Biology subjects

Krishnaswamy, A.

Publications and source records attributed to Krishnaswamy, A..

8 recordsLinked to original sources

bioRxiv2026

Intrinsic Ionic Mechanisms Underlying Burst Firing in Spontaneously Active Dorsal Horn Parvalbumin Interneurons

Parvalbumin-expressing interneurons (PVINs) in the spinal dorsal horn play a key role in preventing touch inputs from engaging nociceptive pathways through fast inhibitory control. Although most PVINs are typically quiescent and require external input to fire, a subset of these neurons exhibits spontaneous activity, including isolated spikes and bursts. The mechanisms underlying this behavior in spontaneously active PVINs (spPVINs) remain unclear. To address this, we developed a stochastic two-compartment Hodgkin-Huxley (HH) type model, consisting of a soma and an axon initial segment (AIS), to investigate the effects of synaptic noise and intrinsic electrical properties of spPVINs in driving their spontaneous firing. The model incorporates two subthreshold currents: the M-type K+ current (Im) and the hyperpolarization-activated current (Ih). The model revealed that, in the presence of Ornstein-Uhlenbeck noise, Ih promotes spontaneous firing by enhancing noise-driven depolarizations. Model simulations closely reproduced the firing patterns of spPVINs observed experimentally, including irregular spiking and bursting. Bifurcation analysis showed that varying the applied current can lead to transitions between quiescent, tonic, and elliptic bursting regimes, allowing stochastic fluctuations to switch between these states, which gives rise to irregular spontaneous activity. Reducing the conductance of Im and increasing the conductance of the fast Na+ current (INa) both enlarge the elliptic bursting regime, thereby enabling noise to promote bursting. Interestingly, when the model was incorporated into a circuit, the downstream inhibitory effects of spPVINs were enhanced by the expression of Ih. Taken together, these results demonstrate how intrinsic electrical properties of spPVINs shape their firing dynamics and circuit activity.

neuroscience↗

bioRxiv2026

Astrocytic FMRP regulates the function of spinal parvalbumin-expressing neurons in Fragile X Syndrome

Tactile hypersensitivity is a common symptom of Fragile X Syndrome (FXS) characterized by over-responsiveness to innocuous touch or textures. Yet, the neural circuitry underlying this altered sensory processing remains incompletely understood. Previous studies have focused on cortical and peripheral neuron dysfunction. However, the spinal dorsal horn circuits, which make up the first central site of somatosensory integration, also comprises elements that could contribute to the hypersensitivity to innocuous stimuli, yet its involvement in this pathology has remained incompletely understood. Here, we show that spinal parvalbumin (PV)-expressing interneurons (PVNs), an inhibitory population that gates touch sensory input from activating nociceptive pathways, are dysfunctional in FXS. Using a mouse model of FXS (global Fmr1 knockout; gKO), we showed that dorsal horn PVNs exhibit impaired function characterized by reduced PV expression and inability to sustain tonic firing. To determine whether these deficits arise through cell-intrinsic mechanisms, we selectively deleted Fmr1 in PVNs. This deletion failed to reproduce the molecular and electrophysiological changes observed in the gKO mice. In contrast, astrocyte-specific deletion of Fmr1 recapitulated key features of the gKO mice, including decreased PV expression and firing. To understand the biophysical basis of this firing deficit, we simulated spinal PVNs using conductance-based Hodgkin-Huxley type modelling. Surprisingly, modifying intrinsic membrane conductances alone was insufficient to account for the experimental data. In fact, PVN firing required incorporation of an additional calcium-dependent extrinsic synaptic component consistent with the experimental finding that astrocytic, but not PVN-specific, loss of FMRP reproduced the PVN phenotype in gKO mice. Together, these findings show that these deficits in spinal PVNs arise primarily from loss of FMRP in astrocytes rather than in PVNs themselves. It reveals astrocyte-dependent dysfunction of dorsal horn inhibitory circuits as a previously uncharacterized consequence of FXS.

neuroscience↗

bioRxiv2026

TRACR: an anterograde transneuronal tracing system for genetic access across synapses and longitudinal circuit analysis

Following neural signals as they converge onto and diverge from individual neurons is central to understanding circuit function and disease-related dysfunction. Existing anterograde transneuronal tracers are limited by cytotoxicity and incomplete genetic control over connected partners. To address these limitations, we adapted synthetic Notch designs to create TRanssynaptic Anterograde Circuit Readout (TRACR). Binding of the engineered ligand-receptor across synapses induces TRE-driven reporter transcription, enabling characterization of postsynaptic neurons. TRACR provides segregated genetic access to pre- and postsynaptic populations, and can be combined with markers, sensors, or effectors to expand circuit analysis. By applying TRACR at multiple synapses in the mouse visual system, we show that TRACR labels postsynaptic partners of sensory neurons, long-range projections and local inhibitory interneurons. TRACR signaling is reversible and fails to activate when synapses are absent or disrupted. Together, TRACR is an accessible, AAV-deliverable transneuronal reporting tool for longitudinal analysis of circuit assembly, degeneration, and repair. HIGHLIGHTSO_LITRACR adapts the synNotch system to signal across synapses for tracing postsynaptic targets. C_LIO_LITRACR identifies local and long-range postsynaptic targets in the mouse visual system. C_LIO_LITRACR activation requires intact synaptic connectivity rather than proximity. C_LIO_LITRACR signals are reversible, diminishing upon synapse loss and activating following assembly. C_LI

neuroscience↗

bioRxiv2025

Visual field specializations in mouse dLGN

Neural circuits throughout the visual system process features differently depending on where they appear in the visual field. While such location-specific processing exists in retina and in superior colliculus, the dorsal lateral geniculate nucleus (dLGN) is thought to lack this specialization. Here, we show systematic visual field biases in dLGNs representation of spatial frequency, orientation, direction, and temporal frequency. Using axon-localized calcium indicators and widefield imaging, we discovered that dLGN boutons show systematic gradients in feature selectivity across the visual cortex (V1), while its retinal inputs lack such gradients for these features. Selective disruption of V1 feedback to dLGN perturbed gradient structure and magnitude. These results suggest that dLGN circuits transform uniformly distributed retinal feature inputs into spatially-biased representations along with cortical feedback. dLGN feature biases would allow a functional stream to detect ethologically salient visual inputs.

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bioRxiv2024

Serotonergic neurons in the dorsal raphe regulate visual attention

Visual attention enhances the neural representation of salient stimuli within the visual cortex. It is generally thought that this enhancement is driven by glutamatergic feedback from frontal cortical areas. Here we report the unexpected observation that dorsal raphe (DR) derived serotonin (5HT) controls visual attention. We developed a behavioral model that captured the way mice allocated attention to cued and uncued visual locations and features. Simultaneous photometry showed reduced DR activity when mice deployed attention to the cued locations and features, whereas high DR activity was observed when mice were less attentive. Optogenetic excitation of DR-5HT neurons impaired attention to the cue and degraded behavioral performance, while optogenetic suppression improved attention and performance. A genetically encoded sensor of 5HT release showed reduced 5HT levels in visual cortex when mice attend and detect stimuli. These results demonstrate that DR-5HT neurons are members of the brains attentional circuit and suggest that 5HT is a novel biological carrier of visual attention.

neuroscience↗

bioRxiv2024

Cadherin 4 assembles a family of color-selective retinal circuits that respond to light offset.

Retinal interneurons and projection neurons (retinal ganglion cells, RGCs) connect in specific combinations in a specialized neuropil called the inner plexiform layer (IPL). The IPL is divided into multiple sublaminae, with neurites of each neuronal type confined to one or a few layers. This laminar specificity is a major determinant of circuit specificity and circuit function. Using a combination of approaches we show that RGCs targeting IPL sublamina 1 and 3a express the adhesion molecule cadherin 4 (Cdh4). Using calcium imaging and iterative immunostaining, we classified Cdh4-RGCs into 9 types that each encode unique aspects of dark visual stimuli. Cdh4 loss selectively disrupted the layer- targeting of these RGCs, reduced their synaptic inputs from interneurons, and severely altered their visual responses. Overexpression of Cdh4 in other retinal neurons directed their neurites to s1-3a through homophilic interactions. Taken together, these results demonstrate that Cdh4 is a novel layer targeting system for nearly a third of all RGC.

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bioRxiv2022

Probing visual sensitivity and attention in mice using reverse correlation

Visual attention is a fundamental cognitive operation that allows the brain to evoke behaviors based on the most important stimulus features. Although mouse models offer immense potential to gain a circuit-level understanding of this phenomenon, links between visual attention and behavioral decisions in mice are not well understood. Here, we describe a new behavioral task for mice that addresses this limitation. We trained mice to detect weak vertical bars in a background of checkerboard noise while audiovisual cues manipulated their spatial attention. We then modified a reverse correlation method from human studies to link behavioral decisions to stimulus locations and features. We show that mice attended to stimulus locations just rostral of their optical axis, which was highly sensitive for vertically oriented stimulus energy whose spatial frequency matched those of the weak vertical bars. We found that the tuning of sensitivity to orientation and spatial frequency grew stronger during training, was multiplicatively scaled with attention, and approached that of an ideal observer. These results provide a new task to measure spatial- and feature-based attention in mice which can be leveraged with new recording methods to uncover attentional circuits.

neuroscience↗

bioRxiv2021

The cell adhesion molecule Sdk1 shapes assembly of a retinal circuit that detects localized edges.

Nearly 50 different mouse retinal ganglion cell (RGC) types sample the visual scene for distinct features. RGC feature selectivity arises from its synapses with a specific subset of amacrine (AC) and bipolar cell (BC) types, but how RGC dendrites arborize and collect input from these specific subsets remains poorly understood. Here we examine the hypothesis that RGCs employ molecular recognition systems to meet this challenge. By combining calcium imaging and type-specific histological stains we define a family of circuits that express the recognition molecule Sidekick 1 (Sdk1) which include a novel RGC type (S1-RGC) that responds to local edges. Genetic and physiological studies revealed that Sdk1 loss selectively disrupts S1-RGC visual responses which result from a loss of excitatory and inhibitory inputs and selective dendritic deficits on this neuron. We conclude that Sdk1 shapes dendrite growth and wiring to help S1-RGCs become feature selective.

neuroscience↗