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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]

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 medial prefrontal cortex (mPFC) is necessary for cognitive flexibility and projects to medial septum (MS). MS activation improves strategy switching, a common measure of cognitive flexibility, likely via its ability to regulate midbrain dopamine (DA) neuron population activity. We hypothesized that the mPFC to MS pathway (mPFC-MS) may be the mechanism by which the MS regulates strategy switching and DA neuron population activity. Methods Male and female rats learned a complex discrimination strategy across 2 different training time points: a constant length (10 days) and a variable length that coincided with each rat meeting an acquisition-level performance threshold (males: 5.3 ± 0.3 days, females: 3.8 ± 0.3 days). We then chemogenetically activated or inhibited the mPFC-MS pathway and measured each rat's ability to inhibit the prior learned discrimination strategy and switch to a prior ignored discrimination strategy (strategy switching). Results Activation of the mPFC-MS pathway improved strategy switching after 10 days of training in both sexes. Inhibition of the pathway produced a modest improvement in strategy switching that was quantitatively and qualitatively different from pathway activation. Neither activation nor inhibition of the mPFC-MS pathway affected strategy switching following the acquisition-level performance threshold training regimen. Activation, but not inhibition, of the mPFC-MS pathway bidirectionally regulated DA neuron activity in the ventral tegmental area and substantia nigra pars compacta, similar to general MS activation. Conclusions This study presents a potential top-down circuit from the prefrontal cortex to the midbrain by which DA activity can be manipulated to promote cognitive flexibility. [ABSTRACT FROM AUTHOR]

The medial septum (MS) contributes in pain processing and regulation, especially concerning persistent nociception. However, the role of MS glutamatergic neurons in pain and the underlying neural circuit mechanisms in pain remain poorly understood. In this study, chronic constrictive injury of the sciatic nerve (CCI) surgery was performed to induce thermal and mechanical hyperalgesia in mice. The chemogenetic activation of MS glutamatergic neurons decreased pain thresholds in naïve mice. In contrast, inhibition or ablation of these neurons has improved nociception thresholds in naïve mice and relieved thermal and mechanical hyperalgesia in CCI mice. Anterograde viral tracing revealed that MS glutamatergic neurons had projections to the lateral hypothalamus (LH) and supramammillary nucleus (SuM). We further demonstrated that MS glutamatergic neurons regulate pain thresholds by projecting to LH but not SuM, because the inhibition of MS-LH glutamatergic projections suppressed pain thresholds in CCI and naïve mice, yet, optogenetic activation or inhibition of MS-SuM glutamatergic projections had no effect on pain thresholds in naïve mice. In conclusion, our results reveal that MS glutamatergic neurons play a significant role in regulating pain perception and decipher that MS glutamatergic neurons modulate nociception via projections to LH. [ABSTRACT FROM AUTHOR]

The vast majority of studies on hippocampal rhythms have been conducted on animals or humans in situations where their attention was focused on external stimuli or solving cognitive tasks. These studies formed the basis for the idea that rhythmical activity coordinates the work of neurons during information processing. However, at rest, when attention is not directed to external stimuli, brain rhythms do not disappear, although the parameters of oscillatory activity change. What is the functional load of rhythmical activity at rest? Hippocampal oscillatory activity during rest is called the non-theta state, as opposed to the theta state, a characteristic activity during active behavior.We dedicate our review to discussing the present state of the art in the research of the non-theta state. The key provisions of the review are as follows: (1) the non-theta state has its own characteristics of oscillatory and neuronal activity; (2) hippocampal non-theta state is possibly caused and maintained by change of rhythmicity of medial septal input under the influence of raphe nuclei; (3) there is no consensus in the literature about cognitive functions of the non-theta-non-ripple state; and (4) the antagonistic relationship between theta and delta rhythms observed in rodents is not always observed in humans. Most attention is paid to the non-theta-nonripple state, since this aspect of hippocampal activity has not been investigated properly and discussed in reviews. [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]

The basal forebrain is one of the three major brain circuits involved in episodic memory formation together with the hippocampus and the diencephalon. The dysfunction of each of these regions is known to cause anterograde amnesia. While the hippocampal pyramidal neurons are known to encode episodic information and the diencephalic structures are known to provide idiothetic information, the contribution of the basal forebrain to memory formation has been exclusively associated with septo-hippocampal cholinergic signaling. Research data from the last decade broadened our understanding about the role of septal region in memory formation. Animal studies revealed that septal neurons process locomotor, rewarding and attentional stimuli. The integration of these signals results in a systems model for the mnemonic function of the medial septum that could guide new therapeutic strategies for basal forebrain impairment (BFI). BFI includes the disorders characterized with basal forebrain amnesia and neurodegenerative disorders that affect the basal forebrain. Here, we demonstrate how the updated model of septal mnemonic function can lead to innovative translational treatment approaches that include pharmacological, instrumental and behavioral techniques. [ABSTRACT FROM AUTHOR]

The medial septum (MS) is critically involved in theta rhythmogenesis and control of the hippocampal network, with which it is reciprocally connected. MS activity is influenced by brainstem structures, including the stress-sensitive, nucleus incertus (NI), the main source of the neuropeptide relaxin-3 (RLN3). In the current study, we conducted a comprehensive neurochemical and electrophysiological characterization of NI neurons innervating the MS in the rat, by employing classical and viral-based neural tract-tracing and electrophysiological approaches, and multiplex fluorescent in situ hybridization. We confirmed earlier reports that the MS is innervated by RLN3 NI neurons and documented putative glutamatergic (vGlut2 mRNA-expressing) neurons as a relevant NI neuronal population within the NI–MS tract. Moreover, we observed that NI neurons innervating MS can display a dual phenotype for GABAergic and glutamatergic neurotransmission, and that 40% of MS-projecting NI neurons express the corticotropin-releasing hormone-1 receptor. We demonstrated that an identified cholecystokinin (CCK)-positive NI neuronal population is part of the NI–MS tract, and that RLN3 and CCK NI neurons belong to a neuronal pool expressing the calcium-binding proteins, calbindin and calretinin. Finally, our electrophysiological studies revealed that MS is innervated by A-type potassium current-expressing, type I NI neurons, and that type I and II NI neurons differ markedly in their neurophysiological properties. Together these findings indicate that the MS is controlled by a discrete NI neuronal network with specific electrophysiological and neurochemical features; and these data are of particular importance for understanding neuronal mechanisms underlying the control of the septohippocampal system and related behaviors. [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]

The medial septum (MS), as part of the basal forebrain, supports many physiological functions, from sensorimotor integration to cognition. With often reciprocal connections with a broad set of peers at all major divisions of the brain, the MS orchestrates oscillatory neuronal activities throughout the brain. These oscillations are critical in generating sensory and emotional salience, locomotion, maintaining mood, supporting innate anxiety, and governing learning and memory. Accumulating evidence points out that the physiological oscillations under septal influence are frequently disrupted or altered in pathological conditions. Therefore, the MS may be a potential target for treating neurological and psychiatric disorders with abnormal oscillations (oscillopathies) to restore healthy patterns or erase undesired ones. Recent studies have revealed that the patterned stimulation of the MS alleviates symptoms of epilepsy. We discuss here that stimulus timing is a critical determinant of treatment efficacy on multiple time scales. On-demand stimulation may dramatically reduce side effects by not interfering with normal physiological functions. A precise pattern-matched stimulation through adaptive timing governed by the ongoing oscillations is essential to effectively terminate pathological oscillations. The time-targeted strategy for the MS stimulation may provide an effective way of treating multiple disorders including Alzheimer's disease, anxiety/fear, schizophrenia, and depression, as well as pain. [ABSTRACT FROM AUTHOR]

Tau accumulation and cholinergic impairment are characteristic pathologies in Alzheimer's disease (AD). However, the causal role of tau accumulation in cholinergic lesion is elusive. Here, we observed an aberrant tau accumulation in the medial septum (MS) of 3xTg and 5xFAD mice, especially in their cholinergic neurons. Overexpressing hTau in mouse MS (MShTau) for 6 months but not 3 months induced spatial memory impairment without changing object recognition and anxiety‐like behavior, indicating a specific and time‐dependent effect of MS‐hTau accumulation on spatial cognitive functions. With increasing hTau accumulation, the MShTau mice showed a time‐dependent cholinergic neuron loss with reduced cholinergic projections to the hippocampus. Intraperitoneal administration of donepezil, a cholinesterase inhibitor, for 1 month ameliorated the MS‐hTau‐induced spatial memory deficits with preservation of MS–hippocampal cholinergic pathway and removal of tau load; and the beneficial effects of donepezil was more prominent at low dose. Proteomics revealed that MS‐hTau accumulation deregulated multiple signaling pathways with numerous differentially expressed proteins (DEPs). Among them, the vacuolar protein sorting‐associated protein 37D (VP37D), an autophagy‐related protein, was significantly reduced in MShTau mice; the reduction of VP37D was restored by donepezil, and the effect was more significant at low dose than high dose. These novel evidences reveal a causal role of tau accumulation in linking MS cholinergic lesion to hippocampus‐dependent spatial cognitive damages as seen in the AD patients, and the new tau‐removal and autophagy‐promoting effects of donepezil may extend its application beyond simple symptom amelioration to potential disease modification. [ABSTRACT FROM AUTHOR]

Aims: Temporal lobe epilepsy (TLE), often associated with cognitive impairment, is one of the most common types of medically refractory epilepsy. Deep brain stimulation (DBS) shows considerable promise for the treatment of TLE. However, the optimal stimulation targets and parameters of DBS to control seizures and related cognitive impairment are still not fully illustrated. Methods: In the present study, we evaluated the therapeutic potential of DBS in the medial septum (MS) on seizures and cognitive function in mouse acute and chronic epilepsy models. Results: We found that DBS in the MS alleviated the severity of seizure activities in both kainic acid‐induced acute seizure model and hippocampal‐kindled epilepsy model. DBS showed antiseizure effects with a wide window of effective stimulation frequencies. The antiseizure effects of DBS were mediated by the hippocampal theta rhythm, as atropine, which reversed the DBS‐induced augmentation of the hippocampal theta oscillation, abolished the antiseizure effects of DBS. Further, in the kainic acid‐induced chronic TLE model, DBS in the MS not only reduced spontaneous seizures, but also improved behavioral performance in novel object recognition. Conclusion: DBS in the MS is a promising approach to attenuate TLE probably through entrainment of the hippocampal theta rhythm, which may be therapeutically significant for refractory TLE treatment. [ABSTRACT FROM AUTHOR]

Temporal lobe epilepsy with distributed hippocampal seizure foci is often intractable and its secondary generalization might lead to sudden death. Early termination through spatially extensive hippocampal intervention is not feasible directly, because of the large size and irregular shape of the hippocampus. In contrast, the medial septum is a promising target to govern hippocampal oscillations through its divergent connections to both hippocampi. Combining this 'proxy intervention' concept and precisely timed stimulation, we report here that closed-loop medial septum electrical stimulation can quickly terminate intrahippocampal seizures and suppress secondary generalization in a rat kindling model. Precise stimulus timing governed by internal seizure rhythms was essential. Cell type-specific stimulation revealed that the precisely timed activation of medial septum GABAergic neurons underlaid the effects. Our concept of time-targeted proxy stimulation for intervening pathological oscillations can be extrapolated to other neurological and psychiatric disorders, and has potential for clinical translation. [ABSTRACT FROM AUTHOR]

• GPR139 activation in the brain ameliorated Aβ 1-42 -induced cognitive impairment. • GPR139 activation alleviated Aβ 1-42 -induced apoptosis and synaptotoxicity in the basal forebrain. • GPR139 overexpression in the MS ameliorated cognitive impairment in APP/PS1 mice. • GPR139 overexpression in the MS alleviated apoptosis and synaptotoxicity in APP/PS1 mice. G-protein coupled receptors (GPCRs) constitute the largest class of cell surface receptors and present prominent drug targets. GPR139 is an orphan GPCR detected in the septum of the brain. However, its roles in cognition are still unclear. Here we first established a mouse model of cognitive impairment by a single intracerebroventricular injection of aggregated amyloid-beta peptide 1–42 (Aβ 1-42). RNA-sequencing data analysis showed that Aβ 1-42 induced a significant decrease of GPR139 mRNA in the basal forebrain. Using GPR139 agonist JNJ-63533054 and behavioral tests, we found that GPR139 activation in the brain ameliorated Aβ 1-42 -induced cognitive impairment. Using western blot, TUNEL apoptosis and Golgi staining assays, we showed that GPR139 activation alleviated Aβ 1-42 -induced apoptosis and synaptotoxicity in the basal forebrain rather than prefrontal cortex and hippocampus. The further study identified that GPR139 was widely expressed in cholinergic neurons of the medial septum (MS). Using the overexpression virus and transgenic animal model, we showed that up-regulation of GPR139 in MS cholinergic neurons ameliorated cognitive impairment, apoptosis and synaptotoxicity in APP/PS1 transgenic mice. These findings reveal that GPR139 of MS cholinergic neurons could be a critical node in cognition and potentially provides insight into the pathogenesis of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Down syndrome (DS) is a genetic disorder caused by triplication of human chromosome 21. In addition to intellectual disability, DS is defined by a premature aging phenotype and Alzheimer's disease (AD) neuropathology, including septohippocampal circuit vulnerability and degeneration of basal forebrain cholinergic neurons (BFCNs). The Ts65Dn mouse model recapitulates key aspects of DS/AD pathology, namely age-associated atrophy of BFCNs and cognitive decline in septohippocampal-dependent behavioral tasks. We investigated whether maternal choline supplementation (MCS), a well-tolerated treatment modality, protects vulnerable BFCNs from age- and genotype-associated degeneration in trisomic offspring. We also examined the effect of trisomy, and MCS, on GABAergic basal forebrain parvalbumin neurons (BFPNs), an unexplored neuronal population in this DS model. Unbiased stereological analyses of choline acetyltransferase (ChAT)-immunoreactive BFCNs and parvalbumin-immunoreactive BFPNs were conducted using confocal z -stacks of the medial septal nucleus and the vertical limb of the diagonal band (MSN/VDB) in Ts65Dn mice and disomic (2N) littermates at 3–4 and 10–12 months of age. MCS trisomic offspring displayed significant increases in ChAT-immunoreactive neuron number and density compared to unsupplemented counterparts, as well as increases in the area of the MSN/VDB occupied by ChAT-immunoreactive neuropil. MCS also rescued BFPN number and density in Ts65Dn offspring, a novel rescue of a non-cholinergic cell population. Furthermore, MCS prevented age-associated loss of BFCNs and MSN/VDB regional area in 2N offspring, indicating genotype-independent neuroprotective benefits. These findings demonstrate MCS provides neuroprotection of vulnerable BFCNs and non-cholinergic septohippocampal BFPNs, indicating this modality has translational value as an early life therapy for DS, as well as extending benefits to the aging population at large. • Investigated maternal choline supplementation in a murine Down syndrome model. • MCS increases BFCN number and density in trisomic offspring. • MCS increases medial septum regional area in offspring independent of genotype. • Trisomic mice have age-associated atrophy of GABAergic basal forebrain neurons. • MCS rescues non-cholinergic neuronal populations from degeneration in trisomic mice. [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]

Interictal spikes (IIS) are a common type of abnormal electrical activity in Alzheimer's disease (AD) and preclinical models. The brain regions where IIS are largest are not known but are important because such data would suggest sites that contribute to IIS generation. Because hippocampus and cortex exhibit altered excitability in AD models, we asked which areas dominate the activity during IIS along the cortical-CA1-dentate gyrus (DG) dorso-ventral axis. Because medial septal (MS) cholinergic neurons are overactive when IIS typically occur, we also tested the novel hypothesis that silencing the MS cholinergic neurons selectively would reduce IIS. We used mice that simulate aspects of AD: Tg2576 mice, presenilin 2 (PS2) knockout mice and Ts65Dn mice. To selectively silence MS cholinergic neurons, Tg2576 mice were bred with choline-acetyltransferase (ChAT)-Cre mice and offspring were injected in the MS with AAV encoding inhibitory designer receptors exclusively activated by designer drugs (DREADDs). We recorded local field potentials along the cortical-CA1-DG axis using silicon probes during wakefulness, slow-wave sleep (SWS) and rapid eye movement (REM) sleep. We detected IIS in all transgenic or knockout mice but not age-matched controls. IIS were detectable throughout the cortical-CA1-DG axis and occurred primarily during REM sleep. In all 3 mouse lines, IIS amplitudes were significantly greater in the DG granule cell layer vs. CA1 pyramidal layer or overlying cortex. Current source density analysis showed robust and early current sources in the DG, and additional sources in CA1 and the cortex also. Selective chemogenetic silencing of MS cholinergic neurons significantly reduced IIS rate during REM sleep without affecting the overall duration, number of REM bouts, latency to REM sleep, or theta power during REM. Notably, two control interventions showed no effects. Consistent maximal amplitude and strong current sources of IIS in the DG suggest that the DG is remarkably active during IIS. In addition, selectively reducing MS cholinergic tone, at times when MS is hyperactive, could be a new strategy to reduce IIS in AD. • Interictal spikes (IIS) occur in 3 mouse lines with Alzheimer's disease features. • IIS in all 3 mouse lines were most frequent during rapid eye movement (REM) sleep. • The dentate gyrus showed larger IIS and earlier current sources vs. CA1 or cortex. • Chemogenetic silencing of medial septum (MS) cholinergic neurons reduced IIS during REM. • MS silencing did not change REM latency, duration, number of REM bouts or theta power during REM. [ABSTRACT FROM AUTHOR]

Objectives Though the immunomodulatory role of medial septum (MS) has been indicated, but the contribution of the muscarinic acetylcholine (mAch) receptors presented in the internal network of the neurons of MS in this regard is not known. The aim of the present study is to assess the contribution of mAch receptors of MS on some immunological parameters. Methods Different immunological parameters i.e. phagocytic activity of peripheral leukocytes, adhesibility and cytotoxicity of splenic mononuclear cells (MNC), delayed type of hypersensitivity (DTH) responses, Total Count (TC) and Differential Count (DC) of WBC with serum corticosterone (CORT) concentration have been measured after stimulation and blocking of mAch receptors of MS in rats. Ach or atropine has been micro infused into MS of separate groups of rats for stimulating or blocking of the mAch receptors respectively. Results In Ach or atropine microinfused rats, the TC of WBC remained unaltered in the present study. The percentage of neutrophil has increased and the percentage of lymphocyte has decreased in Ach microinfused rats, but these parameters remain unaltered in atropine microinfused rats. The observed immunological parameters have increased after microinfusion of 0.60 μM and 0.12 μM of Ach and serum CORT concentration has decreased in those animals. These immunological parameters have decreased and serum CORT has increased after microinfusion of atropine (2 and 4 mM) in MS of rats. Conclusion It appears that the Ach receptors in MS can modulate the observed immunological parameters, and serum CORT plays an important role for these immune changes. [ABSTRACT FROM AUTHOR]

The present study evaluates the roles of serotonergic receptors of the medial septum on amnesia induced by arachidonylcyclopropylamide (ACPA; as selective cannabinoid CB1 receptor agonist) in adult male Wistar rats. Cannulae were implanted in the medial septum of the brain of the rats. The animals were trained in a passive avoidance learning apparatus, and were tested 24 hours after training for step-through latency. Results indicated that post-training medial septum administration of CP94253 (5-HT1B/1D receptor agonist) and cinancerine (as 5-HT2 receptor antagonist) reduced the step-through latency showing an amnesic response, while GR127935 (5-HT1B/1D receptor antagonist) and αm5htm (as 5-HT2A/2B/2D receptor agonist) did not alter memory consolidation by themselves. On continuing the test, the results showed that CP94253 increased and GR127935 did not alter ACPA (0.02 µg/rat)-induced memory impairment, respectively. Other data indicated that αm5htm induced a modulatory effect, while cinancerine restored ACPA-induced amnesia. Using SKF-96365 (inhibitor of transient receptor potential TRPC3/6 and TRPV2 channels) demonstrated that TRPC3, TRPC3 and TRPV2 channels have a significant role, according to our results. [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 septo-hippocampal GABAergic pathway connects inhibitory neurons in the medial septum with hippocampal interneurons. Phasic release of GABA from septo-hippocampal terminals is thought to play an important role in shaping hippocampal network activity during behavior. Here, we found that GABA release from septo-hippocampal terminals is under negative feedback from the hippocampal local inhibitory network. We found that the strength of septo-hippocampal GABAergic inhibition is constrained by presynaptic GABA b receptors that are activated by ambient GABA during states of increased hippocampal network activity. This article is part of the Special Issue entitled ‘GABAergic Signaling in Health and Disease’. [ABSTRACT FROM AUTHOR]

The medial septum (MS) is required for theta rhythmic oscillations and grid cell firing in the medial entorhinal cortex (MEC). While GABAergic, glutamatergic, and cholinergic neurons project from the MS to the MEC, their synaptic targets are unknown. To investigate whether MS neurons innervate specific layers and cell types in the MEC, we expressed channelrhodopsin-2 in mouse MS neurons and used patch-clamp recording in brain slices to determine the response to light activation of identified cells in the MEC. Following activation of MS axons, we observed fast monosynaptic GABAergic IPSPs in the majority (>60%) of fast-spiking (FS) and low-threshold-spiking (LTS) interneurons in all layers of the MEC, but in only 1.5% of nonstellate principal cells (NSPCs) and in no stellate cells. We also observed fast glutamatergic responses to MS activation in a minority (<5%) of NSPCs, FS, and LTS interneurons. During stimulation of MS inputs at theta frequency (10 Hz), the amplitude of GABAergic IPSPs was maintained, and spike output from LTS and FS interneurons was entrained at low (25- 60 Hz) and high (60-180 Hz) gamma frequencies, respectively. By demonstrating cell type-specific targeting of the GABAergic projection from the MS to the MEC, our results support the idea that the MS controls theta frequency activity in the MEC through coordination of inhibitory circuits. [ABSTRACT FROM AUTHOR]

Hippocampal oscillations are critical for information processing, and are strongly influenced by inputs from the medial septum. Hippocamposeptal neurons provide direct inhibitory feedback from the hippocampus onto septal cells, and are therefore likely to also play an important role in the circuit; these neurons fire at either low or high frequency, reflecting hippocampal network activity during theta oscillations or ripple events, respectively. Here, we optogenetically target the long-range GABAergic projection from the hippocampus to the medial septum in rats, and thereby simulate hippocampal input onto downstream septal cells in an acute slice preparation. In response to optogenetic activation of hippocamposeptal fibers at theta and ripple frequencies, we elicit postsynaptic GABAergic responses in a subset (24%) of septal cells, most predominantly in fast-spiking cells. In addition, in another subset of septal cells (19%) corresponding primarily to cholinergic cells, we observe a slow hyperpolarization of the resting membrane potential and a decrease in input resistance, particularly in response to prolonged high-frequency (ripple range) stimulation. This slow response is partially sensitive to GIRK channel and D2 dopamine receptor block. Our results suggest that two independent populations of septal cells distinctly encode hippocampal feedback, enabling the septum to monitor ongoing patterns of activity in the hippocampus. [ABSTRACT FROM AUTHOR]

Highlights: [•] Ketamine induced changes in behaviors and electrophysiology in rats. [•] Behavioral changes included hyperlocomotion and loss of prepulse inhibition. [•] Physiological changes included enhanced hippocampal gamma and reduced auditory gating. [•] Deep brain stimulation of medial septum or n. accumbens normalized the behaviors. [•] Medial septal deep brain stimulation normalized hippocampal gamma and auditory gating. [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]

Novel targets for treating feeding-related diseases are of great importance, and histamine has long been considered an anorexigenic agent. However, understanding its functions in feeding in a circuit-specific way is still limited. Here, we report a medial septum (MS)-projecting histaminergic circuit mediating feeding behavior. This MS-projecting histaminergic circuit is functionally inhibited during food consumption, and bidirectionally modulates feeding behavior via downstream H2, but not H1, receptors on MS glutamatergic neurons. Further, we observed a pathological decrease of histamine 2 receptors (H2Rs) expression in MS glutamatergic neurons in diet-induced obesity (DIO) mice. Genetically, down-regulation of H2Rs expression in MS glutamatergic neurons accelerates body-weight gain. Importantly, chronic activation of H2Rs in MS glutamatergic neurons (with its clinical agonist amthamine) significantly slowed down the body-weight gain in DIO mice, providing a possible clinical utility to treat obesity. Together, our results demonstrate that this MS-projecting histaminergic circuit is critically involved in feeding, and H2Rs in MS glutamatergic neurons is a promising target for treating body-weight problems. [Display omitted] • MS-projecting histaminergic circuit bidirectionally modulates feeding behavior • H2Rs in the MS glutamatergic neurons mediate anorexic effect of histamine • H2Rs are pathologically decreased in MS glutamatergic neurons in DIO mice • Genetic modulation of H2Rs in MS glutamatergic neurons affects body weight Xu et al. reveal a novel medial septum (MS)-projecting histaminergic circuit mediating feeding behavior via downstream H2R-dependent signaling in MS glutamatergic neurons. Notably, the expression of H2R is pathologically decreased in MS of obese mice and genetic targeting H2R in MS glutamatergic neurons bidirectionally modulates body weight. [ABSTRACT FROM AUTHOR]

The immunomodulatory role of medial septum (MS) has been explored so far only in MS lesioned rats. But in MS lesioned rats, all the nerve cells and fibres of the lesioned area are damaged and the specific role of the neural circuits of MS on immunomodulation cannot be assessed from the lesion of MS. Considering the presence of a large number of glutamate receptors in MS, the specific role of glutamate receptors stimulation on some immune responses has been investigated in the present study. Hyperreactive behaviour, TC and DC of WBC, phagocytic activity of peripheral leukocytes, adhesibility and cytotoxicity of splenic mononuclear cells (MNC), delayed type of hypersensitivity (DTH) responses and the serum corticosterone (CORT) were measured after microinfusion of glutamate into MS of rats. To ascertain the specific role of those glutamate receptors, the parameters were also measured after microinfusion of glutamate receptor blocker 6, 7-dinitroquinoxaline-2, 3-dione (DNQX). The hyperreactive behaviour, TC and DC of WBC remained unaltered after stimulation or blocking of glutamate receptors. The phagocytic activity, adhesibility and cytotoxicity of splenic MNC, and DTH responses were increased after infusion of 0.25 and 0.5µM glutamate. But after infusion of higher dose of glutamate (1µM), the phagocytic activity and the adhesibility of splenic MNC were decreased and other parameters remained unaltered in that condition. After infusion of 4 and 8mM DNQX all the observed immunological parameters were decreased. The CORT concentration was decreased after infusion of 0.25 and 0.5µM of glutamate but it was increased after infusion of 1µM glutamate or 4 and 8mM DNQX. Results indicate that the medial septal glutamate receptors play an important role in the modulation of some immune responses. [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: Amyloid β (Aβ) peptides play a central role in the pathophysiology of Alzheimer''s disease (AD). The cellular mechanisms underlying Aβ toxicity, however, are poorly understood. Here we show that Aβ25-35 and Aβ1-40 acutely and differentially affect the characteristics of 3 classes of medial septum (MS) neurons in mice. In glutamatergic neurons Aβ increases firing frequency and blocks the A- and the M-current (IA and IM, respectively). While the IA block is similar in other MS neuron classes, the block of IM is specific to glutamatergic neurons. IM block and a simulated Aβ block mimic the Aβ-induced increase in spontaneous firing in glutamatergic neurons. Calcium imaging shows that under control conditions glutamatergic neurons rarely fire while nonglutamatergic neurons fire coherently at theta frequencies. Aβ increases the firing rate of glutamatergic neurons while nonglutamatergic neurons lose theta firing coherence. Our results demonstrate that Aβ-induced dysfunction of glutamatergic neurons via IM decrease diminishes MS rhythmicity, which may negatively affect hippocampal rhythmogenesis and underlie the memory loss observed in Alzheimer''s disease. [Copyright &y& Elsevier]

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: Layer II of the parasubiculum (PaS) receives excitatory synaptic input from the CA1 region of the hippocampus and sends a major output to layer II of the medial and lateral entorhinal cortex. The PaS also receives heavy cholinergic innervation from the medial septum, which contributes to the generation of theta-frequency (4–12 Hz) electroencephalographic (EEG) activity. Cholinergic receptor activation exerts a wide range of effects in other areas of the hippocampal formation, including membrane depolarization, changes in neuronal excitability, and suppression of excitatory synaptic responses. The present study was aimed at determining how cholinergic receptor activation modulates excitatory synaptic input to the layer II/III neurons of the PaS in acute brain slices. Field excitatory postsynaptic potentials (fEPSPs) in layer II/III of the PaS were evoked by stimulation of either layer I afferents, or ascending inputs from layer V. Bath-application of the cholinergic agonist carbachol (0.5–10 μM) suppressed the amplitude of fEPSPs evoked by both superficial- and deep layer stimulation, and also enhanced paired-pulse facilitation. Constant bath-application of the GABAA antagonist bicuculline (10 μM) failed to eliminate the suppression, indicating that the cholinergic suppression of fEPSPs is not due to increased inhibitory tone. The muscarinic receptor antagonist atropine (1 μM) blocked the suppression of fEPSPs, and the selective M1-preferring receptor antagonist pirenzepine (1 μM), but not the M2-preferring antagonist methoctramine (1–5 μM), also significantly attenuated the suppression. Therefore, cholinergic receptor activation suppresses excitatory synaptic input to layer II/III neurons of the PaS, and this suppression is mediated in part by M1 receptor activation. [Copyright &y& Elsevier]

Abstract: The medial septum/diagonal band complex (MSDB) controls hippocampal excitability, rhythms and plastic processes. Medial septal neuronal populations display heterogeneous firing patterns. In addition, some of these populations degenerate during age-related disorders (e.g. cholinergic neurons). Thus, it is particularly important to examine the intrinsic properties of theses neurons in order to create new agents that effectively modulate hippocampal excitability and enhance memory processes. Here, we have examined the properties of voltage-gated, K+ currents in electrophysiologically-identified neurons. These neurons were taken from young rat brain slices containing the MS/DB complex. Whole-cell, patch recordings of outward currents were obtained from slow firing, fast-spiking, regular-firing and burst-firing neurons. Slow firing neurons showed depolarization-activated K+ current peaks and densities larger than in other neuronal subtypes. Slow firing total current exhibited an inactivating A-type current component that activates at subthreshold depolarization and was reliably blocked by high concentrations of 4-AP. In addition, slow firing neurons expressed a low-threshold delayed rectifier K+ current component with slow inactivation and intermediate sensitivity to tetraethylammonium. Fast-spiking neurons exhibited the smaller I K and I A current densities. Burst and regular firing neurons displayed an intermediate firing phenotype with I K and I A current densities that were larger than the ones observed in fast-spiking neurons but smaller than the ones observed in slow-firing neurons. In addition, the prevalence of each current differed among electrophysiological groups with slow firing and regular firing neurons expressing mostly I A and fast spiking and bursting neurons exhibiting mostly delayer rectifier K+ currents with only minimal contributions of the I A. The pharmacological or genetic modulations of these currents constitute an important target for the treatment of age-related disorders. [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]

Abstract: The median preoptic nucleus (MnPO), part of the anteroventral third ventricular region, plays a key role in body fluid homeostasis and cardiovascular regulation. Recently, a cluster of neurons showing sleep-related c-fos immunoreactivity was found in the rat MnPO, and a subsequent electrophysiological study found that nearly 76% of rat MnPO neurons exhibit increased discharge during sleep. In a recent single unit recording study in mice, we found that sleep-active neurons are not localized in any specific region of the preoptic/basal forebrain (POA/BFB). However, the discharge profiles of mouse MnPO neurons across wake-sleep states remained to be determined. In this study, we therefore examined whether the mouse MnPO contains a high proportion of sleep-active neurons and constitutes a distinct cluster of sleep-promoting neurons in the median preoptic region. We recorded a total of 234 single units in the MnPO, the laterally adjacent peri-MnPO, the dorsally adjacent medial septum (MS), and the ventrally adjacent periventricular (Pe)/medial preoptic (MPO) area (Pe/MPO). We found that the MnPO contained similar proportions of sleep-active (31.9%) and waking (W)-active (33.0%) neurons, together with many waking/paradoxical sleep (W/PS)-active neurons (23.4%), whereas the Pe/MPO and MS contained a high proportion of sleep-active neurons (66.0 and 62.9%, respectively), while the peri-MnPO contained a high proportion of W-active neurons (57.1%). In the MnPO, both W-active and W/PS-active neurons were distributed throughout the nucleus, whereas sleep-active neurons were mostly located on its border. Only slowly discharging (<5 Hz) slow-wave sleep (SWS)/PS-selective neurons were found in the MnPO. During the transition from W to SWS, all of these SWS/PS-selective neurons fired not before, but after, sleep onset, with a gradual increase in discharge rate. In addition to its well-known homeostatic and cardiovascular functions, the MnPO might modulate the sleep-waking cycle by playing different roles in sleep/wake state regulation. [Copyright &y& Elsevier]

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]

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]

The medial septum diagonal band area (MS/DB) projects to the hippocampus through the fornix/fimbria pathway and is implicated in generating hippocampal theta oscillations. The hippocampus also projects back to the MS/DB, but very little is known functionally about this input. Here, we investigated the physiological role of hippocamposeptal feedback to the MS/DB in a complete in vitro septohippocampal preparation containing the intact interconnecting fornix/fimbria pathway. We demonstrated that carbachol-induced rhythmic thetalike hippocampal oscillations recorded extracellularly were synchronized with powerful rhythmic IPSPs in whole-cell recorded MS/DB neurons. Interestingly, we found that these IPSPs evoked rebound spiking in GABAergic MS/DB neurons. In contrast, putative cholinergic and glutamatergic MS/DB neurons responded only weakly with rebound spiking and, as a result, were mostly silent during theta-like oscillations. We next determined the mechanism underlying the rebound spiking that followed the IPSPs in MS/DB GABAergic neurons using phasic electrical stimulation of the fornix/fimbria pathway. We demonstrate that the increased rebound spiking was attributable to the activation of Ih current, because it was significantly reduced by low concentrations of the Ih antagonist ZD7288 [4-(N-ethyl-N-phenylamino)- 1,2-dimethyl-6-(methylamino) pyridinium chloride]. Together, these results suggest that rhythmical activity in hippocampus is transferred to the MS/DB and can preferentially phase the spiking of GABAergic MS/DB neurons because of their significant expression of Ih currents. Our data demonstrate that hippocamposeptal inhibition facilitates theta rhythmic discharges in MS/DB GABAergic neurons while favoring the inhibition of most ACh and glutamate neurons. [ABSTRACT FROM AUTHOR]

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]

Abstract: In the present study, the effects of intra-medial septum injections of histamine and/or the histamine H1 or H2 receptor antagonists on the acquisition of conditioned place preference (CPP) in male Wistar rats have been investigated. Our data showed that the conditioning treatments with intra-medial septum injection of different doses of histamine (0.5–15 μg/rat) induced a significant CPP for the drug-associated place. Using a 3-day schedule of conditioning, it was found that the histamine H1 receptor antagonist, pyrilamine (10 and 15 μg/rat, intra-medial septum) also induced a significant place preference. In addition, pyrilamine inhibited the histamine (7.5 μg/rat)-induced place preference. Intra-medial septum administration of the histamine H2 receptor antagonist, ranitidine (5–15 μg/rat) alone or in combination with histamine did not produce a significant place preference or place aversion. On the other hand, intra-medial septum administration of the dopamine D1 receptor antagonist, SCH 233390 (0.5, 0.75 and 1 μg/rat) inhibited the histamine (7.5 μg/rat) or pyrilamine (15 μg/rat)-induced place preference in a dose-dependent manner, but no effect was observed for the dopamine D2 receptor antagonist, sulpiride on the histamine or pyrilamine response. The administration of histamine (2.5–15 μg/rat) or pyrilamine (10 and 15 μg/rat) during acquisition increased locomotor activity of the animals on the testing days. The results suggest that histaminergic receptors of the medial septum may be involved in CPP and thus it is postulated that dopamine D1 receptors may play an important role in this effect. [Copyright &y& Elsevier]

Abstract: The septal region of the brain consists of a heterogeneous population of GABAergic neurons that play an important role in the generation of hippocampal theta rhythms. While GABAergic neurons employ two isoforms of the enzyme glutamic acid decarboxylase (GAD) for the synthesis of GABA, distribution of GAD isoforms has not been investigated in the septum. Immunohistochemical techniques were used to investigate the expression of GAD enzymes in medial and lateral septum. GAD65 and GAD67 immunohistochemistry revealed dense fibers and punctuated immunoreactivity in septal regions. While few GAD65-positive neuronal somas were detected in medial septum, a significantly higher number of immunoreactive neurons were detected in lateral septum. GAD65- and GAD67-positive neurons in the lateral septum exhibit higher complexity of dendritic arborizations than in the medial septum where staining was mainly restricted to the soma. Presumptive axon terminals (puncta) showed abundant immunoreactivity predominantly for GAD65 isoforms in all septal regions. This suggests that septal GABAergic neurons differentially express GAD enzymes thereby potentially reflecting functional differences. Differences found between medial and lateral septal GABAergic neuronal populations are in agreement with the concept that medial and lateral septum are brain structures with highly different connectivity and function despite anatomical proximity. [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]

Rationale. In rats, 5-HT1A receptors are present in the septal region, e.g. on cholinergic neurons of the medial septum, where they might be a substrate for cognitively relevant interactions between cholinergic and serotonergic systems. Objective. The present experiment assessed the effects of the stimulation of septal 5-HT1A receptors on spatial working memory. Methods. Stimulation of septal 5-HT1A receptors was carried out by infusions targetting the medial septum of the 5-HT1A/5-HT7 receptor agonist 8-hydroxy-2-(di-n-propyl-amino)-tetralin (8-OH-DPAT; 0.5 or 4 µg). Spatial memory was assessed in a water maze using a protocol placing emphasis on spatial working memory. The location of the hidden platform was changed every day and performance was assessed on two consecutive trials each day. Results. In comparison to vehicle injections, the intraseptal infusion of 4 µg 8-OH-DPAT impaired performance significantly: rats treated with 8-OH-DPAT exhibited increased distances to reach the hidden platform on both trials 1 and 2. Rats infused with 0.5 µg showed similar changes that failed to be significant. Such effects were not observed when the platform was visible. Conclusions. These results extend those of a previous experiment which showed that intraseptal injections of 8-OH-DPAT impaired spatial reference memory. Based on the characteristics of the observed deficits, it is suggested that the 8-OH-DPAT-induced impairment, rather than being only the result of a true alteration of working memory, might reflect a more global cognitive deficiency in which alteration of general memory capacities may be biased by disrupted search strategies/exploration and/or dysfunctions of attention. [ABSTRACT FROM AUTHOR]

This experiment examined the effects of co-infusing the GABA agonist muscimol (0.5 nmol) with 33 nmol of glucose, pyruvate, fructose or sorbitol into the medial septum on spontaneous alternation. Only co-infusions of muscimol with glucose or pyruvate impaired spontaneous alternation performance; none of the other infusions had any significant effects. The findings suggest that glucose metabolism rather than hyperosmolarity is involved in the memory-impairing interaction between glucose and muscimol. [Copyright &y& Elsevier]

The induction of hippocampal theta by reticular stimulation involves a relay to the hippocampus via the posterior hypothalamic–supramammillary region and then the medial septum. Interestingly, sensory- or behaviour-induced theta is accompanied by suppression of hippocampal field CA1 synaptic responses. In the present study, performed on anaesthetized rats, we observed that reticular stimulation also induced a suppression of the CA1 pyramidal cell population spike and the corresponding dendritic field excitatory postsynaptic potential evoked by field CA3 stimulation. This suppression was observed at stimulation intensity below the threshold for generation of CA1 theta and was maximal at stimulation intensities at the threshold for theta. The frequency and amplitude of theta waves, by contrast, increased further with increasing reticular stimulation voltage. Neural inactivation by microinjection of the local anaesthetic procaine (20% w/v, 0.1–0.2 µL) or the inhibitory ligand gamma aminobutyric acid (0.8 m, 0.5 µL) in the posterior hypothalamic regions, especially the ipsilateral medial supramammillary region, or the medial septum attenuated both the suppression of CA1 pyramidal cell synaptic excitability and theta generation. However, the effects of microinjection on suppression and theta were not always in parallel. Furthermore, the effect of microinjection of gamma aminobutyric acid on reticularly elicited suppression was observed from relatively fewer sites in the posterior hypothalamus as compared with that on theta activation. These results suggest that reticular stimulation evokes an inhibition of CA1 pyramidal cell excitability that (i) is mediated, at least in part, via medial supramammillary and septal regions, but (ii) involves a separate neural pathway from theta generation. [ABSTRACT FROM AUTHOR]

The role of the nucleus basalis magnocellularis (NBM) and the medial septum (MS) in postoperative memory acquisition and postoperative memory retention was assessed in the eight-arm radial maze task (Olton) NBM lesions and MS lesion significantly decreased choline acetyltransferase (CAT) activity in the innervated areas. Animals with MS lesion, but not NBM lesions, showed significant impairment of memory acquisition. NBM lesions induced a unique strategic pattern, but the development of strategic pattern with training was comparable to the sham-injected group. Animals with MS lesion did not develop strategic pattern with training. NBM and MS lesions did not influence either memory retention or developed strategic pattern. These results suggest that (1) MS contributes to the radial maze task; (2) the two systems have qualitatively different contributions in the radial maze task; (3) the two systems do not contribute to memory retention; (4) the two major cholinergic systems have different functions in the pathophysiology of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Chronic extracellular recordings were obtained from cells of the medial septum and diagonal band of Broca in rats performing a simple behavioural task. The cells were found to display a variety of bursting patterns phase-locked to hippocampal theta rhythm to a greater or lesser degree. Among phase-locked cells, no systematic distribution in preferential phase could be found, and these cells were shown to maintain their preferential phase for extended periods. Cells were classified into those which showed signs of a broadening of the repolarization phase of their action potential (‘inflected’: putative cholinergic) and those without (‘non-inflected’: putative GABAergic). Non-inflected cells tended to fire rhythmic bursts while inflected cells mostly fired in an irregular fashion, although still significantly phase-locked to hippocampal theta. In neither population did the phase-locked cells show any coherent distribution of their preferential phase. Sixty-five per cent of the rhythmically bursting cells showed a significant correlation between the interburst frequency and the animal’s running speed. Five cells displayed rhythmic activity only when the rat ran in a specific direction. These results have implications for models of septohippocampal function and the effects of variable septal rhythmicity on the production of hippocampal theta rhythm. [ABSTRACT FROM AUTHOR]

The medial septum/diagonal band of Broca (MS/DBB) receives direct GABAergic input from the hippocampus via hippocamposeptal (HS) projection neurons as part of a reciprocal loop that mediates cognition and is altered in Alzheimer's disease. Cholinergic and GABAergic interactions occur throughout the MS/DBB, but it is not known how HS GABA release is impacted by these circuits. Most HS neurons contain somatostatin (SST), so to evoke HS GABA release we expressed Cre-dependent mCherry/channelrhodopisin-2 (ChR2) in the hippocampi of SST-IRES-Cre mice and then used optogenetics to stimulate HS fibers while performing whole-cell patch clamp recordings from MS/DBB neurons in acute slices. We found that the acetylcholine receptor (AChR) agonist carbachol and the GABA B receptor (GABA B R) agonist baclofen significantly decreased HS GABA release in the MS/DBB. Carbachol's effects were blocked by eliminating local GABAergic activity or inhibiting GABA B Rs, indicating that it was indirectly decreasing HS GABA release by increasing GABAergic tone. There was no effect of acute exposure to amyloid-β on HS GABA release. Repetitive stimulation of HS fibers increased spontaneous GABA release in the MS/DBB, revealing that HS projections can modulate local GABAergic tone. These results show that HS GABA release has far-reaching impacts on overall levels of inhibition in the MS/DBB and is under regulatory control by cholinergic and GABAergic activity. This bidirectional modulation of GABA release from local and HS projections in the MS/DBB will likely have profound impact not only on activity within the MS/DBB, but also on output to the hippocampus and hippocampal-dependent learning and memory. • Hippocamposeptal GABA release is indirectly modulated by muscarinic receptors. • Hippocamposeptal GABA release is directly modulated by GABA B receptors. • Spontaneous GABA release is increased following train hippocamposeptal stimulation. • Hippocamposeptal GABA release is not affected by acute exposure to amyloid-β. [ABSTRACT FROM AUTHOR]

• Medial septal nucleus ablation caused pronounced increase of water intake of sheep. • Thirst satiety due to acute pre-systemic factors is not affected by septal lesions. • Prolonged primary hyperdipsia occurs by 2 weeks after septal ablation. Previous experiments in rodents showed that ablation of the septal brain region caused hyperdipsia. We investigated which part of the septal region needs ablation to produce hyperdipsia in sheep, and whether increased drinking was a primary hyperdipsia. Following ablation of the medial septal region (n = 5), but not parts of the lateral septal region (n = 4), daily water intake increased from ~2.5–5 L/day up to 10 L/day for up to 3 months post-lesion. In hyperdipsic sheep, plasma osmolality increased on the first day post-lesion and body weight fell, suggesting that initial hyperdipsia was secondary to fluid loss. However hyperosmolality was not sustained long-term and plasma hypo-osmolality persisted from 0.5 to 3 months post-lesion. Acute dipsogenic responses to intravenous hypertonic saline, intravenous or intracerebroventricular angiotensin II, water deprivation for 2 days, or feeding over 5 h were not potentiated by medial septal lesions, showing that the rapid pre-systemic inhibitory influences that cause satiation of thirst upon the act of drinking were intact. However, hyperdipsic sheep continued to ingest water when hyponatremic (plasma [Na] was 127–132 mmol/l) and plasma osmolality was 262–268 mosmol/kg due to retention of ingested fluid resulting from intravenous infusion of vasopressin administered to maintain a basal blood level of antidiuretic hormone. The results show that septal lesion-induced hyperdipsia is not due to disruption of acute pre-systemic influences associated with drinking water that initiates rapid satiation of thirst. Rather, inhibitory influences of hyponatremia, hypo-osmolality or hypervolemia on drinking appear to be disrupted by medial septal lesions. [ABSTRACT FROM AUTHOR]