Synaptic Density and Neuronal Metabolic Function Measured by Positron Emission Tomography in the Unilateral 6-OHDA Rat Model of Parkinson’s Disease

Parkinson’s disease (PD) is caused by progressive neurodegeneration and characterised by motor dysfunction. Neurodegeneration of dopaminergic neurons also causes aberrations within the cortico-striato-thalamo-cortical (CSTC) circuit, which has been hypothesised to lead to non-motor symptoms such as depression. Individuals with PD have both lower synaptic density and changes in neuronal metabolic function in the basal ganglia, as measured using [(11)C]UCB-J and [(18)F]FDG positron emission tomography (PET), respectively. However, the two radioligands have not been directly compared in the same PD subject or in neurodegeneration animal models. Here, we investigate [(11)C]UCB-J binding and [(18)F]FDG uptake in the CSTC circuit following a unilateral dopaminergic lesion in rats and compare it to sham lesioned rats. Rats received either a unilateral injection of 6-hydroxydopamine (6-OHDA) or saline in the medial forebrain bundle and rostral substantia nigra (n = 4/group). After 3 weeks, all rats underwent two PET scans using [(18)F]FDG, followed by [(11)C]UCB-J on a separate day. [(18)F]FDG uptake and [(11)C]UCB-J binding were both lower in the ipsilateral striatal regions compared to the contralateral regions. Using [(11)C]UCB-J, we could detect an 8.7% decrease in the ipsilateral ventral midbrain, compared to a 2.9% decrease in ventral midbrain using [(18)F]FDG. Differential changes between hemispheres for [(11)C]UCB-J and [(18)F]FDG outcomes were also evident in the CSTC circuit’s cortical regions, especially in the orbitofrontal cortex and medial prefrontal cortex where higher synaptic density yet lower neuronal metabolic function was observed, following lesioning. In conclusion, [(11)C]UCB-J and [(18)F]FDG PET can detect divergent changes following a dopaminergic lesion in rats, especially in cortical regions that are not directly affected by the neurotoxin. These results suggest that combined [(11)C]UCB-J and [(18)F]FDG scans could yield a better picture of the heterogeneous cerebral changes in neurodegenerative disorders

Repeated low doses of psilocybin increase resilience to stress, lower compulsive actions, and strengthen cortical connections to the paraventricular thalamic nucleus in rats

Psilocybin (a classic serotonergic psychedelic drug) has received appraisal for use in psychedelic-assisted therapy of several psychiatric disorders. A less explored topic concerns the use of repeated low doses of psychedelics, at a dose that is well below the psychedelic dose used in psychedelic-assisted therapy and often referred to as microdosing. Psilocybin microdose users often report increases in mental health, yet such reports are often highly biased and vulnerable to placebo effects. Here we establish and validate a psilocybin microdose-like regimen in rats using repeated low doses of psilocybin. Dosing is based on in vivo occupancy at rat brain 5-HT2A receptors. The rats tolerated the repeated low doses of psilocybin well and did not manifest signs of anhedonia, anxiety, or altered locomotor activity. There were no deficits in pre-pulse inhibition of the startle reflex, nor did the treatment downregulate or desensitize the 5-HT2A receptor. However, the repeated low doses of psilocybin imparted resilience against the stress of multiple subcutaneous injections, and reduced the frequency of self-grooming, a proxy for human compulsive actions, while also increasing 5-HT7 receptor expression and synaptic density in the paraventricular nucleus of the thalamus. These results establish a well-validated regimen for further experiments into the effects of repeated low doses of psilocybin. They further substantiate anecdotal reports of the benefits of psilocybin microdosing as a therapeutic intervention while pointing to a possible physiological mechanism

Blocking of efflux transporters in rats improves translational validation of brain radioligands

Background Positron emission tomography (PET) is a molecular imaging technique that can be used to investigate the in vivo pharmacology of drugs. Initial preclinical evaluation of PET tracers is often conducted in rodents due to the accessibility of disease models as well as economic considerations. Compared to larger species, rodents display a higher expression and/or activity of efflux transporters such as the P-glycoprotein (P-gp). Low brain uptake could, therefore, be species-specific and uptake in rodents not be predictive for that in humans. We hypothesized that a better prediction from rodent data could be achieved when a tracer is evaluated under P-gp inhibition. Consequently, we compared the performance of eight neuroreceptor tracers in rats with and without P-gp inhibition including a specific binding blockade. This data set was then used to predict the binding of these eight tracers in pigs. Methods PET tracers targeting serotonin 5-HT(2A)receptors ([F-18]MH.MZ, [F-18]Altanserin, [C-11]Cimbi-36, [C-11]Pimavanserin), serotonin 5-HT(7)receptors ([C-11]Cimbi-701, [C-11]Cimbi-717 and [C-11]BA-10) and dopamine D(2/3)receptors ([F-18]Fallypride) were used in the study. The brain uptake and target-specific binding of these PET radiotracers were evaluated in rats with and without inhibition of P-gp. Rat data were subsequently compared to the results obtained in pigs. Results Without P-gp inhibition, the amount of target-specific binding in the rat brain was sufficient to justify further translation for three out of eight evaluated tracers. With P-gp inhibition, results for five out of eight tracers justified further translation. The performance in pigs could correctly be predicted for six out of eight tracers when rat data obtained under P-gp inhibition were used, compared to four out of eight tracers without P-gp inhibition. Conclusions P-gp strongly affects the uptake of PET tracers in rodents, but false prediction outcomes can be reduced by evaluating a tracer under P-gp inhibition

Repeated low doses of psilocybin increase resilience to stress, lower compulsive actions, and strengthen cortical connections to the paraventricular thalamic nucleus in rats.

Psilocybin (a classic serotonergic psychedelic drug) has received appraisal for use in psychedelic-assisted therapy of several psychiatric disorders. A less explored topic concerns the use of repeated low doses of psychedelics, at a dose that is well below the psychedelic dose used in psychedelic-assisted therapy and often referred to as microdosing. Psilocybin microdose users frequently report increases in mental health, yet such reports are often highly biased and vulnerable to placebo effects. Here we establish and validate a psilocybin microdose-like regimen in rats with repeated low doses of psilocybin administration at a dose derived from occupancy at rat brain 5-HT2A receptors in vivo. The rats tolerated the repeated low doses of psilocybin well and did not manifest signs of anhedonia, anxiety, or altered locomotor activity. There were no deficits in pre-pulse inhibition of the startle reflex, nor did the treatment downregulate or desensitize the 5-HT2A receptors. However, the repeated low doses of psilocybin imparted resilience against the stress of multiple subcutaneous injections, and reduced the frequency of self-grooming, a proxy for human compulsive actions, while also increasing 5-HT7 receptor expression and synaptic density in the paraventricular nucleus of the thalamus. These results establish a well-validated regimen for further experiments probing the effects of repeated low doses of psilocybin. Results further substantiate anecdotal reports of the benefits of psilocybin microdosing as a therapeutic intervention, while pointing to a possible physiological mechanism

Newly formed craters on Mars located using seismic and acoustic wave data from InSight

International audienceMeteoroid impacts shape planetary surfaces by forming new craters and alter atmospheric composition. During atmospheric entry and impact on the ground, meteoroids excite transient acoustic and seismic waves. However, new crater formation and the associated impact-induced mechanical waves have yet to be observed jointly beyond Earth. Here we report observations of seismic and acoustic waves from the NASA InSight lander’s seismometer that we link to four meteoroid impact events on Mars observed in spacecraft imagery. We analysed arrival times and polarization of seismic and acoustic waves to estimate impact locations, which were subsequently confirmed by orbital imaging of the associated craters. Crater dimensions and estimates of meteoroid trajectories are consistent with waveform modelling of the recorded seismograms. With identified seismic sources, the seismic waves can be used to constrain the structure of the Martian interior, corroborating previous crustal structure models, and constrain scaling relationships between the distance and amplitude of impact-generated seismic waves on Mars, supporting a link between the seismic moment of impacts and the vertical impactor momentum. Our findings demonstrate the capability of planetary seismology to identify impact-generated seismic sources and constrain both impact processes and planetary interiors

Newly formed craters on Mars located using seismic and acoustic wave data from InSight

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