Biology subjects

Friedrich, L.

Publications and source records attributed to Friedrich, L..

5 recordsLinked to original sources

bioRxiv2026

Remifentanil self-administration promotes circuit- and sex-specific adaptations within the prefrontal-accumbens pathways

The nucleus accumbens (NAc) and its excitatory input from the medial prefrontal cortex (mPFC) form a critical circuit underlying drug-induced plasticity associated with addiction-related behaviors. However, baseline differences in excitatory signaling across NAc subcircuits and sex-specific neuroadaptations following opioid self-administration remain poorly understood. Here, we examined synaptic signaling in mPFC-NAc pathways in drug-naive mice and after abstinence from remifentanil self-administration. Under drug-naive conditions, AMPA receptor- mediated glutamatergic signaling was generally elevated in D2 medium spiny neurons (MSNs) of both the NAc core and shell across sexes, while females exhibited greater excitatory signaling in D1 MSNs of the NAc core compared with males. Pathway-specific analyses revealed that prelimbic cortex (PL) inputs to NAc core D2 MSNs displayed enhanced calcium-permeable AMPA receptor (CP-AMPAR) signaling and increased presynaptic release relative to D1 MSNs. Following abstinence from remifentanil self-administration, miniature excitatory postsynaptic current analyses showed increased excitatory drive at D1 MSNs and decreased drive at D2 MSNs, largely restricted to the NAc core. At PL-Core D1 MSN synapses, remifentanil reduced AMPA/NMDA ratios, consistent with increased CP-AMPAR incorporation in males and females, while increasing presynaptic signaling exclusively in males. In contrast, PL-Core D2 MSN synapses showed a reduction in presynaptic signaling across sex, while ostensibly weakening postsynaptic signaling selectively in males through reductions in CP-AMPAR signaling. At infralimbic cortex (IL)-shell inputs, a reduction in AMPAR rectification indices at D1 MSN synapses was produced by remifentanil, while release probability was decreased at D2 MSN synapses in males only. Together, these findings reveal sex- and pathway-specific synaptic adaptations within mPFC-NAc circuits that may be obscured by global measures of excitatory transmission and identify baseline circuit differences that may shape opioid-induced plasticity.

neuroscience↗

bioRxiv2024

Chronic activation of corticospinal tract neurons after pyramidotomy injury enhances neither behavioral recovery nor axonal sprouting

Modulation of neural activity is a promising strategy to influence the growth of axons and improve behavioral recovery after damage to the central nervous system. The benefits of neuromodulation likely depend on optimization across multiple input parameters. Here we used a chemogenetic approach to achieve continuous, long-term elevation of neural activity in murine corticospinal tract (CST) neurons. To specifically target CST neurons, AAV2-retro-DIO-hM3Dq-mCherry or matched mCherry control was injected to the cervical spinal cord of adult Emx1-Cre transgenic mice. Pilot studies verified efficient transgene expression in CST neurons and effective elevation of neural activity as assessed by cFos immunohistochemistry. In subsequent experiments mice were administered either DIO-hM3Dq-mCherry or control DIO-mCherry, were pre-trained on a pellet retrieval task, and then received unilateral pyramidotomy injury to selectively ablate the right CST. Mice then received continual clozapine via drinking water and weekly testing on the pellet retrieval task, followed by cortical injection of a viral tracer to assess cross-midline sprouting by the spared CST. After sacrifice at eight weeks post-injury immunohistochemistry for cFos verified elevated CST activity in hM3Dq-treated animals and immunohistochemistry for PKC-gamma verified unilateral ablation of the CST in all animals. Despite the chronic elevation of CST activity, however, both groups showed similar levels of cross-midline CST sprouting and similar success in the pellet retrieval task. These data indicate that continuous, long-term elevation of activity that is targeted specifically to CST neurons does not affect compensatory sprouting or directed forelimb movements.

neuroscience↗

bioRxiv2024

CACHE Challenge #1: targeting the WDR domain of LRRK2, a Parkinson's Disease associated protein.

The CACHE challenges are a series of prospective benchmarking exercises meant to evaluate progress in the field of computational hit-finding. Here we report the results of the inaugural CACHE #1 challenge in which 23 computational teams each selected up to 100 commercially available compounds that they predicted would bind to the WDR domain of the Parkinsons disease target LRRK2, a domain with no known ligand and only an apo structure in the PDB. The lack of known binding data and presumably low druggability of the target is a challenge to computational hit finding methods. Seventy-three of the 1955 procured molecules bound LRRK2 in an SPR assay with KD lower than 150 M and were advanced to a hit expansion phase where computational teams each selected up to 50 analogs each. Binding was observed in two orthogonal assays with affinities ranging from 18 to 140 M for seven chemically diverse series. The seven successful computational workflows varied in their screening strategies and techniques. Three used molecular dynamics to produce a conformational ensemble of the targeted site, three included a fragment docking step, three implemented a generative design strategy and five used one or more deep learning steps. CACHE #1 reflects a highly exploratory phase in computational drug design where participants sometimes adopted strikingly diverging screening strategies. Machine-learning accelerated methods achieved similar results to brute force (e.g. exhaustive) docking. First-in-class, experimentally confirmed compounds were rare and weakly potent, indicating that recent advances are not sufficient to effectively address challenging targets.

biochemistry↗

bioRxiv2021

Mechanism of praziquantel action at a parasitic flatworm ion channel

Praziquantel (PZQ) is an essential medicine for treating parasitic flatworm infections such as schistosomiasis, which afflicts over 250 million people. However, PZQ is not universally effective, lacking activity against the liver fluke Fasciola. The reason for this insensitivity is unclear, as the mechanism of PZQ action is unknown. Here, we show PZQ activates a transient receptor potential melastatin ion channel (TRPMPZQ) in schistosomes by engaging a hydrophobic ligand binding pocket within the voltage-sensor like domain to cause Ca2+ entry and worm paralysis. PZQ activates TRPMPZQ homologues in other PZQ-sensitive flukes, but not Fasciola. However, a single amino acid change in the Fasciola TRPMPZQ binding pocket, to mimic schistosome TRPMPZQ, confers PZQ sensitivity. After decades of clinical use, the basis of PZQ action at a druggable TRP channel is resolved.

pharmacology and toxicology↗

bioRxiv2019

How to define and optimize axial resolution in light-sheet microscopy: a simulation-based approach

\"How thick is your light sheet?\" is a question that has been asked frequently after talks showing impressive renderings of 3D data acquired by a light-sheet microscope. This question is motivated by the fact that most of the time the thickness of the light-sheet is uniquely associated to the axial resolution of the microscope. However, the link between light-sheet thickness and axial resolution has never been systematically assessed and it is still unclear how both are connected. The question is not trivial because commonly employed measures cannot readily be applied or do not lead to easily interpretable results for the many different types of light sheet. Here, by using simulation data we introduce a set of intuitive measures that helps to define the relationship between light sheet thickness and axial resolution. Unexpectedly, our analysis revealed a trade-off between better axial resolution and thinner light-sheet thickness. Our results are surprising because thicker light-sheets that provide lower image contrast have previously not been associated with better axial resolution. We conclude that classical Gaussian illumination beams should be used when image contrast is most important, and more advanced types of illumination represent a way to optimize axial resolution at the expense of image contrast.

biophysics↗