Altered low-frequency brain rhythms precede changes in gamma power during tauopathy

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

Plasticity in visual cortex is disrupted in a mouse model of tauopathy

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

Hippocampal place cells encode global location but not connectivity in a complex space

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

BTBR ob/ob mouse model of type 2 diabetes exhibits early loss of retinal function and retinal inflammation followed by late vascular changes

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), spectral domain optical coherence tomography and vitreous fluorophotometry to investigate vascular morphology and permeability. Oscillatory potential and photopic and scotopic electroretinograms helped to differentiate neuronal phenotypes. 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 (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). CONCLUSION/INTERPRETATION: 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

Hippocampal place cells encode global location but not changes in environmental connectivity in a 4-room navigation task

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