Biology subjects

Carter, K. A.

Publications and source records attributed to Carter, K. A..

6 recordsLinked to original sources

bioRxiv2025

Parallel gene expression changes in ventral midbrain dopamine and GABA neurons during normal aging

The consequences of aging can vary dramatically between different brain regions and cell types. In the ventral midbrain, dopaminergic neurons develop physiological deficits with normal aging that likely convey susceptibility to neurodegeneration. While nearby GABAergic neurons are thought to be more resilient, decreased GABA signaling in other areas nonetheless correlates with age-related cognitive decline and the development of degenerative diseases. Here, we used two novel cell type-specific Translating Ribosome Affinity Purification models to elucidate the impact of healthy brain aging on the molecular profiles of dopamine and GABA neurons in the ventral midbrain. By analyzing differential gene expression from young (6-10 month) and old (>21 month) mice, we detected commonalities in the aging process in both neuronal types, including increased inflammatory responses and upregulation of pro-survival pathways. Both cell types also showed downregulation of genes involved in synaptic connectivity and plasticity. Genes involved in serotonergic signaling were upregulated with age only in GABA neurons and not dopamine-releasing cells. In contrast, dopaminergic neurons showed alterations in genes connected with mitochondrial function and calcium signaling, which were markedly downregulated in male mice. Sex differences were detected in both neuron types, but in general were more prominent in dopamine neurons. Multiple sex effects correlated with the differential prevalence for neurodegenerative diseases such as Parkinsons and Alzheimers seen in humans. In summary, these results provide insight into the connection between non-pathological aging and susceptibility to neurodegenerative diseases involving the ventral midbrain, and identify molecular phenotypes that could underlie homeostatic maintenance during normal aging.

neuroscience↗

bioRxiv2024

Genetic and functional adaptations and alcohol-biased signaling in the mediodorsal thalamus of alcohol dependent mice

Alcohol Use Disorder (AUD) is a significant health concern characterized by cognitive dysfunction and an inability to control alcohol intake leading to severe social and health consequences. It is crucial to uncover neuroadaptations and cellular mechanisms responsible for poor decisions surrounding alcohol drinking. Although the mediodorsal thalamus (MD) is an essential brain region for cognitive function and reward-guided choices, the effects of alcohol dependence on MD neuroadaptations and how dependence alters MD activity during choice behaviors for alcohol over natural rewards (i.e., sucrose) are not well understood. Genetic and physiological adaptations in the MD were assessed in mice treated with the chronic intermittent ethanol (CIE) exposure model of dependence, which increased alcohol intake and preference during choice sessions for water or sucrose. Results indicated that CIE exposure induced changes in transcript expression and excitability of MD neurons. Enrichment analysis of alcohol-sensitive genes revealed dysregulation of genes that control glial function and axonal myelination. Fiber photometry was used to record MD calcium signals in CIE mice during choice drinking sessions for alcohol and either water or sucrose. Results demonstrated that MD activity was elevated at the start of and after licking bouts for alcohol, water, or sucrose, although the signal for alcohol was significantly higher than signal for other solutions and this effect persisted after induction of dependence. These findings demonstrate that CIE exposure causes genetic and physiological neuroadaptations in the MD that coincide with alcohol-biased behaviors, with the MD uniquely responsive to alcohol over other solutions.

neuroscience↗

bioRxiv2024

Aged mice exhibit faster acquisition of intravenous opioid self-administration with variable effects on intake

Although opioid abuse is more prevalent in young individuals, opioid use, overdose, and use disorders continue to climb at a rapid rate among the elderly. Little is known about abuse potential in a healthy aged population, in part due to technical and logistical difficulties testing intravenous self-administration in aged rodents. The goal of this study was to address the critical gap in the literature regarding age-dependent differences in opioid (remifentanil and fentanyl) self-administration between old and young mice. Male and female mice were grouped into young (mean: 19 weeks) and old (mean: 101 weeks), and were trained to self-administer intravenous fentanyl or remifentanil in daily sessions. In both old and young mice, acquisition, intake, and cue-responding after forced abstinence were measured for both drugs, and a dose-response curve (remifentanil) and dose-escalation (fentanyl) were conducted. Surprisingly, old mice learned to self-administer both remifentanil and fentanyl faster and more accurately than young mice. Baseline intake of remifentanil was also substantially greater in old mice compared to their young counterparts; however, we did not see increased intake of fentanyl with age at either dose tested. Further, compared to young mice, the old mice showed a greater incubation of responding for cues previously associated with remifentanil after a forced abstinence, but again this was not observed with fentanyl. Together these data suggest that an aged population may have an increased drug-abuse vulnerability for opioids compared to young counterparts and underscore the importance of future work on mechanisms responsible for this increased vulnerability.

animal behavior and cognition↗

bioRxiv2023

VTA dopamine neurons are hyperexcitable in 3xTg-AD mice due to casein kinase 2-dependent SK channel dysfunction

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

neuroscience↗

bioRxiv2019

Effects of the copper IUD on composition of the vaginal microbiota in the olive baboon

ObjectivesAssess the impact of transcervical insertion, use, and removal of copper intrauterine devices (Cu-IUD) on baboon physiology (e.g. weight, menstruation) and vaginal microbiota.\n\nStudy designVaginal swabs were taken before insertion (pre-IUD), during IUD use (IUD), and after removal (post-IUD) and microbiota assessed by 16S rRNA-encoding gene sequence analysis.\n\nResultsNo animals showed physical changes or discomfort during pre-IUD, IUD, or post-IUD phases. There were no changes to the microbiome associated with insertion or use of Cu-IUD over 16 weeks, although removal resulted in perturbation to community structure.\n\nConclusionsBaboons tolerate Cu-IUD insertion with minimal device-associated changes to their vaginal microbiome throughout use and have no significant changes to their physiology or menstrual cycle during any phase.\n\nImplicationsA baboon model of Cu-IUD may allow investigations into the intersection of Cu-IUDs, reproductive tract disorders and pathogens that would not be possible in human studies.

microbiology↗

bioRxiv2019

Target Capture Sequencing Unravels Rubus Evolution

BackgroundRubus (Rosaceae) comprises more than 500 species with additional commercially cultivated raspberries and blackberries. The most recent (> 100 years old) global taxonomic treatment of the genus defined 12 subgenera; two subgenera were subsequently described and some species were rearranged. Intra- and interspecific ploidy levels and hybridization make phylogenetic estimation of Rubus challenging. Our objectives were to: estimate the phylogeny of 94 geographically diverse species and 3 cultivars using chloroplast DNA sequences and target capture of approximately 1,000 low copy nuclear genes; estimate divergence times between major Rubus clades; and examine the historical biogeography of species diversification.\n\nResultsTarget capture sequencing identified eight major groups within Rubus. Subgenus Orobatus and Subg. Anoplobatus were monophyletic, while other recognized subgenera were para- or polyphyletic. Multiple hybridization events likely occurred across the phylogeny at subgeneric levels, e.g., Subg. Rubus (blackberries) x Subg. Idaeobatus (raspberries) and Subg. Idaeobatus x Subg. Cylactis (Arctic berries) hybrids. The raspberry heritage within known cultivated blackberry hybrids was confirmed. The most recent common ancestor of the genus was most likely distributed in North America. Multiple distribution events occurred during the Miocene (about 20 Ma) from North America into Asia and Europe across the Bering land bridge and southward crossing the Panamanian Isthmus. Rubus species diversified greatly in Asia during the Miocene.\n\nConclusionsRubus taxonomy does not reflect phylogenetic relationships and subgeneric revision is warranted. Target capture sequencing confirmed that most subgenera are para- or polyphyletic. The most recent common ancestor migrated from North America towards Asia, Europe, and Central and South America early in the Miocene then diversified. Ancestors of the genus Rubus may have migrated to Oceania by long distance bird dispersal. This phylogeny presents a roadmap for further Rubus taxonomic and phylogenetic research.

evolutionary biology↗