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1.
iScience ; 25(10): 105232, 2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36274955

RESUMO

Neurodegenerative disorders are associated with widespread disruption to brain activity and brain rhythms. Some disorders are linked to dysfunction of the membrane-associated protein Tau. Here, we ask how brain rhythms are affected in rTg4510 mouse model of tauopathy, at an early stage of tauopathy (5 months), and at a more advanced stage (8 months). We measured brain rhythms in primary visual cortex in presence or absence of visual stimulation, while monitoring pupil diameter and locomotion to establish behavioral state. At 5 months, we found increased low-frequency rhythms during resting state in tauopathic animals, associated with periods of abnormally increased neural synchronization. At 8 months, this increase in low-frequency rhythms was accompanied by a reduction of power in the gamma range. Our results therefore show that slower rhythms are impaired earlier than gamma rhythms in this model of tauopathy, and suggest that electrophysiological measurements can track the progression of tauopathic neurodegeneration.

2.
Commun Biol ; 5(1): 77, 2022 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-35058544

RESUMO

Alzheimer's disease and other dementias are thought to underlie a progressive impairment of neural plasticity. Previous work in mouse models of Alzheimer's disease shows pronounced changes in artificially-induced plasticity in hippocampus, perirhinal and prefrontal cortex. However, it is not known how degeneration disrupts intrinsic forms of brain plasticity. Here we characterised the impact of tauopathy on a simple form of intrinsic plasticity in the visual system, which allowed us to track plasticity at both long (days) and short (minutes) timescales. We studied rTg4510 transgenic mice at early stages of tauopathy (5 months) and a more advanced stage (8 months). We recorded local field potentials in the primary visual cortex while animals were repeatedly exposed to a stimulus over 9 days. We found that both short- and long-term visual plasticity were already disrupted at early stages of tauopathy, and further reduced in older animals, such that it was abolished in mice expressing mutant tau. Additionally, visually evoked behaviours were disrupted in both younger and older mice expressing mutant tau. Our results show that visual cortical plasticity and visually evoked behaviours are disrupted in the rTg4510 model of tauopathy. This simple measure of plasticity may help understand how tauopathy disrupts neural circuits, and offers a translatable platform for detection and tracking of the disease.


Assuntos
Doença de Alzheimer/fisiopatologia , Plasticidade Neuronal/fisiologia , Córtex Visual/fisiologia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Transgênicos
3.
Curr Biol ; 31(6): 1221-1233.e9, 2021 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-33581073

RESUMO

Flexible navigation relies on a cognitive map of space, thought to be implemented by hippocampal place cells: neurons that exhibit location-specific firing. In connected environments, optimal navigation requires keeping track of one's location and of the available connections between subspaces. We examined whether the dorsal CA1 place cells of rats encode environmental connectivity in four geometrically identical boxes arranged in a square. Rats moved between boxes by pushing saloon-type doors that could be locked in one or both directions. Although rats demonstrated knowledge of environmental connectivity, their place cells did not respond to connectivity changes, nor did they represent doorways differently from other locations. Place cells coded location in a global reference frame, with a different map for each box and minimal repetitive fields despite the repetitive geometry. These results suggest that CA1 place cells provide a spatial map that does not explicitly include connectivity.


Assuntos
Hipocampo/citologia , Células de Lugar , Percepção Espacial , Potenciais de Ação , Animais , Células de Lugar/citologia , Ratos
4.
Diabetologia ; 61(11): 2422-2432, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30094465

RESUMO

AIMS/HYPOTHESIS: Diabetic retinopathy is increasing in prevalence worldwide and is fast becoming a global epidemic and a leading cause of visual loss. Current therapies are limited, and the development of effective treatments for diabetic retinopathy requires a greater in-depth knowledge of disease progression and suitable modelling of diabetic retinopathy in animals. The aim of this study was to assess the early pathological changes in retinal morphology and neuronal, inflammatory and vascular features consistent with diabetic retinopathy in the ob/ob mouse model of type 2 diabetes, to investigate whether features similar to those in human diabetic retinopathy were present. METHODS: Male and female wild-type (+/+), heterozygous (+/-) and homozygous (-/-) BTBR ob/ob mice were examined at 6, 10, 15 and 20 weeks of age. Animals were weighed and blood glucose was measured. TUNEL and brain-specific homeobox/POU domain protein 3A (BRN3A) markers were used to examine retinal ganglion cells. We used immunostaining (collagen IV and platelet endothelial cell adhesion molecule [PECAM]/CD31) to reveal retinal vessel degeneration. Spectral domain optical coherence tomography was used to reveal changes in the thickness and structure of the retinal layer. Vitreous fluorophotometry was used to investigate vascular permeability. A-waves, b-waves and oscillatory potentials were measured under photopic and scotopic conditions. Concanavalin A leucostasis and immunostaining with glial fibrillary acidic protein (GFAP) and ionised calcium-binding adapter molecule 1 (IBA-1) identified differences in inflammatory status. Paraffin sections and transmission electron microscopy were used to reveal changes in the thickness and structure of the retinal layer. RESULTS: Following the development of obesity and hyperglycaemia in 2-week-old and 3-week-old ob-/ob- mice, respectively (p < 0.001), early functional deficits (p < 0.001) and thinning of the inner retina (p < 0.001) were identified. Glial activation, leucostasis (p < 0.05) and a shift in microglia/macrophage phenotype were observed before microvascular degeneration (p < 0.05) and elevated vascular permeability occurred (p < 0.05). CONCLUSIONS/INTERPRETATION: The present characterisation of the development of diabetic retinopathy in the ob/ob mouse represents a platform that will enable the development of new therapies, particularly for the early stages of disease.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Retina/metabolismo , Retina/patologia , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/genética , Modelos Animais de Doenças , Feminino , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Obesidade/metabolismo , Obesidade/patologia , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia
5.
J Vis Exp ; (96)2015 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-25742031

RESUMO

Progress in understanding the pathophysiology, and providing novel treatments for glaucoma is dependent on good animal models of the disease. We present here a protocol for elevating intraocular pressure (IOP) in the rat, by injecting magnetic microspheres into the anterior chamber of the eye. The use of magnetic particles allows the user to manipulate the beads into the iridocorneal angle, thus providing a very effective blockade of fluid outflow from the trabecular meshwork. This leads to long-lasting IOP rises, and eventually neuronal death in the ganglion cell layer (GCL) as well as optic nerve pathology, as seen in patients with the disease. This method is simple to perform, as it does not require machinery, specialist surgical skills, or many hours of practice to perfect. Furthermore, the pressure elevations are very robust, and reinjection of the magnetic microspheres is not usually required unlike in some other models using plastic beads. Additionally, we believe this method is suitable for adaptation for the mouse eye.


Assuntos
Modelos Animais de Doenças , Magnetismo , Animais , Feminino , Glaucoma , Injeções , Pressão Intraocular/efeitos dos fármacos , Camundongos , Microesferas , Neurônios/efeitos dos fármacos , Nervo Óptico/efeitos dos fármacos , Ratos , Tonometria Ocular
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