Neural grafting of cholinergic neurons in the hippocampal formation.

The cholinergic septohippocampal system plays an important role in spatial learning and memory functions. Transections of the septohippocampal pathway have been shown to result in a near complete loss of cholinergic innervation in the hippocampus and induce severe spatial memory impairments. In this article, we have reviewed the studies which demonstrate the ability of intrahippocampal septal grafts to reinnervate the hippocampal formation and ameliorate spatial learning and memory deficits. Neuroanatomical studies suggest that grafts of cholinergic tissue can innervate the host hippocampal formation in a pattern that mimics that of the normal septohippocampal pathway. This innervation, in turn, is associated with the formation of graft-to-host synaptic connections. Neurochemical studies reveal that intrahippocampal grafts of septal cells can restore choline acetyltransferase activity, acetylcholine synthesis, and high affinity choline uptake in presynaptic terminals of grafted neurons. In addition, these grafts can normalize the upregulation of cholinergic muscarinic receptors seen postsynaptically in the hippocampus following lesions of the septohippocampal pathway. The functional nature of these grafts is also substantiated by electrophysiological recordings which demonstrate stimulus-evoked graft-to-host synaptic transmission as well as the reinstatement of EEG activity typical of septohippocampal connectivity. In addition to graft-to-host connections, behavioral and neurochemical studies also provide evidence for host-to-graft connections that can regulate the activity of grafted cholinergic neurons during the performance of specific behavioral tasks requiring spatial memory function. Together, these studies suggest that grafts of cholinergic neurons from the medial septal nucleus can become anatomically and functionally incorporated into the circuitry of the host hippocampal formation.

Intrahippocampal transplants of septal cholinergic neurons: choline acetyltransferase activity, muscarinic receptor binding, and spatial memory function.

Recent studies have demonstrated that intrahippocampal cholinergic septal grafts can ameliorate deficits in spatial memory function and hippocampal cholinergic neurochemical activity in animals with disruptions of the septohippocampal pathway. Further studies have revealed that hippocampal cholinergic activity, as measured by high affinity choline uptake, correlates significantly with performance on tests of spatial memory function. The present study was designed to examine the effect of cholinergic septal grafts on reversing deficits in hippocampal choline acetyltransferase activity and on normalizing muscarinic receptor binding in animals with lesions of the septohippocampal system, and to examine the correlations between these cholinergic parameters and performance of spatial memory tasks. The results of this study indicated that in animals with lesions plus septal grafts, hippocampal ChAT activity was restored significantly and muscarinic receptor binding was normalized to a level not different from the control animals. Regression analyses indicated that ChAT activity was significantly correlated with performance on spatial reference memory, spatial navigation and spatial working memory, while muscarinic receptor binding correlated significantly with spatial reference memory performance.

Intrahippocampal transplants of septal cholinergic neurons: high-affinity choline uptake and spatial memory function.

Recent studies have demonstrated that intrahippocampal cholinergic septal grafts can ameliorate deficits in spatial memory function and hippocampal cholinergic neurochemical activity in animals with disruptions of the septohippocampal system. However, no study has determined if the restoration of spatial memory function is correlated to the restoration of cholinergic activity, as measured by high-affinity choline uptake (HACU). The present study was designed to determine if such a correlation between behavioral and neurochemical restoration exists. Male Sprague-Dawley rats received either sham lesions (SHAM), bilateral lesions of the septohippocampal pathway (LES), or bilateral lesions along with intrahippocampal septal grafts (SG). After 8 months, rats were tested for their ability to perform spatial reference, spatial navigation and working memory tasks. Upon completion of the behavioral testing, neurochemical activity of the hippocampus was measured by HACU. The results indicate that animals in the SG group had significantly higher behavioral scores and hippocampal HACU rates than animals in the LES group. Regression analysis indicates that a significant correlation exists between performance on each behavioral task and HACU rates. These results demonstrate that hippocampal cholinergic activity, as measured by HACU, correlates significantly with performance on tests of spatial memory function.

Stress-induced changes of norepinephrine uptake sites in the locus coeruleus of C57BL/6J and DBA/2J mice: a quantitative autoradiographic study using [3H]-tomoxetine.

Inbred C57BL/6J (C57) and DBA/2J (DBA) mice were subjected to open-field evaluation and Porsolt swim test after restraint stress. Norepinephrine (NE) uptake sites in the locus coeruleus (LC) of these inbred mice were studied by using [3H]-tomoxetine. Results showed that naive C57 mice were more active in the open field and possessed more NE uptake sites in the LC than naive DBA mice. Previous work has shown that restraint decreases open field activity in C57 mice, but not DBA mice, whereas the present study has demonstrated that, after restraint stress, C57 mice spent more time immobile than DBA mice did in the forced swim test. Furthermore, in these stressed animals, NE uptake sites in the LC were greatly increased with consistently more uptake sites in C57 mice. Collectively, results of this study and the literature suggest that enhanced NE function in the LC of C57 mice is associated with their susceptibility to stress-induced behavioral depression.

Identification of a locus on mouse chromosome 17 associated with high-affinity choline uptake using BXD recombinant inbred mice and quantitative trait loci analysis.

Using the quantitative trait loci (QTL) approach, preliminary identification has been made of a region on mouse chromosome 17 that influences high-affinity choline uptake (HACU) in the mouse brain. The rate of HACU was measured in synaptosomes prepared from the frontal cortex, hippocampus, and striatum of C57BL/6J (B6), DBA/2J (D2), and 25 BXD recombinant inbred (RI) strains of mice, using a final concentration of 0.5 microM [3H]choline. The strain means of HACU in each area were then correlated with the strain distribution pattern of each of 1300 known genetic markers using a point biserial correlation and 0 (B6 allele) and 1 (D2 allele). Correlations of P < 0.00001 were found between striatal HACU and chromosome 17 markers D17Tu50 and Tcp1. Correlations of P < 0.0001 were found between striatal HACU and chromosome 17 markers D17Leh66e, D17Leh119, D17Rp17e, Plg, D17Leh66d, Ckb-rs2, and Trp53-ps. QTL analyses of HACU in the frontal cortex and hippocampus also revealed correlations with these markers at the level of P < 0.05 and P < 0.01. These data suggest that at least one locus located on mouse chromosome 17 near or between 6 and 13 cM from the centromere influences HACU in the striatum and possibly the frontal cortex and hippocampus of the mouse.

Quantitative trait loci associated with the behavioral response of B x D recombinant inbred mice to restraint stress: a preliminary communication.

Quantitative trait loci (QTL) analysis was used to make provisional identification of loci containing genes influencing vulnerability to stress. The effect of restraint stress on open-field activity was measured in C57BL/6J and DBA/2J inbred strains of mice and in 22 B x D recombinant inbred strains of mice. QTL analyses were performed by correlating the behavioral delta scores for each group with the strain distribution pattern of 1300 markers for the B x D mice. A significant association was found between postrestraint rearings during min 5 through 8 in the open field and the Lamb2 marker on chromosome 1 (r = .718, p < .0001). Significant associations at the p < .0001 level were also found between baseline open-field rearings of control mice during min 0 through 5 and the Zp3, Ache, and Mr66-1 markers on chromosome 5, baseline open-field rearings of control mice during min 5 through 8 and the Pmv42 marker on chromosome 15, and open-field rearings of experimental mice during min 0 through 5 and the D11Ncvs61 marker on chromosome 11.