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Social memory, the ability to recognize and remember individuals within a social group, is crucial for social interactions and relationships. Deficits in social memory have been linked to several neuropsychiatric and neurodegenerative disorders. The hippocampus, especially the circuit that links dorsal CA2 and ventral CA1 neurons, is considered a neural substrate for social memory formation. Recent studies have provided compelling evidence of extrahippocampal contributions to social memory. The septal nuclei, including the medial and lateral septum, make up a basal forebrain region that shares bidirectional neuronal connections with the hippocampus and has recently been identified as critical for social memory. The focus of our review is the neural circuit mechanisms that underlie social memory, with a special emphasis on the septum. We also discuss the social memory dysfunction associated with neuropsychiatric and neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Spatial memory encoding depends in part on cholinergic modulation. How acetylcholine supports spatial memory encoding is not well understood. Prior studies indicate that acetylcholine release is correlated with exploration, including epochs of rearing onto hind legs. Here, to test whether elevated cholinergic tone increases the probability of rearing, we tracked rearing frequency and duration while optogenetically modulating the activity of choline acetyltransferase containing (i.e., acetylcholine producing) neurons of the medial septum in rats performing a spatial working memory task (n = 17 rats). The cholinergic neurons were optogenetically inhibited using halorhodopsin for the duration that rats occupied two of the four open arms during the study phase of an 8‐arm radial arm maze win‐shift task. Comparing rats' behaviour in the two arm types showed that rearing frequency was not changed, but the average duration of rearing epochs became significantly longer. This effect on rearing was observed during optogenetic inhibition but not during sham inhibition or in rats that received infusions of a fluorescent reporter virus (i.e., without halorhodopsin; n = 6 rats). Optogenetic inhibition of cholinergic neurons during the pretrial waiting phase had no significant effect on rearing, indicating a context‐specificity of the observed effects. These results are significant in that they indicate that cholinergic neuron activity in the medial septum is correlated with rearing not because it motivates an exploratory state but because it contributes to the processing of information acquired while rearing. [ABSTRACT FROM AUTHOR]

Deficits in hippocampus‐dependent memory processes are common across psychiatric and neurodegenerative disorders such as depression, anxiety and Alzheimer's disease. Moreover, stress is a major environmental risk factor for these pathologies and it exerts detrimental effects on hippocampal functioning via the activation of hypothalamic–pituitary–adrenal (HPA) axis. The medial septum cholinergic neurons extensively innervate the hippocampus. Although, the cholinergic septohippocampal pathway (SHP) has long been implicated in learning and memory, its involvement in mediating the adaptive and maladaptive impact of stress on mnemonic processes remains less clear. Here, we discuss current research highlighting the contributions of cholinergic SHP in modulating memory encoding, consolidation and retrieval. Then, we present evidence supporting the view that neurobiological interactions between HPA axis stress response and cholinergic signalling impact hippocampal computations. Finally, we critically discuss potential challenges and opportunities to target cholinergic SHP as a therapeutic strategy to improve cognitive impairments in stress‐related disorders. We argue that such efforts should consider recent conceptualisations on the dynamic nature of cholinergic signalling in modulating distinct subcomponents of memory and its interactions with cellular substrates that regulate the adaptive stress response. [ABSTRACT FROM AUTHOR]

Women are at a higher risk of cognitive impairments and Alzheimer's disease (AD), particularly after the menopause, when the estrous cycle becomes irregular and diminishes. Numerous studies have shown that estrogen deficiency, especially estradiol (E2) deficiency, plays a key role in this phenomenon. Recently, a novel polymeric drug, hyaluronic acid–17β-estradiol conjugate (HA-E2), has been introduced for the delivery of E2 to brain tissues. Studies have indicated that HA-E2 crosses the blood–brain barrier (BBB) and facilitates a prolonged E2 release profile while lowering the risk of estrogen-supplement-related side effects. In this study, we used ovariohysterectomy (OHE) rats, a postmenopausal cognitive deficit model, to explore the effect of a 2-week HA-E2 treatment (210 ng/kg body weight, twice a week) on the cholinergic septo-hippocampal innervation system, synaptic transmission in hippocampal pyramidal neurons and cognitive improvements. Our study revealed an 11% rise in choline acetyltransferase (ChAT) expression in both the medial septal nucleus (MS nucleus) and the hippocampus, along with a 14–18% increase in dendritic spine density in hippocampal pyramidal neurons, following HA-E2 treatment in OHE rats. These enhancements prompted the recovery of cognitive functions such as spatial learning and memory. These findings suggest that HA-E2 may prevent and improve estrogen-deficiency-induced cognitive impairment and AD. [ABSTRACT FROM AUTHOR]

The left and right hippocampal formation (HF) of the avian brain have been reported to control some different aspects of homing in pigeons. In the current study, we employed GPS-tracking technology and unilateral HF lesions to further explore what if any aspects of a pigeon's homing flight might be under dominant control by either the left or right HF. Pigeons were released from three locations prior to any experimental manipulation and released repeatedly from the same three sites as sham-lesioned control, right HF-lesioned and left HF-lesioned treatment groups. Analyses of homing performance and virtual vanishing bearings revealed no effect of either lesion treatment. A more in-depth analysis of path efficiency during the initial decision-making, en route and near home phases of a homing flight also revealed no effect of either lesion treatment. A last analysis on the learning and memory for positions along a previously flown route, a proxy for investigating the development of route fidelity, also revealed no effect of either unilateral lesion. However, independent of treatment group, some statistically significant effects were observed with respect to changes in performance across training and the different release sites. The current study revealed no detectable difference between the left and right HF-lesioned pigeons with respect to several navigational parameters of a homing flight. Although in need of supporting experimentation, the results are consistent with the hypothesis that both the left and right HF are similarly able to support several aspects of homing pigeon navigation. No effect of unilateral HF-lesions on pigeons' homing was found. Both the left and right HF support local navigation and route fidelity development. [ABSTRACT FROM AUTHOR]

The fighting fish Betta splendens, long studied for its aggressive territorial competitions, has the potential to be a tractable and relevant model for studying the intersection of cognitive ecology and social neuroscience. Yet, few studies have comprehensively assessed Betta behavior across both social and nonsocial contexts. Furthermore, the present study is the first to quantify the expression of phosphorylated ribosomal protein S6 (PS6), a proxy for neural response, in the Betta telencephalon. Here, we assessed male Betta behavior across a suite of tasks and found that response to a mirror, but not neophilia (a novel object) nor anxiety (scototaxis), predicted behavior in a social competition. To then explore the cognitive aspects of social competition, we exposed Betta to either a familiar or novel opponent and compared their competitive behavior as well as their neural responses in the teleost homologs of the hippocampus, basolateral amygdala, and lateral septum. We did not detect any differences between familiar-exposed and novel-exposed individuals, but by implementing the first use of a habituation–dishabituation competition design in a study of Betta, we were able to observe remarkable consistency in competitive outcomes across repeated exposures. Taken together, the present study lays the groundwork for expanding the use of Betta to explore integrative and multidimensional questions of social cognition. [ABSTRACT FROM AUTHOR]

Post-operative sleep disturbance is a common feature of elderly surgical patients, and sleep fragmentation (SF) is closely related to post-operative cognitive dysfunction (POCD). SF is characterized by sleep interruption, increased number of awakenings and sleep structure destruction, similar to obstructive sleep apnea (OSA). Research shows that sleep interruption can change neurotransmitter metabolism and structural connectivity in sleep and cognitive brain regions, of which the medial septum and hippocampal CA1 are key brain regions connecting sleep and cognitive processes. Proton magnetic resonance spectroscopy (1H-MRS) is a non-invasive method for the evaluation of neurometabolic abnormalities. Diffusion tensor imaging (DTI) realizes the observation of structural integrity and connectivity of brain regions of interest in vivo. However, it is unclear whether post-operative SF induces harmful changes in neurotransmitters and structures of the key brain regions and their contribution to POCD. In this study, we evaluated the effects of post-operative SF on neurotransmitter metabolism and structural integrity of medial septum and hippocampal CA1 in aged C57BL/6J male mice. The animals received a 24-h SF procedure after isoflurane anesthesia and right carotid artery exposure surgery. 1H-MRS results showed after postoperative SF, the glutamate (Glu)/creatine (Cr) and glutamate + glutamine (Glx)/Cr ratios increased in the medial septum and hippocampal CA1, while the NAA/Cr ratio decreased in the hippocampal CA1. DTI results showed post-operative SF decreased the fractional anisotropy (FA) of white matter fibers in the hippocampal CA1, while the medial septum was not affected. Moreover, post-operative SF aggravated subsequent Y-maze and novel object recognition performances accompanied by abnormal enhancement of glutamatergic metabolism signal. This study suggests that 24-h SF induces hyperglutamate metabolism level and microstructural connectivity damage in sleep and cognitive brain regions in aged mice, which may be involved in the pathophysiological process of POCD. [ABSTRACT FROM AUTHOR]

Background: The treatment options for cognitive impairments in Parkinson's disease (PD) are limited. Repetitive transcranial magnetic stimulation has been applied in various neurological diseases. However, the effect of intermittent thetaburst stimulation (iTBS) as a more developed repetitive transcranial magnetic stimulation paradigm on cognitive dysfunction in PD remains largely unclear. Objective: Our aim was to explore the effect of acute iTBS on hippocampusdependent memory in PD and the mechanism underlying it. Methods: Different blocks of iTBS protocols were applied to unilateral 6-hydroxidopamine-induced parkinsonian rats followed by the behavioral, electrophysiological and immunohistochemical analyses. The object-place recognition and hole-board test were used to assess hippocampusdependent memory. Results: Sham-iTBS and 1 block-iTBS (300 stimuli) didn't alter hippocampusdependent memory, hippocampal theta rhythm and the density of c-Fos- and parvalbumin-positive neurons in the hippocampus and medial septum. 3 blockiTBS (900 stimuli) alleviated 6-hydroxidopamine-induced memory impairments, and increased the density of hippocampal c-Fos-positive neurons at 80 min post-stimulation but not 30 min compared to sham-iTBS. Interestingly, 3 blockiTBS first decreased and then increased normalized theta power during a period of 2 h following stimulation. Moreover, 3 block-iTBS decreased the density of parvalbumin-positive neurons in the medial septum at 30 min post-stimulation compared to sham-iTBS. Conclusion: The results indicate that multiple blocks of iTBS elicit dose and timedependent effects on hippocampus-dependent memory in PD, which may be attributed to changes in c-Fos expression and the power of theta rhythm in the hippocampus. [ABSTRACT FROM AUTHOR]

Electrical brain stimulation has become an essential treatment option for more than one third of epilepsy patients who are resistant to pharmacological therapy and are not candidates for surgical resection. However, currently approved stimulation paradigms achieve only moderate success, on average providing approximately 75% reduction in seizure frequency and extended periods of seizure freedom in nearly 20% of patients. Outcomes from electrical stimulation may be improved through the identification of novel anatomical targets, particularly those with significant anatomical and functional connectivity to the epileptogenic zone. Multiple studies have investigated the medial septal nucleus (i.e., medial septum) as such a target for the treatment of mesial temporal lobe epilepsy. The medial septum is a small midline nucleus that provides a critical functional role in modulating the hippocampal theta rhythm, a 4–7‐Hz electrophysiological oscillation mechanistically associated with memory and higher order cognition in both rodents and humans. Elevated theta oscillations are thought to represent a seizure‐resistant network activity state, suggesting that electrical neuromodulation of the medial septum and restoration of theta‐rhythmic physiology may not only reduce seizure frequency, but also restore cognitive comorbidities associated with mesial temporal lobe epilepsy. Here, we review the anatomical and physiological function of the septohippocampal network, evidence for seizure‐resistant effects of the theta rhythm, and the results of stimulation experiments across both rodent and human studies, to argue that deep brain stimulation of the medial septum holds potential to provide an effective neuromodulation treatment for mesial temporal lobe epilepsy. We conclude by discussing the considerations necessary for further evaluating this treatment paradigm with a clinical trial. [ABSTRACT FROM AUTHOR]

Cholinergic projection neurons in the medial septum and diagonal band of Broca are the major source of cholinergic modulation of hippocampal circuit functions that support neural coding of location and running speed. Changes in cholinergic modulation are known to correlate with changes in brain states, cognitive functions, and behavior. However, whether cholinergic modulation can change fast enough to serve as a potential speed signal in hippocampal and parahippocampal cortices and whether the temporal dynamics in such a signal depend on the presence of visual cues remain unknown. In this study, we use a fiber-photometric approach to quantify the temporal dynamics of cholinergic activity in freely moving mice as a function of the animal's movement speed and visual cues. We show that the population activity of cholinergic neurons in the medial septum and diagonal band of Broca changes fast enough to be aligned well with changes in the animal's running speed and is strongly and linearly correlated to the logarithm of the animal's running speed. Intriguingly, the cholinergic modulation remains strongly and linearly correlated to the speed of the animal's neck movements during periods of stationary activity. Furthermore, we show that cholinergic modulation is unaltered during darkness. Lastly, we identify rearing, a stereotypic behavior where the mouse stands on its hindlimbs to scan the environment from an elevated perspective, is associated with higher cholinergic activity than expected from neck movements on the horizontal plane alone. Taken together, these data show that temporal dynamics in the cholinergic modulation of hippocampal circuits are fast enough to provide a potential running speed signal in real-time. Moreover, the data show that cholinergic modulation is primarily a function of the logarithm of the animal's movement speed, both during locomotion and during stationary activity, with no significant interaction with visual inputs. These data advance our understanding of temporal dynamics in cholinergic modulation of hippocampal circuits and their functions in the context of neural coding of location and running speed. [ABSTRACT FROM AUTHOR]

Animal species are named social when they develop the capability of complex behaviors based on interactions with conspecifics that include communication, aggression, mating and parental behavior, crucial for well-being and survival. The underpinning of such complex behaviors is social memory, namely the capacity to discriminate between familiar and novel individuals. The Medial Septum (MS), a region localized in the basal forebrain, is part of the brain network involved in social memory formation. MS receives several cortical and subcortical synaptic and neuromodulatory inputs that make it an important hub in processing social information relevant for social memory. Particular attention is paid to synaptic inputs that control both the MS and the CA2 region of the hippocampus, one of the major MS output, that has been causally linked to social memory. In this review article, we will provide an overview of local and long range connectivity that allows MS to integrate and process social information. Furthermore, we will summarize previous strategies used to determine how MS controls social memory in different animal species. Finally, we will discuss the impact of an altered MS signaling on social memory in animal models and patients affected by neurodevelopmental and neurodegenerative disorders, including autism and Alzheimer’s Disease. [ABSTRACT FROM AUTHOR]

A postulated role of subcortical neuromodulators is to control brain states. Mechanisms by which different neuromodulators compete or cooperate at various temporal scales remain an open question. We investigated the interaction of acetylcholine (ACh) and oxytocin (OXT) at slow and fast timescales during various brain states. Although these neuromodulators fluctuated in parallel during NREM packets, transitions from NREM to REM were characterized by a surge of ACh but a continued decrease of OXT. OXT signaling lagged behind ACh. High ACh was correlated with population synchrony and gamma oscillations during active waking, whereas minimum ACh predicts sharp-wave ripples (SPW-Rs). Optogenetic control of ACh and OXT neurons confirmed the active role of these neuromodulators in the observed correlations. Synchronous hippocampal activity consistently reduced OXT activity, whereas inactivation of the lateral septum-hypothalamus path attenuated this effect. Our findings demonstrate how cooperative actions of these neuromodulators allow target circuits to perform specific functions. • Hippocampal acetylcholine and oxytocin interact in a brain-state-dependent manner • Acetylcholine and oxytocin distinguish gamma oscillation from sharp-wave ripples • Acetylcholine suppresses ripples, whereas ripples decrease oxytocin levels • Acetylcholine modulates oxytocin through a long-loop hippocampal-lateral septum path Zhang and Karadas et al. use GRAB sensors and electrophysiology to unravel the interaction of acetylcholine and oxytocin at slow and fast timescales across brain states. Perturbation experiments reveal that acetylcholine modulates oxytocin through the hippocampus-lateral septum path, demonstrating how their cooperative actions enable specific functions. [ABSTRACT FROM AUTHOR]

Takeda G protein–coupled receptor 5 (TGR5) is recognized as a promising target for type 2 diabetes and metabolic syndrome; its expression has been demonstrated in the brain and is thought to be neuroprotective. Here, we hypothesize that dysfunction of central TGR5 may contribute to the pathogenesis of depression. In well-established chronic social defeat stress (CSDS) and chronic restraint stress (CRS) models of depression, we investigated the functional roles of TGR5 in CA3 pyramidal neurons (PyNs) and underlying mechanisms of the neuronal circuit in depression (for in vivo studies, n = 10; for in vitro studies, n = 5–10) using fiber photometry; optogenetic, chemogenetic, pharmacological, and molecular profiling techniques; and behavioral tests. Both CSDS and CRS most significantly reduced TGR5 expression of hippocampal CA3 PyNs. Genetic overexpression of TGR5 in CA3 PyNs or intra-CA3 infusion of INT-777, a specific agonist, protected against CSDS and CRS, exerting significant antidepressant-like effects that were mediated via CA3 PyN activation. Conversely, genetic knockout or TGR5 knockdown in CA3 facilitated stress-induced depression-like behaviors. Re-expression of TGR5 in CA3 PyNs rather than infusion of INT-777 significantly improved depression-like behaviors in T gr 5 knockout mice exposed to CSDS or CRS. Silencing and stimulation of CA3 PyNs→somatostatin–GABAergic (gamma-aminobutyric acidergic) neurons of the dorsolateral septum circuit bidirectionally regulated depression-like behaviors, and blockade of this circuit abrogated the antidepressant-like effects from TGR5 activation of CA3 PyNs. These findings indicate that TGR5 can regulate depression via CA3 PyNs→somatostatin–GABAergic neurons of dorsolateral septum transmission, suggesting that TGR5 could be a novel target for developing antidepressants. [ABSTRACT FROM AUTHOR]

One of the main subcortical targets of hippocampal formation efferents is the lateral septum. Previous studies on the subicular projections, as a main output structure of the hippocampus, have shown a clear topographic organization of septal innervation, related to the origin of the fibres along the dorsoventral axis of the subiculum in the adult brain. In contrast, studies on the developing brain depict an extensive rearrangement of subicular projections during the prenatal period, shifting from the medial septum to the lateral septum. Our study aimed to describe the postnatal development of subicular projections to the septum. We injected anterograde tracers into the subiculum of 57 pups of different postnatal ages. Injections covered the proximodistal and dorsoventral axis of the subiculum. The age of the pups at day of tracer injection ranged from the day of birth to postnatal day 30. Analyses revealed that from the first postnatal day projections from subiculum preferentially target the lateral septum. Sparse innervation in the lateral septum was already present in the first few postnatal days, and during the following 3 weeks, the axonal distribution gradually expanded. Subicular projections to the lateral septum are topographically organized depending on the origin along the dorsoventral axis of the subiculum, in line with the adult innervation pattern. Different origins along the proximodistal axis of the subiculum are reflected in changes in the strength of septal innervation. The findings demonstrate that in case of the development of subicular projections, axonal expansion is more prominent than axonal pruning. [ABSTRACT FROM AUTHOR]

During spatial navigation, the frequency and timing of spikes from spatial neurons including place cells in hippocampus and grid cells in medial entorhinal cortex are temporally organized by continuous theta oscillations (6–11 Hz). The theta rhythm is regulated by subcortical structures including the medial septum, but it is unclear how spatial information from place cells may reciprocally organize subcortical theta-rhythmic activity. Here we recorded single-unit spiking from a constellation of subcortical and hippocampal sites to study spatial modulation of rhythmic spike timing in rats freely exploring an open environment. Our analysis revealed a novel class of neurons that we termed ‘phaser cells,’ characterized by a symmetric coupling between firing rate and spike theta-phase. Phaser cells encoded space by assigning distinct phases to allocentric isocontour levels of each cell’s spatial firing pattern. In our dataset, phaser cells were predominantly located in the lateral septum, but also the hippocampus, anteroventral thalamus, lateral hypothalamus, and nucleus accumbens. Unlike the unidirectional late-to-early phase precession of place cells, bidirectional phase modulation acted to return phaser cells to the same theta-phase along a given spatial isocontour, including cells that characteristically shifted to later phases at higher firing rates. Our dynamical models of intrinsic theta-bursting neurons demonstrated that experience-independent temporal coding mechanisms can qualitatively explain (1) the spatial rate-phase relationships of phaser cells and (2) the observed temporal segregation of phaser cells according to phase-shift direction. In open-field phaser cell simulations, competitive learning embedded phase-code entrainment maps into the weights of downstream targets, including path integration networks. Bayesian phase decoding revealed error correction capable of resetting path integration at subsecond timescales. Our findings suggest that phaser cells may instantiate a subcortical theta-rhythmic loop of spatial feedback. We outline a framework in which location-dependent synchrony reconciles internal idiothetic processes with the allothetic reference points of sensory experience. [ABSTRACT FROM AUTHOR]

Anatomical differences between the medial and lateral septum have associated these nuclei with dissimilar functional roles and behaviours. While the medial septum has been implicated, predominantly, in theta rhythm generation along the septo‐hippocampal axis, the lateral septum has mainly been investigated in the context of septo‐hypothalamic dialogue. Recent advances suggest that medial and lateral septum are more closely functionally related than previously appreciated. Here, we explore the hypothesis that the medial septum mediates ascending septo‐hippocampal theta propagation, while the lateral septum processes a descending hippocampo‐septal and septo‐hypothalamic reinforcement signal that mediates navigation during motivated behaviour. The generation and propagation of theta rhythm are critical for the initiation of exploratory behaviour. Indeed, theta signal processing of medial and lateral septum nuclei may well be involved in the integration of spatial, rewarding and locomotor signals across different brain networks. We review here the structural features, anatomical connectivity and functional properties of the medial and lateral septum. We discuss the heterogeneous anatomy of the lateral septum, which is composed of diverse subregions with distinct ascending and descending projections, and we relate the physiological characteristics of septal nuclei to their functional relationships with the hippocampal formation, the hypothalamus and the brainstem reticular formation during motivated spatial navigation. The review examines the anatomical connectivity and functional properties of the medial and lateral septum in the context of theta oscillations and signal integration. The heterogeneous anatomy of the septal nuclei and their connectivity is linked here to specific behaviours. We discuss the physiological characteristics of septal nuclei to their functional relationships with the hippocampal formation, the hypothalamus and the brainstem reticular formation during motivated spatial navigation. [ABSTRACT FROM AUTHOR]

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 7.7 Hz, 80 μA, 1 ms 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 7.7 Hz 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 7.7 Hz 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. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder with a rising socioeconomic impact on societies. The hippocampus (HPC), which plays an important role in AD, is affected in the early stages. The medial septum (MS) in the forebrain provides major cholinergic input to the HPC and has been shown to play a significant role in generating oscillations in hippocampal neurons. Cholinergic neurons in the basal forebrain are particularly vulnerable to neurodegeneration in AD. To better understand the role of MS neurons including the cholinergic, glutamatergic, and GABAergic subpopulations in generating the well-known brain rhythms in HPC including delta, theta, slow gamma, and fast gamma oscillations, we designed a detailed computational model of the septohippocampal pathway. We validated the results of our model, using electrophysiological recordings in HPC with and without stimulation of the cholinergic neurons in MS using designer receptors exclusively activated by designer drugs (DREADDs) in healthy male ChAT-cre rats. Then, we eliminated 75% of the MS cholinergic neurons in the model to simulate degeneration in AD. A series of selective and non-selective stimulations of the remaining MS neurons were performed to understand the dynamics of oscillation regulation in the HPC during the degenerated state. In this way, appropriate stimulation strategies able to normalize the aberrant oscillations are proposed. We found that selectively stimulating the remaining healthy cholinergic neurons was sufficient for network recovery and compare this to stimulating other subpopulations and a non-selective stimulation of all MS neurons. Our data provide valuable information for the development of new therapeutic strategies in AD and a tool to test and predict the outcome of potential theranostic manipulations. • Computational modeling of the impact of the basal forebrain in hippocampal neuronal oscillations. • Simulation of the effects of cholinergic neuron degeneration on hippocampal neuronal oscillations. • Hippocampal neural activity can be restored by stimulation of the remaining healthy cells in the medial septum. • Selective versus non-selective neuronal stimulation has different effects on the disrupted network. [ABSTRACT FROM AUTHOR]

The medial septum and diagonal band of Broca (MS-DBB) has an essential role for theta rhythm generation in the hippocampus and is critical for learning and memory. The MS-DBB contains cholinergic, GABAergic, and recently described glutamatergic neurons, but their specific contribution to theta generation is poorly understood. Here, we examined the role of MS-DBB glutamatergic neurons in theta rhythm using optogenetic activation and electrophysiological recordings performed in in vitro preparations and in freely behaving mice. The experiments in slices suggest that MS-DBB glutamatergic neurons provide prominent excitatory inputs to a majority of local GABAergic and a minority of septal cholinergic neurons. In contrast, activation of MS-DBB glutamatergic fiber terminals in hippocampal slices elicited weak postsynaptic responses in hippocampal neurons. In the in vitro septo-hippocampal preparation, activation of MS-DBB glutamatergic neurons did increase the rhythmicity of hippocampal theta oscillations, whereas stimulation of septo-hippocampal glutamatergic fibers in the fornix did not have an effect. In freely behaving mice, activation of these neurons in the MS-DBB strongly synchronized hippocampal theta rhythms over a wide range of frequencies, whereas activation of their projections to the hippocampus through fornix stimulations had no effect on theta rhythms, suggesting that MS-DBB glutamatergic neurons played a role in theta generation through local modulation of septal neurons. Together, these results provide the first evidence that MS-DBB glutamatergic neurons modulate local septal circuits, which in turn contribute to theta rhythms in the hippocampus. [ABSTRACT FROM AUTHOR]

The hippocampal circuitry undergoes attentional modulation by the cholinergic medial septum. However, it is unclear how septal activation regulates the spatial properties of hippocampal neurons. We investigated here what is the functional effect of selective-cholinergic and non-selective septal stimulation on septo-hippocampal system. We show for the first time selective activation of cholinergic cells and their differential network effect in medial septum of freely-behaving transgenic rats. Our data show that depolarization of cholinergic septal neurons evokes frequency-dependent response from the non-cholinergic septal neurons and hippocampal interneurons. Our findings provide vital evidence that cholinergic effect on septo-hippocampal axis is behavior-dependent. During the active behavioral state the activation of septal cholinergic projections is insufficient to evoke significant change in the spiking of the hippocampal neurons. The efficiency of septo-hippocampal processing during active exploration relates to the firing patterns of the non-cholinergic theta-bursting cells. Non-selective septal theta-burst stimulation resets the spiking of hippocampal theta cells, increases theta synchronization, entrains the spiking of hippocampal place cells, and tunes the spatial properties in a timing-dependent manner. The spatial properties are augmented only when the stimulation is applied in the periphery of the place field or 400 - 650ms before the animals approached the center of the field. In summary, our data show that selective cholinergic activation triggers a robust network effect in the septo-hippocampal system during inactive behavioral state, whereas the non-cholinergic septal activation regulates hippocampal functional properties during explorative behavior. Together, our findings uncover fast septal modulation on hippocampal network and reveal how septal inputs up-regulate and down-regulate the encoding of spatial representation. [ABSTRACT FROM AUTHOR]

The hippocampus plays a key role in learning and emotional regulation. The hippocampus' function varies along its septotemporal axis, with the septal pole being more frequently involved in spatial learning and memory, and the temporal pole playing a greater role in emotional behaviors. In this study, we present findings aimed at checking the expression level of the genes encoding neurotrophins and their receptors, including nerve growth factor ( NGF), brain-derived neurotrophic factor ( BDNF), neurotrophin-3 ( NT-3), and their receptors ( TrkA, TrkB and TrkC) in the hippocampus along the septotemporal axis. Using real-time PCR, several different expression patterns were observed. Remarkably, the expression of both NT-3 and TrkA genes in the septal hippocampus was higher than in the middle and temporal hippocampus. Higher expression of NT-3 and TrkA may implicate active neurogenesis in the dentate gyrus ( DG) of the septal hippocampus because more neurogenesis occurs in the septal than the temporal DG of rats. Finally, the results obtained in this study emphasize the importance of choosing the hippocampal portion along its septotemporal axis for any hippocampal molecular and biochemical experimental studies. [ABSTRACT FROM AUTHOR]

Abstract: Hippocampal theta activity, which is strongly modulated by the septal medial/Broca׳s diagonal band neurons, has been linked to information processing of the hippocampus. Serotonin from the medial raphe nuclei desynchronises hippocampal theta activity, whereas inactivation or a lesion of this nucleus induces continuous and persistent theta activity in the hippocampus. Hippocampal serotonin depletion produces an increased expression of high-frequency theta activity concurrent with the facilitation of place learning in the Morris maze. The medial septum–diagonal band of Broca complex (MS/DBB) has been proposed as a key structure in the serotonin modulation of theta activity. We addressed whether serotonin depletion of the MS/DBB induces changes in the characteristics of hippocampal theta activity and whether the depletion is associated with learning in a working memory spatial task in the radial arm maze. Sprague Dawley rats were depleted of 5HT with the infusion of 5,7-dihydroxytriptamine (5,7-DHT) in MS/DBB and were subsequently trained in the standard test (win-shift) in the radial arm, while the CA1 EEG activity was simultaneously recorded through telemetry. The MS/DBB serotonin depletion induced a low level of expression of low-frequency (4.5–6.5Hz) and a higher expression of high-frequency (6.5–9.5Hz) theta activity concomitant to a minor number of errors committed by rats on the working memory test. Thus, the depletion of serotonin in the MS/DBB caused a facilitator effect on working memory and a predominance of high-frequency theta activity. [Copyright &y& Elsevier]

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

Adversity during early life can lead to diverging endocrine and behavioral responses to stress in adulthood. In our laboratory, we evaluated the long-term effects of early life adversity and its interaction with chronic stress during adulthood. We propose this as a model of vulnerability to dysregulation of the stress response. We hypothesized that rats subjected to both protocols would show differential expression of corticosteroid receptors measured as number of neurons immunoreactive for glucocorticoid receptors (GR) or mineralocorticoid receptors (MR), in limbic areas related to the control of anxiety-like behavior. We also evaluated the effect of amitriptyline expecting to prevent the outcomes of the model. Male Wistar rats were separated from the mother (MS) for 4.5 h every day for the first 3 weeks of life. From postnatal day 50, rats were subjected to chronic variable stress (CVS) during 24 d (five types of stressor at different times of day). During the stress protocol, the rats were administered amitriptyline (10 mg/kg i.p.) daily. MS evoked lower MR expression in the central amygdaloid nucleus and this was reversed by amitriptyline. Furthermore, CVS increased MR immunoreactivity in the hippocampal area CA2 and increased anxious behavior; both effects were prevented by the antidepressant. When MS was combined with CVS during adulthood, there was a reduction of locomotor activity, with no corrective effect of amitriptyline. The differential effects among groups could mean that MS would promote an alternative phenotype that is expressed when facing CVS (a double hit) later in life. [ABSTRACT FROM AUTHOR]

Memory for odour information may result from temporal coupling between the olfactory and hippocampal systems. Respiration defines the frequency of olfactory perception, but how the respiratory rate affects hippocampal oscillations remains poorly understood. The afferent connectivity of the medial septum/diagonal band of Broca complex ( MS/ DB) proposes this region as a crossroads between respiratory and limbic pathways. Here we investigate if the firing rates of septal neurons integrate respiratory rate signals. We demonstrate that approximately 50% of MS/ DB neurons are temporally correlated with sniffing frequency. Moreover, a group of slow-spiking septal neurons are phase-locked to the sniffing cycle. We show that inter-burst intervals of MS/ DB theta cells relate to the sniff rate. Intranasal odour infusion evokes sniff phase preference for the activity of fast-spiking MS/ DB neurons. Concurrently, the infusion augments the correlation between sniffing and limbic theta oscillations. During periods of sniffing-theta correlation, CA1 place cells fired preferentially during the inhalation phase, suggesting the theta cycle as a coherent time frame for central olfactory processing. Furthermore, injection of the GABAergic agonist muscimol into medial septum induces a parallel decrease of sniffing and theta frequencies. Our findings provide experimental evidence that MS/ DB does not merely generate theta rhythm, but actively integrates sensorimotor stimuli that reflect sniffing rate. Such integration may provide temporal oscillatory synchronisation of MS/ DB-innervated limbic structures with the sniffing cycle. [ABSTRACT FROM AUTHOR]

Highlights: [•] Spontaneous hippocampal region gamma correlates with spatial learning in humans. [•] Gamma in the septal hippocampal subregion is associated with superior learning. [•] Fast gamma between 80 and 140Hz is especially linked to spatial performance. [Copyright &y& Elsevier]

The septohippocampal pathway contains cholinergic, GABAergic, and glutamatergic projections and has an established role in learning, memory, and hippocampal theta rhythm. Both GABAergic and cholinergic neurons in the medial septum-diagonal band of Broca(MSDB) have been associated with spatial memory, but the relationship between the two neuronal populations is not fully understood. The present study investigated the effect of selective GABAergicMSDBlesions on hippocampal acetylcholine (ACh) efflux and spatialmemory during tasks that varied in memory demand. Male Sprague Dawley rats were given GABAergic lesions of the MSDB using GAT1-saporin (GAT1-SAP) and examined on spontaneous exploration (Experiment 1) and non-matching to position without (NMTP; Experiment 2) and with a delay (DNMTP; Experiment 3), while concurrently using in vivo microdialysis to measure hippocampal ACh efflux. Intraseptal GAT1-SAP treatment did not alter baseline or behaviorally stimulated hippocampal ACh efflux or maze exploration (Experiment 1). Moreover, GAT1-SAP did not alter evoked hippocampal ACh efflux related to NMTP nor did it impair working memory in NMTP (Experiment 2). In contrast, both ACh efflux and performance in DNMTP were impaired by intraseptal GAT1-SAP. Thus, GABAergic MSDBneurons are important for spatial working memory and modulate hippocampal ACh efflux under conditions of high memory load. The relationship between the septohippocampal cholinergic and GABAergic systems and working memory will be discussed. [ABSTRACT FROM AUTHOR]

Abstract: Electrolytic lesion of the medial septum, a basal forebrain nucleus that projects to the hippocampus, prolonged the emergence from general anesthesia in rats. Septal lesioned rats required a longer time to recover from a loss of righting reflex (LORR) and a loss of tail-pinch response after injectable (20mg/kg i.p. pentobarbital, 5mg/kg i.v. propofol) or volatile (1.5% halothane, 2% isoflurane) anesthetic. When incremental doses of propofol were given i.p., septal lesioned rats as compared to control rats showed LORR at a lower dose of propofol. Similarly, when the rats were exposed to increasing concentrations of isoflurane, the percent of rats showing LORR was leftward shifted for lesioned rats as compared to control rats. Septal lesioned rats as compared to control rats showed decreased locomotor activity when exposed to 1.5% halothane. Lesion of the medial septum was confirmed by thionin-stained histological sections as well as loss of acetylcholinesterase (AchE) staining in the hippocampus, indicating a depletion of septohippocampal cholinergic afferents. Medial septal lesion resulted in a near complete loss of hippocampal theta rhythm during walking and a general decrease in power of the hippocampal EEG at all frequencies (0–100Hz), during walking or immobility. It is concluded that lesion of medial septum, in part through a loss of septohippocampal cholinergic afferents, increased the anesthesia response to volatile and injectable general anesthetics, during both induction and emergence. It is suggested that the septohippocampal system participates in many components of general anesthesia including hypnosis, immobility, and analgesia. [Copyright &y& Elsevier]

Abstract: The effects of a prolonged seizure, i.e. status epilepticus (SE), on neurogenesis of dentate granule cells (DGCs) in the immature dentate gyrus (DG) and possible changes in the phenotypes of the newborn neurons have remained incompletely characterized. We have now studied neurogenesis of DGCs in 9-day-old (postnatal, P9) rats 1 week after kainate (KA)-induced SE using 5-bromo-2-deoxyuridine (BrdU) immunostaining. The phenotype characterization of the newborn cells was carried out by immunofluorescence double labeling using doublecortin (DCX) and nestin as markers for immature cells, and glial fibrillary acid protein (GFAP) as a marker for glial cells. Newborn GABAergic neurons were further identified with antibodies for parvalbumin, glutamate decarboxylase 67 (GAD67), and the GABAA receptor α1 subunit, and mRNA expression of GABAergic and immature neurons was measured with quantitative real-time PCR (qPCR) in the DG. Our results show that the number of newborn as well as GABAergic neurons was significantly decreased after SE in the superior blade of the septal DG. The majority of the newborn BrdU-stained neurons co-expressed DCX, but neither nestin nor GFAP. In both experimental groups, newborn neurons were frequently localized in close contact, but not co-localized, with the cells positively stained for the GABAergic cell markers. Nestin and calretinin mRNA expression were significantly increased after SE. Our results suggest that SE-induced disruption of DGC neurogenesis and decreased number of GABAergic neurons could modify the connectivity between these cells and disturb the maturation of the GABAergic neurotransmission in the immature DG at the early epileptogenic phase. [Copyright &y& Elsevier]

Highlights: [•] Sleep and hippocampal ACh release are indispensable for memory consolidation. [•] Icv injection of MCH increased REM time and hippocampal ACh effluxes. [•] A significant correlation between REM time and hippocampal ACh effluxes was observed. [•] Injection of MCH into the medial septum increased the ACh effluxes, not REM time. [•] MCH facilitated ACh releases at least in part through the medial septum. [Copyright &y& Elsevier]

The relative size of the avian hippocampus (Hp) has been shown to be related to spatial memory and food storing in two avian families, the pa rids and corvids. Basil et al. [Brain Behav Evol 1996;47:156-1641 examined North American food-storing birds in the corvid family and found that Clark's nutcrackers had a larger relative Hp than pinyon jays and Western scrub jays. These results correlated with the nut- cracker's better performance on most spatial memory tasks and their strong reliance on stored food in the wild. However, Pravosudov and de Kort [Brain Behav Evol 2006;67:1-9] raised questions about the methodology used in the 1996 study, specifically the use of paraffin as an embedding mate- rial and recalculation for shrinkage. Therefore, we measured relative Hp volume using gelatin as the embedding material in four North American species of food-storing corvids (Clark's nutcrackers, pinyon jays, Western scrub jays and blue jays) and one Eurasian corvid that stores little to no food (azure-winged magpies). Although there was a significant overall effect of species on relative Hp volume among the five species, subsequent tests found only one pairwise difference, blue jays having a larger Hp than the azure-winged magpies. We also examined the relative size of the septum in the five species. Although Shiflett et al. [J Neurobiol 2002; 51:215-2221 found a difference in relative septum volume amongst three species of parids that correlated with storing food, we did not find significant differences amongst the five species in relative septum. Finally, we calculated the number of neurons in the Hp relative to body mass in the five species and found statistically significant differences, some of which are in accord with the adaptive specialization hypothesis and some are not. [ABSTRACT FROM AUTHOR]

Changes in the interactions of the hippocampus and medial septal area in the theta range (4-8 Hz) during the generation of convulsive activity in electrical kindling were studied in conscious guinea pigs. Overall electrical activity (EEG)was analyzed by wavelet transformation. Decreases in the coherence of theta oscillations recorded in both structures were seen during generation of convulsive discharges. Phase analysis showed that the phase-leading structure at the initial stage of epileptogenesis was the medial septal area; however, after formation of the pathological focus, the medial septal area lagged the hippocampus in phase. These data may contribute to our understanding of the mechanisms of development of temporal epilepsy. [ABSTRACT FROM AUTHOR]

Abstract: In the present study, we investigated the influence of intra-medial septum (intra-MS) injections of dopamine D1 receptor agents on amnesia induced by intra-CA1 injections of a muscarinic acetylcholine receptor antagonist, scopolamine. This study used a step-through inhibitory (passive) avoidance task to assess memory in adult male Wistar rats. The results showed that in the animals that received post-training intra-MS injections of saline, intra-CA1 administrations of scopolamine (0.75, 1, and 2μg/rat) decreased inhibitory avoidance (IA) memory consolidation as evidenced by a decrease in step-through latency on the test day, which was suggestive of drug-induced amnesia. Post-training intra-MS injections of a dopamine D1 receptor agonist, SKF38393 at doses of 0.1, 0.15, and 0.3μg/rat had no effect, but at dose of 0.5μg/rat impaired IA memory consolidation. Interestingly, intra-MS injections of SKF38393 (0.15, 0.3 and 0.5μg/rat) significantly prevented amnesia induced by intra-CA1 injections of scopolamine (1μg/rat). Intra-MS injections of a dopamine D1 receptor antagonist, SCH23390 (0.5 and 0.75μg/rat) by itself impaired IA memory consolidation, and also at dose of 0.75μg/rat increased amnesia induced by intra-CA1 administrations of an ineffective dose of scopolamine (0.5μg/rat). Post-training intra-MS injections of ineffective doses of SCH23390 (0.1, 0.3 and 0.5μg/rat) prevented an effective dose of SKF38393 response to the impaired effect of scopolamine. These results suggest that dopamine D1 receptors in the MS via projection neurons to the hippocampus affect impairment of memory consolidation induced by intra-CA injections of scopolamine. [Copyright &y& Elsevier]

Abstract: Septum pellucidum (SP) and cavum SP (CSP) were delineated in two samples. The Longitudinal Study examined structural MR-images in first-episode schizophrenia (FESZ) and controls at two time-points. The Cross-Sectional Study examined structural and diffusion-tensor MR measures, including hippocampus and fornix, in chronic schizophrenia (SZ) at one time-point. CSP and SP measurements remained stable over time in FESZ and controls. Compared to controls, CSP were smaller in FESZ, but not in chronic SZ. SP were larger in chronic SZ, but not in FESZ. In chronic SZ only, SP-Length was correlated negatively with fornix-FA and hippocampal volume, and positively with chlorpromazine-equivalent dosage. [Copyright &y& Elsevier]

Oscillatory coupling between distributed areas can constitute a mechanism for neuronal integration. Theta oscillations provide temporal windows for hippocampal processing and only appear during certain active states of animals. Since previous studies have demonstrated that nucleus incertus (NI) contributes to the generation of hippocampal theta activity, in this paper, we evaluated the oscillatory coupling between both structures. We compared hippocampal and NI field potentials that were simultaneously recorded in urethane-anesthetized rats. Electrical and cholinergic stimulations of the reticularis pontis oralis nucleus have been used as hippocampal theta generation models. The spectral analyses reveal that electrical stimulation induced an increase in theta oscillations in both channels, whose frequencies depended on the intensity of stimulation. The intensity range used simultaneously increased the normalized spectral energy in the fast theta band (6-12 Hz) in HPC and NI. Frequencies within the theta range were found to be very similar in both channels. In order to validate coupling, spectral coherence was inspected. The data reveal that coherence in the high theta band also increased while stimuli were applied. Cholinergic activation progressively increased the main frequency in both structures to reach an asymptotic period with stable peak frequency in the low theta range (3-6 Hz), which could be first observed in NI and lasted about 1,500 s. Coherence in this band reached values close to 1. Taken together, these results support an electrophysiological and functional coupling between the hippocampus and the reticular formation, suggesting NI to be part of a distributed network working at theta frequencies. [ABSTRACT FROM AUTHOR]

Introduction: In rats, activation of medial septum (MS) 5-HT receptors with the 5-HT/5-HT receptor agonist 8-OH-DPAT disrupts encoding and consolidation, but not retrieval of a spatial memory in the water maze task. These findings might be explained by an action of 8-OH-DPAT on 5-HT receptors located on cholinergic neurons which the drug could transiently hyperpolarise. If so, selective damage of these neurons should mimic the effects of 8-OH-DPAT, or, at least, synergistically interfere with them. Methods: To test this hypothesis, rats were subjected to intraseptal infusions of 8-OH-DPAT (or phosphate-buffered saline) during acquisition of a water maze task before and/or after 192 IgG-saporin-induced MS cholinergic lesion (vs. sham-operated). Results: We confirmed that only pre-acquisition intraseptal 8-OH-DPAT infusions prevented learning and subsequent drug-free retrieval of the platform location in intact rats and found that (1) the cholinergic lesion did not prevent recall of the platform location, and (2) the impairing effects of 8-OH-DPAT were similar in sham-operated and lesioned rats, whether naïve or not, to the task before lesion surgery. Conclusions: An action of 8-OH-DPAT on only MS cholinergic neurons is not sufficient to account for the drug-induced memory impairments. A concomitant 8-OH-DPAT-induced hyperpolarisation of cholinergic and/or GABAergic and/or glutamatergic neurons (intact rats), or of only GABAergic and/or glutamatergic ones after cholinergic lesion, might be necessary to obliterate task acquisition, confirming that, in the MS, (1) the three neuronal populations could cooperate to process hippocampal-dependent information, and (2) non-cholinergic septohippocampal neurons might be more important than cholinergic ones in serotonin-induced modulation of hippocampus-dependent memory processing. [ABSTRACT FROM AUTHOR]

The effects of injection of L-glutamate into the medial septal area on epileptogenesis associated with stimulation of the perforant pathway were studied in conscious guinea pigs. EEG field potentials were recorded in the hippocampus and medial septal area in the initial state and on formation of epileptic foci in animals given physiological saline (controls) or L-glutamate (glutamate group) into the medial septal area. Administration of glutamate enhanced the theta rhythm in both structures. During kindling in animals given glutamate, there was significantly earlier onset of the convulsive state and secondary epileptiform discharges than in controls. As the epileptic focus formed, sharp weakening of theta oscillations was seen in all animals, though onset was much earlier in the glutamate group. The correlation between the hippocampal and septal EEG decreased sharply in animals given glutamate, while changes in controls were minor. These results are of value in deciphering the mechanisms of temporal epilepsy. [ABSTRACT FROM AUTHOR]

Abstract: The effect of intraseptal injections of lidocaine before a first or a second session in the elevated plus-maze, in a test–retest paradigm, was investigated. In addition to gross session analyses, a minute-by-minute analysis of the sessions was used to evaluate both anxiety and memory. Lidocaine injections before the test session produced increases in the frequency of entries, time spent and distance run in the open arms without affecting activity occurring in the closed arms. During the retest session, saline- and lidocaine-treated rats exhibited increased indices of anxiety and lidocaine-treated rats exhibited decreased closed-arm entries. The minute-by-minute analysis showed a faster decrease in anxiety-related behaviors during the test session by saline- than by lidocaine-treated rats and a significant decrease in closed-arm exploration by saline-treated rats, but not by lidocaine-treated ones. Lidocaine injection before the retest session produced increases in the frequency of entries, time spent and distance run in the open arms in the second session when compared with saline-treated rats. Minute-by-minute analysis showed an increase in the time spent in the open arms by lidocaine animals at the beginning of the retest session in comparison to saline animals and a significant decrease in closed-arm exploration by both groups. These results suggest that inactivation of the medial septum by lidocaine affects the expression of unconditioned and conditioned forms of anxiety in the elevated plus-maze and, in a lesser way, the acquisition and retention of spatial information. [Copyright &y& Elsevier]

Abstract: The medial septum diagonal band complex (MS/DB) projects via cholinergic and GABAergic pathways to the hippocampus and plays a key role in the hippocampal theta rhythm. In the MS/DB we have previously described a population of fast spiking GABAergic neurons that contain parvalbumin and mediate theta frequency activity in vitro. The Kv3.1 potassium channel is a delayed rectifier channel that plays a major role in fast spiking neurons in the CNS, and has previously been localized in the MS/DB. To determine which cell types in the MS/DB express the Kv3.1b ion channel subunit, transgenic mice in which the expression of GABAergic and glutamate markers are associated with the expression of green fluorescent protein (GFP; GAD67-GFP and VGluT2-GFP mice, respectively) were used for immunofluorescence and axonal tract tracing. Electrophysiological studies were also carried out on rat MS/DB slices to examine the role of the Kv3.1 channel in theta frequency oscillations. The results for the MS/DB were as follows: (1) cholinergic cells did not express GFP in either GAD67-GFP or VGluT2-GFP mice, and there was GAD67 immunoreactivity in GFP-positive neurons in GAD67-GFP mice and in a small proportion (6%) of GFP-positive neurons in VGluT2-GFP mice. (2) Kv3.1b immunofluorescence was associated with the somata of GABAergic neurons, especially those that contained parvalbumin, and with a minority of glutamatergic neurons, but not with cholinergic neurons, and with GABAergic axonal terminal-like processes around certain GABAergic neurons. (3) Both Kv3.1b-positive and -negative GABAergic neurons were septo-hippocampal, and there was a minor projection to hippocampus from VGluT2-GFP neurons. (4) Kainate-induced theta oscillations in the MS/DB slice were potentiated rather than inhibited by the Kv3.1 blocker 4-aminopyridine, and this agent on its own produced theta frequency oscillations in MS/DB slices that were reduced by ionotropic glutamate and GABA receptor antagonists and abolished by low extracellular calcium. These studies confirm the presence of heterogeneous populations of septo-hippocampal neurons in the MS/DB, and suggest that presence of Kv3.1 in the GABAergic neurons does not contribute to theta activity through fast spiking properties, but possibly by the regulation of transmitter release from axonal terminals. [Copyright &y& Elsevier]

Abstract: The multiunit activity in the medial septal–diagonal band complex (MSDB) and field potentials of the hippocampus were simultaneously recorded in waking healthy rabbits (control) and in the same animals that were then exposed to kindling stimulation of the perforant path. In the control, the bursts of spikes in one group of rhythmic MSDB neurons phase-locked to the top of theta waves in the hippocampus, and in the second group, to the trough of these waves. The stimulation evoked seizure afterdischarges in the hippocampus and seizure bursts of spikes separated by periods of inhibition in MSDB neurons. In the first group of septal cells, seizure bursts coincided with inhibitory periods between afterdischarges in the hippocampus; in the second group, these bursts were observed during seizure afterdischarges, suggesting that different MSDB cells play opposite roles in the development of seizures. Evoked afterdischarges were spontaneously followed by recurrent ictal events; neuronal oscillations at the theta (6–7 Hz) or “twice-theta” frequency (12–14 Hz) preceded these secondary epileptic discharges. As a result of kindling, interictal spikes were recorded in the hippocampus; at the same time, synchronous bursts of many cells appeared in the MSDB. In the epileptic brain, the frequency of both the hippocampal theta rhythm and MSDB neuronal theta bursts increased; in the septum, an augmentation of neuronal rhythmicity was also observed. Theta oscillations, either spontaneous or evoked by sensory stimulation, abolished the epileptiform events. Evidently, the activities within the theta range during preictal and interictal periods are of different significance in the generation of seizures. [Copyright &y& Elsevier]

Abstract: This study tested the hypothesis that septal cholinergic lesions impair acquisition of a delayed matching to position (DMP) T-maze task in male rats by affecting learning strategy. Rats received either the selective cholinergic immunotoxin, 192 IgG-saporin (SAP) or artificial cerebrospinal fluid directly into the medial septum. Two weeks later, animals were trained to acquire the DMP task. SAP-treated rats took significantly longer to acquire the task than corresponding controls. Both SAP-treated and control rats adopted a persistent turn and utilized a response strategy during early periods of training. By the time rats reached criterion the persistent turn was no longer evident, and all rats had shifted to an allocentric strategy, i.e., were relying on extramaze cues to a significant degree. During the acquisition period, SAP-treated rats spent significantly more days showing a persistent turn and using a response strategy than corresponding controls. The added time spent using a response strategy accounted entirely for the added days required to reach criterion among the SAP-treated rats. This suggests that the principal mechanism by which septal cholinergic lesions impair DMP acquisition in male rats is by increasing the predisposition to use a response vs. a place strategy, thereby affecting the ability to switch from one strategy to another. [Copyright &y& Elsevier]

Abstract: Converging lines of evidence have supported a role for the nucleus basalis magnocellularis (NB) in attentional mechanisms; however, debate continues regarding the role of the medial septum in behavior (MS). Recent studies have supported a role for the septohippocampal system in the online processing of internally generated cues. The current study was designed to investigate a possible double dissociation in rat food protection behavior, a natural behavior that has been shown to depend on external and internal sources of information. The study examined the effects of intraparenchymal injections of 192 IgG-saporin into either the MS or NB on the organization of food protection behavior. NB cholinergic lesions reduced the number of successful food protection behaviors while sparing the temporal organization of food protection behavior. In contrast, MS cholinergic lesions disrupted the temporal organization of food protection behavior while sparing the ability to successfully protect food items. These observations are consistent with a double dissociation of NB and MS cholinergic systems'' contributions to processing external and internal sources of information and provide further evidence for the septohippocampal system''s involvement in processing internally generated cues. [Copyright &y& Elsevier]

Comparative studies of the activity of extracellularly recorded neurons in living slices of the medial septal area of healthy guinea pigs and animals with a model of chronic temporal epilepsy demonstrated differences between them in terms of the frequency and pattern of cell discharges. The brains of animals with experimental epilepsy showed a doubling of the total level of activity as compared with controls, due to increases in the discharge frequencies of irregular and regular non-volleying neurons. There was a sharp (three-fold) increase in the number of cells with rhythmic discharge volleys, along with changes in the parameters of volley activity — both in neurons with the endogenous (pacemaker) pattern and in cells with secondary involvement in rhythmic activity. The possible mechanisms for these changes are discussed. These data widen our understanding of the processes forming pathological synchronization in epilepsy and may assist in the creation of new approaches to the treatment of this disease. [ABSTRACT FROM AUTHOR]

Abstract: Field potentials of the hippocampus and the medial septal-diagonal band complex (MSDB) were recorded in the control and during the kindling stimulation of the perforant path in waking guinea pigs. Changes in the correlation of activities of these structures during stimulation-evoked seizures (model of acute epilepsy) and during epileptogenesis elicited by the kindling (model of chronic epilepsy) were analysed. In the control, a high correlation between the background activities of the hippocampus and MSDB was observed. In the first days of stimulation at the parameters that evoked seizure discharges in the hippocampus, the MSDB did not show the epileptiform activity; however, repeated daily stimulation gave rise to epileptiform discharges, which increased with time. As a result of kindling, the MSDB became capable of generating seizure activity irrespective of the hippocampus. The degree of correlation between the activities of the two structures sharply decreased during “acute” and “chronic” seizures. In the process of kindling, a progressive disintegration of activities of the hippocampus and MSDB was revealed, indicating the disturbance of the functioning of septohippocampal network during epileptogenesis. The data obtained add to the knowledge about the mechanisms of temporal lobe epilepsy and may help to develop new approaches to the therapy of this disease. [Copyright &y& Elsevier]

In the brain, tachykinins acting via the three cloned neurokinin (NK) receptors are implicated in stress-related affective disorders. Hemokinin-1 is a novel tachykinin that reportedly prefers NK1 to NK2 or NK3 receptors. Although NK1 and NK3 receptors are abundantly expressed in the brain, NK2-receptor-mediated electrophysiological effects have rarely been described as NK2 receptors are expressed only in a few brain regions such as the nucleus of the medial septum/diagonal band. Medial septal/diagonal band neurons that control hippocampal mnemonic functions also colocalize NK1 and NK3 receptors. Functionally, intraseptal activation of all three NK receptors increases hippocampal acetylcholine release and NK2 receptors have specifically been implicated in stress-induced hippocampal acetylcholine release. Electrophysiological studies on the effects of NKs on septohippocampal cholinergic neurons are lacking and electrophysiological effects of hemokinin-1 have thus far not been reported in brain neurons. In the present study we examined the electrophysiological and pharmacological effects of multiple NKs on fluorescently tagged septohippocampal cholinergic neurons using whole-cell patch-clamp recordings in a rat brain slice preparation. We demonstrate that a vast majority of septohippocampal cholinergic cells are activated by NK1, NK2 and NK3 receptor agonists as well as by hemokinin-1 via direct post-synaptic mechanisms. Pharmacologically, hemokinin-1 recruits not only NK1 but also NK2 and NK3 receptors to activate septohippocampal cholinergic neurons that are the primary source of acetylcholine for the hippocampus. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the role of corticotropin-releasing factor receptors 1 (CRF1) and 2 (CRF2) in anxiety-like behavior and learning of C57BL/6J mice after exposure to a stressful stimulus. When C57BL/6J mice were exposed to immobilization (1 h) serving as stressful stimulus, context- and tone-dependent fear conditioning were impaired if the training followed immediately after immobilization. The stress-induced impairment of context-dependent fear conditioning was prevented by specific blockade of CRF2 of the lateral septum (LS) with anti-sauvagine-30. Immobilization did not only affect conditioned fear, but also enhanced, through CRF2 of the LS, anxiety-like behavior determined with the elevated plus maze. Recovery from stress-induced anxiety and impairment of context-dependent fear conditioning was observed after 1 h delay of training and required hippocampal CRF1, as indicated by the finding that this recovery was prevented by blockade of intrahippocampal CRF1. It was concluded that exposure to a stressor initially affected both anxiety-like behavior and contextual conditioned fear through septal CRF2, while the later activation of hippocampal CRF1 resulted in the return to baseline levels of both processes. Intraventricular injection of mouse urocortin 2, a CRF2-selective agonist, removed the stress-induced anxiety and learning impairment, but did not reduce the activation of the hypothalamic pituitary adrenal axis indicative of the hormonal stress response. We propose that the enhanced anxiety is the component of the stress response responsible for the memory deficit. [ABSTRACT FROM AUTHOR]

Abstract: Infusion of 192 IgG-saporin (SAP) into the medial septum (MS) of rats selectively destroys cholinergic neurons projecting to the hippocampus and impairs acquisition of a delayed matching to position (DMP) T-maze task. The present study evaluated whether introduction of a mild aversive stimulus 30min prior to training would attenuate the deficit in DMP acquisition caused by the SAP lesions. Male Sprague–Dawley rats received medial septal infusions of either artificial cerebrospinal fluid or SAP (0.22μg in 1.0μl). Fourteen days later, all animals were trained to perform the DMP task. Half of the SAP-treated animals and controls received an intraperitoneal injection of saline each day, 30min prior to training. Results show that intraperitoneal saline attenuated the impairment in DMP acquisition in SAP lesioned rats. These results suggest that a mild aversive stimulus can attenuate cognitive deficits caused by medial septal cholinergic lesions. [Copyright &y& Elsevier]

Abstract: Cholinergic axons originating from the septum form a characteristic layer of preterminal axons and apparent termination in the molecular layer of the hippocampal dentate gyrus. The present study explored the specificity of this characteristic axonal pattern, through the use of organotypic slice co-cultures. Slices of hippocampus were co-cultured with a slice from one of a variety of other potential sources of afferents, and the afferent axons were labeled histochemically or immunocytochemically to determine which afferents distribute within the dentate molecular layer in a pattern similar to that formed by septal cholinergic projections. Acetylcholinesterase (AChE) histochemistry demonstrated that cholinergic axons from septum, substantia innominata, and striatum all consistently targeted the inner molecular layer of the dentate gyrus. AChE-labeled cholinergic axons from dorsal lateral pontine tegmentum and from spinal cord sometimes formed this pattern, while axons from the habenula failed to extend into the dentate gyrus. Immunocytochemically identified monoaminergic axons from the substantia nigra, locus coeruleus, and raphe extended into co-cultured hippocampus; each of these afferent systems displayed a prominent axonal plexus within the hilus of the dentate, but only the raphe axons projected prominently to the molecular layer. These data demonstrate that the molecular layer of the dentate gyrus provides an attractive target zone for some cholinergic and monoaminergic afferents, but not all. Commonalities between neuronal populations that preferentially project to the molecular layer in vitro may offer clues regarding the axon guidance mechanisms that normally direct cholinergic axons to target sites in the dentate gyrus molecular layer. [Copyright &y& Elsevier]

The involvement of the septohippocampal system on the impaired sensorimotor gating induced by phencyclidine (PCP) or by an electrically induced hippocampal seizure was examined in behaving rats. An impaired sensorimotor gating, measured by prepulse inhibition (PPI) of the acoustic startle response, was observed following a hippocampal afterdischarge (AD) or systemic injection of PCP and was accompanied with an increase in hippocampal gamma waves (30–70 Hz). The medial septum infusion with muscimol (0.25 μg), a GABAA receptor agonist, 15 min prior to PCP or a hippocampal AD, prevented the impairment of sensorimotor gating and the increase in gamma waves. By itself, muscimol (0.25 μg) injection into the medial septum did not affect PPI, although it significantly suppressed spontaneous gamma waves. In order to identify subpopulations of neurons mediating the sensorimotor gating deficit and the hippocampal gamma wave increase, 0.14–0.21 μg of p75 antibody conjugated to saporin (192 IgG–saporin) was injected into the medial septum to selectively lesion the septohippocampal cholinergic neurons. Neither the PPI deficit nor the gamma wave increase induced by PCP or a hippocampal AD was affected by 192 IgG–saporin lesion of the medial septum. It is concluded that increase in neural activity in the medial septum participates in the impairment of sensorimotor gating and the increase in hippocampal gamma waves induced by PCP or a hippocampal AD. It is suggested that the GABAergic but not the cholinergic septohippocampal neurons mediate the sensorimotor gating deficit. [Copyright &y& Elsevier]