Biology subjects

Rajan, G.

Publications and source records attributed to Rajan, G..

7 recordsLinked to original sources

bioRxiv2026

SERCA2b loss of function drives pigmentation by inducing adaptive ER stress and enhancing mitochondrial calcium uptake: significance in pathological hyperpigmentation associated with Darier’s Disease

Pigmentation is a critical protective mechanism that safeguards the skin against UV-induced damage, whereas dysregulated pigmentation predisposes to pigmentary disorders and skin malignancies. Although calcium signaling has emerged as an important regulator of melanogenesis, the identity of the calcium-handling proteins and the molecular mechanisms linking calcium dynamics to pigmentation remain poorly understood. Here, we identify the ER calcium pump SERCA2b as a negative regulator of pigmentation through modulation of ER stress and mitochondrial calcium uptake. We demonstrate that SERCA2b expression inversely correlates with pigmentation levels, and gain- and loss-of-function studies establish SERCA2b as a suppressor of melanogenesis. Mechanistically, SERCA2b depletion induces adaptive ER stress, enhances ER-mitochondrial proximity, and promotes mitochondrial calcium uptake. Notably, mutations in SERCA2b are associated with Darier disease, a condition characterized by hyperpigmented skin lesions, although the underlying mechanism remains unknown. To address this, we generated SERCA2b mutants corresponding to variants identified in Indian Dariers disease patients and examined their effects on pigmentation, ER stress, and mitochondrial calcium dynamics. The mutant phenotypes closely recapitulated SERCA2b loss-of-function effects, demonstrating that adaptive ER stress and enhanced mitochondrial calcium signaling underlie hyperpigmentation associated with Dariers disease. Importantly, treatment with 4-phenylbutyrate (4-PBA), an FDA-approved ER stress alleviator, rescued mutant-induced hyperpigmentation, reduced ER stress, and normalized mitochondrial calcium uptake. Collectively, our findings uncover a previously unrecognized role of SERCA2b in skin pigmentation, establish a mechanistic link between SERCA2b mutations and hyperpigmentation, and identify adaptive ER stress pathways as potential therapeutic target for pigmentary disorders.

Cell Biology↗

bioRxiv2022

Event-Related Potentials of Single Sided Deaf Cochlear Implant Users - Using a Semantic Oddball Paradigm in Noise

ObjectiveIn individuals with single sided deafness (SSD), which is characterised by a profound hearing loss in one ear and normal hearing in the contralateral ear, binaural input is no longer present. A cochlear implant (CI) is the only way to restore functional hearing in the profoundly deaf ear, with previous literature demonstrating improvements in speech in noise intelligibility with the provision of a CI. However, we currently have a limited understanding of the neural processes involved (e.g., how the brain integrates the electrical signal produced by the CI with the acoustic signal produced by the normal hearing ear) and how the modulation of these processes with CI contributes to improved speech in noise intelligibility. Using a semantic oddball paradigm presented in the presence of background noise, this study aims to investigate how the provision of CI impacts speech in noise perception of SSD CI users. MethodHigh density electroencephalography (EEG) from twelve SSD-CI participants was recorded whilst they completed a semantic acoustic oddball task. All participants completed the oddball task in three different free field conditions with the speech and noise coming from different speakers. The three tasks were 1) with the CI-On in background noise, 2) with the CI-Off in background noise and 3) with the CI-On without background noise (Control). We examined task-performance (RT, subjective listening effort, and accuracy) and measured N2N4 and P3b event-related brain potentials (ERPs) linked to the discrimination and evaluation of task relevant stimuli. Speech in noise and sound localisation abilities was also measured. ResultsReaction time was significantly different between all tasks with CI-On (M(SE) = 809(39.9) ms) having faster RTs than CI-Off (M(SE) = 845(39.9) ms) and Control (M(SE) = 785(39.9) ms) being the fastest condition. The Control condition exhibited a significantly shorter N2N4 and P3b area latency when compared to the other two conditions. However, despite these differences noticed in RTs and area latency, we observed similar results between all three conditions for N2N4 and P3b difference area. ConclusionThe inconsistency between the behavioural and neural results suggest that EEG may not be a reliable measure of cognitive effort. This rationale is further supported by the different explanations used in past studies to explain N2N4 and P3b effects. Future studies should look to alternative measures of auditory processing (e.g., pupillometry) to get a deeper understanding of the underlying auditory processes that facilitate speech in noise intelligibility.

neuroscience↗

bioRxiv2022

Odd-Even Oddball Task: Evaluating Event-Related Potentials (ERPs) during Word Discrimination Compared to Speech-Token and Tone Discrimination.

The use of tonal and speech token auditory oddball tasks has been used abundantly in past literature; however, it has been argued that tasks using non-word sounds fail to capture the higher-level ability to interpret and discriminate stimuli based on meaning which are critical to language comprehension. As such this study aims to examine how neural signals associated with discrimination and evaluation-processes (P3b) from semantic stimuli compare with those elicited by pure tones and speech tokens. This study comprises of two experiments, both containing thirteen adults (Exp 1: (Mean(SD)age = 25.20(3.89) years and Exp 2: Mean(SD)age = 25.3(3.79) years) with normal hearing in both ears (PTA [≤] 20dB HL). Scalp electroencephalography and auditory event related potentials was recorded in free field whilst they completed three different oddball tasks: 1) Tones, 2) Speech tokens and 3) Odd/Even numbers. In experiment two, the duration of each stimulus was the same. P3b peak latency was significantly different between all three tasks, in both experiments. P3b amplitude was identified to be sensitive to reaction time, with tasks that have a large reaction time variability resulting in the P3b amplitude to be smeared out, thereby reducing the amplitude size. The findings from this study highlight the need to take into consideration all factors of the task before attributing any effects to any additional process such as semantic processing and mental effort. Furthermore, it highlights the need for more cautious interpretation of P3b results in auditory oddball tasks.

neuroscience↗

bioRxiv2022

A Study of Event-Related Potentials during Monaural and Bilateral Hearing in Single Sided Deaf Cochlear Implant Users

ObjectiveSingle sided deafness (SSD) is characterized by a profoundly deaf ear and normal hearing in the contralateral ear. A cochlear implant (CI) is the only method to restore functional hearing in a profoundly deaf ear. In a previous study, we identified that the cortical processing of a CI signal differs from the normal hearing ear (NHE) when directly compared using an auditory oddball paradigms consisting of pure tones. However, it is unclear how the electrical and acoustic signals from each ear are combined. This study aims to understand how the provision of the CI in combination with the NHE may improve SSD CI users ability to discriminate and evaluate auditory stimuli. DesignElectroencephalography (EEG) from ten SSD-CI participants (four participated in the previous pure-tone study) were recorded during a semantic acoustic oddball task, where they were required to discriminate between odd and even numbers. Stimuli were presented in four hearing conditions: directly through the CI, directly to the NHE, or in free field with the CI switched on and off. We examined task-performance (response time and accuracy) and measured N1, P2, N2N4 and P3b event-related brain potentials (ERPs) linked to the detection, discrimination, and evaluation of task relevant stimuli. Sound localization and speech in noise comprehension was also examined. ResultsIn direct presentation, task performance was superior during NHE compared to CI (Shorter and less varied RTs [[~]720 vs. [~]842 ms], higher target accuracy [[~]93 vs. [~]70%]) and early neural responses (N1 and P2) were enhanced for NHE suggesting greater signal saliency. However, the size of N2N4 and P3b target-standard effects did not differ significantly between NHE and CI. In free field, target accuracy was similarly high for both FF-on and -off ([~]95%), with some evidence of CI interference during FF-on (more variable and slightly but significantly delayed RTs [[~]737 vs. [~]709 ms]). Early neural responses and late effects were also greater during FF-on. Performance on sound localization and speech in noise comprehension (SCINNHE configuration only) was significantly greater during CI-on. ConclusionBoth behavioral and neural responses in the semantic oddball task were sensitive to CI in both direct and free-field presentations. Direct conditions revealed that participants could perform the task with the CI alone, although performance was sub-optimal and early neural responses was reduced when compared to the NHE. For free-field, the addition of the CI was associated with enhanced early and later neural responses but did not improved task performance. Enhanced neural responses show that the additional input from the CI is modulating relevant perceptual and cognitive processes, but the benefit of binaural hearing on behavior may not be realized in simple oddball tasks which can be adequately performed with the NHE. Future studies interested in binaural hearing should examine performance under noisy conditions and/or employ spatial cues to allow headroom for the measurement of binaural benefit.

neuroscience↗

bioRxiv2022

The Adaptor Protein 2 (AP2) complex modulates habituation and behavioral selection across multiple pathways and time windows

Animals constantly perceive and integrate information across sensory modalities, and their nervous systems must select behavioral responses appropriate to the current situation and prior experience. Genetic factors supporting this behavioral flexibility are often disrupted in neuropsychiatric conditions, and our previous work revealed the disease-associated ap2s1 gene critically supports habituation learning in acoustically-evoked escape behavior of zebrafish. ap2s1 encodes a subunit of the AP2 endocytosis adaptor complex and has been linked to autism spectrum disorder, though its mechanism and direct behavioral importance have not been established. Here, we show that multiple subunits of the AP2 complex regulate acoustically-evoked behavior selection and habituation learning. Furthermore, ap2s1 biases the choice between distinct escape behaviors in sensory modality-specific manners, and more broadly regulates action selection across different sensory contexts. Using tissue-specific and inducible transgenic rescue, we demonstrate that the AP2 complex functions acutely and in the nervous system to modulate acoustically-evoked habituation learning, suggesting several spatially and/or temporally distinct mechanisms through which AP2 regulates different aspects of escape behavior selection and performance. Altogether, we demonstrate that the AP2 complex coordinates action selection across stimulus modalities and contexts, providing a new vertebrate model for the role of ap2s1 in human conditions including autism spectrum disorder. SIGNIFICANCE STATEMENTThe AP2S1 gene has been linked to learning disabilities and autism spectrum disorders (ASD), though the mechanisms underlying its impact on human behavior are unknown. We explored how, when, and where this gene regulates vertebrate behavior, developing a zebrafish model to identify the roles and mechanisms through which ap2s1 modulates behavior. We find that ap2s1 regulates simple acoustically-evoked learning, as well as how individuals bias behavioral choice in a wide variety of contexts. We show that ap2s1 acts at multiple distinct time periods and locations both within and outside of neuronal tissues, revealing the diverse mechanisms and pathways through which it modulates vertebrate behavior.

neuroscience↗

bioRxiv2021

Evolutionary divergence of locomotion in two related vertebrate species

Locomotion exists in diverse forms in nature and is adapted to the environmental constraints of each species1. However, little is known about how closely related species with similar neuronal circuitry can evolve different navigational strategies to explore their environments. We established a powerful approach in comparative neuroethology to investigate evolution of neuronal circuits in vertebrates by comparing divergent swimming pattern of two closely related larval fish species, Danionella translucida (DT) and Danio rerio or zebrafish (ZF)2,3. During swimming, we demonstrate that DT utilizes lower half tail-beat frequency and amplitude to generate a slower and continuous swimming pattern when compared to the burst-and-glide swimming pattern in ZF. We found a high degree of conservation in the brain anatomy between the two species. However, we revealed that the activity of a higher motor region, referred here as the Mesencephalic Locomotion Maintenance Neurons (MLMN) correlates with the duration of swim events and differs strikingly between DT and ZF. Using holographic stimulation, we show that the activation of the MLMN is sufficient to increase the frequency and duration of swim events in ZF. Moreover, we propose two characteristics, availability of dissolved oxygen and timing of swim bladder inflation, which drive the observed differences in the swim pattern. Our findings uncover the neuronal circuit substrate underlying the evolutionary divergence of navigational strategies and how they are adapted to their respective environmental constraints.

neuroscience↗

bioRxiv2019

An NMDA-R mediated short-term memory resistant to anesthesia in adult Danio rerio

Memory in animals is labile in the early phase post-training. Memory in the early phase has been shown to be disrupted by treatments such as electroconvulsive shock or cold-shock (Quinn and Dudai, 1976). Using hypothermic shock and other pharmacological interventions, the various underlying memory pathways in Drosophila can be identified as an immediate short-lasting anesthesia sensitive memory and a delayed anesthesia resistant memory which is followed by a more stable protein synthesis dependent long-term memory (Margulies et al., 2005). In another ectothermic animal, Danio rerio, a popular vertebrate model, we ask if such a memory component exists which is sensitive to hypothermic disruption. To test this, we developed a fear conditioning assay with a green light at the bottom of the tank as the conditioned stimulus (CS) and electric shock as the unconditioned stimulus (US). We also standardized a cold anesthesia protocol in adult zebrafish to induce stage V anesthesia. The learning/memory was found to be NMDA-R mediated. Cold anesthesia as well as tricaine mediated anesthesia did not significantly affect the early-acting memory trace induced by a fear-conditioning protocol in adult zebrafish. We suggest future directions to tease out the underlying memory components in the early phase of memory in zebrafish.

neuroscience↗