Acetylcholine release from intrahippocampal septal grafts is under control of the host brain.

Abstract

The activity of intrahippocampal transplants of cholinergic neurons was monitored by microdialysis in awake, freely moving rats. Fetal septal-diagonal band tissue was implanted into rats with a complete transection of the fimbria-fornix cholinergic pathway either as a cell suspension injected into the hippocampus or as a solid graft implanted in the lesion cavity. The grafts restored baseline acetylcholine release in the graft-reinnervated hippocampus to normal or supranormal levels. The graft-derived acetylcholine release was dependent on intact axonal impulse flow, and it was markedly increased during behavioral activation by sensory stimulation or by electrical stimulation of the lateral habenula. The results demonstrate that the septal grafts, despite their ectopic location, can become functionally integrated with the host brain and that the activity of the transplanted cholinergic neurons can be modulated from the host brain during ongoing behavior. Anatomical observations, using immunohistochemistry and retrograde tracing, indicate that direct or indirect brainstem afferents to the graft could mediate this functional integration. Host afferent control of the graft may thus play a role in the recovery of lesion-induced functional deficits seen with these types of transplants.Previous behavioral and electrophysiological studies have shown that grafts of fetal cholinergic-rich tissue can restore at least some aspects of normal function in rats with lesions of the septohippocampal cholinergic pathway (1, 2). These results raise the question as to the mechanism(s) of action underlying graft-induced functional recovery in the subcortically deafferented hippocampus. While available data indicate that such grafts can restore synaptic cholinergic neurotransmission in the previously denervated target, it remains unclear to what extent they can become functionally integrated with the host neuronal circuitry.In the intact animal, the activity of the septohippocampal cholinergic neurons is known to change with alterations in ongoing behavior and in response to arousing or behaviorally activating stimuli (3-5). Hippocampal activation, as reflected in the induction of theta rhythm in the hippocampal electroencephalogram, depends on the integrity of the septohippocampal connections, and lesions of the septohippocampal cholinergic pathway by fimbria-fornix (FF) transection or medial septal lesions are known to remove a principal route for subcortical activation ofthe hippocampal formation (1, 5).In the present study, we have used the intracerebral microdialysis technique to monitor acetylcholine (AcCho) release in the subcortically denervated hippocampus reinnervated by fetal septal solid or suspension grafts. The experiment was performed in awake, freely moving rats both under baseline conditions and during behavioral activation of types that are known to induce AcCho release from intact septohippocampal cholinergic neurons (3, 4). METHODSYoung adult female Sprague-Dawley rats (ALAB, Stockholm) were given a unilat...

The Fimbria-Fornix/Cingular Bundle Pathways: A Review of Neurochemical and Behavioural Approaches Using Lesions and Transplantation Techniques

“…Such more functional aspects have been evidenced in several recent reports. Similarly to what they found with tissue block grafts implanted into the fimbriafornix lesion cavity, Nilsson et al (1990b), using a microdialysis technique, reported that after such lesions, intrahippocampal fetal septal cell suspension grafts were able to normalize or even overcompensate the baseline release of acetylcholine. Whilst the addition of KC1 (100 mM) to the perfusion fluid resulted in a 1400/oincrease of the release, an effect which was also partly mimicked by gentle handling of the rats ( + 57Yo) or electrical stimulation of the habenula ( + 68Yo),the addition of TTX reduced the release to the level found in lesion-only rats (see also, Kalen et al, 1991aKalen et al, , 1991b.…”

“…Dunnett et al, 1982;Ezerman and Kromer, 1987;Kelche et al, 1988;Kromer, 1982;Leanza et al, 1993b;Lewis and Cotman, 1983;Low et al, 1982). From a neurochemical point of view, using an in viuo microdialysis technique coupled to HPLC detection of neurotransmitters present in the dialysat, grafts of basal forebrain tissue blocks were found to increase the baseline release of acetylcholine in the fimbria-fornix denervated rat hippocampus to at least normal levels (Nilsson et al, 1990b). This release was stimulated ( + 21OYO) in a manner comparable to that found in intact rats when potassium chloride (KC1, 100 mM) was added to the perfusion fluid, and was reduced to the baseline level found in lesion-only rats by the addition of tetrodotoxin (TTX, 1 ,aM), a sodium channel blocker.…”

Mechanisms and use of neural transplants for brain repair

“…As described above in Section 4, grafts of embryonic cholinergic or noradrenergic neurons implanted into the fimbria-fornix lesion cavity, adjacent to the denervated hippocampus provide rich transmitter specific patterns of reinnervation of the target. Using microdialysis, Nilsson et al, (1990c) found that acetylcholine release from graft-derived neurons in the hippocampus was under precise regulation of the host brain, which was shown by anatomical tracing and immunohistochemistry to be due to rich regulatory ingrowth of brainstem, hypothalamic and septaldiagonal band neurons into the grafts.…”

Modulation of hippocampal acetylcholine release after fimbria-fornix lesions and septal transplantation in rats

“…While grafted neurons may establish new synaptic contacts in the host brain and attenuate or even compensate for a variety of lesion-induced neurophysiological and behavioral dysfunctions [14], the question of whether grafted neurons show normal functional characteristics remains a great concern. Using the microdialysis technique, Nilsson et al [11,12] have reported that basal forebrain grafts placed into the denervated hippocampus were able to release acetylcholine (ACh). An important finding was that this release is to some extent under the control of host afferents; sensory stimulation increased ACh release in sham-operated and grafted rats, but not in lesion-only rats, and the same observation was made after electrical stimulation of the habenula.…”