Dopaminergic regulation of theta activity of septohippocampal neuron in the awake rabbit

The effects of dopamine reuptake blocker nomifensine and nonselective antagonist of dopamine receptors haloperidol on the theta rhythmicity of the medial septal neurons and hippocampal EEG were investigated in the rabbit. Bilateral intracerebroventricular infusion of nomifensine (9 micrograms in each ventriculus) produced an increase in both the rate of firing and the theta modulation of medial septal neurons; the theta power of the hippocampal EEG also augmented. The degree of neuronal theta stability (time constant of damping, tao theta) significantly increased. The frequency of rhythmic bursts in the neuronal firing also substantially elevated. The amplitude, regularity and frequency of theta waves in the hippocampal EEG also increased. The antagonist haloperidol (12.5 mg) caused the opposite effect. The theta activity of medial septal neurons and the theta power of the hippocampal EEG decreased after haloperidol injection. Theta rhythmicity of septal neurons significantly diminished, the rate of rhythmic bursts in the neuronal firing also decreased, although not substantially. The theta amplitude and regularity in the hippocampal EEG also decreased. Effects of both drugs built up rapidly and then gradually attenuated. Nomifensine infusion against the background of exposure to haloperidol provoked neither increasing neuronal firing rate, nor elevating theta activity. These finding suggest that dopaminergic system produces activation of the septohippocampal system in situations that require selective attention to functionally important information.     

Cholinergic Plasticity of Oscillating Neuronal Assemblies in Mouse Hippocampal Slices

The mammalian hippocampus expresses several types of network oscillations which entrain neurons into transiently stable assemblies. These groups of co-active neurons are believed to support the formation, consolidation and recall of context-dependent memories. Formation of new assemblies occurs during theta- and gamma-oscillations under conditions of high cholinergic activity. Memory consolidation is linked to sharp wave-ripple oscillations (SPW-R) during decreased cholinergic tone. We hypothesized that increased cholinergic tone supports plastic changes of assemblies while low cholinergic tone favors their stability. Coherent spatiotemporal network patterns were measured during SPW-R activity in mouse hippocampal slices. We compared neuronal activity within the oscillating assemblies before and after a transient phase of carbachol-induced gamma oscillations. Single units maintained their coupling to SPW-R throughout the experiment and could be re-identified after the transient phase of gamma oscillations. However, the frequency of SPW-R-related unit firing was enhanced after muscarinic stimulation. At the network level, these changes resulted in altered patterns of extracellularly recorded SPW-R waveforms. In contrast, recording of ongoing SPW-R activity without intermittent cholinergic stimulation revealed remarkably stable repetitive activation of assemblies. These results show that activation of cholinergic receptors induces plasticity at the level of oscillating hippocampal assemblies, in line with the different role of gamma- and SPW-R network activity for memory formation and –consolidation, respectively.     

Overnight Fasting Regulates Inhibitory Tone to Cholinergic Neurons of the Dorsomedial Nucleus of the Hypothalamus

The dorsomedial nucleus of the hypothalamus (DMH) contributes to the regulation of overall energy homeostasis by modulating energy intake as well as energy expenditure. Despite the importance of the DMH in the control of energy balance, DMH-specific genetic markers or neuronal subtypes are poorly defined. Here we demonstrate the presence of cholinergic neurons in the DMH using genetically modified mice that express enhanced green florescent protein (eGFP) selectively in choline acetyltransferase (Chat)-neurons. Overnight food deprivation increases the activity of DMH cholinergic neurons, as shown by induction of fos protein and a significant shift in the baseline resting membrane potential. DMH cholinergic neurons receive both glutamatergic and GABAergic synaptic input, but the activation of these neurons by an overnight fast is due entirely to decreased inhibitory tone. The decreased inhibition is associated with decreased frequency and amplitude of GABAergic synaptic currents in the cholinergic DMH neurons, while glutamatergic synaptic transmission is not altered. As neither the frequency nor amplitude of miniature GABAergic or glutamatergic postsynaptic currents is affected by overnight food deprivation, the fasting-induced decrease in inhibitory tone to cholinergic neurons is dependent on superthreshold activity of GABAergic inputs. This study reveals that cholinergic neurons in the DMH readily sense the availability of nutrients and respond to overnight fasting via decreased GABAergic inhibitory tone. As such, altered synaptic as well as neuronal activity of DMH cholinergic neurons may play a critical role in the regulation of overall energy homeostasis.     

Effects of hydrocortisone on electrical activity of the cat spinal cord

The effect of the corticosteroid hormone hydrocortisone on electrical activity in the lumbosacral portion of the spinal cord was studied in acute experiments on cats anesthetized with urethane and chloralose and immobilized with succinylcholine. The amplitude of mono- and polysynaptic discharges arising in the ventral roots in response to stimulation of various afferents of the animal's hind limb was increased by a statistically significant degree after intravenous injection of the hormone. The potentiating action of the hormone was strongest and most stable with respect to early and late postsynaptic potentials of the spinal cord. The dorsal cord potentials were not significantly changed by hydrocortisone. Spontaneous unit activity in the intermediate nucleus of the spinal cord rose sharply after administration of hydrocortisone. Before the action of the hormone the mean frequency of spontaneous discharges of 46 neurons was 7.91/sec, rising to 20/sec after the injection. The number of neurons with a high spontaneous firing rate also was increased. Prolonged extracellular recording of the spontaneous activity of the same neuron before and after administration of hydrocortisone also revealed a marked increase in the frequency of its discharges. The results are evidence of the activating effect of hydrocortisone on spinal interneuronal activity.     

Sensory reactions of hippocampal neurons in rabbit during functional suppression of theta rythm- controlling structures

Responses to sensory stimuli were analyzed in hippocampal CA1 neurons of unanesthetized rabbits in chronic experiments before and after reversible functional blockade of the median raphe nucleus (MR) and medial septal area (MS-DB) by local microinjections of anesthetic lidocaine. The MR blockade, which resulted in an enhancement of theta-modulation of the background activity of the hippocampal neurons, was followed by a depression of sensory responsiveness (only 46.7% of the neurons reactive before the blockade retained their responses). Reactions of all types were blocked, diminished, or inverted, but inhibitory responses were affected most severely. Lidocaine injection into the MS-DB, which blocked also all brain stem afferents ascending to the hippocampus via the MS-DB input, resulted in the total absence of theta-modulation; however, responsiveness to sensory stimuli remained relatively high (76.7% of the responses were preserved); on-effects were especially resistant to the MS-DB blockade. Comparison of evoked activity in two conditions of continuous theta rhythm generation (physostigmine injection and MR blockade) revealed striking similarities. This suggests that the theta-suppressing influence of the MR (presumably serotonergic) is primarily actualized through the control of cholinergic septo-hippocampal theta-generating mechanism. The results provide support for the view that the theta-rhythm acts like an active filter in information processing performed by hippocampal neurons.     

Hippocampal Membranes Contain a Neurotrophic Activity That Stimulates Cholinergic Properties of Fetal Rat Septal Neurons Cultured Under Serum-Free Conditions

Primary cultures of fetal rat septal neurons were used to identify a membrane-associated cholinergic neurotrophic activity. Under serum-free culture conditions, approximately 98% of the septal cells are neurons, and approximately 6% of the neurons are cholinergic as determined immunocytochemically. Crude membranes prepared from rat hippocampal homogenates stimulate choline acetyltransferase (ChAT) activity in treated septal neurons. The membrane-associated trophic activity is apparent at lower protein concentrations than activity present in the soluble fraction and is unevenly distributed in various brain regions; it is highest in hippocampus and striatum and negligible in cerebellum. Membrane trophic activity is developmentally regulated, is heat and trypsin sensitive, and increases the rate of expression of ChAT in septal neurons. Upon gel filtration chromatography of a high-salt membrane extract, trophic activity elutes as a broad peak in the 500 kilodalton (kD) molecular mass range. Stimulation of septal neuronal ChAT activity by either crude membranes or partially purified preparations is not inhibited by antibodies against nerve growth factor (NGF), and its maximal activity is additive to maximally active doses of NGF. The results indicate that hippocampal membranes contain cholinergic neurotrophic activity which may be important for the development of septal cholinergic neurons.     

Corticotropin-Releasing Factor Administered Centrally, but Not Peripherally, Stimulates Hippocampal Acetylcholine Release

Abstract: In addition to corticotropin-releasing factor's well-known role in mediating hormonal and behavioral responses to stress, this peptide also reportedly affects arousal and cognition, processes that classically have been associated with forebrain cholinergic systems. Corticotropin-releasing factor stimulation of cholinergic neurons might thus provide a mechanism for this peptide's cognitive effects. To examine this possibility, the present experiments characterize the effect of corticotropin-releasing factor on cholinergic neurotransmission, using in vivo microdialysis to measure hippocampal acetylcholine release. Corticotropin-releasing factor (0.5–5.0 µg/rat intracerebroventricularly) was found to increase dialysate concentrations of acetylcholine in a dose-dependent manner in comparison with a control injection, the ovine peptide having a greater effect than the same dose of the human/rat peptide. This effect was found to be centrally mediated, independent of the peripheral effects of an exogenous corticotropin-releasing factor injection; subcutaneous injections of the peptide increased plasma concentrations of corticosterone, the adrenal hormone ultimately secreted in the rat's stress response, to the same level as did the central injections, without affecting hippocampal acetylcholine release. These results demonstrate that corticotropin-releasing factor, acting centrally, regulates hippocampal cholinergic activity, and suggest that corticotropin-releasing factor/acetylcholine interactions may underlie some of the previously identified roles of these neurotransmitters in arousal, cognition, and stress.     

Effect of a vasopressin analog on the chemoreactive properties of sensorimotor cortex neurons

Subcutaneous injection of 10 micrograms desglycilargininvasopressin (DG-AVP) does not alter the mean frequency of background unit activity of sensorimotor cortical neurons. However, the pattern of impulse activity is essentially changed. At the same time the reactions of sensorimotor cortical neurons to microiontophoretic administration of acetylcholine and noradrenaline experience definite changes. It is suggested that the DG-AVP-induced changes in chemoreactive properties of neurons underlie the effect of this peptide on the learning and memory.     

The effect of cobrotoxin on cholinergic neurons in the mouse.

By using multiple time-point constant-rate infusions of deuterium-labeled phosphorylcholine, appropriate kinetic parameters were obtained for use in the calculation of the turnover rate of acetylcholine (TRACh) in selected mouse brain regions. After obtaining these data, the relationship between the analgesic agent cobrotoxin (CT) and the activity of central cholinergic neurons was investigated by determination of TRACh in selected mouse brain regions 3 hours following intracerebroventricular (i.c.v.) injection of CT. There were no obvious changes in the concentrations of ACh and choline (Ch) in the cortex, hippocampus, hypothalamus, midbrain, striatum, or thalamus of the mouse after injection of an analgesic dose of CT (2 micrograms, i.c.v.). TRACh in the thalamus and the striatum were significantly increased, as compared to controls. On the other hand, i.c.v. injection of CT was found to significantly reduce TRACh in the hippocampus and midbrain. These results suggest that the activity of hippocampal and midbrain cholinergic neurons is suppressed by CT, whereas the activity of striatal and thalamic cholinergic neurons is increased by CT at a time when a maximum analgesic response to CT is expressed.     

Cholinergic Control of Nerve Growth Factor in Adult Rats: Evidence from Cortical Cholinergic Deafferentation and Chronic Drug Treatment

Abstract: It is well documented that nerve growth factor (NGF) plays an important role in maintaining functions of cholinergic basal forebrain neurons. In the present study, we tested the hypothesis that cholinergic activity controls NGF levels in cholinoceptive neurons of the cerebral cortex and hippocampus. To address that question, we used both cholinergic deafferentation of cerebral cortex and hippocampus by cholinergic immunolesion with 192IgG-saporin and chronic pharmacological treatment of sham-treated and immunolesioned rats with the cholinergic agonist pilocarpine and the cholinergic antagonist scopolamine. We observed an increase in NGF protein levels in the cortex and hippocampus after cholinergic immunolesions and also after muscarinic receptor blockade by chronic intracerebroventricular scopolamine infusion in sham-treated rats after 2 weeks. There was no further increase in the accumulation of NGF after scopolamine treatment of immunolesioned rats. Chronic infusion of pilocarpine had no effect on cortical and hippocampal NGF protein levels in sham-treated rats. In rats with cholinergic immunolesions, however, pilocarpine did prevent the lesion-induced accumulation of NGF. There was no effect of cholinergic lesion and drug treatment on cortical or hippocampal NGF mRNA levels, consistent with the importance of NGF retrograde transport as opposed to its de novo synthesis. This study provides strong evidence for the hypothesis that there is cholinergic control of cortical and hippocampal NGF protein but not mRNA levels in adult rats.     

Electrophysiological and morpho-histochemical study of action of adrenalectomy on hippocampal neurons

Chronic insufficiency of adrenal hormones is a pathology leading to brain dysfunction. By electrophysiological approach there were studied mechanisms of adaptation of neural networks to chronic hormonal deprivation by extracellular recording of the single spike activity of hippocampal neurons (HN), which was caused by high-frequency stimulation of the entorhinal cortex (EC) in rats with unilateral removal of adrenal (adrenalectomy—AE). The balance of excitatory and inhibitory responses recorded in intact rat HN underwent characteristic changes in dynamics of development of neurodegeneration: the inhibitory responses dominating in norm were decreased in all AE terms (from 42% to 25% by 18 weeks). On the contrary, the minimal percentage of excitatory responses in norm was sharply increased at 25–27 days after AE (from 17% to 60%), by indicating a possible increase in cholinergic neurotransmission. The high level of the mean frequency of peristimulus spiking was recorded from the 25–27th day to the 18th week after AE, which indicates the presence of the high level of glutamate or the expressed activation of NMDA receptors. On the whole, the ratio of the excitatory/inhibitory HN responses suggests discrepancy of neural activity in EC HN chains under the AE conditions. Histochemical analysis has shown an increased sensitivity to AE in the CA1 area neurons. After disruption of neuronal structure by the 5th day of AE, 25–27 days after AE, proliferation of cellular elements was observed in the CA1 area, due which the complete filling of the “devastated” areas of hippocampus and a sharp enhancement of phosphatase activity occurred by 8-10 weeks in neuronal nuclei of the dentate gyrus. By 18 weeks after AE, most neurons in the CA1 area were subjected to chromatolysis with a fall of phosphatase activity. The presented make certain contribution to understanding of mechanisms of control of cognitive function and brain plasticity with interconnection with hormonal factors.     

Melanin concentrating hormone induces hippocampal acetylcholine release via the medial septum in rats

Among various actions of melanin concentrating hormone (MCH), its memory function has been focused in animal studies. Although MCH neurons project to various areas in the brain, one main target site of MCH is hippocampal formation for memory consolidation. Recent immunohistochemical study shows that MCH neurons directly project to the hippocampal formation and may indirectly affect the hippocampus through the medial septum nucleus (MS). It has been reported that sleep is necessary for memory and that hippocampal acetylcholine (ACh) release is indispensable for memory consolidation. However, there is no report how MCH actually influences the hippocampal ACh effluxes in accordance with the sleep–wake cycle changes. Thus, we investigated the modulatory function of intracerebroventricular (icv) injection of MCH on the sleep–wake cycle and ACh release using microdialysis techniques. Icv injection of MCH significantly increased the rapid eye movement (REM) and non-REM episode time and the hippocampal, not cortical, ACh effluxes. There was a significant correlation between REM episode time and hippocampal ACh effluxes, but not between REM episode time and cortical ACh effluxes. Microinjection of MCH into the MS increased the hippocampal ACh effluxes with no influence on the REM episode time. It appears that the effect sites of icv MCH for prolongation of REM episode time may be other neuronal areas than the cholinergic neurons in the MS. We conclude that MCH actually increases the hippocampal ACh release at least in part through the MS in rats.     

Effect of anticholinergic drugs alone and in combination with nembutal on burst theta-neurons of the rabbit septum

Activity of neurones with rhythmic theta-bursts was recorded in the medial septum--diagonal band complex of the waking rabbits with intact and deafferented septum. Effects of anticholinergic (scopolamine, atropine) and cholinomimetic (physostigmine) drugs were investigated after i.v. injection. Cholinoblocking drugs in doses, suppressing the theta-rhythm in the hippocampal EEG, eliminated rhythmic activity in some cells with weak theta-modulation. Theta-bursts persisted in cells with stable continuous rhythmicity, though its regularity decreased in some of them. Strong reticular or sensory stimulation evoked an increase of burst frequency, involvement of additional septal cells into rhythmic activity and appearance of the theta-rhythm in the hippocampal EEG. Neither anticholinergic, nor cholinomimetic drugs influenced the frequency and basic characteristics of theta-bursts in any condition tested. The anticholinergic drugs have no selective effect upon low-frequency theta-bursts. The septohippocampal connections contain a significant non-cholinergic component. The theoretical concept of the septum as a sole source of the whole frequency band of the theta-rhythm is proposed.     

SODIUM-DEPENDENT HIGH AFFINITY CHOLINE UPTAKE: A REGULATORY STEP IN THE SYNTHESIS OF ACETYLCHOLINE

The sodium-dependent high affinity choline uptake into synaptosomes from rat brain has been studied after in vivo treatments which would alter the activity of cholinergic neurons. We utilized a number of treatments to reduce the activity of cholinergc neurons in the brain. Administration of pentobarbital (65 mg/kg), chloral hydrate (40 mg/kg) and γbutyrelactone (750 mg/kg) caused a 50-80% reduction in sodium-dependent high affinity choline uptake in several brain regions (30 min). This depression was not found 24 h after injection. Interruption of the cholinergic septal-hippocampal or habenuleinterpeduncular tracts by lesions (10 min-1 h) also caused a similar, large reduction in sodium-dependent high affinity choline uptake in the hippocampus and the interpeduncular nucleus respectively. We reversed the inactivity after pentobarbital administration by direct electrical stimulation of the cholinergic septal-hippocampal tract. Stimulation (40 Hz) for 10-15 min completely reversed the depression in sodium-dependent high affinity choline uptake. Stimulation at lower frequencies or for shorter times caused a partial reversal. Administration of pentylenetetrazol (75 mg/kg), a convulsant, was utilized to increase the activity of central cholinergic neurons. After drug administration, we found a large (60%) increase in sodium-de-pendent high affinity choline uptake. This increase was not found in the hippocampus when cholinergic afferents were interrupted by septal lesion prior to drug administration. We also examined the uptake after administration of cholinergic drugs. Oxotremorine (0.75 mg/kg), a muscarinic agonist which reduces acetylcholine release and turnover, caused a reduction in uptake. On the other hand, administration of scopolamine (5 mg/kg), a cholinergic antagonist which increases acetylcholine turnover, caused an increase in sodium-dependent high affinity choline uptake. Addition of any drug utilized, drectly to uptake samples, did not alter uptake. We examined the conversion of [³H]choline to [³H]acetylcholine in hippocampal synaptosomes after septal lesion, pentylenetetrazol administration and in untreated controls. In all cases, 60-70% of the total sodium-dependent tritium content was present as [³H]acetylcholine. Evidence was presented that homoexchange is not or is less involved in choline uptake than in GABA uptake. A kinetic analysis of sodium-dependent high affinity choline uptake was performed after all treatments. We found changes in V_max, after all treatments, which were consistently in the same direction as the alterations in activity. The proposal is made that the sodium-dependent high affinity choline uptake is coupled to cholinergic activity in such a way as to regulate the entry of choline for the maintenance of acetylcholine synthesis. The findings also lead us to propose that sodium-dependent high affinity choline uptake in vitro be utilized as a rapid, relative measure of the activity of cholinergic nerve terminals in vivo.     

Background neuronal activity in thenucleus supraopticus and its modifications under the influence of parathyroid hormone

In experiments on anesthetized cats, we found that i. v. injection of 5.0 U/kg of parathyroid hormone (PTH) results in modifications of the statistical parameters of the neuronal impulse activity in thenucleus supraopticus (SO) of the hypothalamus. Sliding frequency graphs, histograms of interspike intervals, autocorrelograms, and serial correlation coefficients were plotted and calculated before and after PTH injections; their comparison demonstrates that the hormone significantly modulates the temporal organization of spike trains generated by the neurons of this nucleus. We observed that PTH mostly activated SO neurons and diminished the level of spike grouping in their activity. The effect of PTH to a certain level depended on the initial frequency of background activity: an increase in the spiking frequency was typical of primarily dominating “low-frequency” neurons, while “high-frequency” units were mostly inhibited. The possible mechanisms of the observed modifications are discussed.     

Ultrastructural localization of acetylcholinesterase in the synganglion of the tick,Dermacentor variabilis (Say)

Summary Light- and electron-microscopic enzyme cytochemistry was used to localize acetylcholinesterase (AChE) activity in the synganglion (brain) of the tick Dermacentor variabilis. High AChE activity was observed throughout the neuropil as well as adjacent to most neuronal perikarya. Intracellular activity was not observed by light microscopy. By electron microscopy, reaction product was localized at the plasma membrane of glia and neurons. Enzyme activity was not associated with the olfactory globuli neurons. In other types of neurons, small amounts of reaction product were observed in the Golgi apparatus and nuclear envelope. Large neurosecretory neurons contained activity that appeared to be associated with deep invaginations of the plasma membrane as well as intracellular membranes. AChE activity was also associated with processes of both neurons and glia. In most peripheral nerves AChE activity was associated with virtually all axons. Clearly then, AChE is associated with glia and non-cholinergic neurons as well as with presumed cholinergic neurons. The widespread localization and large amounts of AChE in the tick brain exceeds that reported for other invertebrates and vertebrates. As has been suggested for other animals, AChE in the tick brain may have functions in addition to its known role in cholinergic neurotransmission.     

Modulation of neuronal impulse activity of the anterior hypothalamus as a functional basis of the mechanisms underlying hypothalamic control

We examined the neuronal activity of hypothalamic neurons in acute experiments on cats under ketamine anesthesia. Using glass microelectrodes, we extracellularly recorded the impulse activity (IA) of neurons of the anterior hypothalamus in the absence of controlled influences (background IA, BIA) and after stimulation of evolutionary heterogeneous zones of the brain cortex projecting to the hypothalamus (hippocampal CA3 area, pyriform, cingular, and proreal gyri). Electrical 5-sec-long stimuli were applied with frequencies of 12, 30, or 100 sec⁻¹. In another experimental series, we recorded changes in the IA of hypothalamic neurons induced by visceral stimuli (heating or cooling by 7°C of the foot pad, cooling of the body of the animal, and infusions of 5% glucose, 0.2% NaCl, 3.0% NaCl, or phenylephrine in the carotid artery), modeling in such a way shifts of the constants of homeostasis within physiological limits. We also compared the parameters of neuronal BIA and stimulation-influenced IA in equal epochs of the analysis and classified the types of BIA. About 50% of the cells of the total studied sampling of hypothalamic neurons responded by a considerable modulation of their BIA with a significant change in the frequency in the course of and after stimulations of the above-mentioned modalities. In some neurons after cortical or visceral stimulation, a significant transformation of the temporal structure of the IA with no changes in the mean frequency occurred. We hypothesize that stimulation-induced transformation of the IA pattern with preservation of the mean discharge frequency can be one of the modes of encoding of information necessary for triggering of one efferent reaction or another, which are controlled by the hypothalamus. Examination of the BIA parameters of subcortical neurons, as well as comparison of the parameters of such an activity with the localization of cells and with the modality of stimulation that leads to modification of the IA, should allow one to reveal reasons for the formation and modification of the IA on neurons of the anterior hypothalamus. Since functional peculiarities of the neurons correlate with their BIA pattern, such data can provide an insight into the functional bases of the neurophysiological mechanisms underlying regulatory functions of the hypothalamus. Neirofiziologiya/Neurophysiology, Vol. 37, Nos. 5/6, pp. 463–474, September–December, 2005.     

Effects of dopaminergic drugs and acute medial forebrain bundle lesions on striatal acetylcholine levels.

Placement of radio frequency lesions in the medial forebrain bundle resulted in a 50% depletion of striatal acetylcholine levels but did not change hippocampal levels. A similar result was obtained with the administration of chlorpromazine, haloperidol and pimozide. When these drugs were administered simultaneously with placement of lesions, there was the same 50% depletion of striatal acetylcholine. Apomorphine reversed the depletion due to lesions. These results suggest that the action of antipsychotic drugs on the cholinergic system in the striatum is primarily due to their action at dopamine receptors rather than a direct action on cholinergic receptors which would be due to their anticholinergic activity.     

Improvement in spontaneous and acquired spatial behaviors following lesions of septal dopaminergic afferents in mice: possible relations with hippocampal cholinergic activity

Recent evidence from pharmacological studies support the view that dopaminergic afferents to the septal complex which originate from the mesencephalic A10 area, exert a tonic inhibitory control over the activity of the septal-hippocampal cholinergic neurons. Accordingly one could predict that the release from such an inhibition by lesion of the septal dopaminergic terminals might improve performance in tasks known to be related to hippocampal cholinergic activity. In order to test this hypothesis mice of the C57BL/6 strain received a bilateral injection of 6-hydroxydopamine in the lateral septal nucleus; they were compared to subjects receiving saline and to unoperated control mice in tests performed in a T-maze: spontaneous alternation, acquisition and reversal of spatial discrimination. In all tasks, performance of experimental subjects was improved relative to controls. However, subsequent experiments showed that this improvement was not observed when visual (light/dark) discrimination was used. Finally, 6-hydroxydopamine injected mice exhibited a substantial increase in hippocampal sodium-dependent high affinity choline uptake (+ 16.7%). These results are discussed in relation to the three main theories concerning the role of the septo-hippocampal complex and cholinergic system in the control of behavior (i.e. Pavlovian internal inhibition, spatial mapping and working memory). Only the theory of spatial cognition seems to account for our present findings.     

Cholinergic mechanism involved in the nociceptive modulation of dentate gyrus

Acetylcholine (ACh) causes a wide variety of anti-nociceptive effects. The dentate gyrus (DG) region of the hippocampal formation (HF) has been demonstrated to be involved in nociceptive perception. However, the mechanisms underlying this anti-nociceptive role have not yet been elucidated in the cholinergic pain-related neurons of DG. The electrical activities of pain-related neurons of DG were recorded by a glass microelectrode. Two kinds of pain-related neurons were found: pain-excited neurons (PEN) and pain-inhibited neurons (PIN). The experimental protocol involved intra-DG administration of muscarinic cholinergic receptor (mAChR) agonist or antagonist. Intra-DG microinjection of 1 μl of ACh (0.2 μg/μl) or 1 μl of pilocarpine (0.4 μg/μl) decreased the discharge frequency of PEN and prolonged firing latency, but increased the discharge frequency of PIN and shortened PIN inhibitory duration (ID). Intra-DG administration of 1 μl of atropine (1.0 μg/μl) showed exactly the opposite effects. According to the above experimental results, we can presume that cholinergic pain-related neurons in DG are involved in the modulation of the nociceptive response by affecting the discharge of PEN and PIN.