VTA dopamine neurons are hyperexcitable in 3xTg-AD mice due to casein kinase 2-dependent SK channel dysfunction DOI Creative Commons
Harris E. Blankenship,

Kelsey A Carter,

Nina T. Cassidy

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 17, 2023

Alzheimer's disease (AD) patients exhibit neuropsychiatric symptoms that extend beyond classical cognitive deficits, suggesting involvement of subcortical areas. Here, we investigated the role midbrain dopamine (DA) neurons in AD using amyloid + tau-driven 3xTg-AD mouse model. We found deficits reward-based operant learning mice, possible VTA DA neuron dysregulation. Physiological assessment revealed hyperexcitability and disrupted firing caused by reduced activity small-conductance calcium-activated potassium (SK) channels. RNA sequencing from contents single patch-clamped (Patch-seq) identified up-regulation SK channel modulator casein kinase 2 (CK2). Pharmacological inhibition CK2 restored normal patterns mice. These findings shed light on a complex interplay between circuits AD, paving way for novel treatment strategies.

Language: Английский

Neuronal maturation and axon regeneration: unfixing circuitry to enable repair DOI
Brett J. Hilton, Jarred M. Griffin, James W. Fawcett

et al.

Nature reviews. Neuroscience, Journal Year: 2024, Volume and Issue: 25(10), P. 649 - 667

Published: Aug. 20, 2024

Language: Английский

Citations

19
Neurotrauma—From Injury to Repair: Clinical Perspectives, Cellular Mechanisms and Promoting Regeneration of the Injured Brain and Spinal Cord DOI Creative Commons
Andrew R. Stevens, Antonio Belli, Zubair Ahmed

et al.

Biomedicines, Journal Year: 2024, Volume and Issue: 12(3), P. 643 - 643

Published: March 13, 2024

Traumatic injury to the brain and spinal cord (neurotrauma) is a common event across populations often causes profound irreversible disability. Pathophysiological responses trauma exacerbate damage of an index injury, propagating loss function that central nervous system (CNS) cannot repair after initial resolved. The way in which lost consequence complex array mechanisms continue chronic phase post-injury prevent effective neural repair. This review summarises events traumatic (TBI) (SCI), comprising description current clinical management strategies, summary known cellular molecular secondary their role prevention A discussion emerging approaches promote neuroregeneration CNS presented. barriers promoting neurotrauma are pathways cell types occur on level. presents challenge traditional pharmacological targeting single pathways. It suggested novel multiple or using combinatorial therapies may yield sought-after recovery for future patients.

Language: Английский

Citations

9
The acute spinal cord injury microenvironment and its impact on the homing of mesenchymal stem cells DOI
Jinyi Liu,

Longju Qi,

Shengzhe Bao

et al.

Experimental Neurology, Journal Year: 2024, Volume and Issue: 373, P. 114682 - 114682

Published: Jan. 9, 2024

Language: Английский

Citations

5
Repetitive transcranial magnetic stimulation promotes motor function recovery in mice after spinal cord injury via regulation of the Cx43-autophagy loop DOI Creative Commons

Lechi Zhang,

Zhihang Xiao,

Zelin Su

et al.

Journal of Orthopaedic Surgery and Research, Journal Year: 2024, Volume and Issue: 19(1)

Published: July 2, 2024

Abstract Spinal cord injury (SCI) is a severe condition with an extremely high disability rate. It mainly manifested as the loss of motor, sensory and autonomic nerve functions below site. High-frequency transcranial magnetic stimulation, recently developed neuromodulation method, can increase motor function in mice spinal injury. This study aimed to explore possible mechanism by which stimulation (TMS) restores after SCI. A complete T8 transection model was established mice, were treated daily 15 Hz high-frequency stimulation. The BMS used evaluate Western blotting immunofluorescence detect expression Connexin43 (CX43) autophagy-related proteins vivo vitro, correlation analysis performed relationships among autophagy, CX43 recovery SCI mice. observe effect on mTOR pathway members. In control group, significantly decreased, microtubule-associated protein 1 A/1b light chain 3 (LC3II) P62 increased 4 weeks transection. After level levels LC3II primary astrocytes. group greater than that group. inhibit CX43, negatively regulates autophagic flux. HF-rTMS mTOR, p-mTOR p-S6. Our experiments showed rTMS restore hindlimb via regulation Cx43-autophagy loop activation signalling pathway.

Language: Английский

Citations

5
VTA dopamine neurons are hyperexcitable in 3xTg-AD mice due to casein kinase 2-dependent SK channel dysfunction DOI Creative Commons
Harris E. Blankenship,

Kelsey A Carter,

Kevin D. Pham

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Nov. 8, 2024

Abstract Alzheimer’s disease (AD) patients exhibit neuropsychiatric symptoms that extend beyond classical cognitive deficits, suggesting involvement of subcortical areas. Here, we investigated the role midbrain dopamine (DA) neurons in AD using amyloid + tau-driven 3xTg-AD mouse model. We found deficits reward-based operant learning mice, possible VTA DA neuron dysregulation. Physiological assessment revealed hyperexcitability and disrupted firing caused by reduced activity small-conductance calcium-activated potassium (SK) channels. RNA sequencing from contents single patch-clamped (Patch-seq) identified up-regulation SK channel modulator casein kinase 2 (CK2), which corroborated immunohistochemical protein analysis. Pharmacological inhibition CK2 restored normal patterns mice. These findings identify a mechanism ion dysregulation could contribute to behavioral abnormalities AD, paving way for novel treatment strategies.

Language: Английский

Citations

4
Lipin1 depletion coordinates neuronal signaling pathways to promote motor and sensory axon regeneration after spinal cord injury DOI Creative Commons
Weitao Chen, Junqiang Wu, Chao Yang

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(39)

Published: Sept. 18, 2024

Adult central nervous system (CNS) neurons down-regulate growth programs after injury, leading to persistent regeneration failure. Coordinated lipids metabolism is required synthesize membrane components during axon regeneration. However, also function as cell signaling molecules. Whether lipid contributes remains unclear. In this study, we showed that lipin1 orchestrates mechanistic target of rapamycin (mTOR) and STAT3 pathways determine We established an mTOR-lipin1-phosphatidic acid/lysophosphatidic acid-mTOR loop acts a positive feedback inhibitory signaling, contributing the suppression CNS following injury. addition, knockdown (KD) enhances corticospinal tract (CST) sprouting unilateral pyramidotomy promotes CST complete spinal cord injury (SCI). Furthermore, KD sensory SCI. Overall, our research reveals functions regulator coordinate mTOR in highlights potential promising therapeutic for promoting motor axons

Language: Английский

Citations

3
The transcriptional response of cortical neurons to concussion reveals divergent fates after injury DOI Creative Commons
Mor R. Alkaslasi,

Eliza Y. H. Lloyd,

Austin S. Gable

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 27, 2025

Language: Английский

Citations

0
Optic nerve as a regeneration model for spinal cord injury DOI
Cynthia Gomes,

Seth A. Herr,

Devika Shukla

et al.

Elsevier eBooks, Journal Year: 2025, Volume and Issue: unknown, P. 301 - 314

Published: Jan. 1, 2025

Language: Английский

Citations

0
Nfe2l3 promotes neuroprotection and long-distance axon regeneration after injury in vivo DOI
Agnieszka Łukomska, Matthew P. Frost, William C. Theune

et al.

Experimental Neurology, Journal Year: 2024, Volume and Issue: 375, P. 114741 - 114741

Published: Feb. 21, 2024

Language: Английский

Citations

2
The transcriptional response of cortical neurons to concussion reveals divergent fates after injury DOI Creative Commons
Mor R. Alkaslasi,

Eliza Y. H. Lloyd,

Austin S. Gable

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 28, 2024

Abstract Traumatic brain injury (TBI) is a risk factor for neurodegeneration, however little known about how different neuron types respond to this kind of injury. In study, we follow neuronal populations over several months after single mild TBI (mTBI) assess long ranging consequences at the level single, transcriptionally defined classes. We find that stress responsive Activating Transcription Factor 3 (ATF3) defines population cortical neurons mTBI. show activate ATF3 upregulate stress-related genes while repressing many genes, including commonly used markers these cell types. Using an inducible reporter linked ATF3, genetically mark damaged cells track them time. Notably, in layer V undergoes death acutely injury, another II/III survives term and retains ability fire action potentials. To investigate mechanism controlling death, silenced candidate response pathways. found axon kinase MAP3K12, also as dual leucine zipper (DLK), required death. This work provides rationale targeting DLK signaling pathway therapeutic intervention traumatic Beyond this, our novel approach mild, subclinical can inform understanding susceptibility repeated impacts.

Language: Английский

Citations

1