RESUMO
AbstractMammalian hibernation in ground squirrels is characterized by periods of torpor wherein body temperature approaches ambient temperature and metabolism is reduced to as low as 1/100th of active rates. It is unclear how hibernation affects long-term spatial memory, as tremendous remodeling of neurons is associated with torpor use. Given the suspected links between remodeling and memory formation and retention, we examined long-term spatial memory retention throughout a hibernation season. Animals were trained on a Barnes maze before entering torpor. Animals were tested for memory retention once a month throughout a hibernation season. Results indicate marked variation between individuals. Some squirrels retained memory across multiple torpor bouts, while other squirrels did not. No relationship was found between the number of torpor bouts, duration of bouts, or time spent torpid on long-term memory retention. However, that some squirrels successfully retain memory suggests that the profound remodeling of dendritic spines during torpor does not always lead to memory loss.
Assuntos
Hibernação , Sciuridae , Animais , Temperatura Corporal/fisiologia , Hibernação/fisiologia , Sciuridae/fisiologia , Estações do Ano , Memória EspacialRESUMO
RATIONALE: Diabetes mellitus (DM) is a major risk factor for Alzheimer's disease and vascular dementia. Few animal models exist that focus on the metabolic contributions to dementia onset and progression. Thus, there is strong scientific rationale to explore the effects of streptozotocin (STZ), a diabetogenic compound, on vascular and inflammatory changes within the brain. OBJECTIVE AND METHODS: The present study was designed to evaluate the effect of staggered, low-dose administration of STZ on behavioral and cognitive deficits, neuroinflammation, tau pathology, and histopathological alterations related to dementia. RESULTS: Staggered administration (Days 1, 2, 3, 14, 15) of streptozotocin (40â¯mg/kg/mL) induced a diabetic-like state in mice, resulting in sustained hyperglycemia. STZ-treated animals displayed memory deficits in the novel object recognition task as well as increased tau phosphorylation and increased neuroinflammation. Additionally, STZ led to altered insulin signaling, exhibited by decreased plasma insulin and decreased levels of insulin degrading enzyme and pAKT within the hippocampus. CONCLUSIONS: STZ-treated animals exhibit cognitive deficits and histopathological changes seen in dementia. This model of dementia warrants continued investigation to better understand the role that DM plays in dementia-related alterations.
Assuntos
Doença de Alzheimer/etiologia , Demência Vascular/etiologia , Diabetes Mellitus Experimental/complicações , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Animais , Encéfalo/irrigação sanguínea , Encéfalo/imunologia , Encéfalo/patologia , Demência Vascular/metabolismo , Demência Vascular/patologia , Demência Vascular/psicologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/psicologia , Hemorragia/patologia , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hiperglicemia/psicologia , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Inflamação/psicologia , Insulina/metabolismo , Deficiências da Aprendizagem/metabolismo , Deficiências da Aprendizagem/patologia , Masculino , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Camundongos Endogâmicos C57BL , Microvasos/patologia , Estreptozocina/administração & dosagem , Proteínas tau/metabolismoRESUMO
Lipopolysaccharide (LPS) is often used to investigate the exacerbatory effects of an immune-related challenge in transgenic models of various neurodegenerative diseases. However, the effects of this inflammatory challenge in an insulin resistant brain state, as seen in diabetes mellitus, a major risk factor for both vascular dementia (VaD) and Alzheimer's disease (AD), is not as well characterized. We investigated the effects of an LPS-induced inflammatory challenge on behavioral and biological parameters following intracerebroventricular (ICV) injection of streptozotocin (STZ) in male Sprague-Dawley rats. Subjects received a one-time bilateral ICV infusion of STZ (25 mg/mL, 8 µL per ventricle) or ACSF. One week following ICV infusions, LPS (1 mg/mL, i.p.) or saline was administered to activate the immune system. Behavioral testing began on the 22nd day following STZ-ICV infusion, utilizing the open field and Morris water maze (MWM) tasks. Proteins related to immune function, learning and memory, synaptic plasticity, and key histopathological markers observed in VaD and AD were evaluated. The addition of an LPS-induced immune challenge partially attenuated spatial learning and memory deficits in the MWM in STZ-ICV injected animals. Additionally, LPS administration to STZ-treated animals partially mitigated alterations observed in several protein levels in STZ-ICV alone, including NR2A, GABA(B1), and ß-amyloid oligomers. These results suggest that an acute LPS-inflammatory response has a modest protective effect against some of the spatial learning and memory deficits and protein alterations associated with STZ-ICV induction of an insulin resistant brain state.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Inflamação/induzido quimicamente , Lipopolissacarídeos/toxicidade , Estreptozocina/administração & dosagem , Peptídeos beta-Amiloides/metabolismo , Análise de Variância , Animais , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Inflamação/metabolismo , Inflamação/fisiopatologia , Injeções Intraventriculares , Interleucina-6/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de GABA-B/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Fatores de TempoRESUMO
The GABA transmitter system plays a vital role in modulating synaptic formation and activity during development. The GABAB receptor subtype in particular has been implicated in cell migration, promotion of neuronal differentiation, neurite outgrowth, and synapse formation but it's role in development is not well characterized. In order to investigate the effects of brief alterations in GABAB signaling in development, we administered to rats the GABAB agonist baclofen (2.0mg/kg) or antagonist phaclofen (0.3mg/kg) on postnatal days 7, 9, and 12, and evaluated sensorimotor gating in adulthood. We also examined tissue for changes in multiple proteins associated with GABAB receptor function and proteins associated with synapse formation. Our data indicate that early postnatal alterations to GABAB receptor-mediated signaling produced sex differences in sensorimotor gating in adulthood. Additionally, we found differences in GABAB receptor subunits and kalirin protein levels in the brain versus saline treated controls. Our data demonstrate that a subtle alteration in GABAB receptor function in early postnatal life induces changes that persist into adulthood.
Assuntos
Encéfalo/metabolismo , Transtornos Neurológicos da Marcha/metabolismo , Transtornos Neurológicos da Marcha/patologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Receptores de GABA-B/metabolismo , Transdução de Sinais/fisiologia , Estimulação Acústica , Fatores Etários , Animais , Animais Recém-Nascidos , Baclofeno/análogos & derivados , Baclofeno/toxicidade , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Antagonistas GABAérgicos/toxicidade , Agonistas dos Receptores de GABA-B/toxicidade , Transtornos Neurológicos da Marcha/induzido quimicamente , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Masculino , Gravidez , Inibição Pré-Pulso/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Filtro Sensorial/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
The underlying mechanisms of schizophrenia pathogenesis are not well understood. Increasing evidence supports the glutamatergic hypothesis that posits a hypofunction of the N-methyl D-aspartate (NMDA) receptor on specific gamma amino-butyric acid (GABA)-ergic neurons may be responsible for the disorder. Alterations in the GABAergic system have been observed in schizophrenia, most notably a change in the expression of parvalbumin (PV) in the cortex and hippocampus. Several reports also suggest abnormal neuronal migration may play a role in the etiology of schizophrenia. The current study examined the positioning and distribution of PV-positive cells in the hippocampus following chronic treatment with the NMDA receptor antagonist ketamine. A robust increase was found in the number of PV-positive interneurons located outside the stratum oriens (SO), the layer where most of these cells are normally localized, as well as an overall numerical increase in CA3 PV cells. These results suggest ketamine leads to an abnormal distribution of PV-positive cells, which may be indicative of aberrant migratory activity and possibly related to the Morris water maze deficits observed. These findings may also be relevant to alterations observed in schizophrenia populations.
Assuntos
Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Hipocampo/efeitos dos fármacos , Ketamina/administração & dosagem , Neurônios/efeitos dos fármacos , Parvalbuminas/metabolismo , Animais , Movimento Celular/efeitos dos fármacos , Modelos Animais de Doenças , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Esquizofrenia/metabolismoRESUMO
Subanesthetic administration of the NMDA receptor antagonist ketamine has been suggested to have utility in several therapeutic domains; however, its recreational use has exceeded its therapeutic applications. Ketamine has been utilized to investigate NMDA receptor-mediated learning and memory and to model disorders such as schizophrenia. The utility of ketamine in relation to schizophrenia is based on a proposed mechanism of the disorder being associated with reduced NMDA receptor function within a subset of GABAergic neurons. The examination of ketamine with relevance to the above topics has produced valuable data; however, there exists a great deal of variability in the literature regarding dosage and timing of administration to examine ketamine-induced deficits. In the below experiments we sought to identify the minimal subanesthetic dosage and schedule of ketamine administrations that would produce behavioral deficits in multiple tasks with relevance to the above investigations. We evaluated sensorimotor gating as well as spatial learning and memory in the Morris water task utilizing different doses of ketamine. Our data indicate that an 8 mg/kg subcutaneous dose of ketamine was the minimal dose to produce impairments in both sensorimotor gating and spatial learning.
Assuntos
Antagonistas de Aminoácidos Excitatórios/toxicidade , Transtornos Neurológicos da Marcha/induzido quimicamente , Transtornos Neurológicos da Marcha/diagnóstico , Ketamina/toxicidade , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/diagnóstico , Estimulação Acústica/efeitos adversos , Análise de Variância , Animais , Relação Dose-Resposta a Droga , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Inibição Neural/efeitos dos fármacos , Testes Neuropsicológicos , Psicoacústica , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Filtro Sensorial/efeitos dos fármacos , Fatores de TempoRESUMO
The investigation of GABAergic systems in learning and extinction has principally focused on ionotropic GABA(A) receptors. Less well characterized is the metabotropic GABA(B) receptor, which when activated, induces a more sustained inhibitory effect and has been implicated in regulating oscillatory activity. Few studies have been carried out utilizing GABA(B) ligands in learning, and investigations of GABA(B) in extinction have primarily focused on interactions with drugs of abuse. The current study examined changes in GABA(B) receptor function using the GABA(B) agonist baclofen (2 mg/mL) or the GABA(B) antagonist phaclofen (0.3 mg/mL) on trace cued and contextual fear conditioning and extinction. The compounds were either administered during training and throughout extinction in Experiment 1, or starting 24 h after training and throughout extinction in Experiment 2. All drugs were administered 1 mL/kg via intraperitoneal injection. These studies demonstrated that the administration of baclofen during training and extinction trials impaired animals' ability to extinguish the fear association to the CS, whereas the animals that were administered baclofen starting 24 h after training (Experiment 2) did display some extinction. Further, contextual fear extinction was impaired by baclofen in both experiments. Tissue analyses suggest the cued fear extinction deficit may be related to changes in the GABA(B2) receptor subunit in the amygdala. The data in the present investigation demonstrate that GABA(B) receptors play an important role in trace cued and contextual fear extinction, and may function differently than GABA(A) receptors in learning, memory, and extinction.
Assuntos
Baclofeno/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Agonistas dos Receptores de GABA-B/farmacologia , Ácido gama-Aminobutírico/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Baclofeno/análogos & derivados , Sinais (Psicologia) , Antagonistas GABAérgicos/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto/efeitos dos fármacosRESUMO
The neuropeptide galanin inhibits the evoked release of several neurotransmitters including acetylcholine and modulates adenylate cyclase (AC) activity. Galanin has also been established to impair various forms of learning and memory in rodents. However, whether galanin produces learning deficits by inhibiting cholinergic activity or decreasing AC function has not been clearly established. The current study investigated if donepezil, an acetylcholinesterase inhibitor utilized in Alzheimer's disease, could rescue galanin-induced Morris water task deficits in rats. The results demonstrated that donepezil did not alter the previously established deficits induced by galanin. These findings suggest that galanin-mediated spatial learning deficits may be unrelated to its modulation of the cholinergic system.
Assuntos
Galanina/toxicidade , Indanos/uso terapêutico , Deficiências da Aprendizagem/induzido quimicamente , Deficiências da Aprendizagem/tratamento farmacológico , Nootrópicos/uso terapêutico , Piperidinas/uso terapêutico , Percepção Espacial/efeitos dos fármacos , Análise de Variância , Animais , Modelos Animais de Doenças , Donepezila , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
Alterations in N-methyl-D-aspartate (NMDA) receptor function have been linked to numerous behavioral deficits and neurochemical alterations. Recent investigations have begun to explore the role of NMDA receptor function on principally inhibitory neurons and their role in network function. One of the prevailing models of schizophrenia proposes a reduction in NMDA receptor function on inhibitory interneurons and the resulting disinhibition may give rise to aspects of the disorder. Studies using NMDA receptor antagonists such as PCP and ketamine have induced schizophrenia-like behavioral deficits in animal model systems as well as changes in inhibitory circuits. The current study investigated whether the administration of a subanesthetic dose of ketamine (8 mg/kg subcutaneously), that disrupts sensorimotor gating, also produces impairments in a Pavlovian emotional learning and memory task. We utilized both standard delay and trace cued and contextual fear conditioning (CCF) paradigms to examine if ketamine produces differential effects when the task is more difficult and relies on connectivity between specific brain regions. Rats administered ketamine displayed no significant deficits in cued or contextual fear following the delay conditioning protocol. However, ketamine did produce a significant impairment in the more difficult trace conditioning protocol. Analyses of tissue from the hippocampus and amygdala indicated that the administration of ketamine produced an alteration in GABA receptor protein levels differentially depending on the task. These data indicate that 8 mg/kg of ketamine impairs learning in the more difficult emotional classical conditioning task and may be related to altered signaling in GABAergic systems.