Age-associated decline in septum neuronal activation during spatial learning in homing pigeons (Columba livia).

The relationship between hippocampal aging and spatial-cognitive decline in birds has recently been investigated. However, like its mammalian counterpart, the avian hippocampus does not work in isolation and its relationship to the septum is of particular interest. The current study aimed to investigate the effects of age on septum (medial and lateral) and associated nucleus of the diagonal band (NDB) neuronal activation (as indicated by c-Fos expression) during learning of a spatial, delayed non-match-to-sample task conducted in a modified radial arm maze. The results indicated significantly reduced septum, but not NDB, activation during spatial learning in older pigeons. We also preliminarily investigated the effect of age on the number of cholinergic septum and NDB neurons (as indicated by expression of choline acetyltransferase; ChAT). Although underpowered to reveal a statistical effect, the data suggest that older pigeons have substantially fewer ChAT-expressing cells in the septum compared to younger pigeons. The data support the hypothesis that reduced activation of the septum contributes to the age-related, spatial cognitive impairment in pigeons.

Enhancing adult neurogenesis promotes contextual fear memory discrimination and activation of hippocampal-dorsolateral septal circuits.

Hippocampal circuitry is continuously modified by integration of adult-born dentate granule cells (DGCs). Prior work has shown that enhancing adult hippocampal neurogenesis decreases interference or overlap or conflict between ensembles of similar contexts and promotes discrimination of a shock-associated context from a similar, neutral context. However, the impact of enhanced integration of adult-born neurons on hippocampal network activity or downstream circuits such as the dorsolateral septum that mediate defensive behavioral responses is poorly understood. Here, we first replicated our finding that genetic expansion of the population of adult-born dentate granule cells (8 weeks and younger) promotes contextual fear discrimination. We found that enhanced contextual fear discrimination is associated with greater c-Fos expression in discrete hippocampal subfields along the proximo-distal and dorsoventral axis. Examination of the dorsolateral septum revealed an increase in activation of somatostatin expressing neurons consistent with recent characterization of these cells as calibrators of defensive behavior. Together, these findings begin to shed light on how genetically enhancing adult hippocampal neurogenesis affects activity of hippocampal-dorsolateral septal circuits.

Neural basis of unfamiliar conspecific recognition in domestic chicks (Gallus Gallus domesticus).

Domestic chickens are able to distinguish familiar from unfamiliar conspecifics, however the neuronal mechanisms mediating this behaviour are almost unknown. Moreover, the lateralisation of chicks' social recognition has only been investigated at the behavioural level, but not at the neural level. The aim of the present study was to test the hypothesis that exposure to unfamiliar conspecifics will selectively activate septum, hippocampus or nucleus taeniae of the amygdala of young domestic chicks. Moreover we also wanted to test the lateralisation of this response. For this purpose, we used the immediate early gene product c-Fos to map neural activity. Chicks were housed in pairs for one week. At test, either one of the two chicks was exchanged by an unfamiliar individual (experimental 'unfamiliar' group) or the familiar individual was briefly removed and then placed back in its original cage (control 'familiar' group). Analyses of chicks' interactions with the familiar/unfamiliar social companion revealed a higher number of social pecks directed towards unfamiliar individuals, compared to familiar controls. Moreover, in the group exposed to the unfamiliar individual a significantly higher activation was present in the dorsal and ventral septum of the left hemisphere and in the ventral hippocampus of the right hemisphere, compared to the control condition. These effects were neither present in other subareas of hippocampus or septum, nor in the nucleus taeniae of the amygdala. Our study thus indicates selective lateralised involvement of domestic chicks' septal and hippocampal subregions in responses to unfamiliar conspecific.

Hierarchical prediction errors in midbrain and septum during social learning.

Social learning is fundamental to human interactions, yet its computational and physiological mechanisms are not well understood. One prominent open question concerns the role of neuromodulatory transmitters. We combined fMRI, computational modelling and genetics to address this question in two separate samples (N = 35, N = 47). Participants played a game requiring inference on an adviser's intentions whose motivation to help or mislead changed over time. Our analyses suggest that hierarchically structured belief updates about current advice validity and the adviser's trustworthiness, respectively, depend on different neuromodulatory systems. Low-level prediction errors (PEs) about advice accuracy not only activated regions known to support 'theory of mind', but also the dopaminergic midbrain. Furthermore, PE responses in ventral striatum were influenced by the Met/Val polymorphism of the Catechol-O-Methyltransferase (COMT) gene. By contrast, high-level PEs ('expected uncertainty') about the adviser's fidelity activated the cholinergic septum. These findings, replicated in both samples, have important implications: They suggest that social learning rests on hierarchically related PEs encoded by midbrain and septum activity, respectively, in the same manner as other forms of learning under volatility. Furthermore, these hierarchical PEs may be broadcast by dopaminergic and cholinergic projections to induce plasticity specifically in cortical areas known to represent beliefs about others.

[Septal Activation and Control of Limbic Structures].

Coherent activation of limbic system structures as the main function of theta-rhythm is widely discussed in the literature. However until now does not exist the common view on its generation in these brain structures. The model of septal theta-rhythmic activation and control of limbic structures is suggested basing on the literature and own experimental data.

The spatial periodicity of grid cells is not sustained during reduced theta oscillations.

Grid cells in parahippocampal cortices fire at vertices of a periodic triangular grid that spans the entire recording environment. Such precise neural computations in space have been proposed to emerge from equally precise temporal oscillations within cells or within the local neural circuitry. We found that grid-like firing patterns in the entorhinal cortex vanished when theta oscillations were reduced after intraseptal lidocaine infusions in rats. Other spatially modulated cells in the same cortical region and place cells in the hippocampus retained their spatial firing patterns to a larger extent during these periods without well-organized oscillatory neuronal activity. Precisely timed neural activity within single cells or local networks is thus required for periodic spatial firing but not for single place fields.

Reduction of theta rhythm dissociates grid cell spatial periodicity from directional tuning.

Grid cells recorded in the medial entorhinal cortex of freely moving rats exhibit firing at regular spatial locations and temporal modulation with theta rhythm oscillations (4 to 11 hertz). We analyzed grid cell spatial coding during reduction of network theta rhythm oscillations caused by medial septum (MS) inactivation with muscimol. During MS inactivation, grid cells lost their spatial periodicity, whereas head-direction cells maintained their selectivity. Conjunctive grid-by-head-direction cells lost grid cell spatial periodicity but retained head-direction specificity. All cells showed reduced rhythmicity in autocorrelations and cross-correlations. This supports the hypothesis that spatial coding by grid cells requires theta oscillations, and dissociates the mechanisms underlying the generation of entorhinal grid cell periodicity and head-direction selectivity.

Vasopressin in the septum: not important versus causally involved in learning and memory--two faces of the same coin?

Intraseptal arginine vasopressin (AVP) has been suggested to control in laboratory rodents not only emotionality but also learning and memory. However, depending upon the nature of the test procedure and, thus, the specific memory paradigm under study, administration of synthetic AVP into the lateral septum can have no effect, enhance or even impair learning and memory. Similar contradictory results were obtained after local administration of AVP V1 receptor antagonists in different learning and memory paradigms: blockade of AVP signalling in the lateral septum revealed either no essential function or a significant contribution of the endogenous neuropeptide. Based on the data available from studies investigating the impact of AVP in classical and operant conditioning, olfactory recognition and Morris water maze learning, it is proposed that endogenous AVP released within the lateral septum acts as neurotransmitter and neuromodulator to favour elemental (mono-modal) over complex (multi-modal) stimulus processing. Excessive availability of AVP, for example by intraseptal administration of the synthetic neuropeptide, interferes with memory performance in such tasks in which the integration of complex stimuli by the dorsal hippocampus is required, most likely by an inhibition of the septo-hippocampal pathway. In contrast, performance in tasks which focus on the processing of elemental stimuli such as olfactory recognition and classical and operant conditioning can be improved by intraseptal AVP administration, presumably due to an attenuation of complex stimulus processing.

In vitro activation of the medial septum-diagonal band complex generates atropine-sensitive and atropine-resistant hippocampal theta rhythm: an investigation using a complete septohippocampal preparation.

The medial septum and diagonal band complex (MS-DB) is believed to play a key role in generating theta oscillations in the hippocampus, a phenomenon critical for learning and memory. Although the importance of the MS-DB in hippocampal theta rhythm generation is generally accepted, it remains to be determined whether the MS-DB alone can generate hippocampal oscillations or is only a transducer of rhythmic activity from other brain areas. Secondly, it is known that hippocampal theta rhythm can be separated into an atropine-sensitive and insensitive component. However, it remains to be established if the MS-DB can generate both types of rhythm. To answer these questions, we used a new in vitro rat septohippocampal preparation placed in a hermetically separated two side recording chamber. We showed that carbachol activation of the MS-DB generated large theta oscillations in the CA1 and CA3 regions of the hippocampus. These oscillations were blocked by applying either the GABA(A) receptor antagonist bicuculline or the AMPA/kainate antagonist DNQX to the hippocampus. Interestingly, the application of the muscarinic receptor antagonist atropine produced only a partial decrease in the amplitude, without modification of the frequency, of theta. These results show for the first time, that upon optimal excitation, the MS-DB alone is able to generate hippocampal oscillations in the theta frequency band. Moreover, these MS-DB generated theta oscillations are mediated by muscarinic and nonmuscarinic receptors and have a pharmacological profile similar to theta rhythm observed in awake animals.

Ontogeny and physiology of the cavum septum pellucidum in premature infants.

We report the natural history of the closure of the cavum septum pellucidum in 47 premature infants. In this study, a cavum septum pellucidum was present in all patients at 25 to 26 weeks' postconceptual age, in keeping with previous reports. The data from this study suggest that premature delivery does not change the natural history of the normal closure of the cavum septum pellucidum in most infants by 36 to 40 weeks' postconceptual age. Although not statistically significant, there is a suggestion from these data that higher grades of intraventricular hemorrhage are more frequently associated with loss (early closure) of the cavum septum pellucidum. One particularly illustrative case with a grade 4 intraventricular hemorrhage and subsequent hydrocephalus suggests that increases in pressure and volume in the lateral ventricles can cause the laminae of the septum pellucidum to approximate and appear to fuse earlier than expected. However, the fact that the cavum septum pellucidum reappeared in this case after ventricular pressure was decreased (postventricular shunt) suggests that approximation is not the sole factor in definitive fusion of the laminae of the septum pellucidum.

Sexually dimorphic effects of hippocampal cholinergic deafferentation in rats.

To determine whether the basal forebrain-hippocampal cholinergic system supports sexually dimorphic functionality, male and female Long-Evans rats were given either selective medial septum/vertical limb of the diagonal band (MS/VDB) cholinergic lesions using the neurotoxin 192 IgG-saporin or a control surgery and then postoperatively tested in a set of standard spatial learning tasks in the Morris water maze. Lesions were highly specific and effective as confirmed by both choline acetyltransferase/parvalbumin immunostaining and acetylcholinesterase histochemistry. Female controls performed worse than male controls in place learning and MS/VDB lesions failed to impair spatial learning in male rats, both consistent with previous findings. In female rats, MS/VDB cholinergic lesions facilitated spatial reference learning. A subsequent test of learning strategy in the water maze revealed a female bias for a response, relative to a spatial, strategy; MS/VDB cholinergic lesions enhanced the use of a spatial strategy in both sexes, but only significantly so in males. Together, these results indicate a sexually dimorphic function associated with MS/VDB-hippocampal cholinergic inputs. In female rats, these neurons appear to support sex-specific spatial learning processes.

The medial septum mediates impairment of prepulse inhibition of acoustic startle induced by a hippocampal seizure or phencyclidine.

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 microg), a GABA(A) 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 microg) 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 microg 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.

Selective lesioning of the cholinergic septo-hippocampal pathway does not disrupt spatial short-term memory: a comparison with the effects of fimbria-fornix lesions.

Rats receiving intrahippocampal injections of 192 IgG-saporin (SAP-HPC), fimbria-fornix lesions (FF), or sham control surgeries were tested in a series of delayed matching (DMTP)- and nonmatching (DNMTP)-to-position tasks. The FF group was significantly impaired on a pretrained DNMTP task relative to the control and SAP-HPC groups, which did not differ. All groups then acquired a matching-to- position rule at the same rate, and only the FF group showed a delay-dependent deficit when longer retention intervals were introduced for DMTP testing. Results demonstrate the importance of the fimbria-fornix fiber system in spatial short-term memory but suggest that the cholinergic septohippocampal component of this pathway is not required for successful delayed matching (or nonmatching)-to-position performance.

[The role of medial septal area in the neural control over hibernation]. / Rol' medial'noi septal'noi oblasti v nervnom kontrole gibernatsii.

Hibernation (winter sleep) is a kind of unique adaptive behavior of small mammals subjected to fine and complex central control. One of the most promising approaches to this problem is a search for the mechanisms providing brain control under conditions of a sharp decrease in temperature, (virtually, to zero) and metabolic rate. Studies conducted at the Laboratory of System Organization of Neurons under the supervision of Professor O.S. Vinogradova confirmed the hypothesis of the special role of the septohippocampal system in the control of winter sleep. Together with a brief characterization of hibernation in general, the data obtained at the Laboratory are also summarized in the review. The experimental evidence for the role of the medial septal area as a "sentry post" in hibernation is presented.

[Theta rhythmicity in the medial septum: entraining by the GABA-ergic neurons]. / Teta-ritmichnost' v EEG medial'noi septum: dominantnaia rol' gamkergicheskikh neironov v ee formirovanii.

The medial septal/diagonal band complex (MS/DB) is believed to play an important role in the generation and maintenance of the hippocampal theta rhythm, which has been implicated in the mnemonic and information-processing capacity of the brain. Although the physiological and morphological diversity of the septal neurons indicates their different functions, it is not known which cell type within the population contributes most critically to the theta rhythm. Here we review the chemical identity of different cell groups within the MS/DB complex, the anatomical connectivity between them, the electrophysiological properties of immunochemically-defined cell types, and their contribution to theta rhythmicity in the medial septum and the hippocampal theta rhythm. In order to better understand the mechanisms involved in rhythmic burst firing of the MS/DB neurons, a number of relevant theoretical models related to the generation/synchronization in neural networks are discussed.

[Attention and memory model based on the principle of dominant and comparative function of the hippocampus]. / Model' vnimaniia i pamiati, osnovannaia na printsipe dominanty i komparatornoi funktsii gippokampa.

Six basic problems of attention are described in terms of the dominant focus by Ukhtomsky, which is simulated as a system of phase transitions in the brain. Theoretical and experimental arguments in favor of the existence of metastable states in the brain with the life time of about a second or more are deduced. This forms an approach to resolution of all the problems of interaction between attention and memory, binding, and central control. A neurobiological model of attention and memory is advanced, which integrates the system properties of dominanta by A.A. Ukhtomsky and comparator function of the hippocampus by O.S. Vinogradova. New literature evidence is given for the existence of the brain system of information processing with the hippocampus as a central executive.

[Simulation of the hippocampal theta rhythm]. / Modelirovanie gippokampal'nogo teta-ritma.

Centre of Theoretical and Computational Neuroscience, University of Plymouth, UK Basing on the hypothesis about the mechanisms of the theta rhythm generation, the article presents mathematical and computational models of theta activity in the hippocampus. The problem of the theta rhythm modeling is nontrivial because the slow theta oscillations (about 5 Hz) should be generated by a neural system composed of frequently firing neural populations. We studied a model of neural pacemakers in the septum. In this model, the pacemaker follows the frequency of the external signal if this frequency does not deviate too far from the natural frequency of the pacemaker, otherwise the pacemaker returns to the frequency of its own oscillations. These results are in agreement with the experimental records of medial septum neurons. Our model of the septal pacemaker of the theta rhythm is based on the hypothesis that the hippocampal theta appears as a result of the influence of the assemblies of neurons in the medial septum which are under control of pacemaker neurons. Though the model of the pacemaker satisfies many experimental facts, the synchronization of activity in different neural assemblies of the model is not as strong as it should be. Another model of the theta generation is based on the anatomical data about the existence of the inhibitory GABAergic loop between the medial septum and the hippocampus. This model shows stable oscillations at the frequency of the theta rhythm in a broad range of parameter values. It also provides explanation to the experimental data about the variation of the frequency and the amplitude of the theta rhythm under different external stimulations of the system. The role of the theta rhythm for information processing in the hippocampus is discussed.

Relationships between cholinergic phenotype and acetyl-CoA level in hybrid murine neuroblastoma cells of septal origin.

High susceptibility of cholinergic neurons to neurotoxic signals may result from their utilization of acetyl-CoA for both energy production and acetylcholine synthesis. SN56 cholinergic cells were transfected stably with cDNA for choline acetyltransferase. Transfected cells (SN56ChAT2) expressed choline acetyltransferase activity and acetylcholine content, 17 times and 2 times higher, respectively, than did nontransfected cells. Transfection did not change pyruvate dehydrogenase but decreased the acetyl-CoA level by 62%. Differentiation by cAMP and retinoic acid caused an increase of choline acetyltransferase activity and decrease of acetyl-CoA levels in both cell lines. Negative correlation was found between choline acetyltransferase activity and acetyl-CoA level in these cells. SN56ChAT2 cells were more susceptible to excess NO than were native SN56 cells, as evidenced by the thiazolyl blue reduction assay. Thus, the sensitivity of cholinergic neurons to pathologic conditions may depend on the cholinergic phenotype-dependent availability of acetyl-CoA.

A double dissociation between serial reaction time and radial maze performance in rats subjected to 192 IgG-saporin lesions of the nucleus basalis and/or the septal region.

The cholinergic basal forebrain has been implicated in aspects of cognitive function including memory and attention, but the precise contribution of its major components, the basalocortical and the septohippocampal systems, remains unclear. Rats were subjected to lesions of either the nucleus basalis magnocellularis (Basalis), the medial septum/vertical limb of the diagonal band of Broca (Septum), or both nuclei (Basalis + Septum), using the selective cholinotoxin 192 IgG-saporin. Cognitive performance was evaluated in tasks taxing attention (the five-choice serial reaction time task, 5-CSRTT) and spatial working memory (radial arm maze, RAM). Nucleus basalis lesions disrupted performance of the 5-CSRTT, as demonstrated by decreased choice accuracy, increased incidence of missed trials, increased latencies to respond correctly, and a disrupted pattern of response control. Combined lesions of the Basalis and Septum resulted in qualitatively similar deficits to Basalis lesions alone, although interestingly, these rats were unimpaired on measures of response speed, and showed weaker deficits on accuracy and omissions. Decreasing the attentional load by lengthening stimulus duration reversed some of the deficits in Basalis and Basalis + Septum rats, suggesting an attentional deficit rather than motivation or motor perturbations. Performance in rats with septal lesions was only affected when task difficulty was increased. In the RAM an opposing pattern of effects was observed, with Septum and Basalis + Septum rats showing dramatic impairments, and Basalis rats performing normally. Taken together, these data provide clear evidence for a functional dissociation between septohippocampal and basalocortical cholinergic systems in aspects of cognitive function.