Biology subjects

Dadgar-Kiani, E.

Publications and source records attributed to Dadgar-Kiani, E..

4 recordsLinked to original sources

bioRxiv2025

Focused ultrasound to the bilateral thalamus causally modulates human cognitive attention in a frequency- and intensity-dependent manner

The centromedian nucleus of the thalamus (CMT) is a core arousal center with potential for enhancing cognitive attention. While emergent focused ultrasound can reach this area, the stimulation paradigms which may enhance function in humans remain unknown. Here we performed bilateral stimulation of the CMT using a novel ultrasound neuromodulation wearable device using 3 distinct pulse frequencies. We found that a brief 25Hz stimulation enhanced reaction time in a in a directed attention Oddball task for at least 40 minutes. Pre-post task electrocortical EEG revealed a correlation between reaction time and the prevalence of arousal related alpha and theta cortical activity. Examination of dose dependence revealed bidirectional modulation of arousal state, with lower intensities preferentially enhancing cognitive function. Pre- and post-MRI scans showed no neuroradiological changes due to stimulation. Collectively, these findings demonstrate that targeted LIFU stimulation of the CMT can safely enhance cognitive function in healthy individuals with carefully designed parameters.

neuroscience↗

bioRxiv2024

Quantitative 3D histochemistry reveals region-specific amyloid-β reduction by the antidiabetic drug netoglitazone

A hallmark of Alzheimers disease (AD) is the extracellular aggregation of toxic amyloid-beta (A{beta}) peptides in form of plaques. Here, we identify netoglitazone, an antidiabetic compound previously tested in humans, as an A{beta} aggregation antagonist. Netoglitazone improved cognition and reduced microglia activity in a mouse model of AD. Using quantitative whole-brain three-dimensional histology (Q3D), we precisely identified brain regions where netoglitazone reduced the number and size of A{beta} plaques. We demonstrate the utility of Q3D in preclinical drug evaluation for AD by providing a high-resolution brain-wide view of drug efficacy. Applying Q3D has the potential to improve pre-clinical drug evaluation by providing information that can help identify mechanisms leading to brain region-specific drug efficacy. Significance statementAlzheimers disease (AD) is the most prevalent neurodegenerative disease. Its primary symptom is progressive cognitive decline, which impairs executive brain functions and deprives patients of their autonomy in life. Experimental and clinical evidence points to the critical pathophysiological role of the amyloid-beta (A{beta}) peptide. Despite some limited successes in AD immunotherapy targeting A{beta}, AD is still incurable. Here, we use an innovative pipeline for accurate whole-brain measurements of A{beta} load to test the efficacy of the antidiabetic compound, netoglitazone. We found that netoglitazone decreases A{beta} burden in certain brain areas but not in others. Region-specific assessment of anti-A{beta} efficacy may be useful in the development of effective drugs against Alzheimers disease.

neuroscience↗

bioRxiv2021

Quantitative 3D microscopy reveals a genetic network predicting the local activity of anti-Aβ compounds

Many efforts targeting amyloid-{beta} (A{beta}) plaques for the treatment of Alzheimers Disease thus far have resulted in failures during clinical trials. Regional and temporal heterogeneity of efficacy and dependence on plaque maturity may have contributed to these disappointing outcomes. In this study, we mapped the regional and temporal specificity of various anti-A{beta} treatments through high-resolution light-sheet imaging of electrophoretically-cleared brains. We assessed the effect on amyloid plaque formation and growth in Thy1-APP/PS1 mice subjected to {beta}-secretase inhibitors, polythiophenes, or anti-A{beta} antibodies. Each treatment showed unique spatiotemporal A{beta} clearance, with polythiophenes emerging as a potent anti-A{beta} compound. Furthermore, aligning with a spatial-transcriptomic atlas revealed transcripts that correlate with the efficacy of each A{beta} therapy. As observed in this study, there is a striking dependence of specific treatments on the location and maturity of A{beta} plaques. This may also contribute to the clinical trial failures of A{beta}-therapies, suggesting that combinatorial regimens may be significantly more effective in clearing amyloid deposition.

neuroscience↗

bioRxiv2018

Temporal Evolution of Cortical Ensembles Promoting Remote Memory Retrieval

Studies of amnesic patients and animal models support a systems consolidation model, which posits that explicit memories formed in hippocampus are transferred to cortex over time1-6. Prelimbic cortex (PL), a subregion of the medial prefrontal cortex, is required for the expression of learned fear memories from hours after learning until weeks later7-12. While some studies suggested that prefrontal cortical neurons active during learning are required for memory retrieval13-15, others provided evidence for ongoing cortical circuit reorganization during memory consolidation10,16,17. It has been difficult to causally relate the activity of cortical neurons during learning or recent memory retrieval to their function in remote memory, in part due to a lack of tools18. Here we show that a new version of targeted recombination in active populations, TRAP2, has enhanced efficiency over the past version, providing brain-wide access to neurons activated by a particular experience. Using TRAP2, we accessed PL neurons activated during fear conditioning or 1-, 7-, or 14-day memory retrieval, and assessed their contributions to 28-day remote memory. We found that PL neurons TRAPed at later retrieval times were more likely to be reactivated during remote memory retrieval, and more effectively promoted remote memory retrieval. Furthermore, reducing PL activity during learning blunted the ability of TRAPed PL neurons to promote remote memory retrieval. Finally, a series of whole-brain analyses identified a set of cortical regions that were densely innervated by memory-TRAPed PL neurons and preferentially activated by PL neurons TRAPed during 14-day retrieval, and whose activity co-varied with PL and correlated with memory specificity. These findings support a model in which PL ensembles underlying remote memory undergo dynamic changes during the first two weeks after learning, which manifest as increased functional recruitment of cortical targets.

neuroscience↗