Biology subjects

Chehrazi, P.

Publications and source records attributed to Chehrazi, P..

5 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↗

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↗