Cortical Circuit Dysfunction in a Mouse Model of Alpha-synucleinopathy in Vivo

Abstract Considerable fluctuations in cognitive performance and eventual dementia are an important characteristic of alpha-synucleinopathies, such as Parkinson’s disease (PD) and Lewy Body dementia (LBD) and are linked to cortical dysfunction. The presence of misfolded and aggregated alpha-synuclein (a-syn) in the cerebral cortex of patients has been suggested to play a crucial role in this process. However, the consequences of a-syn accumulation on the function of cortical networks at cellular resolution in vivo are largely unknown. Here we used the striatal seeding model in wildtype mice in order to induce robust a-synuclein pathology in the cerebral cortex. 9 months after a single intrastriatal injection of a-syn preformed fibrils, we performed in vivo two-photon calcium imaging in awake mice. We observed profound alterations of the function of layer 2/3 cortical neurons in somatosensory cortex (S1), as witnessed by an enhanced response to whisking and increased synchrony, accompanied by a decrease in baseline Ca2+ levels. Stereological analyses revealed a reduction in GAD67-positive inhibitory cells in S1 in PFF-injected brains. These findings point to a disturbed excitation/inhibition balance as an important driver of circuit dysfunction in alpha-synucleinopathies, which may underly cognitive changes in these diseases.

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Striatal seeding of protofibrillar alpha-synuclein causes cortical hyperreactivity in behaving mice

10.1101/2020.09.28.314526 ◽

2020 ◽

Author(s):

Sonja Blumenstock ◽

Fanfan Sun ◽

Petar Marinković ◽

Carmelo Sgobio ◽

Sabine Liebscher ◽

...

Keyword(s):

Cortical Neurons ◽

Alpha Synuclein ◽

Cellular Level ◽

Neuronal Function ◽

Two Photon ◽

Neuron Function ◽

The Impact ◽

Self Aggregation ◽

Intrastriatal Injection

SummaryAlpha-synucleinopathies are characterized by self-aggregation of the protein alpha-synuclein (a-syn), causing alterations on the molecular and cellular level. To unravel the impact of transneuronal spreading and templated misfolding of a-syn on the microcircuitry of remotely connected brain areas, we investigated cortical neuron function in awake mice 9 months after a single intrastriatal injection of a-syn preformed fibrils (PFFs), using in vivo two-photon calcium imaging. We found altered function of layer 2/3 cortical neurons in somatosensory cortex (S1) of PFF-inoculated mice, as witnessed by an enhanced response to whisking and increased synchrony, accompanied by a decrease in baseline Ca2+ levels. Stereological analyses revealed a reduction in GAD67-positive inhibitory cells in S1 in PFF-injected brains. These findings point to a disturbed excitation/inhibition balance as an important pathomechanism in alpha-synucleinopathies and demonstrate a clear association between the spread of toxic proteins and the initiation of altered neuronal function in remotely connected areas.

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Cortical circuit alterations precede disease onset in Huntington’s disease mice

10.1101/391771 ◽

2018 ◽

Author(s):

Johanna Neuner ◽

Elena Katharina Schulz-Trieglaff ◽

Sara Gutiérrez-Ángel ◽

Fabian Hosp ◽

Matthias Mann ◽

...

Keyword(s):

Motor Cortex ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Primary Motor Cortex ◽

Disease Onset ◽

Single Neurons ◽

Two Photon ◽

Layer 2 ◽

Cortical Circuit

AbstractHuntington’s disease (HD) is a devastating hereditary movement disorder, characterized by degeneration of neurons in the striatum and cortex. Studies in human patients and mouse HD models suggest that disturbances of neuronal function in the neocortex play an important role in the disease onset and progression. However, the precise nature and time course of cortical alterations in HD have remained elusive. Here, we use chronicin vivotwo-photon calcium imaging to monitor the activity of single neurons in layer 2/3 of the primary motor cortex in awake, behaving R6/2 transgenic HD mice and wildtype littermates. R6/2 mice show age-dependent changes in neuronal activity with a clear increase in activity at the age of 8.5 weeks, preceding the onset of motor and neurological symptoms. Furthermore, quantitative proteomics demonstrate a pronounced downregulation of synaptic proteins in the cortex, and histological analyses in R6/2 mice and HD patient samples reveal reduced inputs from parvalbumin-positive interneurons onto layer 2/3 pyramidal cells. Thus, our study provides a time-resolved description as well as mechanistic details of cortical circuit dysfunction in HD.Significance statementFuntional alterations in the cortex are believed to play an important role in the pathogenesis of Huntington’s disease (HD). However, studies monitoring cortical activity in HD modelsin vivoat a single-cell resultion are still lacking. We have used chronic two-photon imaging to investigate changes in the activity of single neurons in the primary motor cortex of awake presymptomatic HD mice. We show that neuronal activity increases before the mice develop disease symptoms. Our histological analyses in mice and in human HD autopsy cases furthermore demonstrate a loss inhibitory synaptic terminals from parvalbimun-positive interneurons, revealing a potential mechanism of cortical circuit impairment in HD.

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In Vivo Two-photon Imaging Of Experience-dependent Molecular Changes In Cortical Neurons

Journal of Visualized Experiments ◽

10.3791/50148 ◽

2013 ◽

Cited By ~ 4

Author(s):

Vania Y. Cao ◽

Yizhou Ye ◽

Surjeet S. Mastwal ◽

David M. Lovinger ◽

Rui M. Costa ◽

...

Keyword(s):

Cortical Neurons ◽

Molecular Changes ◽

Two Photon ◽

Photon Imaging ◽

Two Photon Imaging

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Lo studio PET/TC delle placche ?-amiloidi con 18F – FlorBetapir, 18F – FlorBetaben e 18F – Flutemetamol

Journal of Advanced Health Care ◽

10.36017/jahc1907-003/ ◽

2019 ◽

Author(s):

Giovanni Trondoli ◽

Dario Saffioti

Keyword(s):

Cerebral Cortex ◽

Basal Ganglia ◽

Home Care ◽

Pet Imaging ◽

Cortical Neurons ◽

Parietal Lobes ◽

Pet Ct ◽

Ct Analysis ◽

Nello Studio

La malattia di Alzheimer uccide circa 53.000 persone all’anno e circa 230.000 soggetti affetti dalla patologia richiedono cure domiciliari. Questa patologia è caratterizzata microscopicamente dalla comparsa di sostanza amiloide a livello della corteccia cerebrale con diminuzione del numero di neuroni corticali, in particolare nei lobi frontali e temporo-parietali. Più nello specifico, colpisce alcune regioni encefaliche quali i nuclei della base, l’ippocampo e il giro dell’ippocampo, aree direttamente coinvolte nell’elaborazione dei ricordi. Negli ultimi anni, lo sviluppo dell’imaging PET ha reso possibile l’utilizzo di traccianti fluorati per lo studio della sostanza amiloide e la sua visualizzazione in vivo. I radiotraccianti più importanti nell’analisi PET/TC sono: l’Amyvid (18F - FlorBetapir), il Neuraceq (18F - FlorBetaben) e il Vizamyl (18F- Flutemetamol) che hanno evidenziato l’efficacia nello studio della sostanza amiloide. Alzheimer’s disease (AD) kills about 53.000 people every year and about 230.000 subjects affected by AD need home care. This disease is microscopically characterized 3 amyloid substance on cerebral cortex with a reduction of cortical neurons, in particular in frontal and temporo-parietal lobes; it damages particularly some encephalic regions such as basal ganglia, hippocampus and hippocampus gyrus, areas directly related to elaboration of memories. In the last years, the development of PET imaging has made possible the use of fluorinated tracers to study amyloid substance and its visualization in vivo. Amyvid (18F - FlorBetapir), Neuraceq (18F - FlorBetaben) and Vizamyl (18F - Flutemetamol) are the most important radiotracers for PET/CT analysis which have been underlined the efficacy in the study of amyloid substance.

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Assessment of brain metabolite correlates of adeno-associated virus-mediated over-expression of human alpha-synuclein in cortical neurons by in vivo 1 H-MR spectroscopy at 9.4 T

Journal of Neurochemistry ◽

10.1111/jnc.13547 ◽

2016 ◽

Vol 137 (5) ◽

pp. 806-819 ◽

Cited By ~ 1

Author(s):

Sandra Cuellar-Baena ◽

Natalie Landeck ◽

Sarah Sonnay ◽

Kerstin Buck ◽

Vladimir Mlynarik ◽

...

Keyword(s):

Mr Spectroscopy ◽

Cortical Neurons ◽

Alpha Synuclein ◽

Adeno Associated Virus ◽

Over Expression ◽

Brain Metabolite

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Non-invasive, opsin-free mid-infrared modulation activates cortical neurons and accelerates associative learning

Nature Communications ◽

10.1038/s41467-021-23025-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jianxiong Zhang ◽

Yong He ◽

Shanshan Liang ◽

Xiang Liao ◽

Tong Li ◽

...

Keyword(s):

Associative Learning ◽

Cortical Neurons ◽

Learning Task ◽

Infrared Light ◽

Mid Infrared ◽

Two Photon ◽

Non Invasive ◽

Learning Speed ◽

Learning Capabilities

AbstractNeurostimulant drugs or magnetic/electrical stimulation techniques can overcome attention deficits, but these drugs or techniques are weakly beneficial in boosting the learning capabilities of healthy subjects. Here, we report a stimulation technique, mid-infrared modulation (MIM), that delivers mid-infrared light energy through the opened skull or even non-invasively through a thinned intact skull and can activate brain neurons in vivo without introducing any exogeneous gene. Using c-Fos immunohistochemistry, in vivo single-cell electrophysiology and two-photon Ca2+ imaging in mice, we demonstrate that MIM significantly induces firing activities of neurons in the targeted cortical area. Moreover, mice that receive MIM targeting to the auditory cortex during an auditory associative learning task exhibit a faster learning speed (~50% faster) than control mice. Together, this non-invasive, opsin-free MIM technique is demonstrated with potential for modulating neuronal activity.

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Dendritic nonlinearities are tuned for efficient spike-based computations in cortical circuits

eLife ◽

10.7554/elife.10056 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 20

Author(s):

Balázs B Ujfalussy ◽

Judit K Makara ◽

Tiago Branco ◽

Máté Lengyel

Keyword(s):

Cortical Neurons ◽

Activity Patterns ◽

Pyramidal Cells ◽

Cortical Circuits ◽

Functional Link ◽

Synaptic Inputs ◽

Two Photon ◽

Highly Nonlinear ◽

Efficient Integration

Cortical neurons integrate thousands of synaptic inputs in their dendrites in highly nonlinear ways. It is unknown how these dendritic nonlinearities in individual cells contribute to computations at the level of neural circuits. Here, we show that dendritic nonlinearities are critical for the efficient integration of synaptic inputs in circuits performing analog computations with spiking neurons. We developed a theory that formalizes how a neuron's dendritic nonlinearity that is optimal for integrating synaptic inputs depends on the statistics of its presynaptic activity patterns. Based on their in vivo preynaptic population statistics (firing rates, membrane potential fluctuations, and correlations due to ensemble dynamics), our theory accurately predicted the responses of two different types of cortical pyramidal cells to patterned stimulation by two-photon glutamate uncaging. These results reveal a new computational principle underlying dendritic integration in cortical neurons by suggesting a functional link between cellular and systems--level properties of cortical circuits.

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