Biology subjects

Chattopadhyaya, B.

Publications and source records attributed to Chattopadhyaya, B..

10 recordsLinked to original sources

bioRxiv2026

The ovarian cycle and estradiol modulate cortical network state and auditory entrainment in mice and women

The human brain is remarkably dynamic, continuously adapting to internal and external signals across rapid and protracted timescales. While both male and female brains are influenced by sex hormones to drive adaptive behavioural and physiological changes, the ovarian cycle in female mammals represents a conserved naturalistic model to understand how hormones such as estradiol (E2) alter cellular and network states to shape brain function. To understand whether and how the ovarian cycle influences sensory cortical processing, we investigated cortical network activity at rest and upon auditory stimulation across the ovarian cycle in mice and human subjects. We recorded EEG activity in men and women and intracortical local field potentials in male and female mice. Female participants were tested during two phases of their ovarian cycle characterized by low E2 levels (early follicular phase in women; late estrus in mice) and high E2 levels (late follicular phase in women; proestrus in mice). Across species, high endogenous or exogenous estradiol was associated with a steeper aperiodic power spectral slope, indicating decreased excitatory/inhibitory drive and attenuated auditory entrainment following a 40Hz stimulation. At the single-cell level, high E2 selectively increased the baseline and sustained 40-Hz firing of putative fast-spiking interneurons while reducing their temporal coherence during both spontaneous and stimulus-evoked activity, suggesting that E2 enhances inhibitory tone, while disrupting the temporal coordination of inhibitory networks. Altogether, these findings demonstrate that estradiol dynamically modulates cortical network states and auditory responsiveness. This underscores the necessity of investigating hormone-brain coupling as an evolutionarily conserved model essential for yielding translational insights into sex-specific neurobiology.

neuroscience↗

bioRxiv2026

Sensory experience and mTORC1 interplay orchestrates the maturation of cortical interneuron connectivity and tactile sensitivity

Sensory abnormalities are core features of neurodevelopmental disorders, including autism. Although interneuron dysfunction is hypothesized to contribute to these deficits, the underlying mechanisms remain unclear. Here, we demonstrate that mTORC1 dysregulation in parvalbumin-expressing (PV) interneurons drives heightened tactile exploration and defensiveness. These behavioral changes coincide with whisker-evoked cortical responses characterized by increased power but degraded temporal precision. Excitatory inputs to PV cells, their intrinsic excitability and in vivo firing rate during tactile exploration are reduced, suggesting that mutant PV cells are hypoactive. Whisker trimming restricted to the third postnatal week prevented mTORC1 hyperactivation, PV cell input and output connectivity deficits as well as abnormal tactile cortical responses and behavior in adult mutant mice. Further, this manipulation rescued sociability deficits. Altogether, these data suggest that the interplay between mTORC1 signaling and sensory experience in PV cells regulates their connectivity, and contributes to the proper development of tactile and social behavior.

neuroscience↗

bioRxiv2025

Subanesthetic ketamine administration decreases deviance detection responses at the cellular, populational and mesoscale connectivity levels

In the neocortex, neuronal processing of sensory events is significantly influenced by their predictability. A common example is the suppression of responses to repetitive stimuli in sensory cortices, a phenomenon known as habituation. Within a sensory information stream, whenever a novel stimulus deviates from expectations, enhanced brain responses are observed. Mismatch negativity (MMN), the electroencephalographic waveform reflecting rule violations, is a well-established biomarker for auditory deviant detection. MMN has been shown to depend on intact NMDA receptor signaling across species; nevertheless, the underlying mechanisms at the neuronal and mesoscale levels are still not fully understood. Using multi-electrode array recordings in awake mice, we identified a specific biphasic spiking response in a subpopulation of primary auditory cortex (A1) neurons elicited by deviant, but not standard, sounds, wherein the second peak is abolished by acute sub-anesthetic injection of ketamine, a partial non-competitive NMDA receptor antagonist. We further showed that the posterior parietal cortex (PPC), a critical hub for multisensory integration and sensorimotor coordination, responds to deviant, but not repetitive, sounds, and this response is dependent upon intact NMDA receptor-mediated signaling. Finally, to explore the effects of ketamine on inter-cortical communication following deviance detection, we performed Weighted Phase Lag Index (wPLI) analyses during the presentation of deviant and standard sounds. This analysis showed a functional connectivity between A1 and PPC following deviant detection, which is impaired by ketamine administration. Altogether, our findings provide novel insights into the NMDA receptor-dependent mechanisms underlying the processing of novelty in auditory stimuli.

neuroscience↗

bioRxiv2024

Syngap1 regulates the synaptic drive and membrane excitability of Parvalbumin-positive interneurons in mouse auditory cortex

SYNGAP1 haploinsufficiency-related intellectual disability (SYNGAP1-ID) is characterized by moderate to severe ID, generalized epilepsy, autism spectrum disorder, sensory processing dysfunction and other behavioral abnormalities. While numerous studies have highlighted a role of Syngap1 in cortical excitatory neurons development, recent studies suggest that Syngap1 plays a role in GABAergic inhibitory neuron development as well. However, the molecular pathways by which Syngap1 acts on GABAergic neurons, and whether they are similar or different from the mechanisms underlying its effects in excitatory neurons, is unknown. Here, we examined whether, and how, embryonic-onset Syngap1 haploinsufficiency restricted to GABAergic interneurons derived from the medial ganglionic eminence (MGE) impacts their synaptic and intrinsic properties in adult primary auditory cortex (A1). We found that Syngap1 haploinsufficiency significantly affected the intrinsic properties, overall leading to increased firing threshold, and decreased excitatory synaptic drive of Parvalbumin (PV)+ neurons in adult Layer IV A1. Further, the AMPA component of thalamocortical evoked-EPSC was decreased in PV+ cells from mutant mice. Mutant somatostatin (SST)+ interneurons exhibited decreased spontaneous excitatory input and impaired evoked firing without alterations in firing threshold. Finally, we found that the selective blocking of voltage-gated D-type K+ currents was sufficient to rescue PV+ mutant cell-intrinsic properties to wild-type levels. Together, these data suggest that Syngap1 plays a specific role in the maturation of PV+ cell intrinsic properties and synaptic drive, and its haploinsufficiency may lead to reduced PV cell recruitment in the adult A1, which could in turn contribute to the auditory processing alterations found in SYNGAP1-ID preclinical models and patients.

neuroscience↗

bioRxiv2024

p75NTR upregulation following perinatal hypoxia leads to deficits in parvalbumin-expressing GABAergic cell maturation, cortical activity and cognitive abilities in adult mice

Children who experienced moderate perinatal hypoxia are at risk of developing long lasting subtle cognitive and behavioral deficits, including learning disabilities and emotional problems. Understanding the underlying mechanisms is an essential step for designing targeted therapy. Fast-spiking, parvalbumin-positive (PV) GABAergic interneurons modulate the generation of gamma oscillations, which in turn regulate many cognitive functions including goal-directed attentional processing and cognitive flexibility. Due to their fast firing rate, PV cell function requires high levels of energy, which may render them highly vulnerable to conditions of metabolic and oxidative stress caused by perinatal hypoxia. Here, we show that adult mice that experienced moderate perinatal hypoxia (MPH) have decreased cortical PV expression levels in addition to specific impairments in the social, recognition memory and cognitive flexibility domain. We further found that the expression level of the neurotrophin receptor p75NTR, which limits PV cell maturation during the first postnatal weeks, is increased in MPH mice. Genetic deletion of p75NTR in GABAergic neurons expressing the transcription factor Nkx2.1, which include PV cells, protects mice from PV expression loss and the long-term cognitive effects of MPH. Finally, one week treatment with a p75NTR inhibitor starting after MPH completely rescues the cognitive and cortical activity deficits in adult mice. All together this data reveals a potential molecular target for the treatment of the cognitive alterations caused by MPH.

neuroscience↗

bioRxiv2023

p75 neurotrophin receptor in pre-adolescent prefrontal PV interneurons promotes cognitive flexibility in adult mice

Parvalbumin (PV)-positive GABAergic cells provide robust perisomatic inhibition to neighboring pyramidal neurons and regulate brain oscillations. Alterations in PV interneuron connectivity and function in the medial prefrontal cortex (PFC) have been consistently reported in psychiatric disorders associated with cognitive rigidity, suggesting that PV cell deficits could be a core cellular phenotype in these disorders. p75 neurotrophin receptor (p75NTR) regulates the time course of PV cell maturation in a cell-autonomous fashion. Whether p75NTR expression during postnatal development affects adult prefrontal PV cell connectivity and cognitive function is unknown. We generated transgenic mice with conditional knockout (cKO) of p75NTR in postnatal PV cells. We analysed PV cell connectivity and recruitment following a tail pinch, by immunolabeling and confocal imaging, in naive mice or following p75NTR re-expression in pre- or post-adolescent mice using Cre-dependent viral vectors. Cognitive flexibility was evaluated using behavioral tests. PV cell-specific p75NTR deletion increased both PV cell synapse density and the number of PV cells surrounded by perineuronal nets, a marker of mature PV cells, in adult PFC but not visual cortex. Both phenotypes were rescued by viral-mediated re-introduction of p75NTR in pre-adolescent but not in post-adolescent PFC. Prefrontal cortical PV cells failed to upregulated c-Fos following a tail-pinch stimulation in adult cKO mice. Finally, cKO mice showed impaired fear memory extinction learning as well as deficits in a rule set-shifting task. These findings suggest that p75NTR expression in adolescent PV cells contributes to the finetuning of their connectivity and promotes cognitive flexibility in adulthood.

neuroscience↗

bioRxiv2022

Enhancing adult neuroplasticity by epigenetic regulation of Parvalbumin-expressing GABAergic cells

Failure of inhibiting fear in response to harmless stimuli contributes to anxiety disorders. Extinction training only temporarily suppresses fear memories in adults, but it is highly effective in juveniles. GABAergic parvalbumin-positive (PV+) cells restrict plasticity in adult brains, thus increasing PV+ cell plasticity could promote the suppression of fear memories following extinction training in adults. Histone deacetylase 2 (Hdac2) restrains both structural and functional synaptic plasticity; however, whether and how Hdac2 controls adult PV+ cell plasticity is unknown. Here, we report that Hdac2 deletion or pharmacological inhibition in PV+ cells attenuate spontaneous recovery of fear memory after fear extinction learning in adults. These manipulations promote a temporally restricted downregulation of Acan, a critical perineuronal net component expressed exclusively by PV+ cells in medial prefrontal cortex. Finally, we show that Acan transient downregulation before extinction training but after fear memory acquisition is sufficient to reduce spontaneous fear memory recovery in wild-type mice.

neuroscience↗

bioRxiv2021

Sensory processing dysregulations as reliable translational biomarkers in SYNGAP1 haploinsufficiency

Amongst the numerous genes associated with intellectual disability, SYNGAP1 stands out for its frequency and penetrance of loss-of-function variants found in patients, as well as the wide range of co-morbid disorders associated with its mutation. Most studies exploring the pathophysiological alterations caused by Syngap1 haploinsufficiency in mouse models have focused on cognitive problems and epilepsy, however whether and to what extent sensory perception and processing are altered by Syngap1 haploinsufficiency is less clear. By performing EEG recordings in awake mice, we identified specific alterations in multiple aspects of auditory and visual processing, including increased baseline gamma oscillation power, increased theta/gamma phase amplitude coupling following stimulus presentation and abnormal neural entrainment in response to different sensory modality-specific frequencies. We also report lack of habituation to repetitive auditory stimuli and abnormal deviant sound detection. Interestingly, we found that most of these alterations are present in human patients as well, thus making them strong candidates as translational biomarkers of sensory-processing alterations associated with SYNGAP1/Syngap1 haploinsufficiency.

neuroscience↗

bioRxiv2020

Inhibition of mTOR during a postnatal sensitive window rescues deficits in GABAergic PV cell connectivity and social behavior caused by loss of TSC1.

Mutations in regulators of the Mechanistic Target Of Rapamycin Complex 1 (mTORC1), such as Tsc1/2, lead to neurodevelopmental disorders associated with autism, intellectual disabilities and epilepsy. Whereas the effects of mTORC1 signaling dysfunction within diverse cell types are likely critical for the onset of the diverse neurological symptoms associated with mutations in mTORC1 regulators, they are not well understood. In particular, the effects of mTORC1 dys-regulation in specific types of inhibitory interneurons are unclear. Here, we showed that Tsc1 haploinsufficiency in parvalbumin (PV)-positive GABAergic interneurons either in cortical organotypic cultures or in vivo caused a premature increase in their perisomatic innervations, followed by a striking loss in adult mice. This effects were accompanied by alterations of AMPK-dependent autophagy in pre-adolescent but not adult mice. PV cell-restricted Tsc1 mutant mice showed deficits in social behavior. Treatment with the mTOR inhibitor Rapamycin restricted to the third postnatal week was sufficient to permanently rescue deficits in both PV cell innervation and social behavior in adult conditional haploinsufficient mice. All together, these findings identify a novel role of Tsc1-mTORC1 signaling in the regulation of the developmental time course and maintenance of cortical PV cell connectivity and provide a mechanistic basis for the targeted rescue of autism-related behaviors in disorders associated with deregulated mTORC1 signaling.

neuroscience↗

bioRxiv2018

p75 Neurotrophin Receptor Regulates the Timing of the Maturation of Cortical Parvalbumin Cell Connectivity and Promotes Ocular Dominance Plasticity in Adult Visual Cortex.

By virtue of their extensive axonal arborisation and perisomatic synaptic targeting, cortical inhibitory Parvalbumin (PV) cells strongly regulate principal cell output and plasticity. An interesting aspect of PV cell connectivity is its prolonged maturation time course, which is completed only by end of adolescence. The p75 neurotrophin receptor (p75NTR) regulates a wide range of cellular function, including apoptosis, neuronal process remodeling and synaptic plasticity, however its role on cortical circuit development is still not well understood, mainly because localizing p75NTR expression with cellular and temporal resolution has, so far, been challenging.\n\nUsing RNAscope and a modified version of the Proximity Ligation Assay (PLA), we show that p75NTR mRNA and protein are expressed in cortical PV cells in the postnatal and adult brain. Further, p75NTR expression in PV cells decreases between postnatal day (P)14 and P26, at a time when PV cell synapse numbers increase dramatically. Conditional knockout of p75NTR in single PV neurons in cortical organotypic cultures and in PV cell networks in vivo leads to precocious formation of PV cell perisomatic innervation and perineural nets around PV cell somata, suggesting that p75NTR expression controls the timing of the maturation of PV cell connectivity in the adolescent cortex.\n\nRemarkably, we found that p75NTR is still expressed, albeit at low level, in PV cells in adult cortex. Interestingly, activation of p75NTR onto PV cells in adult visual cortex in vivo is sufficient to destabilize their connectivity and to reintroduce juvenile-like cortical plasticity following monocular deprivation. Altogether, our results show that p75NTR activation dynamically regulates PV cell connectivity, and represents a novel tool to foster brain plasticity in adults.

neuroscience↗