Stimulation of the medial septum improves performance in spatial learning following pilocarpine-induced status epilepticus.

Temporal lobe epilepsy often leads to hippocampal sclerosis and persistent cognitive deficits, including difficulty with learning and memory. Hippocampal theta oscillations are critical in optimizing hippocampal function and facilitating plasticity. We hypothesized that pilocarpine-induced status epilepticus would disrupt oscillations and behavioral performance and that electrical neuromodulation to entrain theta would improve cognition specifically in injured rats. Rats received a pilocarpine (n=30) or saline injection (n=27) and unilateral bi-polar electrodes were implanted into the medial septum and hippocampus the following day. Hippocampal and septal theta were recorded in a Plexiglas box over the first week following implantation. Control and pilocarpine-treated rats were split into stimulation (continuous 7.7Hz, 80µA, 1ms pulse width) and non-stimulation groups for behavioral analysis. Continuous stimulation was initiated one-minute prior to and throughout an object exploration task (post-injury day seven) and again for each of six trials on the Barnes maze (post-injury days 12-14). There was a significant reduction in hippocampal theta power (p<0.05) and percentage of time oscillating in theta (p<0.05). In addition there was a significant decrease in object exploration in rats post-pilocarpine (p<0.05) and an impairment in spatial learning. Specifically, pilocarpine-treated rats were more likely to use random search strategies (p<0.001) and had an increase in latency to find the hidden platform (p<0.05) on the Barnes maze. Stimulation of the medial septum at 7.7Hz in pilocarpine-treated rats resulted in performance similar to shams in both the object recognition and Barnes maze tasks. Stimulation of sham rats resulted in impaired object exploration (p<0.05) with no difference in Barnes maze latency or strategy. In conclusion, pilocarpine-induced seizures diminished hippocampal oscillations and impaired performance in both an object exploration and a spatial memory task in pilocarpine-treated rats. Theta stimulation at 7.7Hz improved behavioral outcome on the Barnes maze task; this improvement in function was not related to a general cognitive enhancement, as shams did not benefit from stimulation. Therefore, stimulation of the medial septum represents an exciting target to improve behavioral outcome in patients with epilepsy.

Functional evidence that the nucleus of the hippocampal commissure shows an earlier activation from a stressor than the paraventricular nucleus: Implication of an additional structural component of the avian hypothalamo-pituitary-adrenal axis.

Despite extensive data addressing the regulation of the hypothalamo-pituitary-adrenal (HPA) axis in vertebrates, the neuroendocrine regulation of stress in birds remains incomplete. The paraventricular nucleus (PVN) contains the key neuropeptides, corticotropin releasing hormone (CRH) and arginine vasotocin (AVT), containing neurons. However, another population of CRH neurons was recently identified in a septal nucleus called the nucleus of the hippocampal commissure (NHpC). Therefore, the current study investigated changes in gene expression of CRH and AVT in the PVN and CRH in the NHpC, as well as changes in plasma corticosterone concentrations following a stressor, food deprivation. In the NHpC, a rapid increase in CRH mRNA levels was observed as early as 2h, while relative CRH mRNA expression in the PVN increased thereafter from 4 to 12h of food deprivation. On the other hand, relative mRNA levels of AVT in the PVN were not observed until 8h and significantly increased at 12 and 24h following food deprivation. Furthermore, at the level of the anterior pituitary, relative expression of proopiomelanocortin transcripts followed gene expression patterns of CRH and AVT in the brain. In the absence of food, the pattern of plasma CORT showed an initial rise at 2h and a fourfold increase was measured at 4h that was sustained through 24h. Taken together, results from this study suggest that (1) CRH neurons in the NHpC appear to be the first responsive neurons to stress stimuli compared to those in the PVN, (2) CRH is predominantly functional in the early phase of stress while AVT is involved in the later phase of the stress period and (3) in birds, CRH neurons in the NHpC appear to be part of the classical HPA axis.

The GABAergic septohippocampal connection is impaired in a mouse model of tauopathy.

Alzheimer's disease (AD), the most common cause of dementia nowadays, has been linked to alterations in the septohippocampal pathway (SHP), among other circuits in the brain. In fact, the GABAergic component of the SHP, which controls hippocampal rhythmic activity crucial for learning and memory, is altered in the J20 mouse model of AD-a model that mimics the amyloid pathology of this disease. However, AD is characterized by another pathophysiological hallmark: the hyperphosphorylation and aggregation of the microtubule-associated protein Tau. To evaluate whether tauopathies alter the GABAergic SHP, we analyzed transgenic mice expressing human mutated Tau (mutations G272V, P301L, and R406W, VLW transgenic strain). We show that pyramidal neurons, mossy cells, and some parvalbumin (PARV)-positive hippocampal interneurons in 2- and 8-month-old (mo) VLW mice accumulate phosphorylated forms of Tau (P-Tau). By tract-tracing studies of the GABAergic SHP, we describe early-onset deterioration of GABAergic septohippocampal (SH) innervation on PARV-positive interneurons in 2-mo VLW mice. In 8-mo animals, this alteration was more severe and affected mainly P-Tau-accumulating PARV-positive interneurons. No major loss of GABAergic SHP neurons or PARV-positive hippocampal interneurons was observed, thereby indicating that this decline is not caused by neuronal loss but by the reduced number and complexity of GABAergic SHP axon terminals. The decrease in GABAergic SHP described in this study, targeted onto the PARV-positive/P-Tau-accumulating inhibitory neurons in the hippocampus, establishes a cellular correlation with the dysfunctions in rhythmic neuronal activity and excitation levels in the hippocampus. These dysfunctions are associated with the VLW transgenic strain in particular and with AD human pathology in general. These data, together with our previous results in the J20 mouse model, indicate that the GABAergic SHP is impaired in response to both amyloid-ß and P-Tau accumulation. We propose that alterations in the GABAergic SHP, together with a dysfunction of P-Tau-accumulating PARV-positive neurons, contribute to the cognitive deficits and altered patterns of hippocampal activity present in tauopathies, including AD.

Cholinergic neuronal lesions in the medial septum and vertical limb of the diagonal bands of Broca induce contextual fear memory generalization and impair acquisition of fear extinction.

Previous research has shown that the ventral medial prefrontal cortex (vmPFC) and hippocampus (Hipp) are critical for extinction memory. Basal forebrain (BF) cholinergic input to the vmPFC and Hipp is critical for neural function in these substrates, which suggests BF cholinergic neurons may be critical for extinction memory. In order to test this hypothesis, we applied cholinergic lesions to different regions of the BF and observed the effects these lesions had on extinction memory. Complete BF cholinergic lesions induced contextual fear memory generalization, and this generalized fear was resistant to extinction. Animals with complete BF cholinergic lesions could not acquire cued fear extinction. Restricted cholinergic lesions in the medial septum and vertical diagonal bands of Broca (MS/vDBB) mimicked the effects that BF cholinergic lesions had on contextual fear memory generalization and acquisition of fear extinction. Cholinergic lesions in the horizontal diagonal band of Broca and nucleus basalis (hDBB/NBM) induced a small deficit in extinction of generalized contextual fear memory with no accompanying deficits in cued fear extinction. The results of this study reveal that MS/vDBB cholinergic neurons are critical for inhibition and extinction of generalized contextual fear memory, and via this process, may be critical for acquisition of cued fear extinction. Further studies delineating neural circuits and mechanisms through which MS/vDBB cholinergic neurons facilitate these emotional memory processes are needed. © 2015 Wiley Periodicals, Inc.

Understanding alterations in serotonin connectivity in a rat model of depression within the monoamine-deficiency and the hippocampal-neurogenesis frameworks.

The monoamine-deficiency and the hippocampal-neurogenesis hypotheses of depression propose that alterations in the serotonin system and of hippocampal functionality are critical in the pathogenesis of depression. We measured the alterations in the connectivity level of the raphe nucleus in the chronic mild stress (CMS) rat model of depression using the manganese enhanced MRI method (MEMRI). Manganese ions were injected into the median raphe and their anterograde intracellular propagation was followed. Depression-like behavior was demonstrated using the sucrose preference tests. We show that the raphe's connectivity is differentially altered through chronic stress. In line with the monoamine-deficiency hypothesis, the connectivity of the raphe with the basal ganglia (BG) output nuclei, the hippocampus, the habenula and the entorhinal and insular cortices was reduced in CMS rats, suggesting an overall reduction in raphe excitability. Connectivity reductions were predominantly found in the right hemisphere, strengthening previous evidence pointing at a-symmetric hemispheric involvement in depression. Despite the general reduction in raphe connectivity, enhanced connectivity was found between the raphe and the septum, suggesting that alterations are connection-specific. On the basis of our results - while yet equivocal - we further discuss the possible coupling between the serotonergic and dopaminergic systems and two distinct mechanisms (direct and indirect) in which alterations in raphe connectivity may affect hippocampal dysfunction in chronic stress, thus linking the monoamine-deficiency and the hippocampal-neurogenesis hypotheses.

Behavior and the cholinergic parameters in olfactory bulbectomized female rodents: Difference between rats and mice.

Olfactory bulbectomy (OBX) in rodents induces a wide spectrum of functional disturbances, including behavioral, neurochemical, and neuromorphological alterations. We have examined the effects of OBX on behavior and the parameters of the cholinergic system in female rats and mice. In rats, OBX resulted in the appearance of some depressive-like behavioral marks, such as the decreased sucrose consumption, hyperactivity, impaired short-term memory and anxiety-like behavioral features, such as shortened presence in the center of the open field arena or open arms of the elevated plus-maze and an enhancement of avoidance behavior. These behavioral abnormalities could be associated with disturbances in hippocampal function, this suggestion being supported by the presence of cellular changes in this brain structure. No effect of OBX on the number of cholinergic neurons in the medial septum-diagonal band as well as on the acetylcholine content and acetylcholinesterase activity in the septum, hippocampus, and neocortex could be detected. In contrast, in mice, OBX impaired spontaneous alternation behavior and decreased the number of cholinergic neurons in the medial septum-diagonal band. These data demonstrate that rats and mice differently respond to OBX, in particular, OBX does not significantly affect the cholinergic system in rats.

Learning to ignore: a modeling study of a decremental cholinergic pathway and its influence on attention and learning.

Learning to ignore irrelevant stimuli is essential to achieving efficient and fluid attention, and serves as the complement to increasing attention to relevant stimuli. The different cholinergic (ACh) subsystems within the basal forebrain regulate attention in distinct but complementary ways. ACh projections from the substantia innominata/nucleus basalis region (SI/nBM) to the neocortex are necessary to increase attention to relevant stimuli and have been well studied. Lesser known are ACh projections from the medial septum/vertical limb of the diagonal band (MS/VDB) to the hippocampus and the cingulate that are necessary to reduce attention to irrelevant stimuli. We developed a neural simulation to provide insight into how ACh can decrement attention using this distinct pathway from the MS/VDB. We tested the model in behavioral paradigms that require decremental attention. The model exhibits behavioral effects such as associative learning, latent inhibition, and persisting behavior. Lesioning the MS/VDB disrupts latent inhibition, and drastically increases perseverative behavior. Taken together, the model demonstrates that the ACh decremental pathway is necessary for appropriate learning and attention under dynamic circumstances and suggests a canonical neural architecture for decrementing attention.

Behavioral anxiolysis without reduction of hippocampal theta frequency after histamine application in the lateral septum of rats.

Hippocampal theta activity is linked to various processes, including locomotion, learning and memory, and defense and affect (i.e., fear and anxiety). Interestingly, all classes of clinically effective anxiolytics, as well as experimental compounds that decrease anxiety in pre-clinical animal models of anxiety, reduce the frequency of hippocampal theta activity elicited by stimulation of the reticular formation in freely behaving or anesthetized animals. In the present experiments, we found that bilateral histamine infusions (0.5 µg/hemisphere) into the lateral septum (LS) of rats decreased anxiety-like responses in two models of anxiety, the elevated plus maze and novelty-induced suppression of feeding test. Surprisingly, these same infusions significantly increased hippocampal theta frequency elicited by reticular stimulation in urethane-anesthetized rats. In contrast to these findings, additional experiments showed that the clinically effective anxiolytic buspirone (40 mg/kg, i.p.) reduced theta frequency, confirming previous observations. Taken together, the dissociation of behavioral anxiolysis and theta frequency reduction noted here suggest that hippocampal theta frequency is not a direct index of anxiety levels in rodents. Further, the mechanisms underlying the behavioral and physiological effects elicited by histamine in the LS require further study.

Single unit activity in the lateral septum and central nucleus of the amygdala in the elevated plus-maze: a model of exposure therapy?

The central nucleus of the amygdala (CeA) is a major output region of the amygdala involved in organizing the expression of fear. There is also evidence that the lateral septum (LS) provides inhibitory control of neurons in CeA and is involved in the relief of fear. This study examined single unit activity in the lateral septum (LS) and the central nucleus of the amygdala (CeA) in the open and closed arms of the elevated plus-maze, a highly validated animal model of fear and anxiety. The general presumption is that animals normally avoid the open arms because the open arms are relatively more anxiety provoking than the closed arms which represent relative safety. It was expected that neurons in CeA would increase their activity in the open arms relative to the closed arms indicative of increased anxiety and that LS neurons would decrease their activity on the open arms. Contrary to expectations it was found that the preponderance of units in CeA decreased their firing rates on the open arms compared to the closed arms. An increase in firing rates in LS was seen in the open arms compared to the closed arms. The data suggest that when animals are placed on the open arms a compensatory process takes place to suppress fear so that the animal can engage in adaptive behavior. We liken this process to that which takes place in exposure therapy for phobias in humans which involves the inhibition of fear resulting from Pavlovian extinction.

Characterization of cognitive deficits in rats overexpressing human alpha-synuclein in the ventral tegmental area and medial septum using recombinant adeno-associated viral vectors.

Intraneuronal inclusions containing alpha-synuclein (a-syn) constitute one of the pathological hallmarks of Parkinson's disease (PD) and are accompanied by severe neurodegeneration of A9 dopaminergic neurons located in the substantia nigra. Although to a lesser extent, A10 dopaminergic neurons are also affected. Neurodegeneration of other neuronal populations, such as the cholinergic, serotonergic and noradrenergic cell groups, has also been documented in PD patients. Studies in human post-mortem PD brains and in rodent models suggest that deficits in cholinergic and dopaminergic systems may be associated with the cognitive impairment seen in this disease. Here, we investigated the consequences of targeted overexpression of a-syn in the mesocorticolimbic dopaminergic and septohippocampal cholinergic pathways. Rats were injected with recombinant adeno-associated viral vectors encoding for either human wild-type a-syn or green fluorescent protein (GFP) in the ventral tegmental area and the medial septum/vertical limb of the diagonal band of Broca, two regions rich in dopaminergic and cholinergic neurons, respectively. Histopathological analysis showed widespread insoluble a-syn positive inclusions in all major projections areas of the targeted nuclei, including the hippocampus, neocortex, nucleus accumbens and anteromedial striatum. In addition, the rats overexpressing human a-syn displayed an abnormal locomotor response to apomorphine injection and exhibited spatial learning and memory deficits in the Morris water maze task, in the absence of obvious spontaneous locomotor impairment. As losses in dopaminergic and cholinergic immunoreactivity in both the GFP and a-syn expressing animals were mild-to-moderate and did not differ from each other, the behavioral impairments seen in the a-syn overexpressing animals appear to be determined by the long term persisting neuropathology in the surviving neurons rather than by neurodegeneration.

Disturbances of septohippocampal theta oscillations in the epileptic brain: reasons and consequences.

Temporal lobe epilepsy (TLE) is one of the most common forms of epilepsy, characterized by hippocampal sclerosis and memory deficits. It is well-documented that intrinsic neuronal oscillations and provided by them communications between brain structures are of importance for cognition. Epilepsy disturbs these brain rhythms and presumably therefore affects memory. Here we review studies on cellular and systemic levels devoted to the TLE-induced disturbance of theta oscillations in the septohippocampal system. Special attention is paid to the role of damage of septal and hippocampal GABAergic cells in theta activity abnormalities. We also compare differences between native (in vivo) theta oscillations with those obtained in in vitro preparations of hippocampus and medial septum and find that in vitro they resemble epileptiform activity in some respects.

Guilt-selective functional disconnection of anterior temporal and subgenual cortices in major depressive disorder.

CONTEXT: Proneness to overgeneralization of self-blame is a core part of cognitive vulnerability to major depressive disorder (MDD) and remains dormant after remission of symptoms. Current neuroanatomical models of MDD, however, assume general increases of negative emotions and are unable to explain biases toward emotions entailing self-blame (eg, guilt) relative to those associated with blaming others (eg, indignation). Recent functional magnetic resonance imaging (fMRI) studies in healthy participants have shown that moral feelings such as guilt activate representations of social meaning within the right superior anterior temporal lobe (ATL). Furthermore, this area was selectively coupled with the subgenual cingulate cortex and adjacent septal region (SCSR) during the experience of guilt compared with indignation. Despite its psychopathological importance, the functional neuroanatomy of guilt in MDD is unknown. OBJECTIVE: To use fMRI to test the hypothesis that, in comparison with control individuals, participants with remitted MDD exhibit guilt-selective SCSR-ATL decoupling as a marker of deficient functional integration. DESIGN: Case-control study from May 1, 2008, to June 1, 2010. SETTING: Clinical research facility. PARTICIPANTS: Twenty-five patients with remitted MDD (no medication in 16 patients) with no current comorbid Axis I disorders and 22 controls with no personal or family history of MDD. MAIN OUTCOME MEASURES: Between-group difference of ATL coupling with a priori SCSR region of interest for guilt vs indignation. RESULTS: We corroborated the prediction of a guilt-selective reduction in ATL-SCSR coupling in MDD vs controls (familywise error-corrected P=.001 over the region of interest) and revealed additional medial frontopolar, right hippocampal, and lateral hypothalamic areas of decoupling while controlling for medication status and intensity of negative emotions. Lower levels of ATL-SCSR coupling were associated with higher scores on a validated measure of overgeneralized self-blame (67-item Interpersonal Guilt Questionnaire). CONCLUSIONS: Vulnerability to MDD is associated with temporofrontolimbic decoupling that is selective for self-blaming feelings. This provides the first neural mechanism ofMDD vulnerability that accounts for self-blaming biases.

Septohippocampal GABAergic neurons mediate the altered behaviors induced by n-methyl-D-aspartate receptor antagonists.

We hypothesize that selective lesion of the septohippocampal GABAergic neurons suppresses the altered behaviors induced by an N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine or MK-801. In addition, we hypothesize that septohippocampal GABAergic neurons generate an atropine-resistant theta rhythm that coexists with an atropine-sensitive theta rhythm in the hippocampus. Infusion of orexin-saporin (ore-SAP) into the medial septal area decreased parvalbumin-immunoreactive (GABAergic) neurons by ~80%, without significantly affecting choline-acetyltransferase-immunoreactive (cholinergic) neurons. The theta rhythm during walking, or the immobility-associated theta induced by pilocarpine, was not different between ore-SAP and sham-lesion rats. Walking theta was, however, more disrupted by atropine sulfate in ore-SAP than in sham-lesion rats. MK-801 (0.5 mg/kg i.p.) induced hyperlocomotion associated with an increase in frequency, but not power, of the hippocampal theta in both ore-SAP and sham-lesion rats. However, MK-801 induced an increase in 71-100 Hz gamma waves in sham-lesion but not ore-SAP lesion rats. In sham-lesion rats, MK-801 induced an increase in locomotion and an impairment of prepulse inhibition (PPI), and ketamine (3 mg/kg s.c.) induced a loss of gating of hippocampal auditory evoked potentials. MK-801-induced behavioral hyperlocomotion and PPI impairment, and ketamine-induced auditory gating deficit were reduced in ore-SAP rats as compared to sham-lesion rats. During baseline without drugs, locomotion and auditory gating were not different between ore-SAP and sham-lesion rats, and PPI was slightly but significantly increased in ore-SAP as compared with sham lesion rats. It is concluded that septohippocampal GABAergic neurons are important for the expression of hyperactive and psychotic symptoms an enhanced hippocampal gamma activity induced by ketamine and MK-801, and for generating an atropine-resistant theta. Selective suppression of septohippocampal GABAergic activity is suggested to be an effective treatment of some symptoms of schizophrenia.

Septal elicitation of hippocampal theta rhythm did not repair cognitive and emotional deficits resulting from vestibular lesions.

Bilateral vestibular lesions cause atrophy of the hippocampus in humans and subsequent deficits in spatial memory and the processing of emotional stimuli in both rats and humans. Vestibular lesions also impair hippocampal theta rhythm in rats. The aim of the present study was to investigate whether restoring theta rhythm to the hippocampus of a rat, via stimulation of the medial septum, would repair the deficits caused by vestibular lesions. It was hypothesized that the restoration of theta would repair the deficits and the vestibular rats would exhibit behavior and EEG similar to that of the sham rats. Rats were given either sham surgery or bilateral vestibular deafferentation (BVD) followed in a later operation by electrode implants. Half of the lesioned rats received stimulation. Subjects were tested in open field, elevated T-maze and spatial nonmatching to sample tests. BVD caused a deficit in hippocampal theta rhythm. Stimulation restored theta power at a higher frequency in the vestibular-lesioned rats, however, the stimulation did not repair the cognitive and emotional deficits caused by the lesions. It was concluded that stimulation, at least in the form used here, would not be a viable treatment option for vestibular damaged humans.

Septal area lesions impair spatial working memory in homing pigeons (Columba livia).

The septo-hippocampal system in birds resembles that of mammals, motivating research into the function of the avian hippocampus while surprisingly little attention has been given to the septum. To investigate a possible role of the avian septum in memory, the effects of septal area lesions on a spatial working memory (SpWM) task was tested in homing pigeons. After preoperative training on an analogue eight-arm (feeders) radial maze, now sham-operated control and septal lesioned pigeons were then trained again on the same task of locating the four feeders on the test phase of a trial that were not baited during the sample phase of a trial. During the test phase of a working memory trial, septal lesioned pigeons, compared to both their own preoperative performance and the performance of the controls, required significantly more choices to locate the four baited feeders not baited during the sample phase of a trial, and they made significantly fewer correct responses to the now baited feeders on their first four choices. The results demonstrate that, like its mammalian counterpart, the avian septum plays an important role in SpWM, suggesting that at least some functional properties of the septum are evolutionarily conserved in birds and mammals.

[Changes in the electrical activity of the medial septal region, piriform cortex and amygdala during epileptogenesis in the model of temporal lobe epilepsy].

Local field potentials (EEGs) in the medial septal area, amygdala and piriform cortex were recorded in waking guinea pigs in the control and during epileptogenesis in the model of chronic temporal lobe epilepsy (lithium-pilocarpin model of status epilepticus). Analysis of changes in rhythmical activity and interstructural relations was carried out at different stages of epileptogenesis. Increased frequency of rhythmic activity in delta, theta, and alphabands was observed during epileptogenesis. Correlation relations between the activities of the medical septum with the piriform cortex and amygdala clearly decreased to 5 months after development of status epilepticus. Changes in the frequency of oscillations and structural correlations developed in time from two months on and reached a maximum 5 months after the status epilepticus development. It point to intensification of the pathological changes during formation of the epileptic focus. A possible role of the observed EEG changes in the formation of a pathological centre is discussed.

Entrainment for distinguishing atypical atrioventricular node reentrant tachycardia from atrioventricular reentrant tachycardia over septal accessory pathways with long-RP [corrected] tachycardia.

BACKGROUND: The response to right ventricular (RV) entrainment is useful to distinguish atypical AV node reentrant tachycardia from AV reentrant tachycardia using a septal accessory pathway. Whether entrainment can differentiate between AV node reentrant tachycardia and AV reentrant tachycardia in patients with long-RP tachycardia has not been systematically validated. METHODS AND RESULTS: Twenty-four patients with concealed septal accessory pathways who had an electrophysiology study between January 1, 2000, and January 1, 2010, were included (age, 38 ± 17 years; men, 17). Entrainment was performed from the RV apex pacing at cycle length 20 to 40 ms shorter than tachycardia cycle length (TCL). The mean TCL was 390 ± 80 ms, the mean AH interval during tachycardia was 151 ± 57 ms, and the mean ventriculoatrial (VA) time was 182 ± 103 ms. Twelve patients had typical accessory pathways (VA/TCL <40%), and 12 had slowly conducting accessory pathways (VA/TCL ≥ 40%). In all patients with typical accessory pathways, the postpacing interval minus the TCL (PPI-TCL) was <115 ms and the difference in the VA interval during pacing and tachycardia (StimA-VA) was <85 ms. On the other hand, in 6 of the 12 patients in the slowly conducting group, the PPI-TCL was >115 ms, and the StimA-VA was > 85 ms. CONCLUSIONS: Slowly conducting accessory pathways frequently yield RV entrainment criteria traditionally attributable to AV node reentry. Distinguishing AV node reentry from AV reentry in patients with long-RP tachycardia requires other criteria.

Donepezil plus estradiol treatment enhances learning and delay-dependent memory performance by young ovariectomized rats with partial loss of septal cholinergic neurons.

Effects of estrogen therapy on cognitive performance appear to diminish with age and time following the loss of ovarian function. We hypothesize that this is due to a reduction in basal forebrain cholinergic function and that treatment with a cholinergic enhancer can reverse the effect. This study tested whether combining the cholinesterase inhibitor donepezil with estradiol treatment can enhance/restore estradiol effects on cognitive performance in young ovariectomized rats with selective lesions of septal cholinergic neurons. 192IgG-saporin was injected directly into the medial septum to produce selective cholinergic lesions. Rats were then treated with donepezil (Don, daily injections of 3mg/kg/day, i.p.) or vehicle, and then with 17ß-estradiol (E2, administered by silastic capsule implanted s.c.) or an empty capsule. Rats were trained on a delayed matching-to-position (DMP) T-maze task which previous studies have shown is sensitive to ovariectomy and estrogen replacement. Results show that neither estradiol nor donepezil alone significantly enhanced acquisition of the DMP task in rats with cholinergic lesions. Combination therapy was effective, however, depending on the severity of the lesion. Don+E2 significantly enhanced acquisition of the task in rats with partial lesions (<50% loss of cholinergic neurons), but not in rats with severe lesions. This effect was due largely to a reduction in perseverative behavior. Don+E2 also improved working memory in rats with partial lesions, as evidenced by significantly better performance than controls during increased intertrial delays. These findings suggest that even partial loss of septal cholinergic neurons can reduce effects of estrogen therapy on cognitive performance, and demonstrate that combining a cholinesterase inhibitor with estrogen therapy can help to restore beneficial effects on performance. We propose that combination therapy may have similar beneficial effects in women, particularly in older women who have not used estrogen therapy for many years and are beginning to show signs of cognitive impairment or early Alzheimer's disease.

[Coherence and phase analysis of theta-oscillations in the septohippocampal system during seizures].

Interrelations of the hippocampus and medial septal area (MSA) in the theta band (4-8 Hz) were studied during seizures produced by electrical kindling in waking guinea pigs. Field activity (EEG) was analyzed using the wavelet transform. A decrease in coherence of theta-oscillations in the hippocampus and MSA was observed during seizures. Phase analysis showed that in the beginning of kindling the MSA led in phase, but after formation of the pathological focus, MSA lagged the hippocampus. The data may contribute to understanding mechanisms of temporal lobe epilepsy.