Biology subjects

Hinojosa, A.

Publications and source records attributed to Hinojosa, A..

3 recordsLinked to original sources

bioRxiv2025

Locomotion Selectively Amplifies Sensitizing Neurons in Primary Visual Cortex

Sensory processing in the cortex reflects both adaptation to external stimuli and changes in internal state. To investigate how these processes interact in layer 2/3 of mouse V1 we combined calcium imaging, optogenetics and circuit modelling. We find that locomotion preferentially increases the responses of pyramidal cells (PCs) that sensitize during visual stimulation compared to those that depress. A model explains this differential modulation through: (i) variations in the strength of PV and SST connectivity to individual PCs, (ii) broad locomotion-dependent weakening of PC and PV synapses, and (iii) reduced SST inhibition targeting sensitizing PCs. Differences in PV:SST input ratios across sensitizing and depressing PCs can be reproduced by a random-connectivity model based on measured interneuron densities, connection probabilities and synaptic strengths. Thus, stochastic variation in local inhibitory connectivity can explain much of the functional heterogeneity across PCs, while state-dependent modulation of inhibitory synapses reorganizes this balance during locomotion to bias cortical population activity towards sensitizing dynamics. The apparently paradoxical combination of increased PC response but decreased synaptic strength is consistent with a state-dependent gating mechanism that boosts signals leaving V1 while simultaneously preventing disruption of the local excitatory-inhibitory balance required for stable computation.

neuroscience↗

bioRxiv2025

Injectable adhesive hydrogel-drug complexes synchronize the release of chemoimmunotherapy to treat brain tumors in mice

Brain tumor therapy remains limited by an immunosuppressive, monotherapy-resistant tumor microenvironment and by a paucity of technologies capable of controlling therapy delivery kinetics to the tumor. Here, we describe tissue-adhesive hydrogel-drug complexes (HDCs) for the controlled release of combination therapies synchronized with immune cycle responses following intracranial administration. Injected adhesive HDCs enabled the controlled co-delivery of multiple payloads (chemotherapy, stimulator of interferon genes agonist cyclic dinucleotide nanoparticles, immune checkpoint blockade antibodies), leading to enhanced long-term survival (>80%) and protection from contralateral hemisphere rechallenge after a single dose in multiple syngeneic orthotopic glioblastoma mouse models. Mechanistic studies revealed that tumor rejection is a consequence of reprogramming the tumor microenvironment, driven by three key phases: the initial rapid expression of inflammatory cytokines, notably IFN-{gamma}, and tumor sensitization with antigen exposure during chemoimmunotherapy release, followed by the recruitment and subsequent sustained activation of antigen-presenting and effector cells facilitated by the hydrogels multiweek delivery period. These findings point to tissue-adhesive HDCs, and therapeutic release synchronized with biological responses as key considerations for realizing robust immune activation without provoking toxicity in the treatment of solid tumors.

bioengineering↗

bioRxiv2024

Random connectivity generates inhibitory microcircuits that decorrelate adaptation in visual cortex

Inhibitory neurons are fundamental to sensory processing in the cortex but the rules governing their connections with excitatory neurons are unclear. Are pyramidal cells with different functions generated through specific or random connections? We used two-photon imaging, optogenetics and modelling to investigate opposing forms of adaptation in layer 2/3 of mouse visual cortex. We find that a slow modulatory drive acts differentially depending on the relative strength of inputs that individual pyramidal cells receive from parvalbumin-positive and somatostatin-positive interneurons. The number of depressing and sensitizing pyramidal cells could be explained quantitatively by the simplest connectivity rule - all inhbitory synapses made randomly. The functional heterogeneity of the pyramidal cell population therefore begins with general statistics of the connectome - interneurons are much sparser and connect with probabilities far less than one. The resulting "patchwork" of inhibitory microcircuits causes modulatory inputs to strongly decorrelate pyramidal cells on the behavioural time-scale of seconds.

neuroscience↗