From McKinnon Lab
Hypoosmotic stress shifts transcription of circadian genes
Cells respond to hypoosmotic stress by initial swelling followed by intracellular increases in the number of osmolytes and initiation of gene transcription that allow cells to adapt to the stress. Here, we have studied the genes that change expression under mild hypoosmotic stress for 12 and 24 h in rat cultured smooth muscle cells (WKO-3M22). We find shifts in the transcription of many genes, several of which are associated with circadian rhythm, such as per1, nr1d1, per2, dbp, and Ciart. To determine whether there is a connection between osmotic stress and circadian rhythm, we first subjected cells to hypoosmotic stress for 12 h, and find that Bmal1, a transcription factor whose nuclear localization promotes transit through the cell cycle, localizes to the cytoplasm, which may connect osmotic stress to cell cycle. Bmal1 nuclear localization recovers after 24 h and cell cycle resumes even though the osmotic stress remains elevated. We hypothesized that osmotic force is transmitted into the cell by deforming caveolae membrane domains releasing one of its structural proteins, cavin-1, which can travel to the nucleus and affect gene transcription. In support of this idea, we find that Bmal1 localization becomes independent of osmotic stress with cavin-1 downregulation, and Bmal1 localization is independent of osmotic stress in a cell line with low caveolae expression. These studies indicate that osmotic stress transiently arrests circadian rhythm and cell-cycle progression through caveolae deformation.
From Sirotkin Lab
Per- and polyfluoroalkyl substances (PFAS), persistent pollutants found in water sources worldwide, pose significant challenges to conventional remediation methods. This study presents a one-pot, high atom-economy synthesis of porphyrin-based cationic nanocages (oNCs) as a selective, rapid and efficient solution for PFAS removal, addressing critical gaps in current water treatment technologies. Using liquid chromatography–tandem mass spectrometry (LC-MS/MS), the nanocages─[oNC]8PF6, [Co2+-oNC]8PF6, and [Co3+(N≡O)-oNC]8PF6─were evaluated for their ability to sorb a mixture of 38 PFAS, including emerging contaminants like GenX, from various water matrices at a concentration of 50 ng/mL. The nanocages achieved exceptional PFAS removal efficiencies, with optimal results obtained when [oNC]8PF6 and [Co2+-oNC]8PF6 were combined in a 1:4 ratio. This mixture created a synergistic effect, enabling the sorption of both short- and long-chain PFAS, achieving average removal efficiencies of 90% in Nanopure and groundwater, and 80% in influent sewage. The nanocage mixture consistently outperformed activated carbon, particularly in complex matrices such as influent sewage, where activated carbon presented lower efficiency, especially for perfluoroalkane sulfonamido substances. The nanocages reached sorption equilibrium within 15 min and maintained performance across multiple methanolic regeneration cycles, highlighting their operational durability. NMR spectroscopy and computational studies revealed that PFAS sorption occurs via hydrophobic and electrostatic interactions, as well as partial intercalation, with selectivity for PFAS molecules bearing sulfonate and sulfonamide head groups and carbon chain lengths of five or more. Early stage eco-toxicological assessments confirmed the environmental safety of these nanocages, showing no adverse effects below a concentration of 0.005 μM. By combining rapid PFAS removal with modular, scalable and sustainable material synthesis, this study sets a new direction for developing precise, environmentally responsible PFAS water treatment solutions.
From Wollmuth Lab
Regulation of NMDAR activation efficiency by environmental factors and subunit composition
NMDA receptors (NMDAR) convert the major excitatory neurotransmitter glutamate into a synaptic signal. A key question is how efficiently the ion channel opens in response to the rapid exposure to presynaptic glutamate release. Here, we applied glutamate to single channel outside-out patches and measured the successes of channel openings and the latency to first opening to assay the activation efficiency of NMDARs under different physiological conditions and with different human subunit compositions. For GluN1/GluN2A receptors, we find that various factors, including intracellular ATP and GTP, can enhance the efficiency of activation presumably via the intracellular C-terminal domain. Notably, an energy-based internal solution or increasing the time between applications to increase recovery time improved efficiency. However, even under these optimized conditions and with a 1-s glutamate application, there remained around 10–15% inefficiency. Channel activation became more inefficient with brief synaptic-like pulses of glutamate at 2 ms. Of the different NMDAR subunit compositions, GluN2B-containing NMDARs showed the lowest success rate and longest latency to first openings, highlighting that they display the most distinct activation mechanism. In contrast, putative triheteromeric GluN1/GluN2A/GluN2B receptors showed high activation efficiency. Despite the low open probability, NMDARs containing either GluN2C or GluN2D subunits displayed high activation efficiency, nearly comparable with that for GluN2A-containing receptors. These results highlight that activation efficiency in NMDARs can be regulated by environmental surroundings and varies across different subunits.
From the Riessland Lab
Defining and characterizing neuronal senescence, 'neurescence', as G(X) arrested cells.
Abstract: Cellular senescence is a cell state characterized by resistance to apoptosis and stable cell cycle arrest. Senescence was first observed in mitotic cells in vitro. Recent evidence from in vivo studies and human tissue indicates that postmitotic cells, including neurons, may also become senescent. The quiescent cell state of neurons and inconsistent descriptions of neuronal senescence across studies, however, have caused confusion in this burgeoning field. We summarize evidence demonstrating that exit from G0 quiescence may protect neurons against apoptosis and predispose them toward senescence. Additionally, we propose the term 'neurescent' for senescent neurons and introduce the cell state, GX, to describe cell cycle arrest achieved by passing through G0 quiescence. Criteria are provided to identify neurescent cells, distinguish them from G0 quiescent neurons, and compare neurescent phenotypes with classic replicative senescence.
From Fontanini Lab and Maffei Lab
Regulation of NMDAR activation efficiency by environmental factors and subunit composition
Taste preference is a fundamental driver of feeding behavior influencing dietary choices and eating patterns. Extensive experimental evidence indicates that the gustatory cortex (GC) is engaged in taste perception, palatability and preference. However, our knowledge of the neural and neurochemical signals regulating taste preference is rather limited. Neuromodulators can affect preferences, though their effects on neural circuits for taste are incompletely understood. Neurosteroids are of particular interest in view of reports that systemic administration of the neurosteroid allopregnanolone, a potent modulator of tonic GABAergic inhibition, induces hyperphagia and increases intake of energy rich food in human and animal subjects. Tonic inhibition is a powerful modulator of circuit excitability and is primarily mediated by extrasynaptic GABAA receptors containing the delta subunit (δ-GABAARs). These receptors are widely distributed in the brain, but information regarding the expression of δ-GABAARs within gustatory circuits is lacking, and their role in taste preference has not been investigated. Here, we focused on GC to investigate whether activation of δ-GABAARs affects sweet taste preference in adult mice. Our data reveal that δ-GABAARs are expressed in multiple cell types within GC. These receptors mediate an allopregnanolone-sensitive tonic current and decrease sweet taste preference by altering the behavioral sensitivity to sucrose concentration in a cell type-specific manner. Our findings demonstrate that taste sensitivity and preference in the adult mammalian brain are modulated by tonic inhibition mediated by neurosteroid-activated δ-GABAARs in GC.
From the Ge Lab
Abstract: Neurovascular defects are one of the most common alterations in Alzheimer's disease (AD) pathogenesis, but whether these deficits develop before the onset of amyloid beta (Aβ) accumulation remains to be determined. Using in vivo optical imaging in freely moving mice, we explored activity-induced hippocampal microvascular blood flow dynamics in AppSAA knock-in and J20 mouse models of AD at early stages of disease progression. We found that prior to the onset of Aβ accumulation, there was a pathologically elevated blood flow response to context exploration, termed functional hyperemia. After the onset of Aβ accumulation, this context exploration-induced hyperemia declined rapidly relative to that in control mice. Using in vivo electrophysiology recordings to explore the neural circuit mechanism underlying this blood flow alteration, we found that hippocampal interneurons before the onset of Aβ accumulation were hyperactive during context exploration. Chemogenetic tests suggest that hyperactive activation of inhibitory neurons accounted for the elevated functional hyperemia. The suppression of nitric oxide (NO) produced from hippocampal interneurons in young AD mice decreased the accumulation of Aβ. Together, these findings reveal that neurovascular coupling is aberrantly elevated before Aβ deposition, and this hyperactive functional hyperemia declines rapidly upon Aβ accumulation.
From the Reissland Lab
Lipid accumulation drives cellular senescence in dopaminergic neurons
Abstract: Parkinson’s disease (PD) is an age-related movement disorder caused by the loss of dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc) of the midbrain, however, the underlying cause(s) of this DA neuron loss in PD is unknown and there are currently no effective treatment options to prevent or slow neuronal loss or the progression of related symptoms. It has been shown that both environmental factors as well as genetic predispositions underpin PD development and recent research has revealed that lysosomal dysfunction and lipid accumulation are contributors to disease progression, where an age-related aggregation of alpha-synuclein as well as lipids have been found in PD patients. Interestingly, the most common genetic risk factor for PD is Glucosylceramidase Beta 1 (GBA), which encodes a lysosomal glucocerebrosidase (GCase) that cleaves the beta-glucosidic linkage of lipids known as glucocerebrosides (GluCer). We have recently discovered that artificial induction of GluCer accumulation leads to cellular senescence of DA neurons, suggesting that lipid aggregation plays a crucial role in the pathology of PD by driving senescence in these vulnerable DA neurons. Here, we discuss the relevance of the age-related aggregation of lipids as well as the direct functional link between general lipid aggregation, cellular senescence, and inflammaging of DA neurons. We propose that the expression of a cellular senescence phenotype in the most vulnerable neurons in PD can be triggered by lysosomal impairment and lipid aggregation. Importantly, we highlight additional data that perilipin (PLIN2) is significantly upregulated in senescent DA neurons, suggesting an overall enrichment of lipid droplets (LDs) in these cells. These findings align with our previous results in dopaminergic neurons in highlighting a central role for lipid accumulation in the senescence of DA neurons. Importantly, general lipid droplet aggregation and global lysosomal impairment have been implicated in many neurodegenerative diseases including PD. Taken together, our data suggest a connection between age-related lysosomal impairment, lipid accumulation, and cellular senescence in DA neurons that in turn drives inflammaging in the midbrain and ultimately leads to neurodegeneration and PD.
From the Kritzer Lab
Androgen effects on mesoprefrontal dopamine systems in the adult male brain
Abstract: Epidemiological data show that males are more often and/or more severely affected by symptoms of prefrontal cortical dysfunction in schizophrenia, Parkinson’s disease and other disorders in which dopamine circuits associated with the prefrontal cortex are dysregulated. This review focuses on research showing that these dopamine circuits are powerfully regulated by androgens. It begins with a brief overview of the sex differences that distinguish prefrontal function in health and prefrontal dysfunction or decline in aging and/or neuropsychiatric disease. This review article then spotlights data from human subjects and animal models that specifically identify androgens as potent modulators of prefrontal cortical operations and of closely related, functionally critical measures of prefrontal dopamine level or tone. Candidate mechanisms by which androgens dynamically control mesoprefrontal dopamine systems and impact prefrontal states of hypo- and hyper-dopaminergia in aging and disease are then considered. This is followed by discussion of a working model that identifies a key locus for androgen modulation of mesoprefrontal dopamine systems as residing within the prefrontal cortex itself. The last sections of this review critically consider the ways in which the organization and regulation of mesoprefrontal dopamine circuits differ in the adult male and female brain, and highlights gaps where more research is needed.