Intraseptal muscarinic ligands and galanin: influence on hippocampal acetylcholine and cognition

The cholinergic neurons in the septohippocampal projection are implicated in hippocampal functions such as spatial learning and memory. The aim of this study was to examine how septohippocampal cholinergic transmission is modulated by muscarinic inputs and by the neuropeptide galanin, co-localized with acetylcholine (ACh) in septohippocampal cholinergic neurons, and how spatial learning assessed by the Morris water maze test is affected. Muscarinic inputs to the septal area are assumed to be excitatory, whereas galanin is hypothesized to inhibit septohippocampal cholinergic function. To test these hypotheses, compounds were microinjected into the medial septum and hippocampal ACh release was assessed by microdialysis probes in the ventral hippocampus of the rat. Blockade of septal muscarinic transmission by intraseptal scopolamine increased hippocampal ACh release suggesting that septal cholinergic neurons are under tonic inhibition. Stimulation of septal muscarinic receptors by carbachol also increased hippocampal ACh release. Despite this increase, both scopolamine and carbachol tended to impair hippocampus-dependent spatial learning. This finding also suggests a revision of the simplistic notion that an increase in hippocampal ACh may be facilitatory for learning and memory. Galanin infused into the medial septum enhanced hippocampal ACh release and facilitated spatial learning, suggesting that septal galanin, contrary to earlier claims, does not inhibit but excites septohippocampal cholinergic neurons. Galanin receptor stimulation combined with muscarinic blockade in the septal area resulted in an excessive increase of hippocampal ACh release combined with an impairment of spatial learning. This finding suggests that the level of muscarinic activity within the septal area may determine the effects of galanin on hippocampal cognitive functions. In summary, a limited range of cholinergic muscarinic transmission may contribute to optimal hippocampal function, a finding that has important implications for therapeutic approaches in the treatment of disorders of memory function.     

Non-cholinergic afferents determine the distribution of the cholinergic septohippocampal projection: a study of the AChE staining pattern in the rat fascia dentata and hippocampus after lesions,X-irradiation,and intracerebral grafting

Summary The acetylcholinesterase (AChE) activity of the rat hippocampus and fascia dentata depends on an intact septohippocampal connection, and histochemical staining for AChE is commonly used to monitor the distribution of the cholinergic septohippocampal projection. It is also characteristic that the laminae of low or moderate to dense AChE staining in the hippocampus and fascia dentata coincide with the terminal fields of the major non-cholinergic, afferent pathways. While studying lesion-induced collateral sprouting and aberrant axonal growth of these pathways we observed that the AChE staining pattern changed in accordance with the reorganized distribution of the non-cholinergic pathways, and this occurred even without direct interfering with the septohippocampal projection itself. Widening and narrowing of the medial perforant path and mossy fiber terminal zones thus resulted in corresponding changes in the bands of AChE staining normally associated with these zones. Expansion of the commissural-associational hippocampodentate projections and the lateral perforant path was in a similar way paralleled by a widening of the AChE-poor zones which normally overlap with the termination of these projections. Observations of the same kind were made in intracerebral transplants of fascia dentata innervated by various host afferents, and in rats subjected to neonatal X-irradiation, where the mossy fiber projection is reduced and aberrant perforant pathways project into CA3 due to a reduced formation of granule cells. The observed sets of changes with linkage between the different noncholinergic projections and the activity of AChE in their respective terminal fields were accordingly reproduced under several different experimental conditions. It could not be explained alone by interaction between the septal afferents and their target cells. We therefore conclude that the density and laminar distribution of the AChE activities within the hippocampus and fascia dentata are determined at least in part by the major afferent, noncholinergic nerve connections. We suggest that the effect occurs through direct axonal interaction or through changes in the receptiveness of the common dentate and hippocampal target cells.     

Two populations of rhythmically bursting neurons in rat medial septum are revealed by atropine

1. Previous findings, such as the sensitivity of the hippocampal theta rhythm to cholinergic manipulation, support a "pacemaker" role for the cholinergic cells of the medial septal nucleus and the vertical limb of the nucleus of the diagonal band (MSN-NDB). To explore the mechanism(s) of action of systemic antimuscarinic drugs in eliminating the theta rhythm, recordings of hippocampal EEG and rhythmic MSN-NDB neurons that fired in phase with the hippocampal theta rhythm were taken during the administration of atropine in urethane-anesthetized rats. 2. Twenty-two of 33 rhythmic MSN-NDB cells continued to burst at the theta rhythm frequency after administration of a dose of atropine (25 mg/kg iv) that was sufficient to eliminate the theta rhythm (atropine-resistant cells). The remaining 11 cells lost their rhythmic firing pattern over the same time course as the loss of the theta rhythm (atropine-sensitive cells). 3. Both types of rhythmic MSN-NDB cells could be antidromically driven from the fimbria/fornix with similar latencies (range, 0.5-4.0 ms). The extracellularly recorded spike waveforms were not useful in predicting the atropine sensitivity of a given cell. Atropine-resistant cells frequently had higher firing rates than atropine-sensitive cells, but there was sufficient overlap of the two groups to make this a poor predictor of sensitivity. 4. Cooling the fimbria/fornix reversibly eliminated the hippocampal theta rhythm, but had no effect on 21/25 rhythmic MSN-NDB cells tested. This indicates that the atropine-sensitive MSN-NDB cells do not depend on the periodic output from the hippocampus for their rhythmic firing. Recordings from pairs of rhythmic MSN-NDB cells during cooling and/or atropine administration showed unchanged phase relations at the theta rhythm frequency. In rats in which the septohippocampal system was exposed by aspirating the overlying brain tissue, direct application of atropine (10 mg/ml) to the septal nuclei reversibly eliminated the hippocampal theta rhythm. 5. The rhythmic cells of the MSN-NDB are apparently composed of at least two distinct types, both of which potentially contribute to the production of the theta rhythm in the hippocampus. Elimination of hippocampal theta rhythm after local septal atropine application suggests that the loss of rhythmic activity in the group of atropine-sensitive septal cells is sufficient for the elimination of the theta rhythm. A model of the septohippocampal connections necessary for the theta rhythm is presented.     

Reversible septal inactivation disrupts hippocampal slow-wave and unit activity and impairs trace conditioning in rabbits (Oryctolagus cuniculus)

This study investigated the effects of medial septal microinfusion of the local anesthetic, procaine (MS Pro), on hippocampal neurophysiology and learning of the rabbit (Oryctolagus cuniculus) classically conditioned jaw movement (CJM) response. Both the percentage and the amplitude of hippocampal theta decreased after procaine administration, and unit recordings from the MS Pro group showed significantly smaller conditioning-related hippocampal neural responses than those from controls. The MS Pro group took significantly longer to reach learning criterion than did the control group. Interpreted in the context of previous studies, the present result suggests that nonselective blocking of all septal projection systems, as well as fibers of passage, using procaine can be less detrimental to learning than an imbalance between GABAergic and cholinergic septohippocampal projections, as produced by septal infusion of anticholinergics.     

Effects of chronic stressors or corticosterone treatment on the septohippocampal cholinergic system of the rat

The effects of prolonged (2 months) corticosterone (CORT) treatment on several cholinergic markers of various brain areas were compared to the effects of prolonged intermittent exposure to stress. CORT, but not stress, caused a significant reduction in the number of acetylcholinesterase-stained neurons in the medial septal area. Neither treatment resulted in any hippocampal pyramidal cell loss. It is concluded that a time-dependent degeneration of the septohippocampal cholinergic system follows 2 months of CORT administration but not chronic intermittent stress of this duration.     

Increased expression of hippocampal cholinergic neurostimulating peptide-related components and their messenger RNAs in the hippocampus of aged senescence-accelerated mice

Hippocampal cholinergic neurostimulating peptide stimulates cholinergic phenotype development by inducing choline acetyltransferase in the rat medial septal nucleus in vitro. Adult senescence-accelerated-prone mice/8, a substrain of the senescence-accelerated-prone mouse, show a remarkable age-accelerated deterioration in learning and memory. We cloned mouse hippocampal cholinergic neurostimulating peptide precursor protein complementary DNA. The deduced amino acid sequence showed that the neurostimulating peptide itself is the same as that found in the rat. In situ hybridization revealed that the highest expression of the precursor protein messenger RNA was in hippocampal pyramidal neurons. Compared with a strain of senescence-accelerated-resistant mouse (control mouse), adult senescence-accelerated-prone mice/8 showed increased expression of both the precursor messenger RNA and the neurostimulating peptide-related immunodeposits in the hippocampal CA1 field. The deposits were intensely and diffusely precipitated in neuropils throughout the strata oriens and radiatum in senescence-accelerated-prone mice/8, but not in control mice. The neurostimulating peptide content in the hippocampus was higher in senescence-accelerated-prone mice/8 than in control mice, while its precursor protein itself was not different between the two strains. Furthermore, our previous and present data show that the medial septal and hippocampal choline acetyltransferase activity was significantly lower in senescence-accelerated-prone mice/8 than in control mice. The data suggest that, in hippocampal neurons in adult senescence-accelerated-prone mice/8, the production of hippocampal cholinergic neurostimulating peptide precursor protein in neuronal somata, which is associated with an increased expression of its messenger RNA in the CA1 field, occurs as a consequence of low activity in their presynaptic cholinergic neurons. This is followed by accelerated processing to generate bioactive peptide and transport to its functional fields. However, certain mechanisms reduce the release of the peptide and lead to its accumulation in the neuropil. These disturbances of the septohippocampal cholinergic system might be the biochemical mechanism underlying the characteristic deterioration of senescence-accelerated-prone mice/8.     

Effect of bite-raised condition on the hippocampal cholinergic system of aged SAMP8 mice

Occlusal disharmony induces chronic stress, which results in learning deficits in association with the morphologic changes in the hippocampus, e.g., neuronal degeneration and increased hypertrophied glial fibrillary acidic protein-positive cells. To investigate the mechanisms underlying impaired hippocampal function resulting from occlusal disharmony, we examined the effects of the bite-raised condition on the septohippocampal cholinergic system by assessing acetylcholine release in the hippocampus and choline acetyltransferase immunoreactivity in the medial septal nucleus in aged SAMP8 mice that underwent the bite raising procedure. Aged bite-raised mice showed decreased acetylcholine release in the hippocampus and a reduced number of choline acetyltransferase-immunopositive neurons in the medial septal nucleus compared to age-matched control mice. These findings suggest that the bite-raised condition in aged SAMP8 mice enhances the age-related decline in the septohippocampal cholinergic system, leading to impaired learning.     

Timing of administration mediates the memory effects of intraseptal carbachol infusion

Medial septal neurons innervate the entire hippocampal formation. This input provides a potent regulation of hippocampal formation physiology (e.g. theta) and memory function. Medial septal neurons are rich in cholinergic receptors and thus are potential targets for the development of cognitive enhancers. Direct intraseptal infusion of cholinomimetics alters hippocampal physiology and can produce either promnestic or amnestic effects. Several variables (e.g. age of animal, integrity of septohippocampal circuits, task difficulty) may influence treatment outcome. We have previously demonstrated that intraseptal carbachol (12.5-125 ng) infusion immediately after the sample session of a delayed-non-match-to-sample radial maze paradigm produces a dose-dependent amnesia. The present study examined whether manipulating the timing of intraseptal carbachol infusion with respect to the sample session would alter the amnestic effect. A within-subjects design was used to examine the effect of intraseptal carbachol (125 ng/0.5 microl) in a delayed-non-match to sample radial maze task. During a sample session, rats retrieved rewards from six of 12 maze arms. At the test session (3 h later), only the alternate set contained reward and entries into the sample set arms constituted errors. Intraseptal carbachol was administered: 1) 30 min prior; 2) immediately prior; 3) immediately after and 4) 90 min after the sample session. Intraseptal carbachol prior to the sample had no effect on any index of accuracy. Infusion immediately after the sample, or delayed 90 min into the retention interval, produced an acute amnesia. These findings demonstrate that the timing of treatment is a critical variable in determining the memory effects of septohippocampal manipulations and that dynamic changes in cholinergic tone are important for memory.     

Histamine innervation and activation of septohippocampal GABAergic neurones: involvement of local ACh release

Recent studies indicate that the histaminergic system, which is critical for wakefulness, also influences learning and memory by interacting with cholinergic systems in the brain. Histamine-containing neurones of the tuberomammillary nucleus densely innervate the cholinergic and GABAergic nucleus of the medial septum/diagonal band of Broca (MSDB) which projects to the hippocampus and sustains hippocampal theta rhythm and associated learning and memory functions. Here we demonstrate that histamine, acting via H₁ and/or H₂ receptor subtypes, utilizes direct and indirect mechanisms to excite septohippocampal GABA-type neurones in a reversible, reproducible and concentration-dependent manner. The indirect mechanism involves local ACh release, is potentiated by acetylcholinesterase inhibitors and blocked by atropine methylbromide and 4-DAMP mustard, an M₃ muscarinic receptor selective antagonist. This indirect effect, presumably, results from a direct histamine-induced activation of septohippocampal cholinergic neurones and a subsequent indirect activation of the septohippocampal GABAergic neurones. In double-immunolabelling studies, histamine fibres were found in the vicinity of both septohippocampal cholinergic and GABAergic cell types. These findings have significance for Alzheimer's disease and other neurodegenerative disorders involving a loss of septohippocampal cholinergic neurones as such a loss would also obtund histamine effects on septohippocampal cholinergic and GABAergic functions and further compromise hippocampal arousal and associated cognitive functions.     

Cholinergic and GABAergic modulation of medial septal area: effect on working memory

The role of the septohippocampal pathway in working memory was investigated by direct microinfusion of compounds into the medial septal area (MSA). Behavior was measured by performance in a continuous spatial alteration task in a T maze, and hippocampal theta rhythm was also recorded. Intraseptal saline had no effect on choice accuracy or hippocampal theta rhythm. Tetracaine decreased choice accuracy and theta rhythm 10 min, but not 90 min, after infusion. Likewise, muscimol and scopolamine produced a transient, dose-dependent suppression of hippocampal theta rhythm and a simultaneous dose-dependent impairment in choice accuracy. A significant correlation (r = .78) emerged between a compound's influence on theta rhythm and its effect on choice accuracy. The data support a role for the septohippocampal projection in working memory and suggest that gamma-aminobutyric acid and acetylcholine may have opposing influences on neurons in the MSA.     

Modulation of septal influences on hippocampal neurons by cholinergic substances

The effects of electrical stimulation of the medial septal area (MS-DB) for the purpose of distinguishing and assessing the cholinergic component of the septohippocampal input were investigated in awake rabbits in chronic experiments. Initial inhibitory effects of a standard duration of 40–140 msec (54%) predominated in the intact rabbits. In animals with chronic basal undercutting of the MS-DB, initial inhibitory reactions predominated absolutely (90%). An increase in the level of endogenous acetylcholine by administration of eserine led to a partial or complete suppression of all effects of stimulation in 78% of the hippocampal neurons of the intact rabbits against the background of intensification of the theta modulation of the activity of hippocampal neurons. Scopolamine removed theta modulation and restored the reactivity of neurons to stimulation of the MS-DB. These influences of cholinergic substances were maintained in the animals with basal undercutting of the MS-DB. It is inferred that the general initial influence of septal input on neurons of the hippocampus is expressed in the suppression of their activity (“reset”), which depends on the noncholinergic (GABAergic) component of the septohippocampal connections. The cholinergic component limits the effectiveness of both extraseptal (brainstem) and primary inhibitory septal influences on hippocampal neurons. This study was supported by the Russian Basic Research Fund (project No. 93-04-21907). Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino. Translated from Zhurnal Vysshei Nervnoi Deyatel'nosti imeni I. P. Pavlova, Vol. 44, No. 4–5, pp. 751–761, July–October, 1994.     

Septal GABAergic neurons are selectively vulnerable to pilocarpine-induced status epilepticus and chronic spontaneous seizures

The septal region of the basal forebrain plays a critical role modulating hippocampal excitability and functional states. Septal circuits may also play a role in controlling abnormal hippocampal hyperexcitability in epilepsy. Both lateral and medial septal neurons are targets of hippocampal axons. Since the hippocampus is an important epileptogenic area in temporal lobe epilepsy, we hypothesize that excessive excitatory output will promote sustained neurodegeneration of septal region neurons. Pilocarpine-induced status epilepticus (SE) was chosen as a model to generate chronic epileptic animals. To determine whether septal neuronal populations are affected by hippocampal seizures, immunohistochemical assays were performed in brain sections obtained from age-matched control, latent period (7 days post-SE) and chronically epileptic (more than one month post-SE survival) rats. An anti-NeuN (neuronal nuclei) antibody was used to study total neuronal numbers. Anti-ChAT (choline acetyltransferase), anti-GAD (glutamic acid decarboxylase) isoenzymes (65 and 67), and anti-glutamate antibodies were used to reveal cholinergic, GABAergic and glutamatergic neurons, respectively. Our results revealed a significant atrophy of medial and lateral septal areas in all chronically epileptic rats. Overall neuronal density in the septum (medial and lateral septum), assessed by NeuN immunoreactivity, was significantly reduced by approximately 40% in chronically epileptic rats. The lessening of neuronal numbers in both regions was mainly due to the loss of GABAergic neurons (80-97% reduction in medial and lateral septum). In contrast, populations of cholinergic and glutamatergic neurons were spared. Overall, these data indicate that septal GABAergic neurons are selectively vulnerable to hippocampal hyperexcitability, and suggest that the processing of information in septohippocampal networks may be altered in chronic epilepsy.     

Direct projections from Ammon's horn to the septum in the cat

Summary Direct projections from Ammon's horn to the septum were studied in the cat by the anterograde tracing method after injecting WGA-HRP (wheat germ agglutinin-horseradish peroxidase conjugate) into Ammon's horn. The results were further confirmed by the retrograde WGA-HRP method after injecting WGA-HRP into the septum. Pyramidal neurons in fields CA1, CA2 and CA3 were observed to send their axons ipsilaterally to the lateral septal nucleus; the septal parts of the hippocampus sent projection fibers to the dorsomedial portions of the lateral septal nucleus via the medial aspects of the subcallosal fornix, while the hippocampal regions successively more proximal to the temporal pole sent projection fibers to progressively more ventrolateral portions of the lateral septal nucleus via more lateral aspects of the subcallosal fornix. It was also found that the septal parts of fields CA1, CA2 and CA3 sent projection fibers bilaterally to the dorsomedial aspects of the lateral septal nucleus. Field CA4 appeared to send projection fibers only sparsely, if at all, to the medial septal nucleus. The rudimentary parts of the hippocampal formation, taenia tecta and indusium griseum, were found to have reciprocal ipsilateral connections with the dorsal portions of the lateral septal nucleus.     

A study of the rat septohippocampal pathway using anterograde transport of horseradish peroxidase

The projection of the septohippocampal pathway in the rat was studied using anterograde transport of horseradish peroxidase. This technique provides a number of advantages over other methods including the ability to differentiate between terminal and preterminal axon labeling, a very high ‘signal to noise’ ratio, and a short delay in obtaining results. As applied to the septohippocampal projection, anterograde transport of horseradish peroxidase reveals a dense septal input to the dentate hilus and stratum oriens of CA3, a modest input to the dentate molecular layer and stratum radiatum of CA3, and a very sparse input to stratum oriens and stratum lacunosum-moleculare of CA1 with most labeling in this field confined to axons passing through it. In addition, our results suggest that a septal projection to the supragranular region of the dentate is present only within the rostral pole of the hippocampal formation. Potential artifacts such as labeling of fibers-of-passage and ‘collateral’ filling do not appear to interfere with the results but transneuronal transport of horseradish peroxidase may occur when large amounts of the protein are injected.     

Endogenous ciliary neurotrophic factor protects GABAergic,but not cholinergic,septohippocampal neurons following fimbria-fornix transection

Application of neurotrophic proteins including ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF), members of the family of gp130-associated cytokines, can rescue CNS neurons from injury-induced degeneration. However, it is not clear so far if these effects reflect a physiological function of the endogenous cytokines. Using fimbria-fornix transection as a model, we examined whether responses of GABAergic and cholinergic septohippocampal neurons to axotomy are altered in mice lacking CNTF. In addition, we studied the cellular expression of CNTF, LIF and related cytokine receptor components in the septal complex following lesion. Degeneration of septohippocampal GABAergic neurons in the medial septum as indicated by the loss of parvalbumin-immunoreactive neurons was accelerated and permanently enhanced in CNTF(-/-) mice as compared to wild-type animals. Unexpectedly, the number of axotomized cholinergic MS neurons was significantly higher in CNTF-deficient mice during the first 2 weeks postlesion. Both in wild-type and in CNTF(-/-) mutants, expression of mRNA for the CNTF-specific alpha-subunit of the cytokine receptor complex was specifically upregulated in axotomized GABAergic septal neurons, whereas enhanced expression of the LIF-binding beta-subunit was specifically observed in axotomized cholinergic neurons. Following lesion, CNTF expression in wild-type mice was induced in activated astrocytes surrounding the axotomized neurons and at the lesion site. Expression of LIF mRNA was localized in the GABAergic and cholinergic septohippocampal neurons. These results strongly indicate that endogenous CNTF, supplied by reactive glia cells, acts as a neuroprotective factor for axotomized CNS neurons. In the septum, endogenous CNTF specifically supports lesioned GABAergic projection neurons, whereas LIF may play a similar role for the cholinergic counterparts.     

Nerve growth factor improves spatial learning and restores hippocampal cholinergic fibers in rats withdrawn from chronic treatment with ethanol

The cholinergic septohippocampal pathway has long been known to be important for learning and memory. Prolonged intake of ethanol causes enduring memory deficits, which are paralleled by partial depletion of hippocampal cholinergic afferents. We hypothesized that exogenous supply of nerve growth factor (NGF), known to serve as a trophic substance for septal cholinergic neurons, can revert the ethanol-induced changes in the septohippocampal cholinergic system. Adult rats were given a 20% ethanol solution as their only source of fluid for 6 months. During the first 4 weeks after the animals were withdrawn from ethanol, they were intraventricularly infused with either NGF or vehicle alone via implanted osmotic minipumps. The vehicle-infused withdrawn animals showed impaired performance on a spatial reference memory version of the Morris water maze task, both during the task acquisition and on the retention test. In contrast, NGF-treated withdrawn rats were able to learn the task as well as controls, and significantly outperformed the vehicle-infused withdrawn rats. The histological analysis revealed that, in the latter group, the length density of fibers immunoreactive to choline acetyltransferase was reduced relative to control values by approximately 25%, as measured in the dentate gyrus and regio superior of the hippocampal formation. However, in NGF-treated withdrawn rats, the length density of these fibers was identical to that of control rats. These data provide support to the notion that NGF is capable of ameliorating memory deficits and restoring septohippocampal cholinergic projections following chronic treatment with ethanol. Electronic Publication     

A connectionist model of septohippocampal dynamics during conditioning: closing the loop

Septohippocampal interactions determine how stimuli are encoded during conditioning. This study extends a previous neurocomputational model of corticohippocampal processing to incorporate hippocamposeptal feedback and examines how the presence or absence of such feedback affects learning in the model. The effects of septal modulation in conditioning were simulated by dynamically adjusting the hippocampal learning rate on the basis of how well the hippocampal system encoded stimuli. The model successfully accounts for changes in behavior and septohippocampal activity observed in studies of the acquisition, retention, and generalization of conditioned responses and accounts for the effects of septal disruption on conditioning. The model provides a computational, neurally based synthesis of prior learning theories that predicts changes in medial septal activity based on the novelty of stimulus events.     

Effects of fimbria-fornix transection on calpain and choline acetyl transferase activities in the septohippocampal pathway

The ability of fimbria-fornix bilateral axotomy to elicit calpain and caspase-3 activation in the rat septohippocampal pathway was determined using antibodies that selectively recognize either calpain- or caspase-cleaved products of the cytoskeletal protein alphaII-spectrin. Radioenzymatically determined choline acetyl transferase (ChAT) activity was elevated in the septum at day 5, but reduced in the dorsal hippocampus at days 3, 5 and 7, after axotomy. Prominent accumulation of calpain-, but not caspase-3-, cleaved spectrin proteolytic fragments was observed in both the septum and dorsal hippocampus 1-7 days after axotomy. ChAT-positive neuronal cell bodies in the septum also displayed calpain-cleaved spectrin indicating that calpain activation occurred in cholinergic septal neurons as a consequence of transection of the septohippocampal pathway. Calpain-cleaved alphaII-spectrin immunoreactivity was observed in cholinergic fibers coursing through the fimbria-fornix, but not in pyramidal neurons of the dorsal hippocampus, suggesting that degenerating cholinergic nerve terminals were the source of calpain activity in the dorsal hippocampus following axotomy. Accumulation of calpain-cleaved spectrin proteolytic fragments in the dorsal hippocampus and septum at day 5 after axotomy was reduced by i.c.v. administration of two calpain inhibitors. Calpain inhibition partially reduced the elevation of ChAT activity in the septum produced by transection but failed to decrease the loss of ChAT activity in the dorsal hippocampus following axotomy. These findings suggest that calpain activation contributes to the cholinergic cell body response and hippocampal axonal cytoskeletal degradation produced by transection of the septohippocampal pathway.     

Acetylcholine levels increase in rat hippocampus following acute septal lesions: Evidence for interactions between cholinergic and noncholinergic neurons

Acute septal lesions in rat brain resulted in elevation of the amount of particle-bound acetylcholine in the hippocampus irrespective of the extent of damage to the cholinergic septohippocampal projection. Changes in the high affinity choline uptake in the hippocampus were, however, proportional to the degree of destruction of this projection. The results are discussed in terms of possible interactions between the cholinergic and noncholinergic pathways in the system investigated.     

Co-expression of alpha7 and beta2 nicotinic acetylcholine receptor subunit mRNAs within rat brain cholinergic neurons

Nicotine enhances cognitive and attentional processes through stimulation of the basal forebrain cholinergic system. Although muscarinic cholinergic autoreceptors have been well characterized, pharmacological characterization of nicotinic autoreceptors has proven more difficult. The present study used double-labeling in situ hybridization to determine expression of nicotinic acetylcholine receptor (nAChR) subunit mRNAs within basal forebrain cholinergic neurons in order to gain information about possible nAChR autoreceptor properties. Cholinergic cells of the mesopontine tegmentum and striatal interneurons were also examined, as were septohippocampal GABAergic neurons that interact with cholinergic neurons to regulate hippocampal activity. alpha7 and beta2 nAChR mRNAs were found to be co-expressed in almost all cholinergic cells and in the majority of GABAergic neurons examined. alpha4 nAChR mRNA expression was restricted to cholinergic cells of the nucleus basalis magnocellularis, and to non-cholinergic cells of the medial septum and mesopontine tegmentum.These data suggest possible regional differences in the pharmacological properties of nicotinic autoreceptors on cholinergic cells. Whereas most cholinergic cells express rapidly desensitizing alpha7 homomers or alpha7beta2 heteromers, cortical projection neurons may also express a pharmacologically distinct alpha4beta2 nAChR subtype. There may also be differential nAChR regulation of cholinergic and non-cholinergic cells within the mesopontine tegmentum that are implicated in acquisition of nicotine self-administration.