Neuronal diversity and reciprocal connectivity between the vertebrate hippocampus and septum.

A hallmark of the nervous system is the precision with which myriad cell types are integrated into functional networks that control complex behaviors. The limbic system governs evolutionarily conserved processes essential for survival. The septum and the hippocampus are central to the limbic system, and control not only emotion-related behaviors but also learning and memory. Here, we provide a developmental and evolutionary perspective of the hippocampus and septum and highlight the neuronal diversity and circuitry that connects these two central components of the limbic system. This article is categorized under: Nervous System Development > Vertebrates: Regional Development Nervous System Development > Vertebrates: General Principles Comparative Development and Evolution > Regulation of Organ Diversity.

Mapping the brain of the chicken (Gallus gallus), with emphasis on the septal-hypothalamic region.

There has been remarkable progress in discoveries made in the avian brain, particularly over the past two decades. This review first highlights some of the discoveries made in the forebrain and credits the Avian Brain Nomenclature Forum, responsible for changing many of the terms found in the cerebrum and for stimulating collaborative research thereafter. The Forum facilitated communication among comparative neurobiologists by eliminating confusing and inaccurate names. The result over the past 15yearshas been a standardized use of avian forebrain terms. Nonetheless, additional changes are needed. The goal of the paper is to encourage a continuing effort to unify the nomenclature throughout the entire avian brain. To emphasize the need for consensus for a single name for each neural structure, I have selected specific structures in the septum and hypothalamus that our laboratory has been investigating, to demonstrate a lack of uniformity in names applied to conservative brain regions compared to the forebrain. The specific areas reviewed include the distributions of gonadotropin-releasing hormone neurons and their terminal fields in circumventricular organs, deep-brain photoreceptors, gonadotropin inhibitory neurons and a complex structure and function of the nucleus of the hippocampal commissure.

Volumetric analysis of the diagonal band of Broca in patients with schizophrenia and affective disorders: A post-mortem study.

The human diagonal band of Broca is connected to other parts of the limbic system, such as the hippocampus, that are involved in the pathology of schizophrenia. This study aimed to characterize the volume and anterior-to-posterior distance of the human diagonal band of Broca (vertical limb) from post-mortem brains obtained from three groups: healthy control subjects (N = 17), patients with schizophrenia (N = 26), and patients with affective disorders (N = 12). There were no significant differences in the volume or anterior-to-posterior distance in the patients with schizophrenia or affective disorders compared with the healthy control subjects. To date, this is the first post-mortem investigation measuring the volume and the anterior-to-posterior distance of the diagonal band of Broca (vertical limb) in patients with schizophrenia or affective disorders compared with healthy control subjects.

Septal projections to nucleus incertus in the rat: bidirectional pathways for modulation of hippocampal function.

Projections from the nucleus incertus (NI) to the septum have been implicated in the modulation of hippocampal theta rhythm. In this study we describe a previously uncharacterized projection from the septum to the NI, which may provide feedback modulation of the ascending circuitry. Fluorogold injections into the NI resulted in retrograde labeling in the septum that was concentrated in the horizontal diagonal band and areas of the posterior septum including the septofimbrial and triangular septal nuclei. Double-immunofluorescent staining indicated that the majority of NI-projecting septal neurons were calretinin-positive and some were parvalbumin-, calbindin-, or glutamic acid decarboxylase (GAD)-67-positive. Choline acetyltransferase-positive neurons were Fluorogold-negative. Injection of anterograde tracers into medial septum, or triangular septal and septofimbrial nuclei, revealed fibers descending to the supramammillary nucleus, median raphe, and the NI. These anterogradely labeled varicosities displayed synaptophysin immunoreactivity, indicating septal inputs form synapses on NI neurons. Anterograde tracer also colocalized with GAD-67-positive puncta in labeled fibers, which in some cases made close synaptic contact with GAD-67-labeled NI neurons. These data provide evidence for the existence of an inhibitory descending projection from medial and posterior septum to the NI that provides a "feedback loop" to modulate the comparatively more dense ascending NI projections to medial septum and hippocampus. Neural processes and associated behaviors activated or modulated by changes in hippocampal theta rhythm may depend on reciprocal connections between ascending and descending pathways rather than on unidirectional regulation via the medial septum.

The impact of television viewing on brain structures: cross-sectional and longitudinal analyses.

Television (TV) viewing is known to affect children's verbal abilities and other physical, cognitive, and emotional development in psychological studies. However, the brain structural development associated with TV viewing has never been investigated. Here we examined cross-sectional correlations between the duration of TV viewing and regional gray/white matter volume (rGMV/rWMV) among 133 boys and 143 girls as well as correlations between the duration of TV viewing and longitudinal changes that occurred a few years later among 111 boys and 105 girls. After correcting for confounding factors, we found positive effects of TV viewing on rGMV of the frontopolar and medial prefrontal areas in cross-sectional and longitudinal analyses, positive effects of TV viewing on rGMV/rWMV of areas of the visual cortex in cross-sectional analyses, and positive effects of TV viewing on rGMV of the hypothalamus/septum and sensorimotor areas in longitudinal analyses. We also confirmed negative effects of TV viewing on verbal intelligence quotient (IQ) in cross-sectional and longitudinal analyses. These anatomical correlates may be linked to previously known effects of TV viewing on verbal competence, aggression, and physical activity. In particular, the present results showed effects of TV viewing on the frontopolar area of the brain, which has been associated with intellectual abilities.

Differences in relative hippocampus volume and number of hippocampus neurons among five corvid species.

The relative size of the avian hippocampus (Hp) has been shown to be related to spatial memory and food storing in two avian families, the parids and corvids. Basil et al. [Brain Behav Evol 1996;47:156-164] examined North American food-storing birds in the corvid family and found that Clark's nutcrackers had a larger relative Hp than pinyon jays and Western scrub jays. These results correlated with the nutcracker's better performance on most spatial memory tasks and their strong reliance on stored food in the wild. However, Pravosudov and de Kort [Brain Behav Evol 2006;67:1-9] raised questions about the methodology used in the 1996 study, specifically the use of paraffin as an embedding material and recalculation for shrinkage. Therefore, we measured relative Hp volume using gelatin as the embedding material in four North American species of food-storing corvids (Clark's nutcrackers, pinyon jays, Western scrub jays and blue jays) and one Eurasian corvid that stores little to no food (azure-winged magpies). Although there was a significant overall effect of species on relative Hp volume among the five species, subsequent tests found only one pairwise difference, blue jays having a larger Hp than the azure-winged magpies. We also examined the relative size of the septum in the five species. Although Shiflett et al. [J Neurobiol 2002;51:215-222] found a difference in relative septum volume amongst three species of parids that correlated with storing food, we did not find significant differences amongst the five species in relative septum. Finally, we calculated the number of neurons in the Hp relative to body mass in the five species and found statistically significant differences, some of which are in accord with the adaptive specialization hypothesis and some are not.

The anxiolytic effects of somatostatin following intra-septal and intra-amygdalar microinfusions are reversed by the selective sst2 antagonist PRL2903.

Somatostatin (SST) is a polypeptide with two biological isoforms (SST14, and SST28), and five SST receptor subtypes (sst1-5). Together, they mediate a number of neural and hormonal functions. Recently, we found that intracerebroventricular (ICV), intra-amygdalar, and intra-septal microinfusions of SST14, SST28, and a selective sst2 receptor agonist L-779976 all produced anxiolytic-like effects in the elevated plus-maze, a widely used animal model of anxiety. The receptor specificity of these anxiolytic-like effects, however, has not been conclusively established. Accordingly, the anxiolytic effects of SST in the elevated plus-maze were assessed following intra-septal or intra-amygalar microinfusions of 1) SST (1.5µg per hemisphere), 2) the highly selective sst2 receptor antagonist PRL2903 (1.5µg per hemisphere), or 3) the combination of SST and PRL2903 (each 1.5µg per hemisphere). Antagonism of the anxiolytic effects of SST in the plus-maze by PRL2903 should result in open-arm exploration that is equivalent to that of 4) vehicle-injected control rats. Both intra-septal and intra-amygdalar microinfusions of SST produced anxiolytic effects in the elevated plus-maze, consistent with results found previously after ICV microinfusions (see Engin et al., 2008; Engin and Treit, 2009; Yeung et al., 2011). More importantly, infusion of PRL2903 completely reversed the anxiolytic effects of SST in both the amygdala and the septum. These results show that somatostatin's anxiolytic effects are mediated by sst2 receptors contained in the amygdala and septum of the rat brain.

Volume of the human septal forebrain region is a predictor of source memory accuracy.

Septal nuclei, components of basal forebrain, are strongly and reciprocally connected with hippocampus, and have been shown in animals to play a critical role in memory. In humans, the septal forebrain has received little attention. To examine the role of human septal forebrain in memory, we acquired high-resolution magnetic resonance imaging scans from 25 healthy subjects and calculated septal forebrain volume using recently developed probabilistic cytoarchitectonic maps. We indexed memory with the California Verbal Learning Test-II. Linear regression showed that bilateral septal forebrain volume was a significant positive predictor of recognition memory accuracy. More specifically, larger septal forebrain volume was associated with the ability to recall item source/context accuracy. Results indicate specific involvement of septal forebrain in human source memory, and recall the need for additional research into the role of septal nuclei in memory and other impairments associated with human diseases.

Semaphorin 3C is not required for the establishment and target specificity of the GABAergic septohippocampal pathway in vitro.

The septohippocampal (SH) pathway comprises cholinergic and GABAergic fibers. Whereas the former establish synaptic contacts with all types of hippocampal neurons, the latter form complex baskets specifically on interneurons. The GABAergic SH function is associated with the control of hippocampal synchronous networks. Little is known about the mechanisms involved in the formation of the GABAergic SH pathway. Semaphorin (Sema) 3C is expressed in most hippocampal interneurons targeted by these axons. To ascertain whether Sema 3C influences the formation of the SH pathway, we analyzed the development of this connection in Sema 3C-deficient mice. As these animals die at birth, we developed an in vitro organotypic co-culture model reproducing the postnatal development of the SH pathway. In these SH co-cultures, the GABAergic SH pathway developed with target specificity similar to that present in vivo. SH axons formed incipient baskets on several types of hippocampal interneurons at 7 days in vitro, which increased their complexity by 18-25 days in vitro. These SH fibers formed symmetric synaptic contacts on GABAergic interneurons. This synaptic specificity was not influenced by the absence of entorhinal afferents. Finally, the absence of Sema 3C in target neurons or its blockage by neuropilin-1 and -2 ectodomains in slice co-cultures did not lead to major changes in either the target specificity of the GABAergic SH pathway or its density of innervation. We conclude that the formation and synaptic specificity of the GABAergic SH pathway relies on robust molecular mechanisms, independent of Sema 3C, that are retained in our in vitro co-culture model.

Topographical and quantitative distribution of the projecting neurons to main divisions of the septal area.

OBJECTIVE: Septal area is a limbic structure that is involved in the regulation of several autonomic, learning-related and behavioral functions. Participation of this area in various physiologic functions is indicative of its extensive connections with different brain areas. It contains two major divisions: lateral septum (LS) and medial septum/diagonal band of Broca (MS/DBB). In the present work, we examined topographical distribution of projecting neurons to these divisions and quantitatively verified them. METHODS: Horseradish peroxidase (HRP) retrograde tract tracing was performed. RESULTS: Our results show that about two-thirds of projections to the septal area terminate in the LS. They mostly originate ipsilaterally from the septal area itself (8%), hippocampal formation (38%), non-specific thalamic nuclei (23%), lateral pre-optic area, lateral hypothalamus, perifornical area and mammillary complex in hypothalamus (20%), ventral tegmental area, raphe and tegmental nuclei, and also locus coeruleus in brainstem (10%). Most afferents to the MS come ipsilaterally from the septal area itself (18%), hippocampal formation (12%), lateral pre-optic area, lateral hypothalamus and mammillary complex in hypothalamus (42%), ventral tegmental area, raphe and tegmental nuclei, central gray matter and also locus coeruleus in brainstem (20%). Some afferents to the septal area originate contralaterally from the lateral hypothalamus, supramammillary area, raphe nuclei and locus coeruleus. DISCUSSION: Afferents from the interanterodorsal and mediodorsal thalamic nuclei, which increase the role of the septal area in arousal and awareness, are reported for the first time. Projecting cells to the MS support the learning-related function of this area. Projecting cells to the LS that are more scattered throughout the brain indicate its involvement in more diverse functions.

Circuit projection from suprachiasmatic nucleus to ventral tegmental area: a novel circadian output pathway.

The suprachiasmatic nucleus (SCN) is a circadian pacemaker that synchronizes a number of vital processes. Although a great deal of research has focused on input pathways to SCN and on the central clock itself, relatively little is known about SCN output signaling pathways. The ventral tegmental area (VTA) has been extensively studied for its influence in motivated learning and, recently, for a potential role in arousal and sleep-wake regulation. Here we present data that SCN indirectly projects to VTA via the medial preoptic nucleus (MPON). Microinjection of the retrograde, transynaptic tracer pseudorabies virus (PRV) in rat VTA consistently labeled SCN neurons at time points indicative of an indirect circuit projection. To specify intermediate relay nuclei between SCN and VTA, putative relays were lesioned 1 week prior to PRV injections in VTA. Unilateral lesions of MPON reduced PRV labeling in SCN by 81.6% in the ipsilateral hemisphere and 75.8% in the contralateral hemisphere. Bilateral lesions of the caudal-dorsal lateral septum, another putative relay nucleus and dorsal injection control, did not significantly reduce PRV labeling in the SCN. Single-unit extracellular recordings under halothane anesthesia revealed a novel population of VTA neurons that selectively fired during the active circadian phase. These results show that SCN provides an indirect circuit pathway to VTA via MPON, and that VTA neurons exhibit a circadian rhythm in their impulse activity. This pathway may function in the circadian regulation of numerous behavioral processes including arousal and motivation.

The effects of partial and complete masculinization on the sexual differentiation of nuclei that control lordotic behavior in the male rat.

Male rats, under certain experimental conditions, may show lordosis, the typical expression of female sexual receptivity. This work studies the sexual morphological pattern of facilitatory and inhibitory structures that control lordosis. Three groups of males were neonatally subjected to a gradient of androgen exposure (castrated plus injected oil (GxM+oil); castrated plus androstenedione treated (GxM+AND); and sham operated [CM]); a group of control females (CF) was also added. Lordotic response after these different hormonal and neonatal surgical treatments, as well as the volume or number of neurons in facilitatory (ventromedial nucleus of the hypothalamus [VMN]) and inhibitory (the intermediate region of the lateral septum [LSi] and accessory olfactory bulb [AOB]) nuclei involved in lordosis was studied in adults. The inhibition of lordosis in the males seems to be associated to the neonatal presence of testosterone and the consequent masculinization of the VMN, VMNvl, LSi and AOB. It is suggested that one of the functions of the sex differences consistently seen in these structures might be to inhibit the lordosis response in the male.

Neuroanatomical investigation of the gonadotrophin-releasing hormone 1 system in the seasonally breeding Cape dune mole-rat, Bathyergus suillus.

The gonadotrophin-releasing hormone 1 (GnRH1) system has been investigated immunohistochemically in Cape dune mole-rats (Bathyergus suillus), subterranean rodents that normally display severe aggression towards conspecifics. These animals breed seasonally and show a reduced mean plasma level of luteinising hormone during the non-breeding season. GnRH1-immunoreactive (ir) cell bodies and processes are found in the septal/preoptic area and the mediobasal hypothalamus; the cell bodies are found in equal measure in these two regions. Dense aggregations of GnRH1-ir fibres are present in the organum vasculosum of the lamina terminalis and the external zone of the median eminence. The total number of detectable GnRH1-ir cell bodies does not differ between the sexes or within the sexes between breeding and non-breeding seasons. Similarly there is no difference in the distribution of detectable GnRH1-ir cell bodies in male and female mole-rats in and out of the breeding season. Although the average size of GnRH1-ir cell bodies does not differ between the seasons in males, their size in females is significantly smaller in the non-breeding season. Whether this reduced size reflects reduced GnRH1 synthesis remains to be determined.

Anatomical evidence for a ponto-septal pathway via the nucleus incertus in the rat.

Hippocampal theta activity is involved in sensory-motor integration and constitutes a functional basis for mnemonic functions. The medial septum-diagonal band of Broca (MS/DBv) is a key structure as pacemaker of the oscillation. In addition, some brainstem reticular structures are crucial for the activation of MS/DBv. Specifically, the nucleus reticularis pontis oralis (RPO) is considered the most effective pontine site for eliciting theta rhythm. Nevertheless, its connection with the MS/DBv is not direct. A previous study by our group pointed out that the nucleus incertus (NI) could be considered as a relay in this multisynaptic pathway. From this study, the stimulation of RPO increased the discharge rate of NI neurons in anesthetized rats and the lesion of the NI suppressed the RPO-elicited hippocampal theta. Those findings suggested a projection from RPO to NI, although the existing literature did not support this hypothesis. In order to clarify the dichotomy between the anatomical and the electrophysiological data, we performed a set of tracing studies. Anterograde tracer injections into RPO showed a profuse projection to NI. This connection was confirmed by retrograde tracer injections into NI. Injections of retrograde tracer in MS/DBv confirmed the intense NI-MS/DBv projection. Furthermore, simultaneous injections of anterograde and retrograde tracers into RPO and MS/DBv respectively resulted in a high-correlated pattern of terminal-like fibers over labeled somata in the NI. This study provides the first anatomical evidence of a ponto-septal pathway via the NI that contributes to generation and modulation the hippocampal theta activity.

Noradrenergic modulation of arousal.

Through a highly divergent efferent projection system, the locus coeruleus-noradrenergic system supplies norepinephrine throughout the central nervous system. State-dependent neuronal discharge activity of locus coeruleus neurons has long-suggested a role of this system in the induction of an alert waking state. More recent work supports this hypothesis, demonstrating robust wake-promoting actions of the locus coeruleus-noradrenergic system. Norepinephrine enhances arousal, in part, via actions of beta- and alpha1-receptors located within multiple subcortical structures, including the general regions of the medial septal area and the medial preoptic areas. Recent anatomical studies suggest that arousal-enhancing actions of norepinephrine are not limited to the locus coeruleus system and likely include the A1 and A2 noradrenergic cell groups. Thus, noradrenergic modulation of arousal state involves multiple noradrenergic systems acting within multiple subcortical regions. Pharmacological studies indicate that the combined actions of these systems are necessary for the sustained maintenance of arousal levels associated with spontaneous waking. Enhanced arousal state is a prominent aspect of both stress and psychostimulant drug action and evidence indicates that noradrenergic systems likely play an important role in both stress-related and psychostimulant-induced arousal. These and other observations suggest that the dysregulation of noradrenergic neurotransmission could well contribute to the dysregulation of arousal associated with a variety of behavioral disorders including insomnia and stress-related disorders.

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

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

Modulation of normal and altered hippocampal excitability states by septal networks.

The septal region of the basal forebrain plays a dual role: 1) It modulates hippocampal excitability, facilitating synaptic plasticity within hippocampal circuits. Through this mechanism, the septum facilitates diverse cognitive processes that involve hippocampal circuits. 2) Additionally, the septum maintains the hippocampal networks working within normal ranges, decreasing the probability of abnormal excitability states. Through this second mechanism, the septum prevents the occurrence of epileptic discharges. Thus, septal alterations may lead to both decreased cognitive functions and epilepsy, as observed in elderly patients affected with Alzheimer's disease.

Nucleus incertus contribution to hippocampal theta rhythm generation.

The hippocampal theta rhythm is generated by the pacemaker activity of the medial septum-diagonal band of Broca (MS/DBB) neurons. These nuclei are influenced by brainstem structures that modulate the theta rhythm. The aim of the present work is to determine whether the nucleus incertus (NI), which has important anatomical connections with the MS/DBB, contributes to the hippocampal theta rhythm generation in rats. Hippocampal field activity was recorded in urethane-anaesthetized rats. Electrical stimulation of the NI not only evoked theta rhythm in the hippocampus, but also decreased the amplitude of delta waves. Unit recordings in the NI revealed either a non-rhythm discharge pattern in most neurons (76%), or a rhythm activity at 13-25 Hz in the remaining neurons. The firing rate of these neurons increased during the presence of theta rhythm evoked by either sensory or reticularis pontis oralis nucleus (RPO) stimulation. Electrolytic lesions of NI, or the microinjection of the gamma-aminobutyric acid (GABA)A agonist muscimol, abolished the theta rhythm evoked by RPO stimulation. Consequently, the NI may be a relay station between brainstem structures and the MS/DBB in the control of the hippocampal theta rhythm generation.

Medial septal modulation of the ascending brainstem hippocampal synchronizing pathways in the anesthetized rat.

Independent and combined electrical stimulation pairings of the medial septum (MS), posterior hypothalamus (PH), and reticular pontine oralis (RPO) of the brainstem were performed in the acute urethane anesthetized rat, while recording field activity from electrodes in either the stratum oriens or stratum moleculare of the hippocampal formation. Theta frequency and power were measured during independent stimulation of each nuclei and during combined stimulation using three pairings: (1) MS-PH (2) MS-RPO and (3) PH-RPO. Each pairing consisted of parameters known to elicit theta of a high frequency for one nucleus, and parameters known to elicit a low frequency for the second nucleus. This methodology allowed us to observe whether one nucleus preferentially modulated theta activity in the hippocampus in terms of frequency and power. The MS was observed to reset theta frequency in both the upward and downward direction when stimulated in combination with either the PH (Experiment 1) or the RPO (Experiment 2). In Experiment 3 (PH-RPO), the structure receiving the higher intensity stimulation had the predominate effect on theta frequency. With MS stimulation combinations, the power of the elicited theta activity was found to increase over the independent stimulation in some cases during Experiment 1. Likewise, in Experiment 2, the combined stimulation produced a power that in most cases was significantly greater than that measured during the independent stimulations. This effect was not observed with PH and RPO stimulation combinations. The combined stimulation of the PH and RPO yielded a power similar to the independent PH stimulations. The findings support the following conclusions: (1) the major theta generating activity of the ascending brainstem synchronizing pathways involves projections from the RPO to the PH, relayed through the MS, to the hippocampal formation; and (2) that the MS directly controls theta amplitude and secondarily translates the level of ascending brainstem activity into the appropriate frequency of hippocampal theta.

Medial septal modulation of the ascending brainstem hippocampal synchronizing pathways in the freely moving rat.

Rats implanted with hippocampal recording electrodes were tested in a wheel-running apparatus under three conditions: (1) independent electrical stimulation of the medial septal nucleus (MS); (2) independent electrical stimulation of the posterior hypothalamic nucleus (PH); and (3) combined electrical stimulation of the MS and PH using pairings of two stimulation conditions, 7 or 10 Hz stimulation of the MS, and a low- or high-intensity PH stimulation. Quantitative measures of running speed were taken, and hippocampal recordings were subjected to fast-Fourier transform analysis. Electrical stimulation of the PH induced wheel-running behavior; running speed and the accompanying hippocampus (HPC) theta frequency increased with increase in stimulation intensity. Electrical stimulation of the MS failed to induce wheel-running behavior despite the fact that HPC theta was induced at the frequency of the applied stimulation (7 and 10 Hz). Electrical stimulation of the MS reset the frequency of HPC theta induced by PH stimulation in both the upward and downward directions and increased theta power, while wheel-running speed was modulated in a downward direction only.