Biology subjects

Lavin, A.

Publications and source records attributed to Lavin, A..

6 recordsLinked to original sources

bioRxiv2025

The ift140-Deficient Zebrafish: A Model for Renal Cystogenesis and an F0-Based Screen to Identify Genetic Modifiers of Kidney Cysts

Genetic modifiers are believed to play an important role in the onset and severity of polycystic kidney disease (PKD), but identifying these modifiers has been challenging due to the lack of effective methodologies. In this study, we investigated zebrafish mutants of IFT140, a newly identified ADPKD gene, and observed phenotypes similar to those seen in mammalian models, including kidney cysts and bone defects. Using efficient microhomology-mediated end joining (MMEJ)-based genome editing technology, we demonstrated that ift140 CRISPRants recapitulate mutant phenotypes while bypassing the early lethality of the mutants to allow for renal cyst analysis in adult fish. In addition to cilia defects, non-cilia phenotypes, such as disrupted cell polarity and aberrant microtubule stabilization in kidney epithelial cells, may also contribute to ift140-associated cystogenesis. Importantly, the ability to detect ift140-associated renal cysts with ease allowed us to develop an F0-based genetic screen to identify potential protective modifiers. A pilot screen of sixteen genes previously linked to dysregulated signaling pathways in ADPKD revealed both known and novel modifiers, including mtor and ulk1a. Inhibition of mtor and ulk1a reversed both cilia-related and non-cilia-related abnormalities. In summary, our study underscores the potential of using zebrafish as a model for the efficient discovery of genetic modifiers of kidney cysts.

genetics↗

bioRxiv2022

Chronic methamphetamine administration produces cognitive deficits through augmentation of GABAergic synaptic transmission in the prefrontal cortex

BACKGROUNDChronic methamphetamine (METH) abuse is associated with the emergence of cognitive deficits and hypofrontality, a pathophysiological marker of many neuropsychiatric disorders that is produced by altered balance of local excitatory and inhibitory synaptic transmission. However, there is a dearth of information regarding the cellular and synaptic mechanisms underlying METH-induced cognitive deficits and associated hypofrontal states. METHODSRats went through a METH sensitization regime or saline (SAL) consisting of 14 days of METH treatment (day 1 and 14, 1 mg/kg; days 2-13, 5 mg /kg) followed by 7-10 days of home cage abstinence. Temporal Order Memory and Working Memory tests, chemogenetic experiments as well as whole-cell patch recordings on prelimbic PFC ex vivo slices were performed during abstinence. RESULTSWe find here that repeated METH administration in rats produces deficits in working memory and increases in inhibitory synaptic transmission onto pyramidal neurons in the prefrontal cortex (PFC). The increased PFC inhibition is detected by an increase in spontaneous and evoked inhibitory postsynaptic synaptic currents (IPSCs), an increase in GABAergic presynaptic function, and a shift in the excitatory-inhibitory balance onto PFC deep-layer pyramidal neurons. We find that pharmacological blockade of D1 dopamine receptor function reduces the METH-induced augmentation of IPSCs, suggesting a critical role for D1 dopamine signaling in METH-induced hypofrontality. In addition, chronic METH administration increases the intrinsic excitability of parvalbumin-positive interneurons, a key local interneuron population in PFC that controls inhibitory tone. Using a cell type-specific chemogenetic approach, we show that increasing PV+FSI activity in the PFC is necessary and sufficient to cause deficits in temporal order memory similar to those induced by METH. CONCLUSIONTogether, our findings reveal that chronic METH exposure increases PFC inhibitory tone through a D1 dopamine signaling-dependent potentiation of inhibitory synaptic transmission, and that reduction of PV+FSI activity can rescue METH-induced cognitive deficits, suggesting a potential therapeutic approach to treating cognitive symptoms in patients suffering from methamphetamine use disorder.

neuroscience↗

bioRxiv2021

Effects of high dosage methamphetamine on glutamatergic neurotransmission in the nucleus accumbens and prefrontal cortex.

RationaleMethamphetamine (METH) induces changes in the glutamatergic system and elicits cellular alterations in the cortico-accumbens circuit. ObjectiveWhile there is a body of literature on the effects of METH on dopaminergic transmission, there is a gap in knowledge regarding the effects of a high dose of METH on synaptic glutamatergic neurotransmission, specifically in brain regions involved in goal directed behavior (nucleus accumbens core; NAc core) and executive functions (prefrontal cortex;PFC). MethodsIn order to fill that gap we assessed synaptic glutamatergic transmission using a well established METH administration regime (4 x 4 mg/kg ip at 2 hr intervals) followed by 7 days of abstinence. Rats were then sacrificed and whole cell and field recordings were performed in the NAc core and medial PFC. ResultsMETH treatment elicited a significant decrease in paired pulse ratio in NAc core and a significant increase in AMPA/NMDA ratio driven by increases in AMPA currents. On the other hand, there were no significant changes in measures of synaptic glutamate in the PFC. ConclusionThese results suggest that a high dose of METH treatment followed by a period of abstinence elicits significant increases in indices of glutamatergic transmission in the NAc core with no detectable changes in mPFC, denoting that neurons and glutamate terminals in this limbic region have a higher susceptibility to a neurotoxic METH regime.

neuroscience↗

bioRxiv2020

High sensitivity (zeptomole) detection of BODIPY heparan sulfate (HS) disaccharides by ion-paired RP-HPLC and LIF detection enables analysis of HS from mosquito midguts.

The fine structure of heparan sulfate (HS), the glycosaminoglycan polysaccharide component of cell surface and extracellular matrix HS proteoglycans, coordinates the complex cell signalling processes that control homeostasis and drive development in multicellular animals. In addition, HS is involved in the infection of mammals by viruses, bacteria and parasites. The current detection limit for fluorescently labelled HS disaccharides that is in the low femtomole range (10-15 mol), has effectively hampered investigations of HS composition from small, functionally-relevant populations of cells and tissues. Here, an ultra-high sensitivity method is described that utilises a combination of reverse-phase HPLC, with tetraoctylammonium bromide (TOAB) as the ion-pairing reagent and laser-induced fluorescence detection of BODIPY-FI-labelled disaccharides. The method provides an unparalleled increase in the sensitivity of detection by [~] six orders of magnitude, to the zeptomolar range ([~]10-21 moles), enabling detection of <1000 labelled molecules. This facilitates determination of HS disaccharide compositional analysis from minute biological samples, as demonstrated by analysis of HS isolated from the midguts of Anopheles gambiae mosquitoes that was achieved without approaching the limit of detection.

biochemistry↗

bioRxiv2018

Cortical Microcircuits from a Generative Vision Model

Understanding the information processing roles of cortical circuits is an outstanding problem in neuroscience and artificial intelligence. The theoretical setting of Bayesian inference has been suggested as a framework for understanding cortical computation. Based on a recently published generative model for visual inference (George et al., 2017), we derive a family of anatomically instantiated and functional cortical circuit models. In contrast to simplistic models of Bayesian inference, the underlying generative models representational choices are validated with real-world tasks that required efficient inference and strong generalization. The cortical circuit model is derived by systematically comparing the computational requirements of this model with known anatomical constraints. The derived model suggests precise functional roles for the feedforward, feedback and lateral connections observed in different laminae and columns, and assigns a computational role for the path through the thalamus.

neuroscience↗

bioRxiv2018

Explaining Visual Cortex Phenomena using Recursive Cortical Network

The connectivity and information pathways of visual cortex are well studied, as are observed physiological phenomena, yet a cohesive model for explaining visual cortex processes remains an open problem. For a comprehensive understanding, we need to build models of the visual cortex that are capable of robust real-world performance, while also being able to explain psychophysical and physiological observations. To this end, we demonstrate how the Recursive Cortical Network (George et al., 2017) can be used as a computational model to reproduce and explain subjective contours, neon color spreading, occlusion vs. deletion, and the border-ownership competition phenomena observed in the visual cortex.

neuroscience↗