Biology subjects

Lefton, K. B.

Publications and source records attributed to Lefton, K. B..

4 recordsLinked to original sources

bioRxiv2026

Astrocytes mediate the pro-cognitive value of α7nAChRs and of α7nAChR-targeting therapeutics

The 7-nicotinic acetylcholine receptor (7nAChR) has driven extensive research over the past three decades for its pro-cognitive potential. It is the leading druggable target for the cognitive deficits associated with schizophrenia and has motivated major pharmaceutical and clinical efforts to ameliorate similar impairments in other neurological disorders, such as Alzheimers disease (AD). Yet, a systematic evaluation of the role played by 7nAChR in cognition, and its mechanistic underpinnings, is still lacking. Here we report that 7nAChRs on principal and inhibitory forebrain neurons are largely inconsequential to mouse behavior, including in domains that are most sensitive to schizophrenia-related cognitive impairments. By contrast, loss of 7nAChR from astrocytes produces profound behavioral alterations that are cognitive domain-specific, are time-of-day dependent, coincide with reduced levels of the N-methyl D-aspartate receptor (NMDAR) co-agonist D-serine, and are fully restored by D-serine supplementation. Further, an 7nAChR partial agonist previously evaluated in Phase III trials for cognitive enhancement in schizophrenia and AD fails to augment behavior in mice lacking astrocytic 7nAChRs. Together, these findings identify astrocytes and D-serine/NMDAR signaling as a central mechanism through which 7nAChR, a major drug target, promotes cognitive behavior.

neuroscience↗

bioRxiv2024

At the onset of active whisking, the input layer of barrel cortex exhibits a 24 h window of increased excitability that depends on prior experience.

The development of motor control over sensory organs is a critical milestone, enabling active explo-ration and shaping of the sensory environment. Whether the onset of sensory organ motor control directly influences the development of corresponding sensory cortices remains unknown. Here, we confirm and exploit the late onset of whisking behavior in mice to address this question in the somatosensory system. Using ex vivo electrophysiology, we describe a transient increase in the intrinsic excitability of excitatory neurons in layer IV of the barrel cortex, which processes whisker input, immediately following the onset of active whisking around on postnatal days 13 and 14. This increase in neuronal gain is specific to layer IV, independent of changes in synaptic strength, and requires prior sensory experience. Further, these effects are not expressed in inhibitory in-terneurons in barrel cortex. The transient increase in excitability is not evident in layer II/III of barrel cortex or in the visual cortex upon eye opening, suggesting a unique interaction between the development of active sensing and the thalamocortical input layer in the somatosensory iso-cortex. Predictive modeling indicates that, immediately following the onset of active whisking, changes in active membrane conductances alone can reliably distinguish neurons in control but not whisker-deprived hemispheres. Our findings demonstrate an experience-dependent, lamina-specific refinement of neuronal excitability tightly linked to the emergence of active whisking. This tran-sient increase in the gain of the thalamic input layer coincides with a critical period for synaptic plasticity in downstream layers, suggesting a role in cortical maturation and sensory processing.

neuroscience↗

bioRxiv2024

Norepinephrine Signals Through Astrocytes To Modulate Synapses

AbstractLocus coeruleus (LC)-derived norepinephrine (NE) drives network and behavioral adaptations to environmental saliencies by reconfiguring circuit connectivity, but the underlying synapse-level mechanisms are elusive. Here, we show that NE remodeling of synaptic function is independent from its binding on neuronal receptors. Instead, astrocytic adrenergic receptors and Ca2+ dynamics fully gate the effect of NE on synapses as the astrocyte-specific deletion of adrenergic receptors and three independent astrocyte-silencing approaches all render synapses insensitive to NE. Additionally, we find that NE suppression of synaptic strength results from an ATP-derived and adenosine A1 receptor-mediated control of presynaptic efficacy. An accompanying study from Chen et al. reveals the existence of an analogous pathway in the larval zebrafish and highlights its importance to behavioral state transitions. Together, these findings fuel a new model wherein astrocytes are a core component of neuromodulatory systems and the circuit effector through which norepinephrine produces network and behavioral adaptations, challenging an 80-year-old status quo.

neuroscience↗

bioRxiv2024

STARDUST: a pipeline for the unbiased analysis of astrocyte regional calcium dynamics

Calcium imaging has become a popular way to probe astrocyte activity, but few analysis methods holistically capture discrete calcium signals that occur across the astrocyte domain. Here, we introduce STARDUST, a pipeline for the Spatio-Temporal Analysis of Regional Dynamics & Unbiased Sorting of Transients from fluorescence recordings of astrocytes, and provide step-by-step guidelines. STARDUST yields fluorescence time- series from data-defined regions of activity and performs systematic signal detection and feature extraction, enabling the in-depth and unbiased study of astrocyte calcium signals. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/588196v2_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@c6a97aorg.highwire.dtl.DTLVardef@a0b0fdorg.highwire.dtl.DTLVardef@1c3dd73org.highwire.dtl.DTLVardef@1ffa9ec_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗