Biology subjects

Curry, T.

Publications and source records attributed to Curry, T..

4 recordsLinked to original sources

bioRxiv2024

Conditional Knockout of Striatal Gnal Produces Dystonia-like Motor Phenotypes

Loss-of-function mutations in GNAL have been linked to an adult-onset, isolated dystonia that is largely indistinguishable from idiopathic dystonia. GNAL encodes Golf, a heterotrimeric G-protein subunit with a defined molecular function to increase the production of the second messenger cAMP. Golf is abundant in the striatum, and is the only stimulatory G-protein in many cell types of the striatum. Due to the defined molecular signaling pathway and expression pattern of Golf, the clear genetic link to dystonia makes GNAL an exciting target to understand the pathological mechanisms of not only this genetic dystonia, but also the larger idiopathic disease. To better understand GNAL-linked dystonia, we generated a novel genetic mouse model that allows us to conditionally knock out Gnal in a site and time-specific manner. In the current study we used genetic or AAV based approaches to express Cre to knockout striatal Gnal in our novel Gnal fl/fl model. We then performed motor behavioral testing and ex vivo whole-cell patch clamp electrophysiology of striatal spiny projection neurons to interrogate how loss of Gnal leads to dystonia. Mice with conditional striatal knockout of Gnal show hindlimb clasping, other dystonia-like postures, less motor coordination, slowness, and torticollis as compared to age-matched controls. Furthermore, striatal spiny projection neurons show increased excitability in Gnal knockout animals. These exciting data are the first to report uninduced, overt dystonia in a mouse model of GNAL-linked dystonia, and directly correlate these with changes in spiny projection neuron electrophysiological properties. Our results show that adult loss of Gnal in the striatum leads to the development of dystonia, through homeostatic, paradoxical increases in spiny projection neuron excitability, and suggest that therapeutic strategies aimed at decreasing this hyperexcitable phenotype may provide symptomatic relief for patients with disease. One Sentence Summary: When Gnal is knocked out in the striatum of mice we observe overt behavioral symptoms and hyperexcitability in striatal spiny projection neurons.

neuroscience↗

bioRxiv2023

In Vivo Phenotypic Vascular Dysfunction Extends Beyond the Aorta in a Mouse Model for Fibrillin-1 (FBN1) Mutation

In individuals with Marfan Syndrome (MFS), fibrillin-1 gene (FBN1) mutations can lead to vascular wall weakening and dysfunction. The experimental mouse model of MFS (FBN1C1041G/+) has been advantageous in investigating MFS-associated life-threatening aortic aneurysms. Although the MFS mouse model presents an accelerated-aging phenotype in elastic organs (e.g., lung, skin), the impact of FBN1 mutations on other central and peripheral arteries function and structure with the consideration of the impact of sex remains underexplored. In this study, we investigate if FBN1 mutation contributes to sex-dependent alterations in central and cerebral vascular function similar to phenotypic changes associated with normal aging in healthy control mice. In vivo ultrasound imaging of central and cerebral vasculature was performed in 6-month-old male and female MFS and C57BL/6 mice and sex-matched 12-month-old (middle-aged) healthy control mice. Our findings confirm aortic enlargement (aneurysm) and wall stiffness in MFS mice, but with exacerbation in male diameters. Coronary artery blood flow velocity (BFV) in diastole was not different but left pulmonary artery BFV was decreased in MFS and 12-month-old control mice regardless of sex. At 6 months of age, MFS male mice show decreased posterior cerebral artery BFV as compared to age-matched control males, with no difference observed between female cohorts. Reduced mitral valve early-filling velocities were indicated in MFS mice regardless of sex. Male MFS mice also demonstrated left ventricular hypertrophy. Overall, these results underscore the significance of biological sex in vascular function and structure in MFS mice, while highlighting a trend of pre-mature vascular aging phenotype in MFS mice that is comparable to phenotypes observed in older healthy controls.

physiology↗

bioRxiv2023

Aging with TBI vs. Aging: 6-month temporal profiles for neuropathology and astrocyte activation converge in behaviorally relevant thalamocortical circuitry of male and female rats

Traumatic brain injury (TBI) manifests late-onset and persisting clinical symptoms with implications for sex differences and increased risk for the development of age-related neurodegenerative diseases. Few studies have evaluated chronic temporal profiles of neuronal and glial pathology that include sex as a biological variable. After experimental diffuse TBI, late-onset and persisting somatosensory hypersensitivity to whisker stimulation develops at one-month post-injury and persists to at least two months post-injury in male rats, providing an in vivo model to evaluate the temporal profile of pathology responsible for morbidity. Whisker somatosensation is dependent on signaling through the thalamocortical relays of the whisker barrel circuit made up of glutamatergic projections between the ventral posteromedial nucleus of the thalamus (VPM) and primary somatosensory barrel cortex (S1BF) with inhibitory (GABA) innervation from the thalamic reticular nucleus (TRN) to the VPM. To evaluate the temporal profiles of pathology, male and female Sprague Dawley rats (n = 5-6/group) were subjected to sham surgery or midline fluid percussion injury (FPI). At 7-, 56-, and 168-days post-injury (DPI), brains were processed for amino-cupric silver stain and glial fibrillary acidic protein (GFAP) immunoreactivity, where pixel density of staining was quantified to determine the temporal profile of neuropathology and astrocyte activation in the VPM, S1BF, and TRN. FPI induced significant neuropathology in all brain regions at 7 DPI. At 168 DPI, neuropathology remained significantly elevated in the VPM and TRN, but returned to sham levels in the S1BF. GFAP immunoreactivity was increased as a function of FPI and DPI, with an FPI x DPI interaction in all regions and an FPI x Sex interaction in the S1BF. The interactions were driven by increased GFAP immunoreactivity in shams over time in the VPM and TRN. In the S1BF, GFAP immunoreactivity increased at 7 DPI and declined to age-matched sham levels by 168 DPI, while GFAP immunoreactivity in shams significantly increased between 7 and 168 days. The FPI x Sex interaction was driven by an overall greater level of GFAP immunoreactivity in FPI males compared to FPI females. Increased GFAP immunoreactivity was associated with an increased number of GFAP-positive soma, predominantly at 7 DPI. Overall, these findings indicate that FPI, time post-injury, sex, region, and aging with injury differentially contribute to chronic changes in neuronal pathology and astrocyte activation after diffuse brain injury. Thus, our results highlight distinct patterns of pathological alterations associated with the development and persistence of morbidity that supports chronic neuropathology, especially within the thalamus. Further, data indicate a convergence between TBI-induced and age-related pathology where further investigation may reveal a role for divergent astrocytic phenotypes associated with increased risk for neurodegenerative diseases.

neuroscience↗

bioRxiv2019

The Arp2/3 complex and the formin, Diaphanous, are both required to regulate the size of germline ring canals in the developing egg chamber

Intercellular bridges are an essential structural feature found in both germline and somatic cells throughout the animal kingdom. Because of their large size, the germline intercellular bridges, or ring canals, in the developing fruit fly egg chamber are an excellent model to study the formation, stabilization, and expansion of these structures. Within the egg chamber, the germline ring canals connect 15 supporting nurse cells to the developing oocyte, facilitating the transfer of materials required for successful oogenesis. The ring canals are derived from a stalled actomyosin contractile ring; once formed, additional actin and actin-binding proteins are recruited to the ring to support the 20-fold expansion that accompanies oogenesis. These behaviors provide a unique model system to study the actin regulators that control incomplete cytokinesis, intercellular bridge formation, and expansion. By temporally controlling their expression in the germline, we have demonstrated that the Arp2/3 complex and the formin, Diaphanous (Dia), coordinately regulate ring canal size and expansion throughout oogenesis. Dia is required for successful incomplete cytokinesis and the initial stabilization of the germline ring canals. Once the ring canals have formed, the Arp2/3 complex and Dia cooperate to determine ring canal size and maintain their stability. Our data suggest that the nurse cells must maintain a precise balance between the activity of these two nucleators during oogenesis.

developmental biology↗