RESUMO
It is widely known that the degeneration of neural circuits is prominent in the brains of Alzheimer's disease (AD) patients. The reciprocal connectivity of the medial septum (MS) and hippocampus, which constitutes the septo-hippocampo-septal (SHS) loop, is known to be associated with learning and memory. Despite the importance of the reciprocal projections between the MS and hippocampus in AD, the alteration of bidirectional connectivity between two structures has not yet been investigated at the mesoscale level. In this study, we adopted AD animal model, five familial AD mutations (5XFAD) mice, and anterograde and retrograde tracers, BDA and DiI, respectively, to visualize the pathology-related changes in topographical connectivity of the SHS loop in the 5XFAD brain. By comparing 4.5-month-old and 14-month-old 5XFAD mice, we successfully identified key circuit components of the SHS loop altered in 5XFAD brains. Remarkably, the SHS loop began to degenerate in 4.5-month-old 5XFAD mice before the onset of neuronal loss. The impairment of connectivity between the MS and hippocampus was accelerated in 14-month-old 5XFAD mice. These results demonstrate, for the first time, topographical evidence for the degradation of the interconnection between the MS and hippocampus at the mesoscale level in a mouse model of AD. Our results provide structural and functional insights into the interconnectivity of the MS and hippocampus, which will inform the use and development of various therapeutic approaches that target neural circuits for the treatment of AD.
Assuntos
Doença de Alzheimer/patologia , Hipocampo/patologia , Septo do Cérebro/patologia , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Modelos Animais de Doenças , Feminino , Hipocampo/metabolismo , Humanos , Masculino , Camundongos Transgênicos , Mutação , Vias Neurais/metabolismo , Vias Neurais/patologia , Presenilina-1/genética , Septo do Cérebro/metabolismoRESUMO
The transcription factor NKX2-1 is best known for its role in the specification of subsets of cortical, striatal, and pallidal neurons. We demonstrate through genetic fate mapping and intersectional focal septal deletion that NKX2-1 is selectively required in the embryonic septal neuroepithelium for the development of cholinergic septohippocampal projection neurons and large subsets of basal forebrain cholinergic neurons. In the absence of NKX2-1, these neurons fail to develop, causing alterations in hippocampal theta rhythms and severe deficiencies in learning and memory. Our results demonstrate that learning and memory are dependent on NKX2-1 function in the embryonic septum and suggest that cognitive deficiencies that are sometimes associated with pathogenic mutations in NKX2-1 in humans may be a direct consequence of loss of NKX2-1 function.
Assuntos
Neurônios Colinérgicos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Hipocampo/metabolismo , Memória/fisiologia , Septo do Cérebro/metabolismo , Fator Nuclear 1 de Tireoide/genética , Acetilcolina/metabolismo , Animais , Neurônios Colinérgicos/patologia , Cognição/fisiologia , Eletrodos Implantados , Embrião de Mamíferos , Feminino , Hipocampo/patologia , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Teste de Desempenho do Rota-Rod , Septo do Cérebro/patologia , Técnicas Estereotáxicas , Ritmo Teta/fisiologia , Fator Nuclear 1 de Tireoide/deficiênciaRESUMO
The septohippocampal cholinergic neurotransmission has long been implicated in seizures, but little is known about the structural features of this projection system in epileptic brain. We evaluated the effects of experimental epilepsy on the areal density of cholinergic terminals (fiber varicosities) in the dentate gyrus. For this purpose, we used two distinct post-status epilepticus rat models, in which epilepsy was induced with injections of either kainic acid or pilocarpine. To visualize the cholinergic fibers, we used brain sections immunostained for the vesicular acetylcholine transporter. It was found that the density of cholinergic fiber varicosities was higher in epileptic rats versus control rats in the inner and outer zones of the dentate molecular layer, but it was reduced in the dentate hilus. We further evaluated the effects of kainate treatment on the total number, density, and soma volume of septal cholinergic cells, which were visualized in brain sections stained for either vesicular acetylcholine transporter or choline acetyltransferase (ChAT). Both the number of septal cells with cholinergic phenotype and their density were increased in epileptic rats when compared to control rats. The septal cells stained for vesicular acetylcholine transporter, but not for ChAT, have enlarged perikarya in epileptic rats. These results revealed previously unknown details of structural reorganization of the septohippocampal cholinergic system in experimental epilepsy, involving fiber sprouting into the dentate molecular layer and a parallel fiber retraction from the dentate hilus. We hypothesize that epilepsy-related neuroplasticity of septohippocampal cholinergic neurons is capable of increasing neuronal excitability of the dentate gyrus.
Assuntos
Fibras Colinérgicas/patologia , Epilepsia/patologia , Epilepsia/fisiopatologia , Hipocampo/patologia , Septo do Cérebro/patologia , Análise de Variância , Animais , Colina O-Acetiltransferase/metabolismo , Fibras Colinérgicas/metabolismo , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia/induzido quimicamente , Regulação da Expressão Gênica/efeitos dos fármacos , Ácido Caínico/toxicidade , Masculino , Neurônios/metabolismo , Neurônios/patologia , Ratos , Ratos Wistar , Septo do Cérebro/metabolismo , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismoRESUMO
Pyruvate dehydrogenase reaction utilizing glucose-derived pyruvate is an almost exclusive source of acetyl-CoA in different cell mitochondrial compartments of the brain. In neuronal mitochondria, the largest fraction of acetyl-CoA is utilized for energy production and the much smaller one for N-acetyl-L-aspartate (NAA) synthesis. Cholinergic neurons, unlike others, require additional amounts of acetyl-CoA for acetylcholine synthesis. Therefore, several neurotoxic signals, which inhibit pyruvate dehydrogenase, generate deeper shortages of acetyl-CoA and greater mortality of cholinergic neurons than noncholinergic ones. NAA is considered to be a marker of neuronal energy status in neuropathic brains. However, there is no data on putative differential fractional distribution of the acetyl-CoA pool between energy producing and NAA or acetylcholine synthesizing pathways in noncholinergic and cholinergic neurons, respectively. Therefore, the aim of this study was to investigate whether zinc-excess, a common excitotoxic signal, may evoke differential effects on the NAA metabolism in neuronal cells with low and high expression of the cholinergic phenotype. Differentiated SN56 neuronal cells, displaying a high activity of choline acetyltransferase and rates of acetylcholine synthesis, contained lower levels of acetyl-CoA and NAA, being more susceptible to ZnCl2 exposition that the nondifferentiated SN56 or differentiated dopaminergic SHSY5Y neuronal and astroglial C6 cells. Differentiated SN56 accumulated greater amounts of Zn2 + from extracellular space than the other ones, and displayed a stronger suppression of pyruvate dehydrogenase complex activity and acetyl-CoA, NAA, ATP, acetylcholine levels, and loss of viability. These data indicate that the acetyl-CoA synthesizing system in neurons constitutes functional unity with energy generating and NAA or acetylcholine pathways of its utilization, which are uniformly affected by neurotoxic conditions.
Assuntos
Acetilcoenzima A/metabolismo , Ácido Aspártico/análogos & derivados , Neurônios Colinérgicos/metabolismo , Septo do Cérebro/metabolismo , Zinco/toxicidade , Acetiltransferases/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Ácido Aspártico/metabolismo , Cálcio/metabolismo , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Colina O-Acetiltransferase/metabolismo , Neurônios Colinérgicos/patologia , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Espaço Extracelular/metabolismo , Glicerol Quinase , Cetona Oxirredutases/metabolismo , Camundongos , Septo do Cérebro/patologiaRESUMO
BACKGROUND: Cholinergic cell loss in the basal forebrain, the major source of hippocampal cholinergic projections, has been implicated in Alzheimer's disease. OBJECTIVE: To examine whether the septohippocampal pathway is involved in tauopathy model mice and to elucidate the tau-associated mechanism underlying cholinergic alteration. METHODS: Adult (6 to 8 months old) and old (16 to 18 months old) transgenic mice expressing wild-type human tau, Tg601, were examined using Ex vivo diffusion tensor magnetic resonance imaging (DTI) and 2-[18F]fluoro- 2-deoxy-D-glucose positron emission tomography (FDG-PET). Choline acetyltransferase (ChAT)-positive neurons in the medial septum (MS) were counted by stereological methods. Acetylcholinesterase (AChE) activity and AChE mRNA in 6 brain regions were measured. RESULTS: Ex vivo DTI revealed that the number of fractional anisotropy (FA) streamlines in the septohippocampal tract decreased with age in Tg601 mice. The FA value in the septum was lower in old Tg601 mice than in non-tg mice. A voxel-based statistical analysis of FDG-PET revealed the presence of low glucose uptake areas, involving the MS in adults, and spread over regions including the hippocampal dentate gyrus in old mice. In the MS, the number of choline acetyltransferase (ChAT)-positive neurons decreased in old Tg601 mice. AChE activity and AChE mRNA T transcripts were exclusively higher in the septum. CONCLUSION: The upregulation of AChE in the septum may result in the selective degeneration of the septohippocampal cholinergic pathway in the tauopathy mouse model.
Assuntos
Colina O-Acetiltransferase/metabolismo , Hipocampo/metabolismo , Septo do Cérebro/metabolismo , Tauopatias/metabolismo , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Vias Neurais/diagnóstico por imagem , Vias Neurais/metabolismo , Vias Neurais/patologia , Neurônios/metabolismo , Neurônios/patologia , Septo do Cérebro/diagnóstico por imagem , Septo do Cérebro/patologia , Tauopatias/diagnóstico por imagem , Tauopatias/patologia , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
Anxiety and depression in diabetic patients contributes to a poor prognosis, but possible causal relationships have been controversial. Anxiety, fear, and anhedonia are mediated by interactions between different deep structures of the temporal lobe (e.g., amygdala complex and hippocampus) and other forebrain-related structures (e.g., lateral septal nucleus). Connections between these structures and the hypothalamic orexinergic system are necessary for the maintenance of energy and wakefulness. However, few studies have explored the impact of long-term hyperglycemia in these structures on anxiety. We induced long-term hyperglycemia (glucose levels of â¼500mg/dl) in Wistar rats by injecting them with alloxan and simultaneously protecting them from hyperglycemia by injecting them daily with a low dose of insulin (i.e., just enough insulin to avoid death), thus maintaining hyperglycemia and ketonuria for as long as 6 weeks. Compared with controls, long-term hyperglycemic rats exhibited a significant reduction of Fos expression in the lateral septal nucleus and basolateral amygdala, but no differences were found in cerebellar regions. Orexin-A cells appeared to be inactive in the lateral hypothalamus. No differences were found in sucrose consumption or behavior in the elevated plus maze compared with the control group, but a decrease in general locomotion was observed. These data indicate a generalized blunting of the metabolic brain response, accompanied by a decrease in locomotion but no changes in hedonic- or anxiety-like behavior.
Assuntos
Tonsila do Cerebelo/metabolismo , Hiperglicemia/metabolismo , Hipotálamo/metabolismo , Septo do Cérebro/metabolismo , Aloxano , Tonsila do Cerebelo/patologia , Anedonia , Animais , Ansiedade , Doença Crônica , Sacarose Alimentar , Modelos Animais de Doenças , Hiperglicemia/patologia , Hiperglicemia/psicologia , Hipotálamo/patologia , Imuno-Histoquímica , Cetose/metabolismo , Cetose/patologia , Cetose/psicologia , Masculino , Atividade Motora/fisiologia , Orexinas/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Wistar , Septo do Cérebro/patologiaRESUMO
The major challenge in treating methamphetamine addicts is the maintenance of a drug free-state since they experience negative emotional symptoms during abstinence, which may trigger relapse. The neuronal mechanisms underlying long-term withdrawal and relapse are currently not well-understood. There is evidence suggesting a role of the oxytocin (OTR), µ-opioid receptor (MOPr), dopamine D2 receptor (D2R), corticotropin-releasing factor (CRF) systems and the hypothalamic-pituitary-adrenal (HPA)-axis in the different stages of methamphetamine addiction. In this study, we aimed to characterize the behavioral effects of methamphetamine withdrawal in mice and to assess the modulation of the OTR, MOPr, D2R, CRF and HPA-axis following chronic methamphetamine administration and withdrawal. Ten-day methamphetamine administration (2 mg/kg) increased OTR binding in the amygdala, whilst 7 days of withdrawal induced an upregulation of this receptor in the lateral septum. Chronic methamphetamine treatment increased plasma OT levels that returned to control levels following withdrawal. In addition, methamphetamine administration and withdrawal increased striatal MOPr binding, as well as c-Fos(+)/CRF(+) neuronal expression in the amygdala, whereas an increase in plasma corticosterone levels was observed following METH administration, but not withdrawal. No differences were observed in the D2R binding following METH administration and withdrawal. The alterations in the OTR, MOPr and CRF systems occurred concomitantly with the emergence of anxiety-related symptoms and the development of psychomotor sensitization during withdrawal. Collectively, our findings indicate that chronic methamphetamine use and abstinence can induce brain-region specific neuroadaptations of the OTR, MOPr and CRF systems, which may, at least, partly explain the withdrawal-related anxiogenic effects.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores Opioides mu/metabolismo , Receptores de Ocitocina/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/complicações , Transtornos Relacionados ao Uso de Anfetaminas/patologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/patologia , Animais , Ansiedade/etiologia , Ansiedade/metabolismo , Ansiedade/patologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/efeitos adversos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Corticosterona/sangue , Modelos Animais de Doenças , Masculino , Metanfetamina/administração & dosagem , Metanfetamina/efeitos adversos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Distribuição Aleatória , Septo do Cérebro/efeitos dos fármacos , Septo do Cérebro/metabolismo , Septo do Cérebro/patologia , Síndrome de Abstinência a Substâncias/patologia , Síndrome de Abstinência a Substâncias/psicologiaRESUMO
Exercise has been shown to improve cognitive functioning in a range of species, presumably through an increase in neurotrophins throughout the brain, but in particular the hippocampus. The current study assessed the ability of exercise to restore septohippocampal cholinergic functioning in the pyrithiamine-induced thiamine deficiency (PTD) rat model of the amnestic disorder Korsakoff Syndrome. After voluntary wheel running or sedentary control conditions (stationary wheel attached to the home cage), PTD and control rats were behaviorally tested with concurrent in vivo microdialysis, at one of two time points: 24-h or 2-weeks post-exercise. It was found that only after the 2-week adaption period did exercise lead to an interrelated sequence of events in PTD rats that included: (1) restored spatial working memory; (2) rescued behaviorally-stimulated hippocampal acetylcholine efflux; and (3) within the medial septum/diagonal band, the re-emergence of the cholinergic (choline acetyltransferase [ChAT+]) phenotype, with the greatest change occurring in the ChAT+/nestin+ neurons. Furthermore, in control rats, exercise followed by a 2-week adaption period improved hippocampal acetylcholine efflux and increased the number of neurons co-expressing the ChAT and nestin phenotype. These findings demonstrate a novel mechanism by which exercise can modulate the mature cholinergic/nestin neuronal phenotype leading to improved neurotransmitter function as well as enhanced learning and memory.
Assuntos
Acetilcolina/metabolismo , Hipocampo/metabolismo , Nestina/metabolismo , Neurônios/fisiologia , Septo do Cérebro/patologia , Comportamento Espacial/fisiologia , Deficiência de Tiamina/reabilitação , Animais , Antimetabólitos/toxicidade , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Colina O-Acetiltransferase/metabolismo , Modelos Animais de Doenças , Terapia por Exercício , Masculino , Atividade Motora/efeitos dos fármacos , Fator de Crescimento Neural/metabolismo , Piritiamina/toxicidade , Ratos , Ratos Sprague-Dawley , Reconhecimento Psicológico/fisiologia , Deficiência de Tiamina/induzido quimicamente , Deficiência de Tiamina/patologia , Deficiência de Tiamina/fisiopatologia , Fatores de TempoRESUMO
The human diagonal band of Broca is connected to other parts of the limbic system, such as the hippocampus, that are involved in the pathology of schizophrenia. This study aimed to characterize the volume and anterior-to-posterior distance of the human diagonal band of Broca (vertical limb) from post-mortem brains obtained from three groups: healthy control subjects (N = 17), patients with schizophrenia (N = 26), and patients with affective disorders (N = 12). There were no significant differences in the volume or anterior-to-posterior distance in the patients with schizophrenia or affective disorders compared with the healthy control subjects. To date, this is the first post-mortem investigation measuring the volume and the anterior-to-posterior distance of the diagonal band of Broca (vertical limb) in patients with schizophrenia or affective disorders compared with healthy control subjects.
Assuntos
Feixe Diagonal de Broca/anatomia & histologia , Feixe Diagonal de Broca/patologia , Transtornos do Humor/patologia , Esquizofrenia/patologia , Estudos de Casos e Controles , Humanos , Pessoa de Meia-Idade , Septo do Cérebro/anatomia & histologia , Septo do Cérebro/patologiaRESUMO
Olfactory bulbectomy (OBX) in rodents induces a wide spectrum of functional disturbances, including behavioral, neurochemical, and neuromorphological alterations. We have examined the effects of OBX on behavior and the parameters of the cholinergic system in female rats and mice. In rats, OBX resulted in the appearance of some depressive-like behavioral marks, such as the decreased sucrose consumption, hyperactivity, impaired short-term memory and anxiety-like behavioral features, such as shortened presence in the center of the open field arena or open arms of the elevated plus-maze and an enhancement of avoidance behavior. These behavioral abnormalities could be associated with disturbances in hippocampal function, this suggestion being supported by the presence of cellular changes in this brain structure. No effect of OBX on the number of cholinergic neurons in the medial septum-diagonal band as well as on the acetylcholine content and acetylcholinesterase activity in the septum, hippocampus, and neocortex could be detected. In contrast, in mice, OBX impaired spontaneous alternation behavior and decreased the number of cholinergic neurons in the medial septum-diagonal band. These data demonstrate that rats and mice differently respond to OBX, in particular, OBX does not significantly affect the cholinergic system in rats.
Assuntos
Acetilcolina/metabolismo , Acetilcolinesterase/metabolismo , Comportamento Animal/fisiologia , Bulbo Olfatório/fisiopatologia , Especificidade da Espécie , Animais , Transtornos de Ansiedade/patologia , Transtornos de Ansiedade/fisiopatologia , Aprendizagem da Esquiva/fisiologia , Neurônios Colinérgicos/patologia , Neurônios Colinérgicos/fisiologia , Transtornos Cognitivos/patologia , Transtornos Cognitivos/fisiopatologia , Transtorno Depressivo/patologia , Transtorno Depressivo/fisiopatologia , Sacarose Alimentar , Modelos Animais de Doenças , Feminino , Hipocampo/patologia , Hipocampo/fisiopatologia , Memória de Longo Prazo/fisiologia , Camundongos , Neocórtex/patologia , Neocórtex/fisiopatologia , Bulbo Olfatório/cirurgia , Ratos Wistar , Septo do Cérebro/patologia , Septo do Cérebro/fisiopatologiaRESUMO
The recombinant C-terminal domain of tetanus toxin (Hc-TeTx) is a new non-toxic peptide of the tetanus toxin that exerts a protective action against glutamate excitotoxicity in motoneurons. Moreover, its efficacy as a neuroprotective agent has been demonstrated in several animal models of neurodegeneration. The eleven amino acids in the ß amyloid peptide (Aß25-35) mimic the toxic effects of the full ß amyloid peptide (Aß1-42), causing the impairment of the cholinergic system in the medial septum (MS) which, in turn, alters the septo-hippocampal pathway and leads to learning and memory impairments. The aim of this study was to examine the neuroprotective effects of the Hc-TeTx fragment against cholinotoxicity. The Hc-TeTx fragment (100 ng) was injected into the rats intercranially, with the Aß(25-35) (2 µg) then injected into their MS. The animals were tested for spatial learning and memory in the eight-arm radial maze. The brains were removed to assess cholinergic markers, such as choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), and to explore neurodegeneration in the MS and hippocampus, using amino-cupric silver and H&E staining. Finally, capase-3, a marker of apoptosis, was examined in the MS. Our results clearly demonstrate that the application of Hc-TeTx prevents the loss of cholinergic markers (ChAT and AChE), the activation of capase-3, and neurodegeneration in the MS and the CA1 and CA3 subfields of the hippocampus. All these improvements were reflected in spatial learning and memory performance, and were significantly higher compared with animals treated with Aß(25-35). Interestingly, the single administration of Hc-TeTx into the MS modified the ChAT and AChE expression that affect cognitive processes, without inducing neurodegeneration or an increase in capase-3 expression in the MS and hippocampus. In summary, our findings suggest that the recombinant Hc-TeTx fragment offers effective protection for the septo-hippocampal pathway, given that it reduces the neurodegeneration caused by Aß(25-35) and improves learning and memory processes.
Assuntos
Peptídeos beta-Amiloides/toxicidade , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/farmacologia , Toxina Tetânica/farmacologia , Acetilcolinesterase/metabolismo , Animais , Caspase 3/metabolismo , Colina O-Acetiltransferase/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Imuno-Histoquímica , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Nootrópicos/farmacologia , Fragmentos de Peptídeos/toxicidade , Distribuição Aleatória , Ratos Wistar , Septo do Cérebro/efeitos dos fármacos , Septo do Cérebro/metabolismo , Septo do Cérebro/patologia , Memória Espacial/efeitos dos fármacos , Memória Espacial/fisiologiaRESUMO
Previous research has shown that the ventral medial prefrontal cortex (vmPFC) and hippocampus (Hipp) are critical for extinction memory. Basal forebrain (BF) cholinergic input to the vmPFC and Hipp is critical for neural function in these substrates, which suggests BF cholinergic neurons may be critical for extinction memory. In order to test this hypothesis, we applied cholinergic lesions to different regions of the BF and observed the effects these lesions had on extinction memory. Complete BF cholinergic lesions induced contextual fear memory generalization, and this generalized fear was resistant to extinction. Animals with complete BF cholinergic lesions could not acquire cued fear extinction. Restricted cholinergic lesions in the medial septum and vertical diagonal bands of Broca (MS/vDBB) mimicked the effects that BF cholinergic lesions had on contextual fear memory generalization and acquisition of fear extinction. Cholinergic lesions in the horizontal diagonal band of Broca and nucleus basalis (hDBB/NBM) induced a small deficit in extinction of generalized contextual fear memory with no accompanying deficits in cued fear extinction. The results of this study reveal that MS/vDBB cholinergic neurons are critical for inhibition and extinction of generalized contextual fear memory, and via this process, may be critical for acquisition of cued fear extinction. Further studies delineating neural circuits and mechanisms through which MS/vDBB cholinergic neurons facilitate these emotional memory processes are needed. © 2015 Wiley Periodicals, Inc.
Assuntos
Neurônios Colinérgicos/fisiologia , Feixe Diagonal de Broca/fisiopatologia , Medo/fisiologia , Generalização Psicológica/fisiologia , Memória/fisiologia , Septo do Cérebro/fisiopatologia , Animais , Neurônios Colinérgicos/patologia , Condicionamento Clássico/fisiologia , Sinais (Psicologia) , Feixe Diagonal de Broca/patologia , Extinção Psicológica/fisiologia , Reação de Congelamento Cataléptica , Imuno-Histoquímica , Masculino , Testes Neuropsicológicos , Ratos Sprague-Dawley , Septo do Cérebro/patologiaRESUMO
LIS1 is one of principal genes related with Type I lissencephaly, a severe human brain malformation characterized by abnormal neuronal migration in the cortex. The LIS1 gene encodes a brain-specific 45kDa non-catalytic subunit of platelet-activating factor (PAF) acetylhydrolase-1b (PAFAH1b), an enzyme that inactivates the PAF. We have studied the role of Lis1 using a Lis1/sLis1 murine model, which has deleted the first coding exon from Lis1 gene. Homozygous mice are not viable but heterozygous have shown a delayed corticogenesis and neuronal dysplasia, with enhanced cortical excitability. Lis1/sLis1 embryos also exhibited a delay of cortical innervation by the thalamocortical fibers. We have explored in Lis1/sLis1 mice anomalies in forebrain cholinergic neuron development, which migrate from pallium to subpallium, and functionally represent the main cholinergic input to the cerebral cortex, modulating cortical activity and facilitating attention, learning, and memory. We hypothesized that primary migration anomalies and/or disorganized cortex could affect cholinergic projections from the basal forebrain and septum in Lis1/sLis1 mouse. To accomplish our objective we have first studied basal forebrain neurons in Lis1/sLis1 mice during development, and described structural and hodological differences between wild-type and Lis1/sLis1 embryos. In addition, septohippocampal projections showed altered development in mutant embryos. Basal forebrain abnormalities could contribute to hippocampal excitability anomalies secondary to Lis1 mutations and may explain the cognitive symptoms associated to cortical displasia-related mental diseases and epileptogenic syndromes.
Assuntos
Acetilcolinesterase/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Hipocampo , Lisencefalia/patologia , Mutação/genética , Proteínas do Tecido Nervoso/genética , Septo do Cérebro , Fatores Etários , Animais , Animais Recém-Nascidos , Contagem de Células , Proliferação de Células/genética , Modelos Animais de Doenças , Embrião de Mamíferos , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/patologia , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/metabolismo , Proteínas de Fluorescência Verde/genética , Hipocampo/embriologia , Hipocampo/crescimento & desenvolvimento , Hipocampo/patologia , Lisencefalia/genética , Camundongos , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Vias Neurais/embriologia , Vias Neurais/crescimento & desenvolvimento , Vias Neurais/patologia , Septo do Cérebro/embriologia , Septo do Cérebro/crescimento & desenvolvimento , Septo do Cérebro/patologiaRESUMO
Effects of acute and chronic psychological stress in the brain of domestic avian species have not been extensively studied. Experiments were performed using restraint stress to determine groups of neurons activated in the septum and diencephalon of chickens. Using FOS immunoreactivity six brain structures were shown activated by acute stress including: the lateral hypothalamic area (LHy), ventrolateral thalamic nucleus (VLT), lateral septum (LS), lateral bed nucleus of the stria terminalis (BSTL), nucleus of the hippocampal commissure (NHpC) and the core region of the paraventricular nucleus (PVNc). Additionally, the LHy and PVNc showed increased FOS immunoreactive (-ir) cells in the birds chronically stressed when compared to controls. In contrast, the NHpC showed decreased FOS-ir cells following the 10day chronic stress imposed. Thereafter, restraint stress experiments were performed to identify activated arginine vasotocin (AVT) neurons (parvocellular or magnocellular) using immunocytochemistry. Of the six FOS activated structures, the PVN was known to contain distinct size groups of AVT-ir neurons, parvocellular (small), medium sized and magnocellular (large). Using dual immunostaining (AVT/FOS), AVT-ir parvocellular neurons in the PVNc were found activated in both acute and chronic stress. To determine whether these AVT-ir parvocellular neurons are co-localized with corticotropin releasing hormone (CRH), an attempt was made to visualize CRH-ir neurons using colchicine. Although AVT-ir and CRH-ir parvocellular neurons occur in the PVNc, only a few neurons were shown co-localized with AVT and CRH after acute restraint stress. Results of this study suggest that the NHpC, LS, VLT, BSTL, LHy and AVT-ir parvocellular neurons in the PVNc are associated with psychological stress in birds.
Assuntos
Galinhas/metabolismo , Diencéfalo/metabolismo , Neurônios/metabolismo , Restrição Física , Septo do Cérebro/metabolismo , Estresse Psicológico/metabolismo , Vasotocina/metabolismo , Doença Aguda , Animais , Contagem de Células , Galinhas/sangue , Doença Crônica , Corticosterona/sangue , Hormônio Liberador da Corticotropina/metabolismo , Diencéfalo/patologia , Masculino , Neurônios/patologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/patologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Septo do Cérebro/patologia , Estresse Psicológico/sangueRESUMO
The extent of neuronal damage/death in some brain regions is highly correlated to duration time of transient ischemia. In the present study, we carried out neuronal degeneration/death and glial changes in the septum 4 days after 5, 10, 15, and 20 min of transient cerebral ischemia using gerbils. To examine neuronal damage, Fluoro-Jade B (F-J B, a marker for neuronal degeneration) histofluorescence staining was used. F-J B positive ((+)) cells were detected in the septo-hippocampal nucleus (SHN) of the septum only in the 20 min ischemia-group; the mean number of F-J B(+) neurons was 14.9 ± 2.5/400 µm(2) in a section. Gliosis of astrocytes and microglia was examined using anti-glial fibrillary acidic protein (GFAP) and anti-ionized calcium-binding adapter molecule 1 (Iba-1), respectively. In all the ischemia-groups, GFAP- and Iba-1-immunoreactive astrocytes and microglia, respectively, were increased in number, and apparently tended to be increased in their immunoreactivity. Especially, in the 20 min ischemia-group, the number and immunoreactivity of Iba-immunoreactive microglia was highest and strongest in the ischemic SHN 4 days after ischemia-reperfusion. In brief, our findings showed that neuronal damage/death in the SHN occurred and gliosis was apparently increased in the 20 min ischemia-group at 4 days after ischemia-reperfusion.
Assuntos
Isquemia Encefálica/patologia , Fluoresceínas/metabolismo , Gerbillinae/metabolismo , Gliose/metabolismo , Gliose/patologia , Neurônios/patologia , Septo do Cérebro/patologia , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Benzoxazinas , Isquemia Encefálica/complicações , Isquemia Encefálica/metabolismo , Imunofluorescência , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/complicações , Masculino , Proteínas dos Microfilamentos/metabolismo , Microglia/metabolismo , Microglia/patologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Septo do Cérebro/metabolismo , Coloração e RotulagemRESUMO
Intraneuronal inclusions containing alpha-synuclein (a-syn) constitute one of the pathological hallmarks of Parkinson's disease (PD) and are accompanied by severe neurodegeneration of A9 dopaminergic neurons located in the substantia nigra. Although to a lesser extent, A10 dopaminergic neurons are also affected. Neurodegeneration of other neuronal populations, such as the cholinergic, serotonergic and noradrenergic cell groups, has also been documented in PD patients. Studies in human post-mortem PD brains and in rodent models suggest that deficits in cholinergic and dopaminergic systems may be associated with the cognitive impairment seen in this disease. Here, we investigated the consequences of targeted overexpression of a-syn in the mesocorticolimbic dopaminergic and septohippocampal cholinergic pathways. Rats were injected with recombinant adeno-associated viral vectors encoding for either human wild-type a-syn or green fluorescent protein (GFP) in the ventral tegmental area and the medial septum/vertical limb of the diagonal band of Broca, two regions rich in dopaminergic and cholinergic neurons, respectively. Histopathological analysis showed widespread insoluble a-syn positive inclusions in all major projections areas of the targeted nuclei, including the hippocampus, neocortex, nucleus accumbens and anteromedial striatum. In addition, the rats overexpressing human a-syn displayed an abnormal locomotor response to apomorphine injection and exhibited spatial learning and memory deficits in the Morris water maze task, in the absence of obvious spontaneous locomotor impairment. As losses in dopaminergic and cholinergic immunoreactivity in both the GFP and a-syn expressing animals were mild-to-moderate and did not differ from each other, the behavioral impairments seen in the a-syn overexpressing animals appear to be determined by the long term persisting neuropathology in the surviving neurons rather than by neurodegeneration.
Assuntos
Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/fisiopatologia , Dependovirus/genética , Vetores Genéticos/genética , Septo do Cérebro/metabolismo , Área Tegmentar Ventral/metabolismo , alfa-Sinucleína/genética , Animais , Colina O-Acetiltransferase/metabolismo , Transtornos Cognitivos/patologia , Feixe Diagonal de Broca/efeitos dos fármacos , Feixe Diagonal de Broca/metabolismo , Feixe Diagonal de Broca/patologia , Feixe Diagonal de Broca/fisiopatologia , Dopamina/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Espaço Extracelular/efeitos dos fármacos , Espaço Extracelular/metabolismo , Feminino , Expressão Gênica , Proteínas de Fluorescência Verde/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Memória de Curto Prazo/efeitos dos fármacos , Camundongos Transgênicos , Microdiálise , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Recombinação Genética/genética , Septo do Cérebro/patologia , Septo do Cérebro/fisiopatologia , Transgenes , Tirosina 3-Mono-Oxigenase/metabolismo , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/patologia , Área Tegmentar Ventral/fisiopatologiaRESUMO
For over a century epileptic seizures have been known to cluster at specific times of the day. Recent studies have suggested that the circadian regulatory system may become permanently altered in epilepsy, but little is known about how this affects neural activity and the daily pattern of seizures. To investigate, we tracked long-term changes in the rate of spontaneous hippocampal EEG spikes (SPKs) in a rat model of temporal lobe epilepsy. In healthy animals, SPKs oscillated with near 24-h period; however, after injury by status epilepticus, a persistent phase shift of â¼12 h emerged in animals that later went on to develop chronic spontaneous seizures. Additional measurements showed that global 24-h rhythms, including core body temperature and theta state transitions, did not phase shift. Instead, we hypothesized that locally impaired circadian input to the hippocampus might be responsible for the SPK phase shift. This was investigated with a biophysical computer model in which we showed that subtle changes in the relative strengths of circadian input could produce a phase shift in hippocampal neural activity. MRI provided evidence that the medial septum, a putative circadian relay center for the hippocampus, exhibits signs of damage and therefore could contribute to local circadian impairment. Our results suggest that balanced circadian input is critical to maintaining natural circadian phase in the hippocampus and that damage to circadian relay centers, such as the medial septum, may disrupt this balance. We conclude by discussing how abnormal circadian regulation may contribute to the daily rhythms of epileptic seizures and related cognitive dysfunction.
Assuntos
Ritmo Circadiano , Epilepsia do Lobo Temporal/fisiopatologia , Hipocampo/fisiopatologia , Septo do Cérebro/patologia , Ritmo Teta , Animais , Modelos Animais de Doenças , Eletroencefalografia , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
BACKGROUND: Based on our previous findings on the efficacy of ocular applied nerve growth factor as eye drops (oNGF) to act in brain and counteract neuronal damage, we hypothesized that oNGF treatment might revert neuronal atrophy occurring in diabetic brain also by controlling neurotrophin system changes. The major NGF brain target areas, such as the septum and the hippocampus, were used as an experimental paradigma to test this hypothesis. METHODS: Bilateral oNGF treatment was performed twice a day for 2 weeks in full-blown streptozotocin-treated adult male rats. The forebrain distribution of cholinergic and endothelial cell markers and NGF receptors were studied by confocal microscopy. The septo-hippocampal content of NGF mature and precursor form and NGF receptors expression were also analyzed by Elisa and Western blot. RESULTS: oNGF treatment recovers the morphological alterations and the neuronal atrophy in septum and normalized the expression of mature and pro-NGF, as well as NGF receptors in the septum and hippocampus of diabetic rats. In addition, oNGF stimulated brain vascularization and up-regulated the TRKA receptor in vessel endothelium. CONCLUSIONS: Our findings confirm that reduced availability of mature NGF and NGF signaling impairment favors vascular and neuronal alterations in diabetic septo-hippocampal areas and corroborate the ability of oNGF to act as a neuroprotective agent in brain.
Assuntos
Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/tratamento farmacológico , Hipocampo/patologia , Fator de Crescimento Neural/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Septo do Cérebro/patologia , Administração Oftálmica , Animais , Sobrevivência Celular/efeitos dos fármacos , Nefropatias Diabéticas/patologia , Hipocampo/irrigação sanguínea , Masculino , Proteínas do Tecido Nervoso , Ratos , Ratos Sprague-Dawley , Receptor de Fator de Crescimento Neural/análise , Receptor trkA/análise , Receptores de Fatores de Crescimento , Receptores de Fator de Crescimento Neural/análise , EstreptozocinaRESUMO
Accumulation of amyloid-ß peptides (Aß) and cholinergic degeneration are hallmarks of Alzheimer's disease (AD). In a triple transgenic mouse model of AD (3xTg-AD), soluble Aß42 levels were detected in the septum by 2 months of age, reaching their highest levels at 3-6 months and decreasing at 12 months. Deficits in the number of septal cholinergic neurons and the length of hippocampal cholinergic axons were observed starting at 4 months in 3xTg-AD mice. Our results show that septal Aß and septohippocampal cholinergic pathology in 3xTg-AD mice occur at an early stage of disease.