Biology subjects

Alachkar, A.

Publications and source records attributed to Alachkar, A..

7 recordsLinked to original sources

bioRxiv2026

Primary Cilia Loss in Striatal Neurons Disrupts Synaptic Connectivity and Excitatory Transmission and Drives Metabolomic Remodeling

Disruption of striatal circuits is a central feature of many neurological and psychiatric disorders, yet the mechanisms that maintain afferent connectivity and synaptic function in striatal neurons remain incompletely defined. Primary cilia are signaling organelles present on almost all striatal medium spiny neurons that are enriched in neuromodulatory receptors, suggesting a role in coordinating striatal neuronal communication and biochemical state. Here, we show that conditional ablation of primary cilia from striatal neurons by AAV-Cre-mediated deletion of Ift88 disrupts the afferent connectivity, synaptic function, and chemical signature of the striatum. Monosynaptic rabies tracing revealed an approximately threefold reduction in brain-wide input convergence onto striatal neurons. Whole-cell recordings showed reduced miniature excitatory postsynaptic current amplitude and frequency together with a reduced NMDA:AMPA ratio, consistent with weakened glutamatergic synaptic transmission. Untargeted metabolomics revealed broad remodeling of the striatal chemical profile, predominantly toward decreased measured levels, with lipid-associated pathways most affected alongside reductions in polyamines, glutamate-related metabolites, and neuromodulatory, particularly excitatory, signaling molecules. By contrast, the cortex, which was not targeted by the AAV injection, showed fewer and directionally opposite molecular changes. These findings identify cilia as essential regulators of the structural, synaptic, and molecular integrity required for normal striatal circuit function.

neuroscience↗

bioRxiv2026

Ophthalmate tripeptide is a signaling molecule that regulates striatal neurotransmission

Dopamine has long been regarded as the key neurotransmitter governing motor function through the direct and indirect striatal outflow pathways. However, the tripeptide ophthalmate (ophthalmic acid, OA), a glutathione analog, has recently emerged as another regulator of motor function. While the neural mechanisms by which OA regulates motor function remain unknown, we explored how OA behaves as a striatal neuromodulator. Using radiotracer-based uptake and release assays in mouse striatal tissue, combined with whole-cell electrophysiological recordings, we found that OA is taken up through a saturable, glutathione-competitive transport mechanism and is released in a Ca{superscript 2}-dependent manner upon depolarization, consistent with regulated exocytotic release. OA enhanced depolarization-evoked release of {gamma}-aminobutyric acid (GABA) but not glutamate, indicating selective modulation of distinct neurotransmitter systems. OA and dopamine reciprocally regulated one another: OA enhanced dopamine release, while D2 dopamine receptor activation suppressed OA release. Whole-cell recordings from medium spiny neurons (MSNs) showed that OA increased the amplitude of evoked AMPA receptor-mediated currents and shifted short-term plasticity from facilitation toward depression at excitatory synapses onto direct-pathway MSNs (dMSNs). These findings are consistent with an increase in presynaptic glutamate release probability, while sparing synapses onto indirect-pathway MSNs (iMSNs). Together, these findings establish OA as a striatal neuromodulator that interacts with other neurotransmitter systems and preferentially potentiates direct-pathway transmission. This novel discovery identifies a candidate mechanism within the basal ganglia circuitry that governs motor control, with major relevance to Parkinsons disease and other movement disorders.

neuroscience↗

bioRxiv2023

Performance of Large Language Models on Pharmacy Exam: A Comparative Assessment Using the NAPLEX

BackgroundThere has been considerable recent effort in integrating Large Language Models (LLMs) across different fields, including healthcare. However, the possibility of applying LLMs in pharmacy-related sciences is under-explored. ObjectivesThis study aims to evaluate the capabilities and limitations of six LLMs-GPT-3.5, GPT-4, Llama-2-7B, Llama-2-13B, Llama-2-70B, and Mistral-7B, in the field of pharmacy by assessing their reasoning abilities on a sample of the North American Pharmacist Licensure Examination (NAPLEX). Additionally, we explore the potential impacts of LLMs on pharmacy education and practice. MethodsTo evaluate the LLMs, we utilized the sample of the NAPLEX exam comprising 225 multiple-choice questions sourced from the APhA Complete Review for Pharmacy, 13th Edition | Pharmacy Library. These questions were presented to the Large Language Models through either local deployment or the Application programming interface (API), and the answers generated by the LLMs were subsequently compared with the answer key. ResultsThere is a notable disparity in the performance of the LLMs. GPT-4 emerged as the top performer, accurately answering 87.1% of the questions. Among the six LLMs evaluated, GPT-4 was the only model capable of passing the NAPLEX exam. ConclusionWe examined the performance of Large Language Models based on their model size, training methods, and fine-tuning algorithms. Given the continuous evolution of LLMs, it is reasonable to anticipate that future models will effortlessly excel in exams such as the NAPLEX. This highlights the significant potential of LLMs to influence the field of pharmacy. Hence, we must evaluate both the positive and negative implications associated with the integration of LLMs in pharmacy education and practice.

bioinformatics↗

bioRxiv2023

Spatiotemporal Mapping of brain cilia length and orientation reveals region-specific Oscillation

In this study, we conducted high-throughput spatiotemporal analysis of primary cilia length and orientation across 22 mouse brain regions. We developed automated image analysis algorithms, which enabled us to examine over 10 million individual cilia, generating the largest spatiotemporal atlas of cilia. We found that cilia length and orientation display substantial variations across different brain regions and exhibit fluctuations over a 24-hour period, with region-specific peaks during light-dark phases. Our analysis revealed unique orientation patterns of cilia at 45{degrees} intervals, suggesting that cilia orientation within the brain is not random but follows specific patterns. Using BioCycle, we identified circadian rhythms of cilia length in five brain regions: nucleus accumbens core, somatosensory cortex, and three hypothalamic nuclei. Our findings present novel insights into the complex relationship between cilia dynamics, circadian rhythms, and brain function, highlighting cilia crucial role in the brains response to environmental changes and regulation of time-dependent physiological processes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/546950v3_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@153135corg.highwire.dtl.DTLVardef@11c1d7eorg.highwire.dtl.DTLVardef@d47014org.highwire.dtl.DTLVardef@10a65ca_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Clinical Knowledge and Reasoning Abilities of AI Large Language Models in Pharmacy: A Comparative Study on the NAPLEX Exam

ObjectiveThis study aims to evaluate the capabilities and limitations of three large language models (LLMs) - GPT-3, GPT-4, and Bard, in the field of pharmaceutical sciences by assessing their pharmaceutical reasoning abilities on a sample North American Pharmacist Licensure Examination (NAPLEX). We also analyze the potential impacts of LLMs on pharmaceutical education and practice. MethodsA sample NAPLEX exam consisting of 137 multiple-choice questions was obtained from an online source. GPT-3, GPT-4, and Bard were used to answer the questions by inputting them into the LLMs user interface. The answers provided by the LLMs were then compared with the answer key. ResultsGPT-4 exhibited superior performance compared to GPT-3 and Bard, answering 78.8% of the questions correctly. This score was 11% higher than Bard and 27.7% higher than GPT-3. However, when considering questions that required multiple selections, the performance of each LLM decreased significantly. GPT-4, GPT-3, and Bard only correctly answered 53.6%, 13.9%, and 21.4% of these questions, respectively. ConclusionAmong the three LLMs evaluated, GPT-4 was the only model capable of passing the NAPLEX exam. Nevertheless, given the continuous evolution of LLMs, it is reasonable to anticipate that future models will effortlessly pass the exam. This highlights the significant potential of LLMs to impact the pharmaceutical field. Hence, we must evaluate both the positive and negative implications associated with the integration of LLMs in pharmaceutical education and practice.

scientific communication and education↗

bioRxiv2021

Intergenerational Stress Transmission is Associated with Brain Metabotranscriptome Remodeling andMitochondrial Dysfunction

Intergenerational stress increases lifetime susceptibility to depression and other psychiatric disorders. Whether intergenerational stress transmission is a consequence of in utero neurodevelopmental disruptions vs early-life mother-infant interaction is largely unknown. Here, we demonstrated that exposure to traumatic stress in mice during pregnancy, through predator scent exposure, induces in the offspring social deficits and depressive-like behavior. We found, through cross-fostering experiments, that raising of normal pups by traumatized mothers produced a similar behavioral phenotype to that induced in pups raised by their biological traumatized mothers. Good caregiving (by non-traumatized mothers), however, did not completely protect against the prenatal trauma-induced behavioral deficits. These findings support a two-hit stress mechanism of both in utero and early-life parenting (poor caregiving by the traumatized mothers) environments. Associated with the behavioral deficits, we found profound changes in brain metabolomics and transcriptomic (metabotranscriptome). Striking increases in the mitochondrial hypoxia marker and epigenetic modifier 2-hydroxyglutaric acid, in the brains of neonatal and adult pups whose mothers were exposed to stress during pregnancy, indicated mitochondrial metabolism dysfunctions and epigenetic mechanisms. Bioinformatic analyses revealed mechanisms involving stress- and hypoxia-response metabolic pathways in the brains of the neonatal mice, which appear to lead to long-lasting alterations in mitochondrial-energy metabolism, and epigenetic processes pertaining to DNA and chromatin modifications. Most strikingly, we demonstrated that an early pharmacological intervention that can correct mitochondria metabolism - lipid metabolism and epigenetic modifications with acetyl-L-carnitine (ALCAR) supplementation - produces long-lasting protection against the behavioral deficits associated with intergenerational transmission of traumatic stress. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/438868v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1fb2500org.highwire.dtl.DTLVardef@13a5c6forg.highwire.dtl.DTLVardef@8aa512org.highwire.dtl.DTLVardef@5b6906_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Regulation of Brain Primary Cilia Length by MCH Signaling: Evidence from Pharmacological, Genetic, Optogenetic and Chemogenic Manipulations

The melanin concentrating hormone (MCH) system is involved in numerous functions including energy homeostasis, food intake, sleep, stress, mood, aggression, reward, maternal behavior, social behavior, and cognition. MCH acts on a G protein-coupled receptor MCHR1, which expresses ubiquitously in the brain and localizes to neuronal primary cilia. Cilia act as cells antennas and play crucial roles in cell signaling to detect and transduce external stimuli to regulate cell differentiation and migration. Cilia are highly dynamic in terms of their length and morphology; however, it is not known if cilia length is causally regulated by MCH system activation in-vivo. In the current work, we examined the effects of the activation and inactivation of MCH system on cilia lengths by using different methodologies, including pharmacological (MCHR1 agonist and antagonist GW803430), germline and conditional genetic deletion of MCHR1 and MCH, optogenetic, and chemogenetic (Designer Receptors Exclusively Activated by Designer Drugs (DREADD)) approaches. We found that stimulation of MCH system either directly through MCHR1 activation, or indirectly through optogenetic and chemogenetic- mediated excitation of MCH neurons, causes cilia shortening. Contrarily, inactivation of MCH signaling through pharmacological MCHR1 blockade or through genetic manipulations - germline deletion of MCHR1 and conditional ablation of MCH neurons - induces cilia lengthening. Our study is the first to uncover the causal effects of the MCH system in the regulation of the length of brain neuronal primary cilia. These findings place MCH system at a unique position in the ciliary signaling in physiological and pathological conditions, and implicate cilia MCHR1 as a potential therapeutic target for the treatment of pathological conditions characterized by impaired cilia function.

molecular biology↗