Biology subjects

Kreiner, G.

Publications and source records attributed to Kreiner, G..

4 recordsLinked to original sources

bioRxiv2025

L-DOPA induces spatially discrete changes in gene expression in the forebrain of mice with a progressive loss of dopaminergic neurons

L-3,4-Dihydroxyphenylalanine (L-DOPA) is effective at alleviating motor impairments in Parkinsons disease (PD) patients but has mixed effects on nonmotor symptoms and causes adverse effects after prolonged treatment. Here, we analyzed the spatial profile of L-DOPA-induced gene expression in the forebrain of mice with an inducible progressive loss of dopaminergic neurons (the TIF-IADATCreERT2 strain), with a focus on the similarities and differences in areas relevant to different PD symptoms. The animals received a 14-day L-DOPA treatment, and 1 h after the final drug injection, a spatial transcriptome analysis was performed on coronal forebrain sections. A total of 121 genes were identified as being regulated by L-DOPA. We found that the treatment had widespread effects extending beyond the primary areas involved in dopamine-dependent movement control. An unsupervised clustering analysis of the transcripts recapitulated the forebrain anatomy and indicated both ubiquitous and region-specific effects on transcription. The changes were most pronounced in layers 2/3 and 5 of the dorsal cortex and the dorsal striatum, where a robust increase in the abundance of activity-regulated transcripts, including Fos, Egr1, and Junb, was observed. Conversely, transcripts with a decreased abundance, e.g., Plekhm2 or Pgs1, were identified primarily in the piriform cortex, the adjacent endopiriform nucleus, and the claustrum. Taken together, our spatial analysis of L-DOPA-induced alterations in gene expression reveals the anatomical complexity of treatment effects, identifying novel genes affected by the drug, as well as molecular activation in brain areas relevant to the nonmotor symptoms of PD.

neuroscience↗

bioRxiv2023

Dopamine receptor-expressing neurons are differently distributed throughout layers of the motor cortex to control dexterity

The motor cortex comprises the primary descending circuits for flexible control of voluntary movements and is critically involved in motor skill learning. Motor skill learning is impaired in patients with Parkinsons disease, but the precise mechanisms of motor control and skill learning are still not well understood. Here we have used transgenic mice, electrophysiology, in situ hybridization and neural tract-tracing methods to target genetically defined cell types expressing D1 and D2 dopamine receptors (D1+ and D2+, respectively) in the motor cortex. We observed that D1+ and D2+ neurons are organized in highly segregated, non-overlapping populations. Moreover, based on ex vivo patch-clamp recordings, we showed that D1+ and D2+ cells have distinct morphological and electrophysiological properties. Finally, we observed that chemogenetic inhibition of D2+, but not D1+ neurons, disrupts skilled forelimb reaching in adult mice. Overall, these results demonstrate that dopamine receptor-expressing cells in the motor cortex are highly segregated and play a specialized role in manual dexterity.

neuroscience↗

bioRxiv2023

Nonmotor symptoms associated with progressive loss of dopaminergic neurons in a mouse model of Parkinson's disease

Parkinsons disease (PD) is characterized by three main motor symptoms: bradykinesia, rigidity and tremor. PD is also associated with diverse nonmotor symptoms that may develop in parallel or precede motor dysfunctions, ranging from autonomic system dysfunctions and impaired sensory perception to cognitive deficits and depression. Here, we examine the role of the progressive loss of dopaminergic transmission in behaviors related to the nonmotor symptoms of PD in a mouse model of the disease (the TIF-IADATCreERT2 strain). We found that in the period from 5 to 12 weeks after the induction of a gradual loss of dopaminergic neurons, mild motor symptoms became detectable, including changes in the distance between paws while standing as well as the step cadence and sequence. Male mutant mice showed no apparent changes in olfactory acuity, no anhedonia-like behaviors, and normal learning in an instrumental task; however, a pronounced increase in the number of operant responses performed was noted. Similarly, female mice with progressive dopaminergic neuron degeneration showed normal learning in the probabilistic reversal learning task and no loss of sweet-taste preference, but again, a robustly higher number of choices were performed in the task. In both males and females, the higher number of instrumental responses did not affect the accuracy or the fraction of rewarded responses. Taken together, these data reveal discrete, dopamine-dependent nonmotor symptoms that emerge in the early stages of dopaminergic neuron degeneration.

neuroscience↗

bioRxiv2021

Nucleolar stress controls mutant Huntingtin toxicity and monitors Huntington disease progression

Transcriptional and cellular stress surveillance deficits are hallmarks of Huntingtons disease (HD), a fatal autosomal dominant neurodegenerative disorder, caused by a pathological expansion of CAG repeats in the Huntingtin (HTT) gene. The nucleolus, a dynamic nuclear biomolecular condensate and the site of ribosomal RNA (rRNA) transcription, is implicated in the cellular stress response and in protein quality control. While the exact pathomechanisms of HD remain unclear, the impact of nucleolar dysfunction on HD pathophysiology in vivo is elusive. Here we identified aberrant maturation of rRNA and decreased translational rate in association with human mutant Huntingtin (mHTT) expression. Genetic disruption of nucleolar integrity in vulnerable striatal neurons of the R6/2 HD mouse model decreases mHTT disperse state in the nucleus, exacerbating the motor deficits. The protein nucleophosmin 1 (NPM1), important for nucleolar integrity and rRNA maturation, loses its nucleolar localization. NPM1 de-localization occurs in the striatum and in the skeletal muscle of the progressive zQ175 knock-in HD mouse model, mimicking the phenotype of HD patients in skeletal muscle biopsies. Taken together, we showed that nucleolar integrity regulates the formation of mHTT inclusions in vivo, and identified NPM1 as a novel, readily detectable peripheral histopathological marker of HD progression.

neuroscience↗