Biology subjects

Schiavo, J. K.

Publications and source records attributed to Schiavo, J. K..

3 recordsLinked to original sources

bioRxiv2024

Integrin-deficient T cell leukemia accumulates in the central nervous system

T-cell acute lymphoblastic leukemia (T-ALL) spreads aggressively to the central nervous system (CNS), particularly the leptomeninges. Children with T-ALL are treated with high-dose, CNS-directed chemotherapy, which can cause lasting neurotoxicity and is not always effective. Little is known about how T-ALL enters and persists within the CNS. However, normal T cell migration into the CNS has been extensively studied. Two integrins--VLA-4 and LFA-1--mediate normal T cell entry to the CNS, and VLA-4 blockade effectively treats multiple sclerosis by excluding T cells from the brain. We hypothesized that these integrins would likewise be required for T-ALL CNS entry. Unexpectedly, not only were VLA-4 and LFA-1 dispensable for T-ALL to reach the CNS, integrin-deficient T-ALL accumulated in the CNS compared to control. Mechanistically, integrin loss accelerated T-ALL proliferation in the CNS, suggesting that integrin-mediated interactions may promote quiescence in this space. Integrin blockade synergized with chemotherapy targeting proliferating cells, raising the possibility that combination therapy might be a powerful strategy.

immunology↗

bioRxiv2022

Vagus nerve stimulation recruits the central cholinergic system to enhance perceptual learning

Perception can be refined by experience up to certain limits. It is unclear if perceptual limitations are absolute or could be partially overcome via enhanced neuromodulation and/or plasticity. Recent studies suggest the utility of peripheral nerve stimulation - specifically vagus nerve stimulation (VNS) - for altering neural activity and augmenting experience-dependent plasticity, although little is known about central mechanisms recruited by VNS. Here we developed an auditory discrimination task for mice implanted with a VNS electrode. VNS occurring during behavior gradually improved discrimination abilities beyond the level achieved by training alone. Using two-photon imaging, we identified changes to auditory cortical responses and activation of cortically-projecting cholinergic axons with VNS. Anatomical and optogenetic experiments indicated that VNS could enhance task performance via activation of the central cholinergic system. These results highlight the importance of cholinergic modulation for the efficacy of VNS, perhaps enabling further refinement of VNS methodology for clinical conditions.

neuroscience↗

bioRxiv2020

Innate sensitivity and plastic mechanisms in auditory cortex for reliable maternal behavior

Infant cries evoke powerful responses in parents1-4. To what extent are parental animals innately sensitive to neonatal vocalizations, or might instead learn about key vocal cues for appropriate parenting responses? In mice, naive virgins do not recognize the meaning of pup distress calls, but begin to retrieve pups to the nest following cohousing with a mother and litter5-8. These isolation calls can be variable, requiring co-caring virgins to generalize across features for reliable retrieval9, 10. Here, using behavioral studies combined with two-photon imaging and whole-cell recordings, we show that the onset of maternal behavior in mice results from the interaction between innate sensitivities and experience-dependent processes. We found that pup calls with inter-syllable intervals (ISIs) ranging from 75 to 375 ms elicited pup retrieval, and experienced auditory cortex generalized across these ISIs. In contrast, naive cortex was narrowly tuned to the most common or prototypical ISIs due to enhanced short-term depression of inhibitory inputs. Behavioral testing revealed that naive virgins were also more sensitive to prototypical calls than calls at other rates. Inhibitory and excitatory spiking and synaptic responses were initially mismatched in naive cortex, with untuned inhibition and overly-narrow excitation. Monitoring neuronal populations over cohousing revealed that excitatory neuronal responses broadened to represent a wide range of ISIs, while inhibitory neurons sharpened to form a perceptual boundary. Finally, we presented synthetic calls during cohousing and observed that neural and behavioral responses adjusted to match these statistics. Using inhibitory optogenetics, we found that auditory cortical activity was required to learn about specific features, whereas the oxytocinergic system was generally recruited for retrieval learning and plasticity in temporal tuning. Neuroplastic mechanisms therefore build on an innate sensitivity in the auditory cortex, enabling rapid plasticity for reliable parenting behavior.

neuroscience↗