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Electrophysiological studies with acutely prepared cats found that stimulation of deep temporal lobe structures (e.g., amygdala, prepyriform cortex) evoked responses in the nucleus of the diagonal band of Broca. An analysis of field, extra- and intracellular unitary responses points to the existence of a monosynaptic excitatory connection.
The projections of the nucleus of the diagonal band of Broca and of the substantia innominata to the cerebral cortex were studied in the rat, using the anterograde transport of wheat germ agglutinin conjugated with horseradish peroxidase. Following diagonal band injections, fibers were observed ascending in the septum and reaching the cingulate cortex. They had a rostrocaudal, horizontal direction, mostly in layer VI and could be followed over long distances on sagittal sections. The fibers gave off collaterals which were seen ascending in the cerebral cortex and reaching more superficial layers. Following substantia innominata injections, fibers were observed to take two routes: the first one identical to the one described above and a second through the caudate-putamen reaching the temporo-insular cortex. Terminal fields had a more diffuse distribution following substantia innominata than following diagonal band injections. No clear laminar pattern of termination was observed. However the density of terminals was higher in layers IV, V and VI than in layers I, II and III. Since the conjugate used is not taken up by fibers of passage, this pattern of connection is believed to reflect the organization of the projection of the nucleus of the diagonal band and of the substantia innominata to the cerebral cortex.
The postnatal development of the release of acetylcholine (ACh) and of presynaptic, release-inhibiting muscarinic autoreceptors was studied in the lateral septum (LS), the medial septum (MS) and the diagonal band of Broca (DB) of the rat brain. To this end, slices (350 micrometer thick) containing these brain regions from rats of various postnatal ages (postnatal day 3 [P3] to P16, and adult) were pre-incubated with [3H]choline and stimulated twice (S1, S2: 360 pulses, 3 Hz) during superfusion with physiological buffer containing hemicholinium-3 (10 microM). In addition, the activity of choline acetyltransferase (ChAT, in crude homogenates) was determined as a marker for the development of cholinergic functions. At any postnatal age, the electrically-evoked overflow of tritium from slices pre-incubated with [3H]choline was highest in the DB, followed by the MS whereas in slices containing the LS, it was only small. In all septal regions, the evoked [3H]overflow was Ca2+-dependent and tetrodotoxin-sensitive at P3. It increased with postnatal age and reached about 60% of the corresponding adult levels at P16. Presence of the muscarinic agonist oxotremorine (1 microM) during S2 significantly inhibited the evoked overflow of tritium beginning from P5: no significant effect was detected at P3. The ACh esterase inhibitor physostigmine (1 microM) exhibited significant inhibitory effects from P13 onwards, whereas the muscarinic antagonist atropine (1 microM) did not change the evoked ACh release. The activity of ChAT, as measured for these septal regions at various postnatal ages, correlated well with the [3H]overflow induced by electrical stimulation. In conclusion, (1) electrically-evoked release of ACh was measured for the first time in three septal subregions; (2) the postnatal development of the presynaptic cholinergic functions: ChAT activity, ACh release and muscarinic autoreceptors occurs almost synchronously in these regions of the septal complex and parallels that in the hippocampal formation; (3) as in the hippocampus, the postnatal development of autoreceptors was delayed with respect to the exocytotic release of ACh.
Results of previous studies suggested that incertohypothalamic dopamine (IHDA) neurons located in the medial zona incerta (MZI) project to the central nucleus of the amygdala (cAMY), horizontal diagonal band of Broca (HDB), and paraventricular nucleus (PVN). The overall goal of the present study was to determine the relative contribution of IHDA neurons to the DA innervation of these brain regions. A combined fluorescent and in situ hybridization histochemical procedure was employed to localize the retrograde tracer fluoro-gold (FG) in cells expressing tyrosine hydroxylase (TH) mRNA in the MZI following its iontophoretic injection into either the cAMY, HDB or PVN. For comparison, the numbers of dual labeled FG/TH mRNA neurons in the midbrain were also determined. One week after unilateral injection of FG into the cAMY, cells containing FG+TH mRNA were found in the ipsilateral MZI, substantia nigra zona compacta (SNC) and ventral tegmental area (VTA). The total numbers of cells labeled with FG varied with the size of the injection site, but the ratio of dual labeling in the MZI to that of the SNC-VTA remained constant across animals at approximately 1:6. FG injections into the HDB resulted in a ratio of dual labeled cells in the ipsilateral MZI and VTA of approximately 1:2, but no dual labeled cells were found in the SNC. Dual labeled cells were only found in the ipsilateral MZI in animals receiving FG injections in the PVN. Thus, DA terminals in the PVN originate exclusively from IHDA neurons in the MZI, whereas these neurons provide only a portion of the DA innervation of the cAMY and HDB. The similar distribution of dual labeled cells in the MZI following FG injections into the cAMY, HDB and PVN suggests that perikarya of IHDA neurons projecting to these regions are not organized into distinct groups.
Four experiments examined the role of the cholinergic projections from the septum and vertical limb nucleus of the diagonal band of Broca (VDB) in acquisition and performance of a conditional visual discrimination. In experiments 1-3, excitotoxic lesions were made of the septum and VDB in rats using quisqualic acid, which resulted in significant reductions in ChAT activity in the hippocampus and cingulate cortex, but with no effects on cortical monoamines. In experiment 1, there were significant impairments in acquisition of the conditional discrimination, which did not result from motivational impairments. Experiment 2 repeated these results with lesion parameters, which produced variable effects on hippocampal and cingulate ChAT activity. Those rats with reductions in predominantly cingulate ChAT were most impaired in acquisition, but those with predominantly hippocampal reductions were relatively unimpaired. Experiment 3 showed that quisquate-induced lesions of the VDB, but not of the more caudal VDB and horizontal limb nucleus of the diagonal band, produced deficits, and a model incorporating the results of experiments 1-3 showed a highly significant correlation between errors of commission and cingulate cortical ChAT activity (r = -0.82, p < 0.001). Experiment 4 used the excitotoxin AMPA to lesion the VDB in rats pretrained on a modified form of the conditional discrimination task. In one subgroup of rats this excitotoxin produced profound and regionally selective reductions in ChAT activity. This subgroup was also impaired in relearning the discrimination to criterion. Again, there was a significant inverse relationship between the number of errors of commission made in relearning the discrimination and cingulate ChAT activity (r = -0.94, p < 0.001). These experiments suggest that excitotoxic lesions of the septum/VDB produce deficits in conditional discrimination learning and performance, and that the integrity of the projection to the cingulate cortex is more crucial than that to the hippocampus in this effect. Moreover, there is a close relationship between discrimination performance and cholinergic function in the cingulate cortex. In conjunction with other results, these data suggest that different aspects of cognition and memory are modulated by cholinergic activity in different cortical regions.
The morphology, ultrastructure and synaptic relationships of the cholinergic and non-cholinergic neurons in the medial septal nucleus (MS) and vertical limb of the diagonal band of Broca (VDB) in the basal forebrain of the rat were studied at the light and electron microscopic levels. The cholinergic neurons were localized immunocytochemically using a monoclonal antibody against choline acetyltransferase (ChAT). Morphometric and statistical analyses showed that ChAT-labelled cells presented a predominantly oval morphology in both nuclei. The sizes of the neurons were significantly larger in the VDB nucleus. Within the two nuclei, two populations of cholinergic neurons were differentiated. One of the large immunolabelled neurons presented deep indentations and prominent nucleoli in their non-immunoreactive nuclei. Their cytoplasm contained a well-organized endomembrane system composed of short cisternae of rough endoplasmic reticulum (RER). One or two lamellar bodies with a peculiar ultrastructure were frequently found intercalated in this system. The Golgi areas presented numerous coated vesicles, sequestration and multivesicular bodies, which was indicative of an intense metabolic activity in these cells. The second population of small immunolabelled neurons exhibited reduced cytoplasm with a poorly developed endomembrane system and apparent absence of lamellar bodies. The neighbouring non-immunolabelled neurons presented a different type of organization of the endomembrane system which was composed of scattered and loosely arranged elongated cisternae of RER and infrequent lamellar bodies, with a structure different from that seen in the large cholinergic neurons. We propose that the structural differences in composition of the endomembrane system and lamellar bodies observed in the three types of neurons in this study indicate different metabolic activities. Symmetrical and asymmetrical synaptic contacts were observed on somata and dendrites of labelled neurons, the latter being more frequent. ChAT-labelled axon boutons were never seen. The absence of immunolabelled axon terminals and the presence of immunolabelled myelinated axons leads us to suggest that the majority of neurons in these areas are of the long projecting type.
The anatomical organization of projections from the medial septal nucleus (MS), and the vertical (VDB) and horizontal limb (HDB) of the diagonal band of Broca to the dorsal raphe nucleus (NRD) and the central superior raphe nucleus (RCS) of the rat were studied by anterograde [3H]-leucine, and True Blue and Fluoro Gold fluorescent retrograde tracing. Projections from the MS were found to enter the basal mesencephalon at the rostro-medial aspect of the pontine nuclei, curve dorsally and terminate throughout the RCS and in the caudal portion of the NRD. Fibers from the VDB were found to enter these raphe nuclei by two separate routes; some fibers reached the basal mesencephalon, curved dorsally and terminated in the RCS and NRD. Other fibers entered the pedunculopontine nucleus, curved medially and reached the NRD. Presumed terminal labelling was found overlaying the RCS and NRD throughout their rostro-caudal extensions. The brain stem projections from HDB entered the mesencephalon by the same routes as those from VDB, but the labelling over RCS was sparse, and the NRD labelling was preferentially distributed to the rostral portion of the nucleus. The present data indicate a crude topographic organization of the projections from the septal region to the NRD and RCS. In general, the distribution of presumed terminal labelling appeared to be more closely associated with the distribution of NRD and RCS 5-HT immunoreactive cell bodies, than with the cytoarchitectonically defined extensions of these raphe nuclei. By sequential evaluation of the distribution of retrogradely labelled and acetylcholine esterase-stained cells on the same section, and by selective tracing with radiolabelled choline, it appears that the vast majority, if not all, of the neurons in MS and diagonal band which project to the rostral raphe are non-cholinergic.
Changes in the interaction between sex hormones and the cholinergic system are presumed to play a role in cognitive decline in aging and Alzheimer's disease (AD). The hippocampus is one of the most strongly affected brain structures in AD and the vertical limb of the diagonal band of Broca (VDB) is its major source of innervation. In the present study we found, surprisingly, for the first time that the neuronal metabolic activity as measured by the size of the Golgi apparatus in the VDB gradually increases after the age of 50 years in controls and that this process starts earlier and is more pronounced in Alzheimer's disease patients. Neuronal metabolic activity in the VDB was significantly higher in AD than in control patients younger than 70 years of age and was higher in control patients over 70 years than in control patients younger than 70 years of age. The activation of VDB neurons during aging was accompanied by an increased nuclear estrogen receptor (ER) beta staining, which was stronger in patients over 70 years of age than in younger subjects (in both controls and AD patients). Interestingly, as in the nucleus basalis of Meynert, nuclear ERalpha expression was markedly enhanced in AD patients compared to controls independent of age. In addition, evidence was found for the influence of APOE genotype on ERalpha and ERbeta staining in the human VDB in aging and in AD. APOE genotype was positively correlated (epsilon 2 < epsilon 3 < epsilon 4) with the percentage of cytoplasm ERalpha-positive VDB neurons in elderly control male and female subjects and with both nuclear and cytoplasm ERbeta-positive neurons in control women. In conclusion, the VDB is compensatory activated and shows more nuclear ER expression in aging and AD in a sex- and APOE genotype-dependent way. So neither global degeneration or a strongly decreased neuronal metabolism nor a lack of sex hormone receptors in the VDB seems to contribute to the decline in cognition in aging or AD in which the hippocampus plays such a crucial role.
The function of nucleus basalis (NB) and medial septal-vertical diagonal band of Broca (MS-VDBB) in a place navigation task requiring reference memory was investigated. Two subclasses of nucleus basalis ibotenic acid-lesioned rats could be identified: a group having both extensive non-specific subcortical damage and severely impaired learning behavior, and a less impaired group with correspondingly less subcortical damage. The depletion of cortical cholinergic enzymes was slightly higher in the group of NB-lesioned rats with extensive subcortical lesions than in the group with smaller lesioned areas. In the hippocampus of both of these NB-lesioned groups, cholinergic innervation remained unchanged. Ibotenic acid lesioning restricted to the MS-VDBB depleted hippocampal cholinergic innervation, but not the innervation of the frontal cortex, and also led to impaired learning behavior. Of all the lesioned rats, the most impaired were the NB-lesioned rats with large non-specific subcortical lesion.
Previously published theoretical models of olfactory processing suggest that cholinergic modulatory inputs to the olfactory system should be regulated by neural activity in the olfactory bulb. We tested these predictions using in vivo electrophysiology in rats. We show that the activity of approximately 20% of neurons recorded in the horizontal limb of the diagonal band of Broca (HDB), which is the source of cholinergic projections to the olfactory system, can be modulated by electrical stimulation of either the lateral olfactory tract or the cell body layer of piriform cortex. These data suggest a possible physiological pathway for the proposed regulation of neural activity in the HDB by activity in the olfactory bulb or cortex.
Oestrogen is known to influence pyramidal cell spine synapse plasticity in the CA1 subfield of the hippocampus. Apart from direct oestrogen action on the hippocampus, oestrogen effects mediated by subcortical structures are known to be important. The purpose of this study was to investigate whether the medial septum diagonal band of Broca (MSDB) takes part in mediating oestrogen effects to the hippocampus. Special attention was given to the role of cholinergic MSDB neurons that project to the hippocampus, as a rather large population of them contains oestrogen receptors and, consequently, may be sensitive to oestrogen signals. Adult female rats were ovariectomized. Oestradiol- and cholesterol-filled cannulae (control) were implanted into the MSDB. To selectively eliminate the cholinergic population of MSDB neurons of oestrogen-treated animals, a group of rats was injected with 192 IgG-saporin (SAP) into the lateral ventricle 1 week before the cannula implant. Immunostaining with anti-choline acetyltransferase and parvalbumin (PA) showed that cholinergic but not PA-containing GABAergic neurons were substantially reduced in the MSDB of SAP rats. Comparative electron microscopic unbiased stereological analysis on the spine synapse density of CA1 area pyramidal cells was performed between all animal groups. Rats that received oestradiol-filled cannulae showed a higher (30%) spine synapse density than control animals. Oestrogen-treated rats that had received SAP treatment showed no significant difference to controls. Thus, this observation indicates that septo-hippocampal cholinergic neurons are involved in mediating oestrogen effects to the hippocampus. The relevance of this observation to mnemonic functions and Alzheimer's disease is discussed.
The relationship between running, glial cell activation and pro-inflammatory cytokines was studied in the context of neuroprotection against ischemic stroke induced by middle cerebral artery occlusion (MCAO). This was investigated in four groups of rats, namely, (1) nonrunner, (2) runner after 12 weeks of treadmill running, (3) nonrunner with MCAO and (4) runner with MCAO. The horizontal diagonal band of Broca (HDB) in the septum was scrutinized for qualitative cum quantitative changes in the microglia and astrocytes. Reverse transcription-polymerase chain reaction and immunoblot work were carried out in the forebrain homogenate to determine, respectively, the gene and protein expression of several pro-inflammatory cytokines. Our results indicated that the runner exhibited less immunoreactivity and reduced numbers of glial cells within the HDB compared with the nonrunner. Interestingly, the mRNA and protein levels of tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6 and interferon-gamma, were significantly downregulated in the runner. Our data also suggest albeit with some inconsistency that the runner/MCAO rats had benefited from running. These observations suggest that running can result in changes to the microenvironment, in which the microglia and astrocytes exist in a state of quiescence concomitant with a reduced expression of pro-inflammatory cytokines, that may lead to beneficial effects seen in ischemic stroke induced by MCAO.
Quantitative in situ hybridization techniques were used to examine the effects of lesions which sever hippocampal cholinergic and cortical afferents on p75NGFR mRNA-expressing cells located in the medial septum (MS) and the vertical (VDB) and horizontal (HDB) limbs of the diagonal band of Broca. Animals received either bilateral transection of the fimbria/fornix, unilateral transection of the angular bundle, or sham surgery. Four days later, animals were sacrificed and sections through the MS, VDB and HDB were processed for detection of the p75NGFR mRNA using in situ hybridization techniques previously described (Mol. Brain Res., 6 (1989) 275-287). Transection of the fimbria/fornix and angular bundle differentially affected p75NGFR-expressing cells in the MS, VDB and HDB within 4 days after injury, in ways which were consistent and correlate with subsequent effects on cell survival, synaptic reorganization and growth. In particular, in the MS and VDB, transection of the fimbria/fornix resulted in a significant decrease in the size of p75NGFR-expressing cells (reductions of 25.9% and 15.1% respectively) which was accompanied by a significant reduction (37.9% and 12.7% fewer grains/cell) in relative levels of p75NGFR mRNA. In contrast, in the HDB, transection of the fimbria/fornix had no significant effect on the average size of p75NGFR-expressing cells; however, a significant increase (49%) in the mean relative level of p75NGFR mRNA was observed which may, in turn, reflect a large increase (as much as 2-3 fold) in the levels of p75NGFR mRNA expressed by a subpopulation of hippocampally projecting cholinergic neurons located in the HDB. Finally, transection of the angular bundle resulted in small, but significant increases (9.4% and 10.9%) in relative levels of p75NGFR mRNA in the MS and VDB, as well as an increase (19.6%) in the number of p75NGFR mRNA-expressing cells in the HDB, on the injured side. No increases in p75NGFR expression in the MS, VDB or HDB contralateral to the lesion were observed; however, a decrease in the size (6.9%) and message content (19.4%) of p75NGFR-expressing cells was detected in the MS contralateral to the lesion. Most importantly, all of these effects are consistent with the subsequent effects of these lesions on the survival of basal forebrain cholinergic cells, and the reorganization and growth of cholinergic afferents to the hippocampal formation.(ABSTRACT TRUNCATED AT 400 WORDS)
The termination pattern of hippocamposeptal nonpyramidal cells was investigated by injecting Phaseolus vulgaris leucoagglutinin (PHAL) into stratum oriens of the CA1 region. Electron microscopic analysis showed that the majority of the anterogradely labeled boutons formed symmetric synapses with dendrites and occasionally with cell bodies located in the medial septum-diagonal band of Broca complex. We have demonstrated with postembedding GABA immunocytochemistry that the majority of PHAL-labeled axon terminals were GABAergic. The neurochemical character of the postsynaptic target cells was also investigated using immunocytochemical double staining. Our data showed that the majority of the labeled hippocamposeptal axons innervated parvalbumin-immunoreactive cells representing GABAergic projection neurons, and a smaller number of contacts were found on ChAT-positive neurons. Septohippocampal neurons identified by retrograde HRP transport were also shown to reactive direct hippocamposeptal input. According to recent results, the lateral septum is unlikely to relay the hippocampal feedback to the medial septum; therefore, the direct hippocampal projection to the medial septum, arising from GABAergic nonpyramidal cells, seems to be the only feedback pathway to the area containing septohippocampal neurons. A novel circuit diagram, based on our recent morphological-immunocytochemical findings, is shown for the synaptic organization of the septo-hippocampo-septal loop. We suggest that the GABAergic hippocamposeptal feedback controls the activity of septal (mostly GABAergic) projection neurons as a function of hippocampal synchrony. The newly discovered reciprocal interactions may give a better insight into septohippocampal physiology.
The aim of the present study was to investigate the role of the cholinergic innervation of the cingulate cortex in visual attentional function and acquisition of a visual conditional discrimination task. Following AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) lesions of the vertical limb diagonal band of Broca (VDB) which provides the main cholinergic projection to cingulate cortex, animals were not significantly impaired on the 5-choice serial reaction time task. This task, which provides a continuous performance test of visual attention, has previously been shown to be sensitive to AMPA lesions of the nucleus basalis magnocellularis (nbM). In contrast to the results obtained for visual attentional function, lesions of the VDB did significantly affect the acquisition of a visual conditional discrimination. While showing a significant facilitation in the early learning stage of acquiring this task animals with lesions of the VDB were significantly impaired during the late stages of learning this task. This late learning deficit was not the result of the animals being unable to learn the task due to the presence of the lesion throughout task acquisition as the results of a second experiment revealed that when animals were pre-trained to 70% accuracy on the task and then lesioned, the impairment in late learning was still apparent. In light of the results presented in the accompanying paper (Bussey et al., Behav. Brain Res., 1996), these results suggest that the early learning effects may be due to cholinergic denervation of the anterior cingulate cortex while the late learning effects may be due to denervation of the posterior cingulate cortex. Taken together with previous work indicating a role for the nbM cholinergic system in visual attentional function, these results suggest a role for the cholinergic innervation of the cingulate cortex in conditional learning but not for continuous attentional performance.
The projection of neurons in the septal nuclei and the insula magna of the islands of Callaja (IC) was explored together with their response to stimulation of the fornix. The septal nuclei all contained neurons projecting in the medial forebrain bundle (MFB). Only the diagonal band of Broca (DBB) and the lateral septal nucleus (LS) contained many neurons projecting toward the medial basal hypothalamus (MBH). The spatial distribution of neurons excited by stimulation of the fornix in the DBB was almost identical with the distribution of neurons projecting toward the MBH and there was considerable overlap (10/28 cells). In the medial septal nucleus the spatial distribution of neurons excited by stimulation of the fornix and neurons projecting in the MFB was similar and there was considerable overlap (6/21 cells). The connectivity of the IC resembled that of the MS but there was little overlap between the neurons excited by fornix stimulation and those projecting in the MFB (1/27 cells). In the LS there were almost equal numbers of neurons projecting in the MFB and toward the MBH but there was very little input from the fornix. Neurons were significantly more often excited by stimulation of the lateral fornix, carrying axons from the subiculum, than they were by medial stimulation exciting axons from Ammon's horn. Axons projecting toward the MBH or in the MFB had conduction velocities less than 1 m/s.
NGF receptor-expressing cells located in the basal forebrain have recently been shown to contain estrogen (E) receptors (Toran-Allerand and MacLusky. 1989. Soc. Neurosci. Abstr. 15: 954). In the present study, we have examined the effects of E-treatment on p75NGFR and choline acetyltransferase (ChAT) expression by neurons in the medial septum (MS) and the vertical (VDB) and horizontal (HDB) limbs of the diagonal band of Broca using immunocytochemical and in situ hybridization techniques. First, since E-treatment has been shown to affect neuronal survival and to stimulate synaptic reorganization and growth within various regions of the brain, we hypothesized that E-treatment might attenuate the loss of p75NGFR immunoreactivity (IR) which occurs in the MS and VDB following transection of the fimbria/fornix. Contrary to our hypothesis, E-treatment did not attenuate the effects of fimbria/fornix transection. In fact, E-treatment alone produced a significant decrease in the number of p75NGFR-IR cells detected in the MS. Subsequent experiments confirmed that chronic E-treatment produces a down-regulation of both p75NGFR-IR and p75NGFR mRNA in the MS and VDB. In the MS, estrogen appeared to affect a subpopulation of p75NGFR-expressing neurons which were also affected by fimbria/fornix transection since the effects of these two treatments were not additive. In addition, effects of E-treatment on p75NGFR-IR were sex-specific (observed in females but not in males) and were reversible in the MS after 2 weeks, but not after 4 weeks (allowing 2 weeks recovery), of E-treatment. A time-course analysis revealed that effects of E-treatment on p75NGFR-IR were not observed until after 16 days (MS) or 30 days (VDB) of E-treatment and were preceded by a significant and transient increase in ChAT expression in both the MS and VDB. The data are consistent with the possibility that continuous, long-term exposure to gonadal steroids may contribute to a loss of p75NGFR-expressing neurons with age. In addition, the data suggest that p75NGFR expression may play a role in regulating the functioning of specific basal forebrain cholinergic neurons. Different mechanisms by which E-treatment might influence ChAT and p75NGFR expression in brain are discussed.
The neuropeptide galanin is known to inhibit the evoked release of acetylcholine in ventral hippocampus of the rat. Co-localization of this peptide with choline acetyltransferase in neurons of the cholinergic septal nuclei has been demonstrated in the rat and non-human primate. The severe deficiency of the cholinergic hippocampal projection system arising mainly from the vertical limb nucleus of the diagonal band of Broca, also referred to as Ch2 region, is a constant finding in Alzheimer's disease, a disorder which is neuropathologically characterized by the appearance of senile plaques, neurofibrillary tangles and congophilic angiopathy in neo- and archicortical structures. In the present study for the first time galanin immunoreactivity in the human Ch2 region is morphologically investigated and related to the severity of hippocampal plaques and neurofibrillary tangles in Alzheimer's disease. An inverse relationship between decreasing galanin immunoreactivity in the Ch2 region and amounts of senile plaques and neurofibrillary tangles in the hippocampus is indicated. Considering the cholinergic deficiency in Alzheimer's disease as a secondary phenomenon to primary cortical and hippocampal lesions, and realizing the inhibitory effect of galanin upon acetylcholine release in hippocampus, this preliminary study suggests that a decreased galanin immunoreactivity in Ch2 in Alzheimer's disease, reflects a possible negative feedback mechanism to a degenerating cholinergic projection system.