Burnsed, J. C. | bioRxiv Science

bioRxiv2026

Persistent sensory processing and behavioral atypicalities in a mouse model of neonatal encephalopathy

Neonatal hypoxia-ischemia (HI) injury is a major risk factor for lifelong cognitive impairments. Given its systemic impact, the neural mechanisms of impairments associated with HI injury remain unclear. In this study, we used a mouse model of neonatal HI injury to study its impact on goal-directed behavior and neural activity in adulthood using a head-fixed visual discrimination task. While neonatal HI injury did not impair discriminability or learning, it was associated with increased motor output in form of licking, faster reaction times and liberal decision bias, indicating an impulsive-like phenotype. These behavioral changes were accompanied by suppressed neuronal activity in the primary visual cortex (V1) and elevated cue-driven fluctuations in trial-to-trial firing variability in the prefrontal cortex (PFC), the latter of which was predictive of decision bias in HI mice. Our findings identify the long term impact of neonatal HI injury on goal-directed behavior, describe in detail the task-related patterns of neural activity in HI mice, and implicate abnormal neural variability in the PFC as a driver of impulsive-like behavior in adults that suffered neonatal HI injury.

neuroscience↗

bioRxiv2025

Lactate receptor, HCAR1, in neonatal hypoxic-ischemic encephalopathy

IntroductionHydroxycarboxylic acid receptor 1 (HCAR1) is a G-protein coupled receptor for lactate that is expressed in the brain and plays a role in neuronal excitability, angiogenesis, and repair after injury. Hypoxic-ischemic encephalopathy (HIE) is the most common cause of brain injury and seizures in term neonates. The goal of this study was to describe HCAR1 expression and function in the neonatal brain and further understand its role in HIE. MethodsHCAR1 expression was measured using qRT-PCR in developing mice (postnatal day (p)10, 20, 30, 50). Electrophysiology was used to measure neuronal properties and spontaneous excitatory postsynaptic currents (sEPSC) in hippocampal principal neurons from HCAR1 knockout and wildtype mice when exposed to lactate. Then, p10 HCAR1 knockout and wildtype mice were exposed to hypoxia-ischemia (HI) and placed on electroencephalography (EEG) to compare seizure burden. HCAR1 expression after neonatal HI was measured with PCR. ResultsHCAR1 is expressed at p10 at similar levels to adults (n=6/group; 1-way ANOVA, p<0.0004). Lactate decreases amplitudes and sEPSC frequency in wildtype (p<0.0001, p<0.001) but not HCAR1 knockout mice (p<0.26, p=0.91). After HI, HCAR1 knockout mice have higher seizure burden (2318s in WT vs. 6497s in KO (p=0.04)) and behavioral seizure scores (4 in WT vs. 6 in KO (p<0.001)) than wildtypes. HCAR1 expression increased 24h post-HI but drops to below baseline at 48h post-HI. (n=3/group; p=0.02). ConclusionHCAR1 is expressed on neurons in the developing mouse brain. Lactate decreases neuronal excitability via HCAR1. HCAR1 is upregulated post-HI and mice lacking HCAR1 exhibit worse neonatal HI seizures. HighlightsO_LIHCAR1, a G-protein coupled, lactate receptor is expressed in the developing mouse brain C_LIO_LIHCAR1 is expressed on neurons in the neonatal mouse hippocampus C_LIO_LIHCAR1 is upregulated 24 hours after neonatal hypoxia-ischemia C_LIO_LIMice lacking HCAR1, exhibit worse neonatal hypoxic-ischemic seizures C_LI

neuroscience↗