Biology subjects

Palner, M.

Publications and source records attributed to Palner, M..

7 recordsLinked to original sources

bioRxiv2025

Single-dose rapamycin increases brain glucose metabolism but reduces synaptic density in Long-Evans rats: A PET imaging study

Rapamycin, an inhibitor of the mechanistic target of rapamycin (mTOR), has shown promise as a neuroprotective compound in preclinical studies. Reduced brain glucose metabolism and loss of synaptic density are key features of Alzheimers disease that can be measured in vivo using positron emission tomography (PET) imaging, allowing for assessment of treatment effects on brain function. Here, we used PET to investigate the acute effects of a single-dose of rapamycin on glucose metabolism and synaptic density in Long-Evans rats. In a repeated measures design, we quantified changes in brain glucose metabolism using [18F]FDG PET (n=13) at baseline, one day, and one week after intraperitoneal administration of rapamycin (8 mg/kg). In a separate cohort (n=6), we measured synaptic density using [18F]SynVesT-1 PET at baseline and one day after rapamycin administration. Regional standardized uptake values (SUV) were calculated for [18F]FDG while total distribution volumes were estimated for [18F]SynVesT-1 using image-derived input functions of the heart. Rapamycin induced significant increases in [18F]FDG SUV across multiple brain regions one day after administration, an effect that persisted at one-week follow-up. In contrast, [18F]SynVesT-1 binding showed significant decreases throughout the brain at 24 hours post-administration, indicating reduced synaptic density. These opposing effects on glucose metabolism and synaptic density point to multifaceted actions of rapamycin in the brain, possibly reflecting improved metabolic function occurring simultaneously with acute synaptic loss. These results show that [18F]FDG and synaptic density PET imaging could serve as useful biomarkers in human clinical trials evaluating rapamycins mechanistic and therapeutic effects in neurodegenerative disorders.

neuroscience↗

bioRxiv2024

Tbc1d15 knockdown in vivo alleviates α-synuclein-induced neurotoxicity by promoting autophagy.

Parkinsons disease is a neurodegenerative disease, which is associated with accumulation of -synuclein protein aggregates and Lewy Body formation. These neurotoxic inclusions are especially harmful for dopamine-producing neurons in the substantia nigra of the brain. The cellular degradation system autophagy can reduce neurotoxicity caused by accumulated -synuclein, by targeting it for degradation. Previously, we demonstrated that human TBC1D15 inhibits autophagy in vitro, resulting in accumulation of neurotoxic protein aggregates. Conversely, lowering the TBC1D15 expression promotes autophagy and degradation of -synuclein and huntingtin proteins in various cell models. Here we show that knockdown of murine Tbc1d15 in vivo activates autophagy, reduces -synuclein-mediated neurotoxicity, and improves motor performance. Thus, targeting Tbc1d15 expression may be a therapeutic avenue for neurodegenerative diseases.

neuroscience↗

bioRxiv2022

Mapping whole brain effects of infrared neural stimulation with positron emission tomography

The combination of neuroimaging and targeted neuromodulation is a crucial tool to gain a deeper understanding of neural networks at a circuit level. Infrared neurostimulation (INS) is a promising optical modality that allows to evoke neuronal activity with high spatial resolution without need for the introduction of exogenous substances in the brain. Here, we report the use of whole-brain functional [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) imaging during INS in the dorsal striatum, performed using a multifunctional soft neural probe. We demonstrate the possibility to identify multi-circuit connection patterns in both cortical and subcortical brain regions within a single scan. By using a bolus plus infusion FDG-PET scanning protocol, we were able to observe the metabolic rate evolution in these regions during the experiments and correlate its variation with the onset of the INS stimulus. Due to the focality of INS and the large amount of viable molecular targets for PET, this novel approach to simultaneous imaging and stimulation is highly versatile. This pilot study can pave the way to further understand the brain connectivity on a global scale.

neuroscience↗

bioRxiv2022

An in vivo pig model for testing novel PET radioligands targeting cerebral protein aggregates

Positron emission tomography (PET) has become an essential clinical tool for diagnosing neurodegenerative diseases with abnormal accumulation of proteins like amyloid-{beta} or tau. Despite many attempts, it has not been possible to develop an appropriate radioligand for imaging aggregated -synuclein in the brain for diagnosing, e.g., Parkinsons Disease. Access to a large animal model with -synuclein pathology would critically enable a more translationally appropriate evaluation of novel radioligands. We here establish a pig model with cerebral injections of -synuclein preformed fibrils or brain homogenate from postmortem human brain tissue from individuals with Alzheimers disease (AD) or dementia with Lewy body (DLB) into the pigs brain, using minimally invasive surgery and validated against saline injections. In the absence of a suitable -synuclein radioligand, we validated the model with the unselective amyloid-{beta} tracer [11C]PIB, which has a high affinity for {beta}-sheet structures in aggregates. Gadolinium-enhanced MRI confirmed that the blood-brain barrier was intact. A few hours post-injection, pigs were PET scanned with [11C]PIB. Quantification was done with Logan invasive graphical analysis and simplified reference tissue model 2 using the occipital cortex as a reference region. After the scan, we retrieved the brains to confirm successful injection using autoradiography and immunohistochemistry. We found four times higher [11C]PIB uptake in AD-homogenate-injected regions and two times higher uptake in regions injected with -synuclein-preformed-fibrils compared to saline. The [11C]PIB uptake was the same in non-injected (occipital cortex, cerebellum) and injected (DLB-homogenate, saline) regions. With its large brains and ability to undergo repeated PET scans as well as neurosurgical procedures, the pig provides a robust, cost-effective, and good translational model for assessment of novel radioligands including, but not limited to, proteinopathies.

neuroscience↗

bioRxiv2021

Synaptic density and neuronal metabolic function measured by PET in the unilateral 6-OHDA rat model of Parkinson's disease

Parkinsons 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 [11C]UCB-J and [18F]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 [11C]UCB-J binding and [18F]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 three weeks, all rats underwent two PET scans using [18F]FDG, followed by [11C]UCB-J on a separate day. [18F]FDG uptake and [11C]UCB-J binding were both lower in the ipsilateral striatal regions compared to the contralateral regions. Using [11C]UCB-J, we could detect an 8.7% decrease in the ipsilateral ventral midbrain, compared to a 2.9% decrease in ventral midbrain using [18F]FDG. Differential changes between hemispheres for [11C]UCB-J and [18F]FDG outcomes were also evident in the CSTC circuits 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, [11C]UCB-J and [18F]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 [11C]UCB-J and [18F]FDG scans could yield a better picture of the heterogeneous cerebral changes in neurodegenerative disorders.

neuroscience↗

bioRxiv2021

Nigro-striatal dopamine activation lowers behavioral and neuronal phenotypes associated with obsessive-compulsive disorder

Dorsal striatal dopamine transmission engages the cortico-striato-thalamo-cortical (CSTC) circuit, which is implicated in many neuropsychiatric diseases, including obsessive-compulsive disorder (OCD). Yet it is unknown if dorsal striatal dopamine hyperactivity is the cause or consequence of changes elsewhere in the CSTC circuit. Classical pharmacological and neurotoxic manipulations of the CSTC and other brain circuits suffer from various drawbacks related to off-target effects and adaptive changes. Chemogenetics, on the other hand, enables a highly selective targeting of specific neuronal populations within a given circuit. In this study, we developed a chemogenetic method for selective activation of dopamine neurons in the substantia nigra, which innervating the rat dorsal striatum. We used this model to investigate effects of targeted dopamine activation on CSTC circuit function, especially in fronto-cortical regions. We found that chemogenetic activation of these neurons increased movement, as expected from dopamine release, rearings and time spend in center, while it also lowered self-grooming and increased prepulse inhibition in females. Remarkably, we observed reduced [18F]FDG metabolism in frontal cortex, following dopamine activation in the dorsal striatum, yet total glutamate levels-in this region were increased. A finding which may help explain the contradiction in some clinical studies of increased [18F]FDG metabolism and lower glutamate levels in diseases like OCD. Taken together, these results establish the importance of nigro-striatal dopamine transmission for modulating CSTC function, especially with respect to fronto-cortical activity, glutamate levels and behaviors related anxiety and compulsive actions. One Sentence SummaryDorsal striatum dopamine induce fronto-cortical hypoactivity and reduce compulsive behaviors in rats

neuroscience↗

bioRxiv2019

Environment rapidly upregulates serotonin 2A receptor expression via the immediate early gene Egr3

Serotonin 2A receptors (5-HT2ARs) mediate the effects of hallucinogenic drugs and antipsychotic medications, and are reduced in schizophrenia patients brains. However, the mechanisms that regulate 5-HT2AR expression remain poorly understood. We show that an environmental stimulus, sleep deprivation, upregulates 5-HT2ARs in the mouse frontal cortex (FC) in just 6-8 hours. This induction requires the immediate early gene transcription factor early growth response 3 (Egr3). Further, EGR3 binds to the Htr2a promoter in the FC in vivo, and drives reporter construct expression in vitro via two Htr2a promoter binding sites. These findings suggest that EGR3 directly regulates FC Htr2a expression in response to physiologic stimuli, providing a mechanism by which environment rapidly alters levels of a brain receptor that mediates symptoms, and treatment, of mental illness. One Sentence SummaryJust 6-8 hours of sleep deprivation upregulates brain levels of the receptor that mediates the response to hallucinogens.

neuroscience↗