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T Hagg

Publications and source records attributed to T Hagg.

48 records · Page 3Linked to original sources
PubMed1991

Nerve growth factor promotes CNS cholinergic axonal regeneration into acellular peripheral nerve grafts.

Peripheral nerve grafts promote vigorous regeneration of adult mammalian CNS axons. Elimination of nerve-associated cells by freeze-thawing abolishes this promoting quality, possibly by creating inhibitory cellular debris and/or destroying the production of stimulatory factors by living Schwann or other cells. Here, debris-free acellular peripheral nerve segments placed between the disconnected septum and the hippocampal formation acquired almost no cholinergic axons after 1 month. However, such acellular nerve grafts treated before implantation with purified beta-nerve growth factor (NGF) contained nearly as many longitudinally oriented cholinergic axons as did fresh cellular nerve grafts. These results suggest that (i) NGF is required for the regeneration of adult CNS cholinergic axons into nerve grafts and (ii) an important function of living cells within peripheral nerve may be the production of neuronotrophic factors such as NGF.

Acetylcholinesterase↗
PubMed1990

Septohippocampal cholinergic axonal regeneration through peripheral nerve bridges: quantification and temporal development.

Axons of the adult mammalian CNS have been shown to regrow vigorously into peripheral nerve grafts. Using a cholinergic septohippocampal model for adult CNS regeneration, involving complete denervation of the hippocampal formation from its basal forebrain cholinergic afferents, this study has established quantitative parameters and a temporal baseline of cholinergic fiber regeneration into the dorsal hippocampal tissue through a peripheral sciatic nerve graft. In nerve-implanted animals (i) the nerve grafts are maximally invaded by AChE-positive fibers between 2 weeks and 1 month postlesion, (ii) the fibers entering the hippocampal formation from the graft show a peak numerical increase and rate of elongation around the first month and/or in the proximal hippocampal region, (iii) an apparently normal innervation pattern and fiber density in the most rostral 1.5 mm of the dorsal hippocampal formation is reached by 6 months postlesion. The present study provides a basis for future quantitative comparisons of manipulations of different components of the system, e.g., the contributing neurons, the bridging material, and the receiving central nervous tissue. The temporal/spatial pattern of fiber regeneration suggests that the hippocampal CNS tissue can be a good axonal growth-promoting environment, albeit with temporal and/or spatial limitations, and is therefore not an immutably restrictive environment for axonal regeneration.

Acetylcholinesterase↗
PubMed1990

Nerve growth factor infusion into the denervated adult rat hippocampal formation promotes its cholinergic reinnervation.

The well-documented but little-understood failure of lengthy axonal regeneration after injury of the adult mammalian CNS may be caused by an insufficient availability of local growth-promoting factors. If so, identifying and supplying the missing factors may result in better central axonal regeneration. This hypothesis was tested in an adult rat CNS model in which peripheral nerve grafts were placed into a lesion cavity between the septum and hippocampal formation. Continuous infusion of nerve growth factor (NGF) into the dorsal hippocampal tissue dramatically enhanced and accelerated the regrowth and penetration of cholinergic axons into the hippocampal formation. Thus, NGF can overcome the apparent resistance of the hippocampal CNS tissue to cholinergic reinnervation.

Acetylcholinesterase↗
PubMed1989

Nerve growth factor (NGF) reverses axotomy-induced decreases in choline acetyltransferase, NGF receptor and size of medial septum cholinergic neurons.

Intraventricular nerve growth factor (NGF) infusion in the adult rat can prevent and also, if delayed, reverse the disappearance of most of the axotomized medial septum cholinergic neurons immunostained for choline acetyltransferase (ChAT). We have utilized the delayed NGF treatment protocol to (i) extend to 3 months the delay time between axotomy and NGF treatment, (ii) define the time course of their recovery, (iii) determine that immunostaining for the (lower affinity) NGF receptor (NGFR) parallels loss and reversal of the ChAT marker, and (iv) evaluate changes in cholinergic somal size following axotomy and subsequent NGF treatment. While NGF treatments starting only 7 days after the fimbria-fornix transection (axotomy) almost entirely restored the number of both ChAT- and NGFR-positive medial septum neurons, longer delayed (2-3 weeks) treatment brought about recovery from the baseline of 20-25% to only about 70% of the control numbers. This limited recoverability, however, persisted even after a 95 day delay period. In all cases examined maximal recoveries were achieved within 3-7 days of NGF treatment. Neuronal size analyses provided evidence for an axotomy-induced atrophy. NGF treatments, started with 1 or 2 week delays, not only reversed fully the average somal size loss but also induced an actual hypertrophy of several of those neurons. These results provide additional evidence that at least half of the apparent loss of cholinergic medial septum neurons upon axotomy is due to a loss of markers such as the transmitter-related enzyme ChAT and NGFR rather than to actual neuronal cell death. These results also show that NGF exerts a genuine trophic influence by regulating the size of its target neurons as well as their content of several proteins.

Animals↗
PubMed1989

An improved device for continuous intraventricular infusions prevents the introduction of pump-derived toxins and increases the effectiveness of NGF treatments.

The recent demonstrations of the ability of nerve growth factor (NGF) to protect and promote the welfare of certain cholinergic neurons in the adult CNS have increased the need for safe, accurate, and reliable procedures for intracerebral administration of protein and other experimental agents. Osmotic minipumps have been used to infuse NGF into the lateral ventricle of adult rats, but a sustained and harmless performance of such infusions has not been fully evaluated. The study reported here has led to (i) the recognition that cytotoxic substances, released from some minipumps into the infusion fluid, may be responsible for various degrees of periventricular tissue damage, and (ii) the redesigning of an infusion device which, among other modifications, uses the osmotic pump to propel infusion fluid into the ventricle but prevents pump-derived materials from entering the infusate itself. Besides several other advantages, the modified infusion device has permitted the demonstration that NGF can fully protect experimentally axotomized medial septum cholinergic neurons and can do so with less variability than previously observed and without creating tissue damage.

Animals↗
PubMed1989

Nerve growth factor effects on cholinergic neurons of neostriatum and nucleus accumbens in the adult rat.

Following intraventricular nerve growth factor infusion in adult rats, the choline acetyltransferase immunostaining of the neuropil and neuronal cell bodies of the neostriatum (caudate-putamen) and nucleus accumbens was more intense on the side of the infusion. Furthermore, the average cross-sectional size (micron2) of the cholinergic somata was increased by about 40 and 20% in the striatum and accumbens, respectively. This unilateral response could be elicited in intact rats as well as in rats receiving a prior aspirative transection of the fimbria-fornix. The reported lack of (low-affinity) nerve growth factor receptor immunostaining in these neurons suggests that the nerve growth factor effects are most likely transduced by high-affinity receptors. The ability of these apparently undamaged cholinergic interneurons to respond to exogenous nerve growth factor with an increase in choline acetyltransferase content and cell body size suggests that they are benefiting from a less-than-maximal support by endogenous nerve growth factor in the normal young adult rat.

Animals↗
PubMed1989

Laminin-like antigen in rat CNS neurons: distribution and changes upon brain injury and nerve growth factor treatment.

Using several antibodies against rat or human laminin and an avidin-biotin immunocytochemical protocol, laminin-like immunoreactivity was detectable in the rat nervous system in expected locations, i.e., associated with blood vessels and reactive astrocytes. However, laminin staining was also abundantly present within neuronal cell bodies in most parts of the developing and adult rat CNS. Medial septum neuronal immunoreactivity was lost after septo-hippocampal disconnection, but could be preserved or even restored by intraventricular administration of nerve growth factor. Thus, at least for medial septum neurons, this laminin-like molecule can be accumulated or produced independent of direct hippocampal (target) contact. It remains to be determined whether CNS neuronal "laminin" processes activities similar to those found for laminin in vitro.

Aging↗
PubMed1989

Neuronotrophic factors in cellular functional and cognitive repair of adult brain.

Neuronotrophic factors (NTFs) are special proteins that control survival, growth and functional competence of selected neuronal populations during their development. A recently articulated CNS neuronotrophic hypothesis proposes that adult central neurons continue to be dependent on endogenous supplies of their NTFs for maintenance, function and repair capabilities. The hypothesis has important implications in two major neurologic areas:i) involutive and degenerative processes and ii) CNS regeneration. Strong evidence favoring this general hypothesis has come from the recently observed effects of Nerve Growth Factor (NGF) on the forebrain cholinergic neurons in adult rats. Medial septum cholinergic (MSC) neuros project to the hippocampal formation largely via the fimbria-fornix tract. Transection of the fimbria-fornix interrupts the retrograde delivery of hippocampal NGF to the MSC neuronal somata, leading to reduction in their cholinergic enzyme and, possibly, progressive cellular atrophy. Intraventricular administration of exogenous NGF compensates for the loss of endogenous NGF supply and can reverse as well as protect against the neuronal damage. In a second model, intraventricular NGF infusions were applied to 2-year old (aged) rats displaying a deficient cognitive behavior. Four-weeks administration resulted in i) a correction of the cognitive deficit and ii) a increased body size of basal forebrain cholinergic neurons Cholinergic deficits are known to accompany cognitive deficits both in the brain aging process and Alzheimer's disease. The NGF effects on aged rats, therefore, strongly encourage the possibility of future clinical application in both such cases of brain dysfunction.

Aging↗
PubMed1988

Delayed treatment with nerve growth factor reverses the apparent loss of cholinergic neurons after acute brain damage.

Previous studies have shown that the loss after brain injury of adult rat septal cholinergic neurons whose axons are transected can be prevented by immediate intraventricular nerve growth factor (NGF) administration. This loss of axotomized neurons may be due to a reduction in detectability of neurotransmitter-related enzyme rather than to neuronal death. Here we report that NGF treatment, started after most of the neurons were no longer detectable (i.e., 1, 2, and 3 weeks), induced a dramatic reappearance of the apparently lost cholinergic neurons. These results may have important implications for potential trophic factor treatments of CNS trauma and neurodegenerative diseases, such as Alzheimer's dementia, which are characterized by chronic and progressive losses in the function of specific sets of neurons.

Animals↗
PubMedDate not supplied

Ciliary neurotrophic factor (CNTF) promotes low-affinity nerve growth factor receptor and CD4 expression by rat CNS microglia.

Ramified parenchymal microglia may provide immune surveillance in the nervous system and become activated in response to injury, showing increases in antigens found on macrophages, e.g. CD4 and MHCs. We investigated in adult rats the effects of a 2-week intraventricular infusion with ciliary neurotrophic factor (CNTF), a nervous system-associated cytokine, on microglia of the normal and injured corpus callosum. CNTF caused morphological changes, induced the expression of low-affinity nerve growth factor receptor and CD4 and increased the expression of complement receptor 3. Such changes were also observed after treatment of pure cultures of neonatal rat microglial cells with highly purified CNTF, suggesting a direct responsiveness to CNTF. Thus, endogenous astroglial and Schwann cell-derived CNTF may be an important component of the immune responses of the nervous system.

Animals↗
PubMedDate not supplied

Cholinergic medial septum neurons do not degenerate in aged 129/Sv control or p75(NGFR)-/-mice.

Cholinergic medial septum neurons express TrkA and p75 nerve growth factor receptor (p75(NGFR)) and interactions between TrkA and p75(NGFR) are necessary for high-affinity binding and signaling of nerve growth factor (NGF) through TrkA. In adult p75(NGFR)-deficient (-/-) mice, retrograde transport of NGF and other neurotrophins by these neurons is greatly reduced, however, these neurons maintain their cholinergic phenotype and size. Reduced transport of NGF has been proposed to play a role in Alzheimer's disease. Here, we investigated whether chronic and long-term absence of p75(NGFR) (and possibly reduced NGF transport and TrkA binding) would affect the cholinergic septohippocampal system during aging in mice. In young (6-8 months), middle aged (12-18 months), and aged (19-23 months) 129/Sv control mice the total number of choline acetyltransferase-positive medial septum neurons and the mean diameter and cross sectional area of the cholinergic cell bodies were similar. The cholinergic hippocampal innervation, as measured by the density of acetylcholinesterase-positive fibers in the outer molecular layer of the dentate gyrus was also similar across all ages. These parameters also did not change during aging in p75(NGFR) -/- mice and the number and size of the choline acetyltransferase-positive neurons and the cholinergic innervation density were largely similar as in control mice at all ages. These results suggest that p75(NGFR) does not play a major role in the maintenance of the number or morphology of the cholinergic basal forebrain neurons during aging of these mice. Alternatively, p75(NGFR) -/- mice may have developed compensatory mechanisms in response to the absence of p75(NGFR).

Acetylcholinesterase↗