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Pilocytic astrocytoma is mostly a pediatric tumor with the majority of patients under age 20. Although tumors can occur throughout neuraxis, most tumors are in the cerebellum and optic chiasm. Pilocytic astrocytoma in unusual locations is often associated with different genetic alterations than the classic KIAA1549::BRAF fusion. We report a rare adult pilocytic astrocytoma of the septum pellucidum that presented with progressive headache. A detailed genomic evaluation found a fusion between BRAF and a novel partner RIN2, a gene overexpressed in both low-grade glioma and glioblastoma. The RIN2::BRAF transcript encodes a chimeric protein containing a dimerization domain SH2 and an intact kinase domain, consistent with a prototypic oncogenic kinase rearrangement. In addition, we discuss the potential oncogenic mechanisms of BRAF signaling and its implication in targeted therapy with kinase inhibitors., (© 2022. Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: BCORL1, a transcriptional co-repressor, has a role in cortical migration, neuronal differentiation, maturation, and cerebellar development. We describe BCORL1 as a new genetic cause for major brain malformations., Methods and Results: We report three patients from two unrelated families with neonatal onset intractable epilepsy and profound global developmental delay. Brain MRI of two siblings from the first family depicted hypoplastic corpus callosum and septal agenesis (ASP) in the older brother and unilateral perisylvian polymicrogyria (PMG) in the younger one. MRI of the patient from the second family demonstrated complete agenesis of corpus callosum (CC). Whole Exome Sequencing revealed a novel hemizygous variant in NM_021946.5 (BCORL1):c.796C>T (p.Pro266Ser) in the two siblings from the first family and the NM_021946.5 (BCORL1): c.3376G>A; p.Asp1126Asn variant in the patient from the second family, both variants inherited from healthy mothers. We reviewed the patients' charts and MRIs and compared the phenotype to the other published BCORL1-related cases. Brain malformations have not been previously described in association with the BCORL1 phenotype. We discuss the potential influence of BCORL1 on brain development., Conclusions: We suggest that BCORL1 variants present with a spectrum of neurodevelopmental disorders and can lead to major brain malformations originating at different stages of fetal development. We suggest adding BCORL1 to the genetic causes of PMG, ASP, and CC dysgenesis., (© 2021. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Although millions of individuals suffer a traumatic brain injury (TBI) worldwide each year, it is only recently that TBI has been recognized as a major public health problem. Beyond the acute clinical manifestations, there is growing recognition that a single severe TBI (sTBI) or repeated mild TBIs (rTBI) can also induce insidious neurodegenerative processes, which may be associated with early dementia, in particular chronic traumatic encephalopathy (CTE). Identified at autopsy examination in individuals with histories of exposure to sTBI or rTBI, CTE is recognized as a complex pathology featuring both macroscopic and microscopic abnormalities. These include cavum septum pellucidum, brain atrophy and ventricular dilation, together with pathologies in tau, TDP-43, and amyloid-β. However, the establishment and characterization of CTE as a distinct disease entity is in its infancy. Moreover, the relative "dose" of TBI, such as the frequency and severity of injury, associated with risk of CTE remains unknown. As such, there is a clear and pressing need to improve the recognition and diagnosis of CTE and to identify mechanistic links between TBI and chronic neurodegeneration.

Beside its hormonal function in salt and water homeostasis, vasopressin released into distinct brain areas plays a crucial role in stress-related behavior resulting in the enhancement of an anxious/depressive-like state. We aimed to investigate whether correction of the peripheral symptoms of congenital absence of AVP also corrects the behavioral alterations in AVP-deficient Brattleboro rats. Wild type (WT) and vasopressin-deficient (KO) male Brattleboro rats were tested. Half of the KO animals were treated by desmopressin (V2-receptor agonist) via osmotic minipump (subcutaneous) to eliminate the peripheral symptoms of vasopressin-deficiency. Anxiety was studied by elevated plus maze (EPM), defensive withdrawal (DW) and marble burying (MB) tests, while depressive-like changes were monitored in forced swimming (FS) and anhedonia by sucrose preference test. Cell activity was examined in septum and amygdala by c-Fos immunohistochemistry after 10 min FS. KO rats spent more time in the open arm of the EPM, spent less time at the periphery of DW and showed less burying behavior in MB suggesting a reduced anxiety state. KO animals showed less floating behavior during FS revealing a less depressive phenotype. Desmopressin treatment compensated the peripheral effects of vasopressin-deficiency without a significant influence on the behavior. The FS-induced c-Fos immunoreactivity in the medial amygdala was different in WT and KO rats, with almost identical levels in KO and desmopressin treated animals. There were no differences in central and basolateral amygdala as well as in lateral septum. Our data confirmed the role of vasopressin in the development of affective disorders through central mechanisms. The involvement of the medial amygdala in the behavioral alterations of vasopressin deficient animals deserves further attention., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Raman spectroscopy enables non-invasive investigation of chemical composition of biological tissues. Due to similar chemical composition, the analysis of Raman spectra of brain structures and assignment of their spectral features to chemical constituents presents a particular challenge. In this study we demonstrate that standard and independent component analysis of Raman spectra is capable of assessment of differences in chemical composition between functionally related gray and white matter structures. Our results show the ability of Raman spectroscopy to successfully depict variation in chemical composition between structurally similar and/or functionally connected brain structures. The observed differences were attributed to variations in content of proteins and lipids in these structures. Independent component analysis enabled separation of contributions of major constituents in spectra and revealed spectral signatures of low-concentration metabolites. This provided finding of discrepancies between structures of striatum as well as between white matter structures. Raman spectroscopy can provide information about variations in contents of major chemical constituents in brain structures, while the application of independent component analysis performed on obtained spectra can help in revealing minute differences between closely related brain structures., (© 2013 Elsevier B.V. All rights reserved.)

Atypical teratoid/rhabdoid tumor is a highly malignant tumor of the central nervous system, usually occurring in the posterior fossa in infants and young children. Supratentorial example is relatively rare, especially with involvement of the cerebral ventricle system. Herein, we reported 2 cases of atypical teratoid/rhabdoid tumor located in the septum pellucidum within the lateral and third ventricles and right parietooccipital region, respectively. Histopathologically, both of the tumors were composed of rhabdoid tumor cells and mesenchymal components, without primitive neuroectodermal tumor or epithelial differentiation. Immunohistochemical staining showed that these tumor cells reacted positively for vimentin, S-100 protein, synaptophysin, and neuron-specific enolase. Only 1 case was found to be epithelial membrane antigen reactive. The tumor cells lacked nuclear expression of INI1. These cases emphasize that atypical teratoid/rhabdoid tumor should be also considered in the list of differential diagnosis, even when these rhabdoid tumor cells do not arise in the predilection sites.

Early life stress poses a risk for the development of psychopathologies characterized by disturbed emotional, social, and cognitive performance. We used maternal separation (MS, 3h daily, postnatal days 1-14) to test whether early life stress impairs social recognition performance in juvenile (5-week-old) and adult (16-week-old) male Wistar rats. Social recognition was tested in the social discrimination test and defined by increased investigation by the experimental rat towards a novel rat compared with a previously encountered rat. Juvenile control and MS rats demonstrated successful social recognition at inter-exposure intervals of 30 and 60 min. However, unlike adult control rats, adult MS rats failed to discriminate between a previously encountered and a novel rat after 60 min. The social recognition impairment of adult MS rats was accompanied by a lack of a rise in arginine vasopressin (AVP) release within the lateral septum seen during social memory acquisition in adult control rats. This blunted response of septal AVP release was social stimulus-specific because forced swimming induced a rise in septal AVP release in both control and MS rats. Retrodialysis of AVP (1 μg/ml, 3.3 μl/min, 30 min) into the lateral septum during social memory acquisition restored social recognition in adult MS rats at the 60-min interval. These studies demonstrate that MS impairs social recognition performance in adult rats, which is likely caused by blunted septal AVP activation. Impaired social recognition may be linked to MS-induced changes in other social behaviors like aggression as shown previously., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Availability of genome-scale in situ hybridization data allows systematic analysis of genetic neuroanatomical architecture. Within the hippocampus, electrophysiology and lesion and imaging studies demonstrate functional heterogeneity along the septotemporal axis, although precise underlying circuitry and molecular substrates remain uncharacterized. Application of unbiased statistical component analyses to genome-scale hippocampal gene expression data revealed robust septotemporal molecular heterogeneity, leading to the identification of a large cohort of genes with robust regionalized hippocampal expression. Manual mapping of heterogeneous CA3 pyramidal neuron expression patterns demonstrates an unexpectedly complex molecular parcellation into a relatively coherent set of nine expression domains in the septal/temporal and proximal/distal axes with reciprocal, nonoverlapping boundaries. Unique combinatorial profiles of adhesion molecules within these domains suggest corresponding differential connectivity, which is demonstrated for CA3 projections to the lateral septum using retrograde labeling. This complex, discrete molecular architecture provides a novel paradigm for predicting functional differentiation across the full septotemporal extent of the hippocampus.

There is controversy in the literature in the results of various septal lesions on the sleep-waking cycle (SWC) ultradian structure. Current investigation was aimed to study the effects of interruption of septo-hippocampal cholinergic/GABAergic afferentation on the ultradian structure of SWC and on PS major indices. Experiments were carried out on 12 adult cats, operated under overall anesthesia (Nembutal, 35-40 mg/kg). Three groups of animals were used: I. Implanted sham lesioned control; II. With isolated lesion of medial septal part; III. With combined lesion of medial and lateral septal parts. Lesion was made by passing of direct current. Continuous EEG registration of SWC was lasted 12 hour. Results were evaluated statistically with Student's t test. Isolated lesion of medial septum doesn't produce significant changes of motivational-emotional behavior, but combined lesion of medial and lateral septal parts lead to enhancement of food and water motivation, development of hyper emotionality and hyperactivity. Interruption of septo-hippocampal cholinergic/GABAergic input, increased sleep onset latency, incidence and percentage of active waking (AW) and passive waking (PW) and PS latency but the last effect was dependent from sleep latency change. In the period from appearance of first PS episode to the end of EEG registration PS incidence and percentage wasn't changed significantly. This surgery completely abolished theta rhythm in waking and PS. Combined lesion of medial and lateral septal parts increased sleep latency still more. Total time of AW and PW increased twice. DSWS was significantly decreased. In this case PS latency was also increased still more. PS incidence and total percentage in whole 12 h registration period were reduced substantially, but for the period calculated after appearance of first PS episode until to the end of EEG registration PS mean value was the same as in sham lesioned animals. It is concluded that: 1.Septo-hippocampal cholinergic/GABAergic relationship doesn't play significant role in the triggering mechanisms of SWC ultradian structure; 2. GABAergic part of this input as well as hippocampo-mesodiecephalic descending pathways through the lateral septum have powerful modulatory influence on basic triggering mechanisms of SWS; 3. Development of hippocampal theta rhythm is the only event of PS affected after medial septal lesion; 4. Septo-hippocampal cholinergic input is not essential in triggering mechanisms of PS.

Spatial working memory and the ability of a cholinesterase inhibitor to enhance memory were assessed at 4, 10, and 16 months of ages in control and Ts65Dn mice, a partial trisomy model of Down syndrome, with possibly significant relationships to Alzheimer's disease as well. In addition, ACh release during memory testing was measured in samples collected from the hippocampus using in vivo microdialysis at 4, 10, and 22-25 months of age. When tested on a four-arm spontaneous alternation task, the Ts65Dn mice exhibited impaired memory scores at both 4 and 10 months. At 16 months, control performance had declined toward that of the Ts65Dn mice and the difference in scores across genotypes was not significant. Physostigmine (50 microg/kg) fully reversed memory deficits in the Ts65Dn mice in the 4-month-old group but not in older mice. Ts65Dn and control mice exhibited comparable baseline levels of ACh release at all ages tested; these levels did not decline significantly across age in either genotype. ACh release increased significantly during alternation testing only in the young Ts65Dn and control mice. However, the increase in ACh release during alternation testing was significantly greater in control than Ts65Dn mice at this age. The controls exhibited a significant age-related decline in the testing-related increase in ACh release. With only a small increase during testing in young Ts65Dn mice, the age-related decline in responsiveness of ACh release to testing was not significant in these mice. Overall, these results suggest that diminished responsiveness of ACh release in the hippocampus to behavioral testing may contribute memory impairments in Ts65Dn mice.

Although septal infusions of glucose typically have positive effects on memory, we have shown repeatedly that this treatment exacerbates memory deficits produced by co-infusions of gamma-aminobutyric acid (GABA) receptor agonists. The present experiments tested whether this negative interaction between glucose and GABA in the medial septum would be observed in the hippocampus, a brain region where glucose typically has positive effects on memory. Specifically, we determined whether hippocampal infusions of glucose would reverse or exacerbate memory deficits produced by hippocampal co-infusions of the GABA receptor agonist muscimol. Fifteen minutes prior to either assessing spontaneous alternation (SA) or continuous multiple trial inhibitory avoidance (CMIA) training, male Sprague-Dawley-derived rats were given bilateral hippocampal infusions of vehicle (phosphate-buffered saline [PBS], 1 microl/2 min), glucose (33 or 50 nmol), muscimol (0.3 or 0.4 microg, SA or 3 microg, CMIA) or muscimol and glucose combined in one solution. The results indicated that hippocampal infusions of muscimol alone decreased SA scores and CMIA retention latencies. More importantly, hippocampal infusions of glucose, at doses that had no effect when infused alone, attenuated (33 nmol) or reversed (50 nmol) the muscimol-induced memory deficits. Thus, although co-infusions of glucose with muscimol into the medial septum impair memory, the present findings show that an opposite effect is observed in the hippocampus. Collectively, these findings suggest that the memory-impairing interaction between glucose and GABA in the medial septum is not a general property of the brain, but rather is brain region-dependent.

Borderline personality disorder is a disorder with important social and clinical repercussions, which has been treated mainly by psychotherapy. In recent years, the syndromic analysis of this disorder has allowed us to identify different symptoms capable of being improved with psychopharmacology treatment. Thus, its complex symptomatology could be included in four clinical dimensions: impulsive-aggressive, affective instability, cognitive- perceptive and anxiety-inhibition. Antidepressants, mood stabilizers, antipsychotics, anxiolytics, or more recently omega-3 fatty acids have shown efficacy in the treatment of symptomatic dimensions of this disease. We have reviewed scientific articles (reviews, clinical trials or clinical guidelines) published over the last ten years and have proposed therapeutic algorithms for psychopharmacology management in these patients.

Introduction: The personality of alcohol dependant patients as a factor influencing the intensity of the alcohol withdrawal syndrome has been seldom examined. Cloninger's biosocial model of personality describes four temperaments (novelty seeking, harm avoidance, reward dependence, persistence) which, except for persistence, are admittedly linked to specific central neurotransmitters, and three characters. Novelty seeking is linked with low levels of mesencephalic dopamine, harm avoidance with high levels of serotonin in the septo-hippocampic system and reward dependence with low levels of noradrenaline in the ascending pathways from the locus coeruleus to the limbic system. The same neurotransmitters pathways are known to be involved in alcohol withdrawal, with a decrease of dopaminergic activity in the mesolimbic system, a decrease of serotonergic activity in the nucleus accumbens and an increase of the noradrenergic system. In view of the similarities between the neurobiological systems involved in Cloninger's model and in the neurobiological changes occurring during the withdrawal period, one would expect to observe severe withdrawal symptoms more frequently for patients with high novelty seeking, low harm avoidance and low reward dependence., Methods: To test this hypothesis, alcohol dependent patients according to DSM IV classification criteria who have drunk in the last twenty four hours were included in the study and received a standardized withdrawal treatment. The withdrawal syndrome intensity was examined with repeated measures of CIWA-Ar, the scores of which were correlated with TCI-R., Results: Twenty eight patients, between 30 et 65 years old and drinking 22,2 +/- 12 standard drinks per day were included. Antidepressant drugs, benzodiazepines and neuroleptics treatment introduced before hospitalisation were stopped or decreased as much as possible. A correlation matrix was carried out between all the variables which could influence withdrawal intensity (age at the hospitalisation, age at the begining of the dependance, ratio between the time of the dependance and the patients' age, the number of alcohol withdrawals carried out and the number of standard drinks per day), and showed a positive correlation between the number of standard drinks per day and withdrawal intensity at day 3 (r=0.7, p<0.000), at day 4 (r=0.52, p<0.005), at day 7 (r=0.41, p<0.036) and at day 8 (r=0.44, p<0.02); as between the ratio between the time of the dependance and the patients' age and withdrawal intensity at day 2 (r=0.43, p<0.03) and at day 5 (r=0.5, p<0.01). Therefore, partial correlations were calculated between the dimensions of personality and withdrawal intensity. The study showed a positive correlation between withdrawal intensity and harm avoidance from day 5 onwards (r=0.6 and P<0.003 at day 5, r=0.59 and P<0.004 at day 6, r=0.56 and P<0.006 at day 7, r=0.66 and P<0.001 at day 8), a negative correlation between withdrawal intensity and reward dependence at day 7 and 8 (r=- 0.45 and P<0.037 at day 7, r=- 0.49 and P<0.02 at day 8) and a negative correlation between withdrawal intensity and persistence from day 6 onwards (r=- 0.5 and P<0.017 at day 6, r=- 0.5 and P<0.019 at day 7, r=- 0.51 and P<0.014 at day 8). No correlation was found between withdrawal intensity and novelty seeking. The same relevant results were found again with the 22 patients without anti-depressant drugs' population., Discussion: Personality dimensions seem to influence alcohol withdrawal intensity once the severe symptomatology is over, while high doses of anti withdrawal treatment in the first days of abstinence may decrease the influence of personality on withdrawal symptoms. The positive correlation between harm avoidance and withdrawal intensity seems to invalidate our neurobiological hypotheses, but can be explained by clinical observations and corroborate studies assessing the influence of personality in benzodiazepine withdrawal intensity and in pain perception. This result encourages the introduction of support therapy during withdrawal and a cognitive-behavioural therapy before withdrawal in order to decrease patients' sensitivity to anxiety. The negative correlation between reward dependence and withdrawal intensity confirms the neurobiological hypotheses, but the weak correlation demands to be cautious in the interpretation of the results. The negative correlation between persistence and withdrawal intensity was expected., Conclusion: The characteristics associated with persistence seem to act as protective factors during alcohol withdrawal, whereas those associated with harm avoidance appear to increase the symptoms of alcohol withdrawal. In contrast, the neurobiological hypotheses are only partially confirmed.

Social interaction may elicit aggression, establish social rank, and be influenced by changes in central dopaminergic activity. In the lizard Anolis carolinensis, a sign stimulus (darkening of postorbital skin or eyespots) inhibits aggressive response from opponents, in part because it forms more rapidly in dominant males. The authors report that artificially hiding or darkening eyespots influences central dopaminergic activity, social status, and aggression during dyadic social interaction. All males that viewed an opponent with eyespots painted black became subordinate and exhibited elevated dopamine in raphe, lateral amygdala, and medial amygdala but decreased dopamine in septum and locus ceruleus. In contrast, males that viewed opponents with hidden eyespots (painted green) became dominant and had increased dopamine in striatum, nucleus accumbens, hypothalamus, and combined substantia nigra/ventral tegmental area.

Rationale: There is accumulating evidence that the neuropeptide urocortin 1 (Ucn1) is involved in alcohol consumption. Thus far, however, most studies have been performed in mice., Objectives: The purpose of the present study was to characterize Ucn1 expression in rats selectively bred for either high or low alcohol intake., Methods: Brains from naive male rats of five pairs of independently selected lines (iP/iNP, AA/ANA, HARF/LARF, HAD1/LAD1, and HAD2/LAD2) were analyzed by immunohistochemistry., Results: Significant differences were found between iP/iNP, HARF/LARF, and HAD2/LAD2 in number of Ucn1-containing cells in the Edinger-Westphal (EW) nucleus (the main source of Ucn1 in the brain), whereas no significant differences were found between HAD1/LAD1 and AA/ANA. Similarly, significant differences in the optical density of Ucn1 immunoreactivity in EW were found between iP/iNP, HARF/LARF, and HAD2/LAD2, whereas no differences on this measure were found between HAD1/LAD1 and AA/ANA. In the lateral septum (LS, the main projection area of Ucn1-containing neurons in the rat), significant differences were found only between AA/ANA and HAD2/LAD2; however, a meta-analysis indicated that across all five lines, preferring animals had a significantly greater number of Ucn1-positive fibers than nonpreferring animals., Conclusions: These results provide evidence that, in rats, Ucn1 may be involved in regulation of alcohol intake, and that this regulation may occur through the Ucn1 projections to LS.

Recent studies suggested that the cholinergic innervation of the hippocampus is not crucial for spatial learning, but it might be important for other forms of learning. This study assessed the effects of partial immunotoxic cholinergic lesions in the medial septum and concurrent scopolamine challenge in a complex learning task, the Hebb-Williams maze. Long-Evans rats were given intraseptal injections of 192 IgG-saporin (SAPO). Rats injected with phosphate-buffered saline (PBS) served as controls. Starting 25 days after surgery, behavioural performance was assessed in the Hebb-Williams maze test without prior or after injection of scopolamine (0.17 or 0.5 mg/kg, i.p.). In SAPO rats, histochemical analysis showed a 40-45% decrease in the density of hippocampal AChE staining. The number of ChAT-positive cell bodies in the medial septum was also significantly decreased (-56%) and there was a non-significant reduction of the number of parvalbumine-positive neurons. The behavioural results demonstrated that the lesions induced small but significant learning deficits. At 0.17 mg/kg, scopolamine produced more impairments in SAPO rats than in PBS-injected rats, suggesting an additive effect between the partial lesion and the drug. These observations indicate that the Hebb-Williams test may be more sensitive to alterations of septohippocampal cholinergic function, than radial- or water-maze tasks. They also show that subtle learning deficits can be detected after partial lesions of the cholinergic septohippocampal pathways. Finally, the data from the scopolamine challenge are in keeping with clinical results showing higher sensitivity to muscarinic blockade in aged subjects in whom weaker cholinergic functions can be presumed.

Y-receptor-knockout mice have become an important tool to elucidate specific physiological roles of individual Y-receptors. However, their phenotypes are not always confirmatory to results obtained by pharmacological investigations in vivo or in vitro. These discrepancies may, at least in part, be due to compensatory changes in the expression of remaining Y-receptor types. To determine whether deletion of individual Y-receptors results in altered mRNA expression and/or binding toward other Y-receptor types, we applied in-situ hybridization and radioligand-binding studies on brain slices of Npy1r-, Npy2r- or Npy5r-knockout mice. Significant changes were seen in Y1-receptor-deficient mice. Thus, Y2-receptor mRNA and (125)I-peptide YY(3-36) binding in the hippocampus proper were increased by up to 55% and 89%, respectively. Similar increases in (125)I-peptide YY(3-36) binding were observed in the caudo-dorsal extension of the lateral septum, an area heavily targeted by hippocampal projections and involved in Y1-receptor-regulated anxiety. Increased (125)I-peptide YY(3-36) binding and Y2-receptor mRNA levels were also observed in the medial amygdaloid nucleus. In contrast, (125)I-peptide YY(3-36) binding was reduced in the central amygdaloid nucleus. Y2-receptor mRNA in the intermediate part of the lateral septum was reduced by 42%. Only minimal changes were observed in Y2- or Y5-receptor-deficient mice. Our results demonstrate that compensatory changes in the expression of Y2-receptors occur in Y1-receptor-deficient mice. These adaptations are likely to contribute to changed physiological function. Thus, alterations in Y2-receptors have to be taken in account upon discussion of Y1-receptor function, especially in emotional aspects like anxiety and aggression, but also alcoholism.

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.

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.

The evidence for the role of serotonergic and noradrenergic effects on the septohippocampal theta oscillations obtained by the author and her colleagues are reviewed. Analysis of neuronal activity in the medial septal area or hippocampus and hippocampal EEG simultaneously recorded in awake rabbits exposed to different kinds of brainstem influences led to the following conclusions. 1. Serotonergic median raphe nucleus and noradrenergic locus ceruleus act as functional antagonists in theta regulation: the former structure restricts the theta rhythm generation, whereas the latter enhances this process. 2. Both transmitter systems control sensory reactions of septal and hippocampal neurons through up and down regulation of the theta activity. 3. When continuous theta activity induced by various experimental manipulations is recorded, responsiveness of septohippocampal neurons to sensory stimulation is strongly reduced. These findings provide support for the view that the theta oscillations act as an active filter in the information selection and registration. Interaction of different transmitter systems in the theta rhythm control as well as attention and memory is discussed.

Because the GnRH receptor plays a paramount role within the reproductive axis, the understanding of the molecular apparatus that governs the tissue-specific expression and regulation of this gene must lead to a better knowledge of the physiology and the physiopathology of the gonadotrope function. To elucidate these mechanisms, we have used two complementary in vivo and in vitro approaches. Firstly, we have isolated the pituitary promoter of the rat GnRH receptor gene and investigated its activity using transient transfection into two gonadotrope-derived cell lines, the alphaT3-1 and the LbetaT2 cell lines. We have thus defined a primary set of transcription factors involved in the tissue-specific expression of the GnRH receptor gene. These include the steroidogenic factor-1 (SF-1) which plays a decisive role while functionally interacting with proteins related to the GATA and LIM homeodomain families of transcription factors. In addition, we highlighted the critical implication of SF-1 and its functional interaction with a CREB-related factor in the stimulatory action of PACAP (Pituitary Adenylate Cyclase Activating Polypeptide) on promoter activity. These results have led us to analyze the activity of this promoter by transgenesis in the mouse using human placental alkaline phosphatase as a reporter gene. In agreement with the in vitro data, the pituitary promoter was found to confer gonadotrope-specific activity in the pituitary. It was also able to direct transgene expression in several areas of the central nervous system known to express the endogenous GnRH receptor, in particular in the hippocampo-septal complex. Some of these tissue do not express SF-1, suggesting that, in vivo, its role would not be as decisive as suggested by the in vitro experiments. Surprisingly, during pituitary ontogenesis, the transgene is expressed as early as E 13.5 whereas SF-1 is not yet present in the pituitary. Thus, in vivo, SF-1 would not be necessary for the activation of the GnRH receptor gene during the early developmental stages in the pituitary. These results are consistent with data obtained following general or pituitary-specific knockout of the gene encoding SF-1, suggesting that the GnRH receptor is expressed despite the absence of this factor. Identifying the factors responsible for the activation of the GnRH receptor gene at these early developmental stages should make it possible to refine the role of SF-1, not only in gene regulation but more generally, in the physiology and the physiopathology of the gonadotrope function.

The hypothesis that cortical cholinergic inputs mediate attentional functions and capacities has been extensively substantiated by experiments assessing the attentional effects of specific cholinotoxic lesions of cortical cholinergic inputs, attentional performance-associated cortical acetylcholine release, and the effects of pharmacological manipulations of the excitability of basal forebrain corticopetal cholinergic projections on attentional performance. At the same time, numerous animal experiments have suggested that the integrity of cortical cholinergic inputs is not necessary for learning and memory, and a dissociation between the role of the cortical cholinergic input system in attentional functions and in learning and memory has been proposed. We speculate that this dissociation is due, at least in part, to the use of standard animal behavioral tests for the assessment of learning and memory which do not sufficiently tax defined attentional functions. Attentional processes and the allocation of attentional capacities would be expected to influence the efficacy of the acquisition and recall of declarative information and therefore, persistent abnormalities in the regulation of the cortical cholinergic input system may yield escalating impairments in learning and memory. Furthermore, the cognitive effects of loss of cortical cholinergic inputs are augmented by the disruption of the top-down regulation of attentional functions that normally acts to optimize information processing in posterior cortical areas. Because cortical cholinergic inputs play an integral role in the mediation of attentional processing, the activity of cortical cholinergic inputs is hypothesized to also determine the efficacy of learning and memory.

Extensive evidence supports the view that cholinergic mechanisms modulate learning and memory formation. This paper reviews evidence for cholinergic regulation of multiple memory systems, noting that manipulations of cholinergic functions in many neural systems can enhance or impair memory for tasks generally associated with those neural systems. While parallel memory systems can be identified by combining lesions with carefully crafted tasks, most-if not all-tasks require the combinatorial participation of multiple neural systems. This paper offers the hypothesis that the magnitude of acetylcholine (ACh) release in different neural systems may regulate the relative contributions of these systems to learning. Recent studies of ACh release, obtained with in vivo microdialysis samples during training, together with direct injections of cholinergic drugs into different neural systems, provide evidence that release of ACh is important in engaging these systems during learning, and that the extent to which the systems are engaged is associated with individual differences in learning and memory.

The condition of dominance or submission following agonistic encounters in the adult male mouse is known to differentially affect brain nerve growth factor, a neurotrophin playing a role in brain remodeling, in the fine tuning of behaviour and in the regulation of the basal forebrain cholinergic neurons. During development and adult life nerve growth factor regulates brain expression of neurotransmitters and the stimulation of progenitor cells (stem cells) which, under different external stimuli, may differentiate into neuronal and/or glial cells promoting the recovery of the injured brain. However, little information is available for the aged brain. Thus in the present study we investigated the effect of the social status ('dominance' vs. 'submission') in the aged mouse on the presence of nerve growth factor, brain-derived neurotrophic factor, choline acetyltransferase, neuropeptide Y and progenitor cells of selected brain regions. We found that aged dominant mice showed increased brain-derived neurotrophic factor in the subventricular zone and hippocampus and increased choline acetyltransferase in the septum and basal nuclei, which were associated with increased presence of progenitor cells in the subventricular zone. Conversely, in aged subordinate mice the data showed a marked brain increase in nerve growth factor in the subventricular zone and hippocampus, choline acetyltransferase in the septum and basal nuclei and neuropeptide Y in the hippocampus and parietal cortex. The possible functional implications of these findings are discussed.

Previous studies showed that bone morphogenetic protein 9 (BMP-9) induces the expression of choline acetyltransferase and the vesicular acetylcholine (ACh) transporter, and upregulates ACh synthesis in cultured primary neurons from embryonic mouse septum [I. López-Coviella, B. Berse, R. Krauss, R.S. Thies, J.K. Blusztajn, Induction and maintenance of the neuronal cholinergic phenotype in the central nervous system by BMP-9. Science 289 (2000) 313-316]. In the present studies we investigated the effects of BMP-9 on ACh synthesis in the cholinergic mouse SN56T17 septal cell line. BMP-9 increased ACh synthesis in these cells up to 2.5-fold in a time- and dose-dependent, saturable manner. The maximal effect of BMP-9 was observed after a 3-day treatment and the median effective concentration of BMP-9 was 0.5 ng/ml. These data show that SN56T17 cells are a useful model for studies of the effects of BMPs on the cholinergic phenotype.

The present investigation has examined which subunits of the GABA(A) receptor are expressed by gonadotropin-releasing hormone (GnRH) neurons in the juvenile and adult male mouse. Cells of defined morphology, located in the medial septum (MS) and rostral preoptic area (POA), were patch-clamped in the acute brain slice preparation and their cell contents extracted. A reverse transcriptase polymerase chain reaction (RT-PCR) procedure using nested primers was used to establish individual GnRH mRNA-expressing cells which were then evaluated for eleven GABA(A) receptor (alpha1-5, beta1-3, gamma1-3) subunit transcripts. Single and multiple GABA(A) receptor subunit mRNAs were detected in approximately 70% of all GnRH neurons. A range of different subunit mRNAs (alpha1, alpha2, alpha5, beta1, beta2, beta3, gamma2) were found in juvenile GnRH neurons, with the alpha1gamma2 and alpha5gamma2 combinations encountered most frequently within individual cells. The expression profile in adult GnRH neurons was more extensive than that detected in juveniles with alpha1, alpha2, alpha3, alpha5, beta1, beta2, beta3, gamma1 and gamma2 subunits all being detected. The major difference in subunit profile between GnRH neurons located in the MS and POA involved the beta subunits. The principal postnatal developmental change was one of increasing overall subunit heterogeneity in maturing POA GnRH neurons. The profile of GABA(A) receptor subunit mRNAs detected in male GnRH neurons was quite different to that reported by us for female GnRH neurons in the mouse using the same RT-PCR approach. Together, these findings indicate that postnatal GnRH neurons are likely to express a range of GABA(A) receptor subunit mRNAs in a sexually dimorphic and developmentally-regulated manner., (Copyright 2001 S. Karger AG, Basel)

About 45% of the serotonergic raphe neurons are reported to express nerve growth factor (NGF) receptors. We therefore investigated whether selective serotonergic lesions of the median or dorsal raphe nuclei are associated with changes in NGF protein levels of the brain and whether the loss of serotonergic function alters the vulnerability of cholinergic septohippocampal neurons. In adult rats the hippocampal NGF content changed in a biphasic way after lesion of the median raphe nucleus by 5,7-dihydroxytryptamine (5,7-DHT), with a significant increase after 2-3 weeks of up to 35%, followed by a significant reduction of 22% below control levels after 7 weeks, and a return to control levels within the following 4 weeks. By contrast, the decrease in hippocampal serotonin and 5-hydroxyindoleacetic acid remained throughout the observation period of 11 weeks, being still reduced to 15 and 30% of the control levels, respectively. In the frontal cortex the partial loss of the serotonergic innervation projecting from the median raphe was associated 5 weeks after 5,7-DHT injection with an increase in NGF protein of 39.7+/-9.6% (P<0.05), which remained elevated up to 11 weeks. At 9 weeks after 5,7-DHT, the lesion of the septohippocampal cholinergic neurons induced by the cholinotoxin ethylcholine aziridinium (AF64A) was exaggerated (P<0.05) as compared to AF64A-treated rats with intact serotonergic innervation. The present data indicate that a serotonergic lesion of the median raphe nucleus results in biphasic changes of NGF protein content and in a delayed increase in the vulnerability of septohippocampal cholinergic neurons.

The identity of putative oxytocin receptors visualized in autoradiographic studies of primate brain is unclear because the ligand used is much less selective in primate than rodent brains. This study tests the feasibility of utilizing a new monoclonal antibody (MoAb) developed against human uterine OTRs to visualize OTRs in primate brain. A block containing ventral hypothalamus of cynomolgus macaque brain, paraformaldehyde, glutaraldehyde-fixed and paraffin-embedded, and positive control tissue (human endometrium) were sectioned at 8 microm and studied with immunohistochemistry. OTRs were located in fibers in septal nucleus and in both cell bodies and fibers of preoptic area. These results indicate that OTRs in primate brain may be visualized with this MoAb, and are located in primate brain sites linked to the regulation of social behavior.

The present studies employ multitudinous approaches in order to overcome the methodological obstacles in the understanding of the relationship between neurochemical alterations and behavioral deficits induced by heroin during prenatal development. Mice were exposed prenatally to heroin via daily subcutaneous injections of 10 mg/kg, on gestation days 9-18. At age 50 days, the heroin-exposed offspring displayed behavioral deficits as assessed in the eight-arm and Morris mazes, pointing to possible alteration in the septohippocampal cholinergic innervations. Biochemically there was increased presynaptic activity of these innervations as attested to by the increased [3H]hemicholinium-3 (HC-3) binding sites and by K+-stimulated inositol phosphate (IP) formation. Postsynaptically, there was global hyperactivation along the different components of the nerve conduction cascade, including an increase in M1 muscarinic receptor Bmax, a general increase in G-proteins (GP) including the most relevant, G subtype, and an increase in IP formation and in basal protein kinase C (PKC) activity. However, there was desensitization of PKC activity in response to cholinergic agonist in the heroin-exposed offspring. Transplantation of normal embryonic cholinergic cells to the impaired hippocampus reversed the behavioral deficits and both the pre- and postsynaptic hyperactivity and resensitized PKC activity. To support and further strengthen the findings of the neural grafting study, correlation of the heroin-induced behavioral deficits with the biochemical alterations, done within individuals, was applied. The results showed high r values for IP formation, basal PKC, and PKC desensitization. The r values for HC-3 binding were statistically significant but relatively low. Taken together, the findings of the neural grafting and correlation studies bring us closer to understanding the relationship between the prenatal heroin-induced biochemical and behavioral changes. However, mammalian models possess the inherent methodological hindrances, stemming from possible maternal effects. To provide a control for these confounding variables, a chick embryo model was applied in which filial imprinting, a behavior related to a specific hyperstriatal nucleus, served as an endpoint. Heroin was administered to developing chick embryos by injecting the eggs (20 mg/kg) on incubation days (ID) 0 or 5. Prehatch exposure to heroin markedly diminished the ability for filial imprinting in the hatched chicks.

Intra-septal infusions of the gamma-aminobutyric acid (GABA) agonist muscimol impair learning and memory in a variety of tasks. This experiment determined whether hippocampal or entorhinal infusions of the acetylcholinesterase inhibitor physostigmine would reverse such impairing effects on spontaneous alternation performance, a measure of spatial working memory. Male Sprague-Dawley rats were given intra-septal infusions of vehicle or muscimol (1 nmole/0.5 microL) combined with unilateral intra-hippocampal or intra-entorhinal infusions of vehicle or physostigmine (10 microg/microL for the hippocampus; 7.5 microg/microL or 1.875 microg/0.25 microL for the entorhinal cortex). Fifteen minutes later, spontaneous alternation performance was assessed. The results indicated that intra-septal infusions of muscimol significantly decreased percentage-of-alternation scores, whereas intra-hippocampal or intra-entorhinal infusions of physostigmine had no effect. More importantly, intra-hippocampal or intra-entorhinal infusions of physostigmine, at doses that did not influence performance when administered alone, completely reversed the impairing effects of the muscimol infusions. These findings indicate that increasing cholinergic levels in the hippocampus or entorhinal cortex is sufficient to reverse the impairing effects of septal GABA receptor activation and support the hypothesis that the impairing effects of septal GABAergic activity involve cholinergic processes in the hippocampus and the entorhinal cortex.

Introduction: The potential correspondence of precursor cells isolated from different brain regions is partially unknown. Since models and culture conditions used in several studies vary, comparison of precursor characteristics has been limited., Objective: In this paper epidermal growth factor (EGF)-responsive precursors from the striatum and septum were isolated and their growth pattern in vitro were determined. We also evaluated the influence of fibroblast growth factor (FGF) and nerve growth factor (NGF) on the proliferation of these cells., Material and Methods: Dissociated cells from rat septum and striatum were cultivated in suspension with 20 ng/ml of EGF. Total cells quantification, immunocytochemical staining and neuron counts were used to evaluate cell proliferation and cellular phenotypes produced by EGF-generated cells., Results: Considering both culture evolution and cellular growth we demonstrated a similar growth pattern of septal and striatal EGF-responsive precursors. Furthermore, the proliferation of both cells populations was supported by FGF. On the contrary, NGF neither had a proliferative effect nor affected cell survival. Upon differentiation, a small proportion of precursor cells differentiated into neuronal phenotype.

The low-affinity nerve growth factor receptor (p75(NGFR)) apparently can mediate apoptosis in a variety of cells in vitro and in vivo. Previously, our laboratory suggested that p75(NGFR) induced apoptosis in a subpopulation of cholinergic forebrain neurons during postnatal development, i.e., the number of choline acetyltransferase (ChAT)-positive neurons in a control strain of mice decreased whereas it remained higher in p75(NGFR)-deficient (-/-) mice. Discrepancies with subsequent data sets in our laboratory caused us to thoroughly re-analyze the fate of these cholinergic medial septum and neostriatal neurons in new sets of p75(NGFR) -/- and two DNA control strains of mice during development. Between postnatal day (P)6 and P15 the number of ChAT-positive neurons detected in the medial septum of 129/Sv mice and Balb/c mice increased by approximately 64% and approximately 62%, respectively. This increase is contrary to previous reports from our laboratory and indicative of normal postnatal development (including an increase in ChAT-enzyme) of the cholinergic forebrain neurons. In p75(NGFR) -/- mice the number of ChAT-positive neurons in the medial septum remained constant between P6 and P15 and was approximately 31% and approximately 56% higher at P6 than 129/Sv and Balb/c mice, respectively. At P15 and adulthood, p75(NGFR) -/- mice had similar numbers of cholinergic neurons as control mice. In the developing neostriatum, the number of ChAT-positive neurons increased by approximately 56% between P6 and P15 and did not differ between p75(NGFR) -/- and control mice at any time. Analyses for apoptotic DNA fragmentation (TUNEL labeling) at P8 revealed no differences between p75(NGFR) -/- and control mice in 12 forebrain regions, including the septum and neostriatum. At all times, all mice had similar levels of acetylcholinesterase-positive cholinergic innervation of the molecular layer in the dorsal dentate gyrus. These findings suggest that the p75(NGFR) does not necessarily mediate apoptosis in medial septum or neostriatal cholinergic neurons during the postnatal time period. The discrepant results of the previous study are most likely due to a less rigorous application of criteria for data acquisition, including anatomical boundaries that define the nucleus.

Acetylcholine (ACh) is synthesized by choline acetyltransferase (ChAT) in the cytoplasm of cholinergic nerve terminals and transported into synaptic vesicles by vesicular ACh transporter (VAChT). The genes encoding ChAT and VAChT are colocalized within the genome, and their products are known to be coregulated by various neurotrophic factors. In the present study, nerve growth factor (NGF; 100 ng/ml) was shown to enhance expression of VAChT and ChAT mRNA in primary cultured rat embryonic septal cells. By using a radioimmunoassay, we also found that NGF increased both neuronal content and spontaneous release of ACh, which were first detected on day 2 of culture and time-dependently increased up to day 10. Stimulated release of ACh elicited by high K+ (50 mM KCl) was also significantly greater in NGF-treated cells than in control cells. NGF enhanced immunoreactivity to antiserum against VAChT, indicating that the augmented responses were due to, at least in part, increased expression of VAChT protein. In contrast, the numbers of immunocytochemically positive cells were unaffected. Thus, NGF appears to augment ACh synthesis, its transport into synaptic vesicles, and its subsequent release. The data also suggest that NGF facilitates growth and development of cholinergic neurons, but not their survival., (Copyright 1999 Wiley-Liss, Inc.)

Puberty in the male Syrian hamster (Mesocricetus auratus) is characterized by decreased responsiveness to testosterone mediated negative feedback, but the neural mechanism for this change remains elusive. We hypothesized that decreased inhibition of the gonadotropin-releasing hormone (GnRH) system results in increased neurosecretory activity, which includes an increase in GnRH gene expression. This study examined GnRH mRNA in male hamsters before and after puberty, and sought to determine if any increase in mRNA was specific to particular subpopulations of GnRH neurones. Brains were collected from 21-day-old prepubertal males (n = 5) and 56-day-old postpubertal males (n = 5). Alternate 10 microm coronal sections from fresh-frozen brains were collected throughout the septo-hypothalamic region, and 25% of those sections were processed for in-situ hybridization histochemistry using an 35S-riboprobe complementary to hamster GnRH. No differences were observed in the number of GnRH mRNA expressing cells in any region, but in the diagonal band of Broca (DBB)/organum vasculosum of the lamina terminalis (OVLT) there was a significant increase in labelling intensity (defined as area of the cell occupied by silver grains) in postpubertal males. A second analysis compared the frequency distributions of cells based on labelling intensity between prepubertal and postpubertal males. This analysis revealed significant differences between the two frequency distributions in all areas analysed (DBB/OVLT, medial septum (MS), and preoptic area (POA)). Furthermore, examining the distribution of cells in these regions revealed a shift to the right in the postpubertal population of cells, which indicated an increased number of GnRH neurones with greater labelling intensity. These data clearly demonstrate increased GnRH mRNA during puberty. Furthermore, they suggest that the previous observation of brain region specific pubertal decreases in GnRH-immunoreactivity only within the DBB/OVLT and MS but not the POA are not due to differential levels of GnRH gene expression, but could indicate increased release from these neurones during puberty.

Early postnatal application of thyroid hormones to rats results in morphological changes of the septo-hippocampal cholinergic and the hippocampal mossy fiber systems. Modulation in the expression of either neurotrophins and/or their receptors is postulated to be involved in these effects. In a recent study, we showed that, after thyroxine application, the mRNA expression of neurotrophins of the nerve-growth-factor (NGF) family is significantly upregulated both in septum and hippocampus. To test whether the neurotrophin receptors (the low-affinity neurotrophin receptor p75 and the specific high-affinity receptors trkA, trkB, and trkC) were also affected by hormone administration, newborn rats were treated daily with subcutaneous injections of thyroxine until postnatal day 12 (P12) at latest. Control animals received corresponding injections of saline. The pups were sacrificed at defined intervals from P9 to P14. The septal areas and the hippocampi were analyzed using the reverse-transcription polymerase chain reaction (RT-PCR) method for quantification of p75, trkA, trkB, and trkC mRNA levels. Analysis of variance over the total investigation period revealed no significant general increases of the gene expressions of either neurotrophin receptor, neither in the septum nor in the hippocampus, although previous results have shown marked changes in neurotrophin levels. On particular postnatal days, significant upregulation could be observed in hippocampus for trkB and trkC. From these and recent data, we conclude that modulation of neurotrophin expression rather than neurotrophin-receptor expression contributes to the morphological modifications within the hippocampal mossy fiber system and the septo-hippocampal cholinergic system.

Chemical kindling was induced in rats by long-term administration of pentylenetetrazol (PTZ) (30 mg/kg three times a week for 9 weeks). The effects of such kindling on the abundance of transcripts encoding subunits of the gamma-aminobutyric acid type A (GABAA) receptor in the brain were measured by RNase protection assay. Kindled rats were examined either 3 or 30 days after discontinuation of PTZ treatment. The amounts of gamma2L and gamma2S subunit mRNAs were significantly increased in the hippocampus and cerebral cortex of kindled rats 3 and 30 days after treatment discontinuation, compared with those observed in control rats, and these effects were prevented by the concomitant administration of the anticonvulsant abecarnil. In contrast, the amounts of alpha1 and beta2 subunit mRNAs in these two brain regions did not differ significantly between kindled and control rats. The abundance of alpha1, beta2, gamma2L and gamma2S subunit mRNAs was decreased in the septum of rats 3 or 30 days after discontinuation of treatment with PTZ either alone or in combination with abecarnil. The amounts of none of the four subunit mRNAs measured differed significantly between the striatum or frontal cortex of kindled rats and control rats 3 days after drug discontinuation. Immunohistochemical analysis with antibodies to choline acetyltransferase revealed a marked decrease in the number of cholinergic neurons in the septum of kindled rats 30 days after discontinuation of PTZ treatment; this effect was not prevented by the administration of abecarnil. These results suggest that long-term treatment with PTZ induces a loss of GABAA receptors in the septum., (Copyright 1999 Published by Elsevier Science B.V.)

The present study was designed to clarify the time-dependent changes in brain monoamine turnover in the frontal cortex, hypothalamus, hippocampus, septum and amygdala after ovariectomy, and the difference in behavioral responses to psychological stress between sham-operated and ovariectomized (OVX) rats. At 2 and 4 weeks after ovariectomy, the turnover rates of dopamine and norepinephrine in all of the brain regions examined did not differ significantly between the sham-operated and OVX rats. However, 5-hydroxytryptamine (5-HT) turnover in all of the brain regions at 2 weeks after OVX was significantly lower than that in sham-operated rats. This difference was greater in the hypothalamus than in other brain regions. At 4 weeks after ovariectomy, 5-HT turnover in all of the brain regions examined was not significantly different between sham-operated and OVX rats. At 2 and 4 weeks after ovariectomy, exploratory behaviour (e.g., locomotor activity, head- dipping, crossing and rearing behaviours) in a non-stressed ovariectomy group did not differ from that in a non-stressed sham-operation group. Locomotor activity and the number of head-dips and crossings significantly (P<0.05) increased after repeated exposure to psychological stress for 5 days in sham-operated rats, but not in those at 2 weeks after OVX. At 4 weeks after ovariectomy, locomotor activity and the number of crossings and rearings in sham-operated and OVX rats were not significantly different in the psychological stress and non-stress groups. However, the number of head-dips significantly (P<0.05) increased with psychological stress in the sham-operated rats, but not in OVX rats. These results suggest that female gonadal hormones may play an important role in the regulation of brain 5-HTergic systems. These interactions between gonadal hormones and 5-HT metabolism may be related to 5-HT-related neuropsychiatric disorders., (Copyright 1999 Academic Press.)

It has been hypothesized that the dysfunction of the serotonergic and catecholaminergic neurotransmission is involved in the pathogenesis of depression. These hypotheses are being tested in a novel rat model of depression developed by the treatment of antidepressant-clomipramine neonatally from postnatal day 8 to 21. After the attainment of adulthood, these rats mimicked the features of the human endogenous depression showing significant decrease in the aggressive behavior and food intake. Biogenic amine estimations in these rats revealed that the levels of serotonin and noradrenaline were decreased significantly (P < 0.001) in frontal cortex, hippocampus, brain stem, septum and hypothalamus, while the levels of dopamine were decreased significantly (P < 0.001) only in the hippocampus compared to normal control and vehicle treated groups of rats. Our results demonstrate the dysfunction of serotonergic and noradrenergic neurotransmission, with lesser involvement of dopaminergic neurotransmission in the clomipramine induced experimental model of depression.

Pharmacological studies have suggested that the m2 muscarinic receptor functions as an autoreceptor in the cholinergic axons which innervate the cerebral cortex and striatum. To test this hypothesis in the macaque monkey, we used a subtype-specific antibody to the m2 muscarinic receptor. Immunoreactive cells were well visualized in the nucleus basalis, where some of these cells displayed dense m2 immunoreactivity, while others were lightly labeled. This heterogeneity of labeling intensity was not based on peculiarities of the methodology, because cholinergic cells of the striatum expressed uniformly dense m2 immunoreactivity. Concurrent labeling with choline acetyltransferase immunoreactivity proved that most of the heavily m2-labeled cells in the nucleus basalis were also choline acetyl-transferase positive. The findings demonstrate that at least 10-25% of the cholinergic neurons in the nucleus basalis of the monkey are densely m2 immunoreactive. In the striatum, concurrent labeling demonstrated that the majority, if not all, choline acetyltransferase-positive cells also contained m2 immunoreactivity. In addition, these experiments identified a population of smaller striatal cells which were m2 immunoreactive and choline acetyltransferase negative. Consecutive labeling with m2 immunoreactivity and NADPH-diaphorase histochemistry demonstrated that many of these m2-immunoreactive non-cholinergic neurons belonged to the population of nitric oxide-synthesizing medium aspiny neurons. The findings indicate that the m2 muscarinic receptor may be expressed at high levels in only a subset of cholinergic basal forebrain neurons. In contrast, m2 receptors appear to be expressed by all cholinergic cells of the striatum.

The roles of dietary tryptophan (Trp) were evaluated in regulation of production of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin (NT)-3 in the various brain regions in ddY mice. Feeding the mice a Trp-deficient diet for 2 weeks significantly decreased in the hippocampal level of NGF but not those of BDNF and NT-3, as compared with feeding an adequate Trp diet. The mice fed excess Trp did not have different levels of any of these neurotrophins than in the mice fed an adequate Trp diet. The levels of BDNF in the cerebral cortex were also significantly lower in the mice fed on a Trp-deficient diet, while the levels of NGF and NT-3 in the region were not modulated upon feeding of the diet. The dietary Trp level had no significant effect on the levels of NGF, BDNF, or NT-3 in the entorhinal cortex nor septum of the mice. These results demonstrate that the brain levels of NGF and BDNF are dependent on the dietary content of tryptophan.

A potent non-peptide vasopressin (AVP) antagonist, SR-49059, displaying high stability and selective affinity for the V1a AVP receptor subtype, has recently been described. The objective of this study was to assess the binding properties and the penetrability of this compound in the rat brain. Both in vitro and in vivo binding autoradiography experiments were performed. In all studies, the liver was used as a reference V1a tissue. In vitro labelling of rat brain sections with [3H]SR-49059 was similar to that previously detected with [3H]AVP, which confirms that the majority of central AVP binding sites are V1a sites similar to peripheral V1a receptors. As expected, intense specific labelling occurred mainly in the lateral septum, the fundus striatum, the hypothalamic stigmoid nucleus and the area postrema-nucleus of the solitary tract complex. In vivo binding autoradiography showed that [3H]SR-49059 injected intravenously did not enter the brain parenchyma. Specific labelling was however clearly detectable in brain regions with permeable hematoencephalic barrier, the choroid plexus and other circumventricular organs expressing V1a receptors, namely the subfornical organ, the pineal gland and the area postrema. The specificity of [3H]SR-49059 binding in the latter structures was confirmed by the fact that labelling was prevented by pretreatment of animals with high doses of nonradioactive SR-49059. In conclusion, our study shows that [3H]SR-49059 is a suitable probe to investigate V1a receptors in the rat brain. We also demonstrate that although this compound is not able to enter the brain tissue from the peripheral circulation, it does bind specifically to regions devoid of blood-brain barrier and known to be involved in autonomic regulations.

Subcutaneous or intracerebroventricular injection of either arginine8-vasopressin or desglycinamide9-arginine8-vasopressin has been shown to facilitate memory, reduce or reverse the effects of amnesic drugs, and maintain tolerance to some effects of ethanol. These actions of vasopressin (and, by inference, of desglycinamide9-arginine8-vasopressin) are mediated by vasopressin V1 receptors in brain, via a c-fos-dependent mechanism, but the receptors at which the desglycinamide analog acts have not been identified. The precise central sites are also not known, but evidence of several types suggested the anterior hypothalamus and septum as probable loci of vasopressin action. In the present work, this question was studied by immunocytochemistry, using antibodies against Fos and Fos-like proteins. The numbers of Fos-immunoreactive nuclei were counted in several related brain regions and structures, after administration of arginine8-vasopressin, des-Gly9-[Arg8]-vasopressin or saline. A subcutaneous injection of vasopressin, but not of saline, enhanced Fos expression in the paraventricular, supraoptic and suprachiasmatic nuclei of the hypothalamus, but the desglycinamide analog stimulated Fos expression only in the suprachiasmatic nucleus. Vasopressin injection significantly increased the number of Fos-immunoreactive cells in the intermediate lateral septum, medial septum, and dorsal and ventral divisions of the lateral septum. In contrast, the desglycinamide analog increased the numbers of Fos-immunoreactive cells in the dorsal and intermediate portions of the lateral septum, but caused no change in the medial septum, and a decrease in the ventral portion of the lateral septum. Increased Fos expression was also found in the subfornical organ after subcutaneous injection of either vasopressin or the desglycinamide analog. Double labeling with antibodies against Fos protein and against vasopressin revealed that most of the vasopressin-induced Fos-immunoreactive cells in the supraoptic, paraventricular and suprachiasmatic hypothalamic nuclei are also vasopressin immunoreactive, i.e. they are vasopressin-producing neurons. These findings suggest that a circuit involving V1 receptors in the subfornical organ, connecting fibres to the suprachiasmatic nucleus, and vasopressinergic projections from the suprachiasmatic nucleus to the lateral septum, may play a central role in mediating the actions of both vasopressin and its desglycinamide analog in the maintenance of ethanol tolerance.

The role of the p75 nerve growth factor receptor in the retrograde transport of neurotrophins in the adult CNS was investigated by comparing the transport of 125I-labeled neurotrophins by normal and p75 nerve growth factor receptor-deficient cholinergic septohippocampal neurons. In control mice, nerve growth factor was selectively transported from the hippocampal formation to the cholinergic neurons in the septum. Nerve growth factor labeling was found in three to four times as many septal cholinergic neuronal cell bodies than labeling for neurotrophin-3 or neurotrophin-4/5, and transported brain-derived neurotrophic factor was barely detectable. Cells were considered as labeled when the number of grains per cell exceeded five times background. In p75 nerve growth factor receptor-deficient mice, the number of cholinergic neurons labeled with each of the neurotrophins was reduced by 85-95%. Retrograde labeling of septohippocampal neurons with Fluorogold was not obviously reduced in p75 nerve growth factor receptor-deficient mice, suggesting that general transport mechanisms were not impaired. Despite the reduced neurotrophin transport, cholinergic neurons of p75 nerve growth factor receptor-deficient mice were larger than controls and had an apparently normal density of immunostaining for choline acetyltransferase. Since nerve growth factor is reportedly involved in size regulation and choline acetyltransferase expression, this raises the possibility that the retrograde transport itself is not essential for these events. Thus, p75 nerve growth factor receptor plays an important, although not exclusive, role in the transport of neurotrophins by cholinergic basal forebrain neurons, and retrograde transport of nerve growth factor may not be needed for regulating certain cellular processes.

Transection of the fimbria fornix leads to retrograde degeneration of axotomised septal cholinergic neurons as manifested by loss of choline acetyltransferase and p75NGFR immunoreactivity. Intracerebroventricularly administered nerve growth factor initiated at the time of axotomy can prevent these changes. We have shown that concurrent intraperitoneal administration of GM1 with a low and otherwise unprotective intracerebroventricular dose of nerve growth factor, can also prevent the loss of these fimbria fornix axotomised cholinergic neurons, where GM1 alone does not have this effect. This study further confirms the neuroprotective actions of GM1 and suggests that it may interact to potentiate the effect of nerve growth factor on these axotomised septal cholinergic neurons., (Copyright 1998 Elsevier Science B.V.)

In the present study, the regulation of acetylcholine release from the ventral hippocampus by gamma-aminobutyric acid (GABA) was investigated in vivo. GABA receptor agonists and antagonists were administered locally in the medial septum and the adjacent vertical limb of the diagonal band of Broca, or in the hippocampus by retrograde dialysis. Acetylcholine release was measured in the ventral hippocampus. In addition, the modulation of acetylcholine release via septal benzodiazepine binding sites was assessed by intraseptal administration of an agonists and an antagonist at the benzodiazepine binding site. Intraseptal administration of the GABA(A) receptor agonist muscimol and the GABA(B) receptor agonist baclofen, but not the agonist of the benzodiazepine binding site midazolam, decreased acetylcholine release in the hippocampus. The GABA(A) receptor antagonist bicuculline and the antagonist of the benzodiazepine binding site flumazenil, but not the GABA(B) receptor antagonist 3-N-(3,4,-dichlorobenzyl) aminopropyl-P-diethoxymethyphosphinic acid (CGP 52432) increased acetylcholine release in the hippocampus upon intraseptal administration. The same GABA receptor ligands were administered in the ventral hippocampus. CGP 52432 induced a small increase in acetylcholine release, whereas baclofen, muscimol and bicuculline did not affect local acetylcholine release. Thus, endogenous GABA causes tonic inhibition of acetylcholine release in the ventral hippocampus via septal GABA(A) receptors and, to a lesser extent, via GABA(B) receptors in the medial septum and hippocampus. The GABAergic inhibition in the medial septum is reduced by antagonists of the benzodiazepine binding site.

Because chronic ethanol ingestion may perturb thyroid function, we evaluated the effect of 4-wk of oral 10% ethanol ingestion on the hypothalamic-pituitary-thyroid (HPT) axis and septal thyrotropin-releasing hormone (TRH) in 200-g male Wistar rats. Animals were divided into three groups: absolute control receiving tap water and food ad libitum; ethanol group receiving food ad libitum and 10% ethanol as the sole source of drinking fluid; pair-fed group receiving tap water and an amount of food corresponding to the consumption of ethanol group. After 4-wk of treatment, the body weight of the ethanol group was 7% and of the pair-fed rats 19% lower than that of the absolute controls. Both chronic ethanol treatment and food deprivation produced a decrease in plasma thyroid-stimulating hormone (TSH). Pair-fed rats also had a lower plasma T3. Type I iodothyronine 5'-deiodinase activity in the liver was increased in the pair-fed and even more in the ethanol-treated group. The content and secretion in vitro of TRH from the hypothalamic paraventricular nucleus and median eminence were unchanged. TRH content in the septum was increased in both the ethanol and pair-fed groups. TRH secretion from the septum in vitro was lower in the pair-fed, but unchanged in the ethanol group. These data suggest that 4-wk of peroral ethanol intake affects thyroid function mostly at the extrahypothalamic level and that there is a contribution of concomitant food deprivation. Both ethanol treatment and food deprivation increased TRH content in the septum.