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T J Collier

Publications and source records attributed to T J Collier.

At least 37 records · Page 2Linked to original sources
PubMed1995

Astrocytes retrovirally transduced with BDNF elicit behavioral improvement in a rat model of Parkinson's disease.

Neurotrophic factors that improve the survival of specific neuronal types during development and after exposure to various neuronal insults hold potential for treatment of neurodegenerative diseases. In particular, brain-derived neurotrophic factor (BDNF) has been shown to exert trophic and protective effects on dopaminergic neurons, the cell type known to degenerate in Parkinson's disease. To determine whether increased levels of biologically produced BDNF affect the function or regeneration of damaged dopaminergic neurons, the effects of grafting astrocytes transduced with the human BDNF gene into the striatum of the partially lesioned hemiparkinsonian rat were examined. Replication deficient retroviruses carrying either human prepro-BDNF or human alkaline phosphatase (AP) cDNA were used to transduce primary type 1 astrocytes purified from neonatal rat cortex. In vitro, BDNF mRNA was expressed by BDNF transduced astrocytes (BDNF astrocytes), but not control AP transduced astrocytes (AP astrocytes), as determined by reverse transcription polymerase chain reaction (RT-PCR). The modified astrocytes were injected into the right striatum 15 days after partial lesioning of the right substantia nigra with 6-hydroxydopamine. Transplantation of BDNF astrocytes, but not AP astrocytes, significantly attenuated amphetamine-induced rotation by 45% 32 days after grafting. Apomorphine-induced rotation increased over time in both groups, but was not significantly different in the BDNF-treated group. The modified BDNF astrocytes survived well with non-invasive growth in the brain for up to 42 days. Although BDNF mRNA positive cells were not detected within the graft site using in situ hybridization, alkaline phosphatase immunoreactive (IR) cells were present in control graft sites suggesting that the retroviral construct continued to be expressed at 42 days. Analysis of the density of tyrosine hydroxylase (TH)-IR fibers showed no effect of BDNF on TH-IR fiber density in the striatum on the lesioned side. These findings suggest that ex vivo gene therapy with BDNF ameliorates parkinsonian symptoms through a mechanism(s) other than one involving an effect of BDNF on regeneration or sprouting from dopaminergic neurons.

Amphetamine↗
PubMed1995

The detrimental effect of levodopa on behavioral efficacy of fetal dopamine neuron grafts in rats is reversible following prolonged withdrawal of chronic dosing.

In previous studies, we observed that chronic levodopa treatment resulted in impaired morphology and function of grafted dopamine neurons in rats. To begin to better understand how levodopa treatment might influence dopamine neurons, we examined whether subsequent discontinuation of chronic levodopa treatment might allow for recovery of graft efficacy. Function of embryonic mesencephalic tissue grafts was assessed by monitoring rotational behavior elicited by amphetamine in lesioned, grafted rats initially treated for 6 weeks with levodopa followed by a 6 week drug-free period. As observed previously, control grafted animals, but not levodopa treated animals, showed behavioral improvement. However, following a 6 week withdrawal period, the levodopa animals demonstrated a significant reduction in amphetamine rotations which was reminiscent of control animals. This suggests that grafted neurons can recover functionally after levodopa treatment is withdrawn, which may be of significance in clinical transplantation trials.

Animals↗
PubMed1994

Peripheral nerve-dopamine neuron co-grafts in MPTP-treated monkeys: augmentation of tyrosine hydroxylase-positive fiber staining and dopamine content in host systems.

Previous studies of rats in our laboratory indicate that a molecule or molecules released by Schwann cells exert survival and growth-promoting effects on mesencephalic dopamine neurons. In the present study, we have begun to investigate the potential for Schwann cell augmentation of host dopamine fiber systems and embryonic dopamine neuron grafts in non-human primates. Ten adult male St Kitts African Green monkeys treated with the dopaminergic neurotoxin 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine one year previously, but behaviorally asymptomatic, served as hosts for implant studies. A segment of young adult monkey saphenous nerve was collected to serve as an implanted tissue source of Schwann cell-derived growth factors. Nerve was enclosed in a hollow semi-permeable polymer fiber for implantation into the lateral ventricle, with embryonic ventral mesencephalic tissue co-grafts containing developing dopamine neurons aimed at nearby locations in the caudate nucleus. Control implants consisted of an empty polymer fiber co-grafted with embryonic ventral mesencephalon. Our morphological observations indicate that while no clear augmentation of the morphology of grafted dopamine neurons attributable to co-grafted nerve was observed, this lack of influence may be related to the spatial separation of the co-grafted tissues. In contrast, some monkeys with nerve segments in the lateral ventricle exhibited increased tyrosine hydroxylase-positive fiber staining in the immediately adjacent lateral septal area and the ventricular wall of the caudate nucleus. This enhancement was not associated with empty polymer implants. Levels of dopamine and its metabolite homovanillic acid derived from tissue punches in the caudate nucleus and septal area support the view that monkeys exhibiting morphological enhancement of host dopamine systems also show biochemical increases in dopamine levels and changes in the direction of normalization of the homovanillic acid/dopamine ratio. Biochemical values from a single septal area tissue punch in one animal were an exception to this rule. This study suggests that while the utility of peripheral nerve as a source of dopamine graft augmentation in non-human primates remains to be demonstrated, grafted nerve has a stimulatory effect on host brain dopamine systems in adult, dopamine-depleted monkeys, and that this morphological effect can be dissociated from previously hypothesized injury-induced regeneration.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1993

Cryopreservation and storage of embryonic rat mesencephalic dopamine neurons for one year: comparison to fresh tissue in culture and neural grafts.

Blocks of embryonic rat ventral mesencephalic tissue containing the developing A8-A10 dopamine (DA) cell groups were cryopreserved and stored for approximately 1 year, at which time this tissue was thawed, dissociated into a cell suspension, and compared to a similar preparation of fresh mesencephalic tissue for viability in tissue culture and neural grafts. Estimates of total cell number immediately prior to plating in culture indicated that cryopreserved tissue yields fewer cells, but when this reduced cell number is compensated for, and equal numbers of cells were plated in culture, approximately equal total numbers of neurons, as well as tyrosine hydroxylase (TH)-positive neurons, were present in cultures from cryopreserved and fresh tissue. Grafting of equal numbers of fresh and cryopreserved mesencephalic cells into the striatum of adult rats with large unilateral lesions of the nigrostriatal DA pathway tended to yield smaller grafts with fewer surviving TH-positive cells with less extensive neuronal processes when tissue was previously cryopreserved. However, grafts derived from freeze-stored tissue provided a similar time-course and extent of behavioral recovery in amphetamine-induced rotational tests to that provided by fresh tissue grafts. Taken together, our findings indicate that while cryopreservation of mesencephalic tissue has its costs--reduced cell yield in cultures and grafts, and compromised morphology in grafts--sufficient numbers of cryopreserved neurons survive the grafting procedure to ameliorate behavioral signs of DA depletion in the lesioned rat model.

Amphetamine↗
PubMed1993

Fetal dopamine cell survival after transplantation is dramatically improved at a critical donor gestational age in nonhuman primates.

Mesencephalic tissue containing newly generated dopamine neurons was collected from brains of embryonic African green monkeys at 44 and 49 days of gestation and stereotaxically implanted into multiple sites in the caudate nucleus of adult monkeys previously treated with the dopamine protoxin, 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine. Ultrasonography was utilized to assess the developmental stage prior to hysterotomy. Brains were removed for combined histochemical and biochemical analyses at 3 1/2 months after grafting to determine the extent of graft survival and growth. The dopamine content of the target nucleus was assessed from microdissected "punches" placed in proximity to grafts identified in unfixed brain slices prior to fixation. Tissue dopamine levels adjacent to the grafts were elevated markedly, reaching 25-50% of control levels at some sites in the caudate nucleus. Morphometric analysis of graft size and dopamine cell numbers was performed with computer-enhanced, video-based imaging. Exceptionally large grafts that far exceeded their initial size at the time of implantation were seen at each placement site. The dopamine cell count was as high as 3500 in a single graft from E44 tissue, but only as high as 550 from the E49 donor. Up to 15,000 tyrosine hydroxylase-positive neurons were stained in the host monkey that received E44 tissue; only 1/10 as many were seen in each of the recipients of E49 day samples. The earlier donor grafts occupied as much as 15% of the caudate nucleus as seen in a single coronal section; summation of all sections that contained grafts at each placement from the E44 donor revealed average areas occupied by the grafts ranging from 3 to 8% of the caudate nucleus. In comparison, grafts produced from an E49 donor averaged between 2.4 and 5.4% of the area of the target. Qualitatively, grafts from each gestational stage showed well-developed dopamine neurons with morphological characteristics equivalent to those of all three ventral mesencephalic dopamine cell groups. The attainment of large, well-differentiated grafts with thousands of dopaminergic neurons from early gestation tissue suggests that optimal cell survival in primates is dependent on the degree of postgerminal development of the dopamine neuron. Neurite extension may be critical in this regard as well as other, at present, undefined factors. Maximal graft development and cell survival may be a critical element in the ability of neural grafts to reverse a neurological disability and to maintain improvement in the event of continued degeneration of host dopamine neurons.

Animals↗
PubMed1991

Grafting of fetal substantia nigra to striatum reverses behavioral deficits induced by MPTP in primates: a comparison with other types of grafts as controls.

Fetal substantia nigra (SN) cells were transplanted into the caudate nucleus (CN) of four vervet monkeys (Cercopithecus aethiops sabaeus) that had been treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP treatment appears to produce a syndrome similar to that observed in patients with idiopathic Parkinson's disease. Normal and parkinsonian behaviors were quantitated by trained observers 5 days/week. Twenty-eight behaviors based on previous factor analyses were individually scored and rated. Parkinsonian signs included freezing, head and limb tremor, difficulty in eating, delayed initiation of movement, poverty of movement, tremor that stopped with intention, decreased response to threats, and lying immobile in the cage. These signs were combined to give an overall rating of parkinsonism. A summary measure of 'normal' healthy behavior was also examined, including such behaviors as yawning, scratching, self-grooming, shifting, and eating. Overall ratings of parkinsonism increased and those of healthy behavior decreased after MPTP. In the 4 monkeys grafted with fetal SN cells into the CN, behavior returned to pre-treatment levels by the time of sacrifice (2, 5, or 7.5 months after grafting). Three control subjects were transplanted with either SN cells into an inappropriate brain site (cortex) or inappropriate, non-dopaminergic, cells (cerebellar) into the CN. Subjects were also compared with three control animals that did not receive MPTP but received cryopreserved or fresh SN and other cells into the CN. Only MPTP-treated subjects that received SN cells into the CN showed evidence of a reversal of the MPTP syndrome after transplantation. In addition, grafting in animals that were not MPTP-treated did not appear to affect behavior. This paper reports the specific behavioral effects of severe MPTP toxicity that were or were not reversed after transplantation and suggests that only fetal SN cells grafted into the CN may be able to reverse behavioral deficits in MPTP-treated monkeys.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

Chronic levodopa impairs the recovery of dopamine agonist-induced rotational behavior following neural grafting.

The effect of chronic levodopa treatment on the function of embryonic mesencephalic tissue grafts was assessed in rats by monitoring rotational behavior elicited by dopamine (DA) agonists before and after neural grafting. Rats were given unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway and baseline measures of rotational behavior induced by D1 receptor stimulation, D2 receptor stimulation, or amphetamine were determined. Subsequently, DA grafts were implanted into the lesioned striatum and chronic regimens of either saline or levodopa began one day after neural grafting and were continued for 7 weeks. Rotational behavior elicited by the D1 agonist, SKF 38393, was completely attenuated throughout the six-week-period following the commencement of levodopa treatment, regardless of the absence or presence of a DA graft. Conversely, rotational behavior elicited by the D2 agonist, quinpirole, was significantly elevated in ungrafted animals receiving chronic levodopa. Grafted animals receiving chronic levodopa did not show a significant reduction in rotational behavior, whereas grafted animals receiving chronic saline showed a significant 67% reduction in quinpirole-induced rotational behavior. Amphetamine-induced rotational behavior was reduced in both levodopa and saline treated grafted animals, however grafted animals receiving chronic levodopa treatment showed a reduction of rotational behavior that was uncharacteristic and less compensatory than that observed in grafted animals receiving chronic saline treatment. Morphology of grafts indicate that there were areas of impaired neurite outgrowth of TH-positive fibers in animals treated with levodopa. The results of the present study suggest that the impaired recovery in quinpirole- and amphetamine-induced rotational behavior in grafted animals receiving chronic levodopa treatment may be related to (1) impaired graft function, (2) an alteration in pre- and postsynaptic mechanisms in the host DAergic system, or (3) a combined effect of (1) and (2).

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1991

Striatal implants protect the host striatum against quinolinic acid toxicity.

Quinolinic acid (QA) and related excitotoxins produce a pattern of neuronal loss and neurochemical changes in the rat striatum similar to that of patients suffering from Huntington's disease, suggesting neurotoxicity is important in the etiology of that disease. Thus, strategies for limiting excitotoxin-induced striatal damage, like that caused by QA, may be of great benefit to these individuals. Accordingly, we tested the ability of both neural and non-neural tissue implants to protect the rat striatum against a subsequent QA challenge. Our results demonstrated that recipients of fetal striatal grafts were significantly less affected by striatal injections of QA than non-grafted animals. In contrast to the latter, fetal striatal tissue recipients did not exhibit apomorphine-induced rotation behavior and showed a sparing of cholinergic and enkephalinergic systems normally lost following QA injections. Animals grafted with adult rat sciatic nerve, adrenal medulla or adipose tissue all showed a less dramatic behavioral protection and sparing of cholinergic and enkephalinergic systems. These results suggest that fetal striatal tissue exerts an optimal, and perhaps specific protective influence on the host brain.

Adrenal Medulla↗
PubMed1991

Co-grafts of embryonic dopamine neurons and adult sciatic nerve into the denervated striatum enhance behavioral and morphological recovery in rats.

We have recently demonstrated that a diffusible factor(s) derived from explanted adult rat sciatic nerve can increase the number and neurite outgrowth of embryonic rat dopamine (DA) neurons in culture. The present study extends this finding to compare DA neuron-sciatic nerve co-grafts to grafts of DA-rich neural tissue alone for behavioral and morphological effects in rats with unilateral nigrostriatal lesions of the DA pathway. Our results indicate that the presence of a co-grafted segment of sciatic nerve increased the likelihood of rapid behavioral recovery and promoted complete recovery mediated by small grafts that yielded only modest behavioral changes in the absence of co-grafted nerve. These behavioral effects were accompanied by a modest increase in survival of grafted tyrosine hydroxylase-positive neurons in the striatum and a more pronounced increase in the area and density of striatal reinnervation provided by grafted DA neurons in co-grafted animals. This evidence supports the view that a diffusible product of explanted peripheral nerve acts as a growth-promoting factor for embryonic DA neurons and that the presence of this factor augments the behavioral efficacy of grafted DA neurons.

Animals↗
PubMed1990

Diffusible factor(s) from adult rat sciatic nerve increases cell number and neurite outgrowth of cultured embryonic ventral mesencephalic tyrosine hydroxylase-positive neurons.

Dissociated embryonic rat ventral mesencephalon containing the developing A8-A10 dopamine (DA) neurons was cultured alone or in the presence of a 10 mm segment of adult rat sciatic nerve that had been explanted and maintained in separate culture for 72 hours prior to introduction to mesencephalic cultures. Nerve segments were contained in a co-culture basket, so that midbrain cells and nerve shared medium but were not in physical contact. The number and morphology of cultured DA neurons was assessed via immunocytochemistry for tyrosine hydroxylase (TH). Co-cultures of ventral midbrain tissue and nerve exhibited an increased number of TH-positive neurons, with larger neuronal perikarya, and increased length and complexity of neurites, than cultures of midbrain tissue alone. Increased number and growth of TH-positive neurons was obtained with as little as 2 days of exposure to nerve. This evidence suggests that a diffusible, soluble factor(s) from sciatic nerve can enhance the number and development of TH-positive neurons detected in cultures of embryonic ventral mesencephalon.

Animals↗
PubMed1990

Chronic levodopa impairs morphological development of grafted embryonic dopamine neurons.

Degeneration and plasticity of dopamine (DA) neurons may be influenced by their own neurotransmitter and/or metabolic by-products. Substances with known neurotoxic properties, such as hydrogen peroxide and 6-hydroxydopamine, are produced during oxidation of DA. Additionally, DA can directly regulate neurite outgrowth in both invertebrate and vertebrate species. We have begun to investigate the influence of increased local transmitter concentrations on the morphological plasticity of neurons by examining the effect of chronic levodopa, a drug that increases DA synthesis, on grafted embryonic nigral DA neurons in a rat model of experimental parkinsonism and in monolayer cell cultures. Results from our in vivo investigation show that although chronic levodopa does not significantly affect the number of surviving grafted cells, morphological development of these embryonic DA neurons appears impaired. Levodopa administered chronically to fetal DA neurons in culture results in a decreased number of surviving neurons as well as a reduction in neurite outgrowth with increasing concentration of levodopa ranging from 10(-8) to 10(-4) M. This information provides further evidence to support the hypothesis that excess DA or its metabolites can influence the survival and growth of DA neurons. These results may be important in the design of pharmacotherapy for Parkinson's disease and the combination of drug and neural grafting therapies in this disorder.

Animals↗
PubMed1990

Embryonic mesencephalic and striatal co-grafts: development of grafted dopamine neurons and functional recovery.

Previous neural grafting studies have shown that embryonic dopamine neurons survive transplantation into the parenchyma of the brain; however, fiber outgrowth from those cells is often limited to the immediate vicinity of the graft. More extensive outgrowth is desirable for promoting and maintaining functional recovery of damaged neural systems in animal models as well as human neurodegenerative disorders. The present study examined the possibility of stimulating fiber outgrowth of grafted neurons by simultaneously grafting dopamine neurons with their embryonic target cells. Subsequent functional recovery was evaluated in concert with morphological characteristics of these grafts. Co-grafts of embryonic mesencephalic and striatal cells were implanted into the DA-denervated striatum of rats previously given unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway. Two types of co-grafts were implanted into the DA-denervated striatum: mixed or separate cell suspensions. Tyrosine hydroxylase immunocytochemical analysis of brain sections containing co-grafts revealed extensive arborization of TH-positive neurons in both types of co-grafts. When mesencephalic and striatal nerve cells were implanted into separate sites, TH-positive neurons extended projections that appeared to preferentially reach regions occupied by embryonic striatal neurons. Moreover, the average size of TH-positive cell bodies found in mixed or separate co-grafts was significantly larger than the size of those found in single mesencephalic grafts. Amphetamine-induced rotational behavior was used to assess the degree of functional recovery. In the majority of co-grafted animals, rotational behavior was attenuated by 3 weeks and reversed (amphetamine-induced contralateral rotation) by 5 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗
PubMed1990

Improvements in MPTP-induced object retrieval deficits and behavioral deficits after fetal nigral grafting in monkeys.

Improvements in MPTP-induced deficits were only found in subjects that received fetal substantia nigra transplants into the caudate nucleus. The MPTP-induced deficits were assessed using an object retrieval task that examined cognitive and subtle motor performance and by behavioral observation to determine the overall status of the subjects. Subjects that were also moderately or severely impaired by MPTP administration but that received inappropriate donor cells or implant sites (cerebellum to CN or SN to cortex) did not show any evidence of behavioral recovery. These subjects could not respond on the task in the months after grafting and were sacrificed, showing no improvements in parkinsonian signs or healthy behavior signs, up to 5-6 months after surgery. Grafting of SN cells into the striatum of non-MPTP lesioned subjects failed to modify normal behavior or induce abnormal behavior determined by our 2 behavioral assessment methods. In those monkeys that received the appropriate transplants, TH immunohistochemistry revealed that cells of the fetal substantia nigra grafted into the caudate nucleus survived and extended neurites into the host striatum. Indeed, grafted dopamine neurons were often associated with appreciable innervation of the caudate nucleus and appeared to be well incorporated into the host brain. In contrast, examination of the striatum of subjects in the inappropriate-graft group (e.g., cerebellar cells grafted into the caudate) showed no evidence of TH staining within the graft or host caudate nucleus. This indicated that there was no evidence of dopamine neurons present in the grafted tissue and that the mere presence of a fetal graft did not appear to induce sprouting in these MPTP-treated subjects. Although behavioral recovery occurred in only those monkeys that received appropriate transplants (fetal SN to host CN) and not in those that received inappropriate grafts (fetal cerebellum to CN or fetal SN to cortex), the CSF HVA levels did not distinguish those monkeys with improved parkinsonism from those that remained severely parkinsonian. The finding that in some SN-CN grafted subjects reported here, there was evidence of increased dopamine and lowered HVA/dopamine ratio in the vicinity of the SN grafts (cf. Elsworth et al., 1990b) is consistent with the hypothesis that graft-derived or graft-induced dopamine production is responsible for behavioral recovery. In addition, the finding that CSF HVA levels in non-MPTP lesioned subjects were unchanged by fetal SN grafts further indicates that CSF HVA levels may not be sufficiently sensitive to changes in central dopamine production to reflect release of dopamine from relatively small grafts that may, in lesioned subjects, modify behavior.(ABSTRACT TRUNCATED AT 400 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Loss of NGF receptor immunoreactivity in basal forebrain neurons of aged rats: correlation with spatial memory impairment.

Nerve growth factor (NGF) has recently been implicated as a trophic agent in the survival and maintenance of basal forebrain cholinergic neurons. To test the hypothesis that NGF may play a role in the age-related decline of cerebral cholinergic function and loss of cognitive ability, we investigated the possible correlation between the loss of basal forebrain neurons that stain for NGF receptor, and impairment of spatial reference memory performance in aged rats. Our results suggest that NGF receptor-positive basal forebrain neurons undergo marked cell atrophy and loss of neuropil staining in aged rats exhibiting impaired spatial learning and memory performance. Conversely, numerous, densely immunoreactive perikarya and a profuse neuritic plexus within the basal forebrain nuclei was consistently observed in behaviorally intact rats. Overall, the mean number of NGF receptor-positive basal forebrain neurons both in the nucleus of the diagonal band and nucleus basalis correlated with retention of the spatial task (r = 0.84 and r = 0.67, respectively; P less than 0.01). Our results support the view that progressive failure of retrograde trophic support due to the age-related loss of NGF receptors may promote degenerative changes in basal forebrain cholinergic neurons, and contribute to deterioration of cognitive ability in senescence.

Aging↗