Lateral Septal Nucleus Neurons Research Articles

Co-transmitting neurons in the lateral septal nucleus exhibit features of neurotransmitter switching.

The lateral septal nucleus (LSN) is a highly interconnected region of the central brain whose activity regulates widespread circuitry. As such, the mechanisms that govern neuronal activity within the LSN have far-reaching implications on numerous brain-wide nuclei, circuits, and behaviors. We found that GABAergic neurons within the LSN express markers that mediate the release of acetylcholine (ACh). Moreover, we show that these vGATLSN neurons release both GABA and ACh onto local glutamatergic LSN neurons. Using both short-term and long-term neuronal labeling techniques we observed expression of the cholinergic neuron marker Choline Acetyltransferase (ChAT) in vGATLSN neurons. These findings provide evidence of cholinergic neurotransmission from vGATLSN neurons, and provide an impetus to examine dynamic co-neurotransmission changes as a potential mechanism that contributes to neuronal and circuit-wide plasticity within the LSN.

Melanin-concentrating hormone neurons release glutamate for feedforward inhibition of the lateral septum.

Melanin-concentrating hormone (MCH) regulates vital physiological functions, including energy balance and sleep. MCH cells are thought to be GABAergic, releasing GABA to inhibit downstream targets. However, there is little experimental support for this paradigm. To better understand the synaptic mechanisms of mouse MCH neurons, we performed neuroanatomical mapping and characterization followed by optogenetics to test their functional connectivity at downstream targets. Synaptophysin-mediated projection mapping showed that the lateral septal nucleus (LS) contained the densest accumulation of MCH nerve terminals. We then expressed channel rhodopsin-2 in MCH neurons and photostimulated MCH projections to determine their effect on LS activity. Photostimulation of MCH projections evoked a monosynaptic glutamate release in the LS. Interestingly, this led to a feedforward inhibition that depressed LS firing by a robust secondary GABA release. This study presents a circuit analysis between MCH and LS neurons and confirms their functional connection via monosynaptic and polysynaptic pathways. Our findings indicate that MCH neurons are not exclusively GABAergic and reveal a glutamate-mediated, feedforward mechanism that inhibits LS cells.

Depolarization potentials in mouse lateral septal nucleus neurons mediated by TRPC4‐like channels

The lateral septal nucleus (LSN) neurons express high levels of Canonical Transient Receptor Potential type 4 (TRPC4). In this study, we examined electrophysiological properties evoked by manipulations known to activate TRPC4 channels in LSN neurons from mouse brain slices using whole cell current clamp recordings. We show that: 1) pressure injection of (S)‐3,5‐DHPG to LSN neurons induced an instant burst firing on top of a prolonged depolarization plateau, 2) superfusion of the slice with DHPG caused membrane potential oscillations and repetitive burst firing of LSN neurons, 3) depolarization current injection increased the occurrence of depolarization plateau induced by DHPG and prolonged the plateau duration, 4) pretreatment of brain slices with pertussis toxin suppressed DHPG‐induced depolarization plateau in majority of the LSN neurons, 5) the DHPG‐induced depolarization plateau was blocked by a novel TRPC4 channel blocker, shown to be selective for TRPC4 and TRPC5 in heterologous expression systems, suggesting that the major component of the depolarization plateau is mediated by TRPC4 channels. These results demonstrate the involvement of TRPC4 channels in the integration of excitatory inputs of LSN neurons through metabotropic receptor and G protein signaling. Supported by NIH grant DK081654

P03-109 - Involvement of the lateral septal nucleus and GABA a receptors in the antidepressant-like effects of allopregnanolone in wistar rats

IntroductionPharmacological and non-pharmacological antidepressant therapies increase the firing rate of lateral septal nucleus neurons (a brain structure involved in mood state regulation) and reduce immobility in the forced swim test (FST), whereas the neurosteroid allopregnanolone appears to produce antidepressant-like effects through actions at GABAA receptors.ObjectiveTo explore the participation of the lateral septal nucleus and GABAA receptors in the antidepressant-like effects of allopregnanolone in Wistar rats.MethodsFirst, the minimally effective dose of allopregnanolone that produces antidepressant-like effects in the FST was determined. Second, the effect of this minimally effective dose in the FST was evaluated on the firing rate of lateral septal neurons. Third, the antidepressant-like effects of microinjection of allopregnanolone (1.0 μg/rat) into the lateral septal nucleus was evaluated in the FST. Fourth, we explored whether the effects of allopregnanolone on the lateral septal neuron firing rate and FST are blocked by picrotoxin or bicuculline, two GABAA receptor antagonists.ResultsThe minimally effective dose of allopregnanolone with antidepressant-like effects in the FST was 1.0 mg/kg (i.p.) and significantly increased the firing rate of lateral septal neurons. Microinjection of allopregnanolone into the lateral septal nucleus produced antidepressant-like effects in the FST. Pretreatment with picrotoxin and bicuculline blocked the increase in lateral septal neuron firing rate and the antidepressant-like effects of allopregnanolone in the FST.ConclusionThe lateral septal nucleus participates in the antidepressant-like effects of allopregnanolone through actions on GABAA receptors in Wistar rats.

Allopregnanolone reduces immobility in the forced swimming test and increases the firing rate of lateral septal neurons through actions on the GABAAreceptor in the rat

Since allopregnanolone reduces the total time of immobility in rats submitted to the forced swimming test, we decided to explore whether this neuroactive steroid shares other antidepressant-like actions, such as increasing the neuronal firing rate in the lateral septal nucleus (LSN). In order to discard the influence of the oestrous cycle on immobility and on the firing rate of LSN neurons, all Wistar rats used in the study underwent ovariectomy before treatments. A group of rats received different doses of allopregnanolone (0.5, 1.0, 2.0 and 3.0 mg/kg, i.p.) 1 hour before being forced to swim in order to identify the minimum effective dose diminishing immobility. None of the tested doses of allopregnanolone produced significant changes in motor activity in the open-field test. The minimum dose of allopregnanolone producing a significant reduction in the total time of immobility (p<0.05) against the vehicle was 1.0 mg/kg, while 2.0 mg/kg and above also increased the latency to the first period of immobility (p<0.05). The minimum effective dose of allopregnanolone reducing immobility in the forced swimming test (1.0 mg/kg) significantly (p <0.05) produced a higher (twofold) neuronal firing rate in LSN neurons, but did not produce any change in septofimbrial nucleus neurons, which fired at a rate similar to that of vehicle-treated rats. The pretreatment with the non-competitive GABAA receptor antagonist, picrotoxin (1.0 mg/kg), blocked the aforementioned actions of allopregnanolone on both immobility and LSN firing rate. In conclusion, allopregnanolone produces an antidepressant-like effect in the forced swimming test, associated with an increase in the LSN neuronal firing rate, seemingly mediated by the GABAA receptor.

Spontaneous firing rate of lateral septal neurons decreases after forced swimming test in Wistar rat

The systemic or local administration of diverse antidepressants increases the neuronal firing rate of the lateral septal nucleus (LSN), whereas some stressful situations decrease its firing rate; however, any long-lasting effect exerted by the forced swimming (FS) test (15-min pretest and 5-min test 24 h later) on the firing rate of the LSN is unknown. Therefore, single-unit extracellular recordings were obtained from the LSN neurons of control rats (Ctrl, n=6) and FS rats ( n=10) 2 h after the last swimming session. In other rats, spontaneous firing rate of cortical neurons was recorded under the same experimental conditions. The firing rate of the LSN neurons of the animals in the FS group was significantly lower (9.2±1.7 spikes/10 s; P<.004, n=35) in comparison with the Ctrl group (21.1±3.4 spikes/10 s, n=22). The reduced firing rate in the LSN after swimming tests was both evident and generalized given that ∼83% of the total recorded neurons from the FS group fired below the mean±1 S.D. rate obtained from the Ctrl group. Accordingly, the mean first-order interval of neuronal firing rate in the FS group (621.3±22.6 ms) was significantly greater ( P<.05) than that observed in the Ctrl group (391.5±29.2 ms), but no significant differences were found in the variation coefficient of these two experimental groups, illustrating regularity of firing. Nonsignificant differences or even an opposite trend were observed in the firing rate of cortical neurons in the FS group (26.3±8.4 spikes/10 s) as compared with Ctrl group (15.4±1.1 spikes/10 s). Accordingly, no differences were found in the variation coefficient (FS 55.3±7.2%, Ctrl 55.8±3.6%) or average first-order interval (FS 417.8±71.8 ms, Ctrl 494.1±64.5 ms). We conclude that the FS test constitutes a situation whose capacity for inducing long-lasting despair is reflected in a reduction in the firing rate of LSN neurons as it occurs in situations of anxiety and fear, contrary to the actions of antidepressant drugs.

Intraaccumbens dopaminergic lesion suppresses desipramine effects in the forced swim test but not in the neuronal activity of lateral septal nucleus

The nucleus accumbens (NAcc) function is related to locomotor activity, while the lateral septal nucleus (LSN) is related to the motivational aspects of behavior. Thus, a dopaminergic lesion of the NAcc blocks the antiimmobility effect of desipramine (DMI) and this tricyclic increases the firing rate of the LSN; however, it is unknown whether a relation exists between a dopaminergic lesion of the NAcc and the response of LSN neurons to DMI treatment. Therefore, we conducted a longitudinal study to further explore the participation of NAcc dopaminergic terminals in the immobility reduction exerted by DMI in the forced swim test and its relation to the firing rate of the LSN, at the same time exploring motor and motivational aspects of DMI–dopaminergic relationships in the animals. A dopaminergic lesion was bilaterally produced by 6-hydroxydopamine (6-OHDA) injection into the NAcc of adult ovariectomized Wistar rats pretreated with DMI (25 mg/kg ip, 30 min before lesion to protect NA terminals but to destroy DA endings). Treatments with DMI or saline began 24 h after stereotaxic surgery. The results showed that DMI once a day during 9 days (10 mg/kg) reduced immobility in the forced swim test in the sham-lesion group ( P<.02); however, in the dopaminergic lesion group submitted to DMI treatment, immobility remained at control level in agreement with other reports. DMI increased the firing rate of the LSN ( P<.001) independently of the 6-OHDA lesion. In conclusion, the dopaminergic terminals of the NAcc seem to be essential for the motor manifestation associated with motivation induced by DMI in the forced swim test, given that the antiimmobility actions of DMI are blocked after a dopaminergic NAcc lesion; however, the effect on the firing rate of LSN neurons is still present.

Monocarboxylate transporters contribute to the adaptation of neuronal activity to repeated glucose deprivation in the rat lateral septal nucleus.

Using optical recording methods in the rat lateral septal nucleus (LSN) slice, we examined the question of whether antecedent hypoglycemia protects neurons from the adverse effects of subsequent hypoglycemic stimuli. The first exposure of LSN neurons to glucose deprivation for 15 min produced a marked depression of neuronal activity. The neuronal activity recovered by reapplication of glucose to the neurons. In neurons previously exposed to glucose deprivation, subsequent applications of glucose-free artificial cerebrospinal fluid (ACSF) produced only weak depression of the neuronal activity. The contribution of monocarboxylate transporters to this adaptation of neuronal activity to repeated glucose deprivation was examined in LSN neurons. alpha-Cyano-4-hydroxycinnamate (4-CIN, 100 microM), an inhibitor of the monocarboxylate transporters, did not significantly affect the depression of the neuronal activity induced by the first glucose deprivation. However, in the presence of 4-CIN (100 microM), a second glucose deprivation produced a typical depression of the neuronal activity, indicating that 4-CIN had nullified the adaptation of neuronal activity to a second glucose deprivation. Cytochalasin B (CCB, 20 microM), an inhibitor of glucose transporters, depressed the neuronal activity in the presence of 11 mM glucose. Pyruvate (11 mM) partially restored the neuronal activity depressed by pretreatment with CCB (20 microM) for 30-40 min. These results suggest that antecedent glucose deprivation stimulates monocarboxylate-transporters to supply energy substrates to LSN neurons, thus protecting the neurons against subsequent glucose deprivation. .

Activation of inhibitory pathways suppresses the induction of long-term potentiation in neurons of the rat lateral septal nucleus

Long-term potentiation of the hippocampal-septal pathway was examined by intracellular recording techniques. High frequency stimulation (two 100-Hz 1-s trains with a 20-s interval between them) of the hippocampal CA3 area resulted in a transient depolarization in rat lateral septal nucleus neurons. High frequency stimulation was followed by a facilitation of fast and slow inhibitory postsynaptic potentials, lasting for more than 2 h, but not by a long-lasting increase in the excitatory postsynaptic potential in the normal solution. Long-term potentiation (>2 h) of the excitatory postsynaptic potential did not appear in 74% of neurons tested, even when the fast inhibitory postsynaptic potential was blocked by bicuculline (30 μM), a GABA A receptor antagonist. High frequency stimulation produced long-term potentiation of the excitatory postsynaptic potential in the Mg 2+-free solution containing bicuculline. When the fast and slow inhibitory postsynaptic potentials were blocked by GABA A and GABA B receptor antagonists (bicuculline and CGP 55845A respectively), high frequency stimulation produced a large and sustained depolarization followed by long-term potentiation of the excitatory postsynaptic potential. However, the excitatory postsynaptic potential was not enhanced by administration of these drugs after termination of high frequency stimulation. Pretreatment with 2-amino-5-phosphonopentanoate, a NMDA receptor antagonist, resulted in loss of long-term potentiation in both sets of experiments. Paired-pulse stimulation of the hippocampal CA3 region with interstimulus intervals between 200 and 800 ms depressed the second excitatory postsynaptic potential in the presence of bicuculline. CGP 35348, a GABA B receptor antagonist, reversed the depression of excitatory postsynaptic potentials to facilitation. These data suggest that high frequency stimulation of hippocampal CA3 neurons enhances the efficacy of GABAergic inhibitory circuits which, in turn, depress the ability of lateral septal nucleus neurons to express long-term potentiation.

5-Hydroxytryptamine facilitates spatiotemporal propagation of optical signals in the hippocampal-septal pathway.

The role of 5-hydroxytryptamine (5-HT) on the propagation of neuronal excitation in the hippocampal-septal pathway was examined in a brain slice by optical and electrophysiological recording techniques. After electrical stimulation of the fimbrial pathway, optical signals first occurred at the caudal region of lateral septal nucleus (LSN), then propagated toward the rostral region of LSN. All of the evoked optical signals were blocked by tetrodotoxin (TTX). The optical signal that propagated to the LSN was blocked by either the removal of external Ca(2+) or bath-application of 6-cyano-7-nitroquinoxaline-2,3-(1H,4H)-dione (CNQX). Bath-application of 5-HT (1-50 microM) to the LSN for 10 min produced an increase in the propagation area of the optical signal and prolonged the falling phase of the optical signal. Bicuculline blocked the 5-HT-induced facilitation of the optical signal. 8-Hydroxy-di-n-propylamino tetralin (8-OH-DPAT), a selective 5-HT(1A) agonist, mimicked the facilitation of 5-HT. 1-(2-Methoxyphenyl)-4-(4-phthalimidobutyl)piperazine (NAN-190), a 5-HT(1A) antagonist, blocked the facilitation induced by 5-HT. 5-HT enhanced the amplitude of the field potential in septal slices, where the optical signals had been enhanced. These results indicate that 5-HT increases the efficacy of excitatory synaptic transmission in the hippocampal-septal circuit via 5-HT(1A) receptors of LSN neurons.

Lateral septal projections onto tubero-infundibular neurons in the hypothalamus of the guinea pig.

Efferent projections of the lateral septal nucleus (LS) to the preoptic area and the hypothalamus were identified in 20 female guinea pigs after iontophoretic injection of the anterograde axonal tracer Fluoro-Ruby. Tubero-infundibular (TI) neurons of the preoptic area and the hypothalamus were retrogradely labeled after intracardiac injection of Granular Blue or Fluoro-Gold. Magnocellular neurons of the supraoptic and paraventricular nuclei were also labeled. The double labeling procedure allowed an estimation of the extent of the direct relationship between LS efferents and TI neurons. Contacts between lateral septal fibers and TI cell bodies were mainly observed at the light-microscopical level in the preoptic area. A group of labeled fibers coursing along the third ventricle established sparse connections with hypothalamic periventricular TI neurons. A few appositions was observed in the infundibular (arcuate) nucleus, suggestive of a monosynaptic regulation of TI neurons by a septo-arcuate tract. Close association with labeled magnocellular neurons was also noted at the edge of the supraoptic and paraventricular nuclei. The sparse but direct connections between LS and TI neurons may be involved in the neuroendocrine functions of the LS.

Actions of serotonin recorded intracellularly in rat dorsal lateral septal neurons.

The actions of serotonin (5HT) on passive and active membrane properties of neurons in the rat dorsal lateral septal nucleus (LSN) were studied by using intracellular recordings in transverse, septal slices. Superfusion with 10 microM 5HT induced a hyperpolarization of the membrane in almost all neurons tested in the dorsolateral part of the LSN. The hyperpolarization was accompanied by a decrease in membrane resistance. These effects of 5HT persisted in a low-Ca2+/high-Mg2+-containing medium or medium with tetrodotoxin, indicating a post-synaptic site of action for 5HT. The reversal potential for the hyperpolarizing effect was ca. -95 mV. If the extracellular K+-concentration was raised, the reversal potential became less negative. These data suggest that 5HT hyperpolarizes LSN neurons by increasing a K+-conductance. Spontaneous, synaptically evoked action potentials and action potentials induced in LSN neurons by a depolarizing current step typically display a fast Na+-spike with a subsequent K+-afterhyperpolarization, followed by a much slower Ca2+-dependent afterdepolarization. The amplitude of the K+-afterhyperpolarization was decreased by 5HT, while at the same time the afterdepolarization became more pronounced. The Ca2+-spike of LSN neurons was not affected by 5HT. Synaptic responses that were evoked in LSN neurons by stimulation of the dorsal part of the LSN consisted of a fast EPSP or spike, followed by a Cl(-)-dependent fast IPSP and a K+-dependent late IPSP. Of these synaptic responses, 5HT suppressed particularly the late IPSP. The present data indicate that 5HT affects the conductance for active and passive K+-channels in LSN neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Catecholamin innervation of the basal forebrain. I. The septal area.

AbstractThe septal area of the rat is known to receive a rich innervation by axons of catecholamine (CA) neurons. In the present study this innervatic was studied using biochemical assay of CA content and fluorescence histochemical analysis of the distribution of CA‐producing axons to determine the nuclei origin of the septal CA innervation and the effects of lesions on these parameters. The autoradiographic tracing technique and the horseradish peroxidase (HRP)‐retrograde transport technique also were used for this purpose.The norepinephrine (NE) content of the normal septal area is 1,162 ± 127 ng/g and the dopamine (DA) content is 522 ± 106 ng/g. Hemisection of the brainstem caudal to the locus coeruleus results in a 47% decrease in septal NE content and a unilateral locus coeruleus lesion produces a 48% decrease in septal NE content. These observations suggest that the NE innervation of the septal area arises approximately equally from the locus coeruleus and nuclei in the caudal brain stem. This is confirmed, at least in part, by the anterograde and retrograde transport studies. The DA innervation of the septal area is shown by all of the techniques employed to arise almost exclusively from cells of the ventral tegmental area.NE axons arising from the locus coeruleus distribute in the septal area to the hippocampal rudiment, the nucleus of the diagonal band, the interstitial nucleus of the stria terminalis, the medial septal nucleus, the lateral septal nucleus and the nucleus septofimbrialis. In each area the innervation is sparse to moderate in density and has the plexiform organization typical of locus coeruleus innervation. The brainstem NE innervation is very dense in the interstitial nucleus of the stria terminalis, moderately dense in the lateral septal nucleus and sparse in the nucleus of the diagonal band.The DA axons innervating the septum terminate in two distinct patterns. The first is identical to that seen in the neostriatum. Preterminal axons are very fine and non‐varicose. As they reach a terminal area they branch markedly and give rise to extremely numerous, closely‐packed, fine varicosities. This type of DA innervation is found in the medial part of the lateral septal nucleus in a dense band and about some scattered lateral septal nucleus neurons, in the nucleus accumbens and in the interstitial nucleus of the stria terminalis. The second pattern is for non‐varicose preterminal axons to branch and terminate in pericellular baskets about lateral septal nucleus neurons or simply terminate in the lateral septal nucleus neuropil. In each case the terminal branches give off distinct varicosities which are larger than those formed in the first pattern of DA innervation.Thus, the septal area has a complex organization of CA innervation with NE axons arising from caudal brainstem nuclei and the locus coeruleus and DA axons arising from the ventral tegmental area.