RESUMO
Alzheimer's disease patients and mouse models exhibit aberrant neuronal activity and altered excitatory-to-inhibitory synaptic ratio. Using multicolor two-photon microscopy, we test how amyloid pathology alters the structural dynamics of excitatory and inhibitory synapses and their adaptation to altered visual experience in vivo in the visual cortex. We show that the baseline dynamics of mature excitatory synapses and their adaptation to visual deprivation are not altered in amyloidosis. Likewise, the baseline dynamics of inhibitory synapses are not affected. In contrast, visual deprivation fails to induce inhibitory synapse loss in amyloidosis, a phenomenon observed in nonpathological conditions. Intriguingly, inhibitory synapse loss associated with visual deprivation in nonpathological mice is accompanied by subtle broadening of spontaneous but not visually evoked calcium transients. However, such broadening does not manifest in the context of amyloidosis. We also show that excitatory and inhibitory synapse loss is locally clustered under the nonpathological state. In contrast, a fraction of synapse loss is not locally clustered in amyloidosis, indicating an impairment in inhibitory synapse adaptation to changes in excitatory synaptic activity.
Assuntos
Doença de Alzheimer , Amiloidose , Camundongos , Humanos , Animais , Neurônios/fisiologia , Sinapses/fisiologia , Plasticidade Neuronal/fisiologiaRESUMO
While Alzheimer's disease (AD) has been extensively studied with a focus on cognitive networks, sensory network dysfunction has received comparatively less attention despite compelling evidence of its significance in both Alzheimer's disease patients and mouse models. We recently found that neurons in the primary visual cortex of an amyloid mouse model exhibit an imbalance of postsynaptic structures favoring neuronal hyperactivity alongside increased c-Fos expression, which regulates plasticity and memory. Here, we investigate aberrant visual network and brain-wide c-Fos expression and functional connectivity patterns, network responses to light deprivation, and visual system presynaptic deficits of a mouse model of Alzheimer's disease. We found that the mouse model of AD exhibits aberrant c-Fos expression and functional connectivity patterns across multiple brain regions, and functional connectivity between brain regions is a significant predictor for aberrant c-Fos expression. We also show that one week of light deprivation increases c-Fos expression across the brain in nonpathological controls but not the AD model, indicating experience-dependent plasticity deficits in multiple brain regions. Using in vivo and ex vivo imaging of presynaptic termini, we found that aberrant visual cortical c-Fos expression is associated with selective loss of excitatory cortical but not inhibitory or subcortical synapses. Our findings reveal novel structural and functional connectivity deficits in the visual network pre-plaque amyloidosis.
RESUMO
Background: While Alzheimer's disease (AD) has been extensively studied with a focus on cognitive networks, visual network dysfunction has received less attention despite compelling evidence of its significance in AD patients and mouse models. We recently reported c-Fos and synaptic dysregulation in the primary visual cortex of a pre-amyloid plaque AD-model. Objective: We test whether c-Fos expression and presynaptic density/dynamics differ in cortical and subcortical visual areas in an AD-model. We also examine whether aberrant c-Fos expression is inherited through functional connectivity and shaped by light experience. Methods: c-Fos+ cell density, functional connectivity, and their experience-dependent modulation were assessed for visual and whole-brain networks in both sexes of 4-6-month-old J20 (AD-model) and wildtype (WT) mice. Cortical and subcortical differences in presynaptic vulnerability in the AD-model were compared using ex vivo and in vivo imaging. Results: Visual cortical, but not subcortical, networks show aberrant c-Fos expression and impaired experience-dependent modulation. The average functional connectivity of a brain region in WT mice significantly predicts aberrant c-Fos expression, which correlates with impaired experience-dependent modulation in the AD-model. We observed a subtle yet selective weakening of excitatory visual cortical synapses. The size distribution of cortical boutons in the AD-model is downscaled relative to those in WT mice, suggesting a synaptic scaling-like adaptation of bouton size. Conclusions: Visual network structural and functional disruptions are biased toward cortical regions in pre-plaque J20 mice, and the cellular and synaptic dysregulation in the AD-model represents a maladaptive modification of the baseline physiology seen in WT conditions.
RESUMO
Alzheimer's disease patients and mouse models exhibit aberrant neuronal activity and altered excitatory-to-inhibitory synaptic ratio. Using multicolor two-photon microscopy, we test how amyloid pathology alters the structural dynamics of excitatory and inhibitory synapses and their adaptation to altered visual experience in vivo in the visual cortex. We show that the baseline dynamics of mature excitatory synapses and their adaptation to visual deprivation are not altered in amyloidosis. Likewise, the baseline dynamics of inhibitory synapses are not affected. In contrast, visual deprivation fails to induce inhibitory synapse loss in amyloidosis, a phenomenon observed in nonpathological conditions. Intriguingly, inhibitory synapse loss associated with visual deprivation in nonpathological mice is accompanied by the broadening of spontaneous but not visually evoked calcium transients. However, such broadening does not manifest in the context of amyloidosis. We also show that excitatory and inhibitory synapse loss is locally clustered under the nonpathological state. In contrast, a fraction of synapse loss is not locally clustered in amyloidosis, indicating an impairment in inhibitory synapse adaptation to changes in excitatory synaptic activity.
RESUMO
Familiarity creates subjective memory of repeated innocuous experiences, reduces neural and behavioral responsiveness to those experiences, and enhances novelty detection. The neural correlates of the internal model of familiarity and the cellular mechanisms of enhanced novelty detection following multi-day repeated passive experience remain elusive. Using the mouse visual cortex as a model system, we test how the repeated passive experience of a 45° orientation-grating stimulus for multiple days alters spontaneous and non-familiar stimuli evoked neural activity in neurons tuned to familiar or non-familiar stimuli. We found that familiarity elicits stimulus competition such that stimulus selectivity reduces in neurons tuned to the familiar 45° stimulus; it increases in those tuned to the 90° stimulus but does not affect neurons tuned to the orthogonal 135° stimulus. Furthermore, neurons tuned to orientations 45° apart from the familiar stimulus dominate local functional connectivity. Interestingly, responsiveness to natural images, which consists of familiar and non-familiar orientations, increases subtly in neurons that exhibit stimulus competition. We also show the similarity between familiar grating stimulus-evoked and spontaneous activity increases, indicative of an internal model of altered experience.
RESUMO
Familiarity creates subjective memory of repeated innocuous experiences, reduces neural and behavioral responsiveness to those experiences, and enhances novelty detection. The neural correlates of the internal model of familiarity and the cellular mechanisms of enhanced novelty detection following multi-day repeated passive experience remain elusive. Using the mouse visual cortex as a model system, we test how the repeated passive experience of a 45° orientation-grating stimulus for multiple days alters spontaneous and non-familiar stimuli evoked neural activity in neurons tuned to familiar or non-familiar stimuli. We found that familiarity elicits stimulus competition such that stimulus selectivity reduces in neurons tuned to the familiar 45° stimulus; it increases in those tuned to the 90° stimulus but does not affect neurons tuned to the orthogonal 135° stimulus. Furthermore, neurons tuned to orientations 45° apart from the familiar stimulus dominate local functional connectivity. Interestingly, responsiveness to natural images, which consists of familiar and non-familiar orientations, increases subtly in neurons that exhibit stimulus competition. We also show the similarity between familiar grating stimulus-evoked and spontaneous activity increases, indicative of an internal model of altered experience.
Assuntos
Reconhecimento Psicológico , Córtex Visual , Camundongos , Animais , Reconhecimento Psicológico/fisiologia , Neurônios/fisiologia , Estimulação LuminosaRESUMO
Neuronal hyperactivity induces memory deficits in Alzheimer's disease. However, how hyperactivity disrupts memory is unclear. Using in vivo synaptic imaging in the mouse visual cortex, we show that structural excitatory-inhibitory synapse imbalance in the apical dendrites favors hyperactivity in early amyloidosis. Consistent with this, natural images elicit neuronal hyperactivity in these mice. Compensatory changes that maintain activity homeostasis disrupt functional connectivity and increase population sparseness such that a small fraction of neurons dominates population activity. These properties reduce the selectivity of neural response to natural images and render visual recognition memory vulnerable to interference. Deprivation of non-specific visual experiences improves the neural representation and behavioral expression of visual familiarity. In contrast, in non-pathological conditions, deprivation of non-specific visual experiences induces disinhibition, increases excitability, and disrupts visual familiarity. We show that disrupted familiarity occurs when the fraction of high-responsive neurons and the persistence of neural representation of a memory-associated stimulus are not constrained.