GABAergic neurons in the medial septum-diagonal band of Broca (MSDB) are important for acquisition of the classically conditioned eyeblink response

The medial septum and diagonal band of Broca (MSDB) influence hippocampal function through cholinergic, GABAergic, and glutamatergic septohippocampal neurons. Non-selective damage of the MSDB or intraseptal scopolamine impairs classical conditioning of the eyeblink response (CCER). Scopolamine preferentially inhibits GABAergic MSDB neurons suggesting that these neurons may be an important modulator of delay CCER, a form of CCER not dependent on the hippocampus. The current study directly examined the importance of GABAergic MSDB neurons in acquisition of delay CCER. Adult male Sprague–Dawley rats received either a sham (PBS) or GABAergic MSDB lesion using GAT1-saporin (SAP). Rats were given two consecutive days of delay eyeblink conditioning with 100 conditioned stimulus–unconditioned stimulus paired trials. Intraseptal GAT1-SAP impaired acquisition of CCER. The impairment was observed on the first day with sham and lesion groups reaching similar performance by the end of the second day. Our results provide evidence that GABAergic MSDB neurons are an important modulator of delay CCER. The pathways by which MSDB neurons influence the neural circuits necessary for delay CCER are discussed.     

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.     

5-HT1A receptor mRNA and immunoreactivity in the rat medial septum/diagonal band of Broca-relationships to GABAergic and cholinergic neurons

Activation of 5-HT1A receptors results in a variety of physiological responses, depending on their localization on neurons with different phenotypes in the brain. This study investigated the localization of 5-HT1A receptor mRNA and 5-HT1A receptor immunoreactivity in cell bodies of the rat septal complex using in situ hybridization and immunohistochemistry. In adjacent sections of the medial septum/diagonal band of Broca (MSDB), the distribution of cell bodies expressing 5-HT1A receptor mRNA was closely related to cells labeled with oligonucleotide probes to GAD (glutamic acid decarboxylase), VAChT (vesicular acetylcholine transporter) or parvalbumin mRNA. Using antiserum to GAD and antibodies to GABA, 5-HT1A receptor immunoreactivity was demonstrated in a majority of GABAergic cells in the MSDB. 5-HT1A receptor-immunoreactive GABAergic cells in the MSDB were also demonstrated to contain the calcium-binding protein parvalbumin, a marker for septohippocampal projecting GABAergic neurons. In the lateral septum, 5-HT1A receptor immunoreactivity was colocalized with the calcium-binding protein calbindin D-28k, a marker for septal GABAergic somatospiny neurons. 5-HT1A receptor immunoreactivity was also detected in a subpopulation of VAChT-containing cholinergic neurons of the MSDB. In MSDB neurons, colocalization of 5-HT1A and 5-HT2A receptor immunoreactivities was demonstrated. These observations suggest that serotonin via 5-HT1A receptors may represent an important modulator of hippocampal transmission important for cognitive and emotional functions through actions on both GABAergic and cholinergic neurons of the rat septal complex. In addition, 5-HT may exert its effects in the MSDB via cells expressing both 5-HT1A and 5-HT2A receptors.     

Age-related changes in rostral basal forebrain cholinergic and GABAergic projection neurons: relationship with spatial impairment

Both cholinergic and GABAergic projections from the rostral basal forebrain contribute to hippocampal function and mnemonic abilities. While dysfunction of cholinergic neurons has been heavily implicated in age-related memory decline, significantly less is known regarding how age-related changes in codistributed GABAergic projection neurons contribute to a decline in hippocampal-dependent spatial learning. In the current study, confocal stereology was used to quantify cholinergic (choline acetyltransferase [ChAT] immunopositive) neurons, GABAergic projection (glutamic decarboxylase 67 [GAD67] immunopositive) neurons, and total (neuronal nuclei [NeuN] immunopositive) neurons in the rostral basal forebrain of young and aged rats that were first characterized on a spatial learning task. ChAT immunopositive neurons were significantly but modestly reduced in aged rats. Although ChAT immunopositive neuron number was strongly correlated with spatial learning abilities among young rats, the reduction of ChAT immunopositive neurons was not associated with impaired spatial learning in aged rats. In contrast, the number of GAD67 immunopositive neurons was robustly and selectively elevated in aged rats that exhibited impaired spatial learning. Interestingly, the total number of rostral basal forebrain neurons was comparable in young and aged rats, regardless of their cognitive status. These data demonstrate differential effects of age on phenotypically distinct rostral basal forebrain projection neurons, and implicate dysregulated cholinergic and GABAergic septohippocampal circuitry in age-related mnemonic decline.     

Selective immunolesions of CH4 cholinergic neurons do not disrupt spatial memory in rats

Adult male Long-Evans rats were subjected to bilateral lesions of the cholinergic neurons in the nucleus basalis magnocellularis (NBM) by injection of 0.2 or 0.4 microg 192-IgG-saporin in 0.4 microl phosphate-buffered saline. Control rats received an equivalent amount of phosphate-buffered saline. Starting 2 weeks after surgery, all rats were tested for locomotor activity in their home cage, beam-walking performance, T-maze alternation rates (working memory), reference and working memory performance in a water-maze task, and memory capabilities in the eight-arm radial maze task using uninterrupted and interrupted (delay of 2 min, 2 h and 6 h after four arms had been visited) testing procedures. Histochemical analysis showed a significant decrease of acetylcholinesterase (AChE)-positive reaction products (30-66%) in various cortical regions at the 0.2-microg dose. At the dose of 0.4 microg, there was an additional, although weak, damage to the hippocampus (17-30%) and the cingulate cortex (34%). The behavioral results showed only minor impairments in spatial memory tasks, and only during initial phases of the tests (reference memory in the water maze, working memory in the radial maze). The behavioral effects of the dramatic cholinergic lesions do not support the idea of a substantial implication of cholinergic projections from the NBM to the cortex in the memory processes assessed in this study, but they remain congruent with an involvement of these projections in attentional functions.     

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.     

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     

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.     

N-methyl-D-aspartate receptors in the medial septal area have a role in spatial and emotional learning in the rat

Cholinergic and GABAergic neurons in the medial septal/vertical limb of the diagonal band of Broca (MS/vDB) area project to the hippocampus and constitute the septohippocampal pathway, which has been implicated in learning and memory. There is also evidence for extrinsic and intrinsic glutamatergic neurons in the MS/vDB, which by regulating septohippocampal neurons can influence hippocampal functions. The potential role of glutamatergic N-methyl-D-aspartate (NMDA) receptors within the MS/vDB for spatial and emotional learning was studied using the water maze and step-through passive avoidance (PA) tasks, which are both hippocampal-dependent. Blockade of septal NMDA receptors by infusion of the competitive NMDA receptor antagonist D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5) (0.3-5 microg/rat), infused 15 min prior to training, impaired spatial learning and memory at the 5 microg dose of D-AP5, while doses of 0.3 and 1 microg per rat had no effect. The impairment in spatial learning appears not to be caused by sensorimotor or motivational disturbances, or anxiogenic-like behavior. Thus, d-AP5-treated rats were not impaired in swim performance or visuospatial abilities and spent more time in the open arms of the elevated plus-maze. In the PA task, intraseptal D-AP5 infused 15 min before training impaired retention as examined 24 h after training. This impairment was observed already at the 0.3 microg dose, suggesting that NMDA receptors within the MS/vDB may be more important for emotional than spatial memory. In summary, the present data indicate that changes in septal glutamate transmission and NMDA receptor activity can influence activity-dependent synaptic plasticity in the hippocampus and thereby learning and memory.     

Disinhibition of the prefrontal cortex leads to brain-wide increases in neuronal activation that are modified by spatial learning

Deficient prefrontal cortex (PFC) GABA function is hypothesized to play a role in schizophrenia and other psychiatric disorders. In rodents, PFC GABA_A receptor antagonism produces cognitive and behavioral changes relevant to these disorders, including impaired spatial memory assessed with the traditional working/reference memory radial maze task. This aspect of spatial memory does not depend on PFC, suggesting that deficient PFC GABAergic transmission may interfere with non-PFC-dependent cognitive functions via aberrant increases in PFC output. To test this, we assessed whether PFC GABA_A antagonism (50 ng bicuculline methbromide) alters neuronal activation in PFC terminal regions, including the striatum, thalamus, hippocampus, amygdala, and cortical regions, of adult male rats using the immediate early gene, c-Fos, as an activity marker. A subset of these animals were also trained and/or tested on the working/reference memory radial maze task. These treatments caused widespread increases in neuronal activation in animals under baseline conditions, with notable exception of the hippocampus. Furthermore, PFC GABA_A antagonism impaired task performance. In most instances, training and/or testing on the radial maze had no additional effects on neuronal activation. However, in both the hippocampus and rhomboid thalamic nucleus, PFC GABA_A antagonism caused a selective increase in neuronal activation in animals trained on the maze. These results indicate that deficiencies in PFC GABAergic transmission may have widespread impacts on neuronal activity that may interfere with certain PFC-independent cognitive functions. Furthermore, these alterations in activity are modulated by plasticity induced by spatial learning in the hippocampus and rhomboid thalamic nucleus.

     

Grafts of fetal septal cells after cholinergic immunotoxic denervation of the hippocampus: a functional dissociation between dorsal and ventral implantation sites

Three-month-old Long-Evans rats were subjected to intraseptal infusions of 0.8 microg of 192 IgG-saporin followed, 2 weeks later, by intrahippocampal suspension grafts containing fetal cells from the medial septum and the diagonal band of Broca. The suspensions were implanted in the dorsal or the ventral hippocampus. Sham-operated and lesion-only rats were used as controls. Between 18 and 32 weeks after grafting, all rats were tested in a water maze (using protocols placing emphasis on reference memory or on working memory) and an eight-arm radial maze. The lesion produced extensive cholinergic denervation of the hippocampus, as evidenced by reduced acetylcholinesterase-positivity and acetylcholine content. Depending upon their implantation site, the grafts restored an acetylcholinesterase-positive reinnervation pattern in either the dorsal or the ventral hippocampus. Nevertheless, the grafts failed to normalize the concentration of acetylcholine in either region. The cholinergic lesion impaired working memory performance in both the water maze and the radial maze. To a limited degree, reference memory was also altered. Grafts placed in the ventral hippocampus had no significant behavioral effect, whereas those placed in the dorsal hippocampus normalized working memory performance in the water maze. Our data show that infusion of 192 IgG-saporin into the septal region deprived the hippocampus of its cholinergic innervation and altered spatial working memory more consistently than spatial reference memory. Although the cholinergic nature of the graft-induced reinnervation remains to be established more clearly, these results further support the idea of a functional dissociation between the dorsal and the ventral hippocampus, the former being preferentially involved in spatial memory.     

The hormone therapy,Premarin, impairs hippocampus-dependent spatial learning and memory and reduces activation of new granule neurons in response to memory in female rats

Estrogens have been implicated as possible therapeutic agents for improving cognition in postmenopausal women and have been linked to neurodegenerative disorders such as Alzheimer's disease. However, the utility of Premarin (Wyeth Pharmaceuticals, Markham, ON, Canada), a conjugated equine estrogen and the most commonly prescribed hormone therapy, has recently been questioned. The purpose of this study was to investigate the effects of Premarin at 2 different doses (10 or 20 μg) on hippocampus-dependent spatial learning and memory, hippocampal neurogenesis, and new neuronal activation using a rodent model of surgical menopause. Rats were treated daily with subcutaneous injections of Premarin and trained on the spatial working/reference memory version of the radial arm maze. Premarin impaired spatial reference and working learning and memory, increased hippocampal neurogenesis, but either decreased or increased activation of new neurons in response to memory retrieval as indexed by the expression of the immediate early gene product zif268, depending on the maturity of cells examined. This activation of new neurons was related to impaired performance in Premarin-treated but not control-treated female rats. These results indicate that Premarin may be impairing hippocampus-dependent learning and memory by negatively altering the neurogenic environment in the dentate gyrus thus disrupting normal activity of new neurons.     

Electrophysiological characteristics of non-bursting, glutamate decarboxylase messenger RNA-positive neurons of the medial septum/diagonal band nuclei of guinea-pig and rat

Nuclei of the medial septum/diagonal band region of the mammalian forebrain contain neurons that give rise to the septohippocampal pathway, which has separate cholinergic and GABAergic components. This pathway is known to influence hippocampal-dependent memory and learning processes, but the precise role of each component is unclear. In this study, we tested the hypothesis that fast-firing, non-bursting medial septum/diagonal band neurons are GABAergic. We used brain slice preparations from young adult guinea-pigs and rats, or from weanling rats, to perform current-clamp recordings from medial septum/diagonal band neurons. Recorded neurons were injected with biocytin for subsequent visualization with fluorescent avidin, and then hybridized with a 35S-labeled riboprobe for glutamate decarboxylase-67 messenger RNA. As a positive control, guinea-pig cerebellar Purkinje cells were labeled and hybridized with the riboprobe. As expected, labeled Purkinje cells were glutamate decarboxylase-67 messenger RNA positive. Slow-firing, cholinergic (choline acetyltransferase-positive) guinea-pig medial septum/diagonal band neurons were glutamate decarboxylase-67 messenger RNA negative. Contrary to our hypothesis, of the guinea-pig neurons, only three of 11 fast-firing neurons were glutamate decarboxylase-67 positive. Of the rat medial septum/diagonal band neurons, three of four were positive for glutamate decarboxylase-67 messenger RNA.These data suggest that fast-firing, non-bursting neurons of the medial septum/diagonal band, as sampled by sharp-electrode intracellular recordings in brain slices, may be a heterogeneous group of neurons, some of which are GABAergic. Together with recent data demonstrating the presence of another GABAergic marker, parvalbumin, in fast-firing septal neurons, we conclude that GABAergic septohippocampal neurons include a population of fast-firing, non-bursting neurons. The influence of these neurons on the hippocampus is likely to occur on a shorter time-scale and over a wider range of firing frequencies as compared to slowly firing cholinergic septohippocampal neurons.     

Innervation of different peptide-containing neurons in the hippocampus by GABAergic septal afferents

The termination pattern of septohippocampal axons visualized by anterograde transport of Phaseolus vulgaris leucoagglutinin was studied in the hippocampal formation in the rat, with special reference to the innervation of neurons immunoreactive for the neuroactive peptides cholecystokinin, somatostatin or vasoactive intestinal polypeptide. The type I, GABAergic, septohippocampal afferents were shown to terminate on neurons immunoreactive for each of the three peptides. The cholecystokinin-like immunoreactive neurons in all regions, and the somatostatin-immunoreactive cells in stratum oriens of CA1 region were the most preferred targets. Cholecystokinin-immunoreactive cells, especially those in the granule cell layer of the dentate gyrus, were often seen to be contacted by type II (presumed cholinergic) axons as well. The somatostatin-immunoreactive cells in the hilus were also innervated by type I septohippocampal axons, although less frequently than those in stratum oriens of the CA1 subfield. Each type of peptidergic neuron received multiple symmetrical synaptic input from the Phaseolus vulgaris leucoagglutinin-labelled septal afferents, as confirmed by correlated electron microscopy. The majority of these neuropeptide-containing cells are known to be GABAergic, and to have distinct input and output relationships. Thus, the present results demonstrate that the GABAergic septohippocampal pathway can control a wide range of putative inhibitory circuits, and thereby influence the pattern of electrical activity in the hippocampal formation.     

Group I metabotropic glutamate receptor activation produces a direct excitation of identified septohippocampal cholinergic neurons

Septohippocampal cholinergic neurons innervate the hippocampus and provide it with almost its entire acetylcholine. Axon collaterals of these neurons also release acetylcholine within the septum and thereby maintain the firing activity of septohippocampal GABAergic neurons. A loss of septohippocampal cholinergic neurons occurs in various neurodegenerative disorders associated with cognitive dysfunctions. group I metabotropic glutamate receptors have been implicated in septohippocampal-dependent learning and memory tasks. In the present study, we examined the physiological and pharmacological effects of a potent and selective group I metabotropic glutamate receptor (mGluR) agonist S-3,5-dihydroxyphenylglycine (DHPG) on rat septohippocampal cholinergic neurons that were identified in brain slices using a selective fluorescent marker. In whole cell recordings, DHPG produced a reversible, reproducible and a direct postsynaptic and concentration-dependent excitation in 100% of septohippocampal cholinergic neurons tested with an EC(50) of 2.1 microM. Pharmacologically, the effects of DHPG were partially/completely reduced by the mGluR1 antagonists, 7-hydrox-iminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester and (+)-2-methyl-4-carboxyphenylglycine. Addition of the mGluR5 antagonist, 2-methyl-6-(phenylethnyl)pyridine hydrochloride, reduced the remaining response to DHPG, suggesting involvement of both receptor subtypes in a subpopulation of septohippocampal cholinergic neurons. In double-immunolabeling studies, 74% of septohippocampal cholinergic neurons co-localized mGluR1alpha-immunoreactivity and 35% co-localized mGluR5-immunoreactivity. Double-immunolabeling studies at the light and electron-microscopic levels showed that vesicular glutamate transporter 2 terminals make asymmetric synaptic contacts with septohippocampal cholinergic neurons. These findings may be of significance in treatment of cognitive deficits associated with neurodegenerative disorders as a group I mGluR-mediated activation of septohippocampal cholinergic neurons would enhance the release of acetylcholine both in the hippocampus and in the septum.     

Learning and memory deficits after lesions of the nucleus basalis magnocellularis: reversal by physostigmine

The role of the cholinergic nucleus basalis magnocellularis in spatial learning and memory was studied in the rat. Animals received bilateral injections of ibotenic acid (5 micrograms/microliters) into the region of the nucleus basalis magnocellularis. Six weeks postoperatively they were deprived of food and trained for 5 weeks in a 16-arm radial maze in which 9 of the arms were baited with food. The nucleus basalis magnocellularis-lesioned animals showed significant deficits in the acquisition of the task. Further analysis of the data indicated that this was due primarily to a deficit in reference (long-term) as opposed to working (short-term) memory. After the 5-week training period the nucleus basalis magnocellularis-lesioned animals received intraperitoneal injections of physostigmine sulphate (0.5 mg/kg) 30 min before each daily trial for 1 week. This treatment resulted in a significant improvement in the performance of the spatial memory task on all three measures. The ibotenate lesions reduced the activity of choline acetyltransferase by about 40% in the anterior cortex and by 15% in the posterior cortex. Hippocampal choline acetyltransferase activity was not affected, indicating that the septohippocampal cholinergic projection was spared by the lesions. The activity of glutamate decarboxylase was not affected in any of these regions. These results suggest that the cholinergic projections of the nucleus basalis magnocellularis play an important role in the acquisition of a spatial memory task.     

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.     

Infusion of GAT1-saporin into the medial septum/vertical limb of the diagonal band disrupts self-movement cue processing and spares mnemonic function

Degeneration of the septohippocampal system is associated with the progression of Dementia of the Alzheimer’s type (DAT). Impairments in mnemonic function and spatial orientation become more severe as DAT progresses. Although evidence supports a role for cholinergic function in these impairments, relatively few studies have examined the contribution of the septohippocampal GABAergic component to mnemonic function or spatial orientation. The current study uses the rat food-hoarding paradigm and water maze tasks to characterize the mnemonic and spatial impairments associated with infusing GAT1-Saporin into the medial septum/vertical limb of the diagonal band (MS/VDB). Although infusion of GAT1-Saporin significantly reduced parvalbumin-positive cells in the MS/VDB, no reductions in markers of cholinergic function were observed in the hippocampus. In general, performance was spared during spatial tasks that provided access to environmental cues. In contrast, GAT1-Saporin rats did not accurately carry the food pellet to the refuge during the dark probe. These observations are consistent with infusion of GAT1-Saporin into the MS/VDB resulting in spared mnemonic function and use of environmental cues; however, self-movement cue processing was compromised. This interpretation is consistent with a growing literature demonstrating a role for the septohippocampal system in self-movement cue processing.     

The effects of NMDA lesions centered on the postrhinal cortex on spatial memory tasks in the rat

Rats with bilateral N-methyl-D-aspartate lesions centered on the postrhinal cortex (POR) and sham lesions were tested in a series of spatial memory tasks. The POR-lesioned rats were significantly impaired compared with sham rats in the reference memory version of both the water maze and radial arm maze tasks and in the standard radial arm maze working memory task. The POR-lesioned rats displayed a delay-independent impairment in the working memory versions of the water maze and in a delayed nonmatching-to-place (DNMP) version of the radial arm maze task. The POR-lesioned rats were also impaired in a DNMP procedure conducted in the T-maze. These findings indicate that the POR has a delay-independent role in the processing of spatial information.