Biology subjects

Lelievre, V.

Publications and source records attributed to Lelievre, V..

3 recordsLinked to original sources

bioRxiv2026

Maternal behavioral compensation after neonatal separation fails to prevent spinal circuit reprogramming in offspring

Early-life adversity durably alters neural development through complex mother-offspring interactions whose underlying mechanisms remain poorly understood. We investigated how neonatal maternal separation (NMS) affects the large repertoire of maternal behaviors and subsequently influences spinal nociceptive circuit development and pain responses in rat offspring. Rat dams underwent NMS from postnatal day 2 (P2) to P12, 3h/day, and maternal behaviors were assessed before and after the separation period. These behaviors were compared to those of control (non-separated) dams. Offspring spinal cord and dorsal root ganglia were analyzed at P14 and P24 for several neurotrophic, glutamatergic, and GABAergic gene expression patterns. Offspring nociceptive sensitivity was also assessed at P24. NMS induced increased maternal behaviors (including longer arched-back nursing, higher nest occupancy, and better pup retrieval efficiency), alongside reduced self-care behaviors. These behavioral adaptations were correlated with spinal gene reprogramming in offspring, characterized by a biphasic developmental pattern. At P14, we observed elevated neurotrophic signaling alongside increased GABAergic and glutamatergic markers. By P24, neurotrophic factors decreased while compensatory changes emerged, yet persistent excitatory-inhibitory imbalances remained evident. Parallel to these results, NMS rats also showed mechanical and thermal hot hypersensitivity at P24. These findings reveal that despite apparent maternal behavioral compensation following NMS, offspring exhibit neurotrophic-driven developmental dysregulation resulting in persistent spinal circuit alterations. The disconnect between maternal behavioral normalization and sustained molecular changes suggests that early separation stress triggers enduring neurobiological cascades independent of ongoing maternal care quantity, with long-term consequences for sensory processing and pain sensitivity. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/736384v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1769b63org.highwire.dtl.DTLVardef@1d396dforg.highwire.dtl.DTLVardef@5647eeorg.highwire.dtl.DTLVardef@8c8db8_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

Neonatal oxytocin prevents sex-specific spatial memory deficits induced by maternal separation through restoration of hippocampal synaptic plasticity in males

BackgroundStress during critical developmental periods causes lasting neurobiological alterations. Rodent models like neonatal maternal separation (NMS) induce cognitive alterations, particularly spatial memory deficits. Oxytocin (OT) system has been suggested to underlie these consequences, as it is critical for neurodevelopment. This neuropeptide also promotes maternal nurturing, prevents neuroinflammation and displays anxiolytic properties. This study hypothesized that early postnatal OT administration could prevent NMS-induced memory alterations in adult rats. MethodsSprague-Dawley rat pups (both sexes, n=8-12/group) underwent NMS with concomitant intraperitoneal OT injections. At adulthood, novel object recognition and object location tasks were performed. Further investigation was conducted through ex vivo electrophysiological recordings of functional plasticity at Schaffer collateral-CA1 synapses (male, n=7-12/group), alongside RT-qPCR of synaptic, GABAergic, neuro-inflammatory, and oxytocin receptor markers in dorsal CA1 (male, n=4-6/group). ResultsNMS induced male-specific spatial memory impairment without affecting recognition memory. Early OT completely prevented spatial memory deficits in NMS males. Electrophysiological recordings revealed that NMS suppressed CA1 long-term potentiation (LTP), and neonatal OT restored it. NMS induced transcript overexpression of neuro-inflammatory markers, GABAergic markers, and synaptic proteins in dorsal CA1. OT treatment normalized or reduced these mRNA expressions, consistent with restoration of CA1 synaptic function. ConclusionEarly postnatal OT prevents NMS-induced spatial memory deficits and hippocampal LTP impairments in male rats, which is associated with normalized or reduced neuro-inflammatory and GABAergic transcript expressions. These findings establish exogenous oxytocin administration during a critical neonatal window as sufficient to prevent male-specific hippocampal dysfunction and cognitive deficits induced by early-life stress, identifying the oxytocinergic system as a promising target for early neuroprotective interventions.

neuroscience↗

bioRxiv2026

Oxytocin receptor dysfunction during neurodevelopment programs lasting pain hypersensitivity and sex-specific cognitive deficits

Early life stress (ELS), modeled in rodents through neonatal maternal separation (NMS), induces lasting behavioral and molecular alterations including pain hypersensitivity, anxiety-like behaviors, and cognitive deficits. While NMS disrupts the oxytocinergic system, the specific contribution of oxytocin receptor (OTR) dysfunction during critical neurodevelopmental periods remains unclear. Here, we investigated whether neonatal OTR blockade alone could recapitulate key features of the NMS phenotype. Control rats received daily injections of the selective OTR antagonist d(CH2)5-Tyr(Me)-[Orn8]-vasotocin (dOVT) during postnatal days 2-12, matching the NMS period. At adulthood, behavioral assessments revealed that control+dOVT animals exhibited mechanical and cold thermal hypersensitivity similar to NMS rats, though hot thermal sensitivity was unaffected. Anxiety-like behaviors observed in NMS animals were not reproduced by dOVT treatment. Notably, sex-specific spatial memory deficits emerged: male NMS and female control+dOVT rats showed impaired object location recognition, while females and males in their respective opposite groups remained unaffected. Molecular analyses of spinal cord tissue revealed significant downregulation of GAD65, BDNF, and CD11b in control+dOVT animals. Chloride cotransporters NKCC1 and KCC2 exhibited sexual dimorphism with opposite changes in NMS males versus females and different responses to dOVT. These expressions yet converged on an elevated NKCC1/KCC2 ratio in both sexes, indicating compromised chloride homeostasis despite sex-divergent molecular pathways. These findings demonstrate that developmental OTR dysfunction likely contributes to nociceptive and cognitive consequences of ELS, while anxiety-like phenotypes probably involve additional mechanisms. This work highlights OTR as a critical mediator of neurodevelopmental programming and a potential therapeutic target for mitigating ELS-related disorders.

neuroscience↗