Biology subjects

Narayanan, N.

Publications and source records attributed to Narayanan, N..

25 records · Page 2Linked to original sources

bioRxiv2021

Experience-related remapping of temporal encoding by striatal ensembles.

Temporal control of action is key for a broad range of behaviors and is disrupted in human diseases such as Parkinsons disease and schizophrenia. A brain structure that is critical for temporal control is the dorsal striatum. Experience and learning can influence dorsal striatal neuronal activity, but it is unknown how these neurons change with experience in contexts which require precise temporal control of movement. We investigated this question by recording from medium-spiny neurons (MSNs) in the dorsal striatum of mice as they gained experience controlling their actions in time. We leveraged an interval timing task optimized for mice which required them to "switch" response ports after enough time had passed without receiving a reward. We report three main results. First, we found that time-related ramping activity and response-related activity increased with more experience. Second, temporal decoding by MSN ensembles improved with experience and was predominantly driven by time-related ramping activity. Finally, we found that some MSNs had differential modulation on error trials. These findings enhance our understanding of dorsal striatal temporal processing by demonstrating how MSN ensembles can evolve with experience. Our results can be linked to temporal habituation and illuminate striatal flexibility during interval timing, which may be relevant for human disease.

neuroscience↗

bioRxiv2020

A protease-initiated model of wound detection

Wounds trigger surrounding cells to initiate repair, but it is unclear how cells detect wounds. The first known wound response of epithelial cells is a dramatic increase in cytosolic calcium, which occurs within seconds, but it is not known what initiates this calcium response. Specifically, is there an instructive signal detected by cells surrounding wounds? Here we identify a signal transduction pathway in epithelial cells initiated by the G-protein coupled receptor Methuselah-like 10 (Mthl10) activated around wounds by its cytokine ligands, Growth-blocking peptides (Gbps). Gbps are present in unwounded tissue in latent form, requiring proteolytic activation for signaling. Multiple protease families can activate Gbps, suggesting it acts as a detector to signal the presence of several proteases. We present experimental and computational evidence that proteases released during cell lysis serve as the instructive signal from wounds, liberating Gbp ligands to diffuse to the Mthl10 receptors on epithelial cells and activate downstream release of calcium. Thus, the presence of a nearby wound is signaled by the activation of a Gbp protease detector, sensitive to multiple proteases released after cellular damage.

cell biology↗

bioRxiv2020

PTEN Inhibition Ameliorates Muscle Degeneration and Improves Muscle Function in a Mouse Model of Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD) is caused by mutation of the muscle membrane protein dystrophin and characterized by severe degeneration of myofibers, progressive muscle wasting and loss of mobility, ultimately cardiorespiratory failure and premature death. Here we report that skeletal muscle-specific knockout (KO) of Phosphatase and tensin homolog (Pten) gene in an animal model of DMD (mdx mice) alleviates myofiber degeneration and restores muscle function without increasing tumor incidences. Specifically, Pten KO normalizes myofiber size and prevents muscular atrophy, and improves grip strength and exercise performance of mdx mice. Pten KO also reduces fibrosis and inflammation; and ameliorates muscle pathology in mdx mice. Moreover, we found that Pten KO upregulates extracellular matrix and basement membrane components positively correlated to wound healing, but suppresses negative regulators of wound healing and lipid biosynthesis; and restores the integrity of muscle basement membrane in mdx mice. Importantly, pharmacological inhibition of PTEN similarly ameliorates muscle pathology and improves muscle integrity and function in mdx mice. Our finding provides evidence that PTEN inhibition may represent a potential therapeutic strategy to restore muscle function in DMD.

developmental biology↗

bioRxiv2020

Temporal learning among prefrontal and striatal ensembles

Behavioral flexibility requires the prefrontal cortex and striatum. Here, we investigate neuronal ensembles in the medial frontal cortex (MFC) and the dorsomedial striatum (DMS) during one form of behavioral flexibility: learning a new temporal interval. We studied corticostriatal neuronal activity as rodents trained to respond after a 12-second fixed interval (FI12) learned to respond at a shorter 3-second fixed interval (FI3). On FI12 trials, we discovered time-related ramping was reduced in the MFC but not in the DMS in two-interval vs. one-interval sessions. We also found that more DMS neurons than MFC neurons exhibited differential interval-related activity on the first day of two-interval performance. Finally, MFC and DMS ramping was similar with successive days of two-interval performance but DMS temporal decoding increased on FI3 trials. These data suggest that the MFC and DMS play distinct roles during temporal learning and provide insight into corticostriatal circuits.

neuroscience↗

bioRxiv2019

Frontal theta and beta oscillations during lower-limb movement in Parkinson’s disease

BackgroundMotor and cognitive dysfunction has been linked in patients with Parkinsons disease (PD). EEG theta and beta rhythms are reliably associated with cognitive and motor functions, respectively. We tested the hypothesis that PD patients with lower-limb abnormalities would exhibit abnormal beta and theta rhythms in the mid-frontal region during action initiation.\n\nMethodsWe recruited thirty-nine subjects, including PD patients with FOG (PDFOG+; n=13) and without FOG (PDFOG-; n=13), and demographically-matched healthy subjects (n=13). Scalp electroencephalogram (EEG) signals were collected during a lower-limb pedaling motor task, which required intentional initiation and stopping of a motor movement.\n\nResultsFOG scores were correlated with disease severity and cognition. PDFOG+ patients pedaled with reduced speed and decreased acceleration compared to PDFOG- patients and to controls. PDFOG+ patients exhibited attenuated theta-band (4-8 Hz) power and increased beta-band (13-30 Hz) power at mid-frontal electrode Cz during pedaling. Frontal theta- and beta-band oscillations also correlated with lower-limb movement in PD patients.\n\nConclusionsFrontal theta and beta oscillations are predictors of lower-limb motor symptoms in PD. These data provide insight into the mechanism of lower-limb dysfunction in PD, and could be used to design neuromodulation for PD-related lower-limb abnormalities.

neuroscience↗

bioRxiv2019

Scopolamine and medial frontal stimulus-processing during interval timing

Neurodegenerative diseases such as Parkinsons disease (PD), dementia with Lewy Bodies (DLB), and Alzheimers disease (AD) involve loss of cholinergic neurons in the basal forebrain. Here, we investigate how cholinergic dysfunction impacts the frontal cortex during interval timing, a process that can be impaired in PD and AD patients. Interval timing requires participants to estimate an interval of several seconds by making a motor response, and depends on the medial frontal cortex (MFC), which is richly innervated by basal forebrain cholinergic projections. Past work has shown that scopolamine, a muscarinic cholinergic receptor antagonist, reliably impairs interval timing. We tested the hypothesis that scopolamine would attenuate time-related ramping, a key form of temporal processing in the MFC. We recorded neuronal ensembles from 8 mice during performance of a 12-s fixed-interval timing task, which was impaired by the administration of scopolamine. Consistent with past work, scopolamine impaired timing. To our surprise, we found that time-related ramping was unchanged, but stimulus-related activity was enhanced in the MFC. Principal component analyses revealed no consistent changes in time-related ramping components, but did reveal changes in higher components. Taken together, these data indicate that scopolamine changes stimulus-processing rather than temporal processing in the MFC. These data could help understand how cholinergic dysfunction affects cortical circuits in diseases such as PD, DLB, and AD.\n\nHighlightsO_LIThe cholinergic muscarinic inhibitor scopolamine impairs interval timing behavior.\nC_LIO_LIScopolamine does not change time-related ramping activity in the medial frontal cortex.\nC_LIO_LIMedial prefrontal stimulus-related modulation increased\nC_LI

neuroscience↗

bioRxiv2017

Prefrontal D1 dopamine-receptor neurons and delta resonance in interval timing

Considerable evidence has shown that prefrontal neurons expressing D1-type dopamine receptors (D1DRs) are critical for working memory, flexibility, and timing. This line of work predicts that frontal neurons expressing D1DRs mediate cognitive processing. During timing tasks, one form this cognitive processing might take is time-dependent ramping activity -- monotonic changes in firing rate over time. Thus, we hypothesized the prefrontal D1DR+ neurons would strongly exhibited time-dependent ramping during interval timing. We tested this idea using an interval-timing task in which we used optogenetics to tag D1DR+ neurons in the mouse medial frontal cortex (MFC). While 23% of MFC D1DR+ neurons exhibited ramping, this was significantly less than untagged MFC D1DR+ neurons. By contrast, MFC D1DR+ neurons had strong delta-frequency (1-4 Hz) coherence with other MFC ramping neurons. This coherence was phase-locked to cue onset and was strongest early in the interval. To test the significance of these interactions, we optogenetically stimulated MFC D1DR+ neurons early vs. late in the interval. We found that 2-Hz stimulation early in the interval was particularly effective in rescuing timing-related behavioral performance deficits in dopamine-depleted animals. These findings provide insight into MFC networks and have relevance for disorders such as Parkinsons disease and schizophrenia.\n\nSignificance StatementPrefrontal D1DRs are involved in cognitive processing and cognitive dysfunction in human diseases such as Parkinsons disease and schizophrenia. We use optogenetics to identify these neurons, as well as neurons that are putatively connected to MFC D1DR+ neurons. We study these neurons in detail during an elementary cognitive task. These data could have relevance for cognitive deficits for Parkinsons disease, schizophrenia, and other diseases involving frontal dopamine.

neuroscience↗