Medial Septal Area Research Articles

Vasopressin and angiotensin receptors of the medial septal area of the brain in the control of thirst and salt appetite induced by vasopressin in water-deprived and sodium-depleted rats

In this study we investigated the influence of d(CH 2) 5-Tyr (Me)-AVP (A 1AVP) and [Adamanteanacatyl 1,D-ET-D-Tyr 2, Val 4, aminobutyril 6,A 8,9]-AVP (A 2AVP), antagonists of V 1 and V 2 arginine 8-vasopressin (AVP) receptors, respectively, as well as the effects of losartan and CGP42112A, antagonists of angiotensin II (ANGII) AT 1 and AT 2, receptors, respectively, on water and 0.3 M sodium intake induced by water deprivation or sodium depletion (furosemide treatment) and enhanced by AVP injected into the medial septal area (MSA). A stainless steel cannula was implanted into the medial septal area (MSA) of male Holtzman rats AVP injection enhanced water and sodium intake in a dose-dependent manner. Pretreatment with V 1 antagonist injected into the MSA produced a dose-dependent reduction, whereas prior injection of V 2 antagonist increased, in a dose-dependent manner, the water and sodium responses elicited by the administration of AVP. Both AT 1 and AT 2 antagonists administered into the MSA elicited a concentration-dependent decrease in water and sodium intake induced by AVP, while simultaneous injection of the two antagonists was more effective in decreasing AVP responses. These results also indicate that the increase in water and sodium intake induced by AVP was mediated primarily by MSA AT 1 receptors.

Theta driving both inhibits and potentiates the effects of nicotine on dentate gyrus responses

The medial septal area of conscious rats was stimulated through previously implanted electrodes at a frequency of 7.7 Hz for 20 min each day for 7 days to evoke rhythmic slow activity in CA1 at a similar frequency to spontaneous theta. Two weeks later in the anaesthetized rats the effects of a single subcutaneous injection of nicotine (0.4 mg/kg) on fEPSPs, evoked in the dentate gyrus by separate stimulation of the MPP and LPP, were studied and compared with those obtained in controls. Nicotine increased the firing of locus coeruleus neurons and the slope of the fEPSPs evoked by LPP stimulation, but not by MPP stimulation. Prior theta driving considerably increased the effect of nicotine on the responses evoked by stimulation of the MPP and abolished the nicotine-induced potentiation of the responses evoked by stimulation of the LPP. The results are attributed to theta driving increasing the amount of noradrenaline released by nicotine and to noradrenaline producing a beta-adrenoceptor long-lasting potentiation at the medial perforant path synapse and a long-lasting depression at the lateral perforant path synapse.

Anticonvulsant effects of damage to structures involved in seizure induction in rats exposed to soman

In nerve agent research, it is assumed that the regions from which seizure activity is triggered may offer clues for the designing of effective anticonvulsive therapy. In the present study, selective brain lesions were made to identify critical cholinergic pathways and seizure controlling areas involved in the induction of epileptiform activity in rats challenged with soman. The results showed that rats with bilateral aspiration lesion of the seizure controlling substrate, area tempestas (AT) in the piriform cortex, displayed marked anticonvulsant effects, whereas such effects were not seen when substantia nigra was destroyed. Aspiration lesion of the medial septal area (MS) including the vertical limb of the diagonal band nucleus (DBN) caused increased latency to the onset of convulsions, whereas damage to the nucleus basalis magnocellularis (NBM), nucleus accumbens, or both MS and NBM did not cause anticonvulsant effects. Saporin lesion of MS, DBN (horizontal limb), or MS + DBN had no anticonvulsant effects, suggesting that aspiration lesion of MS disrupted pathways beyond cholinergic ones. Severe aphagia/adipsia and reduced body weight occurred in rats with lesions in the septal area. In separate sham operated rats, a strong positive correlation was found between body weight and latency to onset of convulsions in response to soman. Thus, weight loss and a relatively high dose of soman (1.6 × LD 50) in this context may have masked potential anticonvulsant effects among some lesioned animals. It is inferred that MS and AT/piriform cortex occur as prime target areas for induction of seizures by soman.

EFFECTS OF ELECTROLYTIC LESIONS OR CHOLINERGIC BLOCKADE OF THE MEDIAL SEPTAL AREA ON THE SALIVARY SECRETION AND WATER INTAKE INDUCED BY PERIPHERAL PILOCARPINE

Cholinergic receptors are present in the medial septal area (MSA) and the MSA connects with forebrain areas involved in the control of salivary secretion and water intake. In the present study we investigated the effects of electrolytic lesions or the cholinergic blockade of the MSA on the salivary secretion and water intake induced by ip pilocarpine (PILO, 1 mg/kg b. wt.). Male Holtzman rats (280–320 g, n = 7–13/group) with stainless steel cannulas implanted into the MSA or submitted to sham or electrolytic (1 mA × 10 s) MSA lesions (1 or 15 days) were used. Saliva was collected in anesthetized rats using pre-weighed cotton balls inserted into the animal's mouth. Atropine methyl or saline were injected into the MSA 15 min before ip PILO. MSA lesion (1 day) reduced the salivary secretion (334 ± 45 vs. sham: 495 ± 27 mg/7 min) and water intake (2.6±0.4 vs sham: 4.0±0.4 ml/1 h) induced by ip PILO. In 15 day MSA-lesioned rats, ip PILO-induced water intake was still reduced (2.6±0.4 vs. sham: 4.0±0.4 ml/1 h) while the salivary secretion was not different from sham rats. Atropine methyl (4 nmol/0.5 μl) injected into the MSA also reduced PILO-induced salivary secretion (233±49 vs. saline: 489±68 mg/7min) and water intake (1.6±0.4 vs. saline 3.1±0.4 ml/1 h). The results suggest that cholinergic receptors of the MSA are part of the forebrain circuitry involved in salivary secretion and water intake induced by ip pilocarpine. Supported by FAPESP

Effect of Histamine on Muscimol-Induced Working Memory Deficits in Radial Maze Performance

We investigated the participation of γ-aminobutyric acid (GABA) neurons of the medial septal area in eight-arm radial maze performance in rats. The intra-septal injection of muscimol, a GABAA agonist, caused an increase in total error and working memory error. On the other hand, no significant effect was observed with reference memory error. Donepezil and tacrine (cholinesterase inhibitors) antagonized the muscimol-induced spatial memory deficits. Histidine (1500 mg/kg, i.p.) also improved the total error and working memory error induced by muscimol. At this dose, histidine caused a significant increase in the histamine content of the cortex, hippocampus, and hypothalamus in rats. In addition, the intra-hippocampal injection of histamine also antagonized muscimol-induced spatial memory deficits. The practical conclusion is that the GABAA receptor of the medial septal area plays an important role in working memory, and also, the disturbance of working memory induced by muscimol is mediated not only by cholinergic but also by histaminergic systems in the spatial memory of rats.

Glutamatergic synaptic depression by synthetic amyloid β‐peptide in the medial septum

The medial septum/diagonal band region, which participates in learning and memory processes via its cholinergic and GABAergic projection to the hippocampus, is one of the structures affected by beta amyloid (betaA) deposition in Alzheimer's disease (AD). The acute effects of betaA (25-35 and 1-40) on action potential generation and glutamatergic synaptic transmission in slices of the medial septal area of the rat brain were studied using current and patch-clamp techniques. The betaA mechanism of action through M1 muscarinic receptors and voltage-dependent calcium channels was also addressed. Excitatory evoked responses decreased (30-60%) in amplitude after betaA (2 microM) perfusion in 70% of recorded cells. However, the firing properties were unaltered at the same concentration. This depression was irreversible in most cases, and was not prevented or reversed by nicotine (5 microM). In addition, the results obtained using a paired-pulse protocol support pre- and postsynaptic actions of the peptide. The betaA effect was blocked by calcicludine (50 nM), a selective antagonist of L-type calcium channels, and also by blocking muscarinic receptors with atropine (5 muM) or pirenzepine (1 microM), a more specific M1-receptor blocker. We show that in the medial septal area this oligomeric peptide acts through calcium channels and muscarinic receptors. As blocking any of these pathways blocks the betaA effects, we propose a joint action through both mechanisms. These results may contribute to a better understanding of the pathophysiology at the onset of AD. This understanding will be required for the development of new therapeutic agents.

Restoring theta‐like rhythmicity in rats restores initial learning in the Morris water maze

Neural activity often becomes rhythmic during mental processing. But there has been no direct proof that rhythmicity, per se, is important for mental function. We assessed this issue in relation to the contribution of hippocampal theta-frequency rhythmicity to learning in the Morris water maze by blocking theta (and other septal inputs to the hippocampus) and then using electrical stimulation to restore rhythmicity. We injected tetracaine into the medial septal area, and so blocked septal input to the hippocampus in rats throughout 16 consecutive trials in a Morris water maze. Rats with no hippocampal theta also showed no initial learning in the maze. Theta rhythmicity in the supramammillary area remained after septal blockade, and we used this to trigger electrical stimulation of the fornix superior. This substantially restored hippocampal theta-like rhythmicity throughout training at a normal frequency but with abnormal wave forms. This treatment applied throughout training substantially restored initial learning. Fixed frequency (7.7 Hz) stimulation produced rhythmic activity and a brief improvement in learning. Irregular stimulation with an average frequency of 7.7 Hz produced little rhythmicity and little improvement in learning. These results demonstrate that brain rhythmicity, per se, can be important for mental processing even when the detailed information originally carried by neurons is lost and when the reinstated pattern of population firing is not normal. The results suggest that the precise frequency of rhythmicity may be important for hippocampal function. Functional rhythmicity needs, therefore, to be included in neural models of cognitive processing. The success of our procedure also suggests that simple alterations of rhythmicity could be used to ameliorate deficits in learning and memory. (c) 2006 Wiley-Liss, Inc.

Pressor effects of noradrenaline injected into the lateral septal area of unanesthetized rats

The lateral septal area (LSA) is involved in central cardiovascular control. In the present study, we report on the cardiovascular effects of noradrenaline (NA) injection into the LSA of unanesthetized rats, as well as on local receptors and peripheral mechanisms involved in their mediation. Microinjections of NA (9, 15, 21, 27 or 45 nmol) caused long-lasting, dose-related pressor and bradycardic responses in unanesthetized rats. No responses were observed when the dose of 21 nmol of NA was microinjected into medial septal area or lateral ventricle suggesting a main action at the LSA. No changes were observed in arterial pressure and heart rate when NA was injected in the LSA of anesthetized rats. The effects of 21 nmol of NA were abolished by local pretreatment with 10 nmol of the specific α 1-receptor antagonist WB 4101, but were not affected by pretreatment with 10 nmol of the specific α 2-receptor antagonist RX 821002. The magnitude of pressor response to NA in the LSA was increased by i.v. pretreatment with the ganglion blocker pentolinium (10 mg/kg) and significantly reduced by i.v. pretreatment with the V 1-vasopressin receptor antagonist dTyr (CH2)5(Me) AVP (50 μg/kg). No pressor response to NA was observed in hypophysectomized rats. The present observation of α 1-adrenoceptor-mediated pressor responses after local injection of NA confirms earlier evidence of a LSA involvement in central cardiovascular control. Pretreatment with the α 1-adrenoceptor antagonist WB-4101 did not affect baseline blood pressure or heart rate suggesting no tonic involvement of septal adrenergic mechanisms suggesting a modulatory LSA influence on cardiovascular control. Additionally, the blockade of the pressor response by the i.v. pretreatment with a V 1-vasopressin antagonist indicates that noradrenergic LSA mechanisms modulate vasopressin release.

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 μg/rat), infused 15 min prior to training, impaired spatial learning and memory at the 5 μg dose of d-AP5, while doses of 0.3 and 1 μg 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 μg 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.

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

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

Neural Substrates of Psychostimulant-Induced Arousal

Extensive research has provided substantial insight into the neurobiological mechanisms underlying the reinforcing, locomotor-activating and stereotypy-inducing actions of psychostimulants. The diverse behavioral effects of these drugs are superimposed on potent arousal-enhancing actions. Psychostimulant-induced arousal is a prominent contributing factor to the widespread use and abuse of these drugs. Moreover, enhanced arousal may be a critical component of the reinforcing and other behavioral actions of these drugs. Although long overlooked, recent work begins to identify the neural mechanisms involved in psychostimulant-induced arousal. For example, microdialysis studies demonstrate a close relationship between amphetamine-induced waking/arousal and amphetamine-induced increases in norepinephrine and dopamine efflux. Additionally, it is now clear that both norepinephrine and dopamine exert robust wake-promoting actions. The wake-promoting effects of norepinephrine involve synergistic actions of alpha1- and beta-receptors, whereas dopamine-induced waking involves both D1 and D2 receptors. Finally, additional studies have identified subcortical regions involved in the wake-promoting actions of both norepinephrine and amphetamine. These regions include, but may not be limited to, the medial septal area, the medial preoptic area, and the lateral hypothalamus. Combined, these and other observations indicate a prominent involvement of both norepinephrine and dopamine in stimulant-induced arousal via actions within a network of subcortical regions. Although it is clear that both norepinephrine and dopamine contribute to psychostimulant-induced arousal, the degree to which each transmitter system is necessary for the expression of stimulant-induced arousal remains to be fully elucidated.

Frontal cortex lesions eliminate the clock speed effect of dopaminergic drugs on interval timing

Behavioral and pharmacological challenges using methamphetamine (MAP-0.5 and 1.0 mg/kg, i.p.), haloperidol (HAL-0.12 mg/kg, i.p.), and sulfated cholecystokinin octapeptide (CCK-0.05 and 0.1 mg/kg, i.p.) were used to evaluate the effects of excitotoxic lesions of cholinergic cell bodies in the medial septal area and the nucleus basalis magnocellularis, radiofrequency lesions of the fimbria-fornix, and aspiration lesions of the frontal cortex on interval timing in rats trained on a 40-s peak-interval procedure. Results demonstrated that lesions of the nucleus basalis magnocellularis and frontal cortex selectively reduced the modulatory control of clock speed which is likely mediated by dopamine D 2 receptors located on cortico-striatal neurons.

Organization of noradrenergic efferents to arousal‐related basal forebrain structures

Norepinephrine acts within select basal forebrain regions to modulate behavioral state and/or state-dependent processes, including the general regions encompassing the medial septal area, the medial preoptic area, and the substantia innominata. The present study examined the origin and organization of noradrenergic efferents to these basal forebrain regions by using combined immunohistochemical identification of noradrenergic neurons with retrograde tracing. Results indicate that the locus coeruleus provides the majority of noradrenergic input to these regions. Lesser, although at times substantial, contributions from the A1/C1 and A2/C2 adrenergic cell groups were also observed, particularly in the case of the medial preoptic region. Given the prominent state-modulating actions of the locus coeruleus, additional studies examined: 1) lateralization of locus coeruleus efferents to these regions; 2) the topographical organization of basal forebrain-projecting locus coeruleus neurons; and 3) the degree of collateralization of individual locus coeruleus neurons across these regions. Approximately 80-85% of locus coeruleus efferents to these regions project ipsilaterally. In general, basal forebrain-projecting neurons were distributed throughout the entire dorsoventral and rostrocaudal extent of the locus coeruleus. Additionally, a large proportion of locus coeruleus neurons project simultaneously to these basal forebrain terminal fields. Combined, these observations indicate coordinated actions of locus coeruleus neurons across these basal forebrain regions implicated in the regulation of behavioral state and/or state-dependent processes.

Involvement of the Olig2 transcription factor in cholinergic neuron development of the basal forebrain

Cholinergic neurons, which express choline acetyltransferase (ChAT), are a major neuron subset generated in the basal forebrain. Areas presumed to be sites of origin of cholinergic neurons are roughly demarcated by expression of Olig2, a basic helix–loop–helix transcription factor, which includes the medial ganglionic eminence, septal area, and anterior entopeduncular/preoptic area. In the present study, we examined the involvement of Olig2 in cholinergic differentiation. When the Olig2-expressing cells at E12.5 were permanently modified to express the lacZ or EGFP gene by tamoxifen-induced Cre-mediated recombination, the cells marked by reporter gene expression were widely distributed in the basal forebrain by E18.5, some of which expressed neuronal markers. We showed that a small number of cells were double-positive for ChAT and X-gal or EGFP in almost all cases. In addition, the number of ChAT+ cells was reduced to 60% in the Olig2 knockout mouse basal forebrain. No evidence of elevated apoptosis or reduced proliferation was observed in the knockout mouse forebrain. The present study provides the first direct evidence for involvement of the Olig2 gene in cholinergic differentiation in the basal forebrain.

Maternal aggression in Wistar rats: effect of 5-HT2A/2C receptor agonist and antagonist microinjected into the dorsal periaqueductal gray matter and medial septum

The objective of the present study was to assess the role of the 5-HT2A/2C receptor at two specific brain sites, i.e., the dorsal periaqueductal gray matter (DPAG) and the medial septal (MS) area, in maternal aggressive behavior after the microinjection of either a 5-HT2A/2C receptor agonist or antagonist. Female Wistar rats were microinjected on the 7th postpartum day with the selective agonist alpha-methyl-5-hydroxytryptamine maleate (5-HT2A/2C) or the antagonist 5-HT2A/2C, ketanserin. The agonist was injected into the DPAG at 0.2 (N = 9), 0.5 (N = 10), and 1.0 microg/0.2 microl (N = 9), and the antagonist was injected at 1.0 microg/0.2 microl (N = 9). The agonist was injected into the medial septal area (MS) at 0.2 (N = 9), 0.5 (N = 7), and 1.0 microg/0.2 microl (N = 6) and the antagonist was injected at 1.0 microg/0.2 microl (N = 5). For the control, saline was injected into the DPAG (N = 7) and the MS (N = 12). Both areas are related to aggressive behavior and contain a high density of 5-HT receptors. Non-aggressive behaviors such as horizontal locomotion (walking) and social investigation and aggressive behaviors such as lateral threat (aggressive posture), attacks (frontal and lateral), and biting the intruder were analyzed when a male intruder was placed into the female resident's cage. For each brain area studied, the frequency of the behaviors was compared among the various treatments by analysis of variance. The results showed a decrease in maternal aggressive behavior (number of bites directed at the intruder) after microinjection of the agonist at 0.2 and 1.0 microg/0.2 microl (1.6 +/- 0.7 and 0.9 +/- 0.3) into the DPAG compared to the saline group (5.5 +/- 1.1). There was no dose-response relationship with the agonist. The present findings suggest that the 5-HT2A/2C receptor agonist has an inhibitory effect on maternal aggressive behavior when microinjected into the DPAG and no effect when microinjected into the MS. Ketanserin (1.0 microg/0.2 microl) decreased locomotion when microinjected into the DPAG and MS, but did not affect aggressive behavior. We interpret these findings as evidence for a specific role of 5-HT2A/2C receptors in the DPAG in the inhibition of female aggressive behavior, dissociated from those on motor activity.

Neonatal handling and reproductive function in female rats

Neonatal handling induces anovulatory estrous cycles and decreases sexual receptivity in female rats. The synchronous secretion of hormones from the gonads (estradiol (E2) and progesterone (P)), pituitary (luteinizing (LH) and follicle-stimulating (FSH) hormones) and hypothalamus (LH-releasing hormone (LHRH)) are essential for the reproductive functions in female rats. The present study aimed to describe the plasma levels of E2 and P throughout the estrous cycle and LH, FSH and prolactin (PRL) in the afternoon of the proestrus, and the LHRH content in the medial preoptic area (MPOA), median eminence (ME) and medial septal area (MSA) in the proestrus, in the neonatal handled rats. Wistar pup rats were handled for 1 min during the first 10 days after delivery (neonatal handled group) or left undisturbed (nonhandled group). When they reached adulthood, blood samples were collected through a jugular cannula and the MPOA, ME and MSA were microdissected. Plasma levels of the hormones and the content of LHRH were determined by RIA. The number of oocytes counted in the morning of the estrus day in the handled rats was significantly lower than in the nonhandled ones. Neonatal handling reduces E2 levels only on the proestrus day while P levels decreased in metestrus and estrus. Handled females also showed reduced plasma levels of LH, FSH and PRL in the afternoon of the proestrus. The LHRH content in the MPOA was significantly higher than in the nonhandled group. The reduced secretion of E2, LH, FSH and LHRH on the proestrus day may explain the anovulatory estrous cycle in neonatal handled rats. The reduced secretion of PRL in the proestrus may be related to the decreased sexual receptiveness in handled females. In conclusion, early-life environmental stimulation can induce long-lasting effects on the hypothalamus-pituitary-gonad axis.

Sensory Responses of Neurons in the Medial Septal Area in Conditions of Modulation of Theta Activity Using the Alpha-2-Adrenoreceptor Agonist Clonidine

Our previous studies on conscious rabbits showed that administration of the alpha-2-adrenoreceptor agonist clonidine induces dose-dependent changes in theta oscillations in the septohippocampal system. Low doses of clonidine suppressed theta activity, while high doses produced significant potentiation. It was suggested that the different effects of clonidine might be associated with differences in the sensitivities of pre- and postsynaptic alpha-2-adrenoreceptors to clonidine, this agent being a pure agonist of noradrenaline when used at high doses. It was suggested that functional synergism occurs between the activatory reticular formation and the noradrenergic system of the locus ceruleus in controlling the theta rhythm. The present study was performed to identify the nature of the responses of sensory neurons in the medial septal region in conditions of alterations in the magnitude of the theta rhythm induced by different doses of clonidine. Low and high doses of the agonist given bilaterally into the lateral ventricles were found to have different effects on the sensory responses of neurons in the medial septal region. Injection of small clonidine doses (0.5 microg in 5 microl into each lateral ventricle), which decrease theta activity, was found to lead to weakening of activatory processes and enhancement of inhibitory processes in the medial septal region. The number of activatory responses decreased significantly and persisting responses were significantly weakened; inhibitory responses, conversely, were seen more frequently and were significantly more marked. Administration of high clonidine doses (5 microg in 5 microl), which produce sharp increases in theta oscillations, led to significant reductions in the reactivity of cells in the medial septal region to sensory stimuli (from 76.8% in controls to 45% after clonidine), regardless of the nature of the initial responses. Persisting activatory and inhibitory responses were in most cases less marked than the initial responses. These results suggest that alpha-2-adrenoreceptors are involved in controlling the sensory reactivity of neurons in the medial septal region. The impairment of the normal processing of sensory stimuli seen during the continuous generation of rhythmic activity provoked by injection of large clonidine doses supports the role of the theta rhythm in the septohippocampal system as an active filter during the processing and recording of information.

Time course of behavioral changes following basal forebrain cholinergic damage in rats: Environmental enrichment as a therapeutic intervention

The present experiment was designed to study changes in behavior following immunolesioning of the basal forebrain cholinergic system. Rats were lesioned at 3 months of age by injection of the 192 IgG-saporin immunotoxin into the medial septum area and the nucleus basalis magnocellularis, and then tested at different times after surgery (from days 7–500) on a range of behavioral tests, administered in the following order: a nonmatching-to-position task in a T-maze, an object-recognition task, an object-location task, and an open-field activity test. The results revealed a two-way interaction between post-lesion behavioral testing time and memory demands. In the nonmatching-to-position task, memory deficits appeared quite rapidly after surgery, i.e. at a post-lesion time as short as 1 month. In the object-recognition test, memory impairments appeared only when rats were tested at late post-lesion times (starting at 15 months), whereas in the object-location task deficits were apparent at early post-lesion times (starting from 2 months). Taking the post-operative time into account, one can hypothesize that at the shortest post-lesion times, behavioral deficits are due to pure cholinergic depletion, while as the post-lesion time increases, one can speculate the occurrence of a non-cholinergic system decompensation process and/or a gradual degeneration process affecting other neuronal systems that may contribute to mnemonic impairments. Interestingly, when middle-aged rats were housed in an enriched environment, 192 IgG-saporin-lesioned rats performed better than standard-lesioned rats on both the nonmatching-to-position and the object-recognition tests. Environment enrichment had significant beneficial effects in 192 IgG-saporin-lesioned rats, suggesting that lesioned rats at late post-lesion times (over 1 year) still have appreciable cognitive plasticity.

Wake-Promoting Actions of Medial Basal Forebrain β₂ Receptor Stimulation.

The locus coeruleus-noradrenergic system exerts an activating influence on forebrain neuronal and behavioral activity states, in part, through the actions of noradrenergic beta receptors located within the medial septal (MS) and medial preoptic (MPOA) areas. The current study examined the extent to which beta2 receptors located within these medial basal forebrain regions modulate behavioral state. In this study, the sleep-wake effects of microinfusion of the beta2 agonist, clenbuterol, into the MS and MPOA were examined. Clenbuterol infusion into both MS and MPOA elicited a dose-dependent increase in time spent awake. These observations indicate that medial basal forebrain beta-sub-2 receptors participate in the noradrenergic-dependent modulation of behavioral state.

GABA B receptors in the medial septum/diagonal band slice from 16–25 day rat

GABA B receptors are believed to play a role in rhythmic activity in the mammalian brain. The aim of our study was to examine the presynaptic and postsynaptic locations of these receptors in the medial septal diagonal band area (MS/DB), an area known to pace the hippocampus θ rhythm. Whole-cell patch recordings were made from parasagittal MS/DB slices obtained from the 16–25 day rat. Neurons were classified into GABAergic and cholinergic subtypes according to previous electrophysiological criteria. Bath application of the GABA B receptor agonist baclofen in the presence of tetrodotoxin, and brief tetanic fiber stimulation in the presence of ionotropic receptor antagonists, provided evidence for the presence of postsynaptic GABA B receptor transmission to GABAergic but not cholinergic neurons. Bath application of baclofen, at concentrations too low to elicit postsynaptic activity in MS/DB neurons, significantly reduced the amplitudes of stimulus-evoked ionotropic receptor inhibitory postsynaptic potentials (IPSPs) and excitatory postsynaptic potentials (EPSPs) and the paired pulse depression of these evoked potentials. Baclofen also significantly reduced the frequencies but not the amplitudes of miniature inhibitory postsynaptic currents (IPSCs) and excitatory postsynaptic currents (EPSCs), indicating the presence of presynaptic GABA B receptors on GABAergic and glutamatergic terminals in the MS/DB. Baclofen, also at a concentration too low to elicit postsynaptic activity, reduced the frequencies and amplitudes of spontaneous IPSCs and EPSCs recorded in the presence of 200–400 nM kainate. Rhythmic compound IPSCs at θ frequencies were recorded under these conditions in some neurons, and these rhythmic compound IPSCs were disrupted by the activation but not by the inhibition of GABA B receptors. These results suggest that GABA B receptors modulate rather than generate rhythmic activity in the MS/DB, and that this modulatory effect occurs via receptors located on presynaptic terminals.