Biology subjects

Agha, A.

Publications and source records attributed to Agha, A..

2 recordsLinked to original sources

bioRxiv2023

Auditory corticofugal circuits drive vocalization-guided maternal behavior

New parents become highly responsive to infant cries in parallel with auditory cortical plasticity enhancing representations of these calls. To promote caretaking behavior while controlling overall excitability, increased neural activity must be appropriately routed to downstream areas in combination with suppression of circuits that could promote aberrant behavioral responses. We investigated responses to multi-syllable mouse pup calls in cortical output neurons projecting to either the auditory striatum or auditory midbrain (inferior colliculus) using longitudinal 2-photon imaging and in vivo optically-tagged whole-cell recordings. Corticocollicular but not corticostriatal projections responded to pup calls over extended durations and were required for pup retrieval behavior, suggesting that these output units integrated multiple call syllables. The two populations diverged with parental experience, enhancing sustained responses in corticocollicular projections and reduced responses in corticostriatal projections. We performed simultaneous Neuropixels recordings from auditory cortex, thalamus, and midbrain to examine the temporal structure of call responses across areas and to dissect the influences of feedforward and feedback processing. Facilitation of later syllables increased in midbrain of maternally-experienced animals, together with reduced firing rates in a subset of units that were weakly coupled to cortical and midbrain activity. Overall, maternal experience leads to broad suppression of subcortical excitation in response to pup calls while selectively unmasking a subset of midbrain neurons that integrate over multiple syllables.

neuroscience↗

bioRxiv2019

Differential antitumor activity of compounds targeting the ubiquitin-proteasome machinery in gastrointestinal stromal tumors (GIST)

The majority of gastrointestinal stromal tumors (GISTs) are driven by oncogenic KIT signaling and can therefore be effectively treated with the tyrosine kinase inhibitor (TKI) imatinib mesylate. However, most GISTs develop imatinib resistance through secondary KIT mutations. The type of resistance mutation determines sensitivity to approved second-/third-line TKIs but shows high inter- and intratumoral heterogeneity. Therefore, therapeutic strategies that target KIT independently of the mutational status are intriguing. Inhibiting the ubiquitin-proteasome machinery with bortezomib is effective in GIST cells through a dual mechanism of KIT transcriptional downregulation and upregulation of the pro-apoptotic histone H2AX but clinically problematic due to the drugs adverse effects. We therefore tested second-generation inhibitors of the 20S proteasome (delanzomib, carfilzomib and ixazomib) with better pharmacologic profiles as well as compounds targeting regulators of ubiquitination (b-AP15, MLN4924) for their effectiveness and mechanism of action in GIST. All three 20S proteasome inhibitors were highly effective in vitro and in vivo, including in imatinib-resistant models. In contrast, b-AP15 and MLN4924 were only effective at high concentrations or had mostly cytostatic effects, respectively. Our results confirm 20S proteasome inhibitors as promising strategy to overcome TKI resistance in GIST, while highlighting the complexity of the ubiquitin-proteasome machinery as a therapeutic target.

cancer biology↗