A double dissociation of subcortical hippocampal efferents for encoding and consolidation/retrieval of spatial information

CA3 lesions impair encoding, whereas CA1 lesions impair retrieval during learning of a Hebb-Williams maze. CA3 efferents in the fimbria were transected, taking care to spare cholinergic and GABAergic afferents. CA1 efferents in the dorsal fornix were similarly transected. Fimbria transections, but not dorsal fornix transections, resulted in deficits for the encoding of spatial information during learning of a Hebb-Williams maze. Dorsal fornix, but not fimbria, transections resulted in deficits for retrieval of spatial memory during learning of a Hebb-Williams maze. These results reveal a double dissociation for the roles of CA3 and CA1 subcortical efferents in encoding and retrieval processes that mirror the double dissociation seen after excitotoxic lesions of CA1 and CA3. These data provide support for the theory that the cholinergic projections from the septal nuclei modulate the dynamics for encoding and consolidation/retrieval in the hippocampus.     

The Effects of AMPA-induced Lesions of the Septo-hippocampal Cholinergic Projection on Aversive Conditioning to Explicit and Contextual Cues and Spatial Learning in the Water Maze

The environmental context of an animal both subsumes and is associated with the explicit cues that guide its behavioural responses. Recent work in this laboratory suggests that learning about the relationship between the cues which comprise a context depends on the hippocampus. In the present study the role of the cholinergic input to the hippocampus in contextual learning was assessed in rats using a conditioned stimulus/context conditioning paradigm and spatial learning in the Morris water maze. In the former, a place preference apparatus provided the context. The subject was confined in the black chamber and a 'clicker'conditioned stimulus was presented five times in a 20 min period. A trace interval of 5 or 30 s, depending on the group, was interposed between the end of the clicker and a footshock. Theory predicts that animals in the 5 s condition will learn more about the clicker as a predictor of shock and become strongly conditioned, while those in the 30 s condition learn relatively more about the context. Conditioning to the clicker (conditioned stimulus) was measured in a separate lick suppression chamber—presentation of the clicker suppresses drinking, and contextual learning was determined by recording the time spent on the black side of the place preference apparatus when both the black and a familiar white chamber were accessible. Lesions of the medial septum/ diagonal band induced by RS -α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) enhanced contextual learning in this paradigm but disrupted conditioned stimulus conditioning in the 30 s condition. Acquisition of the Morris water maze was largely unimpaired. The results are suggested to reflect a shift towards the use of hippocampal-dependent contextual learning strategies in lesioned animals.     

GABAB receptor blockade enhances theta and gamma rhythms in the hippocampus of behaving rats

The participation of GABA(B) receptors in hippocampal EEG generation was studied by intracerebroventricular (icv) and intracerebral infusions of GABA(B) receptor antagonist p-(3-aminopropyl)-p-diethoxymethyl-phosphinic acid (CGP35348) in freely behaving rats. During awake-immobility, icv CGP35348 induced a theta rhythm and increased gamma waves (30-100 Hz) in the hippocampus. The immobility theta peaked at 6-7 Hz and had a theta phase in CA1 stratum radiatum of approximately 160 degrees with reference to the theta at the alveus, when compared with approximately 130 degrees during walking. Immobility theta power peaks at 6-7 Hz was also found in normal rats, and it was detected in 27% of the EEG segments during immobility. Incidence of immobility theta increased to 87.5% after 480 nmol of CGP35348 icv. Muscarinic antagonist scopolamine (5 mg/kg, ip) suppressed the induction of immobility theta and the gamma power increase after icv CGP35348. CGP35348 icv did not significantly change the hippocampal theta power at 7-8 Hz during walking (theta fundamental), but it increased power at 12-15 Hz, at the second harmonic of theta. CGP35348 icv also increased 30-50 Hz gamma power during walking. Medial septal infusion of CGP35348 (12 nmol in 0.4 microl) increased the power and the frequency of the hippocampal theta second harmonic during walking, but did not increase gamma activity. Infusion of CGP35348 (8 nmol in 0.4 microl) in the hippocampus increased the local gamma activity at 30-100 Hz, but did not induce immobility theta or affect the walking theta rhythm. In conclusion, icv GABA(B) receptor blockade increased an atropine-sensitive input that generated an immobility theta rhythm, while GABA(B) receptor blockade of the medial septum increased atropine-resistant theta harmonics possibly generated by apical dendritic spikes. GABA(B) receptor blockade may enhance cognitive task performance by activating hippocampal theta and gamma rhythms in behaving rats.     

The septal EEG suggests a distributed organization of the pacemaker of hippocampal theta in the rat

Individual neurons in the medial septum and diagonal band fire in phase with, and appear to act as a 'pacemaker' of, the hippocampal theta rhythm. We investigated the relationships of periodic EEG both among various parts of the septum and with dorsal hippocampal theta recorded concurrently in freely moving rats. Most septal sites showed theta rhythm concurrent with hippocampal theta during locomotion. However, periods with theta at hippocampal but not septal sites were more frequent than the reverse. Theta waves in different parts of the septum were synchronized with each other but medial septal sites showed less frequent theta than other sites. The phase delays between medial and lateral septal sites were < 10 ms, suggesting that the hippocampus does not act as a simple relay between the two. Spectral analysis revealed periods (> 5 s) of theta at hippocampal sites co-occurring with rhythms at multiple septal sites that were slower than theta. Even slower were the 'slow septal waves' (mean 2.7 Hz), which were present in the absence of locomotion and did not 'drive' the hippocampus. Our data suggest that the pacemaker of hippocampal theta may best be thought of as a set of functionally differentiated components rather than as a single homogenous unit.     

Behavioural and neurochemical effects of chronic intraventricular injections of nerve growth factor in adult rats with fimbria lesions

Rats received bilateral lesions of the fimbria. These lesions impaired their ability to learn a radial maze. Rats given repeated intraventricular injections of nerve growth factor (NGF, 10 micrograms twice weekly during 4 weeks after the lesion) learned the maze problem more rapidly than rats with the same injury but treated with a control protein (cytochrome c). When retested after a period of 6 weeks without NGF treatment, the performance of NGF-treated and cytochrome c-treated rats with fimbria lesions did not differ. Whereas our previous study showed an increase in choline acetyltransferase (ChAT) activity in the septum and the hippocampus 4 days after the last NGF injection, the present study found that after the retest period (i.e. 10 weeks after the last NGF injection) ChAT activity was increased in the septum but not in the hippocampus. The relationship between the NGF-induced changes in ChAT activity and behaviour is discussed.     

Effects of Pertussis Toxin and Gα-Protein-Specific Antibodies on Phosphoinositide Hydrolysis in Rat Brain Membranes after Cholinergic Denervation and Hippocampal Sympathetic Ingrowth

Cholinergic denervation of the hippocampal formation, via medial septal lesions, induces peripheral noradrenergic fibers, originating from the superior cervical ganglion, to grow into the hippocampus. We have previously reported that cholinergic denervation and hippocampal sympathetic ingrowth differentially affect guanosine-5′-O-(3-thiotriphosphate)- as well as guanosine-5′-O-(3-thiotriphosphate) + carbachol-stimulated polyphosphoinositide hydrolysis, suggesting an alteration in G proteins and/or the entire receptor complex. To examine the type of G protein which may be involved in these effects, rat dorsal hippocampal membranes were preincubated with pertussis toxin in the presence of guanosine-5′-O-(3-thiotriphosphate) and guanosine-5′-O-(3-thiotriphosphate) + carbachol. Pertussis toxin reduced guanosine-5′-O-(3-thiotriphosphate) in all groups, while guanosine-5′-O-(3-thiotriphosphate) + carbachol-stimulated phosphoinositide hydrolysis was reduced in controls and animals without sympathetic ingrowth but not in animals with hippocampal sympathetic ingrowth. This suggests that pertussis toxin-sensitive G proteins may be involved in the mediation of phosphoinositide hydrolysis. To confirm this hypothesis, membranes were preincubated with antibodies to Gαo and Gq/11. The Go antibody significantly decreased guanosine-5′-O-(3-thiotriphosphate) in all groups, while guanosine-5′-O-(3-thiotriphosphate) +carbachol-stimulated phosphoinositide hydrolysis was reduced only in hippocampal sympathetic ingrowth. Impairment of guanosine-5′-O-(3-thiotriphosphate) and carbachol-stimulated phosphoinositide hydrolysis was also decreased in all groups when preincubated with Gq/11 antibody. To determine whether hippocampal sympathetic ingrowth or cholinergic denervation altered the concentration of various G proteins, immunoblotting methodology was utilized. Gq/11 concentrations were found to be equivalent among groups. The density of Go1, Go2, and Go3 isoforms was significantly increased in the cholinergic denervation, while in the hippocampal sympathetic ingrowth only group Go3 was significantly increased. When assessed as total Go protein, density was increased significantly only in the cholinergic denervation group. Overall, these results suggest that hippocampal sympathetic ingrowth and cholinergic denervation induce alterations in phosphoinositide hydrolysis through both the Gq/11 and the Go proteins and that the coupling between muscarinic receptor and G protein is the possible site which affects changes in phosphoinositide turnover. Our results also suggest that cholinergic denervation and hippocampal sympathetic ingrowth may mediate phosphoinositide hydrolysis through an effect on different isoforms of the same G protein.     

Activation of septal 5-HT1A receptors alters spatial memory encoding, interferes with consolidation, but does not affect retrieval in rats subjected to a water-maze task

Using Long-Evans rats tested in a water maze, this study assessed the role of 5-HT1A/5-HT7 receptors of the medial septum in encoding, consolidation, and retrieval of spatial information. The testing protocol (acquisition: daily four-trial sessions over three consecutive days; retention: probe trial on day 4) was first validated by showing that intraseptal infusions of lidocaine (LIDO; 40 microg/0.5 microL) disrupted acquisition and retrieval of the task. 8-OH-DPAT (4 microg/0.5 microL) infused before each acquisition session prevented learning/retention of the platform location, an effect attenuated by pretreatment with the 5-HT1A receptor antagonist WAY 100635. With the 5-HT7 antagonist SB 269970, the 8-OH-DPAT-induced acquisition deficit seemed attenuated, but there was no subsequent retention. When infused immediately, 1, 4, or 6 h after each acquisition session, 8-OH-DPAT did not hinder consolidation. When the infusions were performed 2 h postacquisition, however, consolidation was disrupted. Finally, when infused before a probe trial after drug-free acquisition, 8-OH-DPAT had no effect, suggesting no interference with retrieval processes. We also established that 8-OH-DPAT had no effects when the platform was visible, and altered neither home-cage activity nor anxiety-related behavior (elevated plus-maze). Altogether, these results show that 5-HT1A receptors in the septal region contribute both to declarative-like information encoding and subsequently, within a given postacquisition time window, to its consolidation. They do not participate in the retrieval of recently learned declarative-like information. These observations suggest that 5-HT1A receptors of the medial septum contribute to a serotonin-mediated mechanism involved in the encoding and consolidation, not the retrieval of spatial hippocampal-dependent knowledge. These results might have some relevance to approaches aimed at modifying serotonergic functions in the brain for the treatment of disorders such as depression, anxiety, post-traumatic stress, and amnesia.     

Therapeutic hypothermia achieves neuroprotection via a decrease in acetylcholine with a concurrent increase in carnitine in the neonatal hypoxia-ischemia

Although therapeutic hypothermia is known to improve neurologic outcomes after perinatal cerebral hypoxia-ischemia, etiology remains unknown. To decipher the mechanisms whereby hypothermia regulates metabolic dynamics in different brain regions, we used a two-step approach: a metabolomics to target metabolic pathways responding to cooling, and a quantitative imaging mass spectrometry to reveal spatial alterations in targeted metabolites in the brain. Seven-day postnatal rats underwent the permanent ligation of the left common carotid artery followed by exposure to 8% O₂ for 2.5 hours. The pups were returned to normoxic conditions at either 38°C or 30°C for 3 hours. The brain metabolic states were rapidly fixed using in situ freezing. The profiling of 107 metabolites showed that hypothermia diminishes the carbon biomass related to acetyl moieties, such as pyruvate and acetyl-CoA; conversely, it increases deacetylated metabolites, such as carnitine and choline. Quantitative imaging mass spectrometry demarcated that hypothermia diminishes the acetylcholine contents specifically in hippocampus and amygdala. Such decreases were associated with an inverse increase in carnitine in the same anatomic regions. These findings imply that hypothermia achieves its neuroprotective effects by mediating the cellular acetylation status through a coordinated suppression of acetyl-CoA, which resides in metabolic junctions of glycolysis, amino-acid catabolism, and ketolysis.     

The single place fields of CA3 cells: a two-stage transformation from grid cells

Granule cells of the dentate gyrus (DG) generally have multiple place fields, whereas CA3 cells, which are second order, have only a single place field. Here, we explore the mechanisms by which the high selectivity of CA3 cells is achieved. Previous work showed that the multiple place fields of DG neurons could be quantitatively accounted for by a model based on the number and strength of grid cell inputs and a competitive network interaction in the DG that is mediated by gamma frequency feedback inhibition. We have now built a model of CA3 based on similar principles. CA3 cells receive input from an average of one active DG cell and from 1,400 cortical grid cells. Based on experimental findings, we have assumed a linear interaction of the two pathways. The results show that simulated CA3 cells generally have a single place field, as observed experimentally. Thus, a two-step process based on simple rules (and that can occur without learning) is able to explain how grid cell inputs to the hippocampus give rise to cells having ultimate spatial selectivity. The CA3 processes that produce a single place depend critically on the competitive network processes and do not require the direct cortical inputs to CA3, which are therefore likely to perform some other unknown function.     

Encoding and retrieval of episodic memories: Role of cholinergic and GABAergic modulation in the hippocampus

This research focuses on linking episodic memory function to the cellular physiology of hippocampal neurons, with a particular emphasis on modulatory effects at cholinergic and γ-aminobutyric acid B receptors. Drugs which block acetylcholine receptors (e.g., scopolamine) have been shown to impair encoding of new information in humans, nonhuman primates, and rodents. Extensive data have been gathered about the cellular effects of acetylcholine in the hippocampus. In this research, models of individual hippocampal subregions have been utilized to understand the significance of particular features of modulation, and these hippocampal subregions have been combined in a network simulation which can replicate the selective encoding impairment produced by scopolamine in human subjects. © 1997 Wiley-Liss, Inc.     

Genetic variation in the morphology of the septo-hippocampal cholinergic and GABAergic system in mice. I. Cholinergic and GABAergic markers

In the present study, variations of cholinergic and GABAergic markers in the medial septum/vertical limb of the diagonal band of Broca (MS/vDB) and the hippocampus of eight different inbred mouse strains were investigated. By means of immunocytochemistry against the acetylcholine-synthesizing enzyme choline acetyltransferase (ChAT), the cholinergic neurons were visualized and the number of ChAT-positive neuronal profiles in the MS/vDB was counted. Cholinergic and GABAergic septo-hippocampal projection neurons were detected with a combined retrograde tracing and immunocytochemical approach. In order to quantify the cholinergic innervation of various hippocampal subregions, we estimated the density of acetylcholinesterase (AChE)-containing fibers as visualized by AChE histochemistry. Additionally, the densities of muscarinic receptors (mainly the subtypes M1 and M2) in different hippocampal areas of seven inbred strains were measured by means of quantitative receptor autoradiography. We found significant strain differences for the number of ChAT-positive neurons in the MS/vDB; in the numbers of cholinergic septo-hippocampal projection neurons; in the density of cholinergic fibers in hippocampal subfields CA3c, CA1, and in the dentate gyrus; and in the density of muscarinic receptors in the hippocampus. In contrast, the GABAergic component of the septo-hippocampal projection did not differ between the strains investigated. The number of ChAT-reactive neurons in the MS/vDB was not correlated with either hippocampal cholinergic markers. This might be attributed to different collateralization of cholinergic neurons or to different projections of these neurons to other brain regions. These results show a strong hereditary variability within the septo-hippocampal cholinergic system in mice. In view of the role of the cholinergic system in learning and memory processes, strain differences in cholinergic markers might be helpful in explaining behavioral variation. © 1996 Wiley-Liss, Inc.     

Topographical organization of the thalamic afferent connections to the motor cortex in the cat

The topographical distribution of the cortical afferent connections to the different subdivisions of the motor cortex (MC) was studied in adult cats. The retrograde axonal transport of horseradish peroxidase technique was used. Small single injections of the enzyme were made in the entire MC, including the hidden regions in the depth of the sulcus cruciatus. The areal location and density of the subsequent thalamic neuronal labeling were evaluated in each case. Comparison of the results obtained in the various cases shows that the following: (1) The ventral anterior-ventral lateral complex is the principal thalamic source of afferents to the MC. (2) The ventral medial, dorsal medial, the different components of the posterior thalamic group (lateral, medial, and ventral posteroinferior and suprageniculate nuclei), and the intralaminar, lateral anterior, lateral intermediate, lateral medial, and anteromedial thalamic nuclei are also thalamic sites in which neural projections to the MC arise. (3) The thalamocortical projections to the MC are sequentially organized. The connections arising from the lateral part of the thalamus end in the region of area 4 that is situated medially in the superior lip of the sulcus cruciatus and in the posterior sigmoid gyrus. The projections originating in the most medial thalamic regions terminate in that region of area 6a beta which is located in the medial part of the inferior lip of the cruciate sulcus, and in the anterior sigmoid gyrus. Moreover, the ventral thalamic areas send connections to the most anteriorly located zones of the MC, while the most dorsal thalamic ones project to the most posteriorly located parts of the MC. (4) This shift in the thalamocortical connections is not restrained by cytoarchitectonic boundaries, either in the thalamus or in the cortex. (5) The populations of thalamocortical cells which project to neighboring MC subdivisions exhibit consistent overlapping among themselves. (6) These findings suggest, moreover, that the basal ganglia and the cerebellar projections to the MC through the thalamus are arranged in a number of parallel pathways, which may occasionally overlap.     

The transformation from grid cells to place cells is robust to noise in the grid pattern

Spatial navigation in rodents has been attributed to place‐selective cells in the hippocampus and entorhinal cortex. However, there is currently no consensus on the neural mechanisms that generate the place‐selective activity in hippocampal place cells or entorhinal grid cells. Given the massive input connections from the superficial layers of the entorhinal cortex to place cells in the hippocampal cornu ammonis (CA) regions, it was initially postulated that grid cells drive the spatial responses of place cells. However, recent experiments have found that place cell responses are stable even when grid cell responses are severely distorted, thus suggesting that place cells cannot receive their spatial information chiefly from grid cells. Here, we offer an alternative explanation. In a model with linear grid‐to‐place‐cell transformation, the transformation can be very robust against noise in the grid patterns depending on the nature of the noise. In the two more realistic noise scenarios, the transformation was very robust, while it was not in the other two scenarios. Although current experimental data suggest that other types of place‐selective cells modulate place cell responses, our results show that the simple grid‐to‐place‐cell transformation alone can account for the origin of place selectivity in the place cells. © 2014 Wiley Periodicals, Inc.     

Release of Acetylcholine and Noradrenaline from the Cholinergic and Adrenergic Afferents in Rat Hippocampal CA1, CA3 and Dentate Gyrus Regions

An attempt was made to study the release of acetylcholine (ACh) and noradrenaline and their presynaptic modulation in isolated slice preparations dissected from different subfields of the hippocampus: CA1, CA3 and the dentate gyrus. The slices were perfused and loaded with [³H]choline or with [³H]noradrenaline. The release in response to field stimulation was determined radiochemically and the content of transmitters was assayed by a chemiluminescent method or by HPLC combined with electrochemical detection. After 30 min of loading with [³H]choline there were marked subregional differences in the specific activity of [³H]ACh content. The highest concentration was measured in the dentate gyrus and the lowest in CA3. Evidence was obtained that in all three subfields the cholinergic axon terminals are equipped with inhibitory muscarinic autoreceptors and the noradrenergic terminals with α₂-autoreceptors, as indicated by an increase in transmitter release when the tissue was exposed to selective muscarinic or α₂-adrenoceptor antagonists. In contrast, the cholinergic boutons are not equipped with α₂-adrenoceptors, and noradrenergic terminals do not possess inhibitory muscarinic receptors. It is therefore concluded that while the release of both ACh and noradrenaline is controlled by negative feedback modulation, there is no possibility of establishing a presynaptic inhibitory interaction between the two.     

The role of the medial caudate nucleus, but not the hippocampus, in a matching-to sample task for a motor response

A delayed-match-to-sample task was used to assess memory for motor responses in rats with control, hippocampus, or medial caudate nucleus (MCN) lesions. All testing was conducted on a cheeseboard maze in complete darkness using an infrared camera. A start box was positioned in the centre of the maze facing a randomly determined direction on each trial. On the sample phase, a phosphorescent object was randomly positioned to cover a baited food well in one of five equally spaced positions around the circumference of the maze forming a 180-degree arc 60 cm from the box. The rat had to displace the object to receive food and return to the start box. The box was then rotated to face a different direction. An identical baited phosphorescent object was placed in the same position relative to the start box. A second identical object was positioned to cover a different unbaited well. On the choice phase, the rat must remember the motor response made on the sample phase and make the same motor response on the choice phase to receive a reward. Hippocampus lesioned and control rats improved as a function of increased angle separation used to separate the correct object from the foil (45, 90, 135, and 180 degrees) and matched the performance of controls. However, rats with MCN lesions were impaired across all separations. Results suggest that the MCN, but not the hippocampus, supports working memory and/or a process aimed at reducing interference for motor response selection based on vector angle information.     

Local remapping of place cell firing in the Tolman detour task

The existence of place cells, whose discharge is strongly related to a rat's location in its environment, has led to the proposal that they form part of an integrated neural system dedicated to spatial navigation. It has been suggested that this system could represent space as a cognitive map, which is flexibly used by animals to plan new shortcuts or efficient detours. To further understand the relationships between hippocampal place cell firing and cognitive maps, we examined the discharge of place cells as rats were exposed to a Tolman-type detour problem. In specific sessions, a transparent barrier was placed onto the maze so as to block the shortest central path between the two rewarded end locations of a familiar three-way maze. We found that rats rapidly and consistently chose the shortest alternative detour. Furthermore, both CA1 and CA3 place cells that had a field in the vicinity of the barrier displayed local remapping. In contrast, neither CA1 nor CA3 cells that had a field away from the barrier were affected. This finding, at odds with our previous report of altered CA3 discharge for distant fields in a shortcut task, suggests that the availability of a novel path and the blocking of a familiar path are not equivalent and could lead to different responses of the CA3 place cell population. Together, the two studies point to a specific role of CA3 in the representation of spatial connectivity and sequences.     

Effects of exposure to a predator on behaviour and serotonergic neurotransmission in different brain regions of C57bl/6N mice

Clinical studies and animal models have provided evidence that stress and serotonin may play a role in the aetiology of psychiatric diseases such as depression and anxiety. In addition, reciprocal interactions between stress and serotonergic neurotransmission have been demonstrated. However, the relationships between stress, serotonin and behaviour are far from completely understood. In this integrative study, we aimed to elucidate the effect of the psychological stress model predator exposure on behaviour and serotonergic neurotransmission in mice. We used a high time-resolution microdialysis method to measure extracellular levels of serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in the hippocampus, prefrontal cortex, lateral septum and caudate putamen of C57BL/6N [corrected] mice, before (08:30-10:30 h), during (10:30-11:00 h) and after exposure (11:00-14:00 h) to a rat. Detailed behavioural observations were also made. Rat exposure resulted in behavioural activation, with predominant risk-assessment activities, and in increases in hippocampal, cortical, septal but not striatal 5-HT and 5-HIAA. When rat exposure was repeated on the consecutive day, small behavioural differences and reductions in 5-HIAA levels, but no differences in the 5-HT response, as compared with the first exposure were observed. As increases in 5-HT often coincide with behavioural activation, it was particularly interesting to find that 5-HT also increased in periods when mice only made minor movements such as sniffing, and that an effect of predator stress was absent in the caudate putamen. Our results indicate that the presence of the rat leads to differential activation of serotonergic neurotransmission in higher brain structures, probably involved in the coping response to this potentially life-threatening situation.     

Facilitation of spontaneous and learned spatial behaviours following 6-hydroxydopamine lesions of the lateral septum: a cholinergic hypothesis

Mice received injections of 6-hydroxydopamine (6-OHDA) in the lateral septum; they were tested for spontaneous alternation, acquisition and reversal of a spatial discrimination in a T-maze. In each of these tasks, performance of 6-OHDA lesioned mice was improved relative to controls. Neurochemical analysis revealed that 6-OHDA lesioned mice exhibited a significant increase in the rate of sodium-dependent high affinity choline uptake in the hippocampus. These results are discussed in relation to current theories concerning the role of the septo-hippocampal complex and cholinergic system in the control of behaviour.