Extensive reinnervation of the hippocampus by embryonic basal forebrain cholinergic neurons grafted into the septum of neonatal rats with selective cholinergic lesions

Abstract

Reconstruction of the septohippocampal pathways by axons extending from embryonic cholinergic neuroblasts grafted into the neuron-depleted septum has been explored in the neonatal rat by using a novel lesioning and grafting protocol. Neonatal ablation of the basal forebrain cholinergic projection neurons, accompanied by extensive bilateral cholinergic denervation of the hippocampus and neocortex, was produced at postnatal day (PD) 4 by 192 immunoglobulin (IgG)-saporin intraventricularly. Four days later, cholinergic neuroblasts (from embryonic day 14 rats) were implanted bilaterally into the neuron-depleted septum by using a microtransplantation approach. The results show that homotopically implanted septal neurons survive and integrate well into the developing septal area, extending axons caudally along the myelinated fimbria-fornix and supracallosal pathways that are able to reach the appropriate targets in the denervated hippocampus and cingulate cortex as early as 4 weeks postgrafting. Moreover, the laminar innervation patterns established by the graft-derived axons closely resembled the normal ones and remained essentially unchanged up to at least 6 months, which was the longest postoperative time studied. The reinnervating fibers restored tissue choline acetyltransferase activity (up to 50% of normal) in the dorsal hippocampus and the parietooccipital cortex. Retrograde labeling with Fluoro-Gold from the host hippocampus combined with immunocytochemistry confirmed that most of the projecting neurons, indeed, were cholinergic. The results suggest that the graft-host interactions that are necessary for target-directed axon growth are present in the septohippocampal system during early postnatal maturation. Thus, the present approach may contribute to overcome the functional limitations inherent in the use of ectopically placed intrahippocampal transplants.

Dysfunctional Sensory Modalities, Locus Coeruleus, and Basal Forebrain: Early Determinants that Promote Neuropathogenesis of Cognitive and Memory Decline and Alzheimer’s Disease

“…These results reflect that the age-related changes impact dysfunction of brain cholinergic neurons. Finally, a failure to produce a critical level of ACh by BFB in aging adversely affects survival of the above interconnected chains of neurons, and upregulate a cascade of ongoing neuronal degeneration (Wenk et al 1984;Clarke et al 1986;Leanza et al 1996;Winters and Bussey 2005).…”

“…Consequently, a cascade of neuronal degeneration may ensue (Wenk et al 1984;Clarke et al 1986;Morse et al 1993;Burke et al 1994;Venero et al 1994;Leanza et al 1996;Winters and Bussey 2005). It is, therefore, not surprising that during the progression of initial pathology in AD, cholinergic and interrelated neurons undergo degeneration.…”

Cell Therapy from Bench to Bedside Translation in CNS Neurorestoratology Era

“…Intraretrosplenial cortical grafts of cholinergic neurons can become functionally incorporated with the host neural circuitry, and the activity of the implanted cholinergic neurons can be modulated by the host brain (216) and it can rectify spatial memory deficits produced by the loss of intrinsic cholinergic afferents transfrom the medial septal nucleus (217). Reconstruction of the septohippocampal pathways by axons extending from embryonic cholinergic neuroblasts grafted into the neuron-depleted septum has been confirmed in the neonatal rat (198). Intrahippocampal septal grafts are able to reinnervate the hippocampal formation and ameliorate spatial learning and memory deficits, which are associated with anatomical and functional incorporation into the circuitry of the host hippocampal formation.…”

Neural and behavioral effects of intracranial 192 IgG-saporin in neonatal rats: sexually dimorphic effects?

“…A dose-response curve would have to be generated before this could be detem-ned. Leanza et al (1996b) (Leanza, Nikkhah, Nilsson, Wiley, Bjorklund, 1996a;Leanza et al. 1996b;Pappas et al, 1996).…”