Chronic nigral neuromodulation aggravates behavioral deficits and synaptic changes in an α-synuclein based rat model for Parkinson’s disease

Torre-Muruzabal, Teresa; Devoght, Jens; Haute, Chris Van den; Brône, Bert; Perren, Anke Van der; Baekelandt, Veerle

doi:10.1186/s40478-019-0814-3

Cited by 11 publications

(4 citation statements)

References 79 publications

(65 reference statements)

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“…Our largely-negative data are consistent with reports that chronic 1mg/kg CNO given to non-DREADD-expressing mice does not change behavior/physiology [28,30], but our data importantly show no effect on locomotion and a mixed effect on anxiety-like behavior. While the literature is unanimous that chronic 1mg/kg CNO does not grossly change mouse behavior in non-DREADDexpressing mice, the literature is mixed on the effects of acute CNO given to non-DREADDexpressing rodents.…”

Section: Discussionsupporting

confidence: 92%

Does chronic systemic injection of the DREADD agonists clozapine-N-oxide or compound 21 change behavior relevant to locomotion, exploration, anxiety, and depression in male non-DREADD-expressing mice?

Tran

Spears

Ahn

et al. 2020

Preprint

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Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a chemogenetic tool commonly-used to manipulate rodent brain circuit activity. The most widely-used synthetic ligand for DREADDs is Clozapine-N-oxide (CNO). However, CNO is back-metabolized to clozapine, which itself activates numerous endogenous receptors and therefore may influence rodent behavior. To eliminate potential off-target effects of CNO, a new DREADD agonist, Compound 21 (C21), has been proposed as an alternative as it lacks active metabolites. The literature is mixed on whether acute administration of CNO or C21 changes mouse behavior. In contrast, there is no substantial literature on whether chronic administration of CNO or C21 changes mouse behavior. Here we tested whether chronic injections of these two distinct DREADD agonists change key behaviors in non-designer receptor-expressing mice relative to Vehicle (Veh)-injected control mice. Mice (CamKIIα-icre males) were injected i.p. with Veh (0.5% dimethyl sulfoxide in 0.9% saline, 5ml/kg), CNO (0.2mg/ml, 1mg/kg), or C21 (0.2mg/ml, 1mg/kg) 5 days a week for 16 weeks. All three groups had similar weight gain over the 16 week-experiment, and showed similar measures in behaviors assessed during week 3 (beam breaks in a 30-min locomotion task, time in center of open field or open arms of elevated plus maze) and week 14-16 (ambulatory distance during 240-min activity monitoring, percent marbles buried, grooming time during the sucrose splash test). These data show chronic injections of CNO or C21 do not affect key behaviors as compared to chronic injections of Veh, and may be helpful for behavioral neuroscientists when study design requires repeated injection of these DREADD agonists. Highlights Acute injection of CNO changes behavior of non-DREADD-expressing mice It’s not known if chronic CNO or alternative agonist C21 also changes mouse behavior DREADD agonists or Veh were given chronically to non-DREADD-expressing mice Mice given Veh, CNO, or C21 were similar in regard to locomotion and other behaviors Thus CNO and C21 can be injected repeatedly without non-specific behavior effects

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Section: Discussionsupporting

confidence: 92%

Does chronic systemic injection of the DREADD agonists clozapine-N-oxide or compound 21 change behavior relevant to locomotion, exploration, anxiety, and depression in male non-DREADD-expressing mice?

Tran

Spears

Ahn

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Expression of synthetically designed receptors and binding of these receptors with specific ligands can be used for transient activation or inactivation of targeted brain regions ( 21 , 41 , 42 , 43 ). This DREADD approach has been successfully applied to induce hyper- or hypoactivity of DMnX neurons that was validated using electrophysiological recordings and functional outcomes ( 31 , 44 ).…”

Section: Resultsmentioning

confidence: 99%

Neuronal hyperactivity–induced oxidant stress promotes in vivo α-synuclein brain spreading

et al. 2022

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Interneuronal transfer and brain spreading of pathogenic proteins are features of neurodegenerative diseases. Pathophysiological conditions and mechanisms affecting this spreading remain poorly understood. This study investigated the relationship between neuronal activity and interneuronal transfer of α-synuclein, a Parkinson-associated protein, and elucidated mechanisms underlying this relationship. In a mouse model of α-synuclein brain spreading, hyperactivity augmented and hypoactivity attenuated protein transfer. Important features of neuronal hyperactivity reported here were an exacerbation of oxidative and nitrative reactions, pronounced accumulation of nitrated α-synuclein, and increased protein aggregation. Data also pointed to mitochondria as key targets and likely sources of reactive oxygen and nitrogen species within hyperactive neurons. Rescue experiments designed to counteract the increased burden of reactive oxygen species reversed hyperactivity-induced α-synuclein nitration, aggregation, and interneuronal transfer, providing first evidence of a causal link between these pathological effects of neuronal stimulation and indicating a mechanistic role of oxidant stress in hyperactivity-induced α-synuclein spreading.

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“…In clinics, traumatic brain injuries during adulthood have been associated to an increased incidence of neurodegenerative disorders including chronic traumatic encephalopathies, Alzheimer’s and Parkinson’s diseases 55 . In Parkinson’s preclinical models, an increased neuronal activity in the amygdala or subtantia nigra have been associated with an increased vulnerability to develop disease-related symptoms 56,57 . Further studies are therefore required to investigate whether the early concussion -induced hyperactivity we report here in the somatosensory cortex could potentially contribute to progression of neurodegenerative disorders.…”

Section: Discussionmentioning

confidence: 99%

Endocannabinoid-mediated rescue of somatosensory cortex activity, plasticity and related behaviors following an early in life concussion

Badaut,

Hippauf,

Malinconi

et al. 2024

Preprint

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Due to the assumed plasticity of immature brain, early in life brain alterations are thought to lead to better recoveries in comparison to the mature brain. Despite clinical needs, how neuronal networks and associated behaviors are affected by early in life brain stresses, such as pediatric concussions, have been overlooked. Here we provide first evidence in mice that a single early in life concussion durably increases neuronal activity in the somatosensory cortex into adulthood, disrupting neuronal integration while the animal is performing sensory-related tasks. This represents a previously unappreciated clinically relevant mechanism for the impairment of sensory-related behavior performance. Furthermore, we demonstrate that pharmacological modulation of the endocannabinoid system a year post-concussion is well-suited to rescue neuronal activity and plasticity, and to normalize sensory-related behavioral performance, addressing the fundamental question of whether a treatment is still possible once post-concussive symptoms have developed, a time-window compatible with clinical treatment.

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Chronic nigral neuromodulation aggravates behavioral deficits and synaptic changes in an α-synuclein based rat model for Parkinson’s disease

Cited by 11 publications

References 79 publications

Does chronic systemic injection of the DREADD agonists clozapine-N-oxide or compound 21 change behavior relevant to locomotion, exploration, anxiety, and depression in male non-DREADD-expressing mice?

Does chronic systemic injection of the DREADD agonists clozapine-N-oxide or compound 21 change behavior relevant to locomotion, exploration, anxiety, and depression in male non-DREADD-expressing mice?

Neuronal hyperactivity–induced oxidant stress promotes in vivo α-synuclein brain spreading

Endocannabinoid-mediated rescue of somatosensory cortex activity, plasticity and related behaviors following an early in life concussion

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