to be,
least in urodeles, that the fully differentiated neuronalelements, whichdo not
survive grafting, can be replaced by newly formedneurons regenerating from
undifferentiated neuroepithelial cells (Stone & Zaur 1940, Gaze & Watson
1968). In higher vertebrates there is a clear-cut difference betweenperipheral
ganglionic neurons, whichpartly survive grafting from adult donors (Stenevi et
al 1976, Bj0rklund & Stenevi 1977a), and CNSneurons, which survive
grafting only when taken from embryonicor developing donors.
We(Stenevi et al 1976, Bj/~rklund et al 1976) were the first to study more
systematically the possibilities for goodand reproducible survival of grafts of
central and peripheral neurons in the adult mammalianCNS.In submammalian
vertebrates this has been a classic approach for studies of mechanismsof
neuronal regeneration, especially all in the retino-tectal system. Matthey
(1926), Stone (1944, Stone &Zaur 1940), and Sperry (1945), in particular,
showedthat transplanted or reimplantedeyes can regenerate a newretino-tectal
pathway,with restoration of vision, in adult newts and salamandersor in young
postmetamorphic
frogs. In these grafts of adult or youngadult eyes the retinal
ganglion cells initially degenerate, but are subsequently regenerated from
proliferating cells at the ciliary margin.Withintwoto three mon.thsthe grafted
eyes were shownto regenerate a newretino-tectal c6nnection, and experiments
with reversed and rotated grafts indicated that the newretino-tectal pathway
established a topographically ordered projection over the contralateral tectum
(Stone 1944, 1963, Sperry 1945). Stone &Farthing (1942) reported that
sameeye could be grafted as manyas four times with recoveryof vision in each
of the newhosts.
More recently, the neural grafting technique has also been successfully
applied in the optic tectum of adult goldfish and youngpostmetamorphicfrogs
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INTRACEREBRAL
NEURALIMPLANTS
281
(Sharma & Gaze 1971, Yoon 1973, 1975, 1977, 1979, Levine & Jacobson
1974, Jacobson &Levine 1975a,b). These studies demonstrate that postembryonicor adult tectal tissue survives reimplantationor transposition in the
brain of the sameindividual. Thesegrafts becomereinnervated by the regenerating retino-tectal axons of the host, and in manycases the newafferents have
been observed to be organized in the normal topographic manneraccording to
the original polarity of the graft (see e.g. Yoon1973, 1975, 1977, Levine
Jacobson 1974).
Anotherexampleof functionally successful grafting in submammalian
vertebrates, again with a long tradition, is the transplantation of segmentsof the
spinal cord in developing amphibiansand chicks (Detwiler 1936, Piatt 1940,
Weiss 1950, Szrkely 1963, 1968, Straznicky 1963). Such grafts establish
proper neuromuscular connections and can provide normal coordinated limb
movements.
In salamanderlarvae, grafts of CNStissue also survive well in the
tail fin, relatively isolated fromthe rest of the CNS(Weiss1950). Of particular
interest in the present context are Szrkely’s (1963, 1968) observations that
segmentsof developingspinal cord in such an isolated, ectopic position will
retain their motor pattern generating properties. Segmentsof spinal cord,
grafted together with a developinglimb, werefound not only to reinnervate the
muscles of the limb graft, but to movethe limb in walking-like coordinated
movements,either spontaneously or in response to light touches of the area
aroundthe graft. This capacity of the grafted cord to elicit coordinatedwalkinglike movements
was specific in the sense that it was seen with segmentstaken
from the brachial portion of the cord, normallyinnervating the forelimbs, but
not with segments taken from the thoracic cord, which does not normally
control limb movements.
Althoughthese various experiments in lower vertebrates have revealed a
remarkablefunctional potential of CNStissue grafts, it is only during the last
few years that the possibilities for functional neuronal grafting has been
subjected to more systematic investigations in the mammalian
CNS.As we try
to showin this review, the intracerebral grafting technique, thoughsubjectedto
greater constraints in higher vertebrates, has openedinteresting newpossibilities for neuronal reconstruction after CNSdamagein mammals.
METHODOLOGICALCONSIDERATIONS
A more detailed account of the technical aspects of neural grafting in the
mammalianbrain and spinal cord is beyond the scope of this review. We
therefore limit ourselvesto a brief overviewof somealternative methodological
approachesand discuss somebasic, features and limitations of the intracerebral
grafting techniques.
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BJ6RKLUND& STENEVI
Transplantation
Methods Currently in Use
Descriptionsof a widevariety of techniquesused to implanttissue into the brain
or spinal cord can be foundin the literature. The simplest approach,and the one
that wastried initially, is to insert the graft directly into a slit madein superficial
cortical matter with fine forceps or similar instruments. This technique was
used with poor results by Saltykow (1905) and Del Conte (1907) in adult
recipients, and with morepositive results by Ranson(1914), Tidd (1932),
Das &Altman(1971, 1972) in developing rats. Our ownexperience is that this
approachis highly unreliable and gives at best suboptimalresults, at least in
adult rat recipients.
A variant of this technique, whichgives considerablybetter control over the
placementof the graft and also allowsthe use of larger tissue pieces, is to place
the graft in a surgically preparedtransPlantation cavity. This wasfirst used in
the transected spinal cord, mainlyfor grafts of peripheral nerve, (e.g. see Sugar
&Gerard 1940, Kao et al 1970). Later it was adapted for grafting of neural
tissues into cortical areas by Steneviet al (1976,1980a,b)in the adult rat brain,
and by Lewis & Cotman (1980, 1983) and Graziadei & Kaplan (1980)
neonatal animals. Theprincipal advantageof this type of procedureis that graft
survival can be greatly improvedby preparing the cavity in such a waythat the
graft can be placed on a richly vascularizedsurface (e.g. the pia in the choroidal
fissure) that can serve as a "culturing bed"for the graft (see Steneviet al 1976,
M¢llgaard et al 1978). For areas in which such a surface is not available,
Stenevi et al (1980a; see also Bj6rklundet al 1980a)have devised a two-stage
¯ delayedgrafting procedure:A cavity is first madeby a suction pipette, and the
woundis closed. After usually four to six weeks, whena newvessel-rich pia
has grownover the surfaces of the cavity, the cavity is openedand cleaned and
the graft inserted. This technique has been used in our laboratory for the
transplantation of the embryonicsubstantia nigra region onto the dorsal or
lateral surfaces of the nc. caudatus-putamen
in adult rats (Bj6rklund&Stenevi
1979c, Bj6rklund et al 1980a, 1981, Dunnett et al 1981a-c). The observations
madewith this t6chnique again emphasizethe importance of obtaining rapid
and efficient revasculadzation of the implants, particularly whenworkingwith
grafts of CNStissue in adult recipients.
Injection of tissue pieces by meansof a syringe or a plunger has been used in
various ways. This technique was probably first used by Willis (1935) and
subsequently by LeGrosClark (1940), Flerk6 &Szent~igothai (1957), Halasz
al (1962), and Horvat (1966). Morerecently this approach has been perfected
and used with excellent results in the extensive studies of Das and collaborators, especially in the developingcerebellum(see Das 1974, Das et al 1979,
1980), by Lundand collaborators in the developingrat visual system(see Lund
&Hauschka 1976, Jaeger &Lund1979, 1980a,b, McLoonet al 1981, 1982),
and by Sunde &Zimmer(1981, 1983) in the developing hippocampal forma-
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INTRACEREBRALNEURALIMPLANTS
283
tion. Althoughmost studies employingthis technique have been performedin
early neonatal recipients, Das &Hallas (1978), Hallas et al (1980), and Sunde
&Zimmer(1983) have shownthat the techique can also be applied with good
results in brains of adult recipients. In our ownstudies on grafts of thin sheets of
peripheraltissue (such as iris, heart valve, andportal vein) in the adult rat brain,
wehaveused a flat glass rod to insert, or push, the graft into deepbrain sites
(see BjiSrklund&Stenevi 1971, Svendgaardet al 1975b, 1976, Bj6rklundet al
1975, Emsonet al 1977).
A special variation of this methodwas introduced by Rosenstein &Brightman(1978, 1979) and was later employedby Perlow et al (1979), Freed et
(1980), Gash &Sladek (1980), and Krieger et al (1982). In their experiments
the graft is introducedinto one of the cerebral ventricles by meansof a syringe
or a glass rod. Both adult ganglia and embryonicCNStissues have been shown
to survive well in this relatively isolated position, although goodvolumeand
moreextensive interconnectionswith the host brain seemto be achieved only if
the ependyma
is damagedso that the graft can fuse with the underlying tissue.
More recently, we introduced a technique whereby embryonic central
neurons can be implantedin the form of a dissociated cell suspension(Bj6rklund et al 1980b, 1983d, Schmidt et al 1981). In this method pieces of
embryonicCNStissue are trypsinized and mechanically dissociated into a
milky cell suspension. Small volumes (usually 1-5 v~l) are then injected
stereotaxically into the desired site of the brain or spinal cord by meansof a 10
I~l Hamiltonsyringe. The mainadvantagesof this approachare that it induces
minimaldestruction of the host tissue, it allows precise and multiple placements of the transplanted cells, and it enables accurate monitoring of the
numberof cells injected by countingthe density of cells in the suspension.This
technique has, moreover,the potential advantage of allowing the constituent
cells to be manipulated,mixed, or cultured before implantation. A wide variety
of central neuronalcells types survive grafting to the adult rat brain (Schmidtet
al 1983a). Wehave observed, however,that the noradrenergic neurons of the
developinglocus coeruleus are relatively sensitive to trypsin, and that these
neurons do not survive unless the trypsin incubation step in the dissociation
procedureis omitted (Bj6rklundet al 1983a). Othercentral neuronalcell types
mayshare this sensitivity to trypsin in the suspensiongrafting procedure.
Graft Placement
Theexact site of implantationand the features of the implantation site seemto
be far morecritical for long-termsurvival in the adult rat CNSthan in the CNS
of neonatal, developing hosts. This is probably because the developing host
tissue and the small dimensions of the neonatal rat brain provide generally
better support for survival, sources for revascularization, access to the cerebrospinal fluid (CSF), etc. Thus, direct intraparenchymalplacementof pieces
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BJ6RKLUND& STENEVI
of embryonicor neonatal CNStissue has given excellent results in several areas
of the neonatal rat brain (Das 1974, Das et al 1979, 1980, Sunde &Zimmer
1981, 1983, Arendash&Gorski 1982). In adult recipients, our experience is
that intraparenchymalgrafts of pieces of CNStissue (or ganglia) survive poorly
unless they are placed in direct contact with vessel-rich pial surfaces or the
CSF-filled ventricular system (Stenevi et al 1976). It seems likely that the
conditions of the transplantation site are morecritical for older donor tissue,
wherethe constituent neuronshaveundergonetheir last cell divisions, than for
moreundifferentiated donor tissue where continued cell proliferation maybe
able to compensatefor an initially poor cell survival.
The primary prerequisite for optimal survival in adult hosts seems to be a
rapid and efficient revascularization from the surroundingtissue. Presumably,
the CSFcan act as a sufficient nutrient mediumduring the first few days after
grafting, until a new blood supply has been established. This has been estimatedin the adult rat brain to take about three to five days (Svendgaardet al
1975b). In adult hosts the best results with solid grafts have therefore been
obtained with one-stage or two-stageprepared transplantation cavities, or with
grafts placed directly into the cerebral ventricles (see above). The conditions
are, however,quite different for implants of suspendedcells: with this tech. nique goodsurvival is also obtained in intraparenchymalsites, apparently in
any site within the brain or spinal cord of adult recipients.
Age of
Donor Age of Host
The single most important factor for good survival of neural gr.afts is the
developmentalstage of the donor tissue and, to a lesser degree, the a~-of the
recipient animal. The general rule for grafts of CNStissue is that the younger
the donor, the better the chances for survival and growthof the graft, and that
the tolerance limits with respect to donor age are tighter in more mature
recipients.
The age-of-donorfactor has been most systematically investigated by Seiger
&Olson(1977) and Olsonet al (1982) for intraocular grafts in adult rats.
ownobservations on intracerebral solid grafts (Stenevi et al 1976, Kromer
Bj6rklund 1980, Kromeret al 1983) are consistent with their findings; this
suggeststhat the samerules are applicable for both intraocular and intracerebral
grafts of pieces of nervoustissue, at least in adult recipients.
Althoughin adult recipients the best survival and growthis consistently seen
with embryonicdonors for tissue from all regions of the CNS,the optimal
embryonicdonor age varies for different parts of the neuraxis. In general, the
best survival seemsto coincide with the period of neuronal proliferation and
migration within each area. Thus, regions that differentiate earliest, such as
manybrain stem and spinal cord nuclei, give best results when taken from
relatively
young embryos (approximately days 15-17 of gestation).
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INTRACEREBRALNEURALIMPLANTS
285
(Embryonicdays are given here with day after mating as day 0.) Regionsthat
exhibit a more protracted neurogenesis, such as cerebral cortex and hippocampus, can be grafted with goodresults from a wider range of donor ages (up to
days 20-22of gestation), althoughthe final size, the intrinsic architecture, and
the survival rate of the grafts can be quite different in grafts taken fromearly
and late gestational stages (see Kromeret al 1983for examplesof hippocampal
grafts). Partial exceptionsto this rule are grafts of developingcerebellar tissue,
which producewell-organized grafts only whentaken from a fairly restricted
period of age (approximatelygestational days 11-15), even thoughneurogenesis in the cerebellumcontinues into the postnatal period in the rat (Olsonet al
1982, Kromeret a11983, Alvardo-Mallart &Sotelo 1982). For both hippocampal and cortical tissue the time constraints appear to be less pronouncedwhen
tissue is grafted to the brains of neonatal recipients (Das et al 1979, 1980,
Sunde & Zimmer 1983).
For grafts Of neuronal cell suspensions, donor age seemsto be an even more
critic_al parameter(BjOrklundet al 1980b, Schmidtet al 1983a). Nigral dopaminergic neurons, injected into the adult caudate-putamen,showgoodsurvival
and axonal outgrowth only when taken from donors up to about day 15 of
gestation. Wi~hsuspensions prepared from 16-17 day-old donors the survival
was drastically reduced. Similar observations have been madewith cerebellar
Purkinje cells, of whichlarge numberssurvived in implants prepared from day
15 donors, but not from donorsof day 18, or older, of gestation. By contrast,
cerebellar microneurons,which continue to be generated up into the postnatal
period, survive suspension grafting from the late embryonicstages and the
early posmatalperiod. Theseobservations suggest that central neurons survive
the dissociation and ~raftin$ procedureonly whentaken durin~ their period of
proliferation and migration, which coincides with gestational days 11-15 for
the nigral dopamineneurons (Lauder &Bloom1974) and days 13-15 for the
Purkinje cells (Altman1969). This conclusion finds additional support from
observations by Banker&Cowan(1977) on the survival of different types
hippocampal neurons in dissociated cell cultures. The behavior of nonneuronalelementsin the grafts is probablydifferent, but this so far is poorly
explored.
Immunological
Aspects
Most studies so far on intracerebral neuronal grafts have been carried out
betweendifferent individuals of the same breeder’s stock of rats. Although
these rats mayoriginally derive from an inbred strain they have subsequently
been outbred to the extent that the individuals are, to somedegree at least,
genetically different. This degree of difference seemsto havevery little effect
on the long-term survival of both intracerebral and intraocular grafts. Thus,
intracerebral grafts of CNStissue have beenseen to survive morethan one year
without any signs of rejection, necrosis, or regressionof either the graft tissue
or its neuronal projections into the host. Interestingly, grafts of peripheral
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BJORKLUND& STENEVI
tissue (whichlack a blood-brain barrier) demonstratesigns of regression and
axonal degeneration at long survival times under similar conditions (Svendgaard et al 1975a).
Partial long-termsurvival (up to six months)has beenobservedwith grafts
mesencephalicdopamineneurons to the striatum, transplanted betweenspecies
(from mouseto rat) (Bj6rklundet al 1982b). Other investigators have reported
survival of septal grafts madebetweendifferent strains of rats (Lowet al 1983),
or from rat embryosto adult rabbits (Bragin &Vinogradova1981). In the study
of Lowet al (1983), however, the grafts, analyzed at three months after
transplantation, showeda lymphocyteinfiltration indicative of an on-going
immunereaction. In the study of Bj6rklund et al (1982b) the actual grafted
tissue piece had degenerated by six months, but groups of dopamineneurons,
whichapparently had migrated into the host caudateoputamen(as well as some
apparently avascular clumpsof grafted neurons), had survived. These neurons
were sufficient to provide good dopaminefiber ingrowth and functional compensation in the initially denervatedhost neostriatum,
The brain has been suggested to be an immunologically privileged site,
probably partly because of its protective blood-brain barrier (see Barker
Billingham 1977, Raju & Grogan1977). We(BjiSrldund et al 1982b) proposed
that althoughxenogenicgrafts of pieces of neural tissue will eventually undergo rejection, some neurons can escape rejection by migrating be,hind the
protective blood-brain barrier of the host.
DEVELOPMENT
THE GRAPTS
AND INTRINSIC
ORGANIZATION
OF
In general, the time-courseof development
of the grafted tissue in its newhost
environmentseems to follow relatively closely the normal in situ developmental sequence. The time-course studies of Jaeger &Lund(1980b, 1981; neocortex) and Wells &McAllister(1982; cerebellum)indicate that cell proliferation
and neurogenesis proceeds with a time-course that is very close to the one in
situ, whereasneuronal migrationand differentiation and folia formationmaybe
delayed or, in some cases, abnormal. Thus, Wells & McAllister (1982)
reported for examplethat Purkinje cell monolayerformation was delayed by
five days and folia formation by about ten days in intracortical grafts of
cerebellar primordia. Our own fluorescence histochemical studies on
monoaminergicneurons (Stenevi et al 1976, Bj0rklund et al 1979b, 1980a,
Kromeret al 1983, and Jaeger &Lund’s (1980b) observations on neocortical
neurons with 3H-thymidineautoradiography have shownthat both proliferating
neuroblasts and neurons that have already undergonetheir final cell division
will survive grafting. For the noradrenergic locus coeruleus neurons, taken
after their final cell division, it has been estimated that about 10-30%will
survive grafting to the cortex of adult recipients (Bj6rklundet al 1979b).
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INTRACEREBRALNEURALIMPLANTS
287
Thematuretransplants developintrinsic organizational features that generally resemblethe ones seen in situ. So far this has been studied well only for
tissues grafted as intact pieces, but for suchspecimensit applies also to grafts
placed in ectopic sites and in relative isolation fromthe host brain. Alreadyin
1940 LeGrosClark emphasized the normal-looking lamination of cells developed in an intracortical graft of embryonicneocortex. Relatively normal
cellular architecture, intrinsic fiber connections,and cortical foliation has more
recently been described in intracerebral grafts of cerebellum (Kromeret al
1979, 1983, Alvarado-Mallart &Sotelo 1982, Wells & McAllister 1982),
hippocampus (Kromer et al 1979, 1983, Sunde & Zimmer1981, 1983), and
retina (McLoon& Lund 1980a,b). Each of these regions can develop its
characteristic laminar architecture, and in the case of hippocampal
and cerebellar grafts, also someof its normalfoliations. Thedegree to whichthis happens
seemsto depend,however,on (a) the age of the donor fetus, (b) the dissection,
orientation, and integrity of the grafted piece, and (c) the space available
which the graft can grow. In cerebellar grafts, Alvarado-Mallart & Sotelo.
(1982) demonstrated the presence of all five major categories of neurons
normally present in the cerebellar cortex, as well as several of the normal
intrinsic synaptic connections, such as mossyfiber glomeruli and reciprocal
cortico-nucleo-cortical connections. Similarly, Sunde&Zimmer(1981, 1983)
observedsomeof the major intrinsic fiber connections in hippocampalgrafts,
such as the mo~ssyfiber connections of the granule cells onto CA4and CA3
pyramidalneurons, and the associational fiber connectionsfrom the pyramidal
cells to the molecularlayer of the dentate gyrusregion in the graft. Histochemical studies, finally, haveshownthat different neurontypes within the graft will
retain or express their normalneurotransmitter characteristics, such as synthesis and storage of monoamines
or neuropeptides(Bj/Srklund et a11976,1979a,
1980a, Stenevi et al 1980b, Gash&Sladek 1980, Krieger et al 1982, Schultzberg et al 1983).
Takentogether, these various observations indicate that the organization of
the intrinsic circuitries as well as the functional properties of the component
neurons in intracerebrally implantedgrafts mayrepresent relatively faithful
replicas of the region in situ. This seemsto be the case regardless of whetherthe
graft is well integrated with the host CNStissue, or whetherit occursin relative
isolation, such as in the anterior eye chamber(see e.g. Olsonet al 1982).
RECONSTRUCTIONOF NEURALCIRCUITRIES IN
ADULT RATS
Oneof the most interesting features of the intracerebral neural grafts is their
ability to form extensive axonal connections with the host brain. Several
studies in both developingand adult hosts have demonstratedprojections from
neuronswithin the implant to areas within the host brain (Bj6rklundet al 1976,
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BJORKLUND
& STENEVI
1979a,b, 1980a, Bj6rklund &Stenevi 1977b, |979c, Beebeet al 1979, Jaeger
&Lund1979, 1980a, McLoon& Lund 1980a,b, McLoonet al 1981, 1982,
Kromer& Bj6rklund 1980, Oblinger et al 1980, Oblinger &Das 1982, Lewis
&Cotman1980, 1983), as well as projections from neurons within the host into
the implant (Lund & Hauschka 1976, Oblinger et al 1980, Jaeger &Lund
1980a, Lund & Harvey 1981, Harvey & Lund 1981, Kromer et al 1981a,b,
Segal et al 1981, Oblinger & Das 1982, Hallas et al 1980, Sunde & Zimmer
1983). Althoughthe establishment of connections between implant and host
maybe influenced both by the stage of developmentof the host brain and by the
location of the implant and the surgery involved(see below), it seemsclear that
the connections established by the intracerebral implants can exhibit a high
degree of specificity. In this reviewwe focus on our ownstudies on the ability
of embryonicneural implants to substitute for lesioned pathways and lost
innervationsin adult rats. Someof the parallel workthat has beencarried out in
rats during postnatal developmentis discussed in this context, but for a more
complete coverage of the developmentalstudies the reader is referred to the
reviews by Lundand co-workers (Lund 1980, Lundet a11982)and Das (1983).
Reinnervation
Monoaminergic
of the Denervated Hippocampus by
and Cholinergic
Neurons
In the studies performedin our laboratory over the last few years we have been
particularly concerned with the monoaminergicand cholinergic neuronal systems, taking advantageof the availability of selective and sensitive histochemical methods for tracing of the connections of these systems. The
monoaminergicand cholinergic systems have an additional advantage, in that
their axonal outgrowths can be monitored biochemically (through assays of
their transmitters or transmitter-related enzymes).Moreover,the neurotransmission of these neurons is accessible to pharmacologicalmanipulation, which
provides possibilities for testing the functional signifi6ance of newlyestablished connections.
In a In’st series of experiments(Bj6rklundet al 1976, 1979a,b, Bj6rklund
Stenevi 1977b, Beebeet al 1979), we studied the growthof monoaminergic
and
cholinergic axons from transplants of different embryonicbrainstem regions
into the hippocampalformation in adult recipient rats. The idea behind these
experiments was to test to what extent, and with what degree of precision,
neural transplants are able to reestablish normal cholinergic and
monoaminergic
terminal innervation patterns in a previously denervated brain
region. The hippocampalformation is ideally suited for such studies for two
reasons. First, the terminal fields of the afferent inputs are, for the mostpart,
discretely laminated; this gives each afferent systema characteristic termination pattern. Second,the major afferent fiber inputs to the hippocampalformation are readily accessible to surgical transection, and this makespossible fairly
selective denervationsof this region of the brain.
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INTRACEREBRALNEURALIMPLANTS
289
The transplants, obtained from 16-17-day-oldrat fetuses, comprised(a) the
septal-diagonal band area (which contains an extensive system of cholinergic
neurons normally innervating the hippocampusand large parts of the neocortex), (b) the locus coeruleus region of the pons (whichcontains the nucleus
origin of the hippocampalnoradrenergic innervation), (c) the pontine
mesencephalicraphe region (with major serotonergic cell groups, including
those which innervate the hippocampus), or (d) the dopamine-rich ventral
mesencephalon(which does not normally innervate the hippocampus). These
different transplants weregrafted into the hippocampalcircuitry in such a way
as to allow the grafted neurons to grow toward the denervated hippocampus
along the normal routes of the cholinergic and monoaminergichippocampal
afferents. This was achieved by placing the grafts either in a cavity made
through the hippocampalfimbria, or in a cavity of the occipital-retrosplenial
cortex (transecting the dorsal part of the entorhinal perforant path system),
illustrated in the inset in Figure 1. In both locations, axonsfrom the grafted
neurons were found to invade large parts of the hippocampalformation. The
modeof growth and the patterning of the ingrowing axons in the hippocampus
differed markedly, however,amongthe different grafted neuron types, suggesting that the axonal ingrowthis very precisely regulated in the denervated
hippocampaltarget. Indeed, the septal and the locus coeruleus transplants were
able to form new "septo-hippocampal" and "coeruleo-hippocampal" pathways
in rats whose systems had been damagedbefore the transplantations were
made. The new cholinergic and adrenergic innervations closely mimickedthe
normalcholinergic and adrenergic innervation patterns, respectively, and in
successful cases the entire hippocampus
and dentate gyrus were reached by the
ingrowing axons. The newly formed innervations have been observed to
remainunchangedfor morethan a year after the operation and are thus probably
permanent.
The most remarkable features of the graft-to-hippocampus projections are
their reproducibleand, at least partly, neuron-specificterminal patterning, and
the pronouncedinfluences that are exerted by the presence or absence of
specific groups of hippocampalafferents. This impression is mainly derived
from the following three observations.
1. Different types of grafted neurons, transplanted in the samelocation,
formdistinctly different terminal patterns in the hippocampus.Theupper panel
of Figure 1 illustrates this in rats whosedentate gyrus had beenreinnervatedby
transplants placed in the occipital-retrosplenial cortex (CS). The noradrenergic
axons are seen to avoid, and even to grow through, the denervated terminal
zoneof the entorhinal perforant path fibers, whichnormallyinnervate the outer
half of the dentate molecular layer. Instead, the adrenergic axons growinto
those areas whichnormallyreceive a dense noradrenergic innervation from the
locus coeruleus, whichin the dentate gyrus is the hilar zone. Bycontrast, the
cholinergic, dopaminergic, and serotonergic axons ramify extensively in the
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290
BJ~RKLUND
& STENEVI
(A) Transplantationto caudalsite (CS)
~
entorhinal
perforant path
~_~
~locuscoeruleus,
Lraphe
Mol.
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Adrenergic Serotonergic
Dopaminergic
(B) Transplantationof rostral (RS)or caudalsite (CS)
~
~
~//////////~.
Mol.
entorhinal
perforant path
commissural
(via fimbria)
,~- septal (via fimbria)
~
Cholinergic(septal transplant)
PPintact
PP lesioned
PPlesioned
fimbria
fimbria
fimbria
lesioned
intact
lesioned
(CS)
(CS or RS)
(RS)
~
Septum
~ eolliculus
Figure 1 Schematicrepresentation of the patterning of different types of ingrowingaxons in the
dentate gymsin rats beating transplants in the occipital-retrosplenial cortex (caudal site, CSin
inset), or in the hippocampalfimbria (rostral site, RSin inset)¯ The hatched fields denote the
distribution of ingrowingaxons in the layers of the dentate (mol.: molecularlayer; gran.: granular
layer). Tothe right is giventhe position of the terminal fields of the normalafferent inputs. (A)
different distribution of axons fromlocus coemleustransplants (adrenergic), from raphetransplants
(serotonergic), and from ventral meseneephalistransplants (dopaminergic)placed in the caudal
(CS). In all these cases the entorhinal perforant path axons to the outer molecular layer were
lesioned, and the monoaminergieafferents were removedby neurotoxin pretreatment. (B) Influence of removalof different afferent inputs on the patterning of cholinergic (ACHE
positive) fibers
growinginto the dentate fromseptal transplants placed in the caudal (CS)or rostral (RS) site.
.the normal septal cholinergic input through the fimbria is inthct (left-hand side of figure) the
transplanted cholinergic axons becomerestricted to the denervatedperforant path (PP) zone, but
whenthe normal septal input is removed(middle of the figure), the ingrowingcholinergic axons
also expandinto the terminal fields of the septal afferents. Likewise,the extensioninto the PPzone
is inhibited by the presence of an intact entorhinal input (right-hand side of the figure). (From
BjOrklund & Stenevi 1979b.)
denervated perforant path zone to form a dense band of terminals in the outer
molecular layer of the dentate. Despite their neuroehemical relatedness
to the
noradrenergic
neurons, the transplanted
dopaminergic
neurons show a very
limited growth into the denervated terminal zones of the noradrenergic
afferents.
2. When the ingrowing axons are given a choice between different
dener-
vatedterminalfields, theyshowin certain casesa clear preferencefor the zones
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INTRACEREBRALNEURALIMPLANTS
291
denervatedof the homologous
fiber type. This is illustrated by the abovequoted
exampleof noradrenergic axons growinginto the dentate gyrus .from locus
coeruleus grafts (Figure 1). Anotherexampleis given by septal grafts in the
fimbrial site (lower panel RSin Figure 1): Althoughthe transplantation lesion
in the fimbria removesnot only the septal cholinergie afferents but also the
extensive systemof commissuralnoncholinergic afferents, the ingrowingcholinergic axons from the graft (as monitoredby acetylcholine esterase, ACHE,
histochemistry) becomerestricted to the normalcholinergic terminal fields.
Zonesreceiving densecommissural,but sparse septal, innervations (such as the
stratum radiatum of CA1and CA3,and the supragranular zone in the temporal
parts of the dentate molecularlayer; cf Figure 1B)are largely devoid of fibers
from the transplant.
3. Asseen in experimentswith septal transplants (lower panel in Figure 1),
the extension of ingrowingcholinergic axons into the terminal fields of the
normal cholinergic innervation is markedlymodified by the presence or absence of the intrinsic cholinergic innervation. In our first experiment(Bj6rklund&Stenevi 1977b)the AChEstaining indicated that in the dentate gyrus the
extension of AChE-positiveaxons from the septal graft (placed in the caudal
site in Figure1) wassubstantially reducedinto the normalterminal zonesof the
cholinergic afferents if the fimbria, carrying the intrinsic septo-hippocampal
cholinergicafferents, wereleft intact. Instead, the fibers terminatedheavily in
the entorhinal perforant path zone, denervatedby the transplantation lesion (left
in lower panel in Figure 1). In follow-up experiments using the suspension
grafting technique(F. H. Gageet al, in preparation) we have observedthat the
ingrowthis markedlyreduced but not completelyblocked in animals with intact
fimbrial inputs. The choline acetyltransferase (CHAT)
level in the host hippocampusthus reached about 75%of normalin animals with the fimbria lesioned
at the time of transplantation, as comparedwith about 25%in rats whose
fimbria was left intact until one weekbefore sacrifice. The parallel AChE
histochemistrysuggestedthat the denervatingfibrial lesion, madeat the time of
transplantation, madethe cholinergic axons from the graft growover greater
distances within the host hippocampusand ramify moreextensively in someof
the normalterminal zonesof the intrinsic sept-hippocampal
cholinergic projection. Interestingly, McLoon
&Lund(1980b) have reported a similar effect
removalof the normalretinal input on the ingrowthof axonsfrom retinal grafts
into the superior colliculus in neonatal rats.
These observations suggest that the ingrowth and patterning of axons from
implantedneurons are greatly influenced by the target tissue, and that this
regulatory influence exhibits a relative specificity with respect to different
types of neurons within the graft. The effects of denervating lesions suggest
moreoverthat the proliferation and terminal patterning of the reinnervating
axonsmayin somewaybe related to the filling of vacated terminal space in the
denervated target, analogous to what has been described for lesion-induced
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292
BJI~RKLUND& STENEVI
collateral sprouting in the septo-hippocampalsystem (see Raisman&Field
1973, Cotman& Lynch 1976). The monoaminergicand cholinergic neurons in
the implants can also reinnervate the adult host hippocampus
in a reproducible
and orderly manneralthough the fibers enter from abnormal directions and
along routes that are inconspicuousin normalanimals. The extension, proliferation, and patterning of the ingrowingfibers can be drastically modifiedby
the removalof intrinsic afferents of both homologousand heterologous kinds.
As in the experiments of McLoon&Lund(1980b) in neonatal recipients, the
ingrowing axons in the adult hippocampusthus exhibit in somerespects a
considerable degree of specificity, while being at the same time markedly
flexible and modifiableto the extent that abnormalzonesof termination can be
induced.
Use of Neural Transplants
Axons in the Host
as "Bridges"
for Regenerating
Attemptsto use transplants to promoteaxonal regenerationacross tissue defects
in the CNSdate back to Tello (1911) and Cajal (1928), whointroduced the
of using pieces of peripheral nerve to bridge lesions and stimulate sprouting
from lesioned central axons. Numerousstudies have subsequently been done
along these lines, but it is only recently, with the elegant and importantworkof
Aguayoand collaborators (Richardson et al 1980, 1982, David & Aguayo
1981, Benfey&Aguayo1982), that the viability of this approachhas been well
substantiated.
In our ownexperiments we have asked the questions: To what extent can an
embryonichippocampalimplant replace the normal hippocampusin the formation of connections with the host septum, and to what extent can such an
implant promote regeneration of the septohippocampalpathwayand serve as a
bridge for the regeneration of axons from the septal nuclei to the hippocampus?
From previous studies (Bjrrklund & Stenevi 1971, Bjrrklund et al 1975,
Svendgaard et al 1975b, 1976) we knew that transplants of denervated
peripheral tissues, such as iris, heart, or portal vein, promotethe regeneration
of central axons into the transplanted target. Interestingly, the degree of
adrenergic or cholinergic reinnervation of the transplant appearedto be related
to the property of the target to possessa normaladrenergicor cholinergic nerve
supply. This may suggest that lesioned central neurons are susceptible to
trophic mechanismsnormally operating during reinnervation of denervated
muscle tissue. In the septohippecampalsystem, in particular, implants of
denervated iris have thus been shownto stimulate the cholinergic septal
neurons of the host to reinnervate large parts of the graft in an organotypic
manner (Svendgaard et al 1976, Emsonet al 1977).
Against this background, it seemedreasonable that a graft of embryonic
hippocampus,deprived of its normalexternal afferents, could actively promote
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INTRACEREBRALNEURALIMPLANTS
293
the regenerationof axonsin the septohippocampal
circuitry in order to establish
connections with the deafferented graft. In these experiments (Kromeret al
1981a,b, Segal et al 1981) the rostral tip of the hippocampus
plus the hippocampal fimbria were removedby suction on one side in young adult female
rats, leaving an approximately3 × 3 mmwide cavity that completely severed
the septohippocampal connections. A transplant of embryonic hippocampus
was then placed in the cavity, onto the vessel-rich ependymaoverlying the
anterior thalamus, in contact with the cut fimbria, rostrally, and with the cut
hippocampus,caudally.
In most cases the implant was foundto havefused with the cut surface of the
host hippocampusand formed tissue bridges with both the septum and the
caudate-putamenof the host. Over these tissue bridges AChE-positivefibers
wereseen to invade the implantto give rise to an AChE-positive
neuropile that,
with time, progressedto cover the entire implant. In parellel, the cholinergic
marker enzyme, CHAT,increased progressively to between 40 and 60%of the
normalhippocampallevel by 6-24 weeksafter transplantation. Septal lesions
and HRPinjections into the graft have provided evidence that the principal
origins for the cholinergic afferents were the medial septumand the diagonal
band nucleus of the host brain (Kr0meret al 1981a).
Theseresults suggest that a piece of deafferented embryonicCNStissue-similar to denervated peripheral tissue---can indeed promotethe regeneration
of axotomized central neurons. This effect maybe a fairly specific one,
providinga stimulus for directed sprouting into the denervatedtarget by axons
that normallyinnervate the implanted tissue. The regenerating septohippocampal axons were not restricted, however,to the implant: they also expanded
across the implant-hippocampalborder into the dorsal part of the host hippocampus(Kromeret al 1981b). Due to the axotomycaused by the transplantation cavity, the AChE
positive innervation of the dorsal parts of the hippocampus was initially totally removedand the ChATlevel reduced to 5-10%of
normal. By four to six weeksafter transplantation, newAChE-positivefibers
appeared in parts of the subiculum, hippocampus,and/or dentate gyrus, immediately bordering on the implant. By three months the new fibers had
expandedabout 2.5-3.5 mmfurther caudally to cover the entire dorsal hippocampalformation. In parallel, ChATactivity (not seen in control rats without
implants) reappeared to an average of 30%of normal in the dorsal hippocampus. In the most successful cases, a recovery of as muchas 50%of normal
ChATactivity was recorded. As with the regenerated fibers in the implant, the
newly formed AChE-positive innervation in the host hippocampuscould be
removedby a lesion of the ipsilateral medial septum-diagonalband area, and
HRP-injections, madeinto the host hippocampusbehind the implant, resulted
in labeling of neuronsin this area.
Theseresults mayhave interesting implications for the understandingof the
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BJ(~RKLUND& STENEVI
regulation of regenerative responses in the mammalian
CNS.The effect of the
implant is probably not to induce regeneration per se, but to stimulate and
promotea regenerative responsealready present as a result of the lesion. It is
temptingto suggestthat this effect of the embryonic
neural graft is related to its
¯ normalproperty to receive a certain type of innervation (in the present case
cholinergic one), and thus that the very samefactors that guide axons to their
terminal sites during ontogenesismayin certain cases also operate in the mature
CNSto stimulate and guide regenerating axons back to their original sites of
termination. This interpretation wouldimplythat at least sometypes of neurons
in the matureCNSretain their responsivenessto factors regulating the formation of neuronal connectionsduring embryonicdevelopment.It is conceivable,
therefore, that axonal regeneration after lesions in the adult mammalian
CNS
couldbe limited by the availability (or access to) factors released by (or present
in) the denervatedtarget tissue, rather than by a defective intrinsic regenerative
capacity of the mature central neurons themselves.
Results obtained with intracerebral implants in other modelsystemsindicate,
however, that the mechanismsunderlying the formation of afferents to the
implanted grafts are considerably more complex(Harvey & Lund1981, Lund
& Harvey 1981, Jaeger &Lund1980a, Oblinger et al 1980, Oblinger & Das
1982, David & Aguayo1981, Benfey & Aguayo1982). The following factors
mayinfluence or determinethe formation of afferents to intracerebral grafts:
1. The extent of integration or fusion betweenthe implant and the host brain
tissue: Oblinger &Das (1982), in particular, havepointed out that in neocortical grafts in the adult cerebellumthe area innervatedby afferents from the host
was proportional to the extent of tight fusion betweengraft and host.
2. Theavailability or proximityof axonsin the area of the implant: Observations madeon heterotopically placed grafts (i.e. neocortex to cerbellum and
peripheral nerve into the brain) suggest that axons in close proximity of the
implant wouldbe the ones mostlikely to invade the implant, regardless of their
natural anatomicalrelationship with the grafted tissue (Oblinger et al 1980,
Oblinger & Das 1982, David & Aguayo 1981, Benfey & Aguayo 1982). It
should be kept in mind, however,that anatomically distinct systems mayshare
functional properties, e.g. transmitter characteristics (cf Svendgaardet al
1975b, 1976, Lewis &Cotman1983). Thus, denervated irises will be reinnervated by cholinergic and andrenergic axons regardless of their anatomical
identity.
3. In developing rats the stage to whichdifferent axonal projections have
developedin the host maydeterminetheir abiltiy to expandinto the implant.
This has been proposed, e.g. by Lund et al (1982), as an explanation
differences in the input fromcortical and geniculateareas into tectal transplants
in neonatalrats.
4. In adult rats the site and extent of axotomyof different pathwaysmay
determine their ability to sprout into the implant. This is suggested, for
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INTRACEREBRALNEURALIMPLANTS
295
instance, by the observations of Svendgaardet al (1975b) and Emsonet
(1977) that central monoaminergicaxons will reinnervate intracerebral implants of iris only whenthe iris tissue is in close proximityof transected and
actively sprouting preterminal axon bundles.
5. Specific interactions betweenhost neuronsand grafted target: The studies
of Lundand collaborators (1982), in particular, have shownthat the implants
do not appear as passive receivers of axons, but that the types of afferent
connections formeddependon the particular region that is grafted. This is
exemplifiedby their observationthat discrete areas of tectal implants, grafted
adjacent to the superior colliculus in newbornrats, receive retinal afferents
fromthe host, whereascortical and retinal implants are devoidof such afferents
[cf also the results of Yoon(1979) in adult goldfish]. Specific interactions
between host and target are also supported by our ownobservations on the
reinnervation of intracerebral implants of peripheral target tissues by central
monoaminergicand cholinergic neurons. Our observations suggest that (a)
different monoaminergic
neurontypes differ in their"affinity" for a denervated
iris target, and the appropriate noradrenergic neurons are clearly favored
(Svengaard et al 1975b, Bj6rklund & Stenevi 1979a); (b) tissue normally
innervated by adrenergic neurons (e.g. iris) will permit or stimulate the ingrowth by regenerating central noradrenergic axons, whereastargets normally
lacking such innervation (e.g. uterus muscle) will not do so (Bj6rklund
Stenevi 1971). As during regeneration in the PNS(Olson & Malmfors1970,
Ebendalet a11980),both the density and the patterning of the ingrowingcentral
monoaminergicand cholinergic afferents seem to be under regulation by the
denervated implanted target.
Growth Regulation
and Trophic
Mechanisms
Threemainlines of evidenceindicate that the growthresponseof intracerebrally implantedneuronsis due to a fairly specific interaction with the surrounding
tissue of the adult host brain.
1. Implanted dopamineneurons have been observed to grow preferentially
into areas that are normal targets for the dopamineneurons in the brain
(Bj6rklund & Stenevi 1979c, Bj6rklund et al 1980a, Dunnett et al 1981b).
Further, dopamineneurons implanted in the form of cell suspension into
different regions of the brain exhibit an extensive fiber outgrowthwhenplaced
in the striatum, whichis a normaltarget area, but they showno or very little
fiber outgrowthinto the host tissue whenplaced in parietal cortex, lateral
hypothalamus,or globus pallidus, which are areas that do not belong to the
normal primary targets of the mesencephalicdopamineneurons (Bj6rklund et
al 1983c). Interestingly, this differential growthresponse is similar to that
observedon dopamineneurons in vitro by Di Porzio et al (1980), Prochiantz
al (1981), Hemmendinger
et al (1981), and Appel (1981). They reported
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BJrRKLUND& STENEVI
selective growthstimulatory effect on the cultured dopamineneuronsby striatal
tissue (i.e. the appropriate target tissue) or by membrane
or protein fractions
obtained from that tissue. In intracortical mesencephalicdopaminergicgrafts
innervating the adult neostriatum, Schultzberg et al (1983) have recently
reported immunocytochemical
observations suggesting that only those dopamine neurons which normally innervate the neostriatum (characterized by
lack of the peptide cholecystokinin) grow extensively into the underlying
target. By contrast, the dopamineneurons of the ventral tegmental area (characterized by their concomitant cholecystockinin content), which normally
innervate ventral forebrain areas but not the neostriatum, showedvery poor
ingrowth, This maysuggest that the stimulation of fiber outgrowthfrom the
implant is selective with respect to different subpopulations of dopamine
neurons, and that the subpopulation normally innervating the neostriatum is
favored.
2. As mentioned above, the fiber outgrowth from embryonic neural implants maybe substantially modified by the presence or absence of intrinsic
afferents, and in somecases the fiber outgrowthcan be greatly stimulated by
prior deafferentiation of the target. Wehave studied this in particular with
respect to the outgrowthof cholinergic neuronsin septal implantsgrafted to the
hippocampalformation. Here, the fiber outgrowth into the host hippocampus
(as monitored by measurementsof ChATactivity) is about three-fold greater
whenthe intrinsic cholinergic afferents havebeen removed(F. H. Gageet al, in
preparation). Interestingly, the removalof a noncholinergicset of afferents to
the hippocampus,i.e. the entorhinal perforant path input, has been shownnot
only to modify the patterning of ingrowing axons, but also to accelerate
reinnervation and increase the magnitude of ingrowth by cholinergic axons
(Bjrrklund et al 1979a).
3. In the PNS, target tissues are knownto exert trophic influences on
neurons that innervate the target (see Hamburger1977, Hendry1976, Landmesser& Pilar 1978). Likewise, the growth-stimulating effect of target cell
deafferentiaion has been proposedto be mediatedby retrogradely acting trophic
factors, elaborated by the denervatedtarget (Ebendalet al 1980, Hendersonet
al 1983, Hill & Bennett 1983). The mechanismsoperating during reinnervation
in the CNSmayfor somesystemsby quite similar to those in the PNS.Thus, for
example, a peripheral target tissue normallyrichly innervated by adrenergic
fibers, such as the iris, has been seen to interact with regenerating central
adrenergic neurons (i.e. those of the locus coeruleus) in very muchthe same
wayas it does with peripheral, ganglionic adrenergic neurons (Bjrrklund
Stenevi 1979a). In fact, the growth-stimulating effect of a denervated iris
implant on regeneratingcentral adrenergicneuronsis muchreducedif the iris is
incubated in antiserum to nerve growthfactor (NGF)prior to transplantation
(Bjerre et al 1974). Theseeffects resemblethose exerted by denervatedirides
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INTRACEREBRALNEURALIMPLANTS
297
on peripheral adrenergic neurons in vitro (Johnson et al 1972) and in vivo
(Ebendalet al 1980).
In a recent study (Bj6rldund &Stenevi 1981) we have attempted to monitor
the growth-stimulating effect expressed by the adult rat hippocampusin vivo
after denervating lesions by means of superior cervical ganglia implanted
adjacent to the hippocampalformation. Grafted adult sympathetic ganglia grow
poorly into a hippocampus
with intact septohippocampal
inputs. A lesion of the
septohippocampalpathway(madeat the time of grafting or two months after
grafting) causes a massivestimulation of axonal growthinto the hippocampus.
The increase was more than 100-fold by one monthafter lesion and was still
about ten-fold by three months.The denervating lesion, in addition, induced a
3.6-fold increase in the averagesize of the gangioniccell bodies in the graft,
without any clear-cut effect on the numberof surviving ganglionic neurons. In
a subsequent study (Gageet al 1983c) we have observed that the denervating
lesion also has a dramaticeffect on the survival of similarly grafted neonatal
sympathetic ganglionic neurons. Neonatal sympathetic neurons, which normally are strictly dependenton NGFfor their survival (see Hendry1976), thus
did not survive at all on the surface of the host hippocampusunless the
hippocampuswas deafferented at the time of implantation.
This lesion-induced trophic response (increases in axonal outgrowth, cell
bodysize, and noradrenalinecontent in adult ganglia, and increase of neuronal
survival in neonatal ganglia) is specific for lesions of the septal (probably
primarily cholinergic) innervation of the hippocampus,while lesions of other
majorinputs (entorhinal or commissural)do not have this effect. Lesionsof the
intrinsic adrenergic afferents (from the locus coeruleus) are also ineffective.
These results speak strongly in favor of the notion that a neuronotrophic
factor(s) takes part in the regulation of fiber ingrowth, and perhaps also
neuronal survival, in the establishment of connections from intracerebral implants, and that this factor, or factors, is underthe control of non-adrenergic
(probably cholinergic) afferents originating in the-septal-diagonal band area.
Interestingly, the effects of this putative factor on the sympatheticneurons
resemblethat of NGF,and seemto act over relatively large distances. Crutcher
&Collins (1982) and Nieto-Sampedroet al (1982) have recently been able
demonstrate, in extracts or fluid from the adult rat hippocampus,the presence
of growth factors both similar to and different from NGF,and Barde et al
(1982) have purified a factor from mammalian
brain tissue with chemical (but
not immunological)properties similar tO NGF.It seemsquite possible, therefore, that diffusible growthfactors mayoperate in a very similar manner,both
in the-peripheral and central nervous systems to regulate sprouting and reinnervation of denervatedtargets. Intracerebral neural implants should provide a
newpowerfultool to monitor and explore such growth-regulatingfactors in the
brain in vivo.
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FUNCTIONAL
IMPLANTS
EFFECTS
OF INTRACEREBRAL
A morecompleteaccount of the studies carried out on the functional properties
of intracerebal neural grafts is outside the scope of the present review. In this
section, therefore, we briefly summarizesomeof the key features that have
emerged from experiments carried out in adult recipient rats. For a more
completecoverageof this topic, the reader is referred to the recent reviews by
Durmettet al (1982a,b, 1983a,b) and Bj/Srklund et al (1983b).
Electron
Microscopy
Ultrastructural analysis of transplant-host connections has so far been performedonly in a few cases. Thus, axons from implants of brainstem tissue have
beefi shownto makesynaptic contacts with dendrites in the dentate molecular
layer in adult hosts (Beebeet al 1979), and axons fromretinal grafts have been
shownto establish normal synaptic contacts in the superior colliculus of
developing hosts (McLoonet al 1982). Further, Lund& Hauschka(1976)
Lurid &Harvey(1981) observed in neonatal rats synapses in implants of tectal
tissue, derived from the ingrowinghost retinal afferents.
Biochemistry
Grafted dopamineneurons, reinnervating the initially denervated neostdatum,
exhibit transmitter synthesis and turnover rates close to those of the normal
nigrostriatal dopaminepathway. This has been recorded in animals with solid
grafts of embryonicmesencephalon,placed in an intracortical cavity (Schmidt
et al 1982), as well as with suspendeddopamineneurons injected into the depth
of the neostriatum (Schmidt et al 1983b). Interestingly, these biochemical
studies suggest that the activity of the grafted dopaminergicneurons mayto
someextent be regulated through interactions with the reinnervated target.
Thus, the turnover rates of dopaminewere inversely related to the magnitudeof
fiber ingrowthfrom the graft, and in the moresparsely reinnervated specimens
the turnover was considerably above normal. In the study of Schmidt et al
(1982), the general metabolic activity of the implant, as measuredby ~4Cdeoxyglucoseautoradiography, was found to be close to that of the substantia
nigra region in situ.
P eptide Secretion
Grafts of embryonichypothalamictissue have been shownto restore endocrine
function in animals with congential deficiency of vasopressin (Gash &Sladek
1980, Gash et al 1980) or gonadotrophin-releasing hormone(Krieger et
1982).
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INTRACEREBRALNEURALIMPLANTS
299
Electrophysiology
There are nowseveral electrophysiological studies confirming that functional
connections are established betweenthe graft and the host brain. Electrical
stimulation of locus coeruleus implants (Bj6rklund et al 1979b)and of septal
implants (Lowet al 1982) innervating the host hippocampus,have provided
evidence for the establishment of normal inhibitory and excitatory synaptic
connections, respectively, with neurons in the host hippocampus.Furthermore, in animals with "bridge" grafts of embryonichippocampus,placed in a
cavity in the hippocampalfimbria (see above), Segal et al (1981) have reported
atropin-sensitive evokedresponses from neurons within the implant, as well as
in the reinnervated host hippocampus,after stimulation of the host medial
septum. This suggests that the regenerating cholinergic septo-hippocampal
neurons innervating the hippocampalimplant and the host hippocampusacross
the newly formed tissue bridge indeed form functional connections with
neuronsin the reinnervated areas. Similarly, Harveyet al (1982) haveprovided
electrophysiological evidencefor the formationof functional synaptic contacts
betweenhost cortical afferents and transplanted tectal neurons,in rats grafted
during the neonatal period.
Behavior
Behavioral recovery has been demonstratedon a range of motorand sensorimotor tests in rats with dopamine-richnigral grafts reinnervating the neostriatum
(Bj6rklund &Stenevi 1979c, Perlowet al 1979, Bj6rklund et al 1980a, 1981,
Freed et al 1980, Dunnettet al 1981a-c). Nigral grafts have thus been seen to
provide a complete, or near-complete, recovery of both spontaneous and
drug-inducedturning behavior, postural asymmetries,akinesia, as well as in
the sensorimotordeficits (so-called sensory neglect) that developcontralateral
to a lesion of the intrinsic nigrostriatal dopaminepathway.Interestingly, the
recoveryof the different behavioralparametersare regionally specific, in that
grafts reinnervating the dorsal neostriatum showedpronouncedrecovery of the
turning behavior but no effect on the sensorimotor deficit, whereasgrafts
reinnervating the ventrolateral parts of the neostriatumhad the oppositeeffects
(Dunnett et al 198 lb). The behavioral recoveryinduced by nigral grafts has
far, however,not beencomplete: in particular, the profoundeating and drinking impairments, which develop in rats with bilateral lesions of the
mesotelencephalic dopaminepathway, have not been significantly improved
with the types of implants hitherto studied.
The ability of intracerebral implants to improvethe rats’ behavior in more
complex"cognitive" tasks has been demonstrated in maze-learning tests in
animals with bilateral lesions of the hippocampalfimbria (Lowet al 1982,
Dunnettet al 1982c). Septal implants, grafted either as solid pieces into the
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300
BJ~)RKLUND& STENEVI
fimbrial cavities or as cell suspensionsdirectly into the initially denervated
hippocampus,have thus been found to improvesignificantly the ability of the
lesioned rats to learn spatial memory
tasks in eight-armed(Lowet al 1982)
three-armedradial mazes(Dunnettet al 1982c). This recoverywas only partial,
and in the eight-armedmazetask the recovery was seen only after administration of physostigmine (which enhances cholinergic transmission by blocking
the degrading enzyme, ACHE).The histochemical analysis of these animals
indicated that cholinergic reinnervation of the host hippocampusfrom the
implants was a necessary but not sufficient prerequisite for the behavioral
recovery to occur (Dunnett et al 1982c).
NEURONAL
REPLACEMENT
IN
THE ADULT
CNS
Morphological and behavioral studies, performed mainly on animals with
grafts of monoamine-,acetylcholine-, or peptide-producingneurons, showthat
implanted embryonicnerve cells can in somecases substitute quite well fora
lost intrinsic neuronal system. The intracerebral implants probably exert their
effects in several ways.The functional effects seen with grafts placed into one
of the cerebral ventricles, such as in the studies of Perlowet al (1979), Freed
al (1980, 1981), and Gashet al (1980), are thus probablyexplainedon the basis
of a diffuse release of the active amineor peptide into the host CSFand adjacent
brain tissue. In other instances, such as in animals with dopamine-richgrafts
reinnervating the neostriatum or acetylcholine-rich grafts reinnervating the
hippocampus,we believe that the available data quite strongly showthat the
behavioral recoveryis caused by the ability of the grafted neurons to reinnerrate relevant parts of the host brain. This is illustrated by the studies mentioned
above showing that the degree of functional recovery in rats with nigral
transplants is directly correlated with the extent of striatal dopamine
reinnervation, and that the "profile" of functional recoveryis dependenton whicharea of
the neostriatum is reinnervated by the graft. This point is particularly well
illustrated in a further study (Fray et al 1983), in whichrats with electxodes
implantedinto the center of intracorticai nigral grafts wereallowed to "selfstimulate" via the graft. The results showthat the graft can indeed sustain
self-stimulation behavior, and that the rate of lever pressing is related to the
proximity betweenthe electrode tip and the dopamine-containingneurons in
the graft. This strongly supports the notion that the implanted dopamine
neurons can transmit behaviorally meaningful and temporally organized informationto the host brain via their efferent connections.
To whatextent the intracerebral implants can be functionally integrated with
the host brain is, however,still poorly knownand remainstherefore in interesting topic for further investigation. The chances for extensive integration may
be greatest for neuronal suspensiongrafts implantedas deposits directly into
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INTRACEREBRALNEURALIMPLANTS
301
the depth of the brain. Nevertheless, as discussed above, even solid grafts
inserted as whole pieces into the brain have in several cases been seen to
becomereinnervated from the host brain, both in adult and developingrecipients. The host afferents to the graft can, to somedegree, be derived from
functionally appropriate projections or neurontypes within the host and can
establish functional synaptic connections.
Available data, derived primarily from studies in monoaminergicand cholinergic systems, indicate that implantedembryoniccentral neuronscan substitute to somedegree for a lost set of afferents to a denervatedbrain region in
adult rats, and replace a lost intrinsic neuronalsystemin normalizingthe rat’s
behavior. This indicates a remarkable plasticity of the mature rat CNSin
incorporating newneuronal elements into its already established circuitries.
There is nowabundantevidence that the adult CNScan reorganize and rebuild
itself in reponse to damage(see Cotman& Lynch1976, Tsukahara 1981), and
perhaps in somecases as a way of normal physiological adaptation of the
system (Graziadei & Monti Graziadei 1978, Nottebohm1981, Cotmanet al
1981, Tsukahara1981). Neuronalreplacementby neural implants is a striking
further exampleof howthe brain can allow new elements to be inserted and
linked into its ownfunctional subsystems. Obviouslythere must be definite
limitations as to whichtypes of neuronsor functional subsystemscan successfully be manipulatedin this way. Neural implants wouldseem most likely to
have behaviorally meaningful functional effects with types of neurons that
normally do not convey, or link, specific or patterned messages, e.g. in
sensoric or motoric input and output systems. Indeed, functional or behavioral
recovery in the neuronal replacement paradigmhas so far been demonstrated
only for neuronsof the types that normallyappear to act as tonic regulatory or
level-setting systems. Such a modeof operation makesit conceivable that
imp’lanted neurons can also function well in the absence of some, or perhaps
even all, of their normal afferent inputs. Elsewhere(Bj6rklund et al 1981,
1983b) we have discussed in some detail how implants of neurons with
normal level setting or "command"
function can operate to reactivate damaged
circuitries in the brain or spinal cord.
The use of neuronal implants for neuronal replacement has a particular
interest in the context of animal modelsof neurodegenerativedisorders. As
summarizedabove, the most extensive studies have been performedin rats with
6-hydroxydopamineinduced lesions of the meso-telencephalic dopaminesystem, which is a lesion that has been extensively employedas a modelfor
Parkinson’s disease. It has also proved feasible, however, to implant
embryonicstriatal neurons into the striatum of rats whoseintrinsic striatal
neurons have been destroyed by the neurotoxin, kainic acid (Schmidt et al
1981). Such rats reproduce the neuropathological changes associated with
Huntington’s disease in man. Moreover, Gage et al (1983b) have recently
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302
BJI~RKLUND
& STENEVI
found that suspensions of embryonicseptal or mesencephalictissue will survive and grow well after implantation into the intact hippocampusand neostriatum, respectively, of aging rats. To the extent that the aging process is
associated with a decline in function, or even an actual loss, of selected
neuronal elements in the brain, neuronal implantation mayprovide an interesting newapproachfor the analysis of the cellular events underlyingage-related
functional impairmentsin rats (Gageet al 1983a). In fact, the observations
Gage et al (1983b) have furnished some preliminary evidence that dopamine
neurons implantedinto the depth of the neostriatum in aging rats will not only
establish a newdopamine-containing
terminal plexus in the surroundingstriatal
tissue, but also restore someaspects of the age-related impairmentof motor
performancein these rats.
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