Biology subjects

Tobin, M.

Publications and source records attributed to Tobin, M..

6 recordsLinked to original sources

bioRxiv2025

The role of inhibitory neurons in novelty sound detection in regular and random statistical contexts.

Detecting statistical regularities in sound and responding to violations of these patterns, termed deviance detection, is a core function of the auditory system. In the human brain, studies have shown that deviance responses are enhanced in regular compared to random auditory contexts, but the underlying neuronal circuit mechanisms remain unclear. Here, we examined how inhibitory neurons contribute to context-dependent deviance responses in mouse auditory cortex (AC). Using two-photon calcium imaging in AC of awake head-fixed male and female mice, we recorded neuronal activity during presentation of spectro-temporally rich moving ripple sounds, with deviant ripples embedded in either regular or random ripple sequences. AC neurons exhibited stronger responses to deviant sounds in regular contexts compared to random ones. To identify circuit mechanisms, we selectively inactivated parvalbumin (PV), somatostatin (SST), or vasoactive intestinal polypeptide (VIP) inhibitory neurons during the deviant stimulus presentation. Inactivation of PV and SST neurons broadly increased deviance responses in both contexts. In contrast, VIP inactivation selectively reduced responses to deviant stimuli in the regular, but not random, context, decreasing the context-dependent deviance signal enhancement. At the population level, inactivating all three neuronal subtypes increased detectability of the deviant stimulus, but the effects were context-dependent only for VIP inactivation. These findings reveal a distinct role for VIP neurons in modulating deviance signals based on context regularity, identifying a specific inhibitory neuron type that is critical for context-sensitive auditory processing and predictive coding. SIGNIFICANCE STATEMENTUnderstanding how the brain detects and responds to predictable and unexpected sounds is critical for communication and navigation in complex acoustic environments. Although prior studies have shown that detection of novel sounds is enhanced by regularity in background sound patterns, the underlying circuit mechanisms have remained unknown. Here, we find that neurons in the auditory cortex exhibit stronger deviance responses when the deviant sounds are embedded in regular, predictable sound sequences as compared to random sound sequences. Importantly, we identify a distinct role for specific inhibitory neurons in modulating this context-dependent enhancement. These findings reveal a new insight into how cortical circuits implement predictive coding strategies to optimize sensory processing.

neuroscience↗

bioRxiv2023

Confinement with Myosin-II suppression increases heritable loss of chromosomes, using live-cell ChReporters

Matrix around cells exerts many effects, some of which depend on the putative tumor suppressor Myosin-II, but whether such factors affect DNA sequences in a cell remains unclear. Here, live-cell monitoring of changes to chromosome copy numbers is developed and studied under diverse perturbations, including Myosin-II inhibition in confined mitosis. Squeezing of mitotic cells is seen in vivo and kills in vitro, but stem cells and cancer cells that survive show heritable loss of mono-allelic GFP/RFP-tagged constitutive genes that function as novel Chromosome-reporters (ChReporters). Myosin-II suppression increases such loss in 3D & 2D confinement but not in standard 2D, with "lethal" multipolar divisions proving myosin-dependent. Viable chromosome loss after confined mitosis associates more with mis-segregation than with multipolars or division number. Solid human tumors and teratomas in mice also show ChReporter loss and a confinement-signature of Myosin-II suppression, although losses are selected against in 2D culture. Heritable loss in rigid-confinement also appears independent of a spindle assembly checkpoint that functions in 2D. Confinement and myosin-II thus regulate pathways of heritable mechanogenetic change.

cell biology↗

bioRxiv2023

Localist versus distributed representation of sounds in the auditory cortex controlled by distinct inhibitory neuronal subtypes

Cortical circuits contain multiple types of inhibitory neurons which shape how information is processed within neuronal networks. Here, we asked whether somatostatin-expressing (SST) and vasoactive intestinal peptide-expressing (VIP) inhibitory neurons have distinct effects on population neuronal responses to noise bursts of varying intensities. We optogenetically stimulated SST or VIP neurons while simultaneously measuring the calcium responses of populations of hundreds of neurons in the auditory cortex of male and female awake, head-fixed mice to sounds. Upon SST neuronal activation, noise bursts representations became more discrete for different intensity levels, relying on cell identity rather than strength. By contrast, upon VIP neuronal activation, noise bursts of different intensity level activated overlapping neuronal populations, albeit at different response strengths. At the single-cell level, SST and VIP neuronal activation differentially modulated the response-level curves of monotonic and nonmonotonic neurons. SST neuronal activation effects were consistent with a shift of the neuronal population responses toward a more localist code with different cells responding to sounds of different intensity. By contrast, VIP neuronal activation shifted responses towards a more distributed code, in which sounds of different intensity level are encoded in the relative response of similar populations of cells. These results delineate how distinct inhibitory neurons in the auditory cortex dynamically control cortical population codes. Different inhibitory neuronal populations may be recruited under different behavioral demands, depending on whether categorical or invariant representations are advantageous for the task. SIGNIFICANCEInformation about sounds is represented in the auditory cortex by neuronal population activity that has a characteristic sparse structure. Cortical neuronal populations comprise multiple types of excitatory and inhibitory neurons. Here, we find that activating different types of inhibitory neurons differentially controls population neuronal representations, with one type of inhibitory neurons increasing the differences in the identity of the cells recruited to represent the different sounds, and another inhibitory neuron type changing the relative activity level of overlapping neuronal populations. Such transformations may be beneficial for different types of auditory behaviors, suggesting that these different types of inhibitory neurons may be recruited under different behavioral constraints in optimizing neuronal representations of sounds.

neuroscience↗

bioRxiv2022

Small, fat-filled lipid droplets remain spherical as they indent a nucleus, dilute the lamina, and cause rupture

The nucleus in many cell types is a stiff organelle, and yet fat-filled lipid droplets (FDs) in the cytoplasm can be seen to indent and displace the nucleus. FDs are phase-separated liquids with a poorly understood interfacial tension {gamma} that determines how FDs interact with other organelles. Here, micron-sized FDs remain spherical as they indent both the nucleus and peri-nuclear actomyosin, dilute Lamin-B1 locally independent of Lamin-A,C, and trigger rupture with locally persistent accumulation in the nucleus of cGAS, a cytosolic DNA sensor. FD-nucleus interactions initiate rapid mis-localization of the essential DNA repair factor KU80, and nuclear rupture associates with DNA damage and perturbed cell cycle. Similar results are evident in FD-laden cells after constricted 3D-migration, which is impeded by FDs. Spherical shapes of small FDs are consistent with a high {gamma} that we measure for FDs mechanically isolated from fresh adipose tissue as [~]40_mN/m - which is far higher than other liquid condensates, but typical of oils in water and sufficiently rigid to disrupt cell structures.

cell biology↗

bioRxiv2020

Fast recovery of disrupted tip links induced by mechanical displacement of hair bundles

Hearing and balance rely on the capacity of mechanically sensitive hair bundles to transduce vibrations into electrical signals that are forwarded to the brain. Hair bundles possess tip links that interconnect the mechanosensitive stereocilia and convey force to the transduction channels. A dimer of dimers, each of these links comprises two molecules of protocadherin 15 (PCDH15) joined to two of cadherin 23 (CDH23). The "handshake" that conjoins the four molecules can be disrupted in vivo by intense stimulation and in vitro by exposure to Ca2+ chelators. Using hair bundles from the rats cochlea and the bullfrogs sacculus, we observed that extensive recovery of mechanoelectrical transduction, hair-bundle stiffness, and spontaneous bundle oscillation can occur within seconds after Ca2+ chelation, especially if hair bundles are deflected towards their short edges. Investigating the phenomenon in a two-compartment ionic environment that mimics natural conditions, we combined iontophoretic application of a Ca2+ chelator to selectively disrupt the tip links of individual frog hair bundles with displacement clamping to control hair-bundle motion and measure forces. Our observations suggest that, after the normal Ca2+ concentration has been restored, mechanical stimulation facilitates the reconstitution of functional tip links. Significance StatementEach of the sensory receptors responsible for hearing or balance--a hair cell--has a mechanosensitive hair bundle. Mechanical stimuli pull upon molecular filaments--the tip links--that open ionic channels in the hair bundle. Loud sounds can damage hearing by breaking the tip links; recovery by replacement of the constituent proteins then requires several hours. We disrupted the tip links in vitro by removing the calcium ions that stabilize them, then monitored the electrical response or stiffness of hair bundles to determine whether the links could recover. We found that tip links recovered within seconds if their ends were brought back into contact. This form of repair might occur in normal ears to restore sensitivity after damage.

neuroscience↗

bioRxiv2018

Tonotopy of the mammalian cochlea is associated with stiffness and tension gradients of the hair cell’s tip-link complex

Frequency analysis of sound by the cochlea relies on sharp frequency tuning of mechanosensory hair cells along a tonotopic axis. To clarify the underlying biophysical mechanism, we have investigated the micromechanical properties of the hair cells mechanoreceptive hair bundle in the rat cochlea. We studied both inner and outer hair cells, which send nervous signals to the brain and amplify cochlear vibrations, respectively. We find that tonotopy is associated with gradients of stiffness and resting mechanical tension, with steeper gradients for outer hair cells, emphasizing the division of labor between the two hair-cell types. We demonstrate that tension in the tip links that convey force to the mechano-electrical transduction channels increases at reduced Ca2+. Finally, we reveal tonotopic gradients in stiffness and tension at the level of a single tip link. We conclude that intrinsic mechanical gradients of the tip-link complex help specify the characteristic frequency of the hair cell.

biophysics↗